eLife: latest articles

MftG is crucial for ethanol metabolism of mycobacteria by linking mycofactocin oxidation to respiration

gerald.lackner@uni-bayreuth.de (Ana Patrícia Graça) — Wed, 29 Jan 2025 00:00:00 +0000

Mycofactocin is a redox cofactor essential for the alcohol metabolism of mycobacteria. While the biosynthesis of mycofactocin is well established, the gene mftG, which encodes an oxidoreductase of the glucose-methanol-choline superfamily, remained functionally uncharacterized. Here, we show that MftG enzymes are almost exclusively found in genomes containing mycofactocin biosynthetic genes and are present in 75% of organisms harboring these genes. Gene deletion experiments in Mycolicibacterium smegmatis demonstrated a growth defect of the ∆mftG mutant on ethanol as a carbon source, accompanied by an arrest of cell division reminiscent of mild starvation. Investigation of carbon and cofactor metabolism implied a defect in mycofactocin reoxidation. Cell-free enzyme assays and respirometry using isolated cell membranes indicated that MftG acts as a mycofactocin dehydrogenase shuttling electrons toward the respiratory chain. Transcriptomics studies also indicated remodeling of redox metabolism to compensate for a shortage of redox equivalents. In conclusion, this work closes an important knowledge gap concerning the mycofactocin system and adds a new pathway to the intricate web of redox reactions governing the metabolism of mycobacteria.

PEBP1 amplifies mitochondrial dysfunction-induced integrated stress response

mikael.bjorklund.lab@gmail.com (Christopher G Proud) — Wed, 29 Jan 2025 00:00:00 +0000

Mitochondrial dysfunction is involved in numerous diseases and the aging process. The integrated stress response (ISR) serves as a critical adaptation mechanism to a variety of stresses, including those originating from mitochondria. By utilizing mass spectrometry-based cellular thermal shift assay (MS-CETSA), we uncovered that phosphatidylethanolamine-binding protein 1 (PEBP1), also known as Raf kinase inhibitory protein (RKIP), is thermally stabilized by stresses which induce mitochondrial ISR. Depletion of PEBP1 impaired mitochondrial ISR activation by reducing eukaryotic translation initiation factor 2α (eIF2α) phosphorylation and subsequent ISR gene expression, which was independent of PEBP1’s role in inhibiting the RAF/MEK/ERK pathway. Consistently, overexpression of PEBP1 potentiated ISR activation by heme-regulated inhibitor (HRI) kinase, the principal eIF2α kinase in the mitochondrial ISR pathway. Real-time interaction analysis using luminescence complementation in live cells revealed an interaction between PEBP1 and eIF2α, which was disrupted by eIF2α S51 phosphorylation. These findings suggest a role for PEBP1 in amplifying mitochondrial stress signals, thereby facilitating an effective cellular response to mitochondrial dysfunction. Therefore, PEBP1 may be a potential therapeutic target for diseases associated with mitochondrial dysfunction.

Reproductive health

editorial@elifesciences.org (Wei Yan) — Wed, 29 Jan 2025 00:00:00 +0000

The articles in this special issue highlight the diversity and complexity of research into reproductive health, including the need for a better understanding of the fundamental biology of reproduction and for new treatments for a range of reproductive disorders.

The multifaceted role of the inferior colliculus in sensory prediction, reward processing, and decision-making

yuxiongj@gmail.com (Hangting Ye) — Wed, 29 Jan 2025 00:00:00 +0000

The inferior colliculus (IC) has traditionally been regarded as an important relay in the auditory pathway, primarily involved in relaying auditory information from the brainstem to the thalamus. However, this study uncovers the multifaceted role of the IC in bridging auditory processing, sensory prediction, and reward prediction. Through extracellular recordings in monkeys engaged in a sound duration-based deviation detection task, we observed a 'climbing effect' in neuronal firing rates, indicative of an enhanced response over sound sequences linked to sensory prediction rather than reward anticipation. Moreover, our findings demonstrate reward prediction errors within the IC, highlighting its complex integration in auditory and reward processing. Further analysis revealed a direct correlation between IC neuronal activity and behavioral choices, suggesting its involvement in decision-making processes. This research highlights a more complex role for the IC than traditionally understood, showcasing its integral role in cognitive and sensory processing and emphasizing its importance in integrated brain functions.

Post-retrieval noradrenergic activation impairs subsequent memory depending on cortico-hippocampal reactivation

lars.schwabe@uni-hamburg.de (Anthony D Wagner) — Wed, 29 Jan 2025 00:00:00 +0000

When retrieved, seemingly stable memories can become sensitive to significant events, such as acute stress. The mechanisms underlying these memory dynamics remain poorly understood. Here, we show that noradrenergic stimulation after memory retrieval impairs subsequent remembering, depending on hippocampal and cortical signals emerging during retrieval. In a three-day study, we measured brain activity using fMRI during initial encoding, 24 hr-delayed memory cueing followed by pharmacological elevations of glucocorticoid or noradrenergic activity, and final recall. While post-retrieval glucocorticoids did not affect subsequent memory, the impairing effect of noradrenergic arousal on final recall depended on hippocampal reactivation and category-level reinstatement in the ventral temporal cortex during memory cueing. These effects did not require a reactivation of the original memory trace and did not interact with offline reinstatement during rest. Our findings demonstrate that, depending on the retrieval-related neural reactivation of memories, noradrenergic arousal after retrieval can alter the future accessibility of consolidated memories.

Nutritional state-dependent modulation of insulin-producing cells in Drosophila

jan.ache@uni-wuerzburg.de (Fathima Mukthar Iqbal) — Wed, 29 Jan 2025 00:00:00 +0000

Insulin plays a key role in metabolic homeostasis. Drosophila insulin-producing cells (IPCs) are functional analogues of mammalian pancreatic beta cells and release insulin directly into circulation. To investigate the in vivo dynamics of IPC activity, we quantified the effects of nutritional and internal state changes on IPCs using electrophysiological recordings. We found that the nutritional state strongly modulates IPC activity. IPC activity decreased with increasing periods of starvation. Refeeding flies with glucose or fructose, two nutritive sugars, significantly increased IPC activity, whereas non-nutritive sugars had no effect. In contrast to feeding, glucose perfusion did not affect IPC activity. This was reminiscent of the mammalian incretin effect, where glucose ingestion drives higher insulin release than intravenous application. Contrary to IPCs, Diuretic hormone 44-expressing neurons in the pars intercerebralis (DH44^PINs) responded to glucose perfusion. Functional connectivity experiments demonstrated that these DH44^PINs do not affect IPC activity, while other DH44Ns inhibit them. Hence, populations of autonomously and systemically sugar-sensing neurons work in parallel to maintain metabolic homeostasis. Accordingly, activating IPCs had a small, satiety-like effect on food-searching behavior and reduced starvation-induced hyperactivity, whereas activating DH44Ns strongly increased hyperactivity. Taken together, we demonstrate that IPCs and DH44Ns are an integral part of a modulatory network that orchestrates glucose homeostasis and adaptive behavior in response to shifts in the metabolic state.

Driver lines for studying associative learning in Drosophila

shuaiy@janelia.hhmi.org (Ching-Po Yang) — Wed, 29 Jan 2025 00:00:00 +0000

The mushroom body (MB) is the center for associative learning in insects. In Drosophila, intersectional split-GAL4 drivers and electron microscopy (EM) connectomes have laid the foundation for precise interrogation of the MB neural circuits. However, investigation of many cell types upstream and downstream of the MB has been hindered due to lack of specific driver lines. Here we describe a new collection of over 800 split-GAL4 and split-LexA drivers that cover approximately 300 cell types, including sugar sensory neurons, putative nociceptive ascending neurons, olfactory and thermo-/hygro-sensory projection neurons, interneurons connected with the MB-extrinsic neurons, and various other cell types. We characterized activation phenotypes for a subset of these lines and identified a sugar sensory neuron line most suitable for reward substitution. Leveraging the thousands of confocal microscopy images associated with the collection, we analyzed neuronal morphological stereotypy and discovered that one set of mushroom body output neurons, MBON08/MBON09, exhibits striking individuality and asymmetry across animals. In conjunction with the EM connectome maps, the driver lines reported here offer a powerful resource for functional dissection of neural circuits for associative learning in adult Drosophila.

eIF3 engages with 3’-UTR termini of highly translated mRNAs

j-h-doudna-cate@berkeley.edu (Jamie HD Cate) — Wed, 29 Jan 2025 00:00:00 +0000

Stem cell differentiation involves a global increase in protein synthesis to meet the demands of specialized cell types. However, the molecular mechanisms underlying this translational burst and the involvement of initiation factors remains largely unknown. Here, we investigate the role of eukaryotic initiation factor 3 (eIF3) in early differentiation of human pluripotent stem cell (hPSC)-derived neural progenitor cells (NPCs). Using Quick-irCLIP and alternative polyadenylation (APA) Seq, we show eIF3 crosslinks predominantly with 3’ untranslated region (3’-UTR) termini of multiple mRNA isoforms, adjacent to the poly(A) tail. Furthermore, we find that eIF3 engagement at 3’-UTR ends is dependent on polyadenylation. High eIF3 crosslinking at 3’-UTR termini of mRNAs correlates with high translational activity, as determined by ribosome profiling, but not with translational efficiency. The results presented here show that eIF3 engages with 3’-UTR termini of highly translated mRNAs, likely reflecting a general rather than specific regulatory function of eIF3, and supporting a role of mRNA circularization in the mechanisms governing mRNA translation.

Progesterone induces meiosis through two obligate co-receptors with PLA2 activity

khm2002@qatar-med.cornell.edu (Anna Halama) — Tue, 28 Jan 2025 00:00:00 +0000

The steroid hormone progesterone (P4) regulates multiple aspects of reproductive and metabolic physiology. Classical P4 signaling operates through nuclear receptors that regulate transcription. In addition, P4 signals through membrane P4 receptors (mPRs) in a rapid nongenomic modality. Despite the established physiological importance of P4 nongenomic signaling, the details of its signal transduction cascade remain elusive. Here, using Xenopus oocyte maturation as a well-established physiological readout of nongenomic P4 signaling, we identify the lipid hydrolase ABHD2 (α/β hydrolase domain-containing protein 2) as an essential mPRβ co-receptor to trigger meiosis. We show using functional assays coupled to unbiased and targeted cell-based lipidomics that ABHD2 possesses a phospholipase A2 (PLA2) activity that requires mPRβ. This PLA2 activity bifurcates P4 signaling by inducing clathrin-dependent endocytosis of mPRβ, resulting in the production of lipid messengers that are G-protein coupled receptor agonists. Therefore, P4 drives meiosis by inducing an ABHD2 PLA2 activity that requires both mPRβ and ABHD2 as obligate co-receptors.

Tgfbr1 regulates lateral plate mesoderm and endoderm reorganization during the trunk to tail transition

moises.mallo@gimm.pt (Ana Casaca) — Tue, 28 Jan 2025 00:00:00 +0000

During the trunk to tail transition the mammalian embryo builds the outlets for the intestinal and urogenital tracts, lays down the primordia for the hindlimb and external genitalia, and switches from the epiblast/primitive streak (PS) to the tail bud as the driver of axial extension. Genetic and molecular data indicate that Tgfbr1 is a key regulator of the trunk to tail transition. Tgfbr1 has been shown to control the switch of the neuromesodermal competent cells from the epiblast to the chordoneural hinge to generate the tail bud. We now show that in mouse embryos Tgfbr1 signaling also controls the remodeling of the lateral plate mesoderm (LPM) and of the embryonic endoderm associated with the trunk to tail transition. In the absence of Tgfbr1, the two LPM layers do not converge at the end of the trunk, extending instead as separate layers until the caudal embryonic extremity, and failing to activate markers of primordia for the hindlimb and external genitalia. The vascular remodeling involving the dorsal aorta and the umbilical artery leading to the connection between embryonic and extraembryonic circulation was also affected in the Tgfbr1 mutant embryos. Similar alterations in the LPM and vascular system were also observed in Isl1 null mutants, indicating that this factor acts in the regulatory cascade downstream of Tgfbr1 in LPM-derived tissues. In addition, in the absence of Tgfbr1 the embryonic endoderm fails to expand to form the endodermal cloaca and to extend posteriorly to generate the tail gut. We present evidence suggesting that the remodeling activity of Tgfbr1 in the LPM and endoderm results from the control of the posterior PS fate after its regression during the trunk to tail transition. Our data, together with previously reported observations, place Tgfbr1 at the top of the regulatory processes controlling the trunk to tail transition.

Correction: Gene regulatory patterning codes in early cell fate specification of the C. elegans embryo

Mon, 27 Jan 2025 00:00:00 +0000

How does chronic pain lead to memory loss?

rbsncosta@pharma.ufrj.br (Ivan Tomsic) — Mon, 27 Jan 2025 00:00:00 +0000

A dysfunctional signaling pathway in the hippocampus has been linked to chronic pain-related memory impairment in mice.

Combining radio-telemetry and radar measurements to test optimal foraging in an aerial insectivore bird

itaibloch2@gmail.com (David Troupin) — Mon, 27 Jan 2025 00:00:00 +0000

Optimal foraging theory posits that foragers adjust their movements based on prey abundance to optimize food intake. While extensively studied in terrestrial and marine environments, aerial foraging has remained relatively unexplored due to technological limitations. This study, uniquely combining BirdScan-MR1 radar and the Advanced Tracking and Localization of Animals in Real-Life Systems biotelemetry system, investigates the foraging dynamics of Little Swifts (Apus affinis) in response to insect movements over Israel’s Hula Valley. Insect movement traffic rate (MoTR) substantially varied across days, strongly influencing swift movement. On days with high MoTR, swifts exhibited reduced flight distance, increased colony visit rate, and earlier arrivals at the breeding colony, reflecting a dynamic response to prey availability. However, no significant effects were observed in total foraging duration, flight speed, or daily route length. Notably, as insect abundance increased, inter-individual distances decreased. These findings suggest that Little Swifts optimize their foraging behavior in relation to aerial insect abundance, likely influencing reproductive success and population dynamics. The integration of radar technology and biotelemetry systems provides a unique perspective on the interactions between aerial insectivores and their prey, contributing to a comprehensive understanding of optimal foraging strategies in diverse environments.

Operation of spinal sensorimotor circuits controlling phase durations during tied-belt and split-belt locomotion after a lateral thoracic hemisection

iar22@drexel.edu (Alain Frigon) — Mon, 27 Jan 2025 00:00:00 +0000

Locomotion is controlled by spinal circuits that interact with supraspinal drives and sensory feedback from the limbs. These sensorimotor interactions are disrupted following spinal cord injury. The thoracic lateral hemisection represents an experimental model of an incomplete spinal cord injury, where connections between the brain and spinal cord are abolished on one side of the cord. To investigate the effects of such an injury on the operation of the spinal locomotor network, we used our computational model of cat locomotion recently published in eLife (Rybak et al., 2024) to investigate and predict changes in cycle and phase durations following a thoracic lateral hemisection during treadmill locomotion in tied-belt (equal left-right speeds) and split-belt (unequal left-right speeds) conditions. In our simulations, the ‘hemisection’ was always applied to the right side. Based on our model, we hypothesized that following hemisection the contralesional (‘intact’, left) side of the spinal network is mostly controlled by supraspinal drives, whereas the ipsilesional (‘hemisected’, right) side is mostly controlled by somatosensory feedback. We then compared the simulated results with those obtained during experiments in adult cats before and after a mid-thoracic lateral hemisection on the right side in the same locomotor conditions. Our experimental results confirmed many effects of hemisection on cat locomotion predicted by our simulations. We show that having the ipsilesional hindlimb step on the slow belt, but not the fast belt, during split-belt locomotion substantially reduces the effects of lateral hemisection. The model provides explanations for changes in temporal characteristics of hindlimb locomotion following hemisection based on altered interactions between spinal circuits, supraspinal drives, and somatosensory feedback.

Finding new ways to treat overdoses

jill.turner@uky.edu (Jill R Turner) — Mon, 27 Jan 2025 00:00:00 +0000

Reversing opioid overdoses in rats using a drug that does not enter the brain prevents the sudden and severe withdrawal symptoms associated with therapeutics that target the central nervous system.

Automated cell annotation in multi-cell images using an improved CRF_ID algorithm

yzhang@oeb.harvard.edu (Hang Lu) — Fri, 24 Jan 2025 00:00:00 +0000

Cell identification is an important yet difficult process in data analysis of biological images. Previously, we developed an automated cell identification method called CRF_ID and demonstrated its high performance in Caenorhabditis elegans whole-brain images (Chaudhary et al., 2021). However, because the method was optimized for whole-brain imaging, comparable performance could not be guaranteed for application in commonly used C. elegans multi-cell images that display a subpopulation of cells. Here, we present an advancement, CRF_ID 2.0, that expands the generalizability of the method to multi-cell imaging beyond whole-brain imaging. To illustrate the application of the advance, we show the characterization of CRF_ID 2.0 in multi-cell imaging and cell-specific gene expression analysis in C. elegans. This work demonstrates that high-accuracy automated cell annotation in multi-cell imaging can expedite cell identification and reduce its subjectivity in C. elegans and potentially other biological images of various origins.

Dynamics and regulatory roles of RNA m⁶A methylation in unbalanced genomes

sunlin@bnu.edu.cn (Junhan Wang) — Fri, 24 Jan 2025 00:00:00 +0000

N⁶-methyladenosine (m⁶A) in eukaryotic RNA is an epigenetic modification that is critical for RNA metabolism, gene expression regulation, and the development of organisms. Aberrant expression of m⁶A components appears in a variety of human diseases. RNA m⁶A modification in Drosophila has proven to be involved in sex determination regulated by Sxl and may affect X chromosome expression through the MSL complex. The dosage-related effects under the condition of genomic imbalance (i.e. aneuploidy) are related to various epigenetic regulatory mechanisms. Here, we investigated the roles of RNA m⁶A modification in unbalanced genomes using aneuploid Drosophila. The results showed that the expression of m⁶A components changed significantly under genomic imbalance, and affected the abundance and genome-wide distribution of m⁶A, which may be related to the developmental abnormalities of aneuploids. The relationships between methylation status and classical dosage effect, dosage compensation, and inverse dosage effect were also studied. In addition, we demonstrated that RNA m⁶A methylation may affect dosage-dependent gene regulation through dosage-sensitive modifiers, alternative splicing, the MSL complex, and other processes. More interestingly, there seems to be a close relationship between MSL complex and RNA m⁶A modification. It is found that ectopically overexpressed MSL complex, especially the levels of H4K16Ac through MOF, could influence the expression levels of m⁶A modification and genomic imbalance may be involved in this interaction. We found that m⁶A could affect the levels of H4K16Ac through MOF, a component of the MSL complex, and that genomic imbalance may be involved in this interaction. Altogether, our work reveals the dynamic and regulatory role of RNA m⁶A modification in unbalanced genomes, and may shed new light on the mechanisms of aneuploidy-related developmental abnormalities and diseases.

Risk factors affecting polygenic score performance across diverse cohorts

marylyn@pennmedicine.upenn.edu (Atlas Khan) — Fri, 24 Jan 2025 00:00:00 +0000

Apart from ancestry, personal or environmental covariates may contribute to differences in polygenic score (PGS) performance. We analyzed the effects of covariate stratification and interaction on body mass index (BMI) PGS (PGS_BMI) across four cohorts of European (N = 491,111) and African (N = 21,612) ancestry. Stratifying on binary covariates and quintiles for continuous covariates, 18/62 covariates had significant and replicable R² differences among strata. Covariates with the largest differences included age, sex, blood lipids, physical activity, and alcohol consumption, with R² being nearly double between best- and worst-performing quintiles for certain covariates. Twenty-eight covariates had significant PGS_BMI–covariate interaction effects, modifying PGS_BMI effects by nearly 20% per standard deviation change. We observed overlap between covariates that had significant R² differences among strata and interaction effects – across all covariates, their main effects on BMI were correlated with their maximum R² differences and interaction effects (0.56 and 0.58, respectively), suggesting high-PGS_BMI individuals have highest R² and increase in PGS effect. Using quantile regression, we show the effect of PGS_BMI increases as BMI itself increases, and that these differences in effects are directly related to differences in R² when stratifying by different covariates. Given significant and replicable evidence for context-specific PGS_BMI performance and effects, we investigated ways to increase model performance taking into account nonlinear effects. Machine learning models (neural networks) increased relative model R² (mean 23%) across datasets. Finally, creating PGS_BMI directly from GxAge genome-wide association studies effects increased relative R² by 7.8%. These results demonstrate that certain covariates, especially those most associated with BMI, significantly affect both PGS_BMI performance and effects across diverse cohorts and ancestries, and we provide avenues to improve model performance that consider these effects.

Discriminating neural ensemble patterns through dendritic computations in randomly connected feedforward networks

bhalla@ncbs.res.in (Bhanu Priya Somashekar) — Fri, 24 Jan 2025 00:00:00 +0000

Co-active or temporally ordered neural ensembles are a signature of salient sensory, motor, and cognitive events. Local convergence of such patterned activity as synaptic clusters on dendrites could help single neurons harness the potential of dendritic nonlinearities to decode neural activity patterns. We combined theory and simulations to assess the likelihood of whether projections from neural ensembles could converge onto synaptic clusters even in networks with random connectivity. Using rat hippocampal and cortical network statistics, we show that clustered convergence of axons from three to four different co-active ensembles is likely even in randomly connected networks, leading to representation of arbitrary input combinations in at least 10 target neurons in a 100,000 population. In the presence of larger ensembles, spatiotemporally ordered convergence of three to five axons from temporally ordered ensembles is also likely. These active clusters result in higher neuronal activation in the presence of strong dendritic nonlinearities and low background activity. We mathematically and computationally demonstrate a tight interplay between network connectivity, spatiotemporal scales of subcellular electrical and chemical mechanisms, dendritic nonlinearities, and uncorrelated background activity. We suggest that dendritic clustered and sequence computation is pervasive, but its expression as somatic selectivity requires confluence of physiology, background activity, and connectomics.

A split-GAL4 driver line resource for Drosophila neuron types

meissnerg@janelia.hhmi.org (Alexandra Novak) — Fri, 24 Jan 2025 00:00:00 +0000

Techniques that enable precise manipulations of subsets of neurons in the fly central nervous system (CNS) have greatly facilitated our understanding of the neural basis of behavior. Split-GAL4 driver lines allow specific targeting of cell types in Drosophila melanogaster and other species. We describe here a collection of 3060 lines targeting a range of cell types in the adult Drosophila CNS and 1373 lines characterized in third-instar larvae. These tools enable functional, transcriptomic, and proteomic studies based on precise anatomical targeting. NeuronBridge and other search tools relate light microscopy images of these split-GAL4 lines to connectomes reconstructed from electron microscopy images. The collections are the result of screening over 77,000 split hemidriver combinations. Previously published and new lines are included, all validated for driver expression and curated for optimal cell-type specificity across diverse cell types. In addition to images and fly stocks for these well-characterized lines, we make available 300,000 new 3D images of other split-GAL4 lines.

Projections from thalamic nucleus reuniens to hippocampal CA1 area participate in context fear extinction by affecting extinction-induced molecular remodeling of excitatory synapses

k.radwanska@nencki.edu.pl (Ahmad Salamian) — Thu, 23 Jan 2025 00:00:00 +0000

The ability to extinguish contextual fear in a changing environment is crucial for animal survival. Recent data support the role of the thalamic nucleus reuniens (RE) and its projections to the dorsal hippocampal CA1 area (RE→dCA1) in this process. However, it remains poorly understood how RE impacts dCA1 neurons during contextual fear extinction (CFE). Here, we reveal that the RE→dCA1 pathway contributes to the extinction of contextual fear by affecting CFE-induced molecular remodeling of excitatory synapses. Anatomical tracing and chemogenetic manipulation in mice demonstrate that RE neurons form synapses and regulate synaptic transmission in the stratum oriens (SO) and lacunosum-moleculare (SLM) of the dCA1 area, but not in the stratum radiatum (SR). We also observe CFE-specific structural changes of excitatory synapses and expression of the synaptic scaffold protein, PSD-95, in both strata innervated by RE, but not in SR. Interestingly, only the changes in SLM are specific for the dendrites innervated by RE. To further support the role of the RE→dCA1 projection in CFE, we demonstrate that brief chemogenetic inhibition of the RE→dCA1 pathway during a CFE session persistently impairs the formation of CFE memory and CFE-induced changes of PSD-95 levels in SLM. Thus, our data indicate that RE participates in CFE by regulating CFE-induced molecular remodeling of dCA1 synapses.

Deficiency of orexin receptor type 1 in dopaminergic neurons increases novelty-induced locomotion and exploration

xing.xiao@charite.de (Anna Lena Cremer) — Wed, 22 Jan 2025 00:00:00 +0000

Orexin signaling in the ventral tegmental area and substantia nigra promotes locomotion and reward processing, but it is not clear whether dopaminergic neurons directly mediate these effects. We show that dopaminergic neurons in these areas mainly express orexin receptor subtype 1 (Ox1R). In contrast, only a minor population in the medial ventral tegmental area express orexin receptor subtype 2 (Ox2R). To analyze the functional role of Ox1R signaling in dopaminergic neurons, we deleted Ox1R specifically in dopamine transporter-expressing neurons of mice and investigated the functional consequences. Deletion of Ox1R increased locomotor activity and exploration during exposure to novel environments or when intracerebroventricularely injected with orexin A. Spontaneous activity in home cages, anxiety, reward processing, and energy metabolism did not change. Positron emission tomography imaging revealed that Ox1R signaling in dopaminergic neurons affected distinct neural circuits depending on the stimulation mode. In line with an increase of neural activity in the lateral paragigantocellular nucleus (LPGi) of Ox1R^ΔDAT mice, we found that dopaminergic projections innervate the LPGi in regions where the inhibitory dopamine receptor subtype D2 but not the excitatory D1 subtype resides. These data suggest a crucial regulatory role of Ox1R signaling in dopaminergic neurons in novelty-induced locomotion and exploration.

Multi-study fMRI outlooks on subcortical BOLD responses in the stop-signal paradigm

scott@leeclan.net (Birte Forstmann) — Wed, 22 Jan 2025 00:00:00 +0000

This study investigates the functional network underlying response inhibition in the human brain, particularly the role of the basal ganglia in successful action cancellation. Functional magnetic resonance imaging (fMRI) approaches have frequently used the stop-signal task to examine this network. We merge five such datasets, using a novel aggregatory method allowing the unification of raw fMRI data across sites. This meta-analysis, along with other recent aggregatory fMRI studies, does not find evidence for the innervation of the hyperdirect or indirect cortico-basal-ganglia pathways in successful response inhibition. What we do find, is large subcortical activity profiles for failed stop trials. We discuss possible explanations for the mismatch of findings between the fMRI results presented here and results from other research modalities that have implicated nodes of the basal ganglia in successful inhibition. We also highlight the substantial effect smoothing can have on the conclusions drawn from task-specific general linear models. First and foremost, this study presents a proof of concept for meta-analytical methods that enable the merging of extensive, unprocessed, or unreduced datasets. It demonstrates the significant potential that open-access data sharing can offer to the research community. With an increasing number of datasets being shared publicly, researchers will have the ability to conduct meta-analyses on more than just summary data.

A double dissociation between semantic and spatial cognition in visual to default network pathways

t.gonzalezalam@bangor.ac.uk (Aidan J Horner) — Wed, 22 Jan 2025 00:00:00 +0000

Processing pathways between sensory and default mode network (DMN) regions support recognition, navigation, and memory but their organisation is not well understood. We show that functional subdivisions of visual cortex and DMN sit at opposing ends of parallel streams of information processing that support visually mediated semantic and spatial cognition, providing convergent evidence from univariate and multivariate task responses, intrinsic functional and structural connectivity. Participants learned virtual environments consisting of buildings populated with objects, drawn from either a single semantic category or multiple categories. Later, they made semantic and spatial context decisions about these objects and buildings during functional magnetic resonance imaging. A lateral ventral occipital to fronto-temporal DMN pathway was primarily engaged by semantic judgements, while a medial visual to medial temporal DMN pathway supported spatial context judgements. These pathways had distinctive locations in functional connectivity space: the semantic pathway was both further from unimodal systems and more balanced between visual and auditory-motor regions compared with the spatial pathway. When semantic and spatial context information could be integrated (in buildings containing objects from a single category), regions at the intersection of these pathways responded, suggesting that parallel processing streams interact at multiple levels of the cortical hierarchy to produce coherent memory-guided cognition.

Multisensory integration operates on correlated input from unimodal transient channels

cesare.parise@liverpool.ac.uk (Cesare V Parise) — Wed, 22 Jan 2025 00:00:00 +0000

Audiovisual information reaches the brain via both sustained and transient input channels, representing signals’ intensity over time or changes thereof, respectively. To date, it is unclear to what extent transient and sustained input channels contribute to the combined percept obtained through multisensory integration. Based on the results of two novel psychophysical experiments, here we demonstrate the importance of the transient (instead of the sustained) channel for the integration of audiovisual signals. To account for the present results, we developed a biologically inspired, general-purpose model for multisensory integration, the multisensory correlation detectors, which combines correlated input from unimodal transient channels. Besides accounting for the results of our psychophysical experiments, this model could quantitatively replicate several recent findings in multisensory research, as tested against a large collection of published datasets. In particular, the model could simultaneously account for the perceived timing of audiovisual events, multisensory facilitation in detection tasks, causality judgments, and optimal integration. This study demonstrates that several phenomena in multisensory research that were previously considered unrelated, all stem from the integration of correlated input from unimodal transient channels.

How a gene fuels ear infections

aziz.el-amraoui@pasteur.fr (Aziz El-Amraoui) — Wed, 22 Jan 2025 00:00:00 +0000

The DYRK1A enzyme is a pivotal contributor to frequent and severe episodes of otitis media in Down syndrome, positioning it as a promising target for therapeutic interventions.

Aberrant FGF signaling promotes granule neuron precursor expansion in SHH subgroup infantile medulloblastoma

oryabut@gmail.com (Hector G Gomez) — Tue, 21 Jan 2025 00:00:00 +0000

Mutations in Sonic Hedgehog (SHH) signaling pathway genes, for example, Suppressor of Fused (SUFU), drive granule neuron precursors (GNP) to form medulloblastomas (MB^SHH). However, how different molecular lesions in the Shh pathway drive transformation is frequently unclear, and SUFU mutations in the cerebellum seem distinct. In this study, we show that fibroblast growth factor 5 (FGF5) signaling is integral for many infantile MB^SHH cases and that FGF5 expression is uniquely upregulated in infantile MB^SHH tumors. Similarly, mice lacking SUFU (Sufu-cKO) ectopically express Fgf5 specifically along the secondary fissure where GNPs harbor preneoplastic lesions and show that FGFR signaling is also ectopically activated in this region. Treatment with an FGFR antagonist rescues the severe GNP hyperplasia and restores cerebellar architecture. Thus, direct inhibition of FGF signaling may be a promising and novel therapeutic candidate for infantile MB^SHH.

Tripartite organization of brain state dynamics underlying spoken narrative comprehension

dinggsh@bnu.edu.cn (Guosheng Ding) — Tue, 21 Jan 2025 00:00:00 +0000

Speech comprehension involves the dynamic interplay of multiple cognitive processes, from basic sound perception, to linguistic encoding, and finally to complex semantic-conceptual interpretations. How the brain handles the diverse streams of information processing remains poorly understood. Applying Hidden Markov Modeling to fMRI data obtained during spoken narrative comprehension, we reveal that the whole brain networks predominantly oscillate within a tripartite latent state space. These states are, respectively, characterized by high activities in the sensory-motor (State #1), bilateral temporal (State #2), and default mode networks (DMN; State #3) regions, with State #2 acting as a transitional hub. The three states are selectively modulated by the acoustic, word-level semantic, and clause-level semantic properties of the narrative. Moreover, the alignment with both the best performer and the group-mean in brain state expression can predict participants’ narrative comprehension scores measured from the post-scan recall. These results are reproducible with different brain network atlas and generalizable to two datasets consisting of young and older adults. Our study suggests that the brain underlies narrative comprehension by switching through a tripartite state space, with each state probably dedicated to a specific component of language faculty, and effective narrative comprehension relies on engaging those states in a timely manner.

Paradoxical dominant negative activity of an immunodeficiency-associated activating PIK3R1 variant

rsemple@exseed.ed.ac.uk (Gemma V Brierley) — Tue, 21 Jan 2025 00:00:00 +0000

PIK3R1 encodes three regulatory subunits of class IA phosphoinositide 3-kinase (PI3K), each associating with any of three catalytic subunits, namely p110α, p110β, or p110δ. Constitutional PIK3R1 mutations cause diseases with a genotype-phenotype relationship not yet fully explained: heterozygous loss-of-function mutations cause SHORT syndrome, featuring insulin resistance and short stature attributed to reduced p110α function, while heterozygous activating mutations cause immunodeficiency, attributed to p110δ activation and known as APDS2. Surprisingly, APDS2 patients do not show features of p110α hyperactivation, but do commonly have SHORT syndrome-like features, suggesting p110α hypofunction. We sought to investigate this. In dermal fibroblasts from an APDS2 patient, we found no increased PI3K signalling, with p110δ expression markedly reduced. In preadipocytes, the APDS2 variant was potently dominant negative, associating with Irs1 and Irs2 but failing to heterodimerise with p110α. This attenuation of p110α signalling by a p110δ-activating PIK3R1 variant potentially explains co-incidence of gain-of-function and loss-of-function PIK3R1 phenotypes.

Effects of noise and metabolic cost on cortical task representations

j.stroud@eng.cam.ac.uk (Jake Patrick Stroud) — Tue, 21 Jan 2025 00:00:00 +0000

Cognitive flexibility requires both the encoding of task-relevant and the ignoring of task-irrelevant stimuli. While the neural coding of task-relevant stimuli is increasingly well understood, the mechanisms for ignoring task-irrelevant stimuli remain poorly understood. Here, we study how task performance and biological constraints jointly determine the coding of relevant and irrelevant stimuli in neural circuits. Using mathematical analyses and task-optimized recurrent neural networks, we show that neural circuits can exhibit a range of representational geometries depending on the strength of neural noise and metabolic cost. By comparing these results with recordings from primate prefrontal cortex (PFC) over the course of learning, we show that neural activity in PFC changes in line with a minimal representational strategy. Specifically, our analyses reveal that the suppression of dynamically irrelevant stimuli is achieved by activity-silent, sub-threshold dynamics. Our results provide a normative explanation as to why PFC implements an adaptive, minimal representational strategy.

Endopiriform neurons projecting to ventral CA1 are a critical node for recognition memory

asami.tanimura@biomed.au.dk (Aleksandra Okrasa) — Tue, 21 Jan 2025 00:00:00 +0000

The claustrum complex is viewed as fundamental for higher-order cognition; however, the circuit organization and function of its neuroanatomical subregions are not well understood. We demonstrated that some of the key roles of the CLA complex can be attributed to the connectivity and function of a small group of neurons in its ventral subregion, the endopiriform (EN). We identified a subpopulation of EN neurons by their projection to the ventral CA1 (EN^vCA1-proj. neurons), embedded in recurrent circuits with other EN neurons and the piriform cortex. Although the EN^vCA1-proj. neuron activity was biased toward novelty across stimulus categories, their chemogenetic inhibition selectively disrupted the memory-guided but not innate responses of mice to novelty. Based on our functional connectivity analysis, we suggest that EN^vCA1-proj. neurons serve as an essential node for recognition memory through recurrent circuits mediating sustained attention to novelty, and through feed-forward inhibition of distal vCA1 neurons shifting memory-guided behavior from familiarity to novelty.

Syngeneic natural killer cell therapy activates dendritic and T cells in metastatic lungs and effectively treats low-burden metastases

dms1201@gmail.com (Chin-Ling Chang) — Tue, 21 Jan 2025 00:00:00 +0000

Natural killer (NK) cells can control metastasis through cytotoxicity and IFN-γ production independently of T cells in experimental metastasis mouse models. The inverse correlation between NK activity and metastasis incidence supports a critical role for NK cells in human metastatic surveillance. However, autologous NK cell therapy has shown limited benefit in treating patients with metastatic solid tumors. Using a spontaneous metastasis mouse model of MHC-I⁺ breast cancer, we found that transfer of IL-15/IL-12-conditioned syngeneic NK cells after primary tumor resection promoted long-term survival of mice with low metastatic burden and induced a tumor-specific protective T cell response that is essential for the therapeutic effect. Furthermore, NK cell transfer augments activation of conventional dendritic cells (cDCs), Foxp3^-CD4⁺ T cells and stem cell-like CD8⁺ T cells in metastatic lungs, to which IFN-γ of the transferred NK cells contributes significantly. These results imply direct interactions between transferred NK cells and endogenous cDCs to enhance T cell activation. We conducted an investigator-initiated clinical trial of autologous NK cell therapy in six patients with advanced cancer and observed that the NK cell therapy was safe and showed signs of effectiveness. These findings indicate that autologous NK cell therapy is effective in treating established low burden metastases of MHC-I⁺ tumor cells by activating the cDC-T cell axis at metastatic sites.

Mixed representations of choice direction and outcome by GABA/glutamate cotransmitting neurons in the entopeduncular nucleus

mlwall12@bu.edu (Bernardo Sabatini) — Tue, 21 Jan 2025 00:00:00 +0000

The basal ganglia (BG) are an evolutionarily conserved and phylogenetically old set of sub-cortical nuclei that guide action selection, evaluation, and reinforcement. The entopeduncular nucleus (EP) is a major BG output nucleus that contains a population of GABA/glutamate cotransmitting neurons (EP^Sst+) that specifically target the lateral habenula (LHb) and whose function in behavior remains mysterious. Here, we use a probabilistic switching task that requires an animal to maintain flexible relationships between action selection and evaluation to examine when and how GABA/glutamate cotransmitting neurons contribute to behavior. We find that EP^Sst+ neurons are strongly engaged during this task and show bidirectional changes in activity during the choice and outcome periods of a trial. We then tested the effects of either permanently blocking cotransmission or modifying the GABA/glutamate ratio on behavior in well-trained animals. Neither manipulation produced detectable changes in behavior despite significant changes in synaptic transmission in the LHb, demonstrating that the outputs of these neurons are not required for ongoing action-outcome updating in a probabilistic switching task.

MagIC beads for scarce macromolecules

beat.fierz@epfl.ch (Beat Fierz) — Mon, 20 Jan 2025 00:00:00 +0000

Specialized magnetic beads that bind target proteins to a cryogenic electron microscopy grid make it possible to study the structure of protein complexes from dilute samples.

Systematic evaluation of intratumoral and peripheral BCR repertoires in three cancers

katyaakts@gmail.com (Daria S Myalik) — Mon, 20 Jan 2025 00:00:00 +0000

The current understanding of humoral immune response in cancer patients suggests that tumors may be infiltrated with diffuse B cells of extra-tumoral origin or may develop organized lymphoid structures, where somatic hypermutation and antigen-driven selection occur locally. These processes are believed to be significantly influenced by the tumor microenvironment through secretory factors and biased cell-cell interactions. To explore the manifestation of this influence, we used deep unbiased immunoglobulin profiling and systematically characterized the relationships between B cells in circulation, draining lymph nodes (draining LNs), and tumors in 14 patients with three human cancers. We demonstrated that draining LNs are differentially involved in the interaction with the tumor site, and that significant heterogeneity exists even between different parts of a single lymph node (LN). Next, we confirmed and elaborated upon previous observations regarding intratumoral immunoglobulin heterogeneity. We identified B cell receptor (BCR) clonotypes that were expanded in tumors relative to draining LNs and blood and observed that these tumor-expanded clonotypes were less hypermutated than non-expanded (ubiquitous) clonotypes. Furthermore, we observed a shift in the properties of complementarity-determining region 3 of the BCR heavy chain (CDR-H3) towards less mature and less specific BCR repertoire in tumor-infiltrating B-cells compared to circulating B-cells, which may indicate less stringent control for antibody-producing B cell development in tumor microenvironment (TME). In addition, we found repertoire-level evidence that B-cells may be selected according to their CDR-H3 physicochemical properties before they activate somatic hypermutation (SHM). Altogether, our work outlines a broad picture of the differences in the tumor BCR repertoire relative to non-tumor tissues and points to the unexpected features of the SHM process.

A septo-hypothalamic-medullary circuit directs stress-induced analgesia

arnabbarik@iisc.ac.in (Arnab Barik) — Mon, 20 Jan 2025 00:00:00 +0000

Stress is a potent modulator of pain. Specifically, acute stress due to physical restraint induces stress-induced analgesia (SIA). However, where and how acute stress and pain pathways interface in the brain are poorly understood. Here, we describe how the dorsal lateral septum (dLS), a forebrain limbic nucleus, facilitates SIA through its downstream targets in the lateral hypothalamic area (LHA) of mice. Taking advantage of transsynaptic viral-genetic, optogenetic, and chemogenetic techniques, we show that the dLS→LHA circuitry is sufficient to drive analgesia and is required for SIA. Furthermore, our results reveal that the dLS→LHA pathway is opioid-dependent and modulates pain through the pro-nociceptive neurons in the rostral ventromedial medulla (RVM). Remarkably, we found that the inhibitory dLS neurons are recruited specifically when the mice struggle to escape under restraint and, in turn, inhibit excitatory LHA neurons. As a result, the RVM neurons downstream of LHA are disengaged, thus suppressing nociception. Together, we delineate a poly-synaptic pathway that can transform escape behavior in mice under restraint to acute stress into analgesia.

Sir2 and Fun30 regulate ribosomal DNA replication timing via MCM helicase positioning and nucleosome occupancy

abedalov@fredhutch.org (Antonio Bedalov) — Mon, 20 Jan 2025 00:00:00 +0000

The association between late replication timing and low transcription rates in eukaryotic heterochromatin is well known, yet the specific mechanisms underlying this link remain uncertain. In Saccharomyces cerevisiae, the histone deacetylase Sir2 is required for both transcriptional silencing and late replication at the repetitive ribosomal DNA (rDNA) arrays. We have previously reported that in the absence of SIR2, a de-repressed RNA PolII repositions MCM replicative helicases from their loading site at the ribosomal origin, where they abut well-positioned, high-occupancy nucleosomes, to an adjacent region with lower nucleosome occupancy. By developing a method that can distinguish activation of closely spaced MCM complexes, here we show that the displaced MCMs at rDNA origins have increased firing propensity compared to the nondisplaced MCMs. Furthermore, we found that both activation of the repositioned MCMs and low occupancy of the adjacent nucleosomes critically depend on the chromatin remodeling activity of FUN30. Our study elucidates the mechanism by which Sir2 delays replication timing, and it demonstrates, for the first time, that activation of a specific replication origin in vivo relies on the nucleosome context shaped by a single chromatin remodeler.

Evaluating the transcriptional regulators of arterial gene expression via a catalogue of characterized arterial enhancers

Sarah.deval@dpag.ox.ac.uk (Ian R McCracken) — Fri, 17 Jan 2025 00:00:00 +0000

The establishment and growth of the arterial endothelium require the coordinated expression of numerous genes. However, regulation of this process is not yet fully understood. Here, we combined in silico analysis with transgenic mice and zebrafish models to characterize arterial-specific enhancers associated with eight key arterial identity genes (Acvrl1/Alk1, Cxcr4, Cxcl12, Efnb2, Gja4/Cx37, Gja5/Cx40, Nrp1, and Unc5b). Next, to elucidate the regulatory pathways upstream of arterial gene transcription, we investigated the transcription factors binding each arterial enhancer compared to a similar assessment of non-arterial endothelial enhancers. These results found that binding of SOXF and ETS factors was a common occurrence at both arterial and pan-endothelial enhancers, suggesting neither are sufficient to direct arterial specificity. Conversely, FOX motifs independent of ETS motifs were over-represented at arterial enhancers. Further, MEF2 and RBPJ binding was enriched but not ubiquitous at arterial enhancers, potentially linked to specific patterns of behaviour within the arterial endothelium. Lastly, there was no shared or arterial-specific signature for WNT-associated TCF/LEF, TGFβ/BMP-associated SMAD1/5 and SMAD2/3, shear stress-associated KLF4, or venous-enriched NR2F2. This cohort of well-characterized and in vivo-verified enhancers can now provide a platform for future studies into the interaction of different transcriptional and signaling pathways with arterial gene expression.

Unbiased identification of cell identity in dense mixed neural cultures

winnok.devos@uantwerpen.be (Johanna Van Den Daele) — Fri, 17 Jan 2025 00:00:00 +0000

Induced pluripotent stem cell (iPSC) technology is revolutionizing cell biology. However, the variability between individual iPSC lines and the lack of efficient technology to comprehensively characterize iPSC-derived cell types hinder its adoption in routine preclinical screening settings. To facilitate the validation of iPSC-derived cell culture composition, we have implemented an imaging assay based on cell painting and convolutional neural networks to recognize cell types in dense and mixed cultures with high fidelity. We have benchmarked our approach using pure and mixed cultures of neuroblastoma and astrocytoma cell lines and attained a classification accuracy above 96%. Through iterative data erosion, we found that inputs containing the nuclear region of interest and its close environment, allow achieving equally high classification accuracy as inputs containing the whole cell for semi-confluent cultures and preserved prediction accuracy even in very dense cultures. We then applied this regionally restricted cell profiling approach to evaluate the differentiation status of iPSC-derived neural cultures, by determining the ratio of postmitotic neurons and neural progenitors. We found that the cell-based prediction significantly outperformed an approach in which the population-level time in culture was used as a classification criterion (96% vs 86%, respectively). In mixed iPSC-derived neuronal cultures, microglia could be unequivocally discriminated from neurons, regardless of their reactivity state, and a tiered strategy allowed for further distinguishing activated from non-activated cell states, albeit with lower accuracy. Thus, morphological single-cell profiling provides a means to quantify cell composition in complex mixed neural cultures and holds promise for use in the quality control of iPSC-derived cell culture models.

Prolactin-mediates a lactation-induced suppression of arcuate kisspeptin neuronal activity necessary for lactational infertility in mice

dave.grattan@otago.ac.nz (Allan E Herbison) — Fri, 17 Jan 2025 00:00:00 +0000

The specific role that prolactin plays in lactational infertility, as distinct from other suckling or metabolic cues, remains unresolved. Here, deletion of the prolactin receptor (Prlr) from forebrain neurons or arcuate kisspeptin neurons resulted in failure to maintain normal lactation-induced suppression of estrous cycles. Kisspeptin immunoreactivity and pulsatile LH secretion were increased in these mice, even in the presence of ongoing suckling stimulation and lactation. GCaMP fibre photometry of arcuate kisspeptin neurons revealed that the normal episodic activity of these neurons is rapidly suppressed in pregnancy and this was maintained throughout early lactation. Deletion of Prlr from arcuate kisspeptin neurons resulted in early reactivation of episodic activity of kisspeptin neurons prior to a premature return of reproductive cycles in early lactation. These observations show dynamic variation in arcuate kisspeptin neuronal activity associated with the hormonal changes of pregnancy and lactation, and provide direct evidence that prolactin action on arcuate kisspeptin neurons is necessary for suppressing fertility during lactation in mice.

Altering the redox status of Chlamydia trachomatis directly impacts its developmental cycle progression

scot.ouellette@unmc.edu (Scot P Ouellette) — Fri, 17 Jan 2025 00:00:00 +0000

Chlamydia trachomatis is an obligate intracellular bacterial pathogen with a unique developmental cycle. It differentiates between two functional and morphological forms: the elementary body (EB) and the reticulate body (RB). The signals that trigger differentiation from one form to the other are unknown. EBs and RBs have distinctive characteristics that distinguish them, including their size, infectivity, proteome, and transcriptome. Intriguingly, they also differ in their overall redox status as EBs are oxidized and RBs are reduced. We hypothesize that alterations in redox may serve as a trigger for secondary differentiation. To test this, we examined the function of the primary antioxidant enzyme alkyl hydroperoxide reductase subunit C (AhpC), a well-known member of the peroxiredoxins family, in chlamydial growth and development. Based on our hypothesis, we predicted that altering the expression of ahpC would modulate chlamydial redox status and trigger earlier or delayed secondary differentiation. Therefore, we created ahpC overexpression and knockdown strains. During ahpC knockdown, ROS levels were elevated, and the bacteria were sensitive to a broad set of peroxide stresses. Interestingly, we observed increased expression of EB-associated genes and concurrent higher production of EBs at an earlier time in the developmental cycle, indicating earlier secondary differentiation occurs under elevated oxidation conditions. In contrast, overexpression of AhpC created a resistant phenotype against oxidizing agents and delayed secondary differentiation. Together, these results indicate that redox potential is a critical factor in developmental cycle progression. For the first time, our study provides a mechanism of chlamydial secondary differentiation dependent on redox status.

Realistic mossy fiber input patterns to unipolar brush cells evoke a continuum of temporal responses comprised of components mediated by different glutamate receptors

wade_regehr@hms.harvard.edu (Vincent Huson) — Fri, 17 Jan 2025 00:00:00 +0000

Unipolar brush cells (UBCs) are excitatory interneurons in the cerebellar cortex that receive mossy fiber (MF) inputs and excite granule cells. The UBC population responds to brief burst activation of MFs with a continuum of temporal transformations, but it is not known how UBCs transform the diverse range of MF input patterns that occur in vivo. Here, we use cell-attached recordings from UBCs in acute cerebellar slices to examine responses to MF firing patterns that are based on in vivo recordings. We find that MFs evoke a continuum of responses in the UBC population, mediated by three different types of glutamate receptors that each convey a specialized component. AMPARs transmit timing information for single stimuli at up to 5 spikes/s, and for very brief bursts. A combination of mGluR2/3s (inhibitory) and mGluR1s (excitatory) mediates a continuum of delayed, and broadened responses to longer bursts, and to sustained high frequency activation. Variability in the mGluR2/3 component controls the time course of the onset of firing, and variability in the mGluR1 component controls the duration of prolonged firing. We conclude that the combination of glutamate receptor types allows each UBC to simultaneously convey different aspects of MF firing. These findings establish that UBCs are highly flexible circuit elements that provide diverse temporal transformations that are well suited to contribute to specialized processing in different regions of the cerebellar cortex.

A new preprocedural predictive risk model for post-endoscopic retrograde cholangiopancreatography pancreatitis: The SuPER model

kitachuuou335@yahoo.co.jp (Goro Shibukawa) — Fri, 17 Jan 2025 00:00:00 +0000

CausalXtract, a flexible pipeline to extract causal effects from live-cell time-lapse imaging data

martinelli@ing.uniroma2.it (Arianna Mencattini) — Fri, 17 Jan 2025 00:00:00 +0000

Live-cell microscopy routinely provides massive amounts of time-lapse images of complex cellular systems under various physiological or therapeutic conditions. However, this wealth of data remains difficult to interpret in terms of causal effects. Here, we describe CausalXtract, a flexible computational pipeline that discovers causal and possibly time-lagged effects from morphodynamic features and cell–cell interactions in live-cell imaging data. CausalXtract methodology combines network-based and information-based frameworks, which is shown to discover causal effects overlooked by classical Granger and Schreiber causality approaches. We showcase the use of CausalXtract to uncover novel causal effects in a tumor-on-chip cellular ecosystem under therapeutically relevant conditions. In particular, we find that cancer-associated fibroblasts directly inhibit cancer cell apoptosis, independently from anticancer treatment. CausalXtract uncovers also multiple antagonistic effects at different time delays. Hence, CausalXtract provides a unique computational tool to interpret live-cell imaging data for a range of fundamental and translational research applications.

Outer hair cells stir cochlear fluids

jong-hoon.nam@rochester.edu (Choongheon Lee) — Thu, 16 Jan 2025 00:00:00 +0000

We hypothesized that active outer hair cells drive cochlear fluid circulation. The hypothesis was tested by delivering the neurotoxin, kainic acid, to the intact round window of young gerbil cochleae while monitoring auditory responses in the cochlear nucleus. Sounds presented at a modest level significantly expedited kainic acid delivery. When outer-hair-cell motility was suppressed by salicylate, the facilitation effect was compromised. A low-frequency tone was more effective than broadband noise, especially for drug delivery to apical locations. Computational model simulations provided the physical basis for our observation, which incorporated solute diffusion, fluid advection, fluid–structure interaction, and outer-hair-cell motility. Active outer hair cells deformed the organ of Corti like a peristaltic tube to generate apically streaming flows along the tunnel of Corti and basally streaming flows along the scala tympani. Our measurements and simulations coherently suggest that active outer hair cells in the tail region of cochlear traveling waves drive cochlear fluid circulation.

Target-agnostic identification of human antibodies to Plasmodium falciparum sexual forms reveals cross-stage recognition of glutamate-rich repeats

jean-philippe.julien@sickkids.ca (Amanda Fabra-García) — Thu, 16 Jan 2025 00:00:00 +0000

Circulating sexual stages of Plasmodium falciparum (Pf) can be transmitted from humans to mosquitoes, thereby furthering the spread of malaria in the population. It is well established that antibodies can efficiently block parasite transmission. In search for naturally acquired antibodies targets on sexual stages, we established an efficient method for target-agnostic single B cell activation followed by high-throughput selection of human monoclonal antibodies (mAbs) reactive to sexual stages of Pf in the form of gametes and gametocyte extracts. We isolated mAbs reactive against a range of Pf proteins including well-established targets Pfs48/45 and Pfs230. One mAb, B1E11K, was cross-reactive to various proteins containing glutamate-rich repetitive elements expressed at different stages of the parasite life cycle. A crystal structure of two B1E11K Fab domains in complex with its main antigen, RESA, expressed on asexual blood stages, showed binding of B1E11K to a repeating epitope motif in a head-to-head conformation engaging in affinity-matured homotypic interactions. Thus, this mode of recognition of Pf proteins, previously described only for Pf circumsporozoite protein (PfCSP), extends to other repeats expressed across various stages. The findings augment our understanding of immune-pathogen interactions to repeating elements of the Plasmodium parasite proteome and underscore the potential of the novel mAb identification method used to provide new insights into the natural humoral immune response against Pf.

Encoding of cerebellar dentate neuron activity during visual attention in rhesus macaques

a.badura@erasmusmc.nl (Aleksandra Badura) — Thu, 16 Jan 2025 00:00:00 +0000

The role of cerebellum in controlling eye movements is well established, but its contribution to more complex forms of visual behavior has remained elusive. To study cerebellar activity during visual attention we recorded extracellular activity of dentate nucleus (DN) neurons in two non-human primates (NHPs). NHPs were trained to read the direction indicated by a peripheral visual stimulus while maintaining fixation at the center, and report the direction of the cue by performing a saccadic eye movement into the same direction following a delay. We found that single-unit DN neurons modulated spiking activity over the entire time course of the task, and that their activity often bridged temporally separated intra-trial events, yet in a heterogeneous manner. To better understand the heterogeneous relationship between task structure, behavioral performance, and neural dynamics, we constructed a behavioral, an encoding, and a decoding model. Both NHPs showed different behavioral strategies, which influenced the performance. Activity of the DN neurons reflected the unique strategies, with the direction of the visual stimulus frequently being encoded long before an upcoming saccade. Moreover, the latency of the ramping activity of DN neurons following presentation of the visual stimulus was shorter in the better performing NHP. Labeling with the retrograde tracer Cholera Toxin B in the recording location in the DN indicated that these neurons predominantly receive inputs from Purkinje cells in the D1 and D2 zones of the lateral cerebellum as well as neurons of the principal olive and medial pons, all regions known to connect with neurons in the prefrontal cortex contributing to planning of saccades. Together, our results highlight that DN neurons can dynamically modulate their activity during a visual attention task, comprising not only sensorimotor but also cognitive attentional components.

Discovery of a heparan sulfate binding domain in monkeypox virus H3 as an anti-poxviral drug target combining AI and MD simulations

chenglin252@163.com (Bin Zheng) — Thu, 16 Jan 2025 00:00:00 +0000

Viral adhesion to host cells is a critical step in infection for many viruses, including monkeypox virus (MPXV). In MPXV, the H3 protein mediates viral adhesion through its interaction with heparan sulfate (HS), yet the structural details of this interaction have remained elusive. Using AI-based structural prediction tools and molecular dynamics (MD) simulations, we identified a novel, positively charged α-helical domain in H3 that is essential for HS binding. This conserved domain, found across orthopoxviruses, was experimentally validated and shown to be critical for viral adhesion, making it an ideal target for antiviral drug development. Targeting this domain, we designed a protein inhibitor, which disrupted the H3-HS interaction, inhibited viral infection in vitro and viral replication in vivo, offering a promising antiviral candidate. Our findings reveal a novel therapeutic target of MPXV, demonstrating the potential of combination of AI-driven methods and MD simulations to accelerate antiviral drug discovery.

Early and delayed STAT1-dependent responses drive local trained immunity of macrophages in the spleen

roi.avraham@weizmann.ac.il (Aryeh Solomon) — Thu, 16 Jan 2025 00:00:00 +0000

Trained immunity (TI) is the process wherein innate immune cells gain functional memory upon exposure to specific ligands or pathogens, leading to augmented inflammatory responses and pathogen clearance upon secondary exposure. While the differentiation of hematopoietic stem cells (HSCs) and reprogramming of bone marrow (BM) progenitors are well-established mechanisms underpinning durable TI protection, remodeling of the cellular architecture within the tissue during TI remains underexplored. Here, we study the effects of peritoneal Bacillus Calmette–Guérin (BCG) administration to find TI-mediated protection in the spleen against a subsequent heterologous infection by the Gram-negative pathogen Salmonella Typhimurium (S.Tm). Utilizing single cell RNA-sequencing and flow cytometry, we discerned STAT1-regulated genes in TI-associated resident and recruited splenic myeloid populations. The temporal dynamics of TI were further elucidated, revealing both early and delayed myeloid subsets with time-dependent, cell-type-specific STAT1 signatures. Using lineage tracing, we find that tissue-resident red pulp macrophages (RPM), initially depleted by BCG exposure, are restored from both tissue-trained, self-renewing macrophages and from bone marrow-derived progenitors, fostering long lasting local defense. Early inhibition of STAT1 activation, using specific JAK-STAT inhibitors, reduces both RPM loss and recruitment of trained monocytes. Our study suggests a temporal window soon after BCG vaccination, in which STAT1-dependent activation of long-lived resident cells in the tissue mediates localized protection.

Exploration of the metabolomic mechanisms of postmenopausal hypertension induced by low estrogen state

Lianzx566@163.com (Hui Xin) — Thu, 16 Jan 2025 00:00:00 +0000

Estrogen significantly impacts women’s health, and postmenopausal hypertension is a common issue characterized by blood pressure fluctuations. Current control strategies for this condition are limited in efficacy, necessitating further research into the underlying mechanisms. Although metabolomics has been applied to study various diseases, its use in understanding postmenopausal hypertension is scarce. Therefore, an ovariectomized rat model was used to simulate postmenopausal conditions. Estrogen levels, blood pressure, and aortic tissue metabolomics were analyzed. Animal models were divided into Sham, OVX, and OVX +E groups. Serum estrogen levels, blood pressure measurements, and aortic tissue metabolomics analyses were performed using radioimmunoassay, UHPLC-Q-TOF, and bioinformatics techniques. Based on the above research content, we successfully established a correlation between low estrogen levels and postmenopausal hypertension in rats. Notable differences in blood pressure parameters and aortic tissue metabolites were observed across the experimental groups. Specifically, metabolites that were differentially expressed, particularly L-alpha-aminobutyric acid (L-AABA), showed potential as a biomarker for postmenopausal hypertension, potentially exerting a protective function through macrophage activation and vascular remodeling. Enrichment analysis revealed alterations in sugar metabolism pathways, such as the Warburg effect and glycolysis, indicating their involvement in postmenopausal hypertension. Overall, this current research provides insights into the metabolic changes associated with postmenopausal hypertension, highlighting the role of L-AABA and sugar metabolism reprogramming in aortic tissue. The findings suggest a potential link between low estrogen levels, macrophage function, and vascular remodeling in the pathogenesis of postmenopausal hypertension. Further investigations are needed to validate these findings and explore their clinical implications for postmenopausal women.

Crispant analysis in zebrafish as a tool for rapid functional screening of disease-causing genes for bone fragility

andy.willaert@ugent.be (Andy Willaert) — Thu, 16 Jan 2025 00:00:00 +0000

Heritable fragile bone disorders (FBDs), ranging from multifactorial to rare monogenic conditions, are characterized by an elevated fracture risk. Validating causative genes and understanding their mechanisms remain challenging. We assessed a semi-high throughput zebrafish screening platform for rapid in vivo functional testing of candidate FBD genes. Six genes linked to severe recessive osteogenesis imperfecta (OI) and four associated with bone mineral density (BMD) from genome-wide association studies were analyzed using CRISPR/Cas9-based crispant screening in F0 mosaic founder zebrafish. Next-generation sequencing confirmed high indel efficiency (mean 88%), mimicking stable knock-out models. Skeletal phenotyping at 7, 14, and 90 days post-fertilization (dpf) using microscopy, Alizarin Red S staining, and microCT was performed. Larval crispants showed variable osteoblast and mineralization phenotypes, while adult crispants displayed consistent skeletal defects, including malformed neural and haemal arches, vertebral fractures and fusions, and altered bone volume and density. In addition, aldh7a1 and mbtps2 crispants experienced increased mortality due to severe skeletal deformities. RT-qPCR revealed differential expression of osteogenic markers bglap and col1a1a, highlighting their biomarker potential. Our results establish zebrafish crispant screening as a robust tool for FBD gene validation, combining skeletal and molecular analyses across developmental stages to uncover novel insights into gene functions in bone biology.

Serum metabolome indicators of early childhood development in the Brazilian National Survey on Child Nutrition (ENANI-2019)

gilberto.kac@gmail.com (Dayana R Farias) — Wed, 15 Jan 2025 00:00:00 +0000

Complementary cognitive roles for D2-MSNs and D1-MSNs during interval timing

nandakumar-narayanan@uiowa.edu (Alexandra Bova) — Wed, 15 Jan 2025 00:00:00 +0000

The role of striatal pathways in cognitive processing is unclear. We studied dorsomedial striatal cognitive processing during interval timing, an elementary cognitive task that requires mice to estimate intervals of several seconds and involves working memory for temporal rules as well as attention to the passage of time. We harnessed optogenetic tagging to record from striatal D2-dopamine receptor-expressing medium spiny neurons (D2-MSNs) in the indirect pathway and from D1-dopamine receptor-expressing MSNs (D1-MSNs) in the direct pathway. We found that D2-MSNs and D1-MSNs exhibited distinct dynamics over temporal intervals as quantified by principal component analyses and trial-by-trial generalized linear models. MSN recordings helped construct and constrain a four-parameter drift-diffusion computational model in which MSN ensemble activity represented the accumulation of temporal evidence. This model predicted that disrupting either D2-MSNs or D1-MSNs would increase interval timing response times and alter MSN firing. In line with this prediction, we found that optogenetic inhibition or pharmacological disruption of either D2-MSNs or D1-MSNs increased interval timing response times. Pharmacologically disrupting D2-MSNs or D1-MSNs also changed MSN dynamics and degraded trial-by-trial temporal decoding. Together, our findings demonstrate that D2-MSNs and D1-MSNs had opposing dynamics yet played complementary cognitive roles, implying that striatal direct and indirect pathways work together to shape temporal control of action. These data provide novel insight into basal ganglia cognitive operations beyond movement and have implications for human striatal diseases and therapies targeting striatal pathways.

Correction: Functional and structural segregation of overlapping helices in HIV-1

Wed, 15 Jan 2025 00:00:00 +0000

Leveraging mobility data to analyze persistent SARS-CoV-2 mutations and inform targeted genomic surveillance

riccardo.spott@gmail.com (Aurelia Kimmig) — Wed, 15 Jan 2025 00:00:00 +0000

Given the rapid cross-country spread of SARS-CoV-2 and the resulting difficulty in tracking lineage spread, we investigated the potential of combining mobile service data and fine-granular metadata (such as postal codes and genomic data) to advance integrated genomic surveillance of the pandemic in the federal state of Thuringia, Germany. We sequenced over 6500 SARS-CoV-2 Alpha genomes (B.1.1.7) across 7 months within Thuringia while collecting patients’ isolation dates and postal codes. Our dataset is complemented by over 66,000 publicly available German Alpha genomes and mobile service data for Thuringia. We identified the existence and spread of nine persistent mutation variants within the Alpha lineage, seven of which formed separate phylogenetic clusters with different spreading patterns in Thuringia. The remaining two are subclusters. Mobile service data can indicate these clusters’ spread and highlight a potential sampling bias, especially of low-prevalence variants. Thereby, mobile service data can be used either retrospectively to assess surveillance coverage and efficiency from already collected data or to actively guide part of a surveillance sampling process to districts where these variants are expected to emerge. The latter concept was successfully implemented as a proof-of-concept for a mobility-guided sampling strategy in response to the surveillance of Omicron sublineage BQ.1.1. The combination of mobile service data and SARS-CoV-2 surveillance by genome sequencing is a valuable tool for more targeted and responsive surveillance.

3D genomic features across >50 diverse cell types reveal insights into the genomic architecture of childhood obesity

grants@chop.edu (Alessandra Chesi) — Wed, 15 Jan 2025 00:00:00 +0000

The prevalence of childhood obesity is increasing worldwide, along with the associated common comorbidities of type 2 diabetes and cardiovascular disease in later life. Motivated by evidence for a strong genetic component, our prior genome-wide association study (GWAS) efforts for childhood obesity revealed 19 independent signals for the trait; however, the mechanism of action of these loci remains to be elucidated. To molecularly characterize these childhood obesity loci, we sought to determine the underlying causal variants and the corresponding effector genes within diverse cellular contexts. Integrating childhood obesity GWAS summary statistics with our existing 3D genomic datasets for 57 human cell types, consisting of high-resolution promoter-focused Capture-C/Hi-C, ATAC-seq, and RNA-seq, we applied stratified LD score regression and calculated the proportion of genome-wide SNP heritability attributable to cell type-specific features, revealing pancreatic alpha cell enrichment as the most statistically significant. Subsequent chromatin contact-based fine-mapping was carried out for genome-wide significant childhood obesity loci and their linkage disequilibrium proxies to implicate effector genes, yielded the most abundant number of candidate variants and target genes at the BDNF, ADCY3, TMEM18, and FTO loci in skeletal muscle myotubes and the pancreatic beta-cell line, EndoC-BH1. One novel implicated effector gene, ALKAL2 – an inflammation-responsive gene in nerve nociceptors – was observed at the key TMEM18 locus across multiple immune cell types. Interestingly, this observation was also supported through colocalization analysis using expression quantitative trait loci (eQTL) derived from the Genotype-Tissue Expression (GTEx) dataset, supporting an inflammatory and neurologic component to the pathogenesis of childhood obesity. Our comprehensive appraisal of 3D genomic datasets generated in a myriad of different cell types provides genomic insights into pediatric obesity pathogenesis.

Endocytic recycling is central to circadian collagen fibrillogenesis and disrupted in fibrosis

joan.chang@manchester.ac.uk (Adam Pickard) — Wed, 15 Jan 2025 00:00:00 +0000

Collagen-I fibrillogenesis is crucial to health and development, where dysregulation is a hallmark of fibroproliferative diseases. Here, we show that collagen-I fibril assembly required a functional endocytic system that recycles collagen-I to assemble new fibrils. Endogenous collagen production was not required for fibrillogenesis if exogenous collagen was available, but the circadian-regulated vacuolar protein sorting (VPS) 33b and collagen-binding integrin α11 subunit were crucial to fibrillogenesis. Cells lacking VPS33B secrete soluble collagen-I protomers but were deficient in fibril formation, thus secretion and assembly are separately controlled. Overexpression of VPS33B led to loss of fibril rhythmicity and overabundance of fibrils, which was mediated through integrin α11β1. Endocytic recycling of collagen-I was enhanced in human fibroblasts isolated from idiopathic pulmonary fibrosis, where VPS33B and integrin α11 subunit were overexpressed at the fibrogenic front; this correlation between VPS33B, integrin α11 subunit, and abnormal collagen deposition was also observed in samples from patients with chronic skin wounds. In conclusion, our study showed that circadian-regulated endocytic recycling is central to homeostatic assembly of collagen fibrils and is disrupted in diseases.

Geometry and dynamics of representations in a precisely balanced memory network related to olfactory cortex

rainer.friedrich@fmi.ch (Claire Meissner-Bernard) — Mon, 13 Jan 2025 00:00:00 +0000

Biological memory networks are thought to store information by experience-dependent changes in the synaptic connectivity between assemblies of neurons. Recent models suggest that these assemblies contain both excitatory and inhibitory neurons (E/I assemblies), resulting in co-tuning and precise balance of excitation and inhibition. To understand computational consequences of E/I assemblies under biologically realistic constraints we built a spiking network model based on experimental data from telencephalic area Dp of adult zebrafish, a precisely balanced recurrent network homologous to piriform cortex. We found that E/I assemblies stabilized firing rate distributions compared to networks with excitatory assemblies and global inhibition. Unlike classical memory models, networks with E/I assemblies did not show discrete attractor dynamics. Rather, responses to learned inputs were locally constrained onto manifolds that ‘focused’ activity into neuronal subspaces. The covariance structure of these manifolds supported pattern classification when information was retrieved from selected neuronal subsets. Networks with E/I assemblies therefore transformed the geometry of neuronal coding space, resulting in continuous representations that reflected both relatedness of inputs and an individual’s experience. Such continuous representations enable fast pattern classification, can support continual learning, and may provide a basis for higher-order learning and cognitive computations.

Robust single-nucleus RNA sequencing reveals depot-specific cell population dynamics in adipose tissue remodeling during obesity

hyunroh@iu.edu (Avishek Paul) — Mon, 13 Jan 2025 00:00:00 +0000

Single-nucleus RNA sequencing (snRNA-seq), an alternative to single-cell RNA sequencing (scRNA-seq), encounters technical challenges in obtaining high-quality nuclei and RNA, persistently hindering its applications. Here, we present a robust technique for isolating nuclei across various tissue types, remarkably enhancing snRNA-seq data quality. Employing this approach, we comprehensively characterize the depot-dependent cellular dynamics of various cell types underlying mouse adipose tissue remodeling during obesity. By integrating bulk nuclear RNA-seq from adipocyte nuclei of different sizes, we identify distinct adipocyte subpopulations categorized by size and functionality. These subpopulations follow two divergent trajectories, adaptive and pathological, with their prevalence varying by depot. Specifically, we identify a key molecular feature of dysfunctional hypertrophic adipocytes, a global shutdown in gene expression, along with elevated stress and inflammatory responses. Furthermore, our differential gene expression analysis reveals distinct contributions of adipocyte subpopulations to the overall pathophysiology of adipose tissue. Our study establishes a robust snRNA-seq method, providing novel insights into the biological processes involved in adipose tissue remodeling during obesity, with broader applicability across diverse biological systems.

AI-driven automated discovery tools reveal diverse behavioral competencies of biological networks

michael.levin@allencenter.tufts.edu (Clément Moulin-Frier) — Mon, 13 Jan 2025 00:00:00 +0000

Many applications in biomedicine and synthetic bioengineering rely on understanding, mapping, predicting, and controlling the complex behavior of chemical and genetic networks. The emerging field of diverse intelligence investigates the problem-solving capacities of unconventional agents. However, few quantitative tools exist for exploring the competencies of non-conventional systems. Here, we view gene regulatory networks (GRNs) as agents navigating a problem space and develop automated tools to map the robust goal states GRNs can reach despite perturbations. Our contributions include: (1) Adapting curiosity-driven exploration algorithms from AI to discover the range of reachable goal states of GRNs, and (2) Proposing empirical tests inspired by behaviorist approaches to assess their navigation competencies. Our data shows that models inferred from biological data can reach a wide spectrum of steady states, exhibiting various competencies in physiological network dynamics without requiring structural changes in network properties or connectivity. We also explore the applicability of these ‘behavioral catalogs’ for comparing evolved competencies across biological networks, for designing drug interventions in biomedical contexts and synthetic gene networks for bioengineering. These tools and the emphasis on behavior-shaping open new paths for efficiently exploring the complex behavior of biological networks. For the interactive version of this paper, please visit https://developmentalsystems.org/curious-exploration-of-grn-competencies.

Assessing the balance between excitation and inhibition in chronic pain through the aperiodic component of EEG

markus.ploner@tum.de (Cristina Gil Avila) — Mon, 13 Jan 2025 00:00:00 +0000

Chronic pain is a prevalent and debilitating condition whose neural mechanisms are incompletely understood. An imbalance of cerebral excitation and inhibition (E/I), particularly in the medial prefrontal cortex (mPFC), is believed to represent a crucial mechanism in the development and maintenance of chronic pain. Thus, identifying a non-invasive, scalable marker of E/I could provide valuable insights into the neural mechanisms of chronic pain and aid in developing clinically useful biomarkers. Recently, the aperiodic component of the electroencephalography (EEG) power spectrum has been proposed to represent a non-invasive proxy for E/I. We, therefore, assessed the aperiodic component in the mPFC of resting-state EEG recordings in 149 people with chronic pain and 115 healthy participants. We found robust evidence against differences in the aperiodic component in the mPFC between people with chronic pain and healthy participants, and no correlation between the aperiodic component and pain intensity. These findings were consistent across different subtypes of chronic pain and were similarly found in a whole-brain analysis. Their robustness was supported by preregistration and multiverse analyses across many different methodological choices. Together, our results suggest that the EEG aperiodic component does not differentiate between people with chronic pain and healthy individuals. These findings and the rigorous methodological approach can guide future studies investigating non-invasive, scalable markers of cerebral dysfunction in people with chronic pain and beyond.

Restoring bone healing potential

i.sequeira@qmul.ac.uk (Inês Sequeira) — Mon, 13 Jan 2025 00:00:00 +0000

A combination of intermittent fasting and administering Wnt3a proteins to a bone injury can rejuvenate bone repair in aged mice.

Surprising features of nuclear receptor interaction networks revealed by live-cell single-molecule imaging

dahal.liza472@gmail.com (Alec Heckert) — Fri, 10 Jan 2025 00:00:00 +0000

Type II nuclear receptors (T2NRs) require heterodimerization with a common partner, the retinoid X receptor (RXR), to bind cognate DNA recognition sites in chromatin. Based on previous biochemical and overexpression studies, binding of T2NRs to chromatin is proposed to be regulated by competition for a limiting pool of the core RXR subunit. However, this mechanism has not yet been tested for endogenous proteins in live cells. Using single-molecule tracking (SMT) and proximity-assisted photoactivation (PAPA), we monitored interactions between endogenously tagged RXR and retinoic acid receptor (RAR) in live cells. Unexpectedly, we find that higher expression of RAR, but not RXR, increases heterodimerization and chromatin binding in U2OS cells. This surprising finding indicates the limiting factor is not RXR but likely its cadre of obligate dimer binding partners. SMT and PAPA thus provide a direct way to probe which components are functionally limiting within a complex TF interaction network providing new insights into mechanisms of gene regulation in vivo with implications for drug development targeting nuclear receptors.

Parabrachial CGRP neurons modulate active defensive behavior under a naturalistic threat

ysjo@korea.ac.kr (Byung Min Chung) — Fri, 10 Jan 2025 00:00:00 +0000

Recent studies suggest that calcitonin gene-related peptide (CGRP) neurons in the parabrachial nucleus (PBN) represent aversive information and signal a general alarm to the forebrain. If CGRP neurons serve as a true general alarm, their activation would modulate both passive and active defensive behaviors depending on the magnitude and context of the threat. However, most prior research has focused on the role of CGRP neurons in passive freezing responses, with limited exploration of their involvement in active defensive behaviors. To address this, we examined the role of CGRP neurons in active defensive behavior using a predator-like robot programmed to chase mice. Our electrophysiological results revealed that CGRP neurons encode the intensity of aversive stimuli through variations in firing durations and amplitudes. Optogenetic activation of CGRP neurons during robot chasing elevated flight responses in both conditioning and retention tests, presumably by amplifying the perception of the threat as more imminent and dangerous. In contrast, animals with inactivated CGRP neurons exhibited reduced flight responses, even when the robot was programmed to appear highly threatening during conditioning. These findings expand the understanding of CGRP neurons in the PBN as a critical alarm system, capable of dynamically regulating active defensive behaviors by amplifying threat perception, and ensuring adaptive responses to varying levels of danger.

The NeuroML ecosystem for standardized multi-scale modeling in neuroscience

p.gleeson@ucl.ac.uk (Andrew P Davison) — Fri, 10 Jan 2025 00:00:00 +0000

Data-driven models of neurons and circuits are important for understanding how the properties of membrane conductances, synapses, dendrites, and the anatomical connectivity between neurons generate the complex dynamical behaviors of brain circuits in health and disease. However, the inherent complexity of these biological processes makes the construction and reuse of biologically detailed models challenging. A wide range of tools have been developed to aid their construction and simulation, but differences in design and internal representation act as technical barriers to those who wish to use data-driven models in their research workflows. NeuroML, a model description language for computational neuroscience, was developed to address this fragmentation in modeling tools. Since its inception, NeuroML has evolved into a mature community standard that encompasses a wide range of model types and approaches in computational neuroscience. It has enabled the development of a large ecosystem of interoperable open-source software tools for the creation, visualization, validation, and simulation of data-driven models. Here, we describe how the NeuroML ecosystem can be incorporated into research workflows to simplify the construction, testing, and analysis of standardized models of neural systems, and supports the FAIR (Findability, Accessibility, Interoperability, and Reusability) principles, thus promoting open, transparent and reproducible science.

Valence and salience encoding in the central amygdala

larryz@uw.edu (Daniela M Witten) — Fri, 10 Jan 2025 00:00:00 +0000

The central amygdala (CeA) has emerged as an important brain region for regulating both negative (fear and anxiety) and positive (reward) affective behaviors. The CeA has been proposed to encode affective information in the form of valence (whether the stimulus is good or bad) or salience (how significant is the stimulus), but the extent to which these two types of stimulus representation occur in the CeA is not known. Here, we used single cell calcium imaging in mice during appetitive and aversive conditioning and found that majority of CeA neurons (~65%) encode the valence of the unconditioned stimulus (US) with a smaller subset of cells (~15%) encoding the salience of the US. Valence and salience encoding of the conditioned stimulus (CS) was also observed, albeit to a lesser extent. These findings show that the CeA is a site of convergence for encoding oppositely valenced US information.

The protective roles of eugenol on type 1 diabetes mellitus through NRF2-mediated oxidative stress pathway

jiweiping@wmu.edu.cn (Huilan Wu) — Fri, 10 Jan 2025 00:00:00 +0000

Type 1 diabetes mellitus (T1DM), known as insulin-dependent diabetes mellitus, is characterized by persistent hyperglycemia resulting from damage to the pancreatic β cells and an absolute deficiency of insulin, leading to multi-organ involvement and a poor prognosis. The progression of T1DM is significantly influenced by oxidative stress and apoptosis. The natural compound eugenol (EUG) possesses anti-inflammatory, anti-oxidant, and anti-apoptotic properties. However, the potential effects of EUG on T1DM had not been investigated. In this study, we established the streptozotocin (STZ)-induced T1DM mouse model in vivo and STZ-induced pancreatic β cell MIN6 cell model in vitro to investigate the protective effects of EUG on T1DM, and tried to elucidate its potential mechanism. Our findings demonstrated that the intervention of EUG could effectively induce the activation of nuclear factor E2-related factor 2 (NRF2), leading to an up-regulation in the expressions of downstream proteins NQO1 and HMOX1, which are regulated by NRF2. Moreover, this intervention exhibited a significant amelioration in pancreatic β cell damage associated with T1DM, accompanied by an elevation in insulin secretion and a reduction in the expression levels of apoptosis and oxidative stress-related markers. Furthermore, ML385, an NRF2 inhibitor, reversed these effects of EUG. The present study suggested that EUG exerted protective effects on pancreatic β cells in T1DM by attenuating apoptosis and oxidative stress through the activation of the NRF2 signaling pathway. Consequently, EUG holds great promise as a potential therapeutic candidate for T1DM.

Oversized cells activate global proteasome-mediated protein degradation to maintain cell size homeostasis

shixuan@stanford.edu (Ceryl Tan) — Fri, 10 Jan 2025 00:00:00 +0000

Proliferating animal cells maintain a stable size distribution over generations despite fluctuations in cell growth and division size. Previously, we showed that cell size control involves both cell size checkpoints, which delay cell cycle progression in small cells, and size-dependent regulation of mass accumulation rates (Ginzberg et al., 2018). While we previously identified the p38 MAPK pathway as a key regulator of the mammalian cell size checkpoint (Liu et al., 2018), the mechanism of size-dependent growth rate regulation has remained elusive. Here, we quantified global rates of protein synthesis and degradation in cells of varying sizes, both under unperturbed conditions and in response to perturbations that trigger size-dependent compensatory growth slowdown. We found that protein synthesis rates scale proportionally with cell size across cell cycle stages and experimental conditions. In contrast, oversized cells that undergo compensatory growth slowdown exhibit a superlinear increase in proteasome-mediated protein degradation, with accelerated protein turnover per unit mass, suggesting activation of the proteasomal degradation pathway. Both nascent and long-lived proteins contribute to the elevated protein degradation during compensatory growth slowdown, with long-lived proteins playing a crucial role at the G1/S transition. Notably, large G1/S cells exhibit particularly high efficiency in protein degradation, surpassing that of similarly sized or larger cells in S and G2, coinciding with the timing of the most stringent size control in animal cells. These results collectively suggest that oversized cells reduce their growth efficiency by activating global proteasome-mediated protein degradation to promote cell size homeostasis.

Mapping patterns of thought onto brain activity during movie-watching

raven.wallace@queensu.ca (Adam Turnbull) — Fri, 10 Jan 2025 00:00:00 +0000

Movie-watching is a central aspect of our lives and an important paradigm for understanding the brain mechanisms behind cognition as it occurs in daily life. Contemporary views of ongoing thought argue that the ability to make sense of events in the ‘here and now’ depend on the neural processing of incoming sensory information by auditory and visual cortex, which are kept in check by systems in association cortex. However, we currently lack an understanding of how patterns of ongoing thoughts map onto the different brain systems when we watch a film, partly because methods of sampling experience disrupt the dynamics of brain activity and the experience of movie-watching. Our study established a novel method for mapping thought patterns onto the brain activity that occurs at different moments of a film, which does not disrupt the time course of brain activity or the movie-watching experience. We found moments when experience sampling highlighted engagement with multi-sensory features of the film or highlighted thoughts with episodic features, regions of sensory cortex were more active and subsequent memory for events in the movie was better—on the other hand, periods of intrusive distraction emerged when activity in regions of association cortex within the frontoparietal system was reduced. These results highlight the critical role sensory systems play in the multi-modal experience of movie-watching and provide evidence for the role of association cortex in reducing distraction when we watch films.

Sensory experience controls dendritic structure and behavior by distinct pathways involving degenerins

podbilew@technion.ac.il (Alba Calatayud-Sanchez) — Fri, 10 Jan 2025 00:00:00 +0000

Dendrites are crucial for receiving information into neurons. Sensory experience affects the structure of these tree-like neurites, which, it is assumed, modifies neuronal function, yet the evidence is scarce, and the mechanisms are unknown. To study whether sensory experience affects dendritic morphology, we use the Caenorhabditis elegans’ arborized nociceptor PVD neurons, under natural mechanical stimulation induced by physical contacts between individuals. We found that mechanosensory signals induced by conspecifics and by glass beads affect the dendritic structure of the PVD. Moreover, developmentally isolated animals show a decrease in their ability to respond to harsh touch. The structural and behavioral plasticity following sensory deprivation are functionally independent of each other and are mediated by an array of evolutionarily conserved mechanosensory amiloride-sensitive epithelial sodium channels (degenerins). Calcium imaging of the PVD neurons in a micromechanical device revealed that controlled mechanical stimulation of the body wall produces similar calcium dynamics in both isolated and crowded animals. Our genetic results, supported by optogenetic, behavioral, and pharmacological evidence, suggest an activity-dependent homeostatic mechanism for dendritic structural plasticity, that in parallel controls escape response to noxious mechanosensory stimuli.

The effect of transcutaneous auricular vagus nerve stimulation on cardiovascular function in subarachnoid hemorrhage patients: A randomized trial

leuthardte@wustl.edu (Ananthv K Vellimana) — Thu, 09 Jan 2025 00:00:00 +0000

A new pipeline SPICE identifies novel JUN-IKZF1 composite elements

lip3@nhlbi.nih.gov (Jangsuk Oh) — Thu, 09 Jan 2025 00:00:00 +0000

Transcription factor partners can cooperatively bind to DNA composite elements to augment gene transcription. Here, we report a novel protein-DNA binding screening pipeline, termed Spacing Preference Identification of Composite Elements (SPICE), that can systematically predict protein binding partners and DNA motif spacing preferences. Using SPICE, we successfully identified known composite elements, such as AP1-IRF composite elements (AICEs) and STAT5 tetramers, and also uncovered several novel binding partners, including JUN-IKZF1 composite elements. One such novel interaction was identified at CNS9, an upstream conserved noncoding region in the human IL10 gene, which harbors a non-canonical IKZF1 binding site. We confirmed the cooperative binding of JUN and IKZF1 and showed that the activity of an IL10-luciferase reporter construct in primary B and T cells depended on both this site and the AP1 binding site within this composite element. Overall, our findings reveal an unappreciated global association of IKZF1 and AP1 and establish SPICE as a valuable new pipeline for predicting novel transcription binding complexes.

A high-throughput platform for single-molecule tracking identifies drug interaction and cellular mechanisms

beckh@eikontx.com (Aaron Klammer) — Thu, 09 Jan 2025 00:00:00 +0000

The regulation of cell physiology depends largely upon interactions of functionally distinct proteins and cellular components. These interactions may be transient or long-lived, but often affect protein motion. Measurement of protein dynamics within a cellular environment, particularly while perturbing protein function with small molecules, may enable dissection of key interactions and facilitate drug discovery; however, current approaches are limited by throughput with respect to data acquisition and analysis. As a result, studies using super-resolution imaging are typically drawing conclusions from tens of cells and a few experimental conditions tested. We addressed these limitations by developing a high-throughput single-molecule tracking (htSMT) platform for pharmacologic dissection of protein dynamics in living cells at an unprecedented scale (capable of imaging >10⁶ cells/day and screening >10⁴ compounds). We applied htSMT to measure the cellular dynamics of fluorescently tagged estrogen receptor (ER) and screened a diverse library to identify small molecules that perturbed ER function in real time. With this one experimental modality, we determined the potency, pathway selectivity, target engagement, and mechanism of action for identified hits. Kinetic htSMT experiments were capable of distinguishing between on-target and on-pathway modulators of ER signaling. Integrated pathway analysis recapitulated the network of known ER interaction partners and suggested potentially novel, kinase-mediated regulatory mechanisms. The sensitivity of htSMT revealed a new correlation between ER dynamics and the ability of ER antagonists to suppress cancer cell growth. Therefore, measuring protein motion at scale is a powerful method to investigate dynamic interactions among proteins and may facilitate the identification and characterization of novel therapeutics.

High-resolution awake mouse fMRI at 14 tesla

xyu9@mgh.harvard.edu (Alyssa Murstein) — Thu, 09 Jan 2025 00:00:00 +0000

High-resolution awake mouse functional magnetic resonance imaging (fMRI) remains challenging despite extensive efforts to address motion-induced artifacts and stress. This study introduces an implantable radio frequency (RF) surface coil design that minimizes image distortion caused by the air/tissue interface of mouse brains while simultaneously serving as a headpost for fixation during scanning. Furthermore, this study provides a thorough acclimation method used to accustom animals to the MRI environment minimizing motion-induced artifacts. Using a 14 T scanner, high-resolution fMRI enabled brain-wide functional mapping of visual and vibrissa stimulation at 100 µm×100 µm×200 µm resolution with a 2 s per frame sampling rate. Besides activated ascending visual and vibrissa pathways, robust blood oxygen level-dependent (BOLD) responses were detected in the anterior cingulate cortex upon visual stimulation and spread through the ventral retrosplenial area (VRA) with vibrissa air-puff stimulation, demonstrating higher-order sensory processing in association cortices of awake mice. In particular, the rapid hemodynamic responses in VRA upon vibrissa stimulation showed a strong correlation with the hippocampus, thalamus, and prefrontal cortical areas. Cross-correlation analysis with designated VRA responses revealed early positive BOLD signals at the contralateral barrel cortex (BC) occurring 2 s prior to the air-puff in awake mice with repetitive stimulation, which was not detected using a randomized stimulation paradigm. This early BC activation indicated a learned anticipation through the vibrissa system and association cortices in awake mice under continuous exposure of repetitive air-puff stimulation. This work establishes a high-resolution awake mouse fMRI platform, enabling brain-wide functional mapping of sensory signal processing in higher association cortical areas.

Fractal cycles of sleep, a new aperiodic activity-based definition of sleep cycles

yevgeniabio@yahoo.com (Axel Steiger) — Thu, 09 Jan 2025 00:00:00 +0000

Sleep cycles are defined as episodes of non-rapid eye movement (non-REM) sleep followed by an episode of REM sleep. Fractal or aperiodic neural activity is a well-established marker of arousal and sleep stages measured using electroencephalography. We introduce a new concept of ‘fractal cycles’ of sleep, defined as a time interval during which time series of fractal activity descend to their local minimum and ascend to the next local maximum. We assess correlations between fractal and classical (i.e. non-REM – REM) sleep cycle durations and study cycles with skipped REM sleep. The sample comprised 205 healthy adults, 21 children and adolescents and 111 patients with depression. We found that fractal and classical cycle durations (89±34 vs 90±25 min) correlated positively (r=0.5, p<0.001). Children and adolescents had shorter fractal cycles than young adults (76±34 vs 94±32 min). The fractal cycle algorithm detected cycles with skipped REM sleep in 91–98% of cases. Medicated patients with depression showed longer fractal cycles compared to their unmedicated state (107±51 vs 92±38 min) and age-matched controls (104±49 vs 88±31 min). In conclusion, fractal cycles are an objective, quantifiable, continuous and biologically plausible way to display sleep neural activity and its cycles.

Nitric oxide modulates contrast suppression in a subset of mouse retinal ganglion cells

thomas.euler@cin.uni-tuebingen.de (Dominic Gonschorek) — Thu, 09 Jan 2025 00:00:00 +0000

Neuromodulators have major influences on the regulation of neural circuit activity across the nervous system. Nitric oxide (NO) has been shown to be a prominent neuromodulator in many circuits and has been extensively studied in the retina. Here, it has been associated with the regulation of light adaptation, gain control, and gap junctional coupling, but its effect on the retinal output, specifically on the different types of retinal ganglion cells (RGCs), is still poorly understood. In this study, we used two-photon Ca²⁺ imaging and multi-electrode array (MEA) recordings to measure light-evoked activity of RGCs in the ganglion cell layer in the ex vivo mouse retina. This approach allowed us to investigate the neuromodulatory effects of NO on a cell type-level. Our findings reveal that NO selectively modulates the suppression of temporal responses in a distinct subset of contrast-suppressed RGC types, increasing their activity without altering the spatial properties of their receptive fields. Given that under photopic conditions, NO release is triggered by quick changes in light levels, we propose that these RGC types signal fast contrast changes to higher visual regions. Remarkably, we found that about one-third of the RGC types, recorded using two-photon Ca²⁺ imaging, exhibited consistent, cell type-specific adaptational response changes throughout an experiment, independent of NO. By employing a sequential-recording paradigm, we could disentangle those additional adaptational response changes from drug-induced modulations. Taken together, our research highlights the selective neuromodulatory effects of NO on RGCs and emphasizes the need of considering non-pharmacological activity changes, like adaptation, in such study designs.

Yerba mate (Ilex paraguariensis) genome provides new insights into convergent evolution of caffeine biosynthesis

federico.vignale@embl-hamburg.de (Adrian G Turjanski) — Wed, 08 Jan 2025 00:00:00 +0000

Yerba mate (YM, Ilex paraguariensis) is an economically important crop marketed for the elaboration of mate, the third-most widely consumed caffeine-containing infusion worldwide. Here, we report the first genome assembly of this species, which has a total length of 1.06 Gb and contains 53,390 protein-coding genes. Comparative analyses revealed that the large YM genome size is partly due to a whole-genome duplication (Ip-α) during the early evolutionary history of Ilex, in addition to the hexaploidization event (γ) shared by core eudicots. Characterization of the genome allowed us to clone the genes encoding methyltransferase enzymes that catalyse multiple reactions required for caffeine production. To our surprise, this species has converged upon a different biochemical pathway compared to that of coffee and tea. In order to gain insight into the structural basis for the convergent enzyme activities, we obtained a crystal structure for the terminal enzyme in the pathway that forms caffeine. The structure reveals that convergent solutions have evolved for substrate positioning because different amino acid residues facilitate a different substrate orientation such that efficient methylation occurs in the independently evolved enzymes in YM and coffee. While our results show phylogenomic constraint limits the genes coopted for convergence of caffeine biosynthesis, the X-ray diffraction data suggest structural constraints are minimal for the convergent evolution of individual reactions.

Sibling similarity can reveal key insights into genetic architecture

tade.souaiaia@gmail.com (Clive Hoggart) — Wed, 08 Jan 2025 00:00:00 +0000

The use of siblings to infer the factors influencing complex traits has been a cornerstone of quantitative genetics. Here, we utilise siblings for a novel application: the inference of genetic architecture, specifically that relating to individuals with extreme trait values (e.g. in the top 1%). Inferring the genetic architecture most relevant to this group of individuals is important because they are at the greatest risk of disease and may be more likely to harbour rare variants of large effect due to natural selection. We develop a theoretical framework that derives expected distributions of sibling trait values based on an index sibling’s trait value, estimated trait heritability, and null assumptions that include infinitesimal genetic effects and environmental factors that are either controlled for or have combined Gaussian effects. This framework is then used to develop statistical tests powered to distinguish between trait tails characterised by common polygenic architecture from those that include substantial enrichments of de novo or rare variant (Mendelian) architecture. We apply our tests to UK Biobank data here, although we note that they can be used to infer genetic architecture in any cohort or health registry that includes siblings and their trait values, since these tests do not use genetic data. We describe how our approach has the potential to help disentangle the genetic and environmental causes of extreme trait values, and to improve the design and power of future sequencing studies to detect rare variants.

Complexes of vertebrate TMC1/2 and CIB2/3 proteins form hair-cell mechanotransduction cation channels

sotomayor@uchicago.edu (Alisha J Beirl) — Wed, 08 Jan 2025 00:00:00 +0000

Calcium and integrin-binding protein 2 (CIB2) and CIB3 bind to transmembrane channel-like 1 (TMC1) and TMC2, the pore-forming subunits of the inner-ear mechano-electrical transduction (MET) apparatus. These interactions have been proposed to be functionally relevant across mechanosensory organs and vertebrate species. Here, we show that both CIB2 and CIB3 can form heteromeric complexes with TMC1 and TMC2 and are integral for MET function in mouse cochlea and vestibular end organs as well as in zebrafish inner ear and lateral line. Our AlphaFold 2 models suggest that vertebrate CIB proteins can simultaneously interact with at least two cytoplasmic domains of TMC1 and TMC2 as validated using nuclear magnetic resonance spectroscopy of TMC1 fragments interacting with CIB2 and CIB3. Molecular dynamics simulations of TMC1/2 complexes with CIB2/3 predict that TMCs are structurally stabilized by CIB proteins to form cation channels. Overall, our work demonstrates that intact CIB2/3 and TMC1/2 complexes are integral to hair-cell MET function in vertebrate mechanosensory epithelia.

High-throughput tracking enables systematic phenotyping and drug repurposing in C. elegans disease models

andre.brown@imperial.ac.uk (André EX Brown) — Wed, 08 Jan 2025 00:00:00 +0000

There are thousands of Mendelian diseases with more being discovered weekly and the majority have no approved treatments. To address this need, we require scalable approaches that are relatively inexpensive compared to traditional drug development. In the absence of a validated drug target, phenotypic screening in model organisms provides a route for identifying candidate treatments. Success requires a screenable phenotype. However, the right phenotype and assay may not be obvious for pleiotropic neuromuscular disorders. Here, we show that high-throughput imaging and quantitative phenotyping can be conducted systematically on a panel of C. elegans disease model strains. We used CRISPR genome-editing to create 25 worm models of human Mendelian diseases and phenotyped them using a single standardised assay. All but two strains were significantly different from wild-type controls in at least one feature. The observed phenotypes were diverse, but mutations of genes predicted to have related functions led to similar behavioural differences in worms. As a proof-of-concept, we performed a drug repurposing screen of an FDA-approved compound library, and identified two compounds that rescued the behavioural phenotype of a model of UNC80 deficiency. Our results show that a single assay to measure multiple phenotypes can be applied systematically to diverse Mendelian disease models. The relatively short time and low cost associated with creating and phenotyping multiple strains suggest that high-throughput worm tracking could provide a scalable approach to drug repurposing commensurate with the number of Mendelian diseases.

Psychological stress disturbs bone metabolism via miR-335-3p/Fos signaling in osteoclast

shuxian.lin@hotmail.com (Jiayao Zhang) — Wed, 08 Jan 2025 00:00:00 +0000

It has been well validated that chronic psychological stress leads to bone loss, but the underlying mechanism remains unclarified. In this study, we established and analyzed the chronic unpredictable mild stress (CUMS) mice to investigate the miRNA-related pathogenic mechanism involved in psychological stress-induced osteoporosis. Our result found that these CUMS mice exhibited osteoporosis phenotype that is mainly attributed to the abnormal activities of osteoclasts. Subsequently, miRNA sequencing and other analysis showed that miR-335-3p, which is normally highly expressed in the brain, was significantly downregulated in the nucleus ambiguous, serum, and bone of the CUMS mice. Additionally, in vitro studies detected that miR-335-3p is important for osteoclast differentiation, with its direct targeting site in Fos. Further studies demonstrated FOS was upregulated in CUMS osteoclast, and the inhibition of FOS suppressed the accelerated osteoclastic differentiation, as well as the expression of osteoclastic genes, such as Nfatc1, Acp5, and Mmp9, in miR-335-3p-restrained osteoclasts. In conclusion, this work indicated that psychological stress may downregulate the miR-335-3p expression, which resulted in the accumulation of FOS and the upregulation of NFACT1 signaling pathway in osteoclasts, leading to its accelerated differentiation and abnormal activity. These results decipher a previously unrecognized paradigm that miRNA can act as a link between psychological stress and bone metabolism.

Interneuron FGF13 regulates seizure susceptibility via a sodium channel-independent mechanism

geoffrey.pitt@med.cornell.edu (Allison Galante) — Wed, 08 Jan 2025 00:00:00 +0000

Developmental and epileptic encephalopathies (DEEs), a class of devastating neurological disorders characterized by recurrent seizures and exacerbated by disruptions to excitatory/inhibitory balance in the brain, are commonly caused by mutations in ion channels. Disruption of, or variants in, FGF13 were implicated as causal for a set of DEEs, but the underlying mechanisms were clouded because FGF13 is expressed in both excitatory and inhibitory neurons, FGF13 undergoes extensive alternative splicing producing multiple isoforms with distinct functions, and the overall roles of FGF13 in neurons are incompletely cataloged. To overcome these challenges, we generated a set of novel cell-type-specific conditional knockout mice. Interneuron-targeted deletion of Fgf13 led to perinatal mortality associated with extensive seizures and impaired the hippocampal inhibitory/excitatory balance while excitatory neuron-targeted deletion of Fgf13 caused no detectable seizures and no survival deficits. While best studied as a voltage-gated sodium channel (Na_v) regulator, we observed no effect of Fgf13 ablation in interneurons on Na_vs but rather a marked reduction in K⁺ channel currents. Re-expressing different Fgf13 splice isoforms could partially rescue deficits in interneuron excitability and restore K⁺ channel current amplitude. These results enhance our understanding of the molecular mechanisms that drive the pathogenesis of Fgf13-related seizures and expand our understanding of FGF13 functions in different neuron subsets.

Atlas of Fshr expression from novel reporter mice

liupossible@gmail.com (Clifford J Rosen) — Wed, 08 Jan 2025 00:00:00 +0000

The FSH-FSHR pathway has been considered an essential regulator in reproductive development and fertility. But there has been emerging evidence of FSHR expression in extragonadal organs. This poses new questions and long-term debates regarding the physiological role of the FSH-FSHR, and underscores the need for reliable, in vivo analysis of FSHR expression in animal models. However, conventional methods have proven insufficient for examining FSHR expression due to several limitations. To address this challenge, we developed Fshr-ZsGreen reporter mice under the control of Fshr endogenous promoter using CRISPR-Cas9. With this novel genetic tool, we provide a reliable readout of Fshr expression at single-cell resolution level in vivo and in real time. Reporter animals were also subjected to additional analyses,to define the accurate expression profile of FSHR in gonadal and extragonadal organs/tissues. Our compelling results not only demonstrated Fshr expression in intragonadal tissues but also, strikingly, unveiled notably increased expression in Leydig cells, osteoblast lineage cells, endothelial cells in vascular structures, and epithelial cells in bronchi of the lung and renal tubes. The genetic decoding of the widespread pattern of Fshr expression highlights its physiological relevance beyond reproduction and fertility, and opens new avenues for therapeutic options for age-related disorders of the bones, lungs, kidneys, and hearts, among other tissues. Exploiting the power of the Fshr knockin reporter animals, this report provides the first comprehensive genetic record of the spatial distribution of FSHR expression, correcting a long-term misconception about Fshr expression and offering prospects for extensive exploration of FSH-FSHR biology.

Multi-dimensional oscillatory activity of mouse GnRH neurons in vivo

aeh36@cam.ac.uk (Allan E Herbison) — Wed, 08 Jan 2025 00:00:00 +0000

The gonadotropin-releasing hormone (GnRH) neurons represent the key output cells of the neural network controlling mammalian fertility. We used GCaMP fiber photometry to record the population activity of the GnRH neuron distal projections in the ventral arcuate nucleus where they merge before entering the median eminence to release GnRH into the portal vasculature. Recordings in freely behaving intact male and female mice revealed abrupt ~8 min duration increases in activity that correlated perfectly with the appearance of a subsequent pulse of luteinizing hormone (LH). The GnRH neuron dendrons also exhibited a low level of unchanging clustered, rapidly fluctuating baseline activity in males and throughout the estrous cycle in females. In female mice, a gradual increase in basal activity that exhibited ~80 min oscillations began in the afternoon of proestrus and lasted for 12 hr. This was associated with the onset of the LH surge that ended several hours before the fall in the GCaMP signal. Abrupt 8 min duration episodes of GCaMP activity continued to occur on top of the rising surge baseline before ceasing in estrus. These observations provide the first description of GnRH neuron activity in freely behaving animals. They demonstrate that three distinct patterns of oscillatory activity occur in GnRH neurons. These are comprised of low-level rapid baseline activity, abrupt 8 min duration oscillations that drive pulsatile gonadotropin secretion, and, in females, a gradual and very prolonged oscillating increase in activity responsible for the preovulatory LH surge.

Wavenumber-dependent transmission of subthreshold waves on electrical synapses network model of Caenorhabditis elegans

sykim@dgist.ac.kr (Iksoo Chang) — Wed, 08 Jan 2025 00:00:00 +0000

Recent experimental studies showed that electrically coupled neural networks like in mammalian inferior olive nucleus generate synchronized rhythmic activity by the subthreshold sinusoidal-like oscillations of the membrane voltage. Understanding the basic mechanism and its implication of such phenomena in the nervous system bears fundamental importance and requires preemptively the connectome information of a given nervous system. Inspired by these necessities of developing a theoretical and computational model to this end and, however, in the absence of connectome information for the inferior olive nucleus, here we investigated interference phenomena of the subthreshold oscillations in the reference system Caenorhabditis elegans for which the structural anatomical connectome was completely known recently. We evaluated how strongly the sinusoidal wave was transmitted between arbitrary two cells in the model network. The region of cell-pairs that are good at transmitting waves changed according to the wavenumber of the wave, for which we named a wavenumber-dependent transmission map. Also, we unraveled that (1) the transmission of all cell-pairs disappeared beyond a threshold wavenumber, (2) long distance and regular patterned transmission existed in the body-wall muscles part of the model network, and (3) major hub cell-pairs of the transmission were identified for many wavenumber conditions. A theoretical and computational model presented in this study provided fundamental insight for understanding how the multi-path constructive/destructive interference of the subthreshold oscillations propagating on electrically coupled neural networks could generate wavenumber-dependent synchronized rhythmic activity.

Complement 3a receptor 1 on macrophages and Kupffer cells is not required for the pathogenesis of metabolic dysfunction-associated steatotic liver disease

jlo@med.cornell.edu (Alfonso Rubio-Navarro) — Wed, 08 Jan 2025 00:00:00 +0000

Together with obesity and type 2 diabetes, metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing global epidemic. Activation of the complement system and infiltration of macrophages has been linked to progression of metabolic liver disease. The role of complement receptors in macrophage activation and recruitment in MASLD remains poorly understood. In human and mouse, C3AR1 in the liver is expressed primarily in Kupffer cells, but is downregulated in humans with MASLD compared to obese controls. To test the role of complement 3a receptor (C3aR1) on macrophages and liver resident macrophages in MASLD, we generated mice deficient in C3aR1 on all macrophages (C3aR1-MφKO) or specifically in liver Kupffer cells (C3aR1-KpKO) and subjected them to a model of metabolic steatotic liver disease. We show that macrophages account for the vast majority of C3ar1 expression in the liver. Overall, C3aR1-MφKO and C3aR1-KpKO mice have similar body weight gain without significant alterations in glucose homeostasis, hepatic steatosis and fibrosis, compared to controls on a MASLD-inducing diet. This study demonstrates that C3aR1 deletion in macrophages or Kupffer cells, the predominant liver cell type expressing C3ar1, has no significant effect on liver steatosis, inflammation or fibrosis in a dietary MASLD model.

Neural evidence of functional compensation for fluid intelligence in healthy ageing

kat35@cam.ac.uk (Alexa Morcom) — Wed, 08 Jan 2025 00:00:00 +0000

Functional compensation is a common notion in the neuroscience of healthy ageing, whereby older adults are proposed to recruit additional brain activity to compensate for reduced cognitive function. However, whether this additional brain activity in older participants actually helps their cognitive performance remains debated. We examined brain activity and cognitive performance in a human lifespan sample (N = 223) while they performed a problem-solving task (based on Cattell’s test of fluid intelligence) during functional magnetic resonance imaging. Whole-brain univariate analysis revealed that activity in bilateral cuneal cortex for hard vs. easy problems increased both with age and with performance, even when adjusting for an estimate of age-related differences in cerebrovascular reactivity. Multivariate Bayesian decoding further demonstrated that age increased the likelihood that activation patterns in this cuneal region provided non-redundant information about the two task conditions, beyond that of the multiple demand network generally activated in this task. This constitutes some of the strongest evidence yet for functional compensation in healthy ageing, at least in this brain region during visual problem-solving.

The phytoplasma SAP54 effector acts as a molecular matchmaker for leafhopper vectors by targeting plant MADS-box factor SVP

zigmunds.orlovskis@biomed.lu.lv (Adi Kliot) — Tue, 07 Jan 2025 00:00:00 +0000

Obligate parasites often trigger significant changes in their hosts to facilitate transmission to new hosts. The molecular mechanisms behind these extended phenotypes - where genetic information of one organism is manifested as traits in another - remain largely unclear. This study explores the role of the virulence protein SAP54, produced by parasitic phytoplasmas, in attracting leafhopper vectors. SAP54 is responsible for the induction of leaf-like flowers in phytoplasma-infected plants. However, we previously demonstrated that the insects were attracted to leaves and the leaf-like flowers were not required. Here, we made the surprising discovery that leaf exposure to leafhopper males is required for the attraction phenotype, suggesting a leaf response that distinguishes leafhopper sex in the presence of SAP54. In contrast, this phytoplasma effector alongside leafhopper females discourages further female colonization. We demonstrate that SAP54 effectively suppresses biotic stress response pathways in leaves exposed to the males. Critically, the host plant MADS-box transcription factor short vegetative phase (SVP) emerges as a key element in the female leafhopper preference for plants exposed to males, with SAP54 promoting the degradation of SVP. This preference extends to female colonization of male-exposed svp null mutant plants over those not exposed to males. Our research underscores the dual role of the phytoplasma effector SAP54 in host development alteration and vector attraction - integral to the phytoplasma life cycle. Importantly, we clarify how SAP54, by targeting SVP, heightens leaf vulnerability to leafhopper males, thus facilitating female attraction and subsequent plant colonization by the insects. SAP54 essentially acts as a molecular ‘matchmaker’, helping male leafhoppers more easily locate mates by degrading SVP-containing complexes in leaves. This study not only provides insights into the long reach of single parasite genes in extended phenotypes, but also opens avenues for understanding how transcription factors that regulate plant developmental processes intersect with and influence plant-insect interactions.

Binding of LncDACH1 to dystrophin impairs the membrane trafficking of Nav1.5 protein and increases ventricular arrhythmia susceptibility

yangbf@ems.hrbmu.edu.cn (Changzhu Li) — Tue, 07 Jan 2025 00:00:00 +0000

Dystrophin is a critical interacting protein of Nav1.5 that determines its membrane anchoring in cardiomyocytes. Long noncoding RNAs (lncRNAs) are involved in the regulation of cardiac ion channels, while their influence on sodium channels remains unexplored. Our preliminary data showed that lncRNA-Dachshund homolog 1 (lncDach1) can bind to dystrophin, which drove us to investigate if lncDach1 can regulate sodium channels by interfering with dystrophin. Western blot and immunofluorescent staining showed that cardiomyocyte-specific transgenic overexpression of lncDach1 (lncDach1-TG) reduced the membrane distribution of dystrophin and Nav1.5 in cardiomyocytes. Meanwhile, peak I_Na was reduced in the hearts of lncDach1-TG mice than wild-type (WT) controls. The opposite data of western blot, immunofluorescent staining and patch clamp were collected from lncDach1 cardiomyocyte conditional knockout (lncDach1-cKO) mice. Moreover, increased ventricular arrhythmia susceptibility was observed in lncDach1-TG mice in vivo and ex vivo. The conservative fragment of lncDach1 inhibited membrane distribution of dystrophin and Nav1.5, and promoted the inducibility of ventricular arrhythmia. Strikingly, activation of Dystrophin transcription by dCas9-SAM system in lncDach1-TG mice rescued the impaired membrane distribution of dystrophin and Nav1.5, and prevented the occurrence of ventricular arrhythmia. Furthermore, lncDach1 was increased in transaortic constriction (TAC) induced failing hearts, which promoted the inducibility of ventricular arrhythmia. And the expression of lncDach1 is regulated by hydroxyacyl-CoA dehydrogenase subunit beta (hadhb), which binds to lncDach1 and decreases its stability. The human homologue of lncDACH1 inhibited the membrane distribution of Nav1.5 in human iPS-differentiated cardiomyocytes. The findings provide novel insights into the mechanism of Nav1.5 membrane targeting and the development of ventricular arrhythmias.

Recognition and cleavage of human tRNA methyltransferase TRMT1 by the SARS-CoV-2 main protease

mugridge@udel.edu (Angel D'Oliviera) — Tue, 07 Jan 2025 00:00:00 +0000

The SARS-CoV-2 main protease (M^pro or Nsp5) is critical for production of viral proteins during infection and, like many viral proteases, also targets host proteins to subvert their cellular functions. Here, we show that the human tRNA methyltransferase TRMT1 is recognized and cleaved by SARS-CoV-2 M^pro. TRMT1 installs the N²,N²-dimethylguanosine (m2,2G) modification on mammalian tRNAs, which promotes cellular protein synthesis and redox homeostasis. We find that M^pro can cleave endogenous TRMT1 in human cell lysate, resulting in removal of the TRMT1 zinc finger domain. Evolutionary analysis shows the TRMT1 cleavage site is highly conserved in mammals, except in Muroidea, where TRMT1 is likely resistant to cleavage. TRMT1 proteolysis results in reduced tRNA binding and elimination of tRNA methyltransferase activity. We also determined the structure of an M^pro-TRMT1 peptide complex that shows how TRMT1 engages the M^pro active site in an uncommon substrate binding conformation. Finally, enzymology and molecular dynamics simulations indicate that kinetic discrimination occurs during a later step of M^pro-mediated proteolysis following substrate binding. Together, these data provide new insights into substrate recognition by SARS-CoV-2 M^pro that could help guide future antiviral therapeutic development and show how proteolysis of TRMT1 during SARS-CoV-2 infection impairs both TRMT1 tRNA binding and tRNA modification activity to disrupt host translation and potentially impact COVID-19 pathogenesis or phenotypes.

Partial rejuvenation of the spermatogonial stem cell niche after gender-affirming hormone therapy in trans women

emily.delgouffe@vub.be (Camille Raets) — Tue, 07 Jan 2025 00:00:00 +0000

Although the impact of gender-affirming hormone therapy (GAHT) on spermatogenesis in trans women has already been studied, data on its precise effects on the testicular environment is poor. Therefore, this study aimed to characterize, through histological and transcriptomic analysis, the spermatogonial stem cell niche of 106 trans women who underwent standardized GAHT, comprising estrogens and cyproterone acetate. A partial dedifferentiation of Sertoli cells was observed, marked by the co-expression of androgen receptor and anti-Müllerian hormone which mirrors the situation in peripubertal boys. The Leydig cells also exhibited a distribution analogous to peripubertal tissue, accompanied by a reduced insulin-like factor 3 expression. Although most peritubular myoid cells expressed alpha-smooth muscle actin 2, the expression pattern was disturbed. Besides this, fibrosis was particularly evident in the tubular wall and the lumen was collapsing in most participants. A spermatogenic arrest was also observed in all participants. The transcriptomic profile of transgender tissue confirmed a loss of mature characteristics - a partial rejuvenation - of the spermatogonial stem cell niche and, in addition, detected inflammation processes occurring in the samples. The present study shows that GAHT changes the spermatogonial stem cell niche by partially rejuvenating the somatic cells and inducing fibrotic processes. These findings are important to further understand how estrogens and testosterone suppression affect the testis environment, and in the case of orchidectomized testes as medical waste material, their potential use in research.

Correction: Genome editing of an African elite rice variety confers resistance against endemic and emerging Xanthomonas oryzae pv. oryzae strains

Tue, 07 Jan 2025 00:00:00 +0000

Noncanonical roles of ATG5 and membrane atg8ylation in retromer assembly and function

vderetic@salud.unm.edu (Brett S Phinney) — Tue, 07 Jan 2025 00:00:00 +0000

ATG5 is one of the core autophagy proteins with additional functions such as noncanonical membrane atg8ylation, which among a growing number of biological outputs includes control of tuberculosis in animal models. Here, we show that ATG5 associates with retromer’s core components VPS26, VPS29, and VPS35 and modulates retromer function. Knockout of ATG5 blocked trafficking of a key glucose transporter sorted by the retromer, GLUT1, to the plasma membrane. Knockouts of other genes essential for membrane atg8ylation, of which ATG5 is a component, affected GLUT1 sorting, indicating that membrane atg8ylation as a process affects retromer function and endosomal sorting. The contribution of membrane atg8ylation to retromer function in GLUT1 sorting was independent of canonical autophagy. These findings expand the scope of membrane atg8ylation to specific sorting processes in the cell dependent on the retromer and its known interactors.

Aminoglycoside tolerance in Vibrio cholerae engages translational reprogramming associated with queuosine tRNA modification

didier.mazel@pasteur.fr (Anamaria Babosan) — Mon, 06 Jan 2025 00:00:00 +0000

Tgt is the enzyme modifying the guanine (G) in tRNAs with GUN anticodon to queuosine (Q). tgt is required for optimal growth of Vibrio cholerae in the presence of sub-lethal aminoglycoside concentrations. We further explored here the role of the Q34 in the efficiency of codon decoding upon tobramycin exposure. We characterized its impact on the overall bacterial proteome, and elucidated the molecular mechanisms underlying the effects of Q34 modification in antibiotic translational stress response. Using molecular reporters, we showed that Q34 impacts the efficiency of decoding at tyrosine TAT and TAC codons. Proteomics analyses revealed that the anti-SoxR factor RsxA is better translated in the absence of tgt. RsxA displays a codon bias toward tyrosine TAT and overabundance of RsxA leads to decreased expression of genes belonging to SoxR oxidative stress regulon. We also identified conditions that regulate tgt expression. We propose that regulation of Q34 modification in response to environmental cues leads to translational reprogramming of transcripts bearing a biased tyrosine codon usage. In silico analysis further identified candidate genes which could be subject to such translational regulation, among which DNA repair factors. Such transcripts, fitting the definition of modification tunable transcripts, are central in the bacterial response to antibiotics.

Plural molecular and cellular mechanisms of pore domain KCNQ2 encephalopathy

ecc1@bcm.edu (Aamir R Zuberi) — Mon, 06 Jan 2025 00:00:00 +0000

KCNQ2 variants in children with neurodevelopmental impairment are difficult to assess due to their heterogeneity and unclear pathogenic mechanisms. We describe a child with neonatal-onset epilepsy, developmental impairment of intermediate severity, and KCNQ2 G256W heterozygosity. Analyzing prior KCNQ2 channel cryoelectron microscopy models revealed G256 as a node of an arch-shaped non-covalent bond network linking S5, the pore turret, and the ion path. Co-expression with G256W dominantly suppressed conduction by wild-type subunits in heterologous cells. Ezogabine partly reversed this suppression. Kcnq2^G256W/+ mice have epilepsy leading to premature deaths. Hippocampal CA1 pyramidal cells from G256W/+ brain slices showed hyperexcitability. G256W/+ pyramidal cell KCNQ2 and KCNQ3 immunolabeling was significantly shifted from axon initial segments to neuronal somata. Despite normal mRNA levels, G256W/+ mouse KCNQ2 protein levels were reduced by about 50%. Our findings indicate that G256W pathogenicity results from multiplicative effects, including reductions in intrinsic conduction, subcellular targeting, and protein stability. These studies provide evidence for an unexpected and novel role for the KCNQ2 pore turret and introduce a valid animal model of KCNQ2 encephalopathy. Our results, spanning structure to behavior, may be broadly applicable because the majority of KCNQ2 encephalopathy patients share variants near the selectivity filter.

GnRH pulse generator activity in mouse models of polycystic ovary syndrome

aeh36@cam.ac.uk (Allan E Herbison) — Mon, 06 Jan 2025 00:00:00 +0000

One in ten women in their reproductive age suffer from polycystic ovary syndrome (PCOS) that, alongside subfertility and hyperandrogenism, typically presents with increased luteinizing hormone (LH) pulsatility. As such, it is suspected that the arcuate kisspeptin (ARN^KISS) neurons that represent the GnRH pulse generator are dysfunctional in PCOS. We used here in vivo GCaMP fiber photometry and other approaches to examine the behavior of the GnRH pulse generator in two mouse models of PCOS. We began with the peripubertal androgen (PPA) mouse model of PCOS but found that it had a reduction in the frequency of ARN^KISS neuron synchronization events (SEs) that drive LH pulses. Examining the prenatal androgen (PNA) model of PCOS, we observed highly variable patterns of pulse generator activity with no significant differences detected in ARN^KISS neuron SEs, pulsatile LH secretion, or serum testosterone, estradiol, and progesterone concentrations. However, a machine learning approach identified that the ARN^KISS neurons of acyclic PNA mice continued to exhibit cyclical patterns of activity similar to that of normal mice. The frequency of ARN^KISS neuron SEs was significantly increased in algorithm-identified ‘diestrous stage’ PNA mice compared to controls. In addition, ARN^KISS neurons exhibited reduced feedback suppression to progesterone in PNA mice and their gonadotrophs were also less sensitive to GnRH. These observations demonstrate the importance of understanding GnRH pulse generator activity in mouse models of PCOS. The existence of cyclical GnRH pulse generator activity in the acyclic PNA mouse indicates the presence of a complex phenotype with deficits at multiple levels of the hypothalamo-pituitary-gonadal axis.

The Drosophila hematopoietic niche assembles through collective cell migration controlled by neighbor tissues and Slit-Robo signaling

sdinardo@pennmedicine.upenn.edu (Kara A Nelson) — Fri, 03 Jan 2025 00:00:00 +0000

Niches are often found in specific positions in tissues relative to the stem cells they support. Consistency of niche position suggests that placement is important for niche function. However, the complexity of most niches has precluded a thorough understanding of how their proper placement is established. To address this, we investigated the formation of a genetically tractable niche, the Drosophila Posterior Signaling Center (PSC), the assembly of which had not been previously explored. This niche controls hematopoietic progenitors of the lymph gland (LG). PSC cells were previously shown to be specified laterally in the embryo, but ultimately reside dorsally, at the LG posterior. Here, using live-imaging, we show that PSC cells migrate as a tight collective and associate with multiple tissues during their trajectory to the LG posterior. We find that Slit emanating from two extrinsic sources, visceral mesoderm and cardioblasts, is required for the PSC to remain a collective, and for its attachment to cardioblasts during migration. Without proper Slit-Robo signaling, PSC cells disperse, form aberrant contacts, and ultimately fail to reach their stereotypical position near progenitors. Our work characterizes a novel example of niche formation and identifies an extrinsic signaling relay that controls precise niche positioning.

Why the brown ghost chirps at night

livio.oboti@gmail.com (Federico Pedraja) — Fri, 03 Jan 2025 00:00:00 +0000

Since the pioneering work by Moeller, Szabo, and Bullock, weakly electric fish have served as a valuable model for investigating spatial and social cognitive abilities in a vertebrate taxon usually less accessible than mammals or other terrestrial vertebrates. These fish, through their electric organ, generate low-intensity electric fields to navigate and interact with conspecifics, even in complete darkness. The brown ghost knifefish is appealing as a study subject due to a rich electric ‘vocabulary’, made by individually variable and sex-specific electric signals. These are mainly characterized by brief frequency modulations of the oscillating dipole moment continuously generated by their electric organ, and are known as chirps. Different types of chirps are believed to convey specific and behaviorally salient information, serving as behavioral readouts for different internal states during behavioral observations. Despite the success of this model in neuroethology over the past seven decades, the code to decipher their electric communication remains unknown. To this aim, in this study we re-evaluate the correlations between signals and behavior offering an alternative, and possibly complementary, explanation for why these freshwater bottom dwellers emit electric chirps. By uncovering correlations among chirping, electric field geometry, and detectability in enriched environments, we present evidence for a previously unexplored role of chirps as specialized self-directed signals, enhancing conspecific electrolocation during social encounters.

Nicotine enhances the stemness and tumorigenicity in intestinal stem cells via Hippo-YAP/TAZ and Notch signal pathway

migarashi@m.u-tokyo.ac.jp (Kyoko Naruse) — Fri, 03 Jan 2025 00:00:00 +0000

Cigarette smoking is a well-known risk factor inducing the development and progression of various diseases. Nicotine (NIC) is the major constituent of cigarette smoke. However, knowledge of the mechanism underlying the NIC-regulated stem cell functions is limited. In this study, we demonstrate that NIC increases the abundance and proliferative activity of murine intestinal stem cells (ISCs) in vivo and ex vivo. Moreover, NIC induces Yes-associated protein (YAP) /Transcriptional coactivator with PDZ-binding motif (TAZ) and Notch signaling in ISCs via α7-nicotinic acetylcholine receptor (nAchR) and protein kinase C (PKC) activation; this effect was not detected in Paneth cells. The inhibition of Notch signaling by dibenzazepine (DBZ) nullified the effects of NIC on ISCs. NIC enhances in vivo tumor formation from ISCs after loss of the tumor suppressor gene Apc, DBZ inhibited NIC-induced tumor growth. Hence, this study identifies a NIC-triggered pathway regulating the stemness and tumorigenicity of ISCs and suggests the use of DBZ as a potential therapeutic strategy for treating intestinal tumors.

Capsular polysaccharide restrains type VI secretion in Acinetobacter baumannii

melanie.blokesch@epfl.ch (Loriane Bader) — Fri, 03 Jan 2025 00:00:00 +0000

The type VI secretion system (T6SS) is a sophisticated, contact-dependent nanomachine involved in interbacterial competition. To function effectively, the T6SS must penetrate the membranes of both attacker and target bacteria. Structures associated with the cell envelope, like polysaccharides chains, can therefore introduce spatial separation and steric hindrance, potentially affecting the efficacy of the T6SS. In this study, we examined how the capsular polysaccharide (CPS) of Acinetobacter baumannii affects T6SS’s antibacterial function. Our findings show that the CPS confers resistance against T6SS-mediated assaults from rival bacteria. Notably, under typical growth conditions, the presence of the surface-bound capsule also reduces the efficacy of the bacterium’s own T6SS. This T6SS impairment is further enhanced when CPS is overproduced due to genetic modifications or antibiotic treatment. Furthermore, we demonstrate that the bacterium adjusts the level of the T6SS inner tube protein Hcp according to its secretion capacity, by initiating a degradation process involving the ClpXP protease. Collectively, our findings contribute to a better understanding of the dynamic relationship between T6SS and CPS and how they respond swiftly to environmental challenges.