bluuebunny/crossref_metadata_2025 huggingface dataset:
Microglial MyD88-dependent pathways are regulated in a sex-specific manner in the context of HMGB1-induced anxiety
Authors: Rawls Ashleigh , Nyugen Dang , Dziabis Julia , Anbarci Dilara , Clark Madeline , Dzirasa Kafui , Bilbo Staci D.
Published: April 2024

Chronic stress is a significant risk factor for the development and recurrence of anxiety disorders. Chronic stress impacts the immune system, causing microglial functional alterations in the medial prefrontal cortex (mPFC), a brain region involved in the pathogenesis of anxiety. High mobility group box 1 protein (HMGB1) is an established modulator of neuronal firing and a potent pro-inflammatory stimulus released from neuronal and non-neuronal cells following stress. HMGB1, in the context of stress, acts as a danger-associated molecular pattern (DAMP), instigating robust proinflammatory responses throughout the brain, so much so that localized drug delivery of HMGB1 alters behavior in the absence of any other forms of stress, i.e., social isolation, or behavioral stress models. Few studies have investigated the molecular mechanisms that underlie HMGB1-associated behavioral effects in a cell-specific manner. The aim of this study is to investigate cellular and molecular mechanisms underlying HMGB1-induced behavioral dysfunction with regard to cell-type specificity and potential sex differences. Here, we report that both male and female mice exhibited anxiety-like behavior following increased HMGB1 in the mPFC as well as changes in microglial morphology. Interestingly, our results demonstrate that HMGB1-induced anxiety may be mediated by distinct microglial MyD88-dependent mechanisms in females compared to males. This study supports the hypothesis that MyD88 signaling in microglia may be a crucial mediator of the stress response in adult female mice.
Self-supervised Vision Transformers for image-to-image labeling: a BiaPy solution to the LightMyCells Challenge
Authors: Franco-Barranco Daniel , González-Marfil Aitor , Arganda-Carreras Ignacio
Published: April 2024

Fluorescence microscopy plays a crucial role in cellular analysis but is often hindered by phototoxicity and limited spectral channels. Label-free transmitted light microscopy presents an attractive alternative, yet recovering fluorescence images from such inputs remains difficult. In this work, we address the Cell Painting problem within the LightMyCells challenge at the International Symposium on Biomedical Imaging (ISBI) 2024, aiming to predict optimally focused fluorescence images from label-free transmitted light inputs. Leveraging advancements self-supervised Vision Transformers, our method overcomes the constraints of scarce annotated biomedical data and fluorescence microscopy’s drawbacks. Four specialized models, each targeting a different organelle, are pretrained in a self-supervised manner to enhance model generalization. Our method, integrated within the open-source BiaPy library, contributes to the advancement of image-to-image deep-learning techniques in cellular analysis, offering a promising solution for robust and accurate fluorescence image prediction from label-free transmitted light inputs. Code and documentation can be found athttps://github.com/danifranco/BiaPyand a custom tutorial to reproduce all results is available athttps://biapy.readthedocs.io/en/latest/tutorials/image-to-image/lightmycells.html.
Action Potential Threshold Variability for Different Electrostimulation Models and the Impact on Occupational Exposure Limit Values
Authors: Soyka Florian , Tarnaud Thomas , Alteköster Carsten , Schoeters Ruben , Plovie Tom , Joseph Wout , Tanghe Emmeric
Published: April 2024

Occupational exposure limit values (ELVs) for body internal electric fields can be derived from thresholds for action potential generation. These thresholds can be calculated with electrostimulation models. The spatially extended nonlinear node model (SENN) is often used to determine such thresholds. An important part of these models are the membrane channel dynamics describing the ionic transmembrane currents. This work shows how ELVs change significantly with different ion channel dynamics (up to a factor of 22). Furthermore, two more detailed double-cable models by Gaines et al. (MRG-Sensory and MRG-Motor) are also considered in this work. Thresholds calculated with the SENN model (with Frankenhaeuser-Huxley membrane channel dynamics) and the MRG models are compared for frequencies between 1 Hz and 100 kHz and temperatures between 22 °C and 37 °C. Results show that MRG thresholds are lower than SENN thresholds. In the context of occupational ELVs, using the double cable model would lead to approximately ten times lower limit values. Therefore, future exposure guidelines should take the influence of different electrostimulation models into account when deriving ELVs.

Highlights

Different membrane channel dynamics change derived exposure limit values by more than one order of magnitude.

Double-cable models result in a reduction of derived exposure limit values by one order of magnitude.

Lower temperatures reduce the action potential thresholds at frequencies below 300 Hz.
Pharmaco-resistant temporal lobe epilepsy gradually perturbs the cortex-wide excitation-inhibition balance
Authors: Xie Ke , Royer Jessica , Rodriguez-Cruces Raul , Horwood Linda , Ngo Alexander , Arafat Thaera , Auer Hans , Sahlas Ella , Chen Judy , Zhou Yigu , Valk Sofie L. , Hong Seok-Jun , Frauscher Birgit , Pana Raluca , Bernasconi Andrea , Bernasconi Neda , Concha Luis , Bernhardt Boris
Published: April 2024

Abstract

Excitation-inhibition (E/I) imbalance is theorized as a key mechanism in the pathophysiology of epilepsy, with a mounting body of previous research focusing on elucidating its cellular manifestations. However, there are limited studies into E/I imbalance at macroscale and its microcircuit-level mechanisms and clinical associations. In our current work, we computed the Hurst exponent—a previously validated index of the E/I ratio—from resting-state fMRI time series, and simulated microcircuit parameters using biophysical computational models. We found a broad reduction in the Hurst exponent in pharmaco-resistant temporal lobe epilepsy (TLE), indicative of a shift towards more excitable network dynamics. Connectome decoders pointed to temporolimbic and frontocentral areas as plausible network epicenters of E/I imbalance. Computational simulations further revealed that enhancing cortical excitability in patients likely reflected atypical increases in recurrent connection strength of local neuronal ensembles. Moreover, mixed cross-sectional and longitudinal analyses revealed heightened E/I elevation in patients with longer disease duration, more frequent electroclinical seizures and inter-ictal epileptic spikes, and worse cognitive functioning. Replicated in an independent dataset, our work provides compellingin-vivoevidence of a macroscale shift in E/I balance in TLE patients that undergoes progressive changes and underpins cognitive impairments, potentially informing treatment strategies targeting E/I mechanisms.
The genomic consequences and persistence of sociality in spiders
Authors: Ma Jilong , Bechsgaard Jesper , Aagaard Anne , Villesen Palle , Bilde Trine , Schierup Mikkel
Published: April 2024

In cooperatively breeding social animals, a few individuals account for all reproduction. In some taxa, sociality is accompanied by a transition from outcrossing to inbreeding, in concert, these traits act to reduce effective population size, potentially rendering transitions to sociality evolutionarily dead-ends. We addressed this hypothesis in a comparative genomic study in spiders, where sociality has evolved independently at least 23 times, but social species are recent and evolutionarily short-lived. We present genomic evidence for the evolutionary dead-end hypothesis in three independent transitions to sociality in the spider genusStegodyphus. We sequenced, assembled and annotated high-quality, chromosome-level reference genomes from three pairs of closely related social and subsocialStegodyphusspecies. Genome sizes range from 2.65 Gb to 3.32 Gb with high synteny, and we identify 10,065 single-copy orthologous genes. We timed the divergence between the social and subsocial species pairs to be from 1.3 to 1.8 million years. Social evolution in spiders involves a shift from outcrossing to inbreeding and from equal to female-biased sex ratio, causing severe reductions in effective population size and decreased efficacy of selection. Based on analyses of purifying selection, we determined whether transitions to sociality co-occurred with divergence. We show that transitions to sociality only had full effect on purifying selection at 119 kya (95CI: 71 kya -169 kya), 260 kya (95CI: 231 ky - 289 kya) and 279 kya (95CI: 230 kya - 332 kya) respectively, and follow remarkably similar convergent trajectories of progressive loss of diversity and shifts to an increasingly female-biased sex ratio. This almost deterministic genomic response to sociality may explain why social spider species do not persist. What causes species extinction is not clear, but could be either selfish meiotic drive that eliminates the production of males, or an inability to retain genome integrity in the face of extremely reduced efficacy of selection.
Unified somatic calling and machine learning-based classification enhance the discovery of clonal hematopoiesis of indeterminate potential
Authors: Tian Shulan , Jenkinson Garrett , Ferrer Alejandro , Yan Huihuang , Morales-Rosado Joel A. , Wang Kevin L. , Lasho Terra L. , Yan Benjamin B. , Baheti Saurabh , Olson Janet E. , Baughn Linda B. , Ding Wei , Slager Susan L. , Patnaik Mrinal S. , Lazaridis Konstantinos N. , Klee Eric W.
Published: April 2024

Clonal hematopoiesis (CH) of indeterminate potential (CHIP), driven by somatic mutations in leukemia-associated genes, confers increased risk of hematologic malignancies, cardiovascular disease and all-cause mortality. In blood of healthy individuals, small CH clones can expand over time to reach 2% variant allele frequency (VAF), the current threshold for CHIP. Nevertheless, reliable detection of low-VAF CHIP mutations is challenging, often relying on deep targeted sequencing. Here, we present UNISOM, a streamlined workflow for CHIP detection from whole-genome and whole-exome sequencing data that are underpowered, especially for low VAFs. UNISOM utilizes a meta-caller for variant detection, in couple with machine learning models which classify variants into CHIP, germline and artifact. In whole-exome data, UNISOM recovered nearly 80% of the CHIP mutations identified via deep targeted sequencing in the same cohort. Applied to whole-genome data from Mayo Clinic Biobank, it recapitulated the patterns previously established in much larger cohorts, including the most frequently mutated CHIP genes, predominant mutation types and signatures, as well as strong associations of CHIP with age and smoking status. Notably, 30% of the identified CHIP mutations had <5% VAFs, demonstrating its high sensitivity toward small mutant clones. This workflow is applicable to CHIP screening in population genomic studies.
Multi-scale drivers of daily flow intermittency in a regulated desert river
Authors: Gilbert Eliza. I. , Turner Thomas F. , Moses Melanie E. , Webster Alex J.
Published: April 2024

Fluvial ecosystems are vital for biodiversity and human welfare but face increasing threats from flow intermittency caused by climate change and other human activities. To better understand drivers of flow intermittency, we analyzed long-term and spatially explicit river drying data from the Rio Grande, a regulated river in the North American desert southwest that was historically perennial but is now persistently intermittent. We examined the spatial structure and influences of precipitation, temperature, in-channel infrastructure, and river discharge on flow intermittency using multivariate autoregressive state space (MARSS) models and 12 years of daily data. Our findings indicate that river diversion rates at dams and irrigation return flows significantly structure the spatial occurrence of flow intermittency, but factors (possibly geologic) at distances ≤ 7 kilometers (km) are more influential as predictors of drying. Controlling influences of temperature and precipitation were not detected at the reach level (∼154 km) but were significant at each of the subreach scales (n = 3) investigated. At all subreach scales, temperature’s effect size exceeds precipitation by 2.5 times and is the strongest predictor of drying. Overall, process variance decreased by 98% between our reach- and all subreach models, suggesting that scale-sensitive models have great potential to accurately inform environmental flow management strategies aimed at mitigating negative effects of climate change and water extraction.
QM/MM Free Energy Calculations of Long-Range Biological Protonation Dynamics by Adaptive and Focused Sampling
Authors: Pöverlein Maximilian C. , Hulm Andreas , Dietschreit Johannes C. B. , Kussmann Jörg , Ochsenfeld Christian , Kaila Ville R. I.
Published: April 2024

Water-mediated proton transfer reactions are central for catalytic processes in a wide range of biochemical systems, ranging from biological energy conversion to chemical transformations in the metabolism. Yet, the accurate computational treatment of such complex bio-chemical reactions is highly challenging and requires the application of multiscale methods, in particular hybrid quantum/classical (QM/MM) approaches combined with free energy simulations. Here we combine the unique exploration power of new advanced sampling methods with density functional theory (DFT)-based QM/MM free energy methods for multiscale simulations of long-range protonation dynamics in biological systems. In this regard, we show that combining multiple walkers/well-tempered metadynamics with an extended-system adaptive biasing force method (MWE), provides a powerful approach for exploration of water-mediated proton transfer reactions in complex biochemical systems. We compare and combine the MWE method also with QM/MM-umbrella sampling and explore the sampling of the free energy landscape with both geometric (linear combination of proton transfer distances) and physical (center of excess charge) reaction coordinates, and show how these affect the convergence of the potential of mean force (PMF) and the activation free energy. We find that the QM/MM-MWE method can efficiently explore both direct and water-mediated proton transfer pathways together with forward and reverse hole transfer mechanisms in the highly complex proton channel of respiratory Complex I, while the QM/MM-US approach shows a systematic convergence of selected long-range proton transfer pathways. In this regard, we show that the PMF along multiple proton transfer pathways is recovered by combining the strengths of both approaches in a QM/MM-MWE/focused US (FUS) scheme, and revealing new mechanistic insight into the proton transfer principles of Complex I. Our findings provide a promising basis for the quantitative multi-scale simulations of long-range proton transfer reactions in biological systems.
Benchmarking tools for transcription factor prioritization
Authors: Santana Leonor Schubert , Reyes Alejandro , Hoersch Sebastian , Ferrero Enrico , Kolter Christian , Gaulis Swann , Steinhauser Sebastian
Published: April 2024

Spatiotemporal regulation of gene expression is controlled by transcription factor (TF) binding to regulatory elements, resulting in a plethora of cell types and cell states from the same genetic information. Due to the importance of regulatory elements, various sequencing methods have been developed to localise them in genomes, for example using ChIP-seq profiling of the histone mark H3K27ac that marks active regulatory regions. Moreover, multiple tools have been developed to predict TF binding to these regulatory elements based on DNA sequence. As altered gene expression is a hallmark of disease phenotypes, identifying TFs driving such gene expression programs is critical for the identification of novel drug targets.

In this study, we curated 84 chromatin profiling experiments (H3K27ac ChIP-seq) where TFs were perturbed through e.g., genetic knockout or overexpression. We ran nine published tools to prioritize TFs using these real-world data sets and evaluated the performance of the methods in identifying the perturbed TFs. This allowed the nomination of three frontrunner tools, namely RcisTarget, MEIRLOP and monaLisa. Our analyses revealed opportunities and commonalities of tools that will help to guide further improvements and developments in the field.
Disrupting USP39 deubiquitinase function impairs the survival and migration of multiple myeloma cells through ZEB1 degradation
Authors: Sirera Jessy , Sarlak Saharnaz , Teisseire Manon , Carminati Alexandrine , Savy Coline , Nicolini Victoria J , Brest Patrick , Juel Thierry , Bontoux Christophe , Deckert Marcel , Ohanna Mickael , Giuliano Sandy , Dufies Maeva , Pages Gilles , Luciano Frederic
Published: April 2024

Rationale

Multiple Myeloma (MM) stands as the second most common hematological malignancy characterized by the accumulation of monoclonal plasmocytes within the bone marrow. Despite the introduction of proteasome inhibitors, immunomodulatory agents and CD38-targeting antibodies which have extended survival rates, the disease remains incurable for most patients due to the emergence of resistant clones and frequent relapses. The efficacy of the proteasome inhibitor bortezomib (BTZ) in MM treatment underscores the critical role of the ubiquitin proteasome system (UPS) in this cancer. Deubiquitinases (DUBs), a class of enzymes governing the stability, interactions or localization of cellular proteins by removing ubiquitin modifications, have emerged as promising therapeutic targets across various cancers, including MM.

Methods

Through an exhaustive loss-of-function approach, we have identified for the first time USP39 DUB as a pivotal survival determinant for MM cells.

Results

Our analysis reveals a direct correlation between heightened USP39 mRNA levels and shorter survival in MM patients. Additionally, robust USP39 protein expression is observed in MM patient plasmocytes compared to healthy counterparts. Knockdown of Usp39 not only impedes clonogenic capabilities, but also induces apoptosis, triggers cell cycle arrest and overcomes BTZ resistance. Complementary gain-of-function assays, further elucidate how USP39, by stabilizing the transcription factor ZEB1, enhances the trans-migratory potential of MM cells.

Conclusions

In summary, our findings underscores the pivotal role of the deubiquitinase USP39, suggesting that targeting the USP39/ZEB1 axis hold promise as a prospective diagnostic marker and therapeutic target in MM.
Domainator, a flexible software suite for domain-based annotation and neighborhood analysis, identifies proteins involved in antiviral systems
Authors: Johnson Sean R , Weigele Peter , Fomenkov Alexey , Ge Andrew , Vincze Anna , Roberts Richard J. , Sun Zhiyi
Published: April 2024

The availability of large databases of biological sequences presents an opportunity for in-depth exploration of gene diversity and function. Bacterial defense systems are a rich source of diverse, but difficult to annotate genes with biotechnological applications. In this work, we present Domainator, a flexible and modular software suite for domain-based gene neighborhood and protein search, extraction, and clustering. We demonstrate the utility of Domainator through three examples related to bacterial defense systems. First, we cluster CRISPR-associated Rossman fold (CARF) containing proteins with difficult to annotate effector domains, classifying most of them as likely transcriptional regulators and a subset as likely RNAses. Second, we extract and cluster P4-like phage satellite defense hotspots and identify an abundant system related to Lamassu phage defense systems. Third, we integrate a protein language model into Domainator and use it to identify restriction enzymes with low homology to known reference sequences, validating the activity of one example in-vitro. Domainator is made available as an open-source package with detailed documentation and usage examples.
Microdiversity in marine pelagic ammonia-oxidizing archaeal populations
Authors: Suárez-Moo Pablo , Haro-Moreno Jose M. , Rodriguez-Valera Francisco
Published: April 2024

The knowledge of the different population-level processes operating within a species, and the genetic variability of the individual prokaryotic genomes, is key to understanding the adaptability of microbial populations. Here, we characterized the flexible genome of ammonia-oxidizing archaeal (AOA) populations using a metagenomic recruitment approach and long-read (PacBio HiFi) metagenomic sequencing. In the lower photic zone of the western Mediterranean Sea, the genomesNitrosopelagicus brevisCN25 andNitrosopumilus catalinensisSPOT1 had the highest recruitment values among AOA. These two complete genomes were used to analyze the diversity of flexible genes (variable from strain to strain) by analyzing the long-reads located within the flexible genomic islands (fGIs) identified through their under-recruitment. Both AOA genomes had a large fGI involved in the glycosylation of exposed structures, highly variable and rich in glycosyltransferases.N. brevishad two fGIs related to the transport of phosphorus and ammonium respectively.N. catalinensishad fGIs involved in phosphorus transportation and metal uptake. A flexible genomic island (fGI5) previously reported as “unassigned function” inN. breviscould be associated with defense. These findings demonstrate that the microdiversity of marine microbe populations, including AOA, can be effectively characterized using an approach that incorporates new third-generation sequencing metagenomics.
The effect of a harmful algal bloom (Karenia selliformis) on the benthic invertebrate community and the sea otter (Enhydra lutris) diet in eastern Hokkaido
Authors: Johnstone Jackson , Suzuki Ippei , Konno Natsuki , Murayama Kyohei , Ochiai Satsuki , Davis Randall , Mitani Yoko
Published: April 2024

In recent decades, the locally extinct sea otter (Enhydra lutris lutris) has been recolonizing the coast of eastern Hokkaido. Their diet includes benthic invertebrates such as bivalves, sea urchins, snails, and chitons. In the fall of 2021, a harmful algal bloom (HAB) ofKarenia selliformisoccurred across Hokkaido’s northern and eastern coasts, leading to a massive mortality of sea urchins. This dinoflagellate produces a neurotoxin (gymnodimine) implicated in shellfish poisoning. To determine the effect of the HAB on the marine community, we conducted benthic surveys using SCUBA and visually monitored the prey items of the sea otters in the affected area from 2020 to 2023. Following the HAB, we observed an 82% decrease in benthic sea urchin density (number m2), leading to their complete absence from the diet of sea otters. Conversely, bivalve density increased six-fold, accompanied by a nearly two-fold rise in their percentage in the sea otters’ diet. Minimal changes were observed in the density of chitons and snails, with no significant alteration in the sea otters’ diet. Despite these changes, the impact of the HAB on otters’ dietary preferences was temporary, as the percentage of dietary sea urchins began recovering one year later. Sea otters augmented their diet with bivalves to compensate for the reduced availability of sea urchins during the HAB with no apparent effects on the number of sea otters or their health. Our results highlight the adaptability of sea otters to adjust their diet according to prey availability.
Single-cell allelic transcriptomic analysis unravels intratumoral gene expression heterogeneity linked to TNBC pathogenesis
Authors: Ayyamperumal Parichitran , Naik Hemant Chandru , Naskar Amlan Jyoti , Gayen Srimonta
Published: April 2024

Triple-negative breast cancer (TNBC) is the most aggressive subclass of breast cancer, which exhibits high intratumoral heterogeneity. Intratumoral heterogeneity often drives the evolution of drug resistance towards tumour therapy in TNBC. However, the contributing factors and mechanisms behind the intratumoral heterogeneity in TNBC remain poorly understood. It has been implicated that copy number variations (CNVs) often create allelic imbalance and thereby contribute to intratumoral gene expression heterogeneity. However, other processes, such as epigenetic and transcriptional processes, can also contribute to allelic expression heterogeneity in tumour cells. Here, we have investigated how allelic expression heterogeneity contributes to intratumoral heterogeneity in TNBC by performing genome-wide allelic gene expression analysis, excluding most of the CNVs, using single-cell RNA-sequencing datasets. We found widespread monoallelic expression of many genes across different cell types of TNBC. Notably, we found a profound heterogeneity of allelic expression patterns of many genes within TNBC epithelial cells, creating distinct subpopulations of epithelial cells. Importantly, we show that these genes with allelic expression pattern heterogeneity between subpopulations are linked to TNBC immune-surveillance and drug-resistance related pathways, thereby overall shaping the pathogenesis outcomes. Finally, we show that the promoter regions of these genes with profound monoallelic expression are often hypermethylated in TNBC patients. Altogether, our findings reveal that heterogeneous allelic expression patterns contribute to intratumoral heterogeneity and are linked to TNBC pathogenesis.
Single-nucleus and spatial transcriptomic profiling of human temporal cortex and white matter reveals novel associations with AD pathology
Authors: Gaur Pallavi , Bryois Julien , Calini Daniela , Foo Lynette , Hoozemans Jeroen J M , Malhotra Dheeraj , Menon Vilas
Published: April 2024

Alzheimer’s disease (AD) is a neurodegenerative disorder with complex pathological manifestations and is the leading cause of cognitive decline and dementia in elderly individuals. A major goal in AD research is to identify new therapeutic pathways by studying the molecular and cellular changes in the disease, either downstream or upstream of the pathological hallmarks. In this study, we present a comprehensive investigation of cellular heterogeneity from the temporal cortex region of 40 individuals, comprising healthy donors and individuals with differing tau and amyloid burden. Using single-nucleus transcriptome analysis of 430,271 nuclei from both gray and white matter of these individuals, we identified cell type-specific subclusters in both neuronal and glial cell types with varying degrees of association with AD pathology. In particular, these associations are present in layer specific glutamatergic (excitatory) neuronal types, along with GABAergic (inhibitory) neurons and glial subtypes. These associations were observed in early as well as late pathological progression. We extended this analysis by performing multiplexed in situ hybridization using the CARTANA platform, capturing 155 genes in 13 individuals with varying levels of tau pathology. By modeling the spatial distribution of these genes and their associations with the pathology, we not only replicated key findings from our snRNA data analysis, but also identified a set of cell type-specific genes that show selective enrichment or depletion near pathological inclusions. Together, our findings allow us to prioritize specific cell types and pathways for targeted interventions at various stages of pathological progression in AD.
Three pollen QTLs are sufficient to partially break stylar unilateral incompatibility ofSolanum pennellii
Authors: Ma Wenchun , Li Yumei , He Mingxia , Baldwin Ian T. , Guo Han
Published: April 2024

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In tomato clade, bothself-incompatibility(S-) locus-dependent and –independent mechanisms are present in unilateral incompatibility (UI). Several stylar UI factors mediatingS-locus-independent mechanism have been gradually uncovered, however, related pollen UI (pui) factors still await more studies.

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Quantitative trait loci (QTL) mapping, comparative transcriptomics and introgression lines (ILs) /inbred backcross lines (BILs)-based functional analysis were applied for identification and functional validation ofpuiQTLs between self-compatible (SC)Solanum lycopersicumand SCS. pennelliiLA0716.

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In addition to the reportedpui10.1(SpFPS2), twopuiQTLs (pui6.2andpui12.1) were identified. Pollen tubes of cultivated tomatoes introgressed with threepuiloci could partially break the stylar UI response in LA0716 styles. Furthermore, a conserved function ofpui12.1was found in the styles of SCS.habrochaitesLA0407 and SCS.chmielewskiiLA1028. Three candidate genes linked topui6.2andpui12.1were screened for further analysis.

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This study reveals a potential synergistic relationship of the threepuiQTLs in breaking stylar UI response of LA0716 and will advance our understanding of the genetic mechanisms underlying UI in the tomato clade.

Highlight

Our data revealed that breaking the stylar unilateral incompatibility ofSolanum pennelliiLA0716 requires not only the reported pollen UI (pui) factor but also another twopuiQTLs identified in this study.
Structural basis for molecular assembly of fucoxanthin chlorophylla/c-binding proteins in a diatom photosystem I supercomplex
Authors: Kato Koji , Nakajima Yoshiki , Xing Jian , Kumazawa Minoru , Ogawa Haruya , Shen Jian-Ren , Ifuku Kentaro , Nagao Ryo
Published: April 2024

Photosynthetic organisms exhibit remarkable diversity in their light-harvesting complexes (LHCs). LHCs are associated with photosystem I (PSI), forming a PSI-LHCI supercomplex. The number of LHCI subunits, along with their protein sequences and pigment compositions, has been found to differ greatly among the PSI-LHCI structures. However, the mechanisms by which LHCIs recognize their specific binding sites within the PSI core remain unclear. In this study, we determined the cryo-electron microscopy structure of a PSI supercomplex incorporating fucoxanthin chlorophylla/c-binding proteins (FCPs), designated as PSI-FCPI, isolated from the diatomThalassiosira pseudonanaCCMP1335. Structural analysis of PSI-FCPI revealed five FCPI subunits associated with a PSI monomer; these subunits were identified as RedCAP, Lhcr3, Lhcq10, Lhcf10, and Lhcq8. Through structural and sequence analyses, we identified specific protein-protein interactions at the interfaces between FCPI and PSI subunits, as well as among FCPI subunits themselves. Comparative structural analyses of PSI-FCPI supercomplexes, combined with phylogenetic analysis of FCPs fromT. pseudonanaand the diatomChaetoceros gracilis, underscore the evolutionary conservation of protein motifs crucial for the selective binding of individual FCPI subunits. These findings provide significant insights into the molecular mechanisms underlying the assembly and selective binding of FCPIs in diatoms.
Menopause status- and sex-related differences in age associations with spatial context memory and white matter microstructure at midlife
Authors: Lissaman Rikki , Rajagopal Sricharana , Kearley Julia , Pasvanis Stamatoula , Rajah M. Natasha
Published: April 2024

Decline in spatial context memory emerges in midlife, the time when most females transition from pre-to post-menopause. Recent evidence suggests that, among post-menopausal females, advanced age is associated with functional brain alterations and lower spatial context memory. However, it is unknown whether similar effects are evident for white matter (WM) and, moreover, whether such effects contribute to sex differences at midlife. To address this, we conducted a study on 96 cognitively unimpaired middle-aged adults (30 males, 32 pre-menopausal females, 34 post-menopausal females). Spatial context memory was assessed using a face-location memory paradigm, while WM microstructure was assessed using diffusion tensor imaging. Behaviorally, advanced age was associated with lower spatial context memory in post-menopausal females but not pre-menopausal females or males. Additionally, advanced age was associated with microstructural variability in predominantly frontal WM (e.g., anterior corona radiata, genu of corpus callosum), which was related to lower spatial context memory among post-menopausal females. Our findings suggest that post-menopausal status enhances vulnerability to age effects on the brain’s WM and episodic memory.
Neosynthesized polarized and non-polarized plasma membrane cargoes follow distinct trafficking routes inAspergillus nidulans
Authors: Sagia Georgia Maria , Georgiou Xenia , Chamilos George , Diallinas George , Dimou Sofia
Published: April 2024

Membrane proteins are sorted to the plasma membrane (PM) via Golgi-dependent trafficking. However, our recent studies challenged the essentiality of Golgi in the biogenesis of specific transporters. Here, we investigate the trafficking mechanisms of membrane proteins by following the localization of the polarized R-SNARE SynA versus the non-polarized transporter UapA, synchronously co-expressed in wild-type or isogenic genetic backgrounds repressible for conventional cargo secretion. In wild-type, the two cargoes dynamically label distinct secretory compartments, highlighted by the finding that, unlike SynA, UapA does not colocalize with the late-Golgi. In line with early partitioning into distinct secretory carriers, the two cargoes collapse in distinct ERES in a sec31ts background. Trafficking via distinct cargo-specific carriers is further supported by showing that repression of proteins essential for conventional cargo secretion does not affect UapA trafficking, while blocking SynA secretion. Overall, this work establishes the existence of distinct, cargo-dependent, trafficking mechanisms, initiating at ERES and being differently dependent on Golgi and SNARE interactions.
Exploring differences between depression and bipolar disorder through the urinary proteome
Authors: Liu Yuqing , Li Zhiyu , Dong Yeqing , Yang Jian , Li Meijuan , Zhou Jingjing , Gao Ying , Li Jie , Wang Gang , Gao Youhe
Published: April 2024

How to differentiate the diagnosis of depression and bipolar disorder has always been an important problem that needs to be solved urgently in clinical practice. In this study, from the perspective of urine proteomics, urine samples of similar age were collected from two hospitals to investigate the candidate biomarkers for differentiating the diagnosis of depression and bipolar disorder using both group analysis and one-to-many analysis(1 patient: many control samples). The experimental results of the paired group analysis showed that 108 differential proteins were identified in the depressed group compared to the bipolar group under strict screening conditions with screening criteria of FC ≥ 2 or ≤ 0.5 and a two-tailed unpaired t-test of P < 0.01, with an average of 3.7 randomly generated differential proteins, and a confidence level of 96.6 % for the correlation between these proteins and the disease difference. In the one-to-many analysis, 24 differential proteins were co-identified by the samples of 13 depressed patients, 16 of which showed a completely consistent trend of expression changes in all depressed patients studied, and 6 of which were associated with immunoglobulins; 41 differential proteins were co-identified by the samples of 12 depressed patients out of 13, and 19 of which showed a completely consistent trend of expression change in the These results reflect the strong consistency of differential proteins between the two groups of patients. 12 or more samples from depressed patients were enriched for differential proteins related to multiple biological processes and signaling pathways associated with the immune system, which is consistent with previous studies: immune mechanisms may be one of the pathogenetic mechanisms of major depression and that drugs with major immune targets can improve depressive symptoms. In the future, it may be possible to observe the immune status of patients with depression to provide direction and basis for the precise treatment of depression. The results of this paper show that urine proteomics can differentiate between depression and bipolar disorder, suggest possible mechanisms and potential targets for the treatment of depression and bipolar disorder, and provide a tool for future differential diagnosis and precision treatment of the diseases.
Efficient coding in biophysically realistic excitatory-inhibitory spiking networks
Authors: Koren Veronika , Malerba Simone Blanco , Schwalger Tilo , Panzeri Stefano
Published: April 2024

The principle of efficient coding posits that sensory cortical networks are designed to encode maximal sensory information with minimal metabolic cost. Despite the major influence of efficient coding in neuroscience, it has remained unclear whether fundamental empirical properties of neural network activity can be explained solely based on this normative principle. Here, we derive the structural, coding, and biophysical properties of excitatory-inhibitory recurrent networks of spiking neurons that emerge directly from imposing that the network minimizes an instantaneous loss function and a time-averaged performance measure enacting efficient coding. We assumed that the network encodes a number of independent stimulus features varying with a time scale equal to the membrane time constant of excitatory and inhibitory neurons. The optimal network has biologically-plausible biophysical features, including realistic integrate-and-fire spiking dynamics, spike-triggered adaptation, and a non-specific excitatory external input. The excitatory-inhibitory recurrent connectivity between neurons with similar stimulus tuning implements feature-specific competition, similar to that recently found in visual cortex. Networks with unstructured connectivity cannot reach comparable levels of coding efficiency. The optimal ratio of excitatory vs inhibitory neurons and the ratio of mean inhibitory-to-inhibitory vs excitatory-to-inhibitory connectivity are comparable to those of cortical sensory networks. The efficient network solution exhibits an instantaneous balance between excitation and inhibition. The network can perform efficient coding even when external stimuli vary over multiple time scales. Together, these results suggest that key properties of biological neural networks may be accounted for by efficient coding.
A latent variable model for evaluating mutual exclusivity and co-occurrence between driver mutations in cancer
Authors: Shuaibi Ahmed , Chitra Uthsav , Raphael Benjamin J.
Published: April 2024

A key challenge in cancer genomics is understanding the functional relationships and dependencies between combinations of somatic mutations that drive cancer development. Suchdrivermutations frequently exhibit patterns ofmutual exclusivityorco-occurrenceacross tumors, and many methods have been developed to identify such dependency patterns from bulk DNA sequencing data of a cohort of patients. However, while mutual exclusivity and co-occurrence are described as properties of driver mutations, existing methods do not explicitly disentangle functional, driver mutations from neutral,passengermutations. In particular, nearly all existing methods evaluate mutual exclusivity or co-occurrence at the gene level, marking a gene as mutated if any mutation – driver or passenger – is present. Since some genes have a large number of passenger mutations, existing methods either restrict their analyses to a small subset of suspected driver genes – limiting their ability to identify novel dependencies – or make spurious inferences of mutual exclusivity and co-occurrence involving genes with many passenger mutations. We introduce DIALECT, an algorithm to identify dependencies between pairs ofdrivermutations from somatic mutation counts. We derive a latent variable mixture model for drivers and passengers that combines existing probabilistic models of passenger mutation rates with a latent variable describing the unknown status of a mutation as a driver or passenger. We use an expectation maximization (EM) algorithm to estimate the parameters of our model, including the rates of mutually exclusivity and co-occurrence between drivers. We demonstrate that DIALECT more accurately infers mutual exclusivity and co-occurrence between driver mutations compared to existing methods on both simulated mutation data and somatic mutation data from 5 cancer types in The Cancer Genome Atlas (TCGA).
Alterations in Gut Archaea Composition and Their Bacterial Interactions Linked to Hypertension
Authors: Yuan Wen , Chen Yihang , Liang Lirong , Fan Luyun , Chi Hongjie , Wang Xiucheng , Li Jing , Zhang Xun , Feng Lin , Dong Ying , Su Pixiong , Zhong Jiuchang , Cai Jun , Liu Xiaoyan
Published: April 2024

Alterations in the gut microbiota have been linked to hypertension, with the role of archaea, despite being stable constituents, remaining largely unexplored. Shotgun metagenomic analyses of fecal samples were performed on 341 participants from 3 cohorts: discovery cohort (88 individuals), validation cohort 1 (175 individuals), and validation cohort 2 (78 individuals). Principal Coordinates Analysis (PCoA) based on Bray-Curtis distances revealed significant alterations in the composition of enteric archaea between control individuals and hypertensive patients (P < 0.05). Hypertensive groups showed reduced abundances of halophilic archaea (Halorhabdus, Halovivax, and Halorubrum_lipolyticum) and methanogenic archaea (Methanomassiliicoccus and Candidatus_Methanomassiliicoccus_intestinalis). Eleven archaea species, depleted in fecal samples from hypertensive patients, distinguished them from control individuals, with areas under the receiver operating characteristic curve of 0.85, 0.79, and 0.91 in the discovery, validation cohort 1, and validation cohort 2, respectively. Significant correlations were observed between these archaea and clinical data across cohorts. Additionally, a significant positive correlation in richness between gut bacteria and archaea suggests a close cross-kingdom synergy within the microbiome. This study highlights significant shifts in the archaeal populations of hypertensive patients, underscoring the potential of archaeal biomarkers in hypertension diagnosis and suggesting avenues for future therapeutic research.
Secondhand tobacco exposure assessed using urinary cotinine among 10 years children in Japan: A 11-years repeated cross-sectional study
Authors: Tamada Yudai , Takeuchi Kenji , Tabuchi Takahiro
Published: April 2024

Introduction

The emergence of heated tobacco products (HTPs) has complicated the issue of secondhand tobacco (SHT) exposure. We investigated the trend in SHT exposure in schoolchildren and assessed whether SHT exposure depends on household tobacco use status.

Methods

This repeated cross-sectional study from 2011 to 2021 (15,927 subjects were eligible) was based on data from an annual survey of fourth-grade students (aged 10 years) in Kumagaya City, located in Kanto Region, Japan. Data were collected by questionnaire, and urinary cotinine levels used as an objective indicator of SHT exposure, such as secondhand exposure to combustible cigarette (CC) smoke and HTP-generated aerosols.

Results

SHT exposure has decreased by about one-quarter over the 11-year period, from 18.6% in 2011 to 5.3% in 2021. Regarding household tobacco product use, 68.1% did not use tobacco products, 16.5% were CC-only users, 12.3% were HTP-only users, and 3.0% were both CC and HTP users. The prevalence of SHT exposure among participants was significantly higher compared to participants with no tobacco product users in the household, in the following order: both CC and HTP users, only CC users, and only HTP user.

Conclusions

While the prevalence of SHT exposure showed a decreasing trend during 2011-2021, the prevalence of SHT exposure was higher in schoolchildren from families with tobacco product users than in schoolchildren from families without tobacco product users, regardless of the type of tobacco product.
A dynamic compositional equilibrium governs mRNA recognition by eIF3
Authors: Ide Nicholas A. , Gentry Riley C , Rudbach Margaret A , Yoo Kyungyoon , Velez Paloma K , Communale Victoria M , Hartwick Erik W , Kinz-Thompson Colin D , Gonzalez Ruben L , Aitken Colin Echeverría
Published: April 2024

Eukaryotic translation initiation factor (eIF) 3 is a multi-subunit protein complex that binds both ribosomes and messenger RNAs (mRNAs) to drive a diverse set of mechanistic steps during translation of an mRNA into the protein it encodes. And yet, a unifying framework explaining how eIF3 performs these numerous activities is lacking. Using single-molecule light scattering microscopy, we demonstrate that Saccharomyces cerevisiae eIF3 is in dynamic exchange between the full complex, subcomplexes, and subunits. By extending our microscopy approach to an in vitro reconstituted eIF3 and complementing it with biochemical assays, we define the subspecies comprising this dynamic compositional equilibrium and show that mRNA binding by eIF3 is not driven by the full complex but instead by the eIF3a subunit within eIF3a-containing subcomplexes. Our findings provide a mechanistic model for the role of eIF3 in mRNA recruitment and establish a mechanistic framework for explaining and investigating the other activities of eIF3.
Neural networks representing temporal expectation in mice
Authors: Wendlandt T. Adrian , Wenk Patricia , Henschke Julia U. , Michalek Annika , Noesselt Toemme , Pakan Janelle M.P. , Budinger Eike
Published: April 2024

The ability to attend to specific moments in time is crucial for survival across species facilitating perception and motor performance by leveraging prior temporal knowledge for predictive processing. Despite its importance, the neural mechanisms underlying the utilization of macro-scale and meso-scale neural resources during temporal processing and their relationship to behavioural strategies and motor responses remain largely unexplored. To investigate the capacity for predictive temporal structure of multisensory stimuli to optimize motor behaviour, we established a behavioural paradigm, in which mice were trained to an auditory-cue and visual-target presented at expected or unexpected temporal delays. Using a combination of stimulus-evoked and resting-state functional magnetic resonance imaging, we examined task-related evoked activity in brain-wide networks and found that that the formation of temporal expectations relying on accumulated sensory information and combined multisensory input involves plasticity across large macro-scale cortical networks comprised of primary sensory systems, sensory association areas including posterior parietal cortex, retrosplenial cortex, prefrontal top-down executive control centres of the brain, as well as hippocampal networks. Additionally, employing in vivo two-photon calcium imaging, we explored local single-cell dynamics within the posterior parietal cortex during this task and found that temporal expectation could be decoded directly from neuronal activity within this brain region. Overall, our study provides insights into the neural correlates underlying the formation of multisensory temporal expectations in the mouse brain and highlights the recruitment of neural resources across temporally-driven statistical learning processes.