Miracle-dz/UniFAR-FTUs huggingface dataset:
Genomic basis for RNA alterations revealed by whole-genome analyses of 27 cancer types

We present the most comprehensive catalogue of cancer-associated gene alterations through characterization of tumor transcriptomes from 1,188 donors of the Pan-Cancer Analysis of Whole Genomes project. Using matched whole-genome sequencing data, we attributed RNA alterations to germline and somatic DNA alterations, revealing likely genetic mechanisms. We identified 444 associations of gene expression with somatic non-coding single-nucleotide variants. We found 1,872 splicing alterations associated with somatic mutation in intronic regions, including novel exonization events associated with Alu elements. Somatic copy number alterations were the major driver of total gene and allele-specific expression (ASE) variation. Additionally, 82% of gene fusions had structural variant support, including 75 of a novel class called "bridged" fusions, in which a third genomic location bridged two different genes. Globally, we observe transcriptomic alteration signatures that differ between cancer types and have associations with DNA mutational signatures. Given this unique dataset of RNA alterations, we also identified 1,012 genes significantly altered through both DNA and RNA mechanisms. Our study represents an extensive catalog of RNA alterations and reveals new insights into the heterogeneous molecular mechanisms of cancer gene alterations.
Dynamics of microbial competition, commensalism, and cooperation and its implications for coculture and microbiome engineering

Microbial consortium is a complex adaptive system with higher order dynamic characteristics that are not present by individual members. To accurately predict the social interactions, we formulate a set of unstructured kinetic models to quantitatively capture the dynamic interactions of multiple microbial species. By introducing an interaction coefficient, we analytically derived the steady state solutions for the interacting species and the substrate profile in the chemostat. We analyzed the stability of the possible co-existing states defined by competition, parasitism, amensalism, commensalism and cooperation. Our model predicts that only parasitism, commensalism and cooperation could lead to stable co-existing state. We also determined the optimal social interaction criteria of microbial coculture with sequential metabolic reactions compartmentalized into two distinct species. Coupled with Luedeking–Piret and Michaelis-Menten equations, accumulation of metabolic intermediates in one species and formation of end-product in another species could be derived and assessed. We discovered that parasitism consortia disfavor the bioconversion of intermediate to final product; and commensalism consortia could efficiently convert metabolic intermediates to final product and maintain metabolic homeostasis with a broad range of operational conditions (i.e., dilution rates); whereas cooperative consortia leads to highly nonlinear pattern of precursor accumulation and end-product formation. The underlying dynamics and emergent properties of microbial consortia may provide critical knowledge for us to engineer efficient bioconversion process, deliver effective gut therapeutics as well as elucidate probiotic-pathogen interactions in general.
Hippocampal-medial prefrontal event segmentation and integration contribute to episodic memory formation

How do we encode our continuous life experiences for later retrieval? Theories of event segmentation and integration suggest that the hippocampus binds separately represented events into an ordered narrative. Using a functional Magnetic Resonance Imaging (fMRI) movie watching-recall dataset, we quantified two types of neural similarities (i.e., activation pattern similarity and within-region voxel-based connectivity pattern similarity) between separate events during movie watching and related them to subsequent retrieval of events as well as retrieval of sequential order. We demonstrated that compared to forgotten events, successfully remembered events were associated with distinct activation patterns in the hippocampus and medial prefrontal cortex. By contrast, similar connectivity patterns between events were associated with memory formation and were also relevant for retaining events in the correct order. We applied the same approaches to an independent movie watching fMRI dataset as validation and highlighted again the role of hippocampal activation pattern and connectivity pattern in memory formation. We propose that distinct activation patterns represent neural segmentation of events while similar connectivity patterns encode context information, and therefore integrate events into a narrative. Our results provide novel evidence for the role of hippocampal-medial prefrontal event segmentation and integration in episodic memory formation of real-life experience.
Gene expression in isolated cowpea (Vigna unguiculata L. Walp) cells from meiosis to seed initiation

Molecular knowledge of pathways regulating seed formation in legumes, remains scarce. Thirteen isolated cell-type transcriptomes were developed, spanning temporal events of male and female gametogenesis and seed initiation, to examine pathways involved in cowpea seed formation. In situ hybridization confirmed localization of in silico identified cell-specific genes, verifying transcriptome utility. Cowpea and Arabidopsis reproductive cells showed some conservation in regulators enabling cell-type expression as some cowpea cell-specific genes promoters and their Arabidopsis homologs directed expression to identical reproductive cell-types in transgenic plants. In silico analyses revealed gene expression similarities and differences with genes in pathways regulating reproductive events in other plants. Meiosis-related genes were expressed at mitotic stages of gametogenesis and during sporophytic development in cowpea. Plant hormone pathways showing preferential expression at particular reproductive stages were identified. Expression of epigenetic pathways, resembling those found in Arabidopsis, including microRNA mediated gene silencing, RNA directed DNA methylation and histone modification were associated with particular stages of male and female gametophyte development, suggesting roles in gametogenic cell specification and elaboration. Analyses of cell-cycle related gene expression in mature cowpea female gametophytes, indicated that the egg and central cell were arrested at the G1/S and G2/M cell cycle phases, respectively, prior to fertilization. Pre-fertilization female gametophyte arrest was characterized by barely detectable auxin biosynthesis gene expression levels, and elevated expression of genes involved in RNA-mediated gene silencing and histone modification. These transcriptomes provide a useful resource for additional interrogation to support functional analyses for development of higher yielding cowpea and syntenic legume crops. One sentence summary Analyses of laser capture derived cell-type transcriptomes spanning meiosis to seed initiation revealed gene expression profiles during cell specification and reproductive development in cowpea.
Geography, not food availability, reflects compositional differences in the bacterial communities associated with larval sea urchins

Determining the principles underlying the assembly, structure, and diversity of symbiont communities remains a focal point of animal-microbiome research. Much of these efforts focus on taxonomic variation within or between animal populations, but rarely test the proportional impacts of ecological components that may affect animal-associated microbiota. Using larvae from the sea urchinStrongylocentrotus droebachiensisfrom the Atlantic and Pacific Oceans, we test the hypothesis that inter-population differences in the composition of animal-associated bacterial communities are more pronounced than intra-population variation due to a heterogeneous feeding environment. Despite significant differences in bacterial community structure within eachS. droebachiensislarval population (based on food availability, time, development, and phenotype), variation in OTU membership and community composition correlated more strongly with geography. Moreover, across these three locations, 20-30% of OTUs were specific to a single population while less than 10% were shared. Taken together, these results suggest that inter-populational variation in symbiont communities is more pronounced than intra-populational variation. This difference may suggest that ecological variables over broad geographic scales may mask smaller scale ecological variables; however, explicit testing of this potential principle requires common garden experiments as well as molecular and functional manipulations.
ASSOCIATION OF PANCREAS VOLUME AND INSULIN RESISTANCE WITH ABDOMINAL FAT DISTRIBUTION IN TYPE-2 DIABETES AS EVALUATED BY COMPUTED TOMOGRAPHY.

Purpose We aimed to assess the relationship between the regional body fat distribution and insulin resistance and pancreas volume (PV) in type-2 diabetes (DM) patients. Methods Fifty-three consecutive type-2 diabetic and 51 non-diabetic patients matched by age, gender and body mass index (BMI) were enrolled. Subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), waist circumference, and PV were measured with computed tomography. Insulin resistance was assessed by the homeostasis model assessment of insulin resistance (HOMA-IR). Results Patients with type-2 DM had significantly lower PV than non-diabetic individuals. HOMA-IR ranged from 0.74 to 6.24; and from 0.37 to 3.26, in type-2 DM patients and non-diabetics, respectively. VAT was positively correlated with HOMA-IR in two groups. There were inverse correlations between PV and VAT and VAT/SAT but only in diabetics. Conclusions The VAT/SAT ratio may reflect the possible role of VAT to better understand the pathogenesis of obesity-related disorders in patients with type-2 DM.
Selective gating of retinal information by arousal

How sensory information is processed by the brain can depend on behavioral state. In the visual thalamus and cortex, arousal/locomotion is associated with changes in the magnitude of responses to visual stimuli. Here, we asked whether such modulation of visual responses might already occur at an earlier stage in this visual pathway. We measured neural activity of retinal axons using wide-field and two-photon calcium imaging in awake mouse thalamus across arousal states associated with different pupil sizes. Surprisingly, visual responses to drifting gratings in retinal axonal boutons were robustly modulated by arousal level, in a manner that varied across stimulus dimensions and across functionally distinct subsets of boutons. At low and intermediate spatial frequencies, the majority of boutons were suppressed by arousal. In contrast, at high spatial frequencies, the proportions of boutons showing enhancement or suppression were more similar, particularly for boutons tuned to regions of visual space ahead of the mouse. Arousal-related modulation also varied with a bouton’s sensitivity to luminance changes and direction of motion, with greater response suppression in boutons tuned to luminance decrements vs. increments, and in boutons preferring motion along directions or axes of optic flow. Together, our results suggest that differential filtering of distinct visual information channels by arousal state occurs at very early stages of visual processing, before the information is transmitted to neurons in visual thalamus. Such early filtering may provide an efficient means of optimizing central visual processing and perception of state-relevant visual stimuli.
Cell profiling of mouse acute kidney injury reveals conserved cellular responses to injury

Significance Single nucleus RNA sequencing revealed gene expression changes during repair after acute kidney injury. We describe a small population of proximal tubule cells that fail to repair (FR-PTCs). Since this subpopulation expresses abundant proinflammatory and profibrotic genes, it may represent a new therapeutic target to improve repair and reduce fibrosis after AKI. After acute kidney injury (AKI), patients either recover or alternatively develop fibrosis and chronic kidney disease. Interactions between injured epithelia, stroma, and inflammatory cells determine whether kidneys repair or undergo fibrosis, but the molecular events that drive these processes are poorly understood. Here, we use single nucleus RNA sequencing of a mouse model of AKI to characterize cell states during repair from acute injury. We identify a distinct proinflammatory and profibrotic proximal tubule cell state that fails to repair. Deconvolution of bulk RNA-seq datasets indicates that this failed-repair proximal tubule cell (FR-PTC) state can be detected in other models of kidney injury, increasing during aging in rat kidney and over time in human kidney allografts. We also describe dynamic intercellular communication networks and discern transcriptional pathways driving successful vs. failed repair. Our study provides a detailed description of cellular responses after injury and suggests that the FR-PTC state may represent a therapeutic target to improve repair.
Gaining insights from RNA-Seq data using iDEP 1

5 The analysis and interpretation of the RNA-Seq data can be time-consuming and challenging. We aim to 6 streamline the bioinformatic analyses of gene-level data by developing a user-friendly web application for 7 exploratory data analysis, differential expression, and pathway analysis. iDEP (integrated Differential 8 Expression and Pathway analysis) seamlessly connects 63 R/Bioconductor packages, 208 annotation 9 databases for plant and animal species, and 2 web services. The workflow can be reproduced by 10 downloading customized R code and related files. As demonstrated by two examples, iDEP (http://ge11 lab.org/idep/) democratizes access to bioinformatics resources and empowers biologists to easily gain 12 actionable insights from transcriptomic data. 13 14
Massively parallel encapsulation of single cells with structured microparticles and secretion-based flow sorting

Techniques to analyze and sort single cells based on functional outputs, such as secreted products, have the potential to transform our understanding of cellular biology, as well as accelerate the development of next generation cell and antibody therapies. However, secreted molecules rapidly diffuse away from cells, and analysis of these products requires specialized equipment and expertise to compartmentalize individual cells and capture their secretions. Herein we demonstrate the use of suspendable microcontainers to sort single viable cells based on their secreted products at high-throughput using only commonly accessible laboratory infrastructure. Our microparticles act as solid supports which facilitate cell attachment, partition uniform aqueous compartments, and capture secreted proteins. Using this platform, we demonstrate high-throughput screening of stably- and transiently-transfected producer cells based on relative IgG production as well as screening of B lymphocytes and hybridomas based on antigen-specific antibody production using commercially available flow sorters. Leveraging the high-speed sorting capabilities of standard sorters, we sorted >1,000,000 events in less than an hour. The reported microparticles can be easily stored, and distributed as a consumable reagent amongst researchers, democratizing access to high-throughput functional cell screening.
Testing the reinforcement learning hypothesis of social conformity

Our preferences are influenced by the opinions of others. The past human neuroimaging studies on social conformity have identified a network of brain regions related to social conformity that includes the posterior medial frontal cortex (pMFC), anterior insula, and striatum. It was hypothesized that since these brain regions are also known to play important roles in reinforcement learning (i.e., processing prediction error), social conformity and reinforcement learning have a common neural mechanism. However, these two processes have previously never been directly compared; therefore, the extent to which they shared a common neural mechanism had remained unclear. This study aimed to formally test the hypothesis. The same group of participants (n = 25) performed social conformity and reinforcement learning tasks inside a functional magnetic resonance imaging (fMRI) scanner. Univariate fMRI data analyses revealed activation overlaps in the pMFC and bilateral insula between social conflict and unsigned prediction error and in the striatum between social conflict and signed prediction error. We further conducted multi-voxel pattern analysis (MVPA) for more direct evidence of a shared neural mechanism. MVPA did not reveal any evidence to support the hypothesis in any of these regions but found that activation patterns between social conflict and prediction error in these regions were largely distinct. Taken together, the present study provides no clear evidence of a common neural mechanism between social conformity and reinforcement learning.
III. Unravelling the basis for the extended circulatory lifespan of human red blood cells and for the hyperdense collapse of irreversibly sickled cells

Human red blood cells (RBCs) have a circulatory lifespan of about four months. Under constant oxidative and mechanical stress, but devoid of organelles and deprived of biosynthetic capacity for protein renewal, RBCs undergo substantial homeostatic changes, progressive densification followed by late density reversal among others, changes assumed to have been harnessed by evolution to sustain the rheological competence of the RBCs for as long as possible. The mechanism by which this is achieved is unknown. Each RBC traverses capillaries between 1000 and 2000 times per day, roughly one transit per minute, a total of about 2•105 transits during their lifespan. A dedicated Lifespan model of RBC homeostasis was developed as an extension of the RCM introduced in the first paper of this series to explore the cumulative patterns predicted for repetitive capillary transits over a standardized lifespan period of 120 days, using experimental data to constrain the parameter space. Capillary transits were simulated by periods of elevated cell/medium volume ratios and by transient deformation-induced permeability changes attributed to PIEZO1 channel mediation as outlined in the second paper of this series. The first unexpected finding was that quantal changes generated during single capillary transits cease accumulating after a few days and cannot account for the observed progressive densification of RBCs on their own, thus ruling out the quantal hypothesis. The second unexpected finding was that the documented patterns of RBC densification and late reversal could only be emulated by the implementation of a strict time-course of decay in the activities of the calcium and Na/K pumps, but only in addition to the quantal changes. These results showed that both quantal changes and pump-decay regimes were necessary to account for the documented lifespan pattern, neither sufficient on their own. They also suggested a strong selective component in the pump decay sequence. A third finding was that RBCs exposed to levels of calcium permeation above certain thresholds in the circulation could develop a pattern of late or early hyperdense collapse followed by delayed density reversal. When tested over much reduced lifespan periods the results emulated the known circulatory fate of irreversible sickle cells, the cell subpopulation responsible for vaso-occlusion and for most of the clinical manifestations of sickle cell disease. Analysis of the results provided an insightful new understanding of the mechanisms driving the changes in RBC homeostasis during circulatory aging in health and disease.
Oxytocin differentially modulates amygdala responses during top-down and bottom-up aversive anticipation

The ability to successfully regulate negative emotions such as fear and anxiety is vital for mental health. The neuropeptide oxytocin (OXT) acts as important modulator of emotion regulation, as reflected by reduced amygdala responses but increased amygdala–prefrontal cortex (PFC) functional connectivity in response to threatening stimuli. The present randomized, between-subject, placebo (PLC)-controlled pharmacological study combined intranasal administration of OXT with functional MRI during an explicit (cognitive) emotion regulation (i.e. distancing reappraisal) paradigm in 65 healthy male participants to investigate the modulatory effects of OXT on both bottom-up and top-down emotion regulation. OXT attenuated the activation in posterior insular cortex and amygdala during anticipation of top-down regulation of predictable threat stimuli in participants with high trait anxiety, providing evidence to support the anxiolytic action of OXT. In contrast, OXT enhanced amygdala activity during bottom-up anticipation of an unpredictable threat stimulus in participants with low trait anxiety. OXT may thus facilitate top-down goal-directed attention by attenuating amygdala activity in high anxiety individuals, while promote bottom-up attention/vigilance to unexpected threat by enhancing anticipatory amygdala activity in low anxiety individuals. The opposite effects of OXT on anticipatory amygdala activation in high versus low anxiety individuals may suggest a baseline anxiety level dependent mechanism via which OXT promotes optimal levels of amygdala activation during the anticipation of an imminent threat. OXT may thus have the potential to promote an adaptive balance between bottom-up and top-down attention systems depending on individual levels of pre-treatment trait anxiety levels.
Global & Temporal Patterns of Submicroscopic Plasmodium falciparum 1 Malaria Infection 2

11 Molecular detection of Plasmodium falciparum infection has revealed large numbers of individuals 12 with low-density (yet transmissible) infections undetectable by microscopy. Here we present an 13 updated systematic review of cross-sectional malaria surveys to explore the prevalence and drivers of 14 these submicroscopic infections and define where they are likely to be relevant to malaria control 15 efforts. Our results show that submicroscopic infections predominate in low transmission settings, but 16 also reveal marked geographical variation in their prevalence, being highest in South American surveys 17 and lowest in West African studies. Whilst current transmission levels partly explain these results, we 18 find that historical transmission intensity also represents a crucial determinant of the size of the 19 submicroscopic reservoir. Submicroscopic infection was more likely in adults than children, although 20 we did not observe a statistically significant influence of seasonality. Our results suggest that the 21 contribution of submicroscopic infections to transmission likely varies substantially across settings, 22 potentially warranting different approaches to their targeting in the approach to elimination. 23