Miracle-dz/UniFAR-FTUs huggingface dataset:
Full-length isoform transcriptome of developing human brain provides new insights into autism

Alternative splicing plays important role in brain development, however its global contribution to human neurodevelopmental diseases (NDD) has not been fully investigated. Here, we examined the relationships between full-length splicing isoforms expression in the brain and de novo loss-of-function mutations identified in the patients with NDDs. We analyzed the full-length isoform transcriptome of the developing human brain and observed differentially expressed isoforms and isoform co-expression modules undetectable by gene-level analyses. These isoforms were enriched in loss-of-function mutations and microexons, co-expressed with a unique set of partners, and had higher prenatal expression. We experimentally tested the impact of splice site mutations in five NDD risk genes, including SCN2A, DYRK1A and BTRC, and demonstrated exon skipping. Furthermore, our results suggest that the splice site mutation in BTRC reduces translational efficiency, likely impacting Wnt signaling through impaired degradation of β-catenin. We propose that functional effect of mutations associated with human diseases should be investigated at the isoform-rather than the gene-level resolution. Highlights Differential isoform expression analysis of the human brain transcriptome reveals neurodevelopmental processes and pathways undetectable by differential gene expression analyses. Splicing isoforms impacted by neurodevelopmental disease (NDD) risk mutations exhibit higher prenatal expression, are enriched in microexons and are involved in neuronal-related functions. Isoform co-expression network analysis identifies modules with splicing and synaptic functions that are enriched in NDD mutations. Splice site mutations impacting NDD risk genes cause exon skipping and produce novel isoforms with altered biological properties. Functional impact of mutations should be investigated at the full-length isoform-level rather than the gene-level resolution
Classification of Grain Amaranths Using Chromosome-Level Genome Assembly of Ramdana, A. hypochondriacus

In the age of genomics-based crop improvement, a high-quality genome of a local landrace adapted to the local environmental conditions is critically important. Grain amaranths produce highly nutritional grains with a multitude of desirable properties including C4 photosynthesis highly sought-after in other crops. For improving the agronomic traits of grain amaranth and for the transfer of desirable traits to dicot crops, a reference genome of a local landrace is necessary. Towards this end, our lab had initiated sequencing the genome of Amaranthus (A.) hypochondriacus (A.hyp_K_white) and had reported a draft genome in 2014. We selected this landrace because it is well adapted for cultivation in India during the last century and is currently a candidate for TILLING-based crop improvement. More recently, a high-quality chromosome-level assembly of A. hypochondriacus (PI558499, Plainsman) was reported. Here, we report a chromosome-level assembly of A. hyp_K_white (AhKP) using low-coverage PacBio reads, contigs from the reported draft genome of A. hyp_K_white, raw HiC data and reference genome of Plainsman. The placement of A. hyp_K_white on the phylogenetic tree of grain amaranths of known accessions clearly suggests that A. hyp_K_white is genetically distal from Plainsman and is most closely related to the accession PI619259 from Nepal (Ramdana). Furthermore, the classification of another accession, Suvarna, adapted to the local environment and selected for yield and other desirable traits, is clearly A. cruentus. A classification based on hundreds of thousands of SNPs validated taxonomy-based classification for a majority of the accessions providing the opportunity for reclassification of a few.
Caudal-rostral progression of alpha motoneurone degeneration in the SOD1G93A mouse model of amyotrophic lateral sclerosis

Mice with transgenic expression of human SOD1G93A are a widely used model of ALS, with a caudal-rostral progression of motor impairment. Previous studies have quantified the progression of motoneurone (MN) degeneration based on size, even though alpha (α-) and gamma (γ-) MNs overlap in size. Therefore, using molecular markers and synaptic inputs, we quantified the survival of α-MNs and γ-MNs at the lumbar and cervical spinal segments of 3- and 4-month SOD1G93A mice, to investigate whether there is a caudal-rostral progression of MN death. By 3-months, in the cervical and lumbar spinal cord, there was α-MN degeneration with complete γ-MN sparing. At 3-months the cervical spinal cord had more α-MNs per ventral horn than the lumbar spinal cord, in SOD1G93A mice. A similar spatial trend of degeneration was observed in the corticospinal tract, which remained intact in the cervical spinal cord at 3- and 4-months of age. These findings agree with the corticofugal synaptopathy model, that α-MN and CST of the lumbar spinal cord are more susceptible to degeneration in SOD1G93A mice. Hence, there is spatial and temporal caudal-rostral progression of α-MN and CST degeneration in SOD1G93A mice. Highlights SOD1G93A mice display a caudal-rostral progression of motor impairment. Lumbar spinal cord of SOD1G93A mice has an enhanced susceptibility to degeneration. SOD1G93A mice exhibit a caudal-rostral progression of α-MN and CST degeneration
A conserved role for sleep in supporting spatial learning in Drosophila

Sleep loss and aging impair hippocampus-dependent spatial learning in mammalian systems. Here we use the fly Drosophila melanogaster to investigate the relationship between sleep and spatial learning in healthy and impaired flies. The spatial learning assay is modeled after the Morris Water Maze. The assay uses a ‘thermal maze’ consisting of a 5×5 grid of Peltier plates maintained at 36-37°C and a visual panorama. The first trial begins when a single tile that is associated with a specific visual cue is cooled to 25°C. For subsequent trials, the cold tile is heated, the visual panorama is rotated and the flies must find the new cold-tile by remembering its association with the visual cue. Significant learning was observed with two different wild-type strains – Cs and 2U, validating our design. Sleep deprivation prior to training impaired spatial learning. Learning was also impaired in the classic learning mutant rutabaga (rut); enhancing sleep restored learning to rut mutants. Further we found that flies exhibited dramatic age-dependent cognitive decline in spatial learning starting at 20-24 days of age. These impairments could be reversed by enhancing sleep. Finally, we find that spatial learning requires dopaminergic signaling and that enhancing dopaminergic signaling in aged flies restored learning. Our results are consistent with the impairments seen in rodents and humans. These results thus demonstrate a critical conserved role for sleep in supporting spatial learning, and suggest potential avenues for therapeutic intervention during aging. STATEMENT OF SIGNIFICANCE We have studied the relationship between sleep and plasticity using a Drosophila learning assay modified after the Morris Water Maze. Using this assay, we find that sleep loss impairs spatial learning. As in mammals, flies exhibited age-dependent spatial learning impairments. Importantly, the age-dependent impairments were reversed by enhancing sleep. Interestingly, our results mirror studies on hippocampus dependent memories in rodents and humans. Thus, our data describe an evolutionarily conserved role for sleep in regulating spatial learning. They also support augmenting sleep as a therapeutic strategy to ameliorate learning impairments.
H3K27me3 is dispensable for early differentiation but required to maintain differentiated cell identity

Polycomb repressive complex 2 (PRC2) catalyzes trimethylation of histone H3 on lysine 27 and is required for normal development of complex eukaryotes. The requirement for H3K27me3 in various aspects of mammalian differentiation is not clear. Though associated with repressed genes, the modification is not sufficient to induce gene repression, and in some instances is not required. To examine the role of the modification in mammalian differentiation, we blocked trimethylation of H3K27 with both a small molecule inhibitor, GSK343, and by introducing a point mutation into EZH2, the catalytic subunit of PRC2. We found that cells with substantively decreased H3K27 tri-methylation were able to differentiate, which contrasts with EZH2 null cells. Different PRC2 targets had varied requirements for H3K27me3 in repressive regulation with a subset that maintained normal levels of repression in the absence of methylation. The primary cellular phenotype when H3K27 tri-methylation was blocked was an inability of the altered cells to maintain a differentiated state when challenged. This phenotype was determined by H3K27me3 deposition both in embryonic stem cells and in the first four days of differentiation. H3K27 tri-methylation therefore was not necessary for formation of differentiated cell states but was required to maintain a stable differentiated state.
Dynamic extrinsic pacing of the HOX clock in human axial progenitors controls motor neuron subtype specification

ABSTRACT Rostro-caudal patterning of vertebrates depends on the temporally progressive activation of HOX genes within axial stem cells that fuel axial embryo elongation. Whether the pace of sequential activation of HOX genes, the 'HOX clock', is controlled by intrinsic chromatin-based timing mechanisms or by temporal changes in extrinsic cues remains unclear. Here, we studied HOX clock pacing in human pluripotent stem cell-derived axial progenitors differentiating into diverse spinal cord motor neuron subtypes. We show that the progressive activation of caudal HOX genes is controlled by a dynamic increase in FGF signaling. Blocking the FGF pathway stalled induction of HOX genes, while a precocious increase of FGF, alone or with GDF11 ligand, accelerated the HOX clock. Cells differentiated under accelerated HOX induction generated appropriate posterior motor neuron subtypes found along the human embryonic spinal cord. The pacing of the HOX clock is thus dynamically regulated by exposure to secreted cues. Its manipulation by extrinsic factors provides synchronized access to multiple human neuronal subtypes of distinct rostro-caudal identities for basic and translational applications. This article has an associated ‘The people behind the papers’ interview. Highlighted Article: Control by extrinsic factors of the sequential activation of HOX genes in axial progenitors is revealed by motor neuron subtype specification in human pluripotent stem cells.
No Assembly Required: Using BTyper3 to Assess the Congruency of a Proposed Taxonomic Framework for the Bacillus cereus Group With Historical Typing Methods

The Bacillus cereus group, also known as B. cereus sensu lato (s.l.), is a species complex comprising numerous closely related lineages, which vary in their ability to cause illness in humans and animals. The classification of B. cereus s.l. isolates into species-level taxonomic units is essential for facilitating communication between and among microbiologists, clinicians, public health officials, and industry professionals, but is not always straightforward. A recently proposed genomospecies-subspecies-biovar taxonomic framework aims to provide a standardized nomenclature for this species complex but relies heavily on whole-genome sequencing (WGS), a technology with limited accessibility. It thus is unclear whether popular, low-cost typing methods (e.g., single- and multi-locus sequence typing) remain congruent with the proposed taxonomy. Here, we characterize 2,231 B. cereus s.l. genomes using a combination of in silico (i) average-nucleotide identity (ANI)-based genomospecies assignment, (ii) ANI-based subspecies assignment, (iii) seven-gene multi-locus sequence typing (MLST), (iv) panC group assignment, (v) rpoB allelic typing, and (vi) virulence factor detection. We show that sequence types (STs) assigned using MLST can be used for genomospecies assignment, and we provide a comprehensive list of ST/genomospecies associations. For panC group assignment, we show that an adjusted, eight-group framework is largely congruent with the proposed eight-genomospecies taxonomy and resolves incongruencies observed in the historical seven-group framework among isolates assigned to panC Groups II, III, and VI. We additionally provide a list of loci that capture the topology of the whole-genome B. cereus s.l. phylogeny that may be used in future sequence typing efforts. For researchers with access to WGS, MLST, and/or panC data, we showcase how our recently released software, BTyper3 (https://github.com/lmc297/BTyper3), can be used to assign B. cereus s.l. isolates to taxonomic units within this proposed framework with little-to-no user intervention or domain-specific knowledge of B. cereus s.l. taxonomy. We additionally outline a novel method for assigning B. cereus s.l. genomes to pseudo-gene flow units within proposed genomospecies. The results presented here highlight the backwards-compatibility and accessibility of the proposed taxonomic framework and illustrate that WGS is not a necessity for microbiologists who want to use the proposed taxonomy effectively.
Belief Distortions and Macroeconomic Fluctuations

This paper combines a data rich environment with a machine learning algorithm to provide new estimates of time-varying systematic expectational errors ("belief distortions") embedded in survey responses. We find that distortions are large on average even for professional forecasters, with all respondent-types over-weighting their own belief relative to other information. Fore-casts of inflation and GDP growth oscillate between optimism and pessimism by quantitatively large margins, with over-optimism associated with an increase in aggregate economic activity. Biases in expectations evolve dynamically in response to cyclical shocks. Biases about economic growth display greater initial under -reaction while those about inflation display greater delayed over -reaction.
Epidemiology of paediatric and adolescent fractures admitted to a South African provincial hospital

Background: There are limited studies available that examine the epidemiology of children and adolescents admitted with orthopaedic injuries in developing countries. Several unique factors in South Africa, such as a large socio-economic divide and a public health sector with limited resources, are suggested to influence injury patterns and fracture management. The data emanating from this study may play a role in identifying potential preventative measures. The aims of the study were to determine the age, sex, duration of admission, aetiology and management regimen of paediatric and adolescent patients admitted with fractures in a South African provincial hospital. Patients and methods: We did a cross-sectional review of medical records for the period 1 January 2016 to 31 December 2017 at a South African provincial hospital. Convenience sampling was done, and demographic and clinical data was collected from patient records. All patients younger than 18 years at the time of injury who were admitted with fractures of the limbs, pelvis or spine were included. Patients with incomplete clinical records were excluded. Results: A total of 731 patients were admitted during this period. After excluding patients with incomplete records, 526 (72%) were included in the study. From these records we found a higher percentage of males admitted (73%) and the average age was 7.72 years. The average duration of admission was 8.59 days. A fall on ground level was the most common mechanism of injury (70.0%), followed by pedestrian vehicle accidents (12.2%). The most frequently fractured regions were the forearm (36.4%), humerus (26.5%) and femur (18.9%). Multiple fractures were sustained by 2.4% and additional non-skeletal injuries were sustained by 2.9%. There was one fatality: a patient who presented with gunshot trauma. Conclusion: Despite fall-related injuries being the most common cause for admission, pedestrian vehicle accident prevention can have the greatest effect on admissions. They require significantly longer hospitalisation and present more frequently with additional injuries. By implementing safety strategies and improving road infrastructure, we can theoretically decrease the number of serious paediatric admissions. Level of evidence: Level 4
Joint Speech Dereverberation and Denoising Using Constrained NMF

Reverberation and background noise corrupt the speech recorded using distant microphones. This affects the performance of Automatic Speech Recognition (ASR) systems. The main objective of the thesis is to implement a framework to improve the ASR results for a distant, multi-channel recording corrupted by reverberation and background noise. The work focuses on improving the front-end of the ASR system to obtain an enhanced speech signal for the corresponding degraded utterances. The enhancement consists of multi-channel processing (source localization and beamforming) and single channel enhancement. Beamforming utilizes spatial information available in multi-channel recording to provide a single-channel enhanced output. The residual reverberation and noise present in the enhanced data are suppressed by the Non-negative Matrix Factorization (NMF) based enhancement. In the initial work, many meaningful constraints on Room Impulse Response (RIR) spectrogram are used to improve the dereverberation performance in a NMF context. The later work uses a separability approximation on RIR spectrogram to obtain an NMF model for reverberation as opposed to convolutive NMF (C-NMF) used in literature. This model is extended to have an NMF model for reverberation in presence of noise. The proposed method performs better than existing C-NMF based methods in objec-tive measures, such as cepstral distance (CD) and speech-to-reverberation modulation energy ratio (SRMR). The ASR performance of the complete framework remains to be evaluated.
Species of Dactylogyrus (Monogenoidea: Dactylogyridae) and Trichodina mutabilis (Ciliata) Infesting Koi Carp, Cyprinus carpio, During Mass Mortality at a Commercial Rearing Facility in Utah, U.S.A.

Abstract A die-off of koi carp, Cyprinus carpio, at a commercial rearing facility located in Spanish Fork, Utah, U.S.A. , is reported. Although the cause of mortality in carp remained undetermined, moribund carp became heavily infested with Trichodina mutabilis and 6 species of Dactylogyrus (prevalence = 100%). Dactylogyrus formosus comprised the largest proportion of the dactylogyrid population on infested hosts (38.7%), followed by D. dulkeiti (28.8%), D. anchoratus (14.7%), D. baueri (8.6%), D. intermedius (8.0%), and D. minutus (1.2%). Occurrences of D. dulkeiti and D. baueri on Cy. carpio represent new host records. Dactylogyrus dulkeiti and T. mutabilis on carp in Utah are the first records of these species in the Nearctic.
Poly(I:C) Challenge Alters Brain Expression of Oligodendroglia-Related Genes of Adult Progeny in a Mouse Model of Maternal Immune Activation

Background: Altered white matter connectivity, as evidenced by pervasive microstructural changes in myelination and axonal integrity in neuroimaging studies, has been implicated in the development of autism spectrum disorder (ASD) and related neurodevelopmental conditions such as schizophrenia. Despite an increasing appreciation that such white matter disconnectivity is linked to social behavior deficits, virtually no etiologically meaningful myelin-related genes have been identified in oligodendrocytes, the key myelinating cells in the CNS, to furnish an account on the causes. The impact of neurodevelopmental perturbations during pregnancy such as maternal immune activation (MIA) on these genes in memory-related neural networks has not been experimentally scrutinized. Methods: In this study, a mouse model of MIA by the viral dsRNA analog poly(I:C) was employed to mimic the effects of inflammation during pregnancy. Transcriptional expression levels of selected myelin- or oligodendroglia-related genes implicated in schizophrenia or ASD development were analyzed by in situ hybridization (ISH) and quantitative real-time PCR (qRT-PCR) with brain samples from MIA and control groups. The analysis focused on SOX-10 (SRY-related HMG-box 10), MAG (myelin-associated glycoprotein), and Tf (transferrin) expression in the hippocampus and the surrounding memory-related cortical regions in either hemisphere. Results: Specifically, ISH reveals that in the brain of prenatal poly(I:C)-exposed mouse offspring in the MIA model (gestation day 9), mRNA expression of the genes SOX10, MAG and Tf were generally reduced in the limbic system including the hippocampus, retrosplenial cortex and parahippocampal gyrus on either side of the hemispheres. qRT-PCR further confirms the reduction of SOX10, MAG, and Tf expression in the medial prefrontal cortex, sensory cortex, amygdala, and hippocampus. Conclusions: Our present results provide direct evidence that prenatal exposure to poly(I:C) elicits profound and long-term changes in transcript level and spatial distribution of myelin-related genes in multiple neocortical and limbic regions, notably the hippocampus and its surrounding memory-related neural networks. Our work demonstrates the potential utility of oligodendroglia-related genes as biomarkers for modeling neurodevelopmental disorders, in agreement with the hypothesis that MIA during pregnancy could lead to compromised white matter connectivity in ASD.
Gastric Cancer Tumor Microenvironment Characterization Reveals Stromal-Related Gene Signatures Associated With Macrophage Infiltration

The tumor microenvironment (TME) has attracted attention owing to its essential role in tumor initiation, progression, and metastasis. With the emergence of immunotherapies for various cancers, and their high efficacy, an understanding of the TME in gastric cancer (GC) is critical. The aim of this study was to investigate the effect of various components within the GC TME, and to identify mechanisms that exhibit potential as therapeutic targets. The ESTIMATE algorithm was used to quantify immune and stromal components in GC samples, whose clinicopathological significance and relationship with predicted outcomes were explored. Low tumor mutational burden and high M2 macrophage infiltration, which are considered immune suppressive characteristics and may be responsible for unfavorable prognoses in GC, were observed in the high stromal group (HR = 1.585; 95% CI, 1.112–2.259; P = 0.009). Furthermore, weighted correlation network, differential expression, and univariate Cox analyses were used, along with machine learning methods (LASSO and SVM-RFE), to reveal genome-wide immune phenotypic correlations. Eight stromal-relevant genes cluster (FSTL1, RAB31, FBN1, ANTXR1, LRRC32, CTSK, COL5A2, and ENG) were identified as adverse prognostic factors in GC. Finally, using a combination of TIMER database and single-sample gene set enrichment analyses, we found that the identified genes potentially contribute to macrophage recruitment and polarization of tumor-associated macrophages. These findings provide a different perspective into the immune microenvironment and indicate potential prognostic and therapeutic targets for GC immunotherapies.