Miracle-dz/UniFAR-FTUs huggingface dataset:
NOTCH1 signaling induces pathological vascular permeability in diabetic retinopathy

Significance Diabetic retinopathy is a major cause of blindness in the working population. The most common cause of visual impairment in diabetic patients is diabetic macular edema (DME). Roughly 40% of patients with DME respond poorly to anti-VEGF therapies, which are a standard of care. Here we provide mechanistic insight for the critical role of NOTCH1 signaling in compromising endothelial junction integrity during diabetes. Besides activating canonical transcriptional pathways, we find that NOTCH1 signaling also provokes disruption of endothelial junctions via noncanonical mechanisms, such as production of nitric oxide and activation of Src signaling, leading to vascular endothelial-cadherin and β-catenin dissociation. Our findings have implications for future therapeutic interventions given that we find elevated NOTCH1 ligands in the vitreous of patients with DME and that their neutralization decreases pathologic vascular permeability. Diabetic macular edema is a major complication of diabetes resulting in loss of central vision. Although heightened vessel leakiness has been linked to glial and neuronal-derived factors, relatively little is known on the mechanisms by which mature endothelial cells exit from a quiescent state and compromise barrier function. Here we report that endothelial NOTCH1 signaling in mature diabetic retinas contributes to increased vascular permeability. By providing both human and mouse data, we show that NOTCH1 ligands JAGGED1 and DELTA LIKE-4 are up-regulated secondary to hyperglycemia and activate both canonical and rapid noncanonical NOTCH1 pathways that ultimately disrupt endothelial adherens junctions in diabetic retinas by causing dissociation of vascular endothelial-cadherin from β-catenin. We further demonstrate that neutralization of NOTCH1 ligands prevents diabetes-induced retinal edema. Collectively, these results identify a fundamental process in diabetes-mediated vascular permeability and provide translational rational for targeting the NOTCH pathway (primarily JAGGED1) in conditions characterized by compromised vascular barrier function.
Effects of dietary phytosterols on growth performance, antioxidant status, and meat quality in Partridge Shank chickens.

To investigate the effects of dietary phytosterols (PS) on growth performance, antioxidant status, and meat quality of Partridge Shank chickens, a total of 256 1-day-old male Partridge Shank chicks were randomly assigned into 4 dietary treatments, and each of them replicated 8 times with 8 chicks per replicate. Birds in the 4 treatments were fed a basal diet supplemented with 0 (Control group), 20, 40, and 80 mg/kg PS for 50 D, respectively. Dietary supplementation of PS quadratically increased average daily gain of chickens during the grower and overall periods, whereas linearly decreased the feed-to-gain ratio during the starter period. Compared with control group, a significant increase in average daily gain during the grower and overall periods was observed in chickens fed the basal diet supplemented with 40 mg/kg PS. Increasing PS addition linearly increased serum glutathione peroxidase (GSH-Px) activity at 21 and 50 D and hepatic GSH-Px and superoxide dismutase activities at 21 D, whereas linearly decreased malondialdehyde concentration of breast muscle at 50 D. Meanwhile, 40 mg/kg PS supplementation significantly increased serum GSH-Px activity, and hepatic superoxide dismutase and GSH-Px activities at 21 D as compared with the control. PS supplementation linearly and quadratically decreased drip loss (24 and 48 h postmortem) and luminance value (24 h postmortem) of breast muscle in broilers at 50 D, and there was statistical difference between the control and PS-supplemented group. In conclusion, PS supplementation can improve growth performance, antioxidant status, and meat quality of Partridge Shank chickens, with its optimum level in Partridge Shank chickens' diet being 40 mg/kg.
Cannabidiol modulates the expression of neuroinflammatory factors in stress‐ and drug‐induced reinstatement of methamphetamine in extinguished rats

Methamphetamine (METH) is a highly potent and addictive psychostimulant that is frequently abused worldwide. Although the biggest challenge to the efficient treatment of drug dependence is relapse, its mechanism is completely unclear. Plenty of evidence suggests that inflammation contributes to drug‐induced reward especially in brain regions that are involved in the reward system, but there is no document about relapse. Cannabidiol (CBD) is a nonpsychoactive cannabinoid that has powerful anti‐inflammatory and immunosuppressive properties. A previous research in our laboratory has demonstrated that CBD prevents reinstatement of METH even in 24‐hour rapid eye movement (REM) sleep‐deprived (RSD) rats. The aim of this study was to assess whether CBD prevents reinstatement of METH through change of gene expression of cytokines such as interleukin‐1β, interleukin‐6, interleukin‐10, and tumor necrosis factor α (TNF‐α) in extinguished rats. Real‐time polymerase chain reaction (PCR) was used in this research to assay gene expression of cytokines. We found that stress‐ and drug‐induced reinstatement of METH enhanced mRNA expression of cytokines in the prefrontal cortex (PFC) and hippocampus. Furthermore, CBD treatment significantly reduced the mRNA expression of cytokines in the PFC and hippocampus, but CBD treatment in RSD rats increased expression of cytokines in the hippocampus. It seems that enhancement of cytokines leads to change in neurotransmission and so triggers reinstatement of METH.
The association of indoxyl sulfate with fibroblast growth factor‐23 in cats with chronic kidney disease

Background Indoxyl sulfate (IS) has been reported not only to increase with the severity of impaired renal function, but also possibly to be a factor associated with bone abnormalities linked to fibroblast growth factor‐23 (FGF‐23) in humans with chronic kidney disease (CKD). It is not yet known whether this correlation between IS and FGF‐23 holds true for cats with CKD. Hypothesis Accumulation of IS is related to FGF‐23 secretion in cats with CKD. Animals Twenty clinically healthy cats and 73 cats with CKD cases were evaluated retrospectively. Methods The concentrations of IS and FGF‐23 in plasma were determined by high‐performance liquid chromatography and ELISA, respectively. Progression was defined as an increment of 0.5 mg/dL of serum creatinine concentration within 3 months. Results Plasma IS and FGF‐23 concentrations were significantly increased concurrently with decreasing renal function. Higher concentration of FGF‐23 was significantly associated with higher concentration of IS after adjusting for various confounding factors including creatinine and phosphate. Furthermore, the correlation between IS and phosphate was higher than that between FGF‐23 and phosphate. When the renal progression group was compared with the non‐progression group, both IS and FGF‐23 were found to be significantly increased (P < .05). In addition, the area under receiver operator curve of the combination of IS and FGF‐23 predicted renal progression at a level >0.9. Conclusions and Clinical Importance Both FGF‐23 and IS are associated with phosphate metabolism and CKD progression.
An Ensemble Method to Reconstruct Gene Regulatory Networks Based on Multivariate Adaptive Regression Splines

Gene regulatory networks (GRNs) play a key role in biological processes. However, GRNs are diverse under different biological conditions. Reconstructing gene regulatory networks (GRNs) from gene expression has become an important opportunity and challenge in the past decades. Although there are a lot of existing methods to infer the topology of GRNs, such as mutual information, random forest, and partial least squares, the accuracy is still low due to the noise and high dimension of the expression data. In this paper, we introduce an ensemble Multivariate Adaptive Regression Splines (MARS) based method to reconstruct the directed GRNs from multifactorial gene expression data, called PBMarsNet. PBMarsNet incorporates part mutual information (PMI) to pre-weight the candidate regulatory genes and then uses MARS to detect the nonlinear regulatory links. Moreover, we apply bootstrap to run the MARS multiple times and average the outputs of each MARS as the final score of regulatory links. The results on DREAM4 challenge and DREAM5 challenge datasets show PBMarsNet has a superior performance and generalization over other state-of-the-art methods.
Clinical implications for the use of a biomarker for subclinical rejection – Conflating arguments cause a disconnection between the premise and the conclusion

We read with great interest the recent editorial by Naesens (1); we appreciate his thoughtful review of the CTOT-08 report (2). We agree wholeheartedly with his reaffirmation of the need to develop non-invasive biomarkers to detect subclinical rejection and of the unique stringency of the CTOT-08 study design. However, we feel compelled to address several logical fallacies that underlie his arguments and conclusions. This article is protected by copyright. All rights reserved.
Comparing digital apples to digital apples: Background on NISO's effort to build an infrastructure for new forms of scholarly assessment

Citation metrics and the journal impact factor have been the traditional forms for decades of assessing scholarly impact. These metrics are being challenged in today's digital content environment as no longer being the best methods for research assessment due to issues such as currency and granularity. New alternative metrics - altmetrics - have sprung up, but they are not without their own issues, in particular lack of standardization. The National Information Standards Organization (NISO) launched a project in 2013 to explore, identify, and advance standards and best practices for alternative metrics. A draft white paper summarizing recommendations of the first phase has been issued and will be followed by the second phase of developing one or more of the proposed standards and recommended practices.
Prevention of rheumatic fever and diagnosis and treatment of acute Streptococcal pharyngitis: a scientific statement from the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee of the Council on Cardiovascular Disease in the Young, the Interdisciplinary Council 

Primary prevention of acute rheumatic fever is accomplished by proper identification and adequate antibiotic treatment of group A beta-hemolytic streptococcal (GAS) tonsillopharyngitis. Diagnosis of GAS pharyngitis is best accomplished by combining clinical judgment with diagnostic test results, the criterion standard of which is the throat culture. Penicillin (either oral penicillin V or injectable benzathine penicillin) is the treatment of choice, because it is cost-effective, has a narrow spectrum of activity, and has long-standing proven efficacy, and GAS resistant to penicillin have not been documented. For penicillin-allergic individuals, acceptable alternatives include a narrow-spectrum oral cephalosporin, oral clindamycin, or various oral macrolides or azalides. The individual who has had an attack of rheumatic fever is at very high risk of developing recurrences after subsequent GAS pharyngitis and needs continuous antimicrobial prophylaxis to prevent such recurrences (secondary prevention). The recommended duration of prophylaxis depends on the number of previous attacks, the time elapsed since the last attack, the risk of exposure to GAS infections, the age of the patient, and the presence or absence of cardiac involvement. Penicillin is again the agent of choice for secondary prophylaxis, but sulfadiazine or a macrolide or azalide are acceptable alternatives in penicillin-allergic individuals. This report updates the 1995 statement by the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee. It includes new recommendations for the diagnosis and treatment of GAS pharyngitis, as well as for the secondary prevention of rheumatic fever, and classifies the strength of the recommendations and level of evidence supporting them.
MyROOT: a method and software for the semiautomatic measurement of primary root length in Arabidopsis seedlings

Summary Root analysis is essential for both academic and agricultural research. Despite the great advances in root phenotyping and imaging, calculating root length is still performed manually and involves considerable amounts of labor and time. To overcome these limitations, we developed MyROOT , a software for the semiautomatic quantification of root growth of seedlings growing directly on agar plates. Our method automatically determines the scale from the image of the plate, and subsequently measures the root length of the individual plants. To this aim, MyROOT combines a bottom‐up root tracking approach with a hypocotyl detection algorithm. At the same time as providing accurate root measurements, MyROOT also significantly minimizes the user intervention required during the process. Using Arabidopsis, we tested MyROOT with seedlings from different growth stages and experimental conditions. When comparing the data obtained from this software with that of manual root measurements, we found a high correlation between both methods (R 2 = 0.997). When compared with previous developed software with similar features (BRAT and EZ‐Rhizo), MyROOT offered an improved accuracy for root length measurements. Therefore, MyROOT will be of great use to the plant science community by permitting high‐throughput root length measurements while saving both labor and time.
Neonatal painful stimuli: skin conductance algesimeter index to measure efficacy 24% of sucrose oral solution

Abstract Pain management is one of the main challenges in addressing the improved care of hospitalized newborns. The administration of oral sucrose with and without non-nutritive suction has been proposed as a nonpharmacological intervention to relieve procedural pain in newborns. The effects have not yet been well characterized. The aim of this study is to investigate, using skin conductance algesimeter (SCA) pain monitor index, the effects of 24% sucrose solution on pain perception during capillary and arterial blood sampling. It is a prospective, randomized controlled study: sucrose versus placebo. Sucrose was given orally to infants who were submitted to arterial or capillary sampling. The SCA was measured during, and for 3 min before and after the intervention. Fifty-six infants were enrolled: 31 in the sucrose group and 25 in the placebo group. SCA showed that the measurement of peaks per second of pain during and 3 min after the procedures was lower in the sucrose group than the placebo group and that this difference was statistically significant (p < .05). In conclusion, 24% sucrose administered orally is effective in reducing pain during and after capillary and arterial sampling in newborns and can be used for the prevention and treatment of pain in the Neonatal Intensive Care Unit. Brief rationale To treat neonatal pain, a tiered approach with nonpharmacological and pharmacological method can be used. Among nonpharmacological therapies, sucrose administration is safe and effective in reducing single episodes of minor procedural pain. This study aimed to investigate, the effects of 24% sucrose solution on pain perception during capillary and arterial blood withdrawn by using an objective method: skin conductance algesimeter (SCA) pain monitor index. This randomized controlled trial in which term and/or preterm neonates (postnatal age maximum of 28 days corrected for postmenstrual age) received sucrose for procedural pain. Oral sucrose was administered directly by a disposable plastic vial. SCA was measured by means of a specific device. We demonstrated, using SCA pain monitor index, the efficacy of 24% sucrose solution on pain perception during capillary and arterial blood withdrawn. The results of this study provide an objective evidence of sucrose efficacy for the prevention and treatment of neonatal painful procedures.
Factors influencing subspecialty choice among medical students: a systematic review and meta-analysis

Objective To characterise the contributing factors that affect medical students’ subspecialty choice and to estimate the extent of influence of individual factors on the students’ decision-making process. Design Systematic review and meta-analysis. Methods A systematic search of the Cochrane Library, ERIC, Web of Science, CNKI and PubMed databases was conducted for studies published between January 1977 and June 2018. Information concerning study characteristics, influential factors and the extent of their influence (EOI) was extracted independently by two trained investigators. EOI is the percentage level that describes how much each of the factors influenced students’ choice of subspecialty. The recruited medical students include students in medical school, internship, residency training and fellowship, who are about to or have just made a specialty choice. The estimates were pooled using a random-effects meta-analysis model due to the between-study heterogeneity. Results Data were extracted from 75 studies (882 209 individuals). Overall, the factors influencing medical students’ choice of subspecialty training mainly included academic interests (75.29%), competencies (55.15%), controllable lifestyles or flexible work schedules (53.00%), patient service orientation (50.04%), medical teachers or mentors (46.93%), career opportunities (44.00%), workload or working hours (37.99%), income (34.70%), length of training (32.30%), prestige (31.17%), advice from others (28.24%) and student debt (15.33%), with significant between-study heterogeneity (p<0.0001). Subgroup analyses revealed that the EOI of academic interests was higher in developed countries than that in developing countries (79.66% [95% CI 70.73% to 86.39%] vs 60.41% [95% CI 43.44% to 75.19%]; Q=3.51, p=0.02). The EOI value of prestige was lower in developed countries than that in developing countries (23.96% [95% CI 19.20% to 29.47%] vs 47.65% [95% CI 34.41% to 61.24%]; Q=4.71, p=0.01). Conclusions This systematic review and meta-analysis provided a quantitative evaluation of the top 12 influencing factors associated with medical students’ choice of subspecialty. Our findings provide the basis for the development of specific, effective strategies to optimise the distribution of physicians among different departments by modifying these influencing factors.
A critical role for the nuclear protein Akirin2 in the formation of mammalian muscle in vivo

Evolutionarily conserved Akirin nuclear proteins interact with chromatin remodeling complexes at gene enhancers and promoters, and have been reported to regulate cell proliferation and differentiation. Of the two mouse Akirin genes, Akirin2 is essential during embryonic development, with known in vivo roles in immune system function and the formation of the cerebral cortex. Here we demonstrate that Akirin2 is critical for mouse myogenesis, a tightly regulated developmental process through which myoblast precursors fuse to form mature skeletal muscle fibers. Loss of Akirin2 in somitic muscle precursor cells via Sim1‐Cre‐mediated excision of a conditional Akirin2 allele results in neonatal lethality. Mutant embryos exhibit a complete lack of forelimb, intercostal, and diaphragm muscles due to extensive apoptosis and loss of Pax3‐positive myoblasts. Severe skeletal defects, including craniofacial abnormalities, disrupted ossification, and rib fusions are also observed, attributable to lack of skeletal muscles as well as patchy Sim1‐Cre activity in the embryonic sclerotome. We further show that Akirin2 levels are tightly regulated during muscle cell differentiation in vitro, and that Akirin2 is required for the proper expression of muscle differentiation factors myogenin and myosin heavy chain. Our results implicate Akirin2 as a major regulator of mammalian muscle formation in vivo.
A critical review to traumatic brain injury clinical practice guidelines

Abstract The aim of this study was to assess the quality of clinical practice guidelines of traumatic brain injury (TBI) and investigate the evidence grading systems. A systematic search of relevant guideline websites and literature databases (including PubMed, NGC, SIGN, NICE, GIN, and Google) was undertaken from inception to May 2018 to identify and select TBI guidelines. Four independent reviewers assessed the eligible guidelines using the Appraisal of Guidelines for Research and Evaluation (AGREE II) instrument. The degree of agreement was evaluated with intraclass correlation coefficient (ICC). From 1802 records retrieved, 12 TBI guidelines were included. The mean scores for each AGREE II domain were as follows: scope and purpose (mean ± SD= 74.2 ± 9.09); stakeholder involvement (mean± SD= 54.6 ± 11.6); rigor of development (mean ± SD=70.1 ± 13.6); clarity and presentation (mean ± SD=78.4 ± 11.5); applicability (mean ± SD= 60.5 ± 13.6); and editorial independence (mean ± SD=61.7 ± 14.8). Ten guidelines were rated as “recommended. ” The ICC values ranged from 0.73 to 0.95. Seven grading systems were used by TBI guidelines to rate the level of evidence and the strength of recommendation. Most TBI guidelines got a high-quality rating, whereas a standardized grading system should be adopted to provide clear information about the level of evidence and strength of recommendation in TBI guidelines.
Cost‐Effectiveness of Osteoporosis Screening Using Biomechanical Computed Tomography for Patients With a Previous Abdominal CT

Osteoporosis screening rates by DXA are low (9.5% women, 1.7% men) in the US Medicare population aged 65 years and older. Addressing this care gap, we estimated the benefits of a validated osteoporosis diagnostic test suitable for patients age 65 years and older with an abdominal computed tomography (CT) scan taken for any indication but without a recent DXA. Our analysis assessed a hypothetical cohort of 1000 such patients in a given year, and followed them for 5 years. Separately for each sex, we used Markov modeling to compare two mutually exclusive scenarios: (i) utilizing the CT scans, perform one‐time “biomechanical computed tomography” (BCT) analysis to identify high‐risk patients on the basis of both femoral strength and hip BMD T‐scores; (ii) ignore the CT scan, and rely instead on usual care, consisting of future annual DXA screening at typical Medicare rates. For patients with findings indicative of osteoporosis, 50% underwent 2 years of treatment with alendronate. We found that BCT provided greater clinical benefit at lower cost for both sexes than usual care. In our base case, compared to usual care, BCT prevented hip fractures over a 5‐year window (3.1 per 1000 women; 1.9 per 1000 men) and increased quality‐adjusted life years (2.95 per 1000 women; 1.48 per 1000 men). Efficacy and savings increased further for higher‐risk patient pools, greater treatment adherence, and longer treatment duration. When the sensitivity and specificity of BCT were set to those for DXA, the prevented hip fractures versus usual care remained high (2.7 per 1000 women; 1.5 per 1000 men), indicating the importance of high screening rates on clinical efficacy. Therefore, for patients with a previously taken abdominal CT and without a recent DXA, osteoporosis screening using biomechanical computed tomography may be a cost‐effective alternative to current usual care. © 2019 American Society for Bone and Mineral Research.