Miracle-dz/UniFAR-FTUs huggingface dataset:
Title: Structural neuroimaging signatures of anorexia nervosa features in a mixed sample enriched for disease vulnerability

Brain-behavior relationships that could provide insight into risk-associated pathophysiology have not been thoroughly assessed in anorexia nervosa (AN). Therefore, we sought to identify grey and white matter signatures of AN symptoms and risk factors (trait anxiety, set-shifting impairment) in a sample enriched for AN vulnerability, including acute and remitted AN patients and their unaffected sisters ( n = 72, aged 18 – 48 years). MRI/DTI data were acquired on a 3T scanner and processed with Freesurfer and FSL TBSS. Relationships between clinical variables of interest and regional subcortical volume, vertex-wise cortical surface architecture (thickness, surface area, local gyrification), and voxel-wise white matter microstructure (FA, MD) were tested with separate linear regressions, including age, BMI, lifetime AN diagnosis, and intracranial volume as covariates, where appropriate. Significance was determined using a Bonferroni-corrected threshold, p ( t ) ≤ 0.001. We detected distinct associations linking AN symptoms to lateral occipital cortical thickness and insular/cingulate gyrification and trait anxiety to lingual cortical thickness and superior parietal gyrification, and we detected overlapping associations linking AN symptoms and set-shifting impairment to frontoparietal gyrification. No other brain-behavior relationships emerged. Our findings suggest that variations in site-specific cortical morphology could give rise to core features of AN and shared temperamental and cognitive-behavioral risk factors for AN.
Ennet: construction of potential cancer-driving networks based on somatic enhancer mutations only

Whole genome sequencing technology has facilitated the discovery of a large number of somatic mutations in enhancers (SMEs), whereas the utility of SMEs in tumorigenesis has not been fully explored. Here we present Ennet, a method to comprehensively investigate SMEs enriched networks (SME-networks) in cancer by integrating SMEs, enhancer-gene interactions and gene-gene interactions. Using Ennet, we performed a pan-cancer analysis in 2004 samples from 8 cancer types and found many well-known cancer drivers were involved in the SME-networks, including ESR1, SMAD3, MYC, EGFR, BCL2 and PAX5. Meanwhile, Ennet also identified many new networks with less characterization but have potentially important roles in cancer, including a large SME-network in medulloblastoma (MB), which contains genes enriched in the glutamate receptor and neural development pathways. Interestingly, SME-networks are specific across cancer types, and the vast majority of the genes identified by Ennet have few mutations in gene bodies. Collectively, our work suggests that using enhancer-only somatic mutations can be an effective way to discover potential cancer-driving networks. Ennet provides a new perspective to explore new mechanisms for tumor progression from SMEs.
Research in care homes : issues of participation and citizenship

Across Scotland, there is a lack of research in care homes. This thesis explores this topic by examining links between inclusion, participation in general and participation in research and whether those who work and live in the care home environment experience social citizenship. Using a national survey and interviews with residents, staff, relatives and experts in care home research, this thesis investigated whether participation generally was linked to participation in research for residents, staff and visitors in a care home setting. The thesis further explored how social citizenship functions in a care home environment and whether there is a link between participation and citizenship. The findings suggest there is a lack of general participation which is connected with the leadership style and management within the care homes. There is misunderstanding about research and legislation amongst the care home staff, residents, visitors, as well as the junior research staff which inhibited staff and resident participation. Furthermore, citizenship is not experienced universally by residents or staff due to disempowerment, and exclusion occurs amongst residents due to age, frailty and dementia. By facilitating good leadership, communication and relationship-building such issues may be overcome. In addition, the analysis suggests a link is evident between inclusion, participation and citizenship. Where choice is provided and residents have their social position maintained, as well as have a degree of responsibility for shaping events, this leads to participation and inclusivity as described in Bartlett and O’Connor’s (2010) definition of social citizenship. Furthermore, if inclusion is adapted for cognition and frailty, then participation leads to the experience of social citizenship, encouraging a culture which can welcome research. The explicit emphasis on inclusion and participation in research has enabled this under-researched area of participation and experience of social citizenship in care homes to be more fully explored.
celldeath: A tool for detection of cell death in transmitted light microscopy images by deep learning-based visual recognition

Cell death experiments are routinely done in many labs around the world, these experiments are the backbone of many assays for drug development. Cell death detection is usually performed in many ways, and requires time and reagents. However, cell death is preceded by slight morphological changes in cell shape and texture. In this paper, we trained a neural network to classify cells undergoing cell death. We found that the network was able to highly predict cell death after one hour of exposure to camptothecin. Moreover, this prediction largely outperforms human ability. Finally, we provide a simple python tool that can broadly be used to detect cell death.
Isolation and genome sequencing of 14 Spongia sp. bacterial associates expands the taxonomic and functional breadth of the cultivatable marine sponge microbiome

Marine sponges live with complex microbial consortia, which have been considered as potential sources of novel natural products. However, the usual recalcitrance of host-associated microorganisms to cultivation makes studying sponge symbionts challenging. To tackle this complexity, exploration of cultivated sponge-associated bacteria and their coding potential is unavoidable. In this study, we isolate and report the draft genome sequences of 14 bacterial strains from the marine sponge Spongia sp. using R2A and VXA media. The strains belong to the classes Actinobacteria, Gammaproteobacteria, Alphaproteobacteria, and Cytophagia spanning 11 formally described genera plus two potentially novel genera in the Rhodobacteraceae family and one potentially novel family in the Cytophagales order. Functional genomics revealed presumed symbiosis factors typical of specific taxonomic groups (i.e. taurine metabolism genes among the Alphaproteobacteria, chitinase encoding genes and eukaryotic-like proteins in the Cytophagia genome) while multidrug efflux pumps, also important in host-microbe interactions, were common across all genomes. Moreover, we detected 76 secondary-metabolite biosynthetic gene clusters putatively involved in the production of drug-like compounds or signalling molecules across all genomes, warranting future biotechnologically driven research into their coding potential.
Cell signaling coordinates global Polycomb Repressive Complex 2 recruitment and gene expression in murine embryonic stem cells

The recruitment of Polycomb repressive complex 2 (PRC2) to gene promoters is critical for its function in repressing gene expression in murine embryonic stem cells (mESCs). However, previous studies have demonstrated although the expression of early lineage-specific genes is largely repressed, the genome-wide PRC2 occupancy is unexpectedly reduced in naïve mESCs. In this study, we provide evidence to show the FGF/ERK signaling determines the global PRC2 occupancy through regulating the expression of PRC2-recruting factor JARID2 in naïve mESCs. At the transcriptional level, the de-repression of bivalent genes is predominantly determined by the presence of cell signaling-associated transcription factors but not the status of PRC2 occupancy at gene promoters. Hence, this study not only reveals a key molecular mechanism by which the FGF/ERK signaling in regulating the PRC2 occupancy in mESCs, but also elucidates a fundamental question regarding the functional roles of transcription factors and Polycomb-mediated epigenetic mechanisms in transcriptional regulation.
Differentiation of mild cognitive impairment using an entorhinal cortex-based test of VR navigation

The entorhinal cortex is one of the first regions to exhibit neurodegeneration in Alzheimer’s disease, and as such identification of entorhinal cortex dysfunction may aid detection of the disease in its earliest stages. Extensive evidence demonstrates that the entorhinal cortex is critically implicated in navigation underpinned by the firing of spatially modulated neurons. This study tested the hypothesis that entorhinal-dependent navigation is impaired in pre-dementia Alzheimer’s disease. Forty-five patients with mild cognitive impairment (26 with CSF Alzheimer’s disease biomarker data: 12 biomarker-positive and 14 biomarker-negative) and 41 healthy control participants undertook an immersive virtual reality path integration test, as a measure of entorhinal-dependent navigation. Behavioural performance was correlated with MRI measures of entorhinal cortex volume, and the classification accuracy of the path integration task was compared with a battery of cognitive tests considered sensitive and specific for early Alzheimer’s Disease. Biomarker-positive patients exhibited larger errors in the navigation task than biomarker-negative patients, whose performance did not significantly differ from controls participants. Path-integration errors were negatively correlated with the volumes of the total entorhinal cortex and of its posteromedial subdivision. The path integration task demonstrated higher diagnostic sensitivity and specificity for differentiating biomarker positive versus negative patients (area under the curve = 0.90) than was achieved by the best of the cognitive tests (area under the curve = 0.57). This study demonstrates that an entorhinal cortex-based virtual reality navigation task can differentiate patients with mild cognitive impairment at low and high risk of developing dementia, with classification accuracy superior to reference cognitive tests considered to be highly sensitive to early Alzheimer’s disease. This study provides evidence that navigation tasks may aid early diagnosis of Alzheimer’s disease, and the basis of this in animal cellular and behavioural studies provides the opportunity to answer the unmet need for translatable outcome measures for comparing treatment effect across preclinical and clinical trial phases of future anti-Alzheimer’s drugs.
Deficient uracil base excision repair leads to persistent dUMP in HIV proviruses during infection of monocytes and macrophages

Non-dividing cells of the myeloid lineage such as monocytes and macrophages are target cells of HIV that have low dNTP pool concentrations and elevated levels of dUTP, which leads to frequent incorporation of dUMP opposite to A during reverse transcription (“uracilation”). One factor determining the fate of dUMP in proviral DNA is the host cell uracil base excision repair (UBER) system. Here we explore the relative UBER capacity of monocytes (MC) and monocyte-derived macrophages (MDM) and the fate of integrated uracilated viruses in both cell types to understand the implications of viral dUMP on HIV diversification and infectivity. We find that monocytes are almost completely devoid of functional UBER, while macrophages are mainly deficient in the initial enzyme uracil DNA glycosylase (hUNG2). Accordingly, dUMP persists in viral DNA during the lifetime of a MC and can only be removed after differentiation of MC into MDM. Overexpression of human uracil DNA glycosylase in MDM prior to infection resulted in rapid removal of dUMP from HIV cDNA and near complete depletion of dUMP-containing viral copies. This finding establishes that the low hUNG2 expression level in these cells limits UBER but that hUNG2 is restrictive against uracilated viruses. In contrast, overexpression of hUNG2 after viral integration did not accelerate the excision of uracils, suggesting that they may poorly accessible in the context of chromatin. We found that viral DNA molecules with incorporated dUMP contained unique (+) strand transversion mutations that were not observed when dUMP was absent (G→T, T→A, T→G, A→C). These observations and other considerations suggest that dUMP introduces errors predominantly during (-) strand synthesis when the template is RNA. These mutations may arise from the increased mispairing and duplex destabilizing effects of dUMP relative to dTMP during reverse transcription. Overall, the likelihood of producing a functional virus from in vitro infection of MC is about 50-fold and 300-fold reduced as compared to MDM and activated T cells. The results implicate viral dUMP incorporation in MC and MDM as a potential viral diversification and restriction pathway during human HIV infection.
Estimating the number of protein molecules in a plant cell: a quantitative perspective on proteostasis and amino acid homeostasis during progressive drought stress

During dehydration cellular proteostasis as well as amino acid homeostasis are severely challenged, since the decrease in photosynthesis induces massive proteolysis. Thus, we selected progressive drought stress in Arabidopsis thaliana as a model to investigate the balance between protein and free amino acid homeostasis on a quantitative level. We analyze the mass protein composition of rosette leaves and estimate, how many protein molecules are present in a plant cell and its subcellular compartments. Under control conditions, an average Arabidopsis mesophyll cell contains about 25 billion protein molecules and 80% of them are localized in the chloroplasts. Severe water deficiency leads to degradation of more than 40% of the leaf proteome and thus causes a drastic shift towards the free amino acid pool. Stress induced proteolysis of half of the 400 million RubisCO hexadecamers present in the chloroplasts of an individual mesophyll cell alone doubles the cellular content in free amino acids. A major fraction of the amino acids released from proteins is channeled into the synthesis of proline as a compatible osmolyte. Complete oxidation of the remaining part as an alternative respiratory substrate can fully compensate the lack of carbohydrates derived from photosynthesis for several hours.
The consequences of size-selective fishing mortality for larval production and sustainable yield in species with obligate male care

Size-based harvest limits or gear regulations are often used to manage fishing mortality and ensure the spawning biomass of females is sufficiently protected. Yet, management interactions with species’ mating systems that affect fishery sustainability and yield are rarely considered. For species with obligate male care, it is possible that size-specific harvest of males will decrease larval production. In order to examine how size-based management practices interact with mating systems, we modeled fisheries of two species with obligate care of nests, corkwing wrasse (Symphodus melops, Labridae) and lingcod (Ophiodon elongatus, Hexigrammidae) under two management scenarios, a minimum size limit and a harvest slot limit. We simulated the population dynamics, larval production, and yield to the fishery under a range of fishing mortalities. We also modeled size-dependent male care to determine its interaction with management. In both species, the slot limit decreased yield by less than 12% (relative to minimum size limits) at low fishing mortalities; at higher mortalities, individuals rarely survived to outgrow the slot and spawning potential decreased substantially relative to unfished levels, similar to minimum size limits. Spawning potential decreased less when managed with a slot limit if we included a positive feedback between male size, care, and hatching success, but the benefit of implementing the slot depended both on the relative proportions of each sex selected by the fishery, and on our assumptions regarding male size and care. This work highlights that the effects of size- and sex-selective fisheries management can be nuanced and produce counter-intuitive results.
A simple modification of library length for highly divergent gene capture

Hybridization capture is considered very cost- and time-effective method for enriching a massive amount of target loci distributed separately in a whole genome. However, divergent loci are difficult to enrich for the sequence mismatch between probes and target DNA. After analysis the distributional pattern of divergent loci in mitochondrial genomes (mitogenomes), we notice that the relatively variable regions are intercept by the relatively conservative regions. We propose to extend the length of library to overcome the problem. By using a home-made probe set to bait amphibian mitogeneomes DNA, we demonstrate that using 2 kb DNA libraries generate high sequence coverage in the highly variable regions than using 400 bp DNA libraries. These suggest that longer fragments in the library generally contain both relatively variable regions and relatively conservative regions. The divergent part DNA along with conservative part DNA is captured during hybridization. We present a protocol that allows users to overcome the gap problem for highly divergent gene capture.
Genomic characterization of the adolescent idiopathic scoliosis-associated transcriptome and regulome

Adolescent idiopathic scoliosis (AIS), a sideways curvature of the spine, is the most common pediatric musculoskeletal disorder, affecting ∼3% of the population worldwide. However, its genetic bases and tissues of origin remain largely unknown. Several genome-wide association studies (GWAS) have implicated nucleotide variants in noncoding sequences that control genes with important roles in cartilage, muscle, bone, connective tissue and intervertebral discs (IVDs) as drivers of AIS susceptibility. Here, we set out to define the expression of AIS-associated genes and active regulatory elements by performing RNA-seq and ChIP-seq against H3K27ac in these tissues in mouse and human. Our study highlights genetic pathways involving AIS-associated loci that regulate chondrogenesis, IVD development and connective tissue maintenance and homeostasis. In addition, we identify thousands of putative AIS-associated regulatory elements which may orchestrate tissue-specific expression in musculoskeletal tissues of the spine. Quantification of enhancer activity of several candidate regulatory elements from our study identifies three functional enhancers carrying AIS-associated GWAS SNPs at the ADGRG6 and BNC2 loci. Our findings provide a novel genome-wide catalog of AIS-relevant genes and regulatory elements and aid in the identification of novel targets for AIS causality and treatment.
Genomic data reveal similar genetic differentiation between species with vastly different dispersal capabilities and life histories

Little is known about the life histories, population connectivity, or dispersal mechanisms of shallow groundwater organisms. Here we used RAD-seq to analyze population structure in two aquifer species: Paraperla frontalis, a stonefly with groundwater larvae and aerial adults, and Stygobromus sp. , a groundwater-obligate amphipod. We found similar levels of connectivity in each species between floodplains separated by ~70 river km in the Flathead River basin of NW Montana, USA. Given that Stygobromous lacks the aboveground life stage of P. frontalis, our findings suggest that aquifer-obligate species might have previously unrecognized dispersal capacity.
Generalized displacement of DNA- and RNA-binding factors mediates the toxicity of arginine-rich cell-penetrating peptides

Due to their capability to transport chemicals or proteins into target cells, cell-penetrating peptides (CPPs) are being developed as therapy delivery tools. However, and despite their interesting properties, arginine-rich CPPs often show toxicity for reasons that remain poorly understood. Using a (PR)n dipeptide repeat that has been linked to amyotrophic-lateral sclerosis (ALS) as a model of an arginine-rich CPP, we here show that the presence of (PR)n leads to a generalized displacement of RNA- and DNA-binding proteins from chromatin and mRNA. Accordingly, any reaction involving nucleic acids such as RNA transcription, translation, splicing and degradation or DNA replication and repair are impaired by the presence of the CPP. Interestingly, the effects of (PR)n are fully mimicked by PROTAMINE, a small arginine-rich protein that displaces histones from chromatin during spermatogenesis. We propose that widespread coating of nucleic acids and consequent displacement of RNA- and DNA-binding factors from chromatin and mRNA accounts for the toxicity of arginine-rich CPPs, including those that have been recently associated to the onset of ALS.
Identification of Candida glabrata Transcriptional Regulators That Govern Stress Resistance and Virulence

The mechanisms by which Candida glabrata resists host defense peptides and caspofungin are incompletely understood. To identify transcriptional regulators that enable C. glabrata to withstand these classes of stressors, a library of 215 C. glabrata transcriptional regulatory deletion mutants was screened for susceptibility to both protamine and caspofungin. ABSTRACT The mechanisms by which Candida glabrata resists host defense peptides and caspofungin are incompletely understood. To identify transcriptional regulators that enable C. glabrata to withstand these classes of stressors, a library of 215 C. glabrata transcriptional regulatory deletion mutants was screened for susceptibility to both protamine and caspofungin. We identified eight mutants that had increased susceptibility to both host defense peptides and caspofungin. Of these mutants, six were deleted for genes that were predicted to specify proteins involved in histone modification. These genes were ADA2, GCN5, SPT8, HOS2, RPD3, and SPP1. Deletion of ADA2, GCN5, and RPD3 also increased susceptibility to mammalian host defense peptides. The Δada2 and Δgcn5 mutants had increased susceptibility to other stressors, such as H2O2 and SDS. In the Galleria mellonella model of disseminated infection, the Δada2 and Δgcn5 mutants had attenuated virulence, whereas in neutropenic mice, the virulence of the Δada2 and Δrpd3 mutants was decreased. Thus, histone modification plays a central role in enabling C. glabrata to survive host defense peptides and caspofungin, and Ada2 and Rpd3 are essential for the maximal virulence of this organism during disseminated infection.