Miracle-dz/UniFAR-FTUs huggingface dataset:
Premalignant Nf1, Trp53-null Oligodendrocyte Precursor Cells Become Stalled in a Heterogeneous State of Replication Stress Before Gliomagenesis

Cancer evolves from premalignant clones that accumulate mutations and adopt unusual cell states to achieve transformation. Previously, we pinpointed the oligodendrocyte precursor cell (OPC) as a cell-of-origin for glioma, but the early changes of mutant OPCs during premalignancy remained unknown. Using mice engineered for inducible Nf1–Trp53 loss in OPCs, we acutely isolated labeled mutant OPCs by laser-capture microdissection and determined gene-expression changes by bulk RNA sequencing and a fluctuation analysis, called stochastic profiling, which uses RNA-sequencing measurements from random pools of 10 mutant cells. At 12 days after Nf1–Trp53 deletion, while bulk differences were mostly limited to mitotic hallmarks and genes for ribosome biosynthesis, stochastic profiling revealed a spectrum of stem-progenitor (Axl, Aldh1a1), proneural, and mesenchymal states as potential starting points for gliomagenesis. At 90 days, bulk sequencing detected very few differentially expressed transcripts, whereas stochastic profiling revealed cell states for neurons and mural cells that do not give rise to glial tumors, suggesting cellular dead-ends for gliomagenesis. Importantly, we identified mutant OPCs that strongly expressed key effectors of nonsense-mediated decay (Upf3b) and homology-dependent DNA repair (Rad51c, Slx1b, Ercc4) along with DNA-damage markers suggesting transcription-associated replication stress. Analysis of 10-cell transcriptomes at 90 days identified a locus of elevated gene expression containing an additional repair endonuclease (Mus81) and Rin1, a Ras–Raf antagonist and possible counterbalance to Nf1 loss. At 150 days, Rin1 was microdeleted in some gliomas and downregulated in all others. Replication stress may pose a considerable bottleneck that must be resolved for gliomas to initiate. Statement of significance In situ stochastic profiling of heterogeneous cell states in a mouse model of glioma uncovers regulatory confusion in a glioma cell-of-origin and defines a state of replication stress that precedes tumor initiation.
Overexpression of Mdm36 reveals Num1 foci that mediate dynein-dependent microtubule sliding in budding yeast

ABSTRACT The current model for spindle positioning requires attachment of the microtubule (MT) motor cytoplasmic dynein to the cell cortex, where it generates pulling force on astral MTs to effect spindle displacement. How dynein is anchored by cortical attachment machinery to generate large spindle-pulling forces remains unclear. Here, we show that cortical clustering of Num1, the yeast dynein attachment molecule, is limited by its assembly factor Mdm36. Overexpression of Mdm36 results in an overall enhancement of Num1 clustering but reveals a population of dim Num1 clusters that mediate dynein anchoring at the cell cortex. Direct imaging shows that bud-localized, dim Num1 clusters containing around only six Num1 molecules mediate dynein-dependent spindle pulling via a lateral MT sliding mechanism. Mutations affecting Num1 clustering interfere with mitochondrial tethering but do not interfere with the dynein-based spindle-pulling function of Num1. We propose that formation of small ensembles of attachment molecules is sufficient for dynein anchorage and cortical generation of large spindle-pulling forces. This article has an associated First Person interview with the first author of the paper. Summary: Using Mdm36 as a tool to cluster Num1 at the cell cortex, this study reveals that there are two distinct populations of Num1, each mediating its role in spindle positioning and mitochondrial tethering, respectively.
A network model of the barrel cortex combined with a differentiator detector reproduces features of the behavioral response to single-neuron stimulation

The stimulation of a single neuron in the rat somatosensory cortex can elicit a behavioral response. The probability of a behavioral response does not depend appreciably on the duration or intensity of a constant stimulation, whereas the response probability increases significantly upon injection of an irregular current. Biological mechanisms that can potentially suppress a constant input signal are present in the dynamics of both neurons and synapses and seem ideal candidates to explain these experimental findings. Here, we study a large network of integrate-and-fire neurons with several salient features of neuronal populations in the rat barrel cortex. The model includes cellular spike-frequency adaptation, experimentally constrained numbers and types of chemical synapses endowed with short-term plasticity, and gap junctions. Numerical simulations of this model indicate that cellular and synaptic adaptation mechanisms alone may not be sufficient to account for the experimental results if the local network activity is read out by an integrator. However, a differentiator circuit can detect the single-cell stimulation with a reliability that barely depends on the length or intensity of the stimulus, but that increases when an irregular signal is used. This finding is in accordance with the experimental results obtained for the stimulation of a regularly-spiking excitatory cell. Author summary It is widely assumed that only a large group of neurons can encode a stimulus or control behavior. This tenet of neuroscience has been challenged by experiments in which stimulating a single cortical neuron has had a measurable effect on an animal’s behavior. Recently, theoretical studies have explored how a single-neuron stimulation could be detected in a large recurrent network. However, these studies missed essential biological mechanisms of cortical networks and are unable to explain more recent experiments in the barrel cortex. Here, to describe the stimulated brain area, we propose and study a network model endowed with many important biological features of the barrel cortex. Importantly, we also investigate different readout mechanisms, i.e. ways in which the stimulation effects can propagate to other brain areas. We show that a readout network which tracks rapid variations in the local network activity is in agreement with the experiments. Our model demonstrates a possible mechanism for how the stimulation of a single neuron translates into a signal at the population level, which is taken as a proxy of the animal’s response. Our results illustrate the power of spiking neural networks to properly describe the effects of a single neuron’s activity.
Understanding functional consequences of type 2 diabetes risk loci using the universal data integration and visualization R package CONQUER

Background Numerous large genome-wide association studies (GWASs) have been performed to understand the genetic factors of numerous traits, including type 2 diabetes. Many identified risk loci are located in non-coding and intergenic regions, which complicates the understanding how genes and their downstream pathways are influenced. An integrative data approach is required to understand the mechanism and consequences of identified risk loci. Results Here, we developed the R-package CONQUER. Data for SNPs of interest (build GRCh38/hg38) were acquired from static- and dynamic repositories, such as, GTExPortal, Epigenomics Project, 4D genome database and genome browsers such as ENSEMBL. CONQUER modularizes SNPs based on the underlying co-expression data and associates them with biological pathways in specific tissues. CONQUER was used to analyze 403 previously identified type 2 diabetes risk loci. In all tissues, the majority of SNPs (mean = 13.50, SD = 11.70) were linked to metabolism. A tissue-shared effect was found for four type 2 diabetes-associated SNPs (rs601945, rs1061810, rs13737, rs4932265) that were associated with differential expression of HLA-DQA2, HSD17B12, MAN2C1 and AP3S2 respectively. Seven SNPs were identified that influenced the expression of seven ribosomal proteins in multiple tissues. Finally, one SNP (rs601945) was found to influence multiple HLA genes in all twelve tissues investigated. Conclusion We present an universal R-package that aggregates and visualizes data in order to better understand functional consequences of GWAS loci. Using CONQUER, we showed that type 2 diabetes risk loci have many tissue-shared effects on multiple pathways including metabolism, the ribosome and HLA pathway.
The Stochastic Resonance model of auditory perception: A unified explanation of tinnitus development, Zwicker tone illusion, and residual inhibition

Stochastic Resonance (SR) has been proposed to play a major role in auditory perception, and to maintain optimal information transmission from the cochlea to the auditory system. By this, the auditory system could adapt to changes of the auditory input at second or even sub-second timescales. In case of reduced auditory input, somatosensory projections to the dorsal cochlear nucleus would be disinhibited in order to improve hearing thresholds by means of SR. As a side effect, the increased somatosensory input corresponding to the observed tinnitus-associated neuronal hyperactivity is then perceived as tinnitus. In addition, the model can also explain transient phantom tone perceptions occurring after ear plugging, or the Zwicker tone illusion. Vice versa, the model predicts that via stimulation with acoustic noise, SR would not be needed to optimize information transmission, and hence somatosensory noise would be tuned down, resulting in a transient vanishing of tinnitus, an effect referred to as residual inhibition.
Evolution of cellular diversity in primary motor cortex of human, marmoset monkey, and mouse

The primary motor cortex (M1) is essential for voluntary fine motor control and is functionally conserved across mammals. Using high-throughput transcriptomic and epigenomic profiling of over 450,000 single nuclei in human, marmoset monkey, and mouse, we demonstrate a broadly conserved cellular makeup of this region, whose similarity mirrors evolutionary distance and is consistent between the transcriptome and epigenome. The core conserved molecular identity of neuronal and non-neuronal types allowed the generation of a cross-species consensus cell type classification and inference of conserved cell type properties across species. Despite overall conservation, many species specializations were apparent, including differences in cell type proportions, gene expression, DNA methylation, and chromatin state. Few cell type marker genes were conserved across species, providing a short list of candidate genes and regulatory mechanisms responsible for conserved features of homologous cell types, such as the GABAergic chandelier cells. This consensus transcriptomic classification allowed the Patch-seq identification of layer 5 (L5) corticospinal Betz cells in non-human primate and human and characterization of their highly specialized physiology and anatomy. These findings highlight the robust molecular underpinnings of cell type diversity in M1 across mammals and point to the genes and regulatory pathways responsible for the functional identity of cell types and their species-specific adaptations.
Distinct Vegfa isoforms control endothelial cell proliferation through PI3 kinase signalling mediated regulation of cdkn1a/p21

The formation of appropriately patterned blood vessel networks requires endothelial cell migration and proliferation. Signaling through the Vascular Endothelial Growth Factor A (VEGFA) pathway is instrumental in coordinating these processes. mRNA splicing generates short (diffusible) and long (extracellular matrix bound) Vegfa isoforms. The differences between these isoforms in controlling cellular functions are not understood. In zebrafish, vegfaa generates short and long isoforms, while vegfab only generates long isoforms. We found that mutations in vegfaa affected endothelial cell migration and proliferation. Surprisingly, mutations in vegfab specifically reduced endothelial cell proliferation. Analysis of downstream signaling revealed no change in MAPK (ERK) activation, while inhibiting PI3 kinase signaling phenocopied vegfab mutants. The cell cycle inhibitor cdkn1a/p21 was upregulated in vegfab deficient embryos. Accordingly, reducing cdkn1a/p21 restored endothelial cell proliferation. Together, these results suggest that extracellular matrix bound Vegfa acts through PI3K signaling to specifically control endothelial cell proliferation during angiogenesis independently of MAPK (ERK) regulation.
Dermatological diseases among patients with psychiatric disorders

Background Skin diseases and psychiatric disorders are related to each other. So, the aim of this research is to study the prevalence and distribution of skin diseases among patients with psychiatric disorders in Beni Suef Governorate. Patients and methods A total of 302 patients with psychiatric disorders attending the outpatient clinic of the Psychiatry Hospital in Beni Suef were assessed for psychiatric and dermatological diseases throughout the period between January 2016 and June 2016. Results Out of the 302 patients, 111 (36.7%) were diagnosed as schizophrenia, 91 (30.2%) with major depressive disorder, 36 (11.9%) with bipolar I disorder, 32 (10.6%) with obsessive compulsive disorder, and 32 (10.6%) with anxiety disorders. Of these patients, 267 (88.4%) had dermatological disorders and infectious dermatological disorders constituted 49.8% of the total skin diseases. Conclusion Skin diseases particularly those of infectious pattern were prevalent among patients with psychiatric disorders.
Patterned activation of action potential patterns during offline states in the neocortex: replay and non-replay

Action potential generation (spiking) in the neocortex is organized into repeating non-random patterns during both awake experiential states and non-engaged states ranging from inattention to sleep to anaesthesia—and even occur in slice preparations. Repeating patterns in a given population of neurons between states may imply a common means by which cortical networks can be engaged despite brain state changes, but super-imposed on this common firing is a variability that is both specific to ongoing inputs and can be re-shaped by experience. This similarity with specifically induced variance may allow for a range of processes including perception, memory consolidation and network homeostasis. Here, we review how patterned activity in neocortical populations has been studied and what it may imply for a cortex that must be both static and plastic. This article is part of the Theo Murphy meeting issue ‘Memory reactivation: replaying events past, present and future’.
A sleep spindle framework for motor memory consolidation

Sleep spindle activity has repeatedly been found to contribute to brain plasticity and consolidation of both declarative and procedural memories. Here we propose a framework for motor memory consolidation that outlines the essential contribution of the hierarchical and multi-scale periodicity of spindle activity, as well as of the synchronization and interaction of brain oscillations during this sleep-dependent process. We posit that the clustering of sleep spindles in ‘trains', together with the temporally organized alternation between spindles and associated refractory periods, is critical for efficient reprocessing and consolidation of motor memories. We further argue that the long-term retention of procedural memories relies on the synchronized (functional connectivity) local reprocessing of new information across segregated, but inter-connected brain regions that are involved in the initial learning process. Finally, we propose that oscillatory synchrony in the spindle frequency band may reflect the cross-structural reactivation, reorganization and consolidation of motor, and potentially declarative, memory traces within broader subcortical–cortical networks during sleep. This article is part of the Theo Murphy meeting issue ‘Memory reactivation: replaying events past, present and future'.
Causal Structures of Multidimensional QoE in Haptic-Audiovisual Communications

This article proposes a methodology for building and verifying plausible models that can express causation in multidimensional QoE for haptic-audiovisual interactive communications. For the modeling, we utilize subjective experimental data of five-point scores collected in a previous study where a pair of subjects carry out two kinds of interactive tasks (castanets hitting and object movement) in real space (not in virtual space). The multidimensional QoE is composed of 15 measures for the castanets hitting and 14 measures for the object movement. To reduce the dimension, we classify the QoE measures into three groups as indicators of three constructs (latent variables or factors): AVQ (AudioVisual Quality), HQ (Haptic Quality), and UXQ (User eXperience Quality). We then build two models: (1) a structural equation model in which AVQ and HQ correlated with each other give causal effects on UXQ, and (2) a confirmatory factor analysis model in which the three constructs are only correlated with each other. We refer to the former as 3C-SEM and the latter as 3C-CFA. We further introduce a CFA model with a single construct for which all QoE measures are its indicators (1C-CFA). We perform Bayesian analysis of the three models by means of Markov chain Monte Carlo simulation; in each model, the deviance information criterion is obtained for model comparison, and the posterior predictive p-value is calculated for model checking. As a result, we find that 3C-SEM is the most plausible and that HQ has a stronger causal effect on UXQ than AVQ. We also learn that the correlation between AVQ and UXQ is much higher than the direct causal effect and that the increase in the association as correlation is due to the causal effect of HQ on UXQ through the correlation of AVQ with HQ. Thus, it is suggested that improving haptic performance is more effective in enhancement of QoE than improving audiovisual performance.
A New Hybrid Bat Algorithm Optimizing the Capacitated Vehicle Routing Problem

The Capacitated Vehicle Routing Problem (CVRP), an extension of the Traveling Salesman Problem with two added constraints, a local depot and a capacity constraint for each vehicle, is solved by a Hybrid Bat Algorithm (HBA). This paper investigates how the standard Bat Algorithm must be extended to become a HBA being able to solve the CVRP. The Hybrid Bat Algorithm is tested and compared to three other optimization algorithms for the CVRP, the Clarke & Wright Savings Algorithm, the Holmes and Parker Algorithm, and the Fisher and Jaikumar Method. It is discussed how the HBA is able to deliver decent solutions of the CVRP.
Summer Boost: Challenges and Opportunities in Summer Programs for Rising Kindergarten Students.

year predict student success in later years.1 Yet many children, particularly those from lowincome families, do not start kindergarten with the skills they need to be successful.2 In a national survey of kindergarten teachers, over one-third reported that about half of their students, or more, exhibited adjustment problems at the start of kindergarten, with rates being higher in schools located in high-poverty districts and schools serving a high
The Role of Social Influence and Network Churn in Beliefs about Electronic Medical Record Technology

Abstract The successful implementation of technology often hinges on individual beliefs about the innovation being introduced. Little is known about how social networks shape these beliefs. In this study, we examine: (1) whether individual beliefs about technology are influenced by the beliefs of their peers within their social networks (network content); and (2) whether changes in the composition of the social network over time (network churn) moderates the effect of peer beliefs on individual beliefs. We offer and test hypotheses about these relationships using longitudinal social network survey data from hospital staff collected 2 – 4 months before (N = 256) and 3 – 5 months after (N = 284) the implementation of a new electronic medical record (EMR) system at a large, academic hospital. Our findings suggest that peer beliefs about new technology significantly and negatively affect individual beliefs about technology in the early stages of EMR implementation. We also find that the effect of peer beliefs on individual beliefs is stronger in more stable social networks (i.e., social networks that experience few tie deletions over time) and weaker in less stable social networks (i.e., social networks that experience many tie deletions over time). Our study examines social influence in a novel context – the implementation of EMR systems in the hospital setting – and extends network theory by conceptualizing network churn as a moderating variable that may amplify or dampen the effect of networks.
The Phonology of Hong Kong English and Nigerian English: A Comparison

Based on the firsthand acoustic data from 16 Southern Min varieties used in Huilai and Puning counties, Guangdong, this paper has found four major tonal patterns, which reveals systematic tonal changes. Four kinds of chain shift, namely downward shift of falling tones, upward shift of rising tones, downward shift of level tones, and the V-shaped shift, have been identified which can account for the diversified tonal patterns in the area. This paper also finds different kinds of tonal merger that have interrupted the chain shift.
Risk Factor Profiles Differ for Cancers of Different Regions of the Colorectum.

BACKGROUND & AIMS The molecular features of colorectal tumors differ with their anatomic location. Colorectal tumors are usually classified as proximal or distal. We collected data from 3 cohorts to identify demographic, clinical, anthropometric, lifestyle, and dietary risk factors for colorectal cancer (CRC) at 7 anatomic subsites. We examined whether the associations differ among refined subsites and whether there are trends in associations from cecum to rectum. METHODS We collected data from the Nurses' Health Study, Nurses' Health Study 2, and Health Professionals Follow-up Study (45,351 men and 178,016 women, followed for a median 23 years) on 24 risk factors in relation to risk of cancer in cecum, ascending colon, transverse colon, descending colon, sigmoid colon, rectosigmoid junction, and rectum. Hazard ratios were estimated using Cox proportional hazards regression. We tested for linear and non-linear trends in associations with CRC among subsites and within proximal colon, distal colon, and rectum. RESULTS We documented 3058 cases of CRC (474 in cecum, 633 in ascending colon, 250 in transverse colon, 221 in descending colon, 750 in sigmoid colon, 202 in rectosigmoid junction, and 528 in rectum). The positive associations with cancer risk decreased, from cecum to rectum, for age and family history of CRC. In contrast, the inverse associations with cancer risk increased, from cecum to rectum, for endoscopic screening and intake of whole grains, cereal fiber, and processed red meat. There was a significant non-linear trend in the association between CRC and female sex, with hazards ratios ranging from 1.73 for ascending colon cancer to 0.54 for sigmoid colon cancer. For proximal colon cancers, the association with alcohol consumption and smoking before age 30 years increased from the cecum to transverse colon. For distal colon cancers, the positive association with waist circumference in men was greater for descending vs sigmoid colon cancer. CONCLUSIONS In an analysis of 3058 cases of CRC, we found that risk factor profiles differed for cancers along the colorectum. Proximal vs distal classifications are not sufficient to encompass the regional variations in colorectal tumor features and risk factors.