Miracle-dz/UniFAR-FTUs huggingface dataset:
Mechanisms of 3-dimensional organisation of the human genome

In many ways the (near) complete human genome sequence is only the beginning. We have still much to learn of the packaging and spatial organisation of nearly 2 metres of DNA within each cell nucleus. In recent years we have become increasingly aware that many important cellular factors are compartmentalised within the nucleus, and this is also true of chromatin. The nuclear position of chromosome territories can be correlated to the DNA sequence the overall gene density. Previous work has shown that chromosomes have a radial arrangement, gene-poor chromosomes are situated at or near the nuclear periphery, while more gene-rich chromosomes are in the centre of the nucleus at least in lymphoblast and fibroblast cells. It was not known if this pattern of chromosome territory organisation is particular to these cells and hence, I have investigated the nuclear distribution of chromosomes in a variety of different primary and transformed cell lines. I have also performed FISH and chromosome position analysis on histological tissue sections. The data suggest that the nuclear organisation in cultured cells reflects that of the nuclei in human somatic cells in vivo. It is possible that chromatin composition, especially histone modifications, is involved in the maintenance of chromosome spatial organisation. Using chemical inhibition of histone deacetylation with the drug Trichostatin-A (TSA), endogenous levels of histone acetylation in the nucleus were disrupted. I have then analysed the position of centromeres and chromosomes in cells treated with TSA. I found no detectable rearrangement of chromatin under these conditions. This suggests that histone acetylation does not play a vital role in influencing the spatial organisation of chromatin. Many nuclear membrane and lamina components have chromatin binding domains and are capable of binding chromatin and/or associated proteins in vitro. Interest in the nuclear lamina and a role in spatial organisation of chromatin has recently increased with the discovery of human 'laminopathies', syndromes caused by mutations in lamin A or emerin. Experiments have shown that the spatial organisation of chromosomes is not altered in lymphoblast cells that carry a null mutation of emerin. I have generated stable cell lines overexpressing disease-associated mutations of lamin A protein. Some peripheral chromosomes are no longer present at the nuclear periphery in cells over-expressing lamin A. I also followed the interphase dynamics of different lamin A disease-associated mutants and some mutant proteins are more mobile than the wild-type lamin A in FRAP studies.
Cyclic nucleotide signaling in Arabidopsis thaliana and the identification of cGMP binding proteins

Cyclic nucleotide monophosphates are important signaling molecule in plants. This work gives new insight on the kinetics of these molecules in response to NO2-induced cell death and hypersensitive responses. It was shown that the levels of the 2’3’-isomers of cAMP, cGMP, cCMP and cUMP are differentially regulated in these processes. Furthermore, a cGMP binding protein was identified and was shown to be involved in flavonol-biosynthesis and chloroplast development.
Genetic Risk of Autism Spectrum Disorder in a Pakistani Population

Autism spectrum disorder (ASD) is a group of complex multifactorial neurodevelopmental and neuropsychiatric disorders in children characterized by impairment of communication and social interaction. Several genes with associated single nucleotide polymorphisms (SNPs) have been identified for ASD in different genetic association studies, meta-analyses, and genome-wide association studies (GWAS). However, associations between different SNPs and ASD vary from population to population. Four SNPs in genes CNTNAP2, EIF4E, ATP2B2, CACNA1C, and SNP rs4307059 (which is found between CDH9 and CDH10 genes) have been identified and reported as candidate risk factors for ASD. The aim of the present study was, for the first time, to assess the association of SNPs in these genes with ASD in the Pakistani population. PCR-based genotyping was performed using allele-specific primers in 93 ASD and 93 control Pakistani individuals. All genetic associations, genotype frequencies, and allele frequencies were computed as odds’ ratios (ORs) using logistic regression with a threshold of p ≤ 0.01 to determine statistical significance. We found that the homozygous genotypes of mutant T alleles of CNTNAP2 and ATP2B2 were significantly associated with Pakistani ASD patients in unadjusted ORs (p < 0.01), but their significance score was lost in the adjusted model. Other SNPs such as rs4307059, rs17850950 of EIF4E, and rs1006737 of CACNA1C were not statistically significant. Based on this, we conclude that SNPs are not associated with, or are not the main cause of, autism in the Pakistani population, indicating the involvement of additional players, which need to be investigated in future studies in a large population size. One of the limitations of present study is its small sample size. However, this study, being the first on Pakistani ASD patients, may lay the foundations for future studies in larger samples.
Mechanical and Metabolic Responses during High-intensity Training in Elite 800-m Runners

Abstract The purpose of this study was to describe the mechanical and metabolic responses of a typical high-intensity training session in high-level 800-m athletes. Nine male high-level 800-m athletes (personal best 1:43–1:56 min:ss) performed a typical high-intensity interval training session consisting of 5×200 m with 4 min rest. Countermovement jump and blood lactate were measured at rest and after each running bout. Running times, ground contact times, and stride length were also measured. Running times and lactate (p<0.01) progressively increased from the first to the last running bout. Jump height (p<0.01) and stride length (p<0.05) progressively decreased from the first running bout to the last. A significant negative relationship (p<0.001; r =−0.83) was found between the individual values of jumping height and blood lactate concentration; and a significant positive relationship (p<0.01; r=0.67) was observed between the time in the 200 m and the contact times. In conclusion, the results demonstrated that the typical training session performed by 800-m athletes produced a high level of fatigue as evidenced by significant alterations in the mechanical and metabolic response. The impairments observed in the mechanical and metabolic parameters may indirectly reflect a state of energy deficit of the muscle contractile machinery and a reduction of the force-generating capacity.
Maturation of the Olfactory Sensory Neuron and Its Cilia.

Olfactory sensory neurons (OSNs) are bipolar neurons, unusual because they turn over continuously and have a multiciliated dendrite. The extensive changes in gene expression accompanying OSN differentiation in mice are largely known, especially the transcriptional regulators responsible for altering gene expression, revealing much about how differentiation proceeds. Basal progenitor cells of the olfactory epithelium transition into nascent OSNs marked by Cxcr4 expression and the initial extension of basal and apical neurites. Nascent OSNs become immature OSNs within 24-48 hrs. Immature OSN differentiation requires about a week and at least two stages. Early stage immature OSNs initiate expression of genes encoding key transcriptional regulators and structural proteins necessary for further neuritogenesis. Late stage immature OSNs begin expressing genes encoding proteins important for energy production and neuronal homeostasis that carry over into mature OSNs. The transition to maturity depends on massive expression of one allele of one odorant receptor gene, and this results in expression of the last 8% of genes expressed by mature OSNs. Many of these genes encode proteins necessary for mature function of axons and synapses or for completing the elaboration of nonmotile cilia, which began extending from the newly formed dendritic knobs of immature OSNs. The cilia from adjoining OSNs form a meshwork in the olfactory mucus and are the site of olfactory transduction. Immature OSNs also have a primary cilium but its role is unknown, unlike the critical role in proliferation and differentiation played by the primary cilium of the olfactory epithelium's horizontal basal cell.
Evolutionary and Comparative Analysis of Bacterial Nonhomologous End Joining Repair

Abstract DNA double-strand breaks (DSBs) are a threat to genome stability. In all domains of life, DSBs are faithfully fixed via homologous recombination. Recombination requires the presence of an uncut copy of duplex DNA which is used as a template for repair. Alternatively, in the absence of a template, cells utilize error-prone nonhomologous end joining (NHEJ). Although ubiquitously found in eukaryotes, NHEJ is not universally present in bacteria. It is unclear as to why many prokaryotes lack this pathway. Toward understanding what could have led to the current distribution of bacterial NHEJ, we carried out comparative genomics and phylogenetic analysis across ∼6,000 genomes. Our results show that this pathway is sporadically distributed across the phylogeny. Ancestral reconstruction further suggests that NHEJ was absent in the eubacterial ancestor and can be acquired via specific routes. Integrating NHEJ occurrence data for archaea, we also find evidence for extensive horizontal exchange of NHEJ genes between the two kingdoms as well as across bacterial clades. The pattern of occurrence in bacteria is consistent with correlated evolution of NHEJ with key genome characteristics of genome size and growth rate; NHEJ presence is associated with large genome sizes and/or slow growth rates, with the former being the dominant correlate. Given the central role these traits play in determining the ability to carry out recombination, it is possible that the evolutionary history of bacterial NHEJ may have been shaped by requirement for efficient DSB repair.
Structure and Dynamics of GPCRs in Lipid Membranes: Physical Principles and Experimental Approaches

Over the past decade, the vast amount of information generated through structural and biophysical studies of GPCRs has provided unprecedented mechanistic insight into the complex signalling behaviour of these receptors. With this recent information surge, it has also become increasingly apparent that in order to reproduce the various effects that lipids and membranes exert on the biological function for these allosteric receptors, in vitro studies of GPCRs need to be conducted under conditions that adequately approximate the native lipid bilayer environment. In the first part of this review, we assess some of the more general effects that a membrane environment exerts on lipid bilayer-embedded proteins such as GPCRs. This is then followed by the consideration of more specific effects, including stoichiometric interactions with specific lipid subtypes. In the final section, we survey a range of different membrane mimetics that are currently used for in vitro studies, with a focus on NMR applications.
Measuring Timeliness of Outbreak Response in the World Health Organization African Region, 2017–2019

Large-scale protracted outbreaks can be prevented through early detection, notification, and rapid control. We assessed trends in timeliness of detecting and responding to outbreaks in the African Region reported to the World Health Organization during 2017–2019. We computed the median time to each outbreak milestone and assessed the rates of change over time using univariable and multivariable Cox proportional hazard regression analyses. We selected 296 outbreaks from 348 public reported health events and evaluated 184 for time to detection, 232 for time to notification, and 201 for time to end. Time to detection and end decreased over time, whereas time to notification increased. Multiple factors can account for these findings, including scaling up support to member states after the World Health Organization established its Health Emergencies Programme and support given to countries from donors and partners to strengthen their core capacities for meeting International Health Regulations.
How Can Cattle Be Toilet Trained? Incorporating Reflexive Behaviours into a Behavioural Chain

Simple Summary The mixing of bovine faeces and urine leads to climate-damaging ammonia emissions. If cattle could be taught to use a latrine, this would reduce the area of emissions, the separation of excreta could easily be accomplished by mechanical means, and animal health could be improved. Attempts to train toileting in cattle have shown limited success. In children, toileting is trained mainly by (i) interrupting voiding that starts outside the toilet, then taking the child to the toilet and rewarding the resumption of excretion, or (ii) placing the child on the toilet, waiting for urination/defecation and rewarding appropriate excretory behaviour. The first method is reported to be more successful. Thus, a similar procedure was evaluated for training latrine use for urination in calves. On 95% of occasions, the calves inhibited or stopped urination when receiving a signal to move to the latrine, and on 65% of occasions, they reinitiated urination in the latrine. Furthermore, during 63% of urinations in the latrine, the calves oriented towards the reward location before any food was delivered, providing additional evidence that calves can be successfully toilet trained with food rewards. Abstract Untrained cattle do not defecate or urinate in defined locations. The toilet training of cattle would allow urine and faeces to be separated and stored, reducing climate-damaging emissions and improving animal health. In a proof-of-concept study, we evaluated a novel protocol for toilet training in cattle. Five heifer calves (and yoked controls) were trained in the voluntary (operant) behaviours of a toileting chain. Then, reflexive urinating responses were incorporated into the chain, with toileting signalled by a tactile (vibratory) stimulus. On 95% of occasions, the calves inhibited/interrupted urination when receiving the stimulus, and on 65% of these occasions, reinitiated urination in the latrine. Furthermore, during 63% of urinations in the latrine, the calves oriented to the reward location before any food was delivered, providing additional evidence that calves can be successfully toilet trained with food rewards. Yoked controls failed to learn most of the operant elements and all the reflexive responses of toilet training. The results show that reflexive behaviours can be incorporated into voluntary toileting sequences with cattle and extend the range of species that can be toilet trained. Future refinement of the protocol to allow training under practical farm conditions offers the potential to mitigate climate damage and improve animal health.
Retrospective Valuation of Experienced Outcome Encoded in Distinct Reward Representations in the Anterior Insula and Amygdala

Our ability to evaluate an experience retrospectively is important because it allows us to summarize its total value, and this summary value can then later be used as a guide in deciding whether the experience merits repeating, or whether instead it should rather be avoided. However, when an experience unfolds over time, humans tend to assign disproportionate weight to the later part of the experience, and this can lead to poor choice in repeating, or avoiding experience. Our ability to evaluate an experience retrospectively is important because it allows us to summarize its total value, and this summary value can then later be used as a guide in deciding whether the experience merits repeating, or whether instead it should rather be avoided. However, when an experience unfolds over time, humans tend to assign disproportionate weight to the later part of the experience, and this can lead to poor choice in repeating, or avoiding experience. Using model-based computational analyses of fMRI recordings in 27 male volunteers, we show that the human brain encodes the summary value of an extended sequence of outcomes in two distinct reward representations. We find that the overall experienced value is encoded accurately in the amygdala, but its merit is excessively marked down by disincentive anterior insula activity if the sequence of experienced outcomes declines temporarily. Moreover, the statistical strength of this neural code can separate efficient decision-makers from suboptimal decision-makers. Optimal decision-makers encode overall value more strongly, and suboptimal decision-makers encode the disincentive markdown (DM) more strongly. The separate neural implementation of the two distinct reward representations confirms that suboptimal choice for temporally extended outcomes can be the result of robust neural representation of a displeasing aspect of the experience such as temporary decline. SIGNIFICANCE STATEMENT One of the numerous foibles that prompt us to make poor decisions is known as the “Banker's fallacy,” the tendency to focus on short-term growth at the expense of long-term value. This effect leads to unwarranted preference for happy endings. Here, we show that the anterior insula in the human brain marks down the overall value of an experience as it unfolds over time if the experience entails a sequence of predominantly negative temporal contrasts. By contrast, the amygdala encodes overall value accurately. These results provide neural indices for the dichotomy of decision utility and experienced utility popularized as Thinking fast and slow by Daniel Kahneman.
Complex yet fauna-deficient seagrass ecosystems at risk in southern Myanmar

Abstract Dependence on seafood across Southeast Asia is extensive. Myanmar is no exception, but the country’s provisioning marine ecosystems are threatened. Seagrass is one habitat that is frequently overlooked in management as an important fisheries resource, despite its nursery function. In Myanmar, research on seagrass habitats is particularly sparse, and as a result, our understanding of seagrass exploitation remains limited. In this study, we provide a baseline assessment of the seagrass-associated fish assemblages at four locations in the Myeik Archipelago in southern Myanmar using mono Baited Remote Underwater Video systems. Across the sites surveyed only 12 taxa of motile fauna were recorded. Relative to other regional and global studies, this figure is meagre. Our data adds to a growing literature suggesting that the marine ecosystems of Myanmar are in a worrying state. Despite the lack of recorded seagrass associated fauna, our study revealed minimal impacts to seagrass meadows from eutrophication or sedimentation, and the meadows included appeared to be healthy. The sites with the highest number of motile fauna were within Myanmar’s only National Marine Park offering some optimism for the effectiveness of protection, but further assessments are required to allow targeted management of Myanmar’s seagrass meadows.
Fitness, physical activity, or sedentary patterns? Integrated analysis with obesity surrogates in a large youth sample

Physical fitness (PF) and physical activity (PA) are inversely associated with body mass index and waist circumference (WC), whereas sedentary time (ST) seems to boost obesity in youth. The aim was to examine the associations of each selected PF test, PA‐related exposures, and specific ST patterns with obesity and determine the most relevant ones, in a large sample of a school‐aged adolescent.
The Sandwich Synapse: Trans-glial Signaling Between Neuronal Somata in the Dorsal Root Ganglion

The dorsal root ganglion (DRG) contains the cell bodies of primary somatosensory neurons that form axonal connections for the transfer of sensory input from the peripheral nerve receptor to the spinal cord in the central nervous system. In general, each DRG neuronal soma (NS) is enveloped by an individual satellite glial cell (SGC) sheath. However, in a significant subset, neuronal somata are closely-apposed and separated solely by a thin SGC membrane septum, forming a structural cell trimer. Using patch clamp electrophysiological recording, we reported that repetitive stimulation of one NS evokes a delayed, noisy and long-duration inward current in both itself and its passive partner. Several lines of evidence demonstrate that transmission between the two NS is via a bi-synaptic, trans-glial pathway that we term a ‘Sandwich Synapse’ (SS). The first, NS to glial cell, synapse involves ATP release from the neuron and purinergic activation of the glial cell. The second, glial cell to NS, synapse is glutamatergic. We find that inter-NS transmission at the DRG SS involves Ca 2+ -dependent secretion of ATP from the NS, glial Ca 2+ store discharge via P2Y2 receptors and release of glutamate to activate NS postsynaptic NMDA receptors. SS-type signaling may play a role in regulating DRG sensory function, and may also contribute to inter-neuronal communication in other regions of the nervous system.
Using taxonomic consistency with semi‐automated data pre‐processing for high quality DNA barcodes

In recent years, large‐scale DNA barcoding campaigns have generated an enormous amount of COI barcodes, which are usually stored in NCBI's GenBank and the official Barcode of Life database (BOLD). BOLD data are generally associated with more detailed and better curated meta‐data, because a great proportion is based on expert‐verified and vouchered material, accessible in public collections. In the course of the initiative German Barcode of Life data were generated for the reference library of 2,846 species of Coleoptera from 13,516 individuals. Confronted with the high effort associated with the identification, verification and data validation, a bioinformatic pipeline, “TaxCI” was developed that (1) identifies taxonomic inconsistencies in a given tree topology (optionally including a reference dataset), (2) discriminates between different cases of incongruence in order to identify contamination or misidentified specimens, (3) graphically marks those cases in the tree, which finally can be checked again and, if needed, corrected or removed from the dataset. For this, “TaxCI” may use DNA‐based species delimitations from other approaches (e.g. mPTP) or may perform implemented threshold‐based clustering. The data‐processing pipeline was tested on a newly generated set of barcodes, using the available BOLD records as a reference. A data revision based on the first run of the TaxCI tool resulted in the second TaxCI analysis in a taxonomic match ratio very similar to the one recorded from the reference set (92% vs. 94%). The revised dataset improved by nearly 20% through this procedure compared to the original, uncorrected one. Overall, the new processing pipeline for DNA barcode data allows for the rapid and easy identification of inconsistencies in large datasets, which can be dealt with before submitting them to public data repositories like BOLD or GenBank. Ultimately, this will increase the quality of submitted data and the speed of data submission, while primarily avoiding the deterioration of the accuracy of the data repositories due to ambiguously identified or contaminated specimens.
Patient-Reported Social and Behavioral Determinants of Health and Estimated Risk of Hospitalization in High-Risk Veterans Affairs Patients

Key Points Question Can the estimation of risk of future hospitalization be improved by adding patient-reported social determinants of health to a model that is based on electronic health record data? Findings In this survey study of 4685 respondent Veterans Affairs patients with 1-year risk in the 75th percentile or higher for hospitalization or death, a logistic regression model that included patient-reported social determinants of health outperformed a logistic model that was solely based on electronic health record variables. Meaning Collecting social information from patients could improve health system algorithms that identify individuals at risk for poor outcomes.