bluuebunny/crossref_metadata_2025 huggingface dataset:
Resolving out of Africa event for Papua New Guinean population using neural network
Authors: Mondal Mayukh , André Mathilde , Pathak Ajai K. , Brucato Nicolas , Ricaut François-Xavier , Metspalu Mait , Eriksson Anders
Published: September 2024

The demographic history of the Papua New Guinean population is a subject of significant interest due to its early settlement in New Guinea, at least 50 thousand years ago, and its relative isolation compared to other out of Africa populations. This isolation, combined with substantial Denisovan ancestry, contributes to the unique genetic makeup of the Papua New Guinean population. Previous research suggested the possibility of admixture with an early diverged modern human population, but the extent of this contribution remains debated. This study re-examines the demographic history of the Papua New Guinean population using newly published samples and advanced analytical methods. Our findings demonstrate that the observed shifts in relative cross coalescent rate curves are unlikely to result from technical artefacts or contributions from an earlier out of Africa population. Instead, they are likely due to a significant bottleneck and slower population growth rate within the Papua New Guinean population. Our analysis positions the Papua New Guinean population as a sister group to other Asian populations, challenging the notion of Papua New Guinean as an outgroup to both European and Asian populations. This study provides new insights into the complex demographic history of the Papua New Guinean population and underscores the importance of considering population-specific demographic events in interpreting relative cross coalescent rate curves.
Mapping snoRNA-target RNA interactions in an RNA binding protein-dependent manner with chimeric eCLIP
Authors: Song Zhuoyi , Bae Bongmin , Schnabl Simon , Yuan Fei , Zoysa Thareendra De , Akinyi Maureen , Roux Charlotte Le , Choquet Karine , Whipple Amanda , Nostrand Eric Van
Published: September 2024

Small nucleolar RNAs (snoRNAs) are non-coding RNAs that function in ribosome and spliceosome biogenesis, primarily by guiding modifying enzymes to specific sites on ribosomal RNA (rRNA) and spliceosomal RNA (snRNA). However, many orphan snoRNAs remain uncharacterized, with unidentified or unvalidated targets, and studies on additional snoRNA-associated proteins are limited. We adapted an enhanced chimeric eCLIP approach to comprehensively profile snoRNA-target RNA interactions using both core and accessory snoRNA binding proteins as baits. Using core snoRNA binding proteins, we confirmed most annotated snoRNA-rRNA and snoRNA-snRNA interactions in mouse and human cell lines and called novel, high-confidence interactions for orphan snoRNAs. While some of these interactions result in chemical modification, others may have modification-independent functions. We then showed that snoRNA ribonucleoprotein complexes containing certain accessory proteins, like WDR43 and NOLC1, enriched for specific subsets of snoRNA-target RNA interactions with distinct roles in ribosome and spliceosome biogenesis. Notably, we discovered that SNORD89 guides 2’-O-methylation at two neighboring sites in U2 snRNA that are important for activating splicing, but also appear to ensure imperfect splicing for a subset of near-constitutive exons. Thus, chimeric eCLIP of snoRNA-associating proteins enables a comprehensive framework for studying snoRNA-target interactions in an RNA binding protein-dependent manner, revealing novel interactions and regulatory roles in RNA biogenesis.
Inferring demographic and selective histories from population genomic data using a two-step approach in species with coding-sparse genomes: an application to human data
Authors: Soni Vivak , Jensen Jeffrey D.
Published: September 2024

The demographic history of a population, and the distribution of fitness effects (DFE) of newly arising mutations in functional genomic regions, are fundamental factors dictating both genetic variation and evolutionary trajectories. Although both demographic and DFE inference has been performed extensively in humans, these approaches have generally either been limited to simple demographic models involving a single population, or, where a complex population history has been inferred, without accounting for the potentially confounding effects of selection at linked sites. Taking advantage of the coding-sparse nature of the genome, we propose a 2-step approach in which coalescent simulations are first used to infer a complex multi-population demographic model, utilizing large non-functional regions that are likely free from the effects of background selection. We then use forward-in-time simulations to perform DFE inference in functional regions, conditional on the complex demography inferred and utilizing expected background selection effects in the estimation procedure. Throughout, recombination and mutation rate maps were used to account for the underlying empirical rate heterogeneity across the human genome. Importantly, within this framework it is possible to utilize and fit multiple aspects of the data, and this inference scheme represents a generalized approach for such large-scale inference in species with coding-sparse genomes.
Metabolic Outcomes in Non-Alcoholic and Alcoholic Steatotic Liver Disease in among Korean and Adults: A Population-Based Multi-Cohort Study
Authors: Kim Yeongmin , Lee Taesic , Oh Chang-Myung
Published: September 2024

Background and aims

This study investigated the prevalence and causal relationships of chronic metabolic diseases (diabetes, hypertension, and dyslipidemia) with steatotic liver disease (SLD), specifically metabolically associated alcoholic liver disease (MetALD).

Methods

We conducted a comprehensive analysis using cross-sectional data from the Korea National Health and Nutrition Examination Survey (KNHANES) from 2011 to 2021 and the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2020. Longitudinal data from 2001 to 2014 from the Korean Genome and Epidemiology Study (KoGES) were used. Participants were categorized into the metabolic dysfunction-associated SLD (MASLD), MetALD, and ALD groups based on their hepatic steatosis index (HSI) and alcohol consumption. Logistic and Cox regression analyses were performed to assess the prevalence and incidence of chronic diseases.

Results

In both the KNHANES and NHANES cohorts, an increased HSI was significantly associated with a higher prevalence of chronic metabolic diseases. Longitudinal data from the KoGES cohort showed that MASLD and MetALD were significant predictors of chronic metabolic disease in both men and women. MetALD showed a higher hazard ratio for the development of chronic metabolic diseases than MASLD in Cox regression analysis.

Conclusion

This study highlighted the intertwined nature of SLD and metabolic health, with an emphasis on the role of MetALD. The significant association between MetALD and chronic metabolic diseases underscores the need for integrated management strategies that address both liver health and metabolic risk factors.
Outcome Dimensions and Measurement Approaches for Evaluating the Impact of China’s Family Doctor Contract Services: A Scoping Review Protocol
Authors: Wang Yang , Jin Hua , Yu Dehua
Published: September 2024

Background

Family doctor contract services in mainland China are designed to foster long-term relationships between family doctors and contracted residents, promoting the delivery of primary care services through teamwork and collaboration. By 2035, it is expected that the coverage of these services will exceed 75%, making it a key model for primary care in China. However, the outcome dimensions and measurement approaches used to evaluate the effectiveness of these services remain fragmented and lack a comprehensive framework. This scoping review aims to systematically investigate the outcome dimensions and measurement approaches previously used to evaluate the effectiveness of family doctor contract services in mainland China.

Methods

This scoping review will be conducted in accordance with the JBI methodology for scoping reviews. We will search electronic databases, including CNKI, Wanfang, PubMed, the Cochrane Database of Systematic Reviews, JBI Evidence Synthesis, PROSPERO, and Google Scholar, for literature published since 2006. Eligible sources will include policy documents, quantitative studies, and qualitative studies that assess the outcomes of family doctor contract services. Data extraction will focus on the outcome dimensions and measurement approaches used in these evaluations. Two independent reviewers will screen and extract data from the literature, and any discrepancies will be resolved through group discussions with a third reviewer. Descriptive statistics will be used to analyze the extracted data, and the results will be presented through tables, charts, and a hierarchical tree diagram of outcome dimensions and measurement tools.

Discussion

This scoping review will provide a comprehensive overview of the outcome dimensions and measurement approaches used to evaluate family doctor contract services in mainland China. It will help to identify gaps in the existing literature and offer a clearer framework for future evaluations of these services. By mapping out the outcome dimensions and tools, this review aims to contribute to improving the quality and effectiveness of family doctor contract services in China. The findings will be particularly valuable for policymakers and researchers focused on enhancing primary care systems.

Systematic review registration

Registered in OSF on September 20, 2024 (osf.io/z3eju)
Seroprevalence of teratogenic viruses among women of childbearing age in Botswana
Authors: Gobe I. , Baipoledi K. , Skwenje G. , Ntamo M. , Motswaledi M.
Published: September 2024

Background

Teratogenic viruses are viruses than can cross the placenta and infect a growing foetus, resulting in malformations and birth defects. Some of the commonly known teratogenic viruses include cytomegalovirus (CMV), rubella, herpes simplex and varicella zoster (VZV) viruses. Most birth defects associated with these infections affect the central nervous system and sensory organs leading to symptoms that include mental retardation, hearing loss and blindness. The economic burden caused by congenital birth defects is high, as many affected children require special care, therapeutic and educational services. Despite the risk posed by teratogenic viruses during pregnancy, there is no national screening for active CMV, Rubella or VZV infection during pregnancy in Botswana and most African countries. Furthermore, data on the seroprevalence of these viruses among women of childbearing age is limited.

Methods and setting

This cross-section study used eighty-nine (89) residual plasma samples from Scottish Livingstone Hospital Laboratory in Molepolole-Botswana. Samples were from women between the ages 15-49 years. Samples were tested for antibodies against rubella, VZV and CMV using enzyme linked immunosorbent assay.

Results

Our results show a high seroprevalence of rubella IgG antibodies (97%), even though a small proportion (3%) of women are still susceptible. There was also a high seroprevalence of CMV IgG (100%) which was accompanied by an equally high CMV IgM of 98%. Seroprevalence of VZV IgG was low (63%) and 3% of the samples showed active VZV infection.

Conclusions

Teratogenic viruses are a concern in the population. This calls for preventative measures which include prompt screening and vaccination of susceptible eligible women to prevent congenital abnormalities in children.
Wastewater surveillance overcomes socio-economic limitations of laboratory-based surveillance when monitoring disease transmission: the South African experience during the COVID-19 pandemic
Authors: Maree Gillian , Els Fiona , Naidoo Yashena , Naidoo Laven , Mahamuza Phemelo , Macheke Mokgaetji , Ndlovu Nkosenhle , Rachida Said , Iwu-Jaja Chinwe , Taukobong Setshaba , Maposa Sibonginkosi , O’Reilly Kathleen , Yousif Mukhlid , McCarthy Kerrigan
Published: September 2024

Wastewater and environmental surveillance has been promoted as a communicable disease surveillance tool because it overcomes inherent biases in laboratory-based communicable disease surveillance. Yet, little empirical evidence exists to support this notion, and it remains largely an intuitive, though highly plausible hypothesis. Our interdisciplinary uses WES data to show evidence for underreporting of SARS-CoV-2 in the context of measurable and statistically significant associations between economic conditions and SARS-CoV-2 incidence and testing rates. We obtained geolocated, anonymised, laboratory-confirmed SARS-CoV-2 cases, wastewater SARS-CoV-2 viral load data and socio-demographic data for Gauteng Province, South Africa. We spatially located all data to create a single dataset for sewershed catchments served by two large wastewater treatment plants. We conducted epidemiological, persons infected and principal component analysis to explore the relationships between variables. Overall, we demonstrate the co-contributory influences of socio-economic indicators on access to SARS-CoV-2 testing and cumulative incidence, thus reflecting that apparent incidence rates mirror access to testing and socioeconomic considerations rather than true disease epidemiology. These analyses demonstrate how WES provides valuable information to contextualise and interpret laboratory-based epidemiological data. Whilst it is useful to have these associations established for SARS-CoV-2, the implications beyond SARS-CoV-2 are legion for two reasons, namely that biases inherent in clinical surveillance are broadly applicable across pathogens and all pathogens infecting humans will find their way into wastewater albeit in varying quantities. WES should be implemented to strengthen surveillance systems, especially where economic inequalities limit interpretability of conventional surveillance data.
Allosteric mechanism of membrane fusion activation in a herpesvirus
Authors: González-Del Pino Gonzalo L. , Walsh Richard M. , Atanasiu Doina , Cairns Tina M. , Saw Wan Ting , Cohen Gary H. , Heldwein Ekaterina E.
Published: September 2024

ABSTRACT/SUMMARY

Herpesviridaeinfect nearly all humans for life, causing diseases that range from painful to life-threatening1. These viruses penetrate cells by employing a complex apparatus composed of separate receptor-binding, signal-transmitting, and membrane-fusing components2. But how these components coordinate their functions is unknown. Here, we determined the 4.19-angstrom cryoEM reconstruction of the central signal-transmitting component from herpes simplex virus 2, the gH/gL complex, in its elusive pre-activation state. Analysis of the continuum of conformational ensembles observed in cryoEM data revealed a series of structural rearrangements in gH/gL that allosterically transmit the fusion-triggering signal from the receptor-binding glycoprotein gD to the membrane fusogen gB. Furthermore, we identified a structural “switch” element in gH/gL that refolds and flips 180 degrees during the transition from pre-activation to activated form. Conservation of this “switch” in gH/gL homologs suggests that the proposed fusion triggering mechanism may apply to allHerpesviridaeand points to a new target for subunit-based vaccines and treatment efforts.
Lower limb pointing to assess intersegmental dynamics after incomplete spinal cord injury and the associated role of proprioceptive impairments
Authors: Malik Raza N. , Marigold Daniel S. , Chow Mason , Eginyan Gevorg , Lam Tania
Published: September 2024

Background

Disorders in the recovery of gait strategies in individuals with incomplete spinal cord injury (SCI) suggest difficulties in controlling lower limb intersegmental dynamics, which could relate to proprioceptive impairments. To probe discrete aspects of lower limb interjoint coordination, we present here a novel protocol to assess lower limb motor strategies and evaluate the influence of proprioceptive impairments following SCI.

Methods

Twelve able-bodied controls and 16 participants with SCI performed lower limb pointing to three targets that involved combined hip and knee flexion, or hip or knee flexion only while standing, with either full or obstructed visual feedback. We quantified lower limb proprioceptive sense in individuals with SCI using a robotic gait device. We used motion analysis to determine lower limb joint angles and foot trajectory, computed inverse dynamics to quantify joint and intersegmental dynamics, and derived muscle torque as an indicator of the motor strategies produced to control the motion to each target. We used linear mixed-effects models to assess differences between the control and SCI groups on end-point performance and muscle torque, and to assess the relationship of muscle torque with end-point performance and proprioceptive sense.

Results

Groups differed in motor strategies, but not end-point performance, when pointing to all three targets. Compared to controls, the SCI group had difficulty controlling knee muscle torque when performing the hip-flexion-only target (p = 0.008) or when flexing the hip and knee simultaneously (p = 0.0004). To complete the knee-flexion-only target, the SCI group had difficulties generating the required hip extensor muscle torque to maintain the thigh in neutral (p = 0.0001). These altered motor strategies in individuals with SCI were associated with proprioceptive impairments and end-point performance.

Conclusion

This novel lower limb pointing task can identify disordered motor strategies in individuals with SCI, especially at the knee, and are associated with proprioceptive impairment. Variations of this paradigm can be employed to further understand differences in motor strategies between controls and individuals with SCI, and the impact of proprioceptive deficits.
Comparing alpha-synuclein-interactomes between multiple systems atrophy and Parkinson’s disease reveals unique and shared pathological features
Authors: Choi S.G. , Tittle T. , Barot R , Betts D. , Gallagher J. , Kordower J.H. , Chu Y. , Killinger B.A.
Published: September 2024

Introduction

Primary synucleinopathies, such as Parkinson’s disease (PD), Dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), are neurodegenerative disorders with some shared clinical and pathological features. Aggregates of alpha-synuclein (αsyn) phosphorylated at serine 129 (PSER129) are the hallmark of synucleinopathies, which for PD/DLB are found predominantly in neurons (Neuronal cytoplasmic inclusions “NCIs”), but for MSA, aggregates are primarily found in oligodendroglia (Glial cytoplasmic inclusions “GCIs”). It remains unclear if the distinct pathological presentation of PD/DLB and MSA are manifestations of distinct or shared pathological processes. We hypothesize that the distinct synucleinopathies MSA and PD/DLB share common molecular features.

Methods

Using the in-situ proximity labeling technique biotinylation by antibody recognition (BAR), we compare aggregated αsyn-interactomes (BAR-PSER129) and total αsyn-interactomes (BAR-MJFR1) between MSA (n=5) and PD/DLB (n=10) in forebrain and midbrain structures.

Results

For BAR-PSER129 and BAR-MJFR1 captures, αsyn was the most significantly enriched protein in PD/DLB and MSA. In PD/DLB, BAR-PSER129 identified 194 αsyn-aggregate-interacting proteins, while BAR-MJFR1 identified 245 αsyn interacting proteins. In contrast, in the MSA brain, only 38 and 175 proteins were identified for each capture, respectively. When comparing MSA and PD/DLB, a high overlap (59.5%) was observed between BAR-MJFR1 captured proteins, whereas less overlap (14.4%) was observed for BAR-PSER129. Direct comparison between MSA and PD/DLB revealed 79 PD/DLB-associated proteins and only three MSA-associated proteins (CBR1, CRYAB, and GFAP). Pathway enrichment analysis revealed PD/DLB interactions were dominated by vesicle/SNARE-associated pathways, in contrast to MSA, which strongly enriched for metabolic/catabolic, iron, and cellular oxidant detoxification pathways. A subnetwork of cytosolic antioxidant enzymes called peroxiredoxins drove cellular detoxification pathways in MSA. A common network of 26 proteins, including neuronal-specific proteins (e.g., SNYGR3) with HSPA8 at the core, was shared between MSA and DLB/PD. Extracellular exosome pathways were universally enriched regardless of disease or BAR target protein.

Conclusion

Synucleinopathies have divergent and convergent αsyn-aggregate interactions, indicating unique and shared pathogenic mechanisms. MSA uniquely involves oxidant detoxification processes in glial cells, while vesicular processes in neurons dominate PD/DLB. Shared interactions, specifically SNYGR3 (i.e., a neuronal protein), between MSA and PD/DLB suggest neuronal axons origin for both diseases. In conclusion, we provide αsyn aggregates protein interaction maps for two distinct synucleinopathies.
Vocal Call Locator Benchmark (VCL) for localizing rodent vocalizations from multi-channel audio
Authors: Peterson Ralph E , Tanelus Aramis , Ick Christopher , Mimica Bartul , Francis Niegil , Ivan Violet J , Choudhri Aman , Falkner Annegret L , Murthy Mala , Schneider David M , Sanes Dan H , Williams Alex H
Published: September 2024

Understanding the behavioral and neural dynamics of social interactions is a goal of contemporary neuroscience. Many machine learning methods have emerged in recent years to make sense of complex video and neurophysiological data that result from these experiments. Less focus has been placed on understanding how animals process acoustic information, including social vocalizations. A critical step to bridge this gap is determining the senders and receivers of acoustic information in social interactions. While sound source localization (SSL) is a classic problem in signal processing, existing approaches are limited in their ability to localize animal-generated sounds in standard laboratory environments. Advances in deep learning methods for SSL are likely to help address these limitations, however there are currently no publicly available models, datasets, or benchmarks to systematically evaluate SSL algorithms in the domain of bioacoustics. Here, we present the VCL Benchmark: the first large-scale dataset for benchmarking SSL algorithms in rodents. We acquired synchronized video and multi-channel audio recordings of 767,295 sounds with annotated ground truth sources across 9 conditions. The dataset provides benchmarks which evaluate SSL performance on real data, simulated acoustic data, and a mixture of real and simulated data. We intend for this benchmark to facilitate knowledge transfer between the neuroscience and acoustic machine learning communities, which have had limited overlap.
ERAP1 activity modulates the immunopeptidome but also affects the proteome, metabolism and stress responses in cancer cells
Authors: Nikopaschou Martha , Samiotaki Martina , Stylianaki Ellie-Anna , Król Kamila , Gragera Paula , Raja Aroosha , Aidinis Vassilis , Chroni Angeliki , Fruci Doriana , Panayotou George , Stratikos Efstratios
Published: September 2024

Endoplasmic reticulum (ER) aminopeptidase 1 (ERAP1) metabolizes peptides inside the ER and shapes the peptide repertoire available for binding to Major Histocompatibility Complex Class I molecules (MHC-I). Moreover, it may have additional effects on cellular homeostasis, which have not been explored. To address these questions, we used both genetic silencing of ERAP1 expression as well as treatment with a selective allosteric ERAP1 inhibitor to probe changes in the immunopeptidome and proteome of the A375 melanoma cancer cell line. We observed significant immunopeptidome shifts with both methods of functional ERAP1 disruption, which were distinct for each method. Both methods of inhibition led to an enhancement, albeit slight, in tumor cell killing by stimulated human PBMCs and in significant proteomic alterations in pathways related to metabolism and cellular stress. Similar proteomic changes were also observed in the leukemia cell line THP-1. Biochemical analyses suggested that ERAP1 inhibition affected sensitivity to ER stress, reactive oxygen species production and mitochondrial metabolism. Although the proteomics shifts were significant, their potential in shaping immunopeptidome shifts was limited since only 15.8% of differentially presented peptides belonged to proteins with altered expression and only 5.0% of proteins with altered expression were represented in the immunopeptidome shifts. Taken together, our findings suggest that modulation of ERAP1 activity can generate unique immunopeptidomes, mainly due to altered peptide processing in the ER, but also induce changes in the cellular proteome and metabolic state which may have further effects on tumor cells.
Extinction of innate floral preferences in the pollinatorEristalis tenax
Authors: Rajan Deepa , Mishra Aditi , Sharan Maansi , Gharpure Gauri , Olsson Shannon
Published: September 2024

Innate behaviors allow solitary animals to complete essential tasks in the absence of social learning. However, we know little about the degree to which ecologically relevant innate preferences can change. The hoverflyEristalis tenax, a solitary generalist pollinator, is an ideal model for studying innate behavior in a naturalistic context because its survival depends on the innate ability to identify flowers. Innate behavior inE. tenaxhas previously been considered inalterable, but we hypothesized thatE. tenaxcan modulate their innate behavior after training in a multimodal sensory context, in contrast to the prior work that employed unimodal sensory cues. To test this, we examined ifE. tenaxcan extinguish an innate proboscis extension response (PER) to a multimodal floral object after undergoing aversive conditioning with quinine, and if flies can acquire PER to an innately unattractive object using sucrose as reinforcement. Finally, we assessed long-term memory retention. Here, we report a complete extinction of the proboscis extension response (PER) to an innately attractive floral object following aversive training.E. tenaxcan also acquire PER to an innately unattractive object after appetitive training. Flies can retain these memories for days after training, and aversive memories last longer than appetitive memories. Our results contrast with literature stating that innate preferences cannot be extinguished inE. tenax. This could be because our study uses multimodal objects instead of the unimodal stimuli used in previous work. Ultimately, these findings improve our understanding of how animals navigate the uncertainties of dynamic objects in the natural world.
Nucleation limited assembly and polarized growth of ade novo-designed allosterically modulatable protein filament
Authors: Shen Hao , Lynch Eric M. , Watson Joseph L. , Wu Kejia , Bai Hua , Sheffler William , Derivery Emmanuel , Kollman Justin , Baker David
Published: September 2024

The design of inducibly assembling protein nanomaterials is an outstanding challenge. Here, we describe the computational design of a protein filament formed from a monomeric subunit which binds a peptide ligand. The cryoEM structure of the micron scale fibers is very close to the computational design model. The ligand acts as a tunable allosteric modulator: while not part of the fiber subunit-subunit interfaces, the assembly of the filament is dependent on ligand addition, with longer peptides having more extensive interaction surfaces with the monomer promoting more rapid growth. Seeded growth and capping experiments reveal that the filaments grow primarily from one end. Oligomers containing 12 copies of the peptide ligand nucleate fiber assembly from monomeric subunit and peptide mixtures at concentrations where assembly occurs very slowly, likely by generating critical local concentrations of monomer in the assembly competent conformation. Following filament assembly, the peptide ligand can be exchanged with free peptide in solution, and it can be readily fused to any functional protein of interest, opening the door to a wide variety of tunable engineered materials.
Spinal neuron diversity scales exponentially with swim-to-limb transformation during frog metamorphosis
Authors: Vijatovic David , Toma Florina Alexandra , Harrington Zoe P. M. , Sommer Christopher , Hauschild Robert , Trevisan Alexandra J. , Chapman Phillip , Julseth Mara J. , Brenner-Morton Susan , Gabitto Mariano I. , Dasen Jeremy S. , Bikoff Jay B. , Sweeney Lora B.
Published: September 2024

Vertebrates exhibit a wide range of motor behaviors, ranging from swimming to complex limb-based movements. Here we take advantage of frog metamorphosis, which captures a swim-to-limb-based movement transformation during the development of a single organism, to explore changes in the underlying spinal circuits. We find that the tadpole spinal cord contains small and largely homogeneous populations of motor neurons (MNs) and V1 interneurons (V1s) at early escape swimming stages. These neuronal populations only modestly increase in number and subtype heterogeneity with the emergence of free swimming. In contrast, during frog metamorphosis and the emergence of limb movement, there is a dramatic expansion of MN and V1 interneuron number and transcriptional heterogeneity, culminating in cohorts of neurons that exhibit striking molecular similarity to mammalian motor circuits. CRISPR/Cas9-mediated gene disruption of the limb MN and V1 determinants FoxP1 and Engrailed-1, respectively, results in severe but selective deficits in tail and limb function. Our work thus demonstrates that neural diversity scales exponentially with increasing behavioral complexity and illustrates striking evolutionary conservation in the molecular organization and function of motor circuits across species.
Premature upregulation of miR-92a’s target RBFOX2 hijacks PTBP splicing and impairs cortical neuronal differentiation
Authors: Weißbach Stephan , Todorov Hristo , Schlichtholz Laura , Mühlbauer Sophia , Zografidou Lea , Soliman Azza , Lor-Zade Sarah , Hartwich Dewi , Strand Dennis , Strand Susanne , Vogel Tanja , Heine Martin , Gerber Susanne , Winter Jennifer
Published: September 2024

RBFOX2 is an RNA-binding protein crucial for alternative splicing regulation and implicated in several neurodevelopmental disorders. Here, we show that while RBFOX2 is present only at low levels in neural progenitor cells (NPCs), it is upregulated in differentiating neurons of the mouse embryonic neocortex.In-utero-electroporation-induced overexpression resulted in a cellular phenotype characterized by impaired neuronal migration and differentiation. Genome-wide analysis at E15.5 revealed numerous alternative splicing events associated with a mixed NPC- and neuron-like splicing pattern and a significant deviation from the normal splicing developmental trajectory. Remarkably, prematureRbfox2overexpression induced the inclusion of validated target exons that are otherwise repressed by PTBP2, indicating an antagonistic splicing relationship between these two RNA-binding proteins and highlighting the necessity for strict temporal regulation of their expression during embryonic brain development. Consequently, we showed that the NPC-specific miRNA 92a-3p reduced the expression levels ofRbfox2 in vitro. Furthermore, silencing miR-92a-3pin vivoin the embryonic neocortex led to a significant increase inRbfox2levels. Our results therefore demonstrate that RBFOX2 is a crucial player in the NPC-to-neuron splicing switch. Furthermore, we present a novel post-transcriptional mechanism for controlling RBFOX2 levels during early neuronal differentiation via miR-92a-3p silencing.
Neuralized-like proteins differentially activate Notch ligands
Authors: Airich Alina , Gozlan Oren , Seib Ekaterina , Wilschrey Lena-Sophie , Shaingarten Gittel Leah , Sprinzak David , Klein Thomas
Published: September 2024

Notch signalling is a major signalling pathway coordinating cellular processes between neighbouring animal cells. In Drosophila, two ubiquitin ligases, Neuralized (Neur) and Mindbomb1 (Mib1), regulate Notch ligand activation and are essential for development. However, the mammalian orthologs of Neur, Neuralized-like (NEURL) 1 and 2, do not appear to be crucial for development, as double knock-out mice show no developmental defects. Thus, it is unclear if and how NEURL proteins regulate the four mammalian Notch ligands. To address these questions, we examined NEURL proteins’ ability to activate Notch ligands in humanizedDrosophilaand mammalian cell culture. We found that, unlike MIB1, NEURL proteins activate Notch only with a subset of mammalian ligands, which contain a Neuralized binding motif. This motif has the consensus sequence NxxN, present only in Notch ligands DLL1 and JAG1, but not in DLL4 and JAG2. Overall, we show that NEURL proteins activate specific Notch-ligands, suggesting a differential regulatory mechanism of Notch activation in mammals, which can potentially explain the limited role of NEURL proteins in mammalian development and homeostasis.
Bacterial growth under confinement requires transcriptional adaptation to resist metabolite-induced turgor pressure build-up
Authors: Blanc Laure Le , Alric Baptiste , Rollin Romain , Xénard Laura , Finn Laura Ramirez , Goussard Sylvie , Mazenq Laurent , Ingersoll Molly A. , Piel Matthieu , Tinevez Jean-Yves , Delarue Morgan , Duménil Guillaume , Bonazzi Daria
Published: September 2024

Bacterial proliferation often occurs in confined spaces, during biofilm formation, within host cells, or in specific niches during infection, creating mechanical constraints. We investigated how spatial confinement and growth-induced mechanical pressure affect bacterial physiology. Here, we found that, when proliferating in a confining microfluidic-based device with access to nutrients,Escherichia colicells generate forces in the hundreds of kPa range. This pressure decouples growth and division, producing shorter bacteria with higher protein concentrations. This leads to cytoplasmic crowding, which ultimately arrests division and stalls protein synthesis. In this arrested state, the pressure produced by bacteria keeps increasing. A minimal theoretical model of bacterial growth predicts this novel regime of steady pressure increase in the absence of protein production, that we namedoverpressurization. In this regime, the Rcs pathway is activated and that abnormal shapes appear inrcsmutant populations only when they reach the overpressurized state. A uropathogenic strain ofE. colidisplayed the same confined growth phenotypesin vitroand requirement for Rcs in a mice model of urinary tract infection, suggesting that these pressurized regimes are relevant to understand the physiopathology of bacterial infections.
A characterization of mitotic and centrosomal defects in a continuum model of Breast Cancer
Authors: Santos Alexsandro dos , Diorio Caroline , Durocher Francine , Elowe Sabine
Published: September 2024

Errors in mitosis can contribute to aneuploidy and CIN and play a pivotal role in cancer. So the identification of altered mitotic regulators can contribute to the understanding of the development and progression of breast cancer. In the present study we used anin vitromodel of disease progression (the MCF10A series of BC continuum) and analyzed the errors of chromosome segregation that occur during the progression of the disease. Our findings indicated that the MCF10A series exhibited several abnormalities in chromosome segregation and its frequency increased with the disease progression. These errors included anaphase lagging chromosomes, micronuclei, nuclear buds, nucleoplasmic bridges, errors of chromosome alignment, and centrosome loss/amplification. Moreover, the presence of centrosome amplification disrupted the proper orientation of the mitotic spindle, resulting in the generation asymmetrical cell lines and aneuploidy in the MCF10A series. Hyper stable kinetochore-microtubule (kt-MT) attachment was also found in premalignant, preinvasive, and invasive cell lines, which can also explain the presence of errors of chromosome alignment. The human transcriptome array also determined possible negative regulators of ciliogenesis that can explain the mechanism of chromosome missegregation that lead to CIN found in the MCF10A series. Collectively, these findings highlight the importance of mitotic defects in the progression of breast cancer.
Human medial pulvinar is involved in face and tactile processing and dynamically adjusts its cortical connectivity based on ongoing stimulation
Authors: Gaudet-Trafit M. , Froesel M. , Dali S. , Lamberton F. , Ben Hamed S.
Published: September 2024

Optimal processing of our surrounding environment relies on our ability to detect and integrate external information through multiple sensory modalities to build a coherent representation of the world. Interactions between cortical and subcortical structures contribute to this process. In this context, there is growing evidence that the pulvinar plays a crucial role in visual and face processing. In contrast, its role in auditory, voice and tactile processing has been poorly investigated. Here, we use fMRI localizer tasks to describe pulvinar functional organization and functional connectivity with the brain during face, voice and tactile processing. We reproduce the activation of the ventral part of the medial pulvinar in face perception and we describe an increased pulvinar connectivity with face processing areas and a decreased connectivity with low level visual areas during face processing. In addition, we describe activations of the medial pulvinar during air-puff face, hands and feet tactile stimulations and changes in pulvino-cortical connectivity as a function of which body part is being stimulated. No activations are observed during either voice or non-voice stimulations. Overall, this supports a role of medial pulvinar in multisensory processing and the modulation of cortical areas as a function of the sensory context.
SATAY-Based Chemogenomic Screening uncovers Antifungal Resistance Mechanisms and Key Determinants of ATI-2307 and Chitosan Sensitivity
Authors: Karadzas Matthew T. , Michel Agnès H. , Mosbach Andreas , Giannakopoulos George , McGettigan Ruairi , Scalliet Gabriel , Kornmann Benoît
Published: September 2024

Multidrug-resistant fungal pathogens are a serious threat to public health and global food security. Mitigation requires the discovery of antifungal compounds with novel modes of action, along with a comprehensive understanding of the molecular mechanisms governing antifungal resistance. Here, we apply SAturated Transposon Analysis in Yeast (SATAY), a powerful transposon sequencing method inSaccharomyces cerevisiae, to uncover loss- and gain-of-function mutations conferring resistance to 20 different antifungal compounds. These screens identify a diverse array of novel resistance mechanisms and multiple modes of action. SATAY is performed in drug-sensitive strains to generate chemogenomic profiles for compounds that lack activity against conventional laboratory strains. This study therefore provides a significant resource for exploring cellular responses to chemical stresses. We discover that the natural antifungal Chitosan electrostatically interacts with cell wall mannosylphosphate, and that the transporter Hol1 concentrates the novel antifungal ATI-2307 within yeast. This latter finding presents an avenue for drug design initiatives, but also unveils a straightforward evolutionary path to ATI-2307 resistance with minimal fitness cost.
A role for acetylcholine in reinforcement learning and decision making under uncertainty
Authors: Kurtenbach Hannah , Froböse Monja Isabel , Ort Eduard , Bahners Bahne Hendrik , Hirschmann Jan , Butz Markus , Schnitzler Alfons , Jocham Gerhard
Published: September 2024

The neuromodulator acetylcholine has been suggested to govern learning under uncertainty. Here, we investigated the role of muscarinic receptors in reward-guided learning and decision making under different degrees of uncertainty. We administered the muscarinic M1 antagonist biperiden (4 mg) to healthy male participants (n = 43) in a within-subjects, placebo-controlled design. Participants performed two tasks that both involved choices between options characterized by two attributes, reward probability and magnitude. In the gambling task, both attributes were explicitly provided, whereas in the learning task, reward probabilities had to be inferred from past experience. In addition, uncertainty was manipulated within the learning task by inclusion of a stable phase with fixed reward contingencies, and a volatile phase with frequent contingency reversals. We show that biperiden did not affect decision making in the gambling task, where no learning was required. However, in the learning task, biperiden reduced the sensitivity to the learnt reward probabilities. Notably, this was primarily driven by choices under higher uncertainty in the volatile phase. Using reinforcement learning models, we reveal that the change in behaviour was caused by noisier estimates of probabilities resulting from maladaptively increased learning rates under biperiden. Together, these findings suggest that muscarinic acetylcholine transmission is involved in controlling learning in highly uncertain contexts, when the demand for carefully calibrated adjustments is highest.
Group 15 Pre-emergent Herbicides Differentially Effect Plant Growth, Cuticular Wax Composition, and Fatty Acid Metabolism in Herbicide-Resistant and Herbicide-naïve Blackgrass
Authors: Blyth Hannah R. , Beaudoin Frederic , Haslam Richard P. , Hunt Barrie , Cornette Laurent , MacGregor Dana R.
Published: September 2024

Despite their long history of effective use in agroecosystems, the precise molecular mechanisms of many pre-emergent herbicides are not fully understood. This study investigates the effects of three Group 15 pre-emergent herbicides (Flufenacet, S-ethyl dipropylthiocarbamate (EPTC), and tri-allate) on two well-characterized blackgrass (Alopecurus myosuroides) biotypes. Blackgrass is the predominant weed threatening winter wheat production in North-West Europe and the effective use of pre-emergent herbicides is important for preventing otherwise difficult-to-control blackgrass from establishing in agricultural fields. Using a sterile, agar-based system, we quantified the effects of multiple doses of flufenacet, EPTC, or tri-allate on plant physiology, including germination and early seedling growth, as well as the effects of a single dose on key biochemical pathways, specifically cuticular wax composition and fatty acid metabolism in biotypes exhibiting either non-target site herbicide resistance or complete sensitivity to all tested herbicides. Our data demonstrate that the three Group 15 pre-emergent herbicides alter cuticular wax composition and fatty acid profiles differently and that the resistant and herbicide-naïve biotypes show distinct responses to each herbicide. The GC-FID and GC-MS data from the different Group 15 pre-emergent herbicides are consistent with the observed differences in physiology and identify potential differences in how and where these herbicides act in these biotypes. Our findings provide novel molecular insights into the mechanisms of action of and tolerance to flufenacet, EPTC, or tri-allate in blackgrass.
A large cohort study (n = 591) on the impact of the presence or absence of the interthalamic adhesion: cognitive, neuroimaging, and genetic results
Authors: Vidal Julie P. , Gouarderes Alexa , Rabenantenaina Marie Stéphanie , Péran Patrice , Pariente Jérémie , Danet Lola , Barbeau Emmanuel J.
Published: September 2024

Both thalami can be connected by an Interthalamic Adhesion (IA). The extent of its presence varies among individuals and remains poorly understood. This study examines the IA’s prevalence, anatomical variations, genetic determinants, and cognitive associations. Data from 591 healthy subjects (25-35 years) from the Human Connectome Project were analyzed and grouped as monozygotic (MZ) twins, dizygotic (DZ) twins, non-twin siblings, and unrelated individuals. MRI was used to characterize the IA, while neuropsychological assessments and Freesurfer parcellations were used to assess cognition and anatomical differences between subjects with or without an IA. The IA was absent in 12.7% of subjects, more commonly in males (20.0%) than females (6.3%), with no significant differences in age, education, or cognition between those with and without an IA. IA absence was associated with increased cerebrospinal fluid volumes, enlarged third ventricles, and thinning in several cortical areas. Genetic analysis revealed a higher concordance of IA presence among MZ twins (96%) than in other groups, indicating a strong genetic influence. The remaining 4% discrepancy was observed in male pairs only. This study underscores the genetic basis of IA, highlighting sexual dimorphism and neuroanatomical differences associated with its absence, though it does not affect cognition in healthy individuals.
A climate and population dependent diffusion model forecasts the spread of Aedes Albopictus mosquitoes in Europe
Authors: Barman Sandra , Semenza Jan , Singh Pratik , Sjodin Henrik , Rocklov Joacim , Wallin Jonas
Published: September 2024

Vectors of Dengue, Chikungunya, Zika, and Yellow Fever are emerging in new areas, posing increasing public health risks. Aedes albopictus, a key vector for these diseases, is expanding its range beyond its tropical and subtropical origins, driven by suitable climate, population mobility, trade, and urbanization. Since its introduction to Europe, Ae. albopictus has rapidly spread and triggered recurrent outbreaks. Past model attempts have handled vector suitability and vector introduction as independent drivers. Here we develop a novel, highly predictive spatio-temporal vector diffusion model based on minimum temperature, median temperature, relative humidity and human population as predictors. The model predicts areas of presence or absence with an accuracy of 99% and 79% for new established vector populations. The model explains how short- and long-range spread of Ae. albopictus interacts with vector suitability. These results show that the expansion of Ae. albopictus in Europe is predictable and closely linked to climate suitability, and human population. The new model integrates in one simultaneous model framework the climate and mobility drivers, providing a better basis for anticipating future outbreaks in situations of dependent interacting co-drivers.
A megatransposon drives the adaptation ofThermoanaerobacter kivuito carbon monoxide
Authors: Hocq Rémi , Horvath Josef , Stumptner Maja , Thallinger Gerhard G. , Pflügl Stefan
Published: September 2024

Acetogens are promising industrial biocatalysts for upgrading syngas, a gas mixture containing CO, H2and CO2into fuels and chemicals. However, CO severely inhibits growth of many acetogens, often requiring extensive adaptation to enable efficient CO conversion (“carboxydotrophy”). Here, we adapted the thermophilic acetogenThermoanaerobacter kivuito use CO as sole carbon and energy source. Isolate CO-1 exhibited extremely rapid growth on CO and syngas (co-utilizing CO, H2and CO2) in batch and continuous cultures (µmax∼ 0.25 h−1). The carboxydotrophic phenotype was attributed to the mobilization of a CO-inducible megatransposon originating from the locus responsible for autotrophy inT. kivui. Transcriptomics illuminated the crucial role maintaining redox balance likely plays during carboxydotrophic growth. These novel insights were exploited to rationally engineerT. kivuito grow on CO. Collectively, our work elucidates a primary mechanism responsible for the acquisition of carboxydotrophy in homoacetogens and showcases how transposons can orchestrate evolution.