bluuebunny/crossref_metadata_2025_split huggingface dataset:
Whole exome sequencing in multi-incident families identifies novel candidate genes for multiple sclerosis
Authors: Horjus J. , Banda T. , Heerings M. , Hakobjan M. , Witte W. De , Heersema D.J. , Jansen A.J. , Strijbis E.M.M. , de Jong B.A. , Slettenaar A.E.J. , Zeinstra E.M.P.E. , Hoogervorst E.L.J. , Franke B. , Kruijer W. , Jongen P.J. , Visser L. , Poelmans G. 
Published: March 2022

AbstractMultiple sclerosis (MS) is a degenerative disease of the central nervous system in which auto-immunity-induced demyelination occurs. MS is thought to be caused by a complex interplay of environmental and genetic risk factors. While most genetic studies have focused on identifying common genetic variants for MS through genome-wide association studies, the objective of the present study was to identify rare genetic variants contributing to MS susceptibility. We used whole exome sequencing (WES) followed by co-segregation analyses in nine multi-incident families with 2 to 4 affected individuals. WES was performed in 31 family members with and without MS. After applying a suite of selection criteria, co-segregation analyses for a number of rare variants selected from the WES results were performed, adding 24 family members. This approach resulted in 12 exonic rare variants that showed acceptable co-segregation with MS within the nine families, implicating the genes MBP, PLK1, MECP2, MTMR7, TOX3, CPT1A, SORCS1, TRIM66, ITPR3, TTC28, CACNA1F, and PRAM1. Of these, three genes (MBP, MECP2, and CPT1A) have been previously reported as carrying MS-related rare variants. Six additional genes (MTMR7, TOX3, SORCS1, ITPR3, TTC28, and PRAM1) have also been implicated in MS through common genetic variants. The proteins encoded by all twelve genes containing rare variants interact in a molecular framework that points to biological processes involved in (de-/re-)myelination and auto-immunity. Our approach provides clues to possible molecular mechanisms underlying MS that should be further studied in cellular and/or animal models.
Convergent coexpression of autism associated genes suggests some novel risk genes may not be detectable in large-scale genetic studies
Authors: Liao Calwing , Moyses-Oliveira Mariana , De Esch Celine EF , Bhavsar Riya , Nuttle Xander , Li Aiqun , Yu Alex , Burt Nicholas D. , Erdin Serkan , Fu Jack M. , Wang Minghui , Morley Theodore , Han Lide ,   CommonMind Consortium, Dion Patrick A. , Rouleau Guy A. , Zhang Bin , Brennand Kristen J. , Talkowski Michael E. , Ruderfer Douglas M. 
Published: March 2022

AbstractAutism spectrum disorder (ASD) is a highly heritable neurodevelopmental disorder characterized by deficits in social interactions and communication. Protein function altering variants in many genes have been shown to contribute to ASD risk; however, understanding the biological convergence across so many genes has been difficult and genetic studies depending on presence of deleterious variation may be limited in implicating highly intolerant genes with shorter coding sequences. Here, we demonstrate that coexpression patterns from human post-mortem brain samples (N = 993) are significantly correlated with the transcriptional consequences of CRISPR perturbations (gene editing, interference and activation) in human neurons (N = 17). Across 71 ASD risk genes, there is significant tissue-specific transcriptional convergence that implicates synaptic pathways. Tissue specific convergence of risk genes is a generalizable phenomenon, shown additionally in schizophrenia (brain) and atrial fibrillation (heart). The degree of this convergence in ASD is significantly correlated with the level of association to ASD from sequencing studies (rho = -0.32, P = 3.03 ×10−65) as well as differential expression in post-mortem ASD brains (rho = -0.23, P = 2.39×10−43). After removing all genes statistically associated with ASD, the remaining positively convergent genes showed intolerance to functional mutations, had shorter coding lengths than the ASD genes and were enriched for genes with clinical reports of potential pathogenic contribution to ASD. These results indicate that leveraging convergent coexpression can identify potentially novel risk genes that are unlikely to be discovered by sequencing studies. Overall, this work provides a simple approach to functionally proxy CRISPR perturbation, demonstrates significant context-specific transcriptional convergence among known risk genes of multiple diseases, and proposes novel ASD risk gene candidates.
Risk of Suicide Ideation in Comorbid Substance Use Disorder and Major Depression
Authors: Onaemo Vivian N. , Fawehinmi Timothy O. , D’Arcy Carl 
Published: March 2022

ABSTRACTBackgroundSuicidal behaviour is commonly associated with major depression (MD) and substance use disorders (SUDs). However, there is a paucity of research on risk for suicide ideation among individuals with comorbid SUDs and MD in the general population.ObjectivesThis study investigated the associated risk of suicide ideation in comorbid SUDs - cannabis use disorder (CUD), alcohol use disorder (AUD), drug use disorder (DUD) with depression in a nationally representative sample.MethodsMultilevel logistic regression models were used to analyze the 2012 Canadian Community Health Survey (CCHS-MHC) data. This is a cross-sectional survey of nationally representative samples of Canadians (n = 25,113) aged 15 years and older residing in the ten Canadian provinces between January and December 2012. Diagnoses of MD episode, AUD, DUD, CUD, and suicide risk were based on the WHO-CIDI-3.0 derived from DSM-IV diagnostic criteria.ResultsComorbidity was found to be the strongest predictor of suicide ideation. Compared to those with no diagnosis, individuals with a comorbid diagnosis of AUD with MDE, CUD with MDE, or DUD with MDE were 9 to 16 times more likely to have suicide ideation. A diagnosis of MDE was a significant predictor of suicide ideation with about a 7-fold increased risk.ConclusionSuicide is a preventable public health issue. Our study found a significantly increased risk of suicide ideation among persons who have comorbid SUD with MD. Effective integration of mental health and addictions services could mitigate the risk of suicide and contribute to better outcomes.
Belowground plant responses to root herbivory depend on the composition and structure of their root-colonising arbuscular mycorrhizal fungi
Authors: Ng Anna , Wilson Bree A.L. , Frew Adam 
Published: March 2022

ABSTRACTThere is growing interest in managing arbuscular mycorrhizal (AM) fungi in agriculture to support plant production. These fungi can support crop growth and nutrient uptake but also affect plant-herbivore interactions. Our knowledge of how native AM fungal diversity and community composition influence these interactions is limited, while our understanding of this in relation to root-herbivory is lacking altogether.To begin to address these knowledge gaps, plants were grown with no AM fungi or were inoculated with native fungal communities sourced from either a crop field (field community), a sclerophyll forest (forest community), or a crop field in fallow (fallow community). We then explored how the composition and structure (species richness and relative abundance) of root-colonising AM fungal communities was associated with the growth and belowground nutrient responses of a major crop (Sorghum bicolor) to attack from a root-feeding insect (Dermolepida albohirtum).DNA metabarcoding revealed plants associated with three distinct root-colonising AM fungal communities. Fungal taxon richness in roots was highest in the field community and lowest in the fallow community. Both the field and fallow communities were dominated by the putatively ruderal genera Glomus and Claroideoglomus, while the forest-derived community contained greater proportions of Paraglomus and Ambispora.In response to root herbivory, plants without AM fungi and plants colonised by the forest community exhibited root biomass losses of 61% and 44%, respectively. Similarly, these two groups also had reductions of 59% and 65% in their root phosphorus content, respectively, when subjected to the root herbivore. In contrast, plants associating with communities harbouring greater proportions of Glomus and Claroideoglomus (the field and fallow communities) did not exhibit reductions in root biomass or nutrient content.Our results show that plant responses to root-herbivory vary with root-colonising AM fungal community composition and structure. In a community context, our findings suggest that stronger associations with the genera Claroideoglomus and Glomus may potentially support crop tolerance-associated responses belowground. There is an urgent need for more exploration of how natural assemblages of AM fungi differentially mediate plant-herbivore interactions if we are to effectively manage soil fungi in sustainable agricultural systems.
Orthogonal synthetases for polyketide precursors
Authors: Fricke Riley , Swenson Cameron V. , Roe Leah Tang , Hamlish Noah , Ad Omer , Smaga Sarah , Gee Christine L. , Schepartz Alanna 
Published: March 2022

AbstractThe absence of orthogonal aminoacyl-tRNA synthetases that accept non-L-α-amino acids is the primary bottleneck hindering the in vivo translation of sequence-defined hetero-oligomers. Here we report PylRS enzymes that accept α-hydroxy acids, α-thio acids, N-formyl-L-α-amino acids, and α-carboxyl acid monomers (malonic acids) that are formally precursors to polyketide natural products. These monomers are all accommodated and accepted by the translation apparatus in vitro. High-resolution structural analysis of the complex between one such PylRS enzyme and a meta-substituted 2-benzylmalonate derivative reveals an active site that discriminates pro-chiral carboxylates and accommodates the large size and distinct electrostatics of an α-carboxyl acid substituent. This work emphasizes the potential of PylRS-derived enzymes for acylating tRNA with monomers whose α-substituent diverges significantly from the α-amine embodied in proteinogenic amino acids. These enzymes could act in synergy with natural or evolved ribosomes to generate diverse sequence-defined non-protein hetero-oligomers.
Rac1 controls cell turnover and mammary gland reversibility in post-partum involution
Authors: Mironov Aleksander , Fisher Matthew , Elsayed Randa , Karabulutoglu Melis , Akhtar Nasreen 
Published: March 2022

AbstractCell turnover in adult tissues is essential for maintaining tissue homeostasis over a lifespan and for inducing the morphological changes associated with the reproductive cycle. However, the underlying mechanisms that coordinate the balance of cell death and proliferation remain unsolved. Using the mammary gland we have discovered that Rac1 acts as a nexus to control cell turnover. Post-lactational tissue regression is characterized by the death of milk secreting alveoli, but the process is reversible within the first 48h if feeding recommences. In mice lacking epithelial Rac1, alveolar regression was delayed. This defect did not result from failed cell death but rather increased cell turnover. Fitter progenitor cells inappropriately divided, regenerating the alveoli but cell death also concomitantly accelerated. We discovered that progenitor cell hyperproliferation was linked to non-autonomous effects of Rac1 deletion on the macrophageal niche with heightened inflammation. Moreover, loss of Rac1 impaired cell death with autophagy but switched the cell death route to apoptosis. Finally, mammary gland reversibility failed in the absence of Rac1 as the regenerated alveoli failed to recommence lactation upon re-suckling.
Genetic structure analysis on leopard cat reveals the effects of habitat fragmentation on subpopulation differentiation in Beijing
Authors: Teng Yang , Yang Jing , Ju Longfei , Gai Lixin , Li Jian , Gao Fuli , Bao Weidong 
Published: March 2022

AbstractIn the face of habitat shrinkage and segregation, the survival of wild cats looks bleak. Interpreting the population genetic structure during habitat fragmentation is critical to planning effective management strategies. To reveal the segregation effects of road construction and human settlement on population genetic structure, we noninvasively analyzed fecal DNA samples from leopard cats (Prionailurus bengalensis) from five nature reserves in mountainous areas around Beijing. We focused on molecular microsatellite markers and the mitochondrial control region. A total of 112 individual leopard cats were identified among 601 samples of scat, and generally moderate population genetic diversity was detected. Microsatellite marker–based gene flow (Nm) and STRUCTURE analyses showed no obvious discrepancies among the subpopulations; however, the calculation of genetic distance and construction of a phylogenetic tree of the mitochondrial control region revealed a trend toward differentiation from the other subpopulations in the Songshan subpopulation, which indicates habitat fragmentation effects. Because the isolated Songshan subpopulation may evolve independently, we suggest that its genetic structure be monitored every 5 years to detect any changes and that individuals be introduced as needed to maintain the viability of this subpopulation.
Image segmentation and separation of spectrally similar dyes in fluorescence microscopy by dynamic mode decomposition of photobleaching kinetics
Authors: Wüstner Daniel 
Published: March 2022

AbstractBackgroundImage segmentation in fluorescence microscopy is often based on spectral separation of fluorescent probes (color-based segmentation) or on significant intensity differences in individual image regions (intensity-based segmentation). These approaches fail, if dye fluorescence shows large spectral overlap with other employed probes or with strong cellular autofluorescence.ResultsHere, a novel model-free approach is presented which determines bleaching kinetics based on dynamic mode decomposition (DMD) and uses the inferred photobleaching kinetics to distinguish different probes or dye molecules from autofluorescence. DMD is a data-driven computational method for detecting and quantifying dynamic events in complex spatiotemporal data. Here, DMD is used to determine photobleaching characteristics of a fluorescent sterol probe, dehydroergosterol (DHE), compared to that of cellular autofluorescence in the nematode Caenorhabditis elegans. It is shown that decomposition of those dynamic modes allows for precise image segmentation, thereby separating probe from autofluorescence without invoking a particular model for the bleaching process. In a second application, DMD of dye-specific photobleaching is used to separate two green-fluorescent dyes, an NBD-tagged sphingolipid and Alexa488-transferrin, thereby assigning them to different cellular compartments.ConclusionsData-based decomposition of dynamic modes can be employed to analyze spatially varying photobleaching of fluorescent probes in cells and tissues for image segmentation, discrimination of probe from autofluorescence and image denoising. The new method should find wide application in analysis of dynamic fluorescence imaging data.
Rate-distortion theory of neural coding and its implications for working memory
Authors: Jakob Anthony M.V. , Gershman Samuel J. 
Published: March 2022

AbstractRate-distortion theory provides a powerful framework for understanding the nature of human memory by formalizing the relationship between information rate (the average number of bits per stimulus transmitted across the memory channel) and distortion (the cost of memory errors). Here we show how this abstract computational-level framework can be realized by a model of neural population coding. The model reproduces key regularities of visual working memory, including some that were not previously explained by population coding models. We verify a novel prediction of the model by reanalyzing recordings of monkey prefrontal neurons during an oculomotor delayed response task.
IntegronFinder 2.0: identification and analysis of integrons across Bacteria, with a focus on antibiotic resistance in Klebsiella
Authors: Néron Bertrand , Littner Eloi , Haudiquet Matthieu , Perrin Amandine , Cury Jean , Rocha Eduardo P.C. 
Published: March 2022

AbstractIntegrons are mobile genetic elements that contain multiple cassettes encoding accessory genes whose order is shuffled by a specific integrase. Integrons within mobile genetic elements often contain multiple antibiotic resistance genes that they spread among nosocomial pathogens and contribute to the current antibiotic resistance crisis. However, most integrons are presumably sedentary and encode a much broader diversity of functions. IntegronFinder is a widely used software to identify novel integrons in bacterial genomes, but has aged and lacks some useful functionalities to handle very large datasets of draft genomes or metagenomes. Here, we present IntegronFinder version 2. We have updated the code, improved its efficiency and usability, adapted the output to incomplete genome data, and added a few novel functions. We describe these changes and illustrate the relevance of the program by analyzing the distribution of integrons across more than 20,000 fully sequenced genomes. We also take full advantage of its novel capabilities to analyze close to 4 thousandKlebsiella pneumoniaegenomes for the presence of integrons and antibiotic resistance genes within them. Our data shows thatK. pneumoniaehas a large diversity of integrons and the largest mobile integron in our database of plasmids. The pangenome of these integrons contains a total of 165 different gene families with most of the largest families being related with resistance to numerous types of antibiotics. IntegronFinder is a free and open-source software available athttps://github.com/gem-pasteur/Integron_Finder.
Multiscale structural anisotropy in pulvinus motor organs of the sensitive plant Mimosa pudica
Authors: Sleboda David A. , Geitmann Anja , Sharif-Naeini Reza 
Published: March 2022

AbstractPulvini are joint-like motor organs that power active leaf movement in many plants. Multiple structural specializations spanning subcellular, cellular, and tissue scales of pulvinus organization have been described; however, the impacts of multiscale mechanics on pulvinus physiology remain poorly understood. To investigate the influence of multiscale morphology on turgor-induced deformation, we visualized Mimosa pudica pulvinus morphology at multiple hierarchical scales of organization and used osmotic perturbations to experimentally swell pulvini in incremental states of dissection. We observed directional cellulose microfibril reinforcement, oblong, spindle-shaped primary pit fields, and flattened, disk-like cell geometries in the parenchyma of M. pudica. Consistent with these observations, isolated parenchyma tissues displayed highly anisotropic swelling behaviors indicating a high degree of mechanical anisotropy. Swelling behaviors at higher scales of pulvinus organization were also influenced by the presence of the pulvinus epidermis, which displayed oblong epidermal cells oriented transverse to the pulvinus long axis. Our findings indicate that structural specializations spread across multiple hierarchical scales of organization guide hydraulic deformation of pulvini, suggesting that multiscale mechanics are crucial to the translation of cell-level turgor variations into organ-scale pulvinus motion in vivo.
A2A Receptor contributes to tumor progression in P2X7 null mice
Authors: De Marchi Elena , Pegoraro Anna , Turiello Roberta , Di Virgilio Francesco , Morello Silvana , Adinolfi Elena 
Published: March 2022

AbstractATP and adenosine are key constituents of the tumor niche where they exert opposite and complementary roles. ATP promotes tumor growth but also immune eradicating responses mainly via the P2X7 receptor (P2X7R), while adenosine acts as a potent immune suppressor and facilitates neovascularization thanks to A2A receptor (A2AR) activity. However, studies exploring the interplay between P2X7R and A2AR in the tumor microenvironment are as yet missing. Here we investigated tumor growth in C57/bl6 P2X7 null mice inoculated with B16-F10 melanoma cells, showing that several pro-inflammatory cytokines (IL1-β, TNF-α, IL-6, IL-12, IL-17, IFN-γ) were significantly decreased while the immune suppressant TGF-β was almost three-fold increased. Interestingly, tumors growing in P2X7-null mice also upregulated tumor-associated and splenic A2AR, suggesting that immunosuppression associated to lack of the P2X7R might depend upon A2AR overexpression. Immunohistochemical analysis showed that tumor cells A2AR expression was increased, especially around necrotic areas, and that VEGF and the endothelial marker CD31 were also upregulated. The A2AR antagonist SCH-58261 reduced tumor growth similarly in the P2X7 WT, or null mice strain. However, SCH-58261only reduced VEGF in the P2X7-KO mice, thus supporting the hypothesis of an A2AR mediated increase in vascularisation in P2X7-null host. SCH-58261 administration also significantly reduced intratumor TGF-β, thus supporting a key immune suppressive role of A2AR in our model. This study shows a novel direct correlation between P2X7R and A2AR in oncogenesis and paves the way for new combined therapies promoting anti-cancer immune responses and reducing tumor vascularization.
Time-Dependent Increase in Susceptibility and Severity of Secondary Bacterial Infection during SARS-CoV-2 Infection
Authors: Smith Amanda P. , Williams Evan P. , Plunkett Taylor R. , Selvaraj Muneeswaran , Lane Lindey C. , Zalduondo Lillian , Xue Yi , Vogel Peter , Channappanavar Rudragouda , Jonsson Colleen B. , Smith Amber M. 
Published: March 2022

AbstractSecondary bacterial infections can exacerbate SARS-CoV-2 infection, but their prevalence and impact remain poorly understood. Here, we established that a mild to moderate SARS-CoV-2 infection increased the risk of pneumococcal coinfection in a time-dependent, but sexindependent, manner in the transgenic K18-hACE mouse model of COVID-19. Bacterial coinfection was not established at 3 d post-virus, but increased lethality was observed when the bacteria was initiated at 5 or 7 d post-virus infection (pvi). Bacterial outgrowth was accompanied by neutrophilia in the groups coinfected at 7 d pvi and reductions in B cells, T cells, IL-6, IL-15, IL-18, and LIF were present in groups coinfected at 5 d pvi. However, viral burden, lung pathology, cytokines, chemokines, and immune cell activation were largely unchanged after bacterial coinfection. Examining surviving animals more than a week after infection resolution suggested that immune cell activation remained high and was exacerbated in the lungs of coinfected animals compared with SARS-CoV-2 infection alone. These data suggest that SARS-CoV-2 increases susceptibility and pathogenicity to bacterial coinfection, and further studies are needed to understand and combat disease associated with bacterial pneumonia in COVID-19 patients.