Miracle-dz/UniFAR-FTUs huggingface dataset:
Splicing regulation in brain and testis: common themes for highly specialized organs

ABSTRACT Expansion of the coding and regulatory capabilities of eukaryotic transcriptomes by alternative splicing represents one of the evolutionary forces underlying the increased structural complexity of metazoans. Brain and testes stand out as the organs that mostly exploit the potential of alternative splicing, thereby expressing the largest repertoire of splice variants. Herein, we will review organ-specific as well as common mechanisms underlying the high transcriptome complexity of these organs and discuss the impact exerted by this widespread alternative splicing regulation on the functionality and differentiation of brain and testicular cells.
Application of the Flood-Grjotheim Thermodynamic Treatment to the Slag-Metal Equilibria

AbstractFlood-Grjotheim thermodynamic treatment of slag-metal exchange equilibria has been applied to the experimental results of several authors investigating phosphorous and manganese distribution between slags and molten metal.For the phosphorous reaction, the equilibrium constants calculated from the experimental data showed linear dependence on the electrical equivalent fraction of calcium ions in the slag. Values of log K extrapolated to Nt′ca = 1 were in good agreement for all data analyzed, and did not greatly depend on the assumption of either the Fe3+ or FeO5−4 state for trivalent iron. Good agreement of all data was attributed to the high dephosphorizing power of calcium, and to its high concentration in all the slags. Agreement of the value of the experimental equilibrium constant with one calculated from the thermodynamic data was satisfactory.For the manganese reaction, the linear relation was obtained by plotting log K values versus the electrically equivalent ionic fraction of oxygen. Valu.
Cardiac extracellular volume fraction in cats with preclinical hypertrophic cardiomyopathy

Abstract Background Cardiac magnetic resonance imaging (CMR) allows for detection of fibrosis in hypertrophic cardiomyopathy (HCM) by quantification of the extracellular volume fraction (ECV). Hypothesis/Objectives To quantify native T1 mapping and ECV in cats. We hypothesize that native T1 mapping and ECV will be significantly increased in HCM cats compared with healthy cats. Animals Seventeen healthy and 12 preclinical HCM, age‐matched, client‐owned cats. Methods Prospective observational study. Tests performed included indirect blood pressure, CBC, biochemical analysis including total thyroid, urinalysis, transthoracic echocardiogram, and CMR. Cats were considered healthy if all tests were within normal limits and a diagnosis of HCM was determined by the presence of left ventricular concentric hypertrophy ≥6 mm on echocardiography. Results There were statistically significant differences in LV mass (healthy = 5.87 g, HCM = 10.3 g, P < .0001), native T1 mapping (healthy = 1122 ms, HCM = 1209 ms, P = .004), and ECV (healthy = 26.0%, HCM = 32.6%, P < .0001). Variables of diastolic function including deceleration time of early diastolic transmitral flow (DTE), ratio between peak velocity of early diastolic transmitral flow and peak velocity of late diastolic transmitral flow (E : A), and peak velocity of late diastolic transmitral flow (A wave) were significantly correlated with ECV (DTE; r = 0.73 P = .007, E : A; r = −0.75 P = .004, A wave; r = 0.76 P = .004). Conclusions and Clinical Importance Quantitative assessment of cardiac ECV is feasible and can provide additional information not available using echocardiography.
Deleterious point mutations in T‐cell acute lymphoblastic leukemia: Mechanistic insights into leukemogenesis

T‐cell acute lymphoblastic leukemia (T‐ALL) is characterized by the leukemogenic transformation of immature T cells, which accumulate an array of genetic and epigenetic lesions, leading to a sustained proliferation of abnormal T cells. Genetic alterations in the DNA repair genes, protooncogenes, transcription factors, and epigenetic modifiers have been studied in the past decade using next‐generation sequencing and high‐resolution copy number arrays. While other genomic lesions like chromosomal rearrangements, inversions, insertions, and gene fusions have been well studied at functional level, the mechanism of generation of driver mutations in T‐ALL is the subject of current investigation. Novel oncogenic mutations in the TP53, BRCA2, PTEN, IL7R, RAS, NOTCH1, ETV6, BCL11B, WT1, DNMT3A, PRC2, PHF6, USP7, KDM6A and an array of other genes disrupt the genetic and epigenetic homeostasis in T‐ALL. In this review, we have summarized the mechanistic role of deleterious driver mutations in T‐ALL initiation and progression. We speculate that the formation of non‐B DNA structures could be one of the primary reasons for the occurrence of different genomic lesions seen in T‐ALL, which warrants further investigation. Understanding the mechanism behind the genesis of oncogenic mutations will pave the way to develop targeted therapies that can improve the overall survival and treatment outcome.
Functionalized single walled carbon nanotube containing amino acid based hydrogel: a hybrid nanomaterial

Fmoc-protected amino acid based (Fmoc-Phe-OH) hydrogel has been developed in our laboratory previously (S. Roy and A. Banerjee, Soft Matter, 2011, 7, 5300–5308). This hydrogel has been used to incorporate and disperse functionalized single-walled carbon nanotube (f-SWCNT) within the gel phase to make a hybrid hydrogel at physiological pH and temperature and this is a convenient procedure to create a f-SWCNT based hybrid nanomaterial. The hybrid hydrogel has been characterized using different microscopic studies including transmission electron microscopic imaging (TEM) and atomic force microscopic imaging (AFM) and rheological studies. The AFM study demonstrates a nice 1D alignment of f-SWCNTs on the surface of the gel nanofibers. Functionalized SWCNT containing hybrid hydrogels are more thermally stable than the native gel. Rheological experiments show that the hybrid hydrogel is a more elastic material than the native hydrogel obtained from the Fmoc-Phe-OH. Moreover, G′ (storage modulus) of the native hydrogel has been increased about 16 times upon the inclusion of f-SWCNT into the gel matrix. Conductivity of the f-SWCNT containing hydrogel has been found to be 3.12 S cm−1 and conductivity of the f-SWCNT has dropped after incorporation of f-SWCNT into the hydrogel system.
Elective neck dissection versus positron emission tomography–computed tomography–guided management of the neck in clinically node‐negative early oral cavity cancer: A cost–utility analysis

In early oral cavity cancer, elective neck dissection (END) for the clinically node‐negative (cN0) neck improves survival compared with observation. This paradigm has been challenged recently by the use of positron emission tomography–computed tomography (PET‐CT) imaging in the cN0 neck. To inform this debate, we performed an economic evaluation comparing PET‐CT–guided therapy with routine END in the cN0 neck.
Susceptibility-Associated Genetic Variation in NEDD9 Contributes to Prostate Cancer Initiation and Progression

A prostate cancer susceptibility genetic variation in NEDD9, which is strongly associated with the increased risk of patients with African ancestry, increases NEDD9 expression and promotes initiation and progression of prostate cancer. Although American men of European ancestry represent the largest population of patients with prostate cancer, men of African ancestry are disproportionately affected by prostate cancer, with higher prevalence and worse outcomes. These racial disparities in prostate cancer are due to multiple factors, but variations in genomic susceptibility such as SNP may play an important role in determining cancer aggressiveness and treatment outcome. Using public databases, we have identified a prostate cancer susceptibility SNP at an intronic enhancer of the neural precursor expressed, developmentally downregulated 9 (NEDD9) gene, which is strongly associated with increased risk of patients with African ancestry. This genetic variation increased expression of NEDD9 by modulating the chromatin binding of certain transcription factors, including ERG and NANOG. Moreover, NEDD9 displayed oncogenic activity in prostate cancer cells, promoting prostate cancer tumor growth and metastasis in vitro and in vivo. Together, our study provides novel insights into the genetic mechanisms driving prostate cancer racial disparities. Significance: A prostate cancer susceptibility genetic variation in NEDD9, which is strongly associated with the increased risk of patients with African ancestry, increases NEDD9 expression and promotes initiation and progression of prostate cancer. See related commentary by Mavura and Huang, p. 3764
A Phase 2 Trial of Selumetinib in Children with Recurrent Optic Pathway and Hypothalamic Low-Grade Glioma without NF1: A Pediatric Brain Tumor Consortium Study.

BACKGROUND Pediatric low-grade gliomas (pLGGs) are the most common childhood brain tumor. Progression-free survival (PFS) is much lower than overall survival, emphasizing the need for alternative treatments. Sporadic (without neurofibromatosis type-1) optic pathway and hypothalamic glioma (OPHGs) are often multiply recurrent and cause significant visual deficits. Recently, there has been a prioritization of functional outcomes. METHODS We present results from children with recurrent/progressive OPHGs treated on a PBTC phase 2 trial evaluating efficacy of selumetinib, (AZD6244, ARRY-142886) a MEK-1/2 inhibitor. Stratum 4 of PBTC-029 included patients with sporadic recurrent/progressive OPHGs treated with selumetinib at the recommended phase 2 dose (25mg/m 2 /dose BID) for a maximum of 26 courses. RESULTS Twenty-five eligible and evaluable patients were enrolled with a median of 4 (1-11) previous therapies. Six of 25 (24%) had partial response, 14/25 (56%) had stable disease and 5 (20%) had progressive disease while on treatment. The median treatment courses were 26 (2-26); 14/25 patients completed all 26 courses. Two-year PFS was 78 ± 8.5%. Nineteen of 25 patients were evaluable for visual acuity which improved in 4/19 patients (21%), was stable in 13/19 (68%) and worsened in 2/19 (11%). Five of 19 patients (26%) had improved visual fields and 14/19 (74%) were stable. The most common toxicities were grade 1/2 CPK elevation, anemia, diarrhea, headache, nausea/emesis, fatigue, AST and ALT increase, hypoalbuminemia and rash. CONCLUSIONS Selumetinib was tolerable and led to responses and prolonged disease stability in children with recurrent/progressive OPHGs based upon radiographic response, PFS and visual outcomes.
PROTACs in Treatment of Cancer: A review.

Cancer treatment has become a major challenge amidst the resistance and relapse caused by the various treatments available. The PROteolysis TAargeting Chimera (PROTAC) technology involves the degradation of target protein against the inhibition by small drug molecules. The PROTACs with high potency and activity have been frequently reported; however, no PROTAC acting against cancer has reached the clinical trials so far. The concept of PROTACs involves the reduction in the disease causing protein by its degradation through ubiquitin-proteosomal enzyme system. This concept has attracted a lot of attention from both industry and academia due to its potential in drug discovery (in the form of PROTACs) which can conquer the resistance associated with current treatments of cancer. Thus, it is the need of hour to identify and synthesize more PROTACs for a viable treatment of cancer. This article reviews the design, activity and the effects produced in cancer by some recently developed PROTACs.
Direct and Indirect Associations of Personality With Audiovisual Technology Acceptance Through General Self-Efficacy

Increasing consensus among information systems researchers suggests that personality accounts for the effective use of several technologies, yet less is known about the process through which personality affects user perceptions of technology acceptance. This study, therefore, examined whether personality is associated with student perceptions of audiovisual technology acceptance, and whether general self-efficacy mediates this association. In total, 244 students completed an online survey including measures of personality, general self-efficacy, and perceptions of audiovisual technology acceptance. Canonical correlation uncovered significant associations between personality and student beliefs about technology use. Results further revealed that general self-efficacy fully mediated the effects of openness to experience and neuroticism on Perceived Ease of Use, whereas the association between agreeableness and Perceived Usefulness was partially mediated by self-efficacy beliefs. The fact that personality influences students’ perceptions of technology acceptance both directly and indirectly should not remain unnoticed, especially when designing intervention programs to enhance their academic performance.
Chronic Disease in the Community (CDCom) Program: Hypertension and non-communicable disease care by village health workers in rural Uganda

Background Although hypertension, the largest modifiable risk factor in the global burden of disease, is prevalent in sub-Saharan Africa, rates of awareness and control are low. Since 2011 village health workers (VHWs) in Kisoro district, Uganda have been providing non-communicable disease (NCD) care as part of the Chronic Disease in the Community (CDCom) Program. The VHWs screen for hypertension and other NCDs as part of a door-to-door biannual health census, and, under the supervision of health professionals from the local district hospital, also serve as the primary providers at monthly village-based NCD clinics. Objective/Methods We describe the operation of CDCom, a 10-year comprehensive program employing VHWs to screen and manage hypertension and other NCDs at a community level. Using program records we also report hypertension prevalence in the community, program costs, and results of a cost-saving strategy to address frequent medication stockouts. Results/Conclusions Of 4283 people ages 30–69 screened for hypertension, 22% had a blood pressure (BP) ≥140/90 and 5% had a BP ≥ 160/100. All 163 people with SBP ≥170 during door-to-door screening were referred for evaluation in CDCom, of which 91 (59%) had repeated BP ≥170 and were enrolled in treatment. Of 761 patients enrolled in CDCom, 413 patients are being treated for hypertension and 68% of these had their most recent blood pressure below the treatment target. We find: 1) The difference in hypertension prevalence between this rural, agricultural population and national rates mirrors a rural-urban divide in many countries in sub-Saharan Africa. 2) VHWs are able to not only screen patients for hypertension, but also to manage their disease in monthly village-based clinics. 3) Mid-level providers at a local district hospital NCD clinic and faculty from an academic center provide institutional support to VHWs, stream-line referrals for complicated patients and facilitate provider education at all levels of care. 4) Selective stepdown of medication doses for patients with controlled hypertension is a safe, cost-saving strategy that partially addresses frequent stockouts of government-supplied medications and patient inability to pay. 5) CDCom, free for village members, operates at a modest cost of 0.20 USD per villager per year. We expect that our data-informed analysis of the program will benefit other groups attempting to decentralize chronic disease care in rural communities of low-income regions worldwide.
Genetic relationships between feed efficiency and gut microbiome in pig lines selected for residual feed intake

Abstract This study aimed to evaluate the genetic relationship between faecal microbial composition and five feed efficiency (FE) and production traits, residual feed intake (RFI), feed conversion ratio (FCR), daily feed intake (DFI), average daily gain (ADG) and backfat thickness (BFT). A total of 588 samples from two experimental pig lines developed by divergent selection for RFI were sequenced for the 16 rRNA hypervariable V3‐V4 region. The 75 genera with less than 20% zero values (97% of the counts) and two α‐diversity indexes were analysed. Line comparison of the microbiota traits and estimations of heritability (h2) and genetic correlations (r g) were analysed. A non‐metric multidimensional scaling showed line differences between genera. The α‐diversity indexes were higher in the LRFI line than in the HRFI line (p < .01), with h2 estimates of 0.19 ± 0.08 (Shannon) and 0.12 ± 0.06 (Simpson). Forty‐eight genera had a significant h2 (>0.125). The r g of the α‐diversities indexes with production traits were negative. Some r g of genera belonging to the Lachnospiraceae, Ruminococcaceae, Prevotellaceae, Lactobacillaceae, Streptococcaceae, Rikenellaceae and Desulfovibrionaceae families significantly differed from zero (p < .05) with FE traits, RFI (3), DFI (7) and BFT (11). These results suggest that a sizable part of the variability of the gut microbial community is under genetic control and has genetic relationships with FE, including diversity indicators. It offers promising perspectives for selection for feed efficiency using gut microbiome composition in pigs.
Risk factors for short-term postoperative complications in the 8 weeks after tibial plateau leveling osteotomy in dogs weighing less than 15 kilograms: A retrospective study

The purpose of this retrospective study was to evaluate the risk factors for short-term postoperative complications in the 8 weeks after unilateral tibial plateau leveling osteotomy (TPLO) for cranial cruciate ligament rupture in small dogs weighing less than 15 kg. Medical records were retrospectively reviewed for 90 dogs weighing <15 kg that underwent medial parapatellar arthrotomy with inspection of the meniscus and TPLO performed by the same surgeon between January 2012 and December 2017. The overall complication rate was 4.44% (4/90 dogs). There were four cases of partial incisional dehiscence, none of which required surgical revision. Complications were significantly more likely in dogs that had undergone placement of a 2.4-mm TPLO plate. Overall, the complication rate was less than that in previous studies of dogs weighing > 15kg. In this study, patients in which 2.4-mm TPLO plates were used were more likely to develop postoperative complications. Dogs weighing <15 kg that underwent TPLO had good short-term outcomes with minimal complications. In our study, the overall complication rate after TPLO in dogs weighing <15 kg is less than that historically reported in heavier dogs. Our data suggests that TPLO is a safe treatment option in small dogs with cranial cruciate ligament rupture.
Evaluation of Exercise Interventions and Outcomes After Hip Arthroplasty

Key Points Question What clinical outcomes are associated with preoperative and postoperative exercise training for hip joint replacement? Findings In this systematic review and meta-analysis including 32 studies, there was very low– to moderate-quality evidence relevant to preoperative and postoperative supervised exercise interventions. Compared with usual care or no or minimal intervention, supervised exercise interventions were not associated with improved self-reported physical function. Meaning These findings suggest that supervised preoperative and postoperative exercise interventions was probably not necessary for patients with total hip replacement.
Genetic contributions to autism spectrum disorder

Abstract Autism spectrum disorder (autism) is a heterogeneous group of neurodevelopmental conditions characterized by early childhood-onset impairments in communication and social interaction alongside restricted and repetitive behaviors and interests. This review summarizes recent developments in human genetics research in autism, complemented by epigenetic and transcriptomic findings. The clinical heterogeneity of autism is mirrored by a complex genetic architecture involving several types of common and rare variants, ranging from point mutations to large copy number variants, and either inherited or spontaneous (de novo). More than 100 risk genes have been implicated by rare, often de novo, potentially damaging mutations in highly constrained genes. These account for substantial individual risk but a small proportion of the population risk. In contrast, most of the genetic risk is attributable to common inherited variants acting en masse, each individually with small effects. Studies have identified a handful of robustly associated common variants. Different risk genes converge on the same mechanisms, such as gene regulation and synaptic connectivity. These mechanisms are also implicated by genes that are epigenetically and transcriptionally dysregulated in autism. Major challenges to understanding the biological mechanisms include substantial phenotypic heterogeneity, large locus heterogeneity, variable penetrance, and widespread pleiotropy. Considerable increases in sample sizes are needed to better understand the hundreds or thousands of common and rare genetic variants involved. Future research should integrate common and rare variant research, multi-omics data including genomics, epigenomics, and transcriptomics, and refined phenotype assessment with multidimensional and longitudinal measures.
An aspartyl protease-mediated cleavage regulates structure and function of a flavodoxin-like protein and aids oxidative stress survival

A family of eleven glycosylphosphatidylinositol-anchored aspartyl proteases, commonly referred to as CgYapsins, regulate a myriad of cellular processes in the pathogenic yeast Candida glabrata, but their protein targets are largely unknown. Here, using the immunoprecipitation-mass spectrometry approach, we identify the flavodoxin-like protein (Fld-LP), CgPst2, to be an interactor of one of the aspartyl protease CgYps1. We also report the presence of four Fld-LPs in C. glabrata, which are required for survival in kidneys in the murine model of systemic candidiasis. We further demonstrated that of four Fld-LPs, CgPst2 was solely required for menadione detoxification. CgPst2 was found to form homo-oligomers, and contribute to cellular NADH:quinone oxidoreductase activity. CgYps1 cleaved CgPst2 at the C-terminus, and this cleavage was pivotal to oligomerization, activity and function of CgPst2. The arginine-174 residue in CgPst2 was essential for CgYps1-mediated cleavage, with alanine substitution of the arginine-174 residue also leading to elevated activity and oligomerization of CgPst2. Finally, we demonstrate that menadione treatment led to increased CgPst2 and CgYps1 protein levels, diminished CgYps1-CgPst2 interaction, and enhanced CgPst2 cleavage and activity, thereby implicating CgYps1 in activating CgPst2. Altogether, our findings of proteolytic cleavage as a key regulatory determinant of CgPst2, which belongs to the family of highly conserved, electron-carrier flavodoxin-fold-containing proteins, constituting cellular oxidative stress defense system in diverse organisms, unveil a hidden regulatory layer of environmental stress response mechanisms.