Miracle-dz/UniFAR-FTUs huggingface dataset:
Rhapsody: predicting the pathogenicity of human missense variants

Abstract Motivation The biological effects of human missense variants have been studied experimentally for decades but predicting their effects in clinical molecular diagnostics remains challenging. Available computational tools are usually based on the analysis of sequence conservation and structural properties of the mutant protein. We recently introduced a new machine learning method that demonstrated for the first time the significance of protein dynamics in determining the pathogenicity of missense variants. Results Here, we present a new interface (Rhapsody) that enables fully automated assessment of pathogenicity, incorporating both sequence coevolution data and structure- and dynamics-based features. Benchmarked against a dataset of about 20 000 annotated variants, the methodology is shown to outperform well-established and/or advanced prediction tools. We illustrate the utility of Rhapsody by in silico saturation mutagenesis studies of human H-Ras, phosphatase and tensin homolog and thiopurine S-methyltransferase. Availability and implementation The new tool is available both as an online webserver at http://rhapsody.csb. pitt.edu and as an open-source Python package (GitHub repository: https://github.com/prody/rhapsody; PyPI package installation: pip install prody-rhapsody). Links to additional resources, tutorials and package documentation are provided in the 'Python package' section of the website. Supplementary information Supplementary data are available at Bioinformatics online.
Dynamics at the serine loop underlie differential affinity of cryptochromes for CLOCK:BMAL1 to control circadian timing

Mammalian circadian rhythms are generated by a transcription-based feedback loop in which CLOCK:BMAL1 drives transcription of its repressors (PER1/2, CRY1/2), which ultimately interact with CLOCK:BMAL1 to close the feedback loop with ~24 hr periodicity. Here we pinpoint a key difference between CRY1 and CRY2 that underlies their differential strengths as transcriptional repressors. Both cryptochromes bind the BMAL1 transactivation domain similarly to sequester it from coactivators and repress CLOCK:BMAL1 activity. However, we find that CRY1 is recruited with much higher affinity to the PAS domain core of CLOCK:BMAL1, allowing it to serve as a stronger repressor that lengthens circadian period. We discovered a dynamic serine-rich loop adjacent to the secondary pocket in the photolyase homology region (PHR) domain that regulates differential binding of cryptochromes to the PAS domain core of CLOCK:BMAL1. Notably, binding of the co-repressor PER2 remodels the serine loop of CRY2, making it more CRY1-like and enhancing its affinity for CLOCK:BMAL1.
Gut Microbiome-Based Diagnostic Model to Predict Coronary Artery Disease.

In the present study, we aimed to characterise gut microbiome and develop a gut microbiome-based diagnostic model in patients with coronary artery disease (CAD). Prospectively, we collected 309 faecal samples from Central China and Northwest China which were carried out sequencing of the V3-V4 regions of the 16S rRNA gene. The gut microbiome was characterised and microbial biomarkers were identified in 152 CAD patients and 105 healthy controls (Xinjiang cohort, n=257). Using the biomarkers, we constructed a diagnostic model and validated it externally in 34 CAD patients and 18 healthy controls (Zhengzhou cohort, n=52). Faecal microbial diversity was increased in CAD patients compared to that in healthy controls (P=0.021). Phylum Bacteroidetes was increased in CAD patients versus healthy controls (P=0.001). Correspondingly, forty eight microbial markers were identified through a 10-fold cross-validation on a random forest model and achieved an area under the curve (AUC) of 87.7% (95%CI: 0.832 to 0.916, P<0.001) in Xinjiang cohort (development cohort, n=257). Notably, combined analysis of gut microbial markers and clinical variables the AUC achieved 90.4% (95%CI: 0.848 to 0.928, P<0.001). This model provided a robust tool for prediction of CAD. It could be widely employed to complement clinical assessment and prevention of CAD.
Detection of kneeling and squatting during work using wireless triaxial accelerometers

Abstract Occupational kneeling and squatting are well-documented risk factors for knee disorders. A method using 3 wireless accelerometers to detect and discriminate kneeling and squatting during work were developed based on data from a semi-standardised laboratory protocol. The method was tested for validity under free-living working conditions. The developed method showed high sensitivity (88–99%) and specificity (98–99%) for detection of kneeling and squatting during the semi-standardised laboratory conditions. During free-living working conditions, kneeling showed very high sensitivity (94%) and specificity (99%), while squatting results were non-conclusive due to limited duration of squatting during the free-living working conditions. This method shows great promise for long-term technical measurement of kneeling and squatting during normal working conditions using wireless accelerometers. The method opens up possibilities for using technical measurements to provide valid exposure assessments and intervention evaluations of kneeling and squatting, as well as increased feasibility for technical measurements in large cohort studies. Practitioner summary: Quantification of kneeling and squatting during work is important for prevention, but limited by either imprecise or costly methods. This study developed and validated an inexpensive wireless accelerometer-based measurement method that can be used by practitioners and researchers for long-term measurements of kneeling and squatting during free-living working conditions.
Clinical and Histologic Liver Improvement in Siblings with Lysosomal Acid Lipase Deficiency After Enzyme Replacement.

OBJECTIVES To assess the effect of long-term (104 weeks) treatment with recombinant sebelipase alpha (rhSA) on serum lipid and hepatic transaminase levels, and liver histopathology in four siblings diagnosed with lysosomal acid lipase deficiency (LAL-D). METHODS Four male siblings from the same non-consanguineous parents were diagnosed with the late-onset phenotype of LAL-D in 2015. Liver specimens were obtained by biopsy at baseline and after 104 weeks of enzyme replacement with rhSA (1 mg/kg, IV, every 2 weeks). Hepatic transaminase, lipid and lipoprotein levels were assessed at baseline and sequentially every 16 weeks for 104 weeks. Hepatic steatosis was evaluated from hematoxylin and eosin stained specimens, and fibrosis was evaluated (Metavir scoring system) from trichrome-stained specimens obtained at baseline and following 104 weeks of treatment with rhSA. RESULTS All four siblings had improvement in their serum lipid and hepatic transaminase levels after treatment with rhSA. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels decreased from baseline by an average of 47% and 56%, respectively. The fasting triglyceride and low-density lipoprotein cholesterol (LDL-C) levels decreased from baseline by an average of 43% and 60%, respectively. Hepatic steatosis decreased from baseline grade 3 to post-treatment grade 1. Hepatic fibrosis did not advance following 104 weeks of treatment with rhSA and regressed in one sibling. CONCLUSION Treatment with rhSA for 104 weeks in four siblings with LAL-D demonstrated improvement in their hepatic transaminase and serum lipid levels, accompanied by reduction of hepatic steatosis and no progression of fibrosis.
Stroke effort and relative lung volume influence heart rate in diving sea lions

ABSTRACT The dive response, bradycardia (decreased heart rate) and peripheral vasoconstriction, is the key mechanism allowing breath-hold divers to perform long-duration dives while actively swimming and hunting prey. This response is variable and modulated by factors such as dive duration, depth, exercise and cognitive control. This study assessed the potential role of exercise and relative lung volume in the regulation of heart rate (fH) during dives of adult female California sea lions instrumented with electrocardiogram (ECG), depth and tri-axial acceleration data loggers. A positive relationship between activity (minimum specific acceleration) and fH throughout dives suggested increased muscle perfusion associated with exercise. However, apart from late ascent, fH during dives was still less than or equal to resting fH (on land). In addition, the activity–fH relationship was weaker in long, deep dives consistent with prioritization of blood oxygen conservation over blood oxygen delivery to muscle in those dives. Pulmonary stretch receptor reflexes may also contribute to fH regulation as fH profiles generally paralleled changes in relative lung volume, especially in shallower dives and during early descent and late ascent of deeper dives. Overall, these findings support the concept that both exercise and pulmonary stretch receptor reflexes may influence the dive response in sea lions. Summary: California sea lion diving heart rate is influenced by exercise and relative lung volume.
Physical exercise prepartum to support metabolic adaptation in the transition period of dairy cattle: A proof of concept

Abstract In dairy cattle, the hormonal changes around calving induce large metabolic changes to support milk production. Mobilization of adipose reserves is one of the changes involved, imposing a metabolic load on the liver. We hypothesized that the risk for excessive lipolysis and hepatic lipidosis postpartum can be reduced by starting fat mobilization and processing during the prepartum period by physical exercise, especially in cows with a high body condition score (BCS). As a proof of concept, 32 pregnant Holstein‐Friesian dairy cows were selected for a 2 × 2 experimental design. Sixteen cows had a BCS < 3.25 (group LOW) and 16 cows a BCS ≥ 3.25 (group HIGH). Cows within each group were randomly allocated to one of two treatments: group STEP was walked twice daily for 45 min during the dry period while group CON remained indoors. Treatment was stopped at calving and cows were monitored until 6 weeks after calving. Liver biopsies were taken in a subset of 16 cows to determine liver triglyceride (TG) concentration. We found that calculated energy balance was more negative for group STEP prepartum, resulting in higher plasma non‐esterified fatty acids and β‐hydroxybutyrate concentrations. During the first 6 weeks postpartum, neither dry matter intake nor milk yield was affected by exercise. As expected, the cows in group HIGH had increased liver TG concentrations postpartum relative to group LOW with increased plasma non‐esterified fatty acids directly after calving. Exercise during the dry period mitigated postpartal liver TG accumulation, but this did not seem to be related to increased plasma lipoprotein transport. We conclude that substantial physical activity prepartum can induce lipolysis and lipid utilization, thereby starting an early adaptation to lactation. This may be instrumental to reduce the risk for excessive liver TG accumulation postpartum, especially in cows with a high BCS at dry‐off.
Preliminary Survey of Alternaria Toxins Reduction during Fermentation of Whole Wheat Dough

The aim of this study was to investigate the fate of the most common Alternaria toxins found in wheat—tenuazonic acid (TeA), alternariol (AOH), and alternariol monomethyl ether (AME) during sourdough processing. For this purpose, spiked whole wheat flour, 3% sourdough starter, 0.5% of baker’s yeast, and 105% of water calculated on flour weight as a base were used as raw materials. Spiked whole wheat dough was fermented for 4 h, 8 h, 12 h, 24 h, and 48 h at 25 °C, and at each point the fermented dough samples were taken, frozen, lyophilized, grounded, and stored until further analysis. To study the effect of sourdough processing on TeA, AOH and AME content, the validated method of high-performance liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) for these mycotoxins was used. Mathematical models of Alternaria toxins reduction were developed in the form of Four Parameter Logistic Regression function. The maximum reduction of TeA, AOH, and AME levels was archived at 48 h of dough fermentation at 25 °C compared with dough after kneading (0 h). Under these conditions, a reduction of the toxin levels of 60.3 %, 41.5%, and 24.1% was observed for TeA, AOH, and AME, respectively.
Simulation can replace part of speech-language pathology placement time: A randomised controlled trial

Abstract Purpose Simulation is increasingly used within speech-language pathology education. Research has primarily explored students’ perceptions of learning in simulation. The aim of this study was to determine if speech-language pathology students achieved a statistically-equivalent level of competency when a mean of 20% of placement time was replaced with simulation compared to placements without a simulation component. Method This non-inferiority randomised controlled trial involved students from six Australian universities. Students were randomised to either a simulation + traditional placement group attending 5 days of simulation prior to their traditional placement, or a traditional only placement group. Their end-placement clinical competency was assessed using Competency Assessment in Speech Pathology (COMPASS®). Result Final data were available for 325 students: 150 students in traditional placements, 138 students in protocol-compliant simulation + traditional placements, and 37 students in non-protocol simulation + traditional placements. There were no statistically significant differences between groups (traditional vs protocol-compliant simulation + traditional Mann–Whitney–Wilcoxon z = 1.23, df = 286, p = 0.22; traditional vs intention-to-treat simulation + traditional Mann–Whitney–Wilcoxon z = 0.23, df = 323, p = 0.81). Conclusion This research contributes to the evidence base which suggests that simulation can partially replace traditional placement time for speech-language pathology students without loss of competency, substantiating its value as an alternative placement model in speech-language pathology programmes.
A Comparison of Hospitalized Patients With Heart Failure and Cancer Referred to Palliative Care

Key Points Question How do hospitalized patients with heart failure who are referred to palliative care differ from patients with cancer in their characteristics, reasons for referral, and outcomes of referral? Findings In this cohort study of 57 272 adults, patients with heart failure were referred for palliative care later in their disease course than patients with cancer. Fewer patients with heart failure were referred for symptom management but they had similar rates of symptom improvement after referral. Meaning Hospitalized patients with heart failure are being referred later to palliative care, suggesting that there are opportunities to integrate palliative care earlier in the disease trajectory for symptom management.
Footprints of natural selection at the mannose-6-phosphate isomerase locus in barnacles

Significance The rocky intertidal is a natural laboratory to study how natural selection acts on the genes and proteins responsible for organismal survival and reproduction. Alternative forms of enzymes that differ across the intertidal have been known for decades and have provided examples of selection, but the genetic basis of such enzyme variation is known in only a few cases. In this paper, we present molecular evidence of natural selection at the Mpi gene, a key enzyme in energy metabolism that alters survival of barnacles living across the stress gradient imposed by the intertidal. Our study demonstrates how natural selection can facilitate survival in highly heterogeneous environments through the maintenance of multiple molecular solutions to ecological stresses. The mannose-6-phosphate isomerase (Mpi) locus in Semibalanus balanoides has been studied as a candidate gene for balancing selection for more than two decades. Previous work has shown that Mpi allozyme genotypes (fast and slow) have different frequencies across Atlantic intertidal zones due to selection on postsettlement survival (i.e., allele zonation). We present the complete gene sequence of the Mpi locus and quantify nucleotide polymorphism in S. balanoides, as well as divergence to its sister taxon Semibalanus cariosus. We show that the slow allozyme contains a derived charge-altering amino acid polymorphism, and both allozyme classes correspond to two haplogroups with multiple internal haplotypes. The locus shows several footprints of balancing selection around the fast/slow site: an enrichment of positive Tajima’s D for nonsynonymous mutations, an excess of polymorphism, and a spike in the levels of silent polymorphism relative to silent divergence, as well as a site frequency spectrum enriched for midfrequency mutations. We observe other departures from neutrality across the locus in both coding and noncoding regions. These include a nonsynonymous trans-species polymorphism and a recent mutation under selection within the fast haplogroup. The latter suggests ongoing allelic replacement of functionally relevant amino acid variants. Moreover, predicted models of Mpi protein structure provide insight into the functional significance of the putatively selected amino acid polymorphisms. While footprints of selection are widespread across the range of S. balanoides, our data show that intertidal zonation patterns are variable across both spatial and temporal scales. These data provide further evidence for heterogeneous selection on Mpi.
Basic study on improvement of plastic drape adhesion for surgery: effect of adhesive layer thickness on drape detachment from wound edge

Plastic drapes are used in surgery for a wide range of purposes, but currently marketed drapes often become detached from the wound edge during surgery. The purpose of this study was to determine the appropriate adhesive layer thickness for optimal peel and shear strength and the smallest peeled area to improve surgical drape wound adhesion.
Ku80-Targeted pH-Sensitive Peptide–PNA Conjugates Are Tumor Selective and Sensitize Cancer Cells to Ionizing Radiation

The development of therapeutic agents that specifically target cancer cells while sparing healthy tissue could be used to enhance the efficacy of cancer therapy without increasing its toxicity. Specific targeting of cancer cells can be achieved through the use of pH-low insertion peptides (pHLIP), which take advantage of the acidity of the tumor microenvironment to deliver cargoes selectively to tumor cells. We developed a pHLIP–peptide nucleic acid (PNA) conjugate as an antisense reagent to reduce expression of the otherwise undruggable DNA double-strand break repair factor, KU80, and thereby radiosensitize tumor cells. Increased antisense activity of the pHLIP–PNA conjugate was achieved by partial mini-PEG sidechain substitution of the PNA at the gamma position, designated pHLIP-αKu80(γ). We evaluated selective effects of pHLIP-αKu80(γ) in cancer cells in acidic culture conditions as well as in two subcutaneous mouse tumor models. Fluorescently labeled pHLIP-αKu80(γ) delivers specifically to acidic cancer cells and accumulates preferentially in tumors when injected i.v. in mice. Furthermore, pHLIP-αKu80(γ) selectively reduced KU80 expression in cells under acidic conditions and in tumors in vivo. When pHLIP-αKu80(γ) was administered to mice prior to local tumor irradiation, tumor growth was substantially reduced compared with radiation treatment alone. Furthermore, there was no evidence of acute toxicity associated with pHLIP-αKu80(γ) administration to the mice. These results establish pHLIP-αKu80(γ) as a tumor-selective radiosensitizing agent. Implications: This study describes a novel agent, pHLIP-αKu80(γ), which combines PNA antisense and pHLIP technologies to selectively reduce the expression of the DNA repair factor KU80 in tumors and confer tumor-selective radiosensitization.
Feasibility, safety, and acute efficacy of the fourth‐generation cryoballoon for ablation of atrial fibrillation: Another step forward?

The second‐generation cryoballoon (CB2) is widely used for pulmonary vein (PV) isolation (PVI) in patients with paroxysmal atrial fibrillation (AF). Recently, the novel fourth‐generation CB (CB‐Advance PRO) was introduced, incorporating a shortened catheter tip.
The ESAS-score: A histological severity grading system of subarachnoid hemorrhage using the modified double hemorrhage model in rats

Objective The amount of extravasated blood is an established surrogate marker for subarachnoid hemorrhage (SAH) severity, which varies in different experimental SAH (eSAH) models. A comprehensive eSAH grading system would allow a more reliable correlation of outcome parameters with SAH severity. The aim of this study was to define a severity score for eSAH related to the Fisher-Score in humans. Material and methods SAH was induced in 135 male rats using the modified double hemorrhage model. A sham group included 8 rats, in which saline solution instead of blood was injected. Histological analysis with HE(hematoxylin-eosin)-staining for the visualization of blood was performed in all rats on day 5. The amount and distribution of blood within the subarachnoid space and ventricles (IVH) was analyzed. Results The mortality rate was 49.6% (71/143). In all except five SAH rats, blood was visible within the subarachnoid space. As expected, no blood was detected in the sham group. The following eSAH severity score was established (ESAS-score): grade I: no SAH visible; grade II: local or diffuse thin SAH, no IVH; grade III: diffuse / thick layers of blood, no IVH; grade IV: additional IVH. Grade I was seen in five rats (7.9%), grade II in 28.6% (18/63), grade III in 41.3% (26/63) and grade IV in 22.2% (14/63) of the rats with eSAH. Conclusion The double hemorrhage model allows the induction of a high grade SAH in more than 60% of the rats, making it suitable for the evaluation of outcome parameters in severe SAH.
Effect of Mo Concentration on the Microstructure Evolution and Properties of High Boron Cast Steel

The microstructure evolution, mechanical properties, and tribological properties of high boron cast steel (HBCS) with various Mo concentrations are investigated. The results indicate that Mo addition can significantly modify the microstructure and enhance the comprehensive properties. With the increase of Mo concentration, borides change from the original fish-bone Fe-rich and Cr-rich M2B to dendritic Fe-rich M2B, blocky and cluster-like Cr-rich M2B, and grainy Mo-rich M2B. The hardness of HBCS increases gradually with the increase of Mo content due to the solid solution strengthening and the refinement of M2B. It can be found that all the samples exhibit quasi-cleavage, but the impact toughness increases firstly and reaches the maximum value when the concentration of Mo is 2.10 wt. %, which is the result of the dispersive distribution of M2B rather than the original fish-bone M2B. Subsequently, the impact toughness begins to decrease as the concentration of Mo further increases because of the extensive formation of grainy Mo-rich M2B at the grain boundary. Meanwhile, the wear results reveal that the average friction coefficient and wear ratio decrease with the increase of Mo content, and the wear mechanism changes from abrasive wear and adhesive wear to abrasive wear when the concentration of Mo exceeds 2.10 wt. %.