bluuebunny/crossref_metadata_2025 huggingface dataset:
Receptor tyrosine kinase AXL regulates Golgi organization and function through an adhesion-Arf1 signaling axis in breast and lung cancers
Authors: Joshi Prachi , Saha Arnav , Malaviya Radhika , Panda Debiprasad , Mehta Grishma , Pattanayak Manojeet , Singh Vibha , Balasubramanian Nagaraj
Published: February 2025

Cell-matrix adhesion regulates membrane trafficking, Golgi organisation and function. Differential Golgi organisation in cancer cells could drive changes in trafficking and processing of cargoes. A simple screen evaluating Golgi organisation identifies breast (MDAMB231 vs MCF7) and lung cancer (A549 vs CaLu1) cell line pairs with differently organised Golgi, regulated differentially by loss of adhesion. In silico analysis of differentially expressed genes in the CCLE database, evaluated for their association with the Golgi in interaction networks and literature, identified AXL as a putative regulator of Golgi in these cancers. AXL prominently localized at the Golgi, undergoes displacement from the Golgi when inhibited by R428 and knocked down using siRNA, causing the Golgi to disorganize. AXL-dependent regulation of Golgi organisation is also dependent on cell-matrix adhesion. AXL binds active Arf1, whose recruitment to the Golgi is vital for its organisation. On loss of adhesion, loss of AXL and active Arf1 from the Golgi, drives its disorganization to affect Golgi-dependent microtubule acetylation and cell surface glycosylation in MDAMB231 and A549 cells respectively. Together, this validates our screen to identify novel regulators of the Golgi, and identifies AXL-Arf1 crosstalk as a vital mediator of its organisation and function in cancer cells.
Neural circuit mechanisms to transform cerebellar population dynamics for motor control in monkeys
Authors: Herzfeld David J. , Lisberger Stephen G.
Published: February 2025

We exploit identification of neuron types during extracellular recording to demonstrate how the cerebellar cortex’s well-established architecture transforms inputs into outputs. During smooth pursuit eye movements, the floccular complex performs distinct input-output transformations of temporal dynamics and directional response properties. The responses of different interneuron types localize the circuit mechanisms of each transformation. Mossy fibers and unipolar brush cells emphasize eye position dynamics uniformly across the cardinal axes; Purkinje cells and molecular layer interneurons code eye velocity along directionally biased axes; Golgi cells show unmodulated firing. Differential directional response properties of different neuron types localize the directional input-output transformation to the last-order inputs to Purkinje cells. Differential temporal dynamics pinpoint the site of the temporal input-output transformation to granule cells. Specific granule cell population dynamics allow the temporal transformations required in the area we study and generalize to many temporal transformations, providing a complete framework to understand cerebellar circuit computation.

Impact statement

We dissect the circuit computations performed by the floccular complex of the cerebellum during an exemplar sensory-motor behavior, taking advantage of knowledge of the circuit architecture, existence of discrete neuron types, and a newfound ability to identify neuron types from extracellular recordings. Our results describe the contributions of the major neuron types to the cerebellar input-output computations, identify the population dynamics needed in granule cells to support those computations, and to create a basis set to enable temporally-specific motor behavior and motor learning.
Dynamic Organellar Mapping in yeast reveals extensive protein localization changes during ER stress
Authors: Platzek Anna , Schessner Julia P , Odehnalová Klára , Borner Georg H H , Schuck Sebastian
Published: February 2025

Sophisticated techniques are available for systematic studies of yeast cell biology. However, it remains challenging to investigate protein subcellular localization changes on a proteome-wide scale. Here, we apply Dynamic Organellar Maps (DOMs) by label-free mass spectrometry to detect localization changes of native, untagged proteins during endoplasmic reticulum (ER) stress. We find that hundreds of proteins shift between cellular compartments. For example, we show that numerous secretory pathway proteins accumulate in the ER, thus defining the extent and selectivity of ER retention of misfolded proteins. Furthermore, we identify candidate cargo proteins of the ER reflux pathway, determine constituents of reticulon clusters that segregate from the remainder of the ER and provide evidence for altered nuclear pore complex composition and nuclear import. These findings uncover protein relocalization as a major aspect of cellular reorganization during ER stress and establish DOMs as a powerful discovery tool in yeast.
Opposing control of the respiratory brainstem on multiple timescales achieved by transmitter co-release from the locus coeruleus
Authors: Varga Adrienn G. , Reid Brandon T. , Maletz Sebastian N. , Dossat Amanda M. , Levitt Erica S.
Published: February 2025

The locus coeruleus (LC) provides widespread noradrenergic (NAergic) modulation throughout the brain to influence a wide range of functions, including breathing. Although both anatomical and physiological evidence supports the involvement of the LC in both the upstream integration and the downstream modulation of breathing, the circuitry behind the latter is unknown. Here, we show that NAergic LC neurons send projections to the Kӧlliker-Fuse nucleus (KF), a critical site in the control of breathing. Long duration activation of NAergic LC neuron terminals in pontine slices induces persistent inhibitory and excitatory NA currents or increases firing rate in postsynaptic KF neurons. Short stimulation on the other hand leads to the VGluT2-dependent release of glutamate that may be co-released with NA in a monosynaptic circuit. Together these results demonstrate that LC neurons can exert flexible, opposing effects on different timescales via glutamatergic and NAergic signaling onto a key respiratory brainstem nucleus.
Cell motility influences microfluidics capturing in scRNA-seq
Authors: López-Escobar Lara , Nascimento Ana M. , Figueiredo Luisa M.
Published: February 2025

Microfluidic isolation methods for single-cell RNA sequencing (scRNA-seq) have primarily been designed for immotile cells, with limited consideration for motile cells, such as those with flagella or cilia. By studying the encapsulation efficiency of the flagellatedTrypanosoma bruceiusing the 10x Genomics platform, we found that maintaining parasites at room temperature results in a low encapsulation yield. We implemented a rapid cooling method to 0ºC prior to encapsulation, which reduced parasite motility and preventing undesired transcriptomic change. This allowed for a representative scRNA-seq dataset, avoiding the disproportionate loss of the most motile forms. This study highlights the challenges of using motile cells in microfluidic systems and the biases caused by losing specific subpopulations, emphasizing the need for optimized protocols for non-standard mammalian cells.

PLAIN LANGUAGE SUMMARY

Single-cell RNA sequencing (scRNA-seq) is a powerful technique used to study individual cells, but most methods have been designed for cells that do not move. This can be a challenge when working with motile cells, likeTrypanosoma brucei, a flagellated parasite responsible for sleeping sickness. In our study, we found that these parasites are poorly captured in microfluidic systems, such as the 10x Genomics platform, when kept at room temperature. Their movement reduces the efficiency of encapsulation, leading to biased results. To overcome this, we developed a simple cooling method that quickly lowers the temperature to 0°C before processing. This reduces parasite motility, improving capture rates while minimizing unwanted changes in gene expression. By applying this approach, we obtained a representative transcriptomic dataset, ensuring that all parasite forms were included. Our findings highlight the importance of adapting microfluidic techniques for motile cells to avoid losing key subpopulations and ensure accurate biological insights.
Chromosome compartment assembly is essential for subtelomeric gene silencing in trypanosomes
Authors: Antunes Luiza Berenguer , Isebe Tony , Kutova Oksana , Cestari Igor
Published: February 2025

Genome three-dimensional organization is essential for the coordination of eukaryote gene expression. The chromosomes of the pathogenTrypanosoma bruceicontain hundreds of silent variant surface glycoprotein (VSGs) genes in subtelomeric regions. However,T. bruceitranscribes a single VSG gene and periodically changes the VSG expressed by transcriptional or recombination mechanisms, altering its surface coat to escape host antibodies by antigenic variation. We show that VSG-rich silent subtelomeric regions form distinct chromosome compartments from transcribed regions, with subtelomeric compartments of different chromosomes co-interacting. We uncovered chromatin-associating factors at the boundaries of transcribed and silent compartments. Among these, repressor activator-protein 1 (RAP1) marks the compartment boundaries and spreads over silent regions. Inactivation of phosphatidylinositol phosphate 5-phosphatase removed RAP1 from compartment boundaries and subtelomeric regions, disrupting compartment assembly and derepressing all VSG genes. The data show spatial segregation of repressed from transcribed chromatin and phosphoinositides regulation of silent compartment assembly and genome organization.
DateBack, a digital open access repository of archaeobotanical data for reconstructing date palm history
Authors: Besseiche Margot , Chambraud Elora , Dabrowski Vladimir , Brandstätt Elisa , Sabot François , Bouchaud Charlène , Gros-Balthazard Muriel
Published: February 2025

The date palm (Phoenix dactyliferaL.) has been a cornerstone of oasis agrosystems in West Asia and North Africa for millenia, yet the timeline and processes of its domestication and spread remain poorly documented. Archaeobotanical remains provide critical insights into its cultivation history, but no comprehensive review or dedicated platform currently exists to synthesize and analyze these data.

To address this gap, we conducted an extensive literature review and developedDateBack(https://cloudapps.france-bioinformatique.fr/dateback), a digital open access repository of archaeobotanical remains ofPhoenixspp. In its first version,DateBackrecords macroremains (e.g., seeds, fruits, stems, petioles) from prehistoric to Late Antiquity contexts in Southwest and South Asia.

We assembled 140 entries from 99 archaeological sites across 110 references, along with a separate table of 55 radiocarbon-dated entries from 17 sites, refining chronological assessments. Most entries comprise charred seeds (55.7%), with a smaller proportion of charred vegetative parts or desiccated remains. Our findings highlight regional disparities in remain distribution, concentrated in the Levant and Gulf, while Saudi Arabia and southern Iran are underrepresented, and in data reliability, particularly dating resolution, complicating the reconstruction of date cultivation history. Our evidence shows that the earliest securely dated remains, indicating date consumption, appear in the Gulf around 5000 BCE, while cultivation emerges later, first in southern Mesopotamia and the northern Gulf in the 4thmillennium BCE, then in eastern Arabia and the Indus Valley in the 3rdmillennium BCE. The Levant presents challenges, with numerous presumed early finds but significant uncertainties, with secure evidence of cultivation only appearing by the late 2ndmillennium BCE, as in northwestern Arabia, while in the southern Arabian Peninsula, it is not attested until the 1stmillennium BCE.

By compiling and standardizing archaeobotanical data,DateBackfacilitates advanced spatiotemporal analyses and supports additional archaeobotany-based research including ancient DNA studies. Moreover, the platform is dynamic, scalable, and collaborative, enhancing data integration and refinement, with future expansions planned to include additional periods (Islamic era and beyond), geographic regions (North Africa), and new types of evidence, such as plant microremains and iconography.
Gut3Gel: A High Throughput Mucus Model for Culturing Human Intestinal Microbiota
Authors: Vargas Natalia Suárez , Antunes Miguel , Sobral João , Silva Carolina , Sousa Francisco , Garbero Olga Valentina , Kolková Anna , Visai Livia , Medana Claudio , Visentin Sonja , Petrini Paola , van Uden Sebastião , Pacheco Daniela
Published: February 2025

The human intestinal microbiota plays a crucial role in health and disease, yet recreating its complex interactionsin vitroremains a significant challenge. Gut3Gel introduced herein as a novelin vitromucus model, designed for culturing complex microbial communities without the need for anaerobic conditions. Intestinal microbiota samples from five donors were individually inoculated in Gut3Gel and cultured for 72 hours. Taxonomic composition assessment revealed that Gut3Gel sustains diverse microbial species and particularly promotes the growth of mucus-associated bacteria includingBifidobacterium,Lactobacillus, andFaecalibacterium. Microbial metabolic activity within Gut3Gel was confirmed by the increased production of acetate and butyrate, as well as of exopolysaccharides. Gut3Gel reproduces physiological features of intestinal mucus, providing a reproducible and scalable culturing platform. These features make Gut3Gel a promising tool for advancing microbiota research with potential applications in drug screening, microbiome mining, and high throughput testing of microbiome-modulating molecules.
Arabidopsis REM transcription factors and GDE1 shape the DNA methylation landscape through the recruitment of RNA Polymerase IV transcription complexes
Authors: Wu Zhongshou , Xue Yan , Wang Shuya , Shih Yuan-Hsin , Zhong Zhenhui , Feng Suhua , Draper Jonathan , Lu Allen , Sha Jihui , Li Lu , Wohlschlegel James , Wu Keqiang , Jacobsen Steven E.
Published: February 2025

DNA methylation plays crucial roles in gene regulation and transposon silencing. In plants, the maintenance of DNA methylation is controlled by several self-reinforcing loops involving histone methylation and non-coding RNAs. However, how methylation is initially patterned at specific loci is unknown. Here, we describe four Arabidopsis REM transcription factors, VDD, VAL, REM12 and REM13, that recognize specific sequence regions, and together with the proteinGENETICSDETERMINESEPIGENETICS1 (GDE1), recruit RNA polymerase IV transcription complexes to generate 24-nucleotide small interfering RNAs (24nt-siRNAs) that guide DNA methylation to specific loci. In the absence ofGDE1, Pol IV transcription complexes redistribute to sites bound by a different factor called REM8. These results suggest that REM proteins act as sequence specific DNA binding proteins that pattern siRNAs and methylation at specific sites in the genome, highlighting the role of genetic information in determining epigenetic patterns.
Social context and dopamine signaling converge in the mushroom body to drive impulsivity
Authors: Sabandal Paul Rafael , Kim Young-Cho , Sabandal John Martin , Han Kyung-An
Published: February 2025

Organisms adapt their behaviors flexibly in response to various internal and environmental factors. However, how and where these factors converge in the brain to alter behavior is not well understood. In this study, we examine how social context interacts with dopamine activity to influence inhibitory control inDrosophila. We found that, regardless of social context—whether isolated or in groups—wild-type flies consistently showed strong movement suppression in a go/no-go task that measures action restraint. In contrast, flies with enhanced dopamine activity suppressed their movements when tested alone or with potential mates but exhibited impulsive behaviors when exposed to same-sex peers. This social-context-dependent impulsivity was shown to rely on dopamine-D1 receptor-cAMP signaling in mushroom body (MB) neurons. Remarkably, activating the MB was sufficient to induce impulsivity, even without dopamine input or a social context. Our findings highlight MB as a critical hub where social context and dopamine signaling converge to regulate impulsive behavior inDrosophila.

Signficance statement

This study demonstrates that impulsivity results from the interplay between elevated dopamine levels and social context, rather than dopamine alone, with the mushroom body (MB) serving as a key neural hub for integrating these signals inDrosophila. Social stimuli, such as the presence of same-sex peers, disrupt inhibitory control in a context-dependent manner, highlighting the importance of multimodal sensory inputs and MB activity. These findings challenge the isolation-focused approach in traditional impulsivity research and underscore the need to account for social influences when investigating cognitive processes and disorders like ADHD, autism, and substance use, where social settings often amplify symptoms.

Classification

Genetics / Neuroscience
Phage interactions may contribute to the population structure and dynamics of hydrothermal vent microbial symbionts
Authors: Hauer Michelle A. , Klier Katherine M. , Langwig Marguerite V. , Anantharaman Karthik , Beinart Roxanne A.
Published: February 2025

Deep-sea hydrothermal vent ecosystems are sustained by chemoautotrophic bacteria that symbiotically provide organic matter to their animal hosts through the oxidation of chemical reductants in vent fluids. Hydrothermal vents also support unique viral communities that often exhibit high host-specificity and frequently integrate into host genomes as prophages; however, little is known about the role of viruses in influencing the chemosynthetic symbionts of vent foundation fauna. Here, we present a comprehensive examination of contemporary lysogenic and lytic bacteriophage infections, auxiliary metabolic genes, and CRISPR spacers associated with the intracellular bacterial endosymbionts of snails and mussels at hydrothermal vents in the Lau Basin (Tonga). Our investigation of contemporary phage infection among bacterial symbiont species and across distant vent locations indicated that each symbiont species interacts with different phage species across a large geographic range. However, our analysis of historical phage interactions via assessment of CRISPR spacer content suggested that phages may contribute to strain-level variation within a symbiont species. Surprisingly, prophages were absent from almost all symbiont genomes, suggesting that phage interactions with intracellular symbionts may differ from free-living microbes at vents. Altogether, these findings suggest that species-specific phages play a key role in regulating chemosynthetic symbionts via lytic infections, potentially shaping strain-level diversity and altering the composition and dynamics of symbiont populations.
A Critical Role for the Fascin Family of Actin Bundling Proteins in Axon Development, Brain Wiring and Function
Authors: Hardin Katherine R. , Penas Arjolyn B. , Joubert Shuristeen , Ye Changtian , Myers Kenneth R. , Zheng James Q.
Published: February 2025

Actin-based cell motility drives many neurodevelopmental events including guided axonal growth. Fascin is a major family of F-actin bundling proteins, but its role in axon development and brain wiring is unknown. Here, we report that fascin is required for axon development, brain wiring and function. We show that fascin is enriched in the motile filopodia of axonal growth cones and its inhibition impairs axonal extension and branching of hippocampal neurons in culture. We next provide evidence that fascin is essential for axon development and brain wiring usingDrosophila melanogasteras anin vivomodel.Drosophilaexpress a single ortholog of mammalian fascin called Singed (SN), which is highly expressed in the mushroom body (MB) of the central nervous system. We observe that loss of SN results in drastic MB disruption, highlighted by α- and β-lobe defects that are consistent with altered axonal guidance. SN-null flies also exhibit defective sensorimotor behaviors as assessed by the negative geotaxis assay. MB-specific expression of SN in SN-null flies rescues MB structure and sensorimotor deficits, indicating that SN functions autonomously in MB neurons. Together, our data from primary neuronal culture andin vivomodels highlight a critical role for fascin in brain development and function.

Significance statement

Fascin is a major family of actin-binding proteins (ABPs) that crosslink and bundle actin filaments to underline membrane protrusions essential for cell motility and neuronal development.

Inhibition of fascin in cultured cells causes it to dissipate from F-actin-rich membrane protrusions and become cytosolic, reduces filopodia formation, and decreases axon outgrowth and branching.

In fruit flies, loss of the fascin orthologue, Singed, causes defects in brain development, specifically in mushroom body (MB) lobes, and leads to behavioral impairments which can be rescued upon MB-specific expression of Singed.
Hyperreflexia after corticospinal tract lesion reflects 1A afferent circuit changes not increased KCC2 hyperexcitability
Authors: Bethea Thelma , Adegbenro Temitope , Martin John H.
Published: February 2025

Hyperreflexia, spasticity, and a loss of skilled motor function are consequences of spinal cord injury (SCI). Multiple potential mechanisms underpinning hyperreflexia have been reported, including: aberrant proprioceptive afferent (PA) sprouting, which could enhance reflex signaling; reduced GABAergic inhibitory presynaptic regulation of 1A terminals (GABApre); and increased excitability produced by reduced motor neuron membrane-bound potassium-chloride co-transporter #2 (KCC2), which has only studied after SCI and bilateral CST lesion. Here we examine how selective CST injury allows for specific investigation of the different mechanisms to determine their contributions to hyperreflexia. Hoffmann (H)-reflex rate-dependent depression (RDD) of the forelimb and hindlimb 5th-digit abductor muscles was used to assess hyperreflexia. We compared RDD in naïve and unilateral-PTX animals at 7-dpi and 42-dpi, supplemented with additional timed tests to examine the time-course of hyperreflexia development.

Immunohistochemistry was used to identify PA synapses (VGlut1) and GABApre (GABApre), motor neurons (ChAT), and KCC2. Following unilateral PTX, which eliminates the CST from one hemisphere, we observed significant hyperreflexia in the contralesional forelimb only. Membrane-bound KCC2 was unchanged in contralesional cervical motor neurons. Whereas both cervical and lumbar motor neurons showed increased PA sprouting contralesionally, there was a concomitant increase in GABApre terminals for the lumbar not cervical cord. Our findings show that KCC2 is disassociated from hyperreflexia in the uniPTX model. Instead, forelimb hyperreflexia can be explained by cervical motor neuron PA sprouting and an uncompensated GABApre regulation.
Transcription factors instruct DNA methylation patterns in plant reproductive tissues
Authors: Xu Guanghui , Chen Yuhan , Wang Fuxi , Li En , Law Julie A.
Published: February 2025

DNA methylation is maintained by forming self-reinforcing connections with other repressive chromatin modifications, resulting in stably silenced genes and transposons. However, these mechanisms fail to explain how new methylation patterns are generated. In Arabidopsis, CLASSY3 (CLSY3) targets the RNA-directed DNA methylation (RdDM) machinery to different loci in reproductive tissues, generating distinct epigenomes via unknown mechanism(s). Here, we discovered that several different REPRODUCTIVE MERISTEM (REM) transcription factors are required for methylation at CLSY3 targets specific to male or female reproductive tissues. We designate these factors as REM INSTRUCT METHYLATION (RIMs) and demonstrate that disruption of their DNA binding domains, or the motifs they recognize, blocks RdDM. These findings not only reveal RIMs as the first sex-specific RdDM proteins but also establish a critical role for genetic information in targeting DNA methylation. This novel mode of targeting expands our understanding of how methylation is regulated to include inputs from both genetic and epigenetic information.
Composition and RNA binding specificity of metazoan RNase MRP
Authors: Liu Yuan , He Shiyang , Pyo Anzie , Zheng Shanshan , Chen Meijuan , Cheloufi Sihem , Slavov Nikolai , Marzluff William F , Murn Jernej
Published: February 2025

Ribonuclease (RNase) MRP is a conserved RNA-based enzyme that is essential for maturation of ribosomal RNA (rRNA) in eukaryotes. However, the composition and RNA substrate specificity of this multisubunit ribonucleoprotein complex in higher eukaryotes remain a mystery. Here, we identify NEPRO and C18ORF21 as constitutive subunits of metazoan RNase MRP. Both proteins are specific to RNase MRP and are the only ones distinguishing this enzyme from the closely related RNase P, which selectively cleaves transfer RNA-like substrates. We find that NEPRO and C18ORF21 each form a complex with all other subunits of RNase MRP, stabilize its catalytic RNA, and are required for rRNA maturation and cell proliferation. We harness our discovery to identify a full suite ofin vivoRNA targets of each enzyme, including positions of potential cleavage sites at nucleotide resolution. These findings resolve the general composition of metazoan RNase MRP, illuminate its RNA binding specificity, and provide valuable assets for functional exploration of this essential eukaryotic enzyme.
Mutations in ASH1L cause a neurodevelopmental disorder with sex differences in epilepsy and autism
Authors: Papendorp Carin M. , Nolan Elizabeth , Higashimori Haruki , Goicouria Luis , Pieplow Cosmo A. , Whitely Kirsten , Elacio Jennifer , Nie Duyu , Kavanaugh Brian , Best Carrie R. , Lizarraga Sofia B. , Liu Judy S.
Published: February 2025

To understand brain phenotypes associated with ASH1L, we used a mouse model, performing analysis in different genetic backgrounds: C57BL/6 and CD-1. We found that in both lines, ASH1L mutations result in seizures. Mice from both lines have microcephaly, and also less complex dendritic morphology. We also found differential effects of ASH1L between C57BL/6 and CD-1 strains on a number of different measures identifying aspects of ASH1L function that may be influenced by genetic background. When we analyzed human subjects based on biological sex, for epilepsy, intellectual disability, and ASD, we found sex differences in epilepsy and autism, with epilepsy predominantly in female and ASD in male subjects. Functional evaluation by whole cell patch clamp electrophysiology in mice demonstrated hyperexcitability female compared with male hippocampal CA1 neurons. Thus, the role of ASH1L in specific circuits may be sex-dependent leading to sexual dimorphic effects from haploinsufficiency of this gene.
A vectorial code for semantics in human hippocampus
Authors: Franch Melissa , Mickiewicz Elizabeth A. , Belanger James L. , Chericoni Assia , Chavez Ana G. , Katlowitz Kalman A. , Mathura Raissa , Bartoli Eleonora , Kemmer Suzanne , Piantadosi Steven T. , Provenza Nicole R. , Watrous Andrew J. , Sheth Sameer A. , Hayden Benjamin Y.
Published: February 2025

As we listen to speech, our brains actively compute the meaning of individual words. Inspired by the success of large language models (LLMs), we hypothesized that the brain employs vectorial coding principles, such that meaning is reflected in distributed activity of single neurons. We recorded responses of hundreds of neurons in the human hippocampus, which has a well-established role in semantic coding, while participants listened to narrative speech. We find encoding of contextual word meaning in the simultaneous activity of neurons whose individual selectivities span multiple unrelated semantic categories. Like embedding vectors in semantic models, distance between neural population responses correlates with semantic distance; however, this effect was only observed in contextual embedding models (like BERT) and was reversed in non-contextual embedding models (like Word2Vec), suggesting that the semantic distance effect depends critically on contextualization. Moreover, for the subset of highly semantically similar words, even contextual embedders showed an inverse correlation between semantic and neural distances; we attribute this pattern to the noise-mitigating benefits of contrastive coding. Finally, in further support for the critical role of context, we find that range of neural responses covaries with lexical polysemy. Ultimately, these results support the hypothesis that semantic coding in the hippocampus follows vectorial principles.
Hematologic, Immunologic and Outcome Characteristics of Severe acute respiratory syndrome 2 (SARS-COV-2) among People Living with HIV in Eastern Uganda: A Retrospective Study
Authors: Otaala Timothy , Opito Ronald , Mugisha Kenneth , Oryokot Bonniface , Bakashaba Baker , Esabu Moses , Nbidde Susan Nabadda , Watmon Benedicto , Etolu Wilson , Lubaale Moses Yovani , Olupot-Olupot Peter
Published: February 2025

Introduction

Globally People Living with HIV (PLWHIV) are prone to severe opportunistic infections with Coronavirus disease of 2019 (COVID-19) inclusive. Dual infection of HIV and COVID-19 could complicate the clinical outcomes of these patients. This study sought to determine hematologic, immunologic, virologic and outcome characteristics of people with HIV and COVID-19 co-infections in two Mbale and Soroti Regional Referral Hospitals in Eastern Uganda.

Methods

A retrospective review of medical records of PLHIV and contracted COVID-19 virus was conducted in two large regional referral hospitals in Eastern Uganda using a data abstraction tool. Data was captured using Kobo collect toolbox, downloaded in Microsoft Excel and analyzed using STATA version 15.0. Descriptive statistics was reported as frequencies and proportions, while contingency and comparisons were done at the bivariate level analysis. The penalized logistic regression was conducted at multivariate level to establish the factors associated with COVID-19 severity among PLHIV.

Results

A total of 100 patient records had 38%(n=38) of individuals aged 40-50 years and 62%(n=62) females. Most patients (6 in 10) were peasants with 79%(n=79) having low-income levels. Other than HIV, 3 out of 10 patients had comorbidities. Also, 30 had haematological records, of which 9 (30%) had leucocytosis and 3, leucopoenia. Further, 67% had immunologic records, of which 22 (33%) had CD4 counts <200 cells/mm3. Only 22% of patients had viral load results, of which 8 (36) were unsuppressed. Nineteen percent (19/100) patients had severe COVID-19 and 14% (14/100) died. Socio-demographic factors significantly associated with severe COVID-19 outcomes were being male (P=0.026) and having other comorbidities (P<0.001).

Conclusion

A significant proportion of PLHIV co-infected with COVID-19 had abnormal hematological and virological status possibly due to varying socio-demographic characteristics. Clinical outcomes of HIV and COVID-19 co-infection may therefore vary depending on an interplay between host factors, viral factors, and comorbidities.
Ambient temperature structural studies of Penicillin-binding Protein 2a ofMethicillin-Resistant Staphylococcus aureuswith XFELs and synchrotrons
Authors: Grieco Alice , Quereda-Moraleda Isabel , Botha Sabine , Dörner Katerina , Schmidt Christina , Han Huijong , Vakili Mohammad , Schulz Joachim , Koua Faisal , de Wijn Raphael , Kharitonov Konstantin , Round Adam , Bielecki Johan , Kupitz Christopher , Lisova Stella , Schleissner Pamela , Sierra Ray , Mariani Valerio , Basu Shibom , Orlans Julien , Rose Samuel , de Sanctis Daniele , Gee Leland B. , Bean Richard , Mobashery Shahriar , Chang Mayland , Hermoso Juan A. , Martin-Garcia Jose Manuel
Published: February 2025

Penicillin-binding protein 2a (PBP2a) is a transpeptidase responsible for the β-lactam resistance in methicillin-resistantStaphylococcus aureus(MRSA), posing significant challenges to antibiotic therapy. PBP2a’s unique structural features, including its highly flexible active site and allosteric regulation, enable it to maintain catalytic activity even in the presence of β-lactam antibiotics. Despite extensive characterization using cryogenic crystallography, key questions remain about its dynamic properties and conformational changes under near-physiological conditions. Room-temperature crystallography methods, particularly serial femtosecond X-ray crystallography (SFX) at XFELs, provide a powerful approach to capture these dynamics. Unlike cryogenic conditions that can constrain protein flexibility, SFX enables the study of conformational variability and interaction networks closer to physiological states. Here, we present the first room-temperature structures of PBP2a obtained using SFX to uncover insights into the enzyme’s flexibility, allosteric communication, and catalytic mechanisms. These findings are built upon optimized large-scale production and crystallization protocols for PBP2a, ensuring high-quality microcrystals suitable for SFX data collection. The room-temperature structures reveal novel interaction patterns, including unique salt bridge networks and dynamic structural elements absent in cryogenic studies. Furthermore, comparative analyses highlight how environmental conditions influence the conformational states of PBP2a, providing new perspectives on its resistance mechanisms. By integrating structural data from EuXFEL and LCLS, this study not only enhances our understanding of PBP2a’s functional dynamics but also underscores the value of room-temperature crystallography in studying antibiotic resistance. These insights could guide the design of next-generation β-lactam antibiotics capable of overcoming PBP2a-mediated resistance.
A spatial transcriptomics atlas of live donors reveals unique zonation patterns in the healthy human liver
Authors: Yakubovsky Oran , Afriat Amichay , Egozi Adi , Halpern Keren Bahar , Barkai Tal , Harnik Yotam , Kohanim Yael Korem , Novoselsky Roy , Golani Ofra , Goliand Inna , Addadi Yoseph , Kedmi Merav , Keren-Shaul Hadas , Fellus-Alyagor Liat , Hirsch Dana , Mayer Chen , Pery Ron , Pencovich Niv , Taner Timucin , Nachmany Ido , Itzkovitz Shalev
Published: February 2025

Reconstructing gene expression atlases for human tissues is challenging due to limited access to healthy samples from live donors. Neurologically deceased donors often show ischemic changes, while tissues near diseased regions may have altered gene expression. The liver, with its unique regenerative capacity, allows analysis from live healthy donors (LHDs). Using spatial transcriptomics (Visum, Visium HD and MERFISH), we analyzed 16 liver samples: eight from young LHDs and eight from patients with liver pathology, sampling ‘adjacent normal’ tissue. LHD livers displayed significant gene expression differences from ‘adjacent normal’ tissues. Hepatocytes exhibited marked zonation along the porto-central axis of liver lobules, with key functions pericentrally shifted compared to other mammals. Our atlas identified dynamic programs in early steatotic hepatocytes, showing transitions from lipid uptake in low-lipid regions to insulin hypersensitivity in high-lipid regions. This study presents a spatial gene expression reference for the healthy human liver and insights into hepatocyte adaptations in steatosis.
Emergent modularity in large language models: Insights from aphasia simulations
Authors: Wang Chengcheng , Fan Zhiyu , Han Zaizhu , Bi Yanchao , Li Jixing
Published: February 2025

Recent large language models (LLMs) have demonstrated remarkable proficiency in complex linguistic tasks and have been shown to share certain computational principles with human language processing. However, whether LLMs’ internal components perform distinct functions, like semantic and syntactic processing in human language systems, remains unclear. Here, we systematically disrupted components of LLMs to simulate the behavioral profiles of aphasia—a disorder characterized by specific language deficits resulting from brain injury. Our findings showed that lesioning specific components of LLMs could replicate behaviors characteristic of different aphasia subtypes. Notably, while semantic deficits as those observed in Wernicke’s and Conduction aphasia, were relatively straightforward to simulate, reproducing syntactic and lexical impairments, as seen in Broca’s and Anomic aphasia, proved more challenging. Together, these results highlight both parallels and discrepancies between emergent modularity in LLMs and the human language system, providing new insights into how information is represented and processed in artificial and biological intelligence.
Subthreshold electric fields bidirectionally modulate neurotransmitter release through axon polarization
Authors: Aberra Aman S. , Miles Madelyn W. , Hoppa Michael B.
Published: February 2025

1.

Subthreshold electric fields modulate brain activity and demonstrate potential in several therapeutic applications. Electric fields are known to generate heterogenous membrane polarization within neurons due to their complex morphologies. While the effects of somatic and dendritic polarization in postsynaptic neurons have been characterized, the functional consequences of axonal polarization on neurotransmitter release from the presynapse are unknown. Here, we combined noninvasive optogenetic indicators of voltage, calcium and neurotransmitter release to study the subcellular response within single neurons to subthreshold electric fields. We first captured the detailed spatiotemporal polarization profile produced by uniform electric fields within individual neurons. Small polarization of presynaptic boutons produces rapid and powerful modulation of neurotransmitter release, with the direction – facilitation or inhibition – depending on the direction of polarization. We determined that subthreshold electric fields drive this effect by rapidly altering the number of synaptic vesicles participating in neurotransmission, producing effects which resemble short-term plasticity akin to presynaptic homeostatic plasticity. These results provide key insights into the mechanisms of subthreshold electric fields at the cellular level.

Abstract Figure
Perinatal environmental enrichment affects murine neonates’ brain structure before their active engagement with environment
Authors: Kaller Malte S. , Ligneul Clémence , Allemang-Grand Rylan , Zhang Tie Yuan , Ellegood Jacob , Meaney Michael , Lerch Jason P.
Published: February 2025

Early life experiences shape individuals. Environmental enrichment, an experimental paradigm used to study the effect of increased environmental complexity and novelty in animal models, has long been recognised for its broad effect on nervous system function and behaviour. In adult rodents, structural changes in the brain due to enriched environments are well documented, notably in the hippocampus. However, the effect of environmental enrichment on the developing brain during early life is not well understood. This study aims to investigate how environmental enrichment affects brain development during the critical perinatal period, and how such effects compare to those observed during adulthood.

We use high-resolution MRI to measure the brain structure of mouse neonates at postnatal day 7, born either in an enriched or a standard environment. We show that rodents exhibit brain structure differences as early as postnatal day 7. However, the regional changes observed differ from those in adulthood: hippocampal changes are limited, but changes in the hindbrain, the dorsal striatum, and the medial habenula are strong.

Given the lack of direct interaction between neonates and the environment at P7, we hypothesised that maternal care may mediate these effects. We show that maternal care differs between enriched and standard environments, that maternal care correlates with brain structure changes in the neonates, and that maternal care and enriched environment affect brain structure similarly. This suggests that early changes in brain structure due to environmental enrichment are at least partly mediated by maternal care. This study provides novel insight into the differential effect of enriched environment on early brain development in rodents.
Strong amplification of quantitative genetic variation under a balance between mutation and fluctuating stabilizing selection
Authors: Bertram Jason , Shafiei Zahra
Published: February 2025

The observation of high heritability in most quantitative traits has been a long-standing puzzle. There is a general consensus that simple models of quantitative genetic variation, which are mostly founded on the assumption of mutation-selection balance in a constant environment, have failed to explain high heritability. To make matters worse, the reasons for failure are unknown, leaving little to guide future model developments. Here we revisit this puzzle by taking the canonical Latter-Bulmer model and relaxing the assumption of perfect environmental stasis. Instead we assume that the trait optimum changes slowly but steadily in a random walk (specifically, an Ornstein-Uhlenbeck process), similar to standard models used for phylogenetic comparative methods. We show that our model behaves qualitatively differently to its stationary optimum counterpart even though the optimum only changes slowly. This is the result of a feedback between the adaptation rate and selection coefficient fluctuations. The heritability predictions resulting from this feedback are more consistent with observations and also less sensitive to evolutionary parameters than the classical LB model. We derive a simple formula to predict genetic variation under random walk optimum fluctuations which helps to explain some of our counter-intuitive results and which should be useful for understanding the potential influence of fluctuations in future work. Since the feedback driving our results should also occur in more complex models e.g. with multiple traits, we argue that environmental change has been an essential biological ingredient missing in previous mutation-selection balance models of quantitative trait heritability.
The morphology and small subunit rDNA gene phylogeny of the novel goniomonad genusEbisugoniomonasand two novelPoseidogoniomonasspecies
Authors: Zavadska Daryna , Sachs Maria , Arndt Hartmut , Richter Daniel J.
Published: February 2025

Goniomonads are heterotrophic representatives of Cryptista, sister lineage to the phototrophic Cryptists. Goniomonads are morphologically and genetically diverse, comprising nine genera described so far. Besides morphologically described genera, SSU rDNA sequencing data has revealed the existence of at least one more monophyletic genus-level lineage within goniomonads, as well as more novel species within the described genera. Furthermore, the diversity of SSU rDNA sequences within goniomonads is not fully investigated, and addition of novel sequences can be crucial for understanding the evolution and diversity of goniomonads and for providing a basis for taxonomic descriptions. The morphological data record available for goniomonads is relatively limited: many cellular features remain undescribed, or described only for a few isolates.

In this study, we describe the new genus and speciesEbisugoniomonas hispanican. gen. n. sp., and two novel species withinPoseidogoniomonas:P. posteriocircusn. sp. andP. zopfkaesiformisn. sp. We report a range of observations on the cellular features of goniomonads: periplast plate arrangement pattern and intracellular structures. We also update the SSU rDNA phylogeny of goniomonads by adding sequences from novel isolates and environmental DNA studies.

Several sequences recovered from novel isolates and environmental DNA datasets likely represent highly divergent lineages of goniomonads in the SSU rDNA phylogeny.
Discriminating sub-TeV gamma and hadron-induced showers through their footprints
Authors: Conceição R. , González B. S. , Guillén A. , Pimenta M. , Tomé B.
Published: February 2025

Gamma/hadron discrimination in ground-based gamma-ray observatories at the sub-TeV energy range is challenging as traditional muon-based methods become less effective at lower energies. This work explores a novel gamma/hadron discrimination method for extensive air shower arrays that analyzes the shower signal footprint patterns using a state-of-the-art pretrained vision transformer. The resilience of the method to background noise, such as atmospheric muons and low-energy proton showers, along with its adaptability to different zenith angles and array configurations, demonstrates its potential for application in current and future ground-based gamma-ray observatories.

Published by the American Physical Society
2025
Spin-lattice couplings in
3d
ferromagnets: Analysis from first principles
Authors: Miranda I. P. , Pankratova M. , Weißenhofer M. , Klautau A. B. , Thonig D. , Pereiro M. , Sjöqvist E. , Delin A. , Katsnelson M. I. , Eriksson O. , Bergman A.
Published: February 2025

Magnetoelasticity plays a crucial role in numerous magnetic phenomena, including magnetocalorics, magnon excitation via acoustic waves, and ultrafast demagnetization, or the Einstein–de Haas effect. Despite a long-standing discussion on anisotropy-mediated magnetoelastic interactions of relativistic origin, the exchange-mediated magnetoelastic parameters within an atomistic framework have only recently begun to be investigated. As a result, many of their behaviors and values for real materials remain poorly understood. Therefore, by using a proposed simple modification of the embedded cluster approach that reduces the computational complexity, we critically analyze the properties of exchange-mediated spin-lattice coupling parameters for elemental 3d ferromagnets (bcc Fe, fcc Ni, and fcc Co), comparing methods used for their extraction and relating their realistic values to symmetry considerations and orbitally decomposed contributions. Additionally, we investigate the effects of noncollinearity (spin temperature) and applied pressure on these parameters. For Fe, we find that single-site rotations, associated with spin temperatures around 100 K, induce significant modifications, particularly in Dzyaloshinskii-Moriya-type couplings; in contrast, such interactions in Co and Ni remain almost configuration independent. Moreover, we demonstrate a notable change in the exchange-mediated magnetoelastic constants for Fe under isotropic contraction. Finally, the conversion between atomistic, quantum-mechanically derived parameters and the phenomenological magnetoelastic theory is discussed, which can be a useful tool towards larger and more realistic dynamics simulations involving coupled subsystems.

Published by the American Physical Society
2025
Design and experimental verification of a bunch length monitor based on coherent Cherenkov diffraction radiation
Authors: Davut C. , Xia G. , Apsimon O. , McGunigal J. , Karataev P. , Lefevre T. , Mazzoni S. , Senes E.
Published: February 2025

This paper presents the design and experimental commissioning of a noninvasive electron bunch length monitor based on the detection of coherent Cherenkov diffraction radiation (ChDR). The measurement technique effectively eliminates the influence of bunch-by-bunch charge fluctuations, as each detector measures the signal from the same bunch while mitigating the impact of bunch position jitter on the measurements, providing a potential real-time diagnostic tool with significant operational advantages. The sensitivity of the measurements to both bunch length and longitudinal bunch profile was experimentally demonstrated, with results validated against invasive radio frequency deflector measurements at the CLEAR electron test facility at CERN. The ChDR bunch length monitor can be applied to accelerators operating with ultrashort bunches.

Published by the American Physical Society
2025