bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multi-omic analysis along the gut-brain axis points to a functional architecture of autism
Authors: Morton James T. , Jin Dong-Min , Mills Robert H. , Shao Yan , Rahman Gibraan , McDonald Daniel , Berding Kirsten , Needham Brittany D. , Zurita María Fernanda , David Maude , Averina Olga V. , Kovtun Alexey S. , Noto Antonio , Mussap Michele , Wang Mingbang , Frank Daniel N. , Li Ellen , Zhou Wenhao , Fanos Vassilios , Danilenko Valery N. , Wall Dennis P. , Cárdenas Paúl , Baldeón Manuel E. , Xavier Ramnik J. , Mazmanian Sarkis K. , Knight Rob , Gilbert Jack A. , Donovan Sharon M. , Lawley Trevor D. , Carpenter Bob , Bonneau Richard , Taroncher-Oldenburg Gaspar 
Published: February 2022

AbstractAutism is a highly heritable neurodevelopmental disorder characterized by heterogeneous cognitive, behavioral and communication impairments. Disruption of the gut-brain axis (GBA) has been implicated in autism, with dozens of cross-sectional microbiome and other omic studies revealing autism-specific profiles along the GBA albeit with little agreement in composition or magnitude. To explore the functional architecture of autism, we developed an age and sex-matched Bayesian differential ranking algorithm that identified autism-specific profiles across 10 cross-sectional microbiome datasets and 15 other omic datasets, including dietary patterns, metabolomics, cytokine profiles, and human brain expression profiles. The analysis uncovered a highly significant, functional architecture along the GBA that encapsulated the overall heterogeneity of autism phenotypes. This architecture was determined by autism-specific amino acid, carbohydrate and lipid metabolism profiles predominantly encoded by microbial species in the generaPrevotella, Enterococcus, Bifidobacterium, andDesulfovibrio, and was mirrored in brain-associated gene expression profiles and restrictive dietary patterns in individuals with autism. Pro-inflammatory cytokine profiling and virome association analysis further supported the existence of an autism-specific architecture associated with particular microbial genera. Re-analysis of a longitudinal intervention study in autism recapitulated the cross-sectional profiles, and showed a strong association between temporal changes in microbiome composition and autism symptoms. Further elucidation of the functional architecture of autism, including of the role the microbiome plays in it, will require deep, multi-omic longitudinal intervention studies on well-defined stratified cohorts to support causal and mechanistic inference.
Decoupling diet from microbiome dynamics results in model mis-specification that implicitly annuls potential associations between the microbiome and disease phenotypes—ruling out any role of the microbiome in autism (Yap et al. 2021) likely a premature conclusion
Authors: Morton James T. , Donovan Sharon M. , Taroncher-Oldenburg Gaspar 
Published: March 2022

AbstractRecently, and in a tour de force effort, Yap et al. performed a comprehensive association analysis of factors such as demographics, psychometrics, diet, stool metagenomics, stool consistency, and genome-wide SNP genotypes with autism in 247 Australian children. Surprisingly, the authors suggest their data show a strong correlation between diet and autism spectrum disorder (ASD) but only negligible, if any, ASD-specific microbiome signals. While the first conclusion comes as no surprise, we were rather puzzled by the second conclusion given the growing evidence of strong associations between the microbiome and ASD phenotype and the wide consensus on a close connection between diet and microbiome composition and function. The causal model proposed by Yap et al. seemed to imply that diet and the microbiome were two independent variables. A careful review of the approach used by the authors confirmed our suspicions that the statistical models were mis-specified, i.e. they had a questionable biological assumption—the independence of diet and microbiome—embedded in them. We have run side-by-side simulations of the causal linear model proposed by Yap et al. and of an analogous model in which diet and the microbiome are treated as co-dependent variables. We show how the Yap et al. model can preemptively exclude any potential host-microbe interactions if the diet-microbiome independence assumption is violated. We believe large-scale efforts such as the one described by Yap et al. are essential to advance our understanding of the potential role of the microbiome in ASD and other diseases. But these are highly complex systems to analyze and thus ensuring that the statistical methods used are accurate is essential to avoid drawing any potentially misleading conclusions due to subtle causal assumptions propagated by the statistical models themselves.
Early events in reovirus infection influence induction of innate immune response
Authors: Abad Andrew T. , Danthi Pranav 
Published: February 2022

ABSTRACTMammalian orthoreovirus (reovirus) is a double-stranded (ds)RNA virus which encapsidates its 10 genome segments within a double-layered viral particle. Reovirus infection triggers an antiviral response in host cells which serves to limit viral replication. This antiviral response is initiated by recognition of the incoming viral genome by host sensors present in the cytoplasm. However, how host sensors gain access to the reovirus genome is unclear as this dsRNA is protected by the viral particle proteins throughout infection. To initiate infection, reovirus particles are endocytosed and the outer viral particle layer is disassembled through the action of host proteases. This disassembly event is required for viral escape into the cytoplasm to begin replication. We show that even after disassembly is complete, endosomal proteases are required to induce an immune response to reovirus. Additionally, counter to dogma, our data demonstrate at least some viral dsRNA genome is exposed and detectable during entry. We hypothesize that some proportion of reovirus particles remain trapped within endosomes, allowing for the breakdown of these particles and release of their genome. We show that rapidly uncoating mutants escape the endosome more rapidly and induce a diminished immune response. Further, we show that particles entering through dynamin-independent pathways evade detection by host sensors. Overall, our data provide new insight into how genomes from entering reovirus particles are detected by host cells.IMPORTANCEViruses must infect host cells to replicate, often killing the host cell in the process. However, hosts can activate defenses to limit viral replication and protect the organism. To trigger these host defenses to viral infections, host cells must first recognize they are infected. Mammalian orthoreovirus (reovirus) is a model system used to study host-virus interactions. This study identifies aspects of host and virus biology which determine the capacity of host cells to detect infection. Notably, entry of reovirus into host cells plays a critical role in determining the magnitude of immune response triggered during infection. Mutants of reovirus which can enter cells more rapidly are better at avoiding detection by the host. Additionally, reovirus can enter cells through multiple routes. Entry through some of these routes also helps reovirus evade detection.
NEURONAL AND ASTROCYTIC TETRAPLOIDY IS INCREASED IN DRUG-RESISTANT EPILEPSY
Authors: Sanz-García Ancor , Sánchez-Jiménez Patricia , Granero-Cremades Inmaculada , De Toledo María , Pulido Paloma , Navas Marta , Frade Jose Maria , Pereboom Desirée , Torres-Díaz Cristina Virginia , Carmen Ovejero-Benito María 
Published: March 2022

ABSTRACTBackgroundEpilepsy is one of the most prevalent neurological diseases, a third of patients remain drug-resistant. The exact etiology of drug-resistant epilepsy (DRE) is still unknown. Neural tetraploidy has been associated with neuropathology. The aim of this study was to assess the presence of tetraploid neurons and astrocytes in DRE.Materials & methodsCortex, hippocampus and amygdala samples were obtained from patients subjected to surgical resection of the epileptogenic zone. Postmortem brain tissue of subjects without previous records of neurological, neurodegenerative or psychiatric diseases were used as controls. The percentage of tetraploid cells was measured by immunostaining of neurons (NeuN) or astrocytes (S100β) followed by flow cytometry analysis. Results were confirmed by image cytometry (ImageStream X Amnis System Cytometer) and with an alternative astrocyte biomarker (NDRG2). Statistical comparison was performed using univariate tests.ResultsA total of 22 patients and 10 controls were included. Tetraploid neurons and astrocytes were found both in healthy individuals and DRE patients in the three brain areas analyzed: cortex, hippocampus and amygdala. DRE patients presented a higher number of tetraploid neurons (p=0.020) and astrocytes (p=0.002) in the hippocampus compared to controls. These results were validated by image cytometry.ConclusionWe demonstrated the presence of both tetraploid neurons and astrocytes in healthy subjects and increased levels of both cell types in DRE patients. This is the first time that tetraploid astrocytes are described in healthy subjects. Furthermore, these results provide new insights into epilepsy, opening new avenues for future treatment.
Fusing spheroids to aligned μ-tissues in a Heart-on-Chip featuring oxygen sensing and electrical pacing capabilities
Authors: Schneider Oliver , Moruzzi Alessia , Fuchs Stefanie , Grobel Alina , Schulze Henrike S. , Mayr Torsten , Loskill Peter 
Published: March 2022

AbstractOver the last decade Organ-on-Chip (OOC) emerged as a promising technology for advanced in vitro models, recapitulating key physiological cues. OOC approaches tailored for cardiac tissue engineering resulted in a variety of platforms, some of which integrate stimulation or probing capabilities. Due to manual handling processes, however, a large-scale standardized and robust tissue generation, applicable in an industrial setting, is still out of reach. Here, we present a novel cell injection and tissue generation concept relying on spheroids, which can be produced in large quantities and uniform size from induced pluripotent stem cell-derived human cardiomyocytes. Hydrostatic flow transports and accumulates spheroids in dogbone-shaped cultivation chambers, which subsequently fuse and form aligned, contracting cardiac muscle fibers. Furthermore, we demonstrate electrical stimulation capabilities by utilizing fluidic media connectors as electrodes and provide the blueprint of a low-cost, open-source, scriptable pulse generator. We report on a novel integration strategy of optical O2 sensor spots into resin-based microfluidic systems, enabling in situ determination of O2 partial pressures. Finally, proof-of-concept demonstrating electrical stimulation combined with in situ monitoring of metabolic activity in cardiac tissues is provided. The developed system thus opens the door for advanced OOCs integrating biophysical stimulation as well as probing capabilities and serves as blueprint for the facile and robust generation of high density microtissues in microfluidic modules amenable for scale-up and automation.
The chromatin landscape of Th17 cells reveals mechanisms of diversification of regulatory and pro-inflammatory states
Authors: Thakore Pratiksha I. , Schnell Alexandra , Zhao Maryann , Huang Linglin , Hou Yu , Christian Elena , Zaghouani Sarah , Wang Chao , Singh Vasundhara , Ma Sai , Sankar Venkat , Notarbartolo Samuele , Buenrostro Jason D. , Sallusto Federica , Patsopoulos Nikolaos A. , Rozenblatt-Rosen Orit , Kuchroo Vijay K. , Regev Aviv 
Published: February 2022

AbstractTh17 cells are a heterogenous cell population consisting of non-pathogenic Th17 cells (npTh17) that contribute to tissue homeostasis and pathogenic Th17 cells (pTh17) that are potent mediators of tissue inflammation. To reveal regulatory mechanisms underlying Th17 heterogeneity, we performed combined ATAC-seq and RNA-seq and discovered substantial differences in the chromatin landscape of npTh17 and pTh17 cells bothin vitroandin vivo. Compared to other CD4+T cell subsets, npTh17 cells share accessible chromatin programs with Tregs, and pTh17 cells have an intermediate profile spanning features of npTh17 cells and Th1 cells. Integrating single-cell ATAC-seq and single-cell RNA-seq, we inferred self-reinforcing and mutually exclusive regulatory networks controlling the different cell states and predicted transcription factors (TFs) shaping the chromatin landscape of Th17 cell pathogenicity. We validated one novel TF, BACH2, which promotes immunomodulatory npTh17 programs and restrains pro-inflammatory Th1-like programs in Th17 cells and showed genetic evidence for protective variants in the human BACH2 locus associated with multiple sclerosis. Our work uncovered mechanisms that regulate Th17 heterogeneity, revealed shared regulatory programs with other CD4+T cell subsets, and identified novel drivers of Th17 pathogenicity as potential targets to mitigate autoimmunity.
Distinct chromosomal “niches” in the genome ofS. cerevisiaeprovide the background for genomic innovation and shape the fate of gene duplicates
Authors: Stavropoulou Athanasia , Tassios Aimilios , Kalyva Maria , Georgoulopoulos Michalis , Vakirlis Nikolaos , Iliopoulos Ioannis , Nikolaou Christoforos 
Published: February 2022

AbstractGene duplication is a major source of genomic innovation in all eukaryotes, with large proportions of genes being the result of either small-scale (SSD) or genome-wide duplication (WGD) events. In the model unicellular eukaryoteSaccharomyces cerevisiae, of which nearly one third of the genome corresponds to gene duplicates, the two modes of duplication have been shown to follow different evolutionary fates, with SSD genes being more prone to acquire novel functionalities (neofunctionalization) and WGD more likely to retain different parts of the original ancestral function (subfunctionalization). Having previously described aspects of functional compartmentalization for the genes ofS. cerevisiae, in this work we set out to investigate the existence of positional preferences of gene duplicates. We found that SSD and WGD genes are organized in distinct gene clusters that are, furthermore, segregated, occupying different regions, with SSD being more peripheral and WGD more centrally positioned close to centromeric chromatin.Duplicate gene clusters differ from the rest of the genome in terms of gene size and spacing, gene expression variability and regulatory complexity. What is more interesting, some of these properties are also shared by singleton genes residing in duplicate-rich regions in a position-dependent manner. Our analysis further reveals particular chromatin architectures in the promoters of duplicate genes, which are generally longer, with less pronounced nucleosome-free regions, strong structural constraints and a larger number of regulatory elements. Such structural features appear to be important for gene evolution as we find SSD gene-pair co-expression to be strongly associated with the similarity of nucleosome positioning patterns.We propose that specific regions of the yeast genome provide a favourable environment for the generation and maintenance of small-scale gene duplicates. The existence of such genomic “niches” is supported by the enrichment of these regions in singleton genes bearing similarities with gene “relics”, remnants of recent duplications that have reverted to single gene status. Our findings provide a valuable framework for the study of genomic innovation and suggest taking into account positional preferences in the study of gene emergence and fixation in experimentally and naturally evolving populations.
Numerical discrimination in Drosophila melanogaster
Authors: Bengochea Mercedes , Sitt Jacobo D. , Preat Thomas , Izard Veronique , Cohen Laurent , Hassan Bassem A. 
Published: March 2022

AbstractSensitivity to numbers is a crucial and evolutionarily conserved cognitive ability. The lack of experimental models amenable to systematic genetic and neural manipulation has precluded discovering circuits required for numerical cognition. Here, we demonstrate that in a two-choice task Drosophila fruit flies spontaneously prefer sets containing more objects. This preference is determined by the ratio between the two numerical quantities tested, a characteristic signature of numerical cognition across species. Individual flies maintained their numerical choice over consecutive days. Using a numerical visual conditioning paradigm, we found that flies are capable of associating sucrose with numerical quantities and can be trained to reverse their spontaneous preference for large quantities. Finally, we show that silencing LC11 neurons reduces the preference for more objects, thus identifying a neuronal substrate for numerical cognition in invertebrates. This discovery paves the way for the systematic analysis of the behavioral and neural mechanisms underlying sensitivity to numerosity.
Constructive Connectomics: how neuronal axons get from here to there using gene-expression maps derived from their family trees
Authors: Kerstjens Stan , Michel Gabriela , Douglas Rodney J. 
Published: February 2022

AbstractDuring brain development, billions of axons must navigate over multiple spatial scales to reach specific neuronal targets, and so build the processing circuits that generate the intelligent behavior of animals. However, the limited information capacity of the zygotic genome puts a strong constraint on how, and which, axonal routes can be encoded. We propose and validate a mechanism of development that can provide an efficient encoding of this global wiring task. The key principle, confirmed through simulation, is that basic constraints on mitoses of neural stem cells—that mitotic daughters have similar gene expression to their parent and do not stray far from one another—induce a global hierarchical map of nested regions, each marked by the expression profile of its common progenitor population. Thus, a traversal of the lineal hierarchy generates a systematic sequence of expression profiles that traces a staged route, which growth cones can follow to their remote targets. We have analyzed gene expression data of developing and adult mouse brains published by the Allen Institute for Brain Science, and found them consistent with our simulations: gene expression indeed partitions the brain into a global spatial hierarchy of nested contiguous regions that is stable at least from embryonic day 11.5 to postnatal day 56. We use this experimental data to demonstrate that our axonal guidance algorithm is able to robustly extend arbors over long distances to specific targets, and that these connections result in a qualitatively plausible connectome. We conclude that, paradoxically, cell division may be the key to uniting the neurons of the brain.Author SummaryThe embryological development of each brain installs an essentially identical communication network between its cells that is roughly as complex as that between the billions of people living on Earth. Although vast scientific resources are currently applied to identifying the final pattern of connections, the connectome, there has until now been relatively little effort to answer the fundamental question of how this complex network across billions of neurons realized through the mitotic elaboration of the initial embryonic cell. The problem is sharpened by the constraints that construction of the network is limited by the information budget of the initial genome, and that it has no pre-existing address space for placing neurons and guiding axons. We explain how Biology can solve this problem by using the family tree of neurons to install a global space of molecular addresses, which axons can use to navigate from their source neuron to its relatives. We provide experimental evidence for this familial address space in gene expression patterns of the developing mouse brain, and demonstrate through simulation that the experimentally observed address space indeed supports global navigation to produce a qualitatively plausible default connectome.
RNA fluorescence in situ hybridization (FISH) to visualize microbial colonization and infection in the Caenorhabditis elegans intestines
Authors: Rivera Dalaena E , Lažetić Vladimir , Troemel Emily R , Luallen Robert J 
Published: March 2022

ABSTRACTThe intestines of wild Caenorhabditis nematodes are inhabited by a variety of microorganisms, including gut microbiome bacteria and pathogens, such as microsporidia and viruses. Because of the similarities between Caenorhabditis elegans and mammalian intestinal cells, as well as the power of the C. elegans system, this host has emerged as a model system to study host intestine-microbe interactions in vivo. While it is possible to observe some aspects of these interactions with bright-field microscopy, it is difficult to accurately classify microbes and characterize the extent of colonization or infection without more precise tools.This protocol introduces RNA fluorescence in situ hybridization (FISH) as a tool used for the identification, visualization, and quantification of the microbes within the intestines of C. elegans. FISH probes that label the highly abundant small subunit ribosomal RNA can produce a bright signal for bacteria and microsporidian cells, and similar probes can be used to label viral RNA. FISH probes can be ordered from a commercial source as single-stranded DNA end-labeled with fluorophores. One limitation is that FISH may not provide robust signal against low copy targets, although signal can be boosted by using multiple probes (so-called ‘single-molecule FISH’). FISH staining involves collecting colonized or infected animals, washing to eliminate external contamination, followed by fixation in either paraformaldehyde or acetone. After fixation, FISH probes are incubated with samples to allow for the hybridization of probes to the desired target. To remove excess background, the animals are washed again, and then examined on microscope slides or using automated approaches.Overall, this protocol enables detection, identification, and quantification of the microbes that inhabit the C. elegans intestine, including microbes for which there are no genetic tools available.SUMMARYGut microbiome bacteria and intestinal intracellular pathogens, like the Orsay virus and microsporidia, are often found associated with wild Caenorhabditis nematodes. This protocol presents RNA FISH as a method for the detection, quantification, and identification of colonizing or infectious microbes within the context of intact C. elegans nematodes.