Takshan/R1 huggingface dataset:
A maximum likelihood algorithm for reconstructing 3D structures of human chromosomes from chromosomal contact data.

BACKGROUND: The development of chromosomal conformation capture techniques, particularly, the Hi-C technique, has made the analysis and study of the spatial conformation of a genome an important topic in bioinformatics and computational biology. Aided by high-throughput next generation sequencing techniques, the Hi-C technique can generate genome-wide, large-scale intra- and inter-chromosomal interaction data capable of describing in details the spatial interactions within a genome. These data can be used to reconstruct 3D structures of chromosomes that can be used to study DNA replication, gene regulation, genome interaction, genome folding, and genome function. RESULTS: Here, we introduce a maximum likelihood algorithm called 3DMax to construct the 3D structure of a chromosome from Hi-C data.  3DMax employs a maximum likelihood approach to infer the 3D structures of a chromosome, while automatically re-estimating the conversion factor (α) for converting Interaction Frequency (IF) to distance. Our results show that the models generated by 3DMax from a simulated Hi-C dataset match the true models better than most of the existing methods. 3DMax is more robust to structural variability and noise. Compared on a real Hi-C dataset, 3DMax constructs chromosomal models that fit the data better than most methods, and it is faster than all other methods. The models reconstructed by 3DMax were consistent with fluorescent in situ hybridization (FISH) experiments and existing knowledge about the organization of human chromosomes, such as chromosome compartmentalization. CONCLUSIONS: 3DMax is an effective approach to reconstructing 3D chromosomal models. The results, and the models generated for the simulated and real Hi-C datasets are available here: http://sysbio.rnet.missouri.edu/bdm_download/3DMax/ . The source code is available here: https://github.com/BDM-Lab/3DMax . A short video demonstrating how to use 3DMax can be found here: https://youtu.be/ehQUFWoHwfo .
The benefits of introducing electronic health records in residential aged care facilities: a multiple case study.

PURPOSE: Information and communications technology solutions have been introduced into the residential aged care system in order to improve the effectiveness and efficiency of aged care, however to date, the actual benefits have not been systematically analysed. The aim of this study was to identify the benefits of electronic health records (EHR) in residential aged care services and to examine how the benefits have been achieved. METHOD: A qualitative interview study was conducted in nine residential aged care facilities (RACFs) belonging to three organisations in the Australian Capital Territory (ACT), New South Wales (NSW) and Queensland, Australia. A longitudinal investigation after the implementation of the aged care EHR systems was conducted at two data points: January 2009 to December 2009 and December 2010 to February 2011. Semi-structured interviews were conducted with 110 care staff members selected through theoretical sampling, representing all levels of care staff who worked in those facilities. RESULTS: Three categories of benefits were perceived by the care staff members according to who gain the benefits: the benefits to individual care staff members, to residents and to the RACFs. The benefits to individual care staff members include an improvement of documentation efficiency, information and knowledge growth as well as empowering the staff; the benefits to residents are an improvement in the quality of individual residents' health records, the higher quality of care and smoother communication between the residents and aged care staff; the RACFs gain an increased ability to manage information and acquire funding, an increase in their ability to control the care quality and improvements in the working environment and educational benefits. Three factors leading to these benefits were examined: the nature of the aged care EHR systems in comparison with paper-based records; the way the systems were used by the staff and one benefit that could lead to another. CONCLUSIONS: In this study, EHR systems were perceived to have substantial benefits for care staff, residents and the aged care organisations introducing the systems. The benefits were derived from the nature of the aged care EHR systems, staff members' continuous use of the systems, and one benefit led to the other.
Structural basis for DNA recognition by STAT6.

STAT6 participates in classical IL-4/IL-13 signaling and stimulator of interferon genes-mediated antiviral innate immune responses. Aberrations in STAT6-mediated signaling are linked to development of asthma and diseases of the immune system. In addition, STAT6 remains constitutively active in multiple types of cancer. Therefore, targeting STAT6 is an attractive proposition for treating related diseases. Although a lot is known about the role of STAT6 in transcriptional regulation, molecular details on how STAT6 recognizes and binds specific segments of DNA to exert its function are not clearly understood. Here, we report the crystal structures of a homodimer of phosphorylated STAT6 core fragment (STAT6(CF)) alone and bound with the N3 and N4 DNA binding site. Analysis of the structures reveals that STAT6 undergoes a dramatic conformational change on DNA binding, which was further validated by performing molecular dynamics simulation studies and small angle X-ray scattering analysis. Our data show that a larger angle at the intersection where the two protomers of STAT meet and the presence of a unique residue, H415, in the DNA-binding domain play important roles in discrimination of the N4 site DNA from the N3 site by STAT6. H415N mutation of STAT6(CF) decreased affinity of the protein for the N4 site DNA, but increased its affinity for N3 site DNA, both in vitro and in vivo. Results of our structure-function studies on STAT6 shed light on mechanism of DNA recognition by STATs in general and explain the reasons underlying STAT6's preference for N4 site DNA over N3.
Cerebral small vessel disease and incident parkinsonism: The RUN DMC study.

OBJECTIVE: To investigate the relation between baseline cerebral small vessel disease (SVD) and the risk of incident parkinsonism using different MRI and diffusion tensor imaging (DTI) measures. METHODS: In the Radboud University Nijmegen Diffusion Tensor and Magnetic Resonance Cohort (RUN DMC) study, a prospective cohort study, 503 elderly participants with SVD and without parkinsonism were included in 2006. During follow-up (2011-2012), parkinsonism was diagnosed according to UK Brain Bank criteria. Cox regression analysis was used to investigate the association between baseline imaging measures and incident all-cause parkinsonism and vascular parkinsonism (VP). Tract-based spatial statistics analysis was used to identify differences in baseline DTI measures of white matter (WM) tracts between participants with VP and without parkinsonism. RESULTS: Follow-up was available from 501 participants (mean age 65.6 years; mean follow-up duration 5.2 years). Parkinsonism developed in 20 participants; 15 were diagnosed with VP. The 5-year risk of (any) parkinsonism was increased for those with a high white matter hyperintensity (WMH) volume (hazard ratio [HR] 1.8 per SD increase, 95% confidence interval [CI] 1.3-2.4) and a high number of lacunes (HR 1.4 per number increase, 95% CI 1.1-1.8) at baseline. For VP, this risk was also increased by the presence of microbleeds (HR 5.7, 95% CI 1.9-16.8) and a low gray matter volume (HR 0.4 per SD increase, 95% CI 0.2-0.8). Lower fractional anisotropy values in bifrontal WM tracts involved in movement control were observed in participants with VP compared to participants without parkinsonism. CONCLUSIONS: SVD at baseline, especially a high WMH volume and a high number of lacunes, is associated with incident parkinsonism. Our findings favor a role of SVD in the etiology of parkinsonism.
Progressive inner nuclear layer dysfunction in non-optic neuritis eyes in MS.

Objective: To investigate primary retinal functional changes in non-optic neuritis (ON) eyes of patients with MS by full-field electroretinography (ERG). Methods: Seventy-seven patients with relapsing-remitting MS with no history of clinical ON in at least 1 eye and 30 healthy controls were recruited in the cohort study. Full-field ERGs were recorded, and retinal optical coherence tomography scans were performed to assess the thicknesses of peripapillary retinal nerve fiber layer (RNFL) and retinal ganglion cell layer-inner plexiform layer (GCL-IPL). Annual MRI scans were also carried out to evaluate the disease activity in the brain. Patients were followed up for 3 years. Results: At baseline, a delayed b-wave peak time was observed in the cone response (p < 0.001), which was associated with the thicknesses of RNFL and GCL-IPL. The peak time of the delayed b-wave also correlated with the Expanded Disability Status Scale, T2 lesion volume, and disease duration. During the 3-year follow-up, progressive ERG amplitude reduction was observed (both a- and b-waves, p < 0.05). There was a correlation between the b-wave amplitude reduction and longitudinal RNFL loss (p = 0.001). However, no correlation was found between longitudinal ERG changes and disease activity in the brain. Conclusions: This study demonstrated progressive inner nuclear layer dysfunction in MS. The borderline a-wave changes suggested some outer retinal dysfunction as well. The correlation between full-field ERG changes and retinal ganglion cell loss suggested that there might be subclinical retinal pathology in MS affecting both outer and inner retinal layers.
Protein-protein binding affinity prediction on a diverse set of structures.

MOTIVATION: Accurate binding free energy functions for protein-protein interactions are imperative for a wide range of purposes. Their construction is predicated upon ascertaining the factors that influence binding and their relative importance. A recent benchmark of binding affinities has allowed, for the first time, the evaluation and construction of binding free energy models using a diverse set of complexes, and a systematic assessment of our ability to model the energetics of conformational changes. RESULTS: We construct a large set of molecular descriptors using commonly available tools, introducing the use of energetic factors associated with conformational changes and disorder to order transitions, as well as features calculated on structural ensembles. The descriptors are used to train and test a binding free energy model using a consensus of four machine learning algorithms, whose performance constitutes a significant improvement over the other state of the art empirical free energy functions tested. The internal workings of the learners show how the descriptors are used, illuminating the determinants of protein-protein binding. AVAILABILITY: The molecular descriptor set and descriptor values for all complexes are available in the Supplementary Material. A web server for the learners and coordinates for the bound and unbound structures can be accessed from the website: http://bmm.cancerresearchuk.org/~Affinity. CONTACT: paul.bates@cancer.org.uk. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
Deciphering the Origin, Evolution, and Physiological Function of the Subtelomeric Aryl-Alcohol Dehydrogenase Gene Family in the Yeast Saccharomyces cerevisiae.

Homology searches indicate that Saccharomyces cerevisiae strain BY4741 contains seven redundant genes that encode putative aryl-alcohol dehydrogenases (AAD). Yeast AAD genes are located in subtelomeric regions of different chromosomes, and their functional role(s) remain enigmatic. Here, we show that two of these genes, AAD4 and AAD14, encode functional enzymes that reduce aliphatic and aryl-aldehydes concomitant with the oxidation of cofactor NADPH, and that Aad4p and Aad14p exhibit different substrate preference patterns. Other yeast AAD genes are undergoing pseudogenization. The 5' sequence of AAD15 has been deleted from the genome. Repair of an AAD3 missense mutation at the catalytically essential Tyr73 residue did not result in a functional enzyme. However, ancestral-state reconstruction by fusing Aad6 with Aad16 and by N-terminal repair of Aad10 restores NADPH-dependent aryl-alcohol dehydrogenase activities. Phylogenetic analysis indicates that AAD genes are narrowly distributed in wood-saprophyte fungi and in yeast that occupy lignocellulosic niches. Because yeast AAD genes exhibit activity on veratraldehyde, cinnamaldehyde, and vanillin, they could serve to detoxify aryl-aldehydes released during lignin degradation. However, none of these compounds induce yeast AAD gene expression, and Aad activities do not relieve aryl-aldehyde growth inhibition. Our data suggest an ancestral role for AAD genes in lignin degradation that is degenerating as a result of yeast's domestication and use in brewing, baking, and other industrial applications. IMPORTANCE Functional characterization of hypothetical genes remains one of the chief tasks of the postgenomic era. Although the first Saccharomyces cerevisiae genome sequence was published over 20 years ago, 22% of its estimated 6,603 open reading frames (ORFs) remain unverified. One outstanding example of this category of genes is the enigmatic seven-member AAD family. Here, we demonstrate that proteins encoded by two members of this family exhibit aliphatic and aryl-aldehyde reductase activity, and further that such activity can be recovered from pseudogenized AAD genes via ancestral-state reconstruction. The phylogeny of yeast AAD genes suggests that these proteins may have played an important ancestral role in detoxifying aromatic aldehydes in ligninolytic fungi. However, in yeast adapted to niches rich in sugars, AAD genes become subject to mutational erosion. Our findings shed new light on the selective pressures and molecular mechanisms by which genes undergo pseudogenization.
Pegylated Filgrastim Versus Filgrastim for Stem Cell Mobilization in Multiple Myeloma After Novel Agent Induction.

BACKGROUND: The current standard of care for transplant-eligible myeloma patients is novel agent-based induction, followed by high-dose chemotherapy and autologous stem cell rescue. Chemo-mobilization of peripheral blood CD34+ stem cells (PBSCs) with pegylated filgrastim (pegfilgrastim), a sustained-duration formulation of filgrastim, has been used as an alternative to filgrastim in several studies involving heterogeneous cohorts of lymphoma and multiple myeloma (MM) patients and shown to be equivalent in PBSC yield and cost-effectiveness. The present study focused on the efficacy of pegfilgrastim in PBSC mobilization compared with filgrastim exclusively after novel agent-based induction in a homogeneous group of MM patients. PATIENTS AND METHODS: We analyzed the data from 89 patients with MM treated at 2 transplant centers in Singapore who had received novel agent-based induction chemotherapy, PBSC mobilization with vinorelbine/cyclophosphamide, high-dose melphalan conditioning, and autologous stem cell rescue. Of the 89 patients, 61 were included in the pegfilgrastim group and 28 in the filgrastim group, with a similar median age and disease characteristics. PBSC harvesting was performed at a similar median time of 9.51 ± 0.84 days for both, and the peak peripheral blood CD34+ stem cell count was 19.90 × 106/kg for pegfilgrastim and 32.50 × 106/kg for filgrastim (95% confidence interval, -4.36 to 0.70 × 106/kg). RESULTS: No significant difference was found in the median PBSC collection between the 2 groups (pegfilgrastim, 7.90 × 106/kg vs. filgrastim, 10.10 × 106/kg; P = .16). CONCLUSION: The present study has demonstrated that a single dose of pegfilgrastim is comparable to filgrastim in terms of the timing and efficacy of PBSC harvest and could potentially spare the patient 6 days of filgrastim injections. In addition, ours is the first study to compare these growth factors using vinorelbine/cyclophosphamide as mobilization chemotherapy.
Development of the Suicide Risk Scale for Medical Inpatients.

BACKGROUND: Inpatient suicide is one of the major issues related with hospital patient safety. Although there are many studies addressing suicide in the psychiatric unit, little is known about suicide in a medical setting. This study included the development and validation of a screening tool for the assessment of suicide risk, specialized for medical inpatients. METHODS: The preliminary questionnaire was based on review of previous suicide ideation scales, mood scales, and clinical experiences of psychiatrists and clinical psychologists in Korea. Initially, the questionnaire consisted of 12 questions. One hundred adult medical inpatients were asked to perform the questionnaire. Explorative factor analysis was used to examine construct validity. Concurrent validity was evaluated by comparison with the Korean versions of the Beck Scale for Suicide Ideation (BSI), the Beck Hopelessness Scale (BHS), and the Hospital Anxiety and Depression Scale (HADS). RESULTS: Five questions were removed from the preliminary questionnaire by explorative factor analysis and seven questions remained to comprise the Suicide Risk Scale for Medical inpatients (SRSM). Explorative factor analysis showed that the SRSM is composed of a single factor. SRSM was highly reliable in terms of internal consistency (Cronbach's alpha 0.91). Concurrent validity with the BSI, BHS, and HADS was statistically significant. The proposed cut-off score of the SRSM was five. CONCLUSION: In conclusion, the SRSM is a valid and reliable measure for screening suicide risks in medical inpatients.
Significance of clinical observations and biochemical alterations in buffalo calves with dietary abomasal impaction.

BACKGROUND: The present study aimed to throw light on the clinical characteristics of abomasal impaction in buffalo calves and its associated biochemical alterations. For this reason, a total of 20 male buffalo calves (Bubalus bubalis) with abomasal impaction were studied. The investigated calves were at 6 to 12 months of age and were belonged to three private farms in Dakahlia Governorate besides sporadic cases admitted to the Veterinary Teaching Hospital, Faculty of Veterinary Medicine, Mansoura University, Egypt. Ten apparently healthy buffalo calves were also included as controls. According to the clinical outcome, the diseased calves were categorized into survivors (n = 11) and non-survivors (n = 9). Blood samples were collected from all animals to estimate blood gases besides a panel of selected biochemical parameters. The definitive diagnosis of dietary abomasal impaction was achieved by either left flank exploratory laparotomy or by necropsy. RESULTS: Both survivors and non-survivors demonstrated common clinical findings including distension of ventro-lateral aspect of the right abdomen, and varying degrees of dehydration. The great majority of survivors (81%) and 100% of non-survivors were anorexic and had rumen stasis as well as hard texture upon ballottement of the left flank. Approximately 45% of non-survivors had frothy salivation, expiratory grunting and were being tender when strong percussion was applied on the right flank. Diseased calves had metabolic alkalosis, while plasma potassium and chloride were significantly lower in non-survivors than those of survivors (P < 0.05). Serum malondialdehyde, superoxide dismutase and uric acid were significantly higher in diseased buffalo than controls and in non-survivors than survivors (P < 0.05). Serum total protein, albumin, creatinine, urea, aspartate aminotransferase, gamma-glutamyl transferase, and total bilirubin levels were also higher in non-survivors than those of survivors (P < 0.05). CONCLUSION: Buffalo calves with dietary abomasal impaction were associated with marked clinical and biochemical alterations that could be helpful for an accurate diagnosis of the disease.
A novel prototype 3/5 laparoscopic needle driver: A validation study with conventional laparoscopic needle driver.

INTRODUCTION: The challenges in laparoscopic suturing include need to expertise to suture. Laparoscopic needle holder is a "key" instrument to accomplish this arduous task. INSTRUMENT: The objective of this new invention was to develop a laparoscopic needle holder which would be adapted to avoid any wobble (with a shaft diameter same as a 5mm port), ensure accurate and dexterous suturing not just in adult patients but pediatric patients alike (with a short shaft diameter) and finally ensure seamless throw of knots with a narrow tip configuration Validation: We did an initial evaluation to evaluate the validity of the prototype needle holder and its impact on laparoscopic suturing skills by experienced laparoscopic surgeons and novice laparoscopic Surgeons. Both the groups of surgeons performed two tasks. The first task was to grasp the needle and position it in an angle deemed ideal for suturing. The second task was to pass suture through two fixed points and make a single square knot. At the end of the tasks each participant was asked to complete a 5- point Likert's scale questionnaire (8 items; 4 items of handling and 4 items of suturing) rating each needle holder. In expert group, the mean time to complete task 1 was shorter with prototype 3/5 laparoscopic needle holder (11.8 sec Vs 20.8 sec). The mean time to complete task 2 was also shorter with prototype 3/5 laparoscopic needle holder (103.2 sec Vs 153.2 sec). In novice group, mean time to complete both the task was shorter with prototype 3/5 laparoscopic needle holder. CONCLUSION: The expert laparoscopic surgeons as well as novice laparoscopic surgeons performed laparoscopic suturing faster and with more ease while using the prototype 3/5 laparoscopic needle holder.
MAPK pathway control of stem cell proliferation and differentiation in the embryonic pituitary provides insights into the pathogenesis of papillary craniopharyngioma.

Despite the importance of the RAS-RAF-MAPK pathway in normal physiology and disease of numerous organs, its role during pituitary development and tumourigenesis remains largely unknown. Here, we show that the over-activation of the MAPK pathway, through conditional expression of the gain-of-function alleles BrafV600E and KrasG12D in the developing mouse pituitary, results in severe hyperplasia and abnormal morphogenesis of the gland by the end of gestation. Cell-lineage commitment and terminal differentiation are disrupted, leading to a significant reduction in numbers of most of the hormone-producing cells before birth, with the exception of corticotrophs. Of note, Sox2(+) stem cells and clonogenic potential are drastically increased in the mutant pituitaries. Finally, we reveal that papillary craniopharyngioma (PCP), a benign human pituitary tumour harbouring BRAF p.V600E also contains Sox2(+) cells with sustained proliferative capacity and disrupted pituitary differentiation. Together, our data demonstrate a crucial function of the MAPK pathway in controlling the balance between proliferation and differentiation of Sox2(+) cells and suggest that persistent proliferative capacity of Sox2(+) cells may underlie the pathogenesis of PCP.