bluuebunny/crossref_metadata_2025_split huggingface dataset:
MicroRNA-218 instructs proper assembly of hippocampal networks
Authors: Taylor Seth R. , Kobayashi Mariko , Vilella Antonietta , Tiwari Durgesh , Zolboot Norjin , Hartzell Andrea , Girgiss Carol , Abaci Yusuf , De Sanctis Claudia , Bellenchi Gian Carlo , Darnell Robert B. , Gross Christina , Zoli Michele , Berg Darwin K. , Lippi Giordano 
Published: August 2022

ABSTRACTThe assembly of the mammalian brain is orchestrated by temporally coordinated waves of gene expression. A key aspect of this developmental program is mediated at the post-transcriptional level by microRNAs (miRNAs). Deletion of neuronal enriched miRNAs induces strong developmental phenotypes, and multiple reports have found altered levels of miRNAs in patients with neurodevelopmental disorders. However, cellular and molecular mechanisms used by miRNAs to instruct proper brain development remain largely unexplored.Here, through multiple screens, we identified miR-218 as a critical regulator of hippocampal assembly in mice. MiR-218 is highly expressed in the hippocampus and enriched in both excitatory principal neurons and GABAergic inhibitory interneurons. Transient inhibition of miR-218 in early life results in an adult brain with heightened network activity and a predisposition to seizures. We used RNA-seq and FACS-seq (fluorescence-activated cell sorting followed by RNA-seq) to identify global and cell type-specific changes in gene expression in the absence of miR-218 and narrow down which altered developmental processes would lead to long-term network instability. We find that miR-218 inhibition results in the disruption of early depolarizing GABAergic signaling, structural defects in dendritic spines, and altered intrinsic membrane excitability. Finally, conditional knockout of miR-218 in interneurons, but not pyramidal neurons is sufficient to recapitulate the effects on long-term stability. Taken together, the data suggest that miR-218 orchestrates hippocampal network assembly to produce a stable network in the adult, primarily by regulating interneuron function in early postnatal life.
Sex separation unveils the functional plasticity of the vomeronasal organ in rabbits
Authors: Villamayor PR , Gullón J , Quintela L , Sánchez-Quinteiro P , Martínez P , Robledo D 
Published: August 2022

ABSTRACTBackgroundChemosensory cues are vital for social and sexual behaviours and are primarily detected and processed by the vomeronasal system (VNS), whose plastic capacity has been investigated in mice. However, studying chemosensory plasticity outside of laboratory conditions may give a more realistic picture of how the VNS adapts to a changing environment. Rabbits are a well-described model of chemocommunication since the discovery of the rabbit mammary pheromone and their vomeronasal organ (VNO) transcriptome was recently characterized, a first step to further study plasticity-mediated transcriptional changes. In this study, we assess the plastic capacity of the rabbit male and female VNO under sex-separation vs sex-combined scenarios, including adults and juveniles, to determine whether the rabbit VNO is plastic and, if so, whether such plasticity is already established at early stages of life.ResultsFirst, we characterized the number of differentially expressed genes (DEGs) between the VNO of rabbit male and female under sex-separation and compared it to sex-combined individuals, both in adults and juveniles, finding that differences between male and female were larger in a sex-separated scenario. Secondly, we analyzed the number of DEGs between sex-separated and sex-combined scenarios, both in males and females. In adults, both sexes showed a high number of DEGs while in juveniles only females showed differences. Additionally, the vomeronasal receptor genes were strikingly down-regulated in sex-separated adult females, whereas in juveniles up-regulation was shown for the same condition, suggesting a role of VRs in puberty onset. Finally, we described the environment-modulated plastic capacity of genes involved in reproduction, immunity and VNO functional activity, including G-protein coupled receptors.ConclusionsOur results show that sex-separation induces sex- and stage- specific gene expression differences in the VNO of male and female rabbit, both in adults and juveniles. These results bring out for the first time the plastic capacity of the rabbit VNO, supporting its functional adaptation to specifically respond to a continuous changing environment. Finally, species-specific differences and individual variability should always be considered in VNO studies and overall chemocommunication research.
Doomed by popularity: The broad use of the Pm8 resistance gene in wheat resulted in hypermutation of the AvrPm8 gene in the powdery mildew pathogen
Authors: Kunz Lukas , Sotiropoulos Alexandros G. , Graf Johannes , Razavi Mohammad , Müller Marion C. , Keller Beat 
Published: August 2022

SummaryThe Pm8 resistance gene against the powdery mildew disease has been introgressed from rye into wheat as part of a large 1BL.1RS chromosomal translocation. Due to its high agronomic value, this translocation has seen continuous global use since the 1960’s on large growth areas, even after Pm8 resistance was overcome. This allows studying the effect of long and widespread resistance gene use on a pathogen population.Using genome wide association studies in a global population of wheat mildew isolates, we identified the avirulence effector AvrPm8 specifically recognized by Pm8.Haplovariant mining in the global population revealed 17 virulent haplotypes of the AvrPm8 gene that grouped into two categories. The first one from geographically diverse regions comprised two single amino acid polymorphisms at the same position in the AvrPm8 protein, which we confirmed to be crucial for recognition by Pm8. The second category consisted of numerous destructive mutations to the AvrPm8 open reading frame.Most individual gain-of-virulence mutations were found in geographically restricted regions, indicating they occurred recently as a consequence of the frequent Pm8 use. We conclude that both standing genetic variation as well as locally occurring new mutations contributed to the global breakdown of the Pm8 resistance gene introgression.
Combining phylogeny and coevolution improves the inference of interaction partners among paralogous proteins
Authors: Gandarilla-Pérez Carlos A. , Pinilla Sergio , Bitbol Anne-Florence , Weigt Martin 
Published: August 2022

AbstractPredicting protein-protein interactions from sequences is an important goal of computational biology. Various sources of information can be used to this end. Starting from the sequences of two interacting protein families, one can use phylogeny or residue coevolution to infer which paralogs are specific interaction partners within each species. We show that these two signals can be combined to improve the performance of the inference of interaction partners among paralogs. For this, we first align the sequence-similarity graphs of the two families through simulated annealing, yielding a robust partial pairing. We next use this partial pairing to seed a coevolution-based iterative pairing algorithm. This combined method improves performance over either separate method. The improvement obtained is striking in the difficult cases where the average number of paralogs per species is large or where the total number of sequences is modest.Author summaryWhen two protein families interact, their sequences feature statistical dependencies. First, interacting proteins tend to share a common evolutionary history. Second, maintaining structure and interactions through the course of evolution yields coevolution, detectable via correlations in the amino-acid usage at contacting sites. Both signals can be used to computationally predict which proteins are specific interaction partners among the paralogs of two interacting protein families, starting just from their sequences. We show that combining them improves the performance of interaction partner inference, especially when the average number of potential partners is large and when the total data set size is modest. The resulting paired multiple-sequence alignments might be used as input to machine-learning algorithms to improve protein-complex structure prediction, as well as to understand interaction specificity in signaling pathways.
Increasing quantitation in spatial single-cell metabolomics by using fluorescence as ground truth
Authors: Molenaar Martijn R. , Shahraz Mohammed , Delafiori Jeany , Eisenbarth Andreas , Ekelöf Måns , Rappez Luca , Alexandrov Theodore 
Published: August 2022

AbstractImaging mass spectrometry (MS) is becoming increasingly applied for single-cell analyses. Multiple methods for imaging MS-based single-cell metabolomics were proposed, including our recent method SpaceM. An important step in imaging MS-based single-cell metabolomics is the assignment of MS intensities from individual pixels to single cells. In this process, referred to as pixel-cell deconvolution, the MS intensities of regions sampled by the imaging MS laser are assigned to the segmented single cells. The complexity of the contributions from multiple cells and the background, as well as lack of full understanding of how input from molecularly-heterogeneous areas translates into mass spectrometry intensities make the cell-pixel deconvolution a challenging problem.Here, we propose a novel approach to evaluate pixel-cell deconvolution methods by using a molecule detectable both by mass spectrometry and fluorescent microscopy, namely fluorescein diacetate (FDA). FDA is a cell-permeable small molecule that becomes fluorescent after internalisation in the cell and subsequent cleavage of the acetate groups. Intracellular fluorescein can be easily imaged using fluorescence microscopy. Additionally, it is detectable by matrix-assisted laser desorption/ionisation (MALDI) imaging MS. The key idea of our approach is to use the fluorescent levels of fluorescein as the ground truth to evaluate the impact of using various pixel-cell deconvolution methods onto single-cell fluorescein intensities obtained by the SpaceM method.Following this approach, we evaluated multiple pixel-cell deconvolution methods, the ‘weighted average’ method originally proposed in the SpaceM method as well as the novel ‘linear inverse modelling’ method. Despite the potential of the latter method in resolving contributions from individual cells, this method was outperformed by the weighted average approach. Using the ground truth approach, we demonstrate the extent of the ion suppression effect which considerably worsens the pixel-cell deconvolution quality. For compensating the ion suppression, we propose a novel data-driven approach. We show that compensating the ion suppression effect in a single-cell metabolomics dataset of co-cultured HeLa and NIH3T3 cells considerably improved the separation between both cell types. Finally, using the same ground truth, we evaluate the impact of drop-outs in the measurements and discuss the optimal filtering parameters of SpaceM processing steps before pixel-cell deconvolution.
Data Fusion by Matrix Completion for Exposome Target Interaction Prediction
Authors: Wang Kai , Kim Nicole , Bagherian Maryam , Li Kai , Chou Elysia , Colacino Justin A. , Dolinoy Dana C. , Sartor Maureen A. 
Published: August 2022

AbstractHuman exposure to toxic chemicals presents a huge health burden and disease risk. Key to understanding chemical toxicity is knowledge of the molecular target(s) of the chemicals. Because a comprehensive safety assessment for all chemicals is infeasible due to limited resources, a robust computational method for discovering targets of environmental exposures is a promising direction for public health research. In this study, we implemented a novel matrix completion algorithm named coupled matrix-matrix completion (CMMC) for predicting exposome-target interactions, which exploits the vast amount of accumulated data regarding chemical exposures and their molecular targets. Our approach achieved an AUC of 0.89 on a benchmark dataset generated using data from the Comparative Toxicogenomics Database. Our case study with bisphenol A (BPA) and its analogues shows that CMMC can be used to accurately predict molecular targets of novel chemicals without any prior bioactivity knowledge. Overall, our results demonstrate the feasibility and promise of computational predicting environmental chemical-target interactions to efficiently prioritize chemicals for further study.
Patterns and predictors of human-sloth bear conflict in Nepal: Implications for coexistence in unprotected forest landscapes
Authors: Pokharel Manoj , Aryal Chandramani , Adhikary Bidhan , Rai Jeevan 
Published: August 2022

AbstractHuman-sloth bear conflict, generally in the form of human attacks, is common throughout most areas where sloth bears co-occur with humans. The situation is more prevalent in multi-use forest landscapes outside protected areas. Although sloth bears are a conflict-prone species in Nepal, there is a clear lack of systematic studies that can inform human safety and conflict mitigation. We used data from questionnaire-based interviews with conflict-affected people and witnesses to provide detailed information about human-sloth bear conflict (1990– 2021) in the Trijuga forest, an important sloth bear stronghold outside protected areas in Nepal. The data were analyzed using descriptive statistics, chi-square tests, and regression analysis. For the time period, 66 conflict incidents involving 69 human individuals were recorded, with an annual average of 2.06 (SD = 1.48) incidents and 1.75 (SD = 1.34) attacks. Conflicts primarily impacted working-age group (25–55 years old) men, whose primary occupation was farming and who frequented the forest regularly. They typically occurred between 0900 and 1500, inside forests, and in habitats associated with poor land cover visibility. Poor visibility was also a significant positive determinant of bear attacks on humans. Fifty-six conflict incidents resulted in attacks that injured 59 people, with a fatality rate of 8.47%. Victims of bear attacks frequently had serious injuries, especially to the head and neck areas of the body. Serious injuries were more likely to occur to lone individuals than to people who were in groups of two or more. We suggest identification of conflict-risk habitats through a participatory mapping approach and education programs for the local people for effective human-sloth bear conflict management in Nepal’s unprotected forests.
Computational Multiplex Panel Reduction to Maximize Information Retention in Breast Cancer Tissue Microarrays
Authors: Ternes Luke , Gray Joe W. , Chang Young Hwan 
Published: August 2022

ABSTRACTRecent state-of-the-art multiplex imaging techniques have expanded the depth of information that can be captured within a single tissue sample by allowing for panels with dozens of markers. Despite this increase in capacity, space on the panel is still limited due to technical artifacts, tissue loss, and long imaging acquisition time. As such, selecting which markers to include on a panel is important, since removing important markers will result in a loss of biologically relevant information, but identifying redundant markers will provide a room for other markers. To address this, we propose computational approaches to determine the amount of shared information between markers and select an optimally reduced panel that captures maximum amount of information with the fewest markers. Here we examine several panel selection approaches and evaluate them based on their ability to reconstruct the full panel images and information within breast cancer tissue microarray datasets using cyclic immunofluorescence as a proof of concept. We show that all methods perform adequately and can re-capture cell types using only 18 of 25 markers (72% of the original panel size). The correlation-based selection methods achieved the best single-cell marker mean intensity predictions with a Spearman correlation of 0.90 with the reduced panel. Using the proposed methods shown here, it is possible for researchers to design more efficient multiplex imaging panels that maximize the amount of information retained with the limited number of markers with respect to certain evaluation metrics and architecture biases.Author SummaryMultiplex tissue imaging techniques utilize large panels of markers that attempt to gather as much information as possible, but increasing the number of stains does come with the downsides of increased autofluorescence and tissue degradation. There exists a theoretical subsampling of markers that is able to recreate the same information as a full panel; therefore, removing the self-correlating information with such a subset would increase the efficiency of the imaging process and maximize the information collected. By selecting an idealized subsample of markers, a deep learning model can be trained to predict the same information as a full dataset with fewer rounds of staining. Here we evaluate several methods of subsample marker selection and demonstrate their ability to reconstruct the full panel’s information.
Lifestyles shape genome size and gene content in fungal pathogens
Authors: Fijarczyk Anna , Hessenauer Pauline , Hamelin Richard C. , Landry Christian R. 
Published: August 2022

SummaryFungi display a wide range of lifestyles and hosts. We still know little about the impact of lifestyles, including pathogenicity, on their genome architecture. Here, we combined and annotated 552 fungal genomes from the class Sordariomycetes and examined the association between 12 genomic features and two lifestyle traits: pathogenicity and insect association. We found that pathogens on average tend to have a larger number of protein-coding genes, including effectors, and tRNA genes. In addition, the non-repetitive size of their genomes is larger than that of non-pathogenic species. However, this pattern is not consistent across all groups. Insect endoparasites and symbionts have smaller genome sizes and genes with longer exons; moreover, insect-vectored pathogens possess fewer genes compared to those not transmitted by insects. Our study shows that genes are the main contributors to genome size variation in Sordariomycetes and that seemingly similar pathogens can exhibit distinct genome architectures, depending on their host and vector interactions.
Protein mishandling and impaired lysosomal proteolysis generated through calcium dysregulation in Alzheimer’s disease
Authors: Mustaly-Kalimi Sarah , Marr Robert A. , Gilman-Sachs Alice , Peterson Daniel A. , Sekler Israel , Stutzmann Grace E. 
Published: August 2022

AbstractImpairments in neural lysosomal- and autophagic-mediated degradation of cellular debris contribute to neuritic dystrophy and synaptic loss. While these are well-characterized features of neurodegenerative disorders such as Alzheimer’s disease (AD), the upstream cellular processes driving deficits in pathogenic protein mishandling are less understood. Using a series of fluorescent biosensors and optical imaging in model cells, AD mouse models and human neurons derived from AD patients, we reveal a novel cellular signaling cascade underlying protein mishandling mediated by intracellular calcium dysregulation, an early component of AD pathogenesis. Increased Ca2+ release via the endoplasmic reticulum (ER) resident ryanodine receptor (RyR) is associated with reduced expression of the lysosome proton pump vATPase subunits (V1B2 and V0a1), resulting in lysosome deacidification and disrupted proteolytic activity in AD mouse models and human induced neurons (HiN). As a result of impaired lysosome digestive capacity, mature autophagosomes with hyperphosphorylated tau accumulated in AD murine neurons and AD HiN, exacerbating proteinopathy. Normalizing AD-associated aberrant RyR-Ca2+ signaling with the negative allosteric modulator, dantrolene (Ryanodex), restored vATPase levels, lysosomal acidification and proteolytic activity, and autophagic clearance of intracellular protein aggregates in AD neurons. These results highlight that prior to overt AD histopathology or cognitive deficits, aberrant upstream Ca2+ signaling disrupts lysosomal acidification and contributes to pathological accumulation of intracellular protein aggregates. Importantly, this is demonstrated in animal models of AD, and in human iPSC-derived neurons from AD patients. Furthermore, pharmacological suppression of RyR-Ca2+ release rescued proteolytic function, revealing a target for therapeutic intervention that has demonstrated effects in clinically-relevant assays.Significance StatementWe demonstrate in model cells, murine neuronal cultures, and iPSC-derived human neurons, that AD associated RyR-Ca2+ dyshomeostasis impairs lysosomal acidification, lysosomal proteolytic activity and hinders autophagic-mediated protein aggregate clearance, which are processes vital to neuronal survival. These deficits were reversed by restoring intracellular Ca2+ homeostasis. Notably, this provides a therapeutic target and emphasizes the pathogenic relationship between ER-Ca2+ handling, that is known to be altered in AD, to pathogenic protein accumulation as a critical turning point in early stages of Alzheimer’s disease.
Schizophrenia-associatedNRXN1deletions induce developmental-timing- and cell-type-specific vulnerabilities in human brain organoids
Authors: Sebastian Rebecca , Jin Kang , Pavon Narciso , Bansal Ruby , Potter Andrew , Song Yoonjae , Babu Juliana , Gabriel Rafael , Sun Yubing , Aronow Bruce , Pak ChangHui 
Published: August 2022

AbstractDe novomutations and copy number deletions inNRXN1(2p16.3) pose a significant risk for schizophrenia (SCZ). It is unclear howNRXN1deletions impact cortical development in a cell type-specific manner and disease background modulates these phenotypes. Here, we leveraged human pluripotent stem cell-derived forebrain organoid models carryingNRXN1heterozygous deletions in isogenic and SCZ patient genetic backgrounds and conducted single-cell transcriptomic analysis over the course of brain organoid development from 3 weeks to 3.5 months. Intriguingly, while both deletions similarly impacted molecular pathways associated with ubiquitin-proteasome system, alternative splicing, and synaptic signaling in maturing glutamatergic and GABAergic neurons, SCZ-NRXN1deletions specifically perturbed developmental trajectories of early neural progenitors and accumulated disease-specific transcriptomic signatures. Using calcium imaging, we found that both deletions led to long-lasting changes in spontaneous and synchronous neuronal networks, implicating synaptic dysfunction. Our study reveals developmental-timing- and cell-type-dependent actions ofNRXN1deletions in unique genetic contexts.