Miracle-dz/UniFAR-FTUs huggingface dataset:
Drug-target binding quantitatively predicts optimal antibiotic dose levels in quinolones

Antibiotic resistance is rising and we urgently need to gain a better quantitative understanding of how antibiotics act, which in turn would also speed up the development of new antibiotics. Here, we describe a computational model (COMBAT-COmputational Model of Bacterial Antibiotic Target-binding) that can quantitatively predict antibiotic dose-response relationships. Our goal is dual: We address a fundamental biological question and investigate how drug-target binding shapes antibiotic action. We also create a tool that can predict antibiotic efficacy a priori. COMBAT requires measurable biochemical parameters of drug-target interaction and can be directly fitted to time-kill curves. As a proof-of-concept, we first investigate the utility of COMBAT with antibiotics belonging to the widely used quinolone class. COMBAT can predict antibiotic efficacy in clinical isolates for quinolones from drug affinity (R2>0.9). To further challenge our approach, we also do the reverse: estimate the magnitude of changes in drug-target binding based on antibiotic dose-response curves. We overexpress target molecules to infer changes in antibiotic-target binding from changes in antimicrobial efficacy of ciprofloxacin with 92–94% accuracy. To test the generality of our approach, we use the beta-lactam ampicillin to predict target molecule occupancy at MIC from antimicrobial action with 90% accuracy. Finally, we apply COMBAT to predict antibiotic concentrations that can select for resistance due to novel resistance mutations. Using ciprofloxacin and ampicillin as well defined test cases, our work demonstrates that drug-target binding is a major predictor of bacterial responses to antibiotics. This is surprising because antibiotic action involves many additional effects downstream of drug-target binding. In addition, COMBAT provides a framework to inform optimal antibiotic dose levels that maximize efficacy and minimize the rise of resistant mutants.
Estimated 24 h Urinary Sodium-to-Potassium Ratio Is Related to Renal Function Decline: A 6-Year Cohort Study of Japanese Urban Residents

The effect of the sodium-to-potassium ratio (Na/K) on renal function within the clinically normal range of renal function are limited. We investigated the effects of an estimated 24 h urinary Na/K (e24hUNa/K) on a 6-year renal function decline among 927 urban Japanese community dwellers with no history of cardiovascular diseases and medication for hypertension, diabetes, or dyslipidemia. We partitioned the subjects into quartiles according to the e24hUNa/K. The estimated glomerular filtration rate (eGFR) was calculated using the chronic kidney disease epidemiology collaboration (CKD/EPI) formula and renal function decline was defined as an absolute value at or above the third quartile of the eGFR decline rate. A multivariable logistic regression model was used for estimation. Compared with the first quartile of the e24hUNa/K, multivariable-adjusted odds ratios (ORs) for eGFR decline in the second, third, and fourth quartiles were 0.96 (95% confidence interval: 0.61–1.51), 1.06 (0.67–1.66), and 1.65 (1.06–2.57), respectively. These results were similar when the simple spot urine Na/K ratio was used in place of the e24hUNa/K. Apparently healthy urban residents with an almost within normal range mean baseline eGFR and high e24hUNa/K ratios had an increased risk for a future decline in renal function. Reducing the Na/K ratio may be important in the prevention of chronic kidney disease in its early stage.
Characterization of primary cilia features reveal cell-type specific variability in in vitro models of osteogenic and chondrogenic differentiation

Primary cilia are non-motile sensory antennae present on most vertebrate cell surfaces. They serve to transduce and integrate diverse external stimuli into functional cellular responses vital for development, differentiation and homeostasis. Ciliary characteristics, such as length, structure and frequency are often tailored to distinct differentiated cell states. Primary cilia are present on a variety of skeletal cell-types and facilitate the assimilation of sensory cues to direct skeletal development and repair. However, there is limited knowledge of ciliary variation in response to the activation of distinct differentiation cascades in different skeletal cell-types. C3H10T1/2, MC3T3-E1 and ATDC5 cells are mesenchymal stem cells, preosteoblast and prechondrocyte cell-lines, respectively. They are commonly employed in numerous in vitro studies, investigating the molecular mechanisms underlying osteoblast and chondrocyte differentiation, skeletal disease and repair. Here we sought to evaluate the primary cilia length and frequencies during osteogenic differentiation in C3H10T1/2 and MC3T3-E1 and chondrogenic differentiation in ATDC5 cells, over a period of 21 days. Our data inform on the presence of stable cilia to orchestrate signaling and dynamic alterations in their features during extended periods of differentiation. Taken together with existing literature these findings reflect the occurrence of not only lineage but cell-type specific variation in ciliary attributes during differentiation. These results extend our current knowledge, shining light on the variabilities in primary cilia features correlated with distinct differentiated cell phenotypes. It may have broader implications in studies using these cell-lines to explore cilia dependent cellular processes and treatment modalities for skeletal disorders centered on cilia modulation.
Capillary-Driven Flow Microfluidics Combined with Smartphone Detection: An Emerging Tool for Point-of-Care Diagnostics

Point-of-care (POC) or near-patient testing allows clinicians to accurately achieve real-time diagnostic results performed at or near to the patient site. The outlook of POC devices is to provide quicker analyses that can lead to well-informed clinical decisions and hence improve the health of patients at the point-of-need. Microfluidics plays an important role in the development of POC devices. However, requirements of handling expertise, pumping systems and complex fluidic controls make the technology unaffordable to the current healthcare systems in the world. In recent years, capillary-driven flow microfluidics has emerged as an attractive microfluidic-based technology to overcome these limitations by offering robust, cost-effective and simple-to-operate devices. The internal wall of the microchannels can be pre-coated with reagents, and by merely dipping the device into the patient sample, the sample can be loaded into the microchannel driven by capillary forces and can be detected via handheld or smartphone-based detectors. The capabilities of capillary-driven flow devices have not been fully exploited in developing POC diagnostics, especially for antimicrobial resistance studies in clinical settings. The purpose of this review is to open up this field of microfluidics to the ever-expanding microfluidic-based scientific community.
Trimethoprim-sulfamethoxazole-induced hyponatremia in an elderly lady with Achromobacter xylosoxidans pneumonia

Abstract Rationale: Hyponatremia occurs frequently in the hospital setting and may be attributable to a host of etiologies. Drugs are frequently implicated. Trimethoprim-sulfamethoxazole (TMP/SMX) represents a well-recognized pharmacologic precipitant of drug-induced hyponatremia, with several reports extant in the retrievable literature. Nephrologists thus debate the mechanisms giving rise to TMP/SMX-induced hyponatremia and the precise mechanism by which treatment with TMP/SMX generates reductions of serum sodium concentration remain controversial. The agent has a well-known effect of antagonizing the effects of aldosterone upon the distal nephron. Renal salt wasting and the syndrome of inappropriate antidiuretic hormone secretion represent implicated mechanistic intermediaries in TMP/SMX-induced hyponatremia. Patient concerns: The patient endorsed no explicit concerns. Diagnoses: We describe the case of an 83-year-old female clinically diagnosed with pneumonia found to have an initial serum sodium in the range of 130 to 134 mEq/L consistent with mild hyponatremia upon admission. Sputum cultures grew Achromobacter xylosoxidans susceptible to TMP/SMX. The patient's serum sodium concentration precipitously decline following institution of treatment with TMP/SMX to 112 to 114 mEq/L during the course of 5 days. Interventions: Severe hyponatremia proved recalcitrant to initial therapy with supplemental salt tabs and standard doses of the vasopressin receptor antagonist tolvaptan. Outcomes: Escalating doses of tolvaptan increased the patient's sodium to 120 to 124 mEq/L. The patient was transferred to another hospital for further management. During her stay, the patient did not exhibit frank or obvious clinical features consistent with hyponatremia nor readily appreciable evidence of volume depletion. Lessons: TMP/SMX represents a frequent, though underreported cause of hyponatremia in the hospital setting several authors believe natriuresis may represent the most common mechanism underlying TMP/SMX-induced hyponatremia. Evidence implicating natriuresis to be mechanistic in TMP/SMX-induced hyponatremia include clinically appreciable hypovolemia and resolution of hyponatremia with oral or intravenous salt repletion. Salt repletion failed to monotherapeutically enhance our patient's hyponatremiadisfavoring renal salt wasting as originately mechanistic. Contemporaneous refractoriness of serum sodium to fluid restriction nor standard doses of tolvaptan confounded our initial attempts to mechanistically attribute the patient's hyponatremia to a specific cause. Clinical euvolemia and rapid response of hyponatremia to exceptionally high doses of tolvaptan strongly favors syndrome of inappropriate antidiuretic hormone to represent the chief mechanism by which TMP/SMX exacerbates hyponatremia.
New Benzofuran N-Acylhydrazone Reduces Cardiovascular Dysfunction in Obese Rats by Blocking TNF-Alpha Synthesis

Introduction Diabetic obese patients are susceptible to the development of cardiovascular disease, including hypertension and cardiac dysfunction culminating in diabetic cardiomyopathy (DC), which represents a life-threatening health problem with increased rates of morbidity and mortality. The aim of the study is to characterize the effects of a new benzofuran N-acylhydrazone compound, LASSBio-2090, on metabolic and cardiovascular alterations in Zucker diabetic fatty (ZDF) rats presenting DC. Methods Male non-diabetic lean Zucker rats (ZL) and ZDF rats treated with vehicle (dimethylsulfoxide) or LASSBio-2090 were used in this study. Metabolic parameters, cardiovascular function, left ventricle histology and inflammatory protein expression were analyzed in the experimental groups. Results LASSBio-2090 administration in ZDF rats reduced glucose levels to 85.0 ± 1.7 mg/dL (p < 0.05). LASSBio-2090 also lowered the cholesterol and triglyceride levels from 177.8 ± 31.2 to 104.8 ± 5.3 mg/dL and from 123.0 ± 11.4 to 90.9 ± 4.8 mg/dL, respectively, in obese diabetic rats (p < 0.05). LASSBio-2090 normalized plasma insulin, insulin sensitivity and endothelial function in aortas from diabetic animals (p < 0.05). It also enhanced systolic and diastolic left-ventricular function and reverted myocardial remodeling by blocking the threefold elevation of TNF-α levels in hearts from ZDF rats. Conclusion LASSBio-2090 alleviates metabolic disturbance and cardiomyopathy in an obese and diabetic rat model, thus representing a novel strategy for the treatment of cardiovascular complications in obesity-associated type 2 diabetes mellitus.
Effect of renal dialysis on mortality and complications following hip fracture surgery in elderly patients

Abstract Hip fractures in older patients requiring dialysis are associated with high mortality. The primary aim of this study was to evaluate the specific burden of dialysis on 30-day mortality following hip fracture surgery. The secondary aim was to determine the burden of dialysis on overall survival as well as several postoperative complications. A retrospective cohort study was conducted using data from the Korean National Health Insurance Research Database. Patients were aged ≥65 years and underwent hip fracture surgery during the period from 2009 to 2015. To construct a matched cohort, each dialysis patient was matched to 4 non-dialysis patients based on age, sex, hospital type, anesthesia type, and comorbidities. Survival status was determined 30 days after surgery and at the end of the study period. In total, 96,289 patients were identified. Among them, 1614 dialysis patients were included and matched to 6198 non-dialysis patients. During the 30-day postoperative period, there were 102 mortality events in the dialysis group and 127 in the non-dialysis group, for an adjusted hazard ratio of 3.12 (95% confidence interval, 2.42–4.09). Overall, by the end of the study period, there were 1120 mortality events in the dialysis group and 2731 in the non-dialysis group, for an adjusted hazard ratio of 1.97 (95% confidence interval, 1.83–2.1). These findings may be limited by the characteristics of the administrative database. The 30-day mortality rate was 3-fold higher in the dialysis group than in the non-dialysis group, while the overall mortality rate was approximately 2-fold higher in the dialysis group than in the non-dialysis group. These findings suggest that caution in the perioperative period is required in dialysis patients undergoing hip fracture surgery. The results of our study represent only an association between dialysis and mortality. Further studies are necessary to investigate the possible causal effect of dialysis on mortality and complications after hip fracture surgery.
Humanistic care and psychological counseling on psychological disorders in medical students after COVID-19 outbreak

Abstract Background: The objective of this study is to investigate the effects of humanistic care and psychological counseling (HCPC) on psychological disorders (PD) in medical students after coronavirus disease 2019 (COVID-19) outbreak. Methods: We will search randomized controlled trials or case-controlled studies of HCPC on PD in medical students after COVID-19 outbreak in the following electronic databases: PUBMED/MEDLINE, EMBASE, Cochrane Library, CINAHL, AMED, WANGFANG, and CNKI. The time is restricted from the construction of each database to the present. All process of study selection, data collection, and study quality evaluation will be carried out by two independent authors. Any different opinions will be solved by a third author through discussion. We will employ RevMan 5.3 software to conduct statistical analysis. Results: This study will provide a better understanding of HCPC on PD in medical students after COVID-19 outbreak. Conclusions: This study may offer strong evidence for clinical practice to treat PD in medical students after COVID-19 outbreak. Study registration: CRD42020193199.
Genetic diversity and population structure of Quercus fabri Hance in China revealed by genotyping‐by‐sequencing

Abstract Analysis of genetic diversity and population structure among Quercus fabri populations is essential for the conservation and utilization of Q. fabri resources. Here, the genetic diversity and structure of 158 individuals from 13 natural populations of Quercus fabri in China were analyzed using genotyping‐by‐sequencing (GBS). A total of 459,564 high‐quality single nucleotide polymorphisms (SNPs) were obtained after filtration for subsequent analysis. Genetic structure analysis revealed that these individuals can be clustered into two groups and the structure can be explained mainly by the geographic barrier, showed gene introgression from coastal to inland areas and high mountains could significantly hinder the mutual introgression of genes. Genetic diversity analysis indicated that the individual differences within groups are greater than the differences between the two groups. These results will help us better understand the genetic backgrounds of Q. fabri.
Social cognition in multiple sclerosis and its subtypes

Abstract Background: Multiple sclerosis (MS) is an inflammatory and degenerative neurological disorder of the central nervous system. Cognitive impairment is frequent in MS patients, which not only includes deficits in abilities assessed by traditional neuropsychological batteries, but also often features impairments in social cognition (including theory of mind and facial emotion recognition). Recently, numerous studies have assessed social cognition performance in MS. However, there have been inconsistent findings. Besides, it is not clear how social cognitive abilities are affected in MS subtypes. The aim of this study is to conduct a meta-analysis to characterize social cognition performance in MS and its subtypes (clinically isolated syndrome, relapsing-remitting MS, progressive primary MS, and secondary progressive MS). Methods: Literature sources will be divided into 2 sections: electronic sources and manual sources. A systematic literature search will be performed for eligible studies published up to June 10, 2020 in 3 international databases (Embase, PubMed, and Web of Science). In addition, manual sources will be searched, such as the references of all included studies. Two researchers will independently conduct the work such as article retrieval, screening, quality evaluation, data collection. Meta-analysis will be conducted using Stata 15.0 software. Results: The results of this study will be published in a peer-reviewed journal. Conclusions: This meta-analysis will provide a high-quality synthesis from existing evidence for social cognition performance in MS and its subtypes. PROSPERO registration number: INPLASY202070028.
Effects of corn distillers dried grains on dough properties and quality of Chinese steamed bread

Abstract Chinese steamed bread (CSB) accounts for 30% of the wheat end‐use in China. CSB was studied as a platform for fiber and protein enrichment, employing corn distillers dried grains. Food grade distiller's grain (FDDG) processed from co‐products from the corn ethanol industry was used as the enrichment ingredient. Since CSB uses a lean formula with little or no added sugar or fat, it relies entirely on fermentation and steaming for flavor and texture development. FDDG was used to replace 0%–25% all‐purpose flour (APF) in CSB formulations. Effects of FDDG on dough properties and quality of CSB were evaluated by instrumental (Farinograph, Mixolab, and Texture Analyzer), nutritional, and sensory methods. Protein and dietary fiber contents showed significant increases to 18.8% and 15.3%, respectively, for 100 g of steamed bread (25% FDDG db). Fiber in 100 g of fresh FDDG CSB ranged from 2.8 to 7.7 g. FDDG fortified doughs demonstrated higher water absorption, while dough development time, dough stability, and dough extensibility decreased significantly with partial APF replacement. FDDG contributed to increased hardness and adhesiveness in the CSB. Crumb analysis revealed reduced number of gas cells at higher FDDG substitution. FDDG enrichment reduced brightness (L*) of flour blends and CSB. Rheological and sensory analysis showed an upper level of FDDG substitution of 15% was acceptable without detriment to dough functionality, texture, and taste.
Ratiometric quorum sensing governs the trade-off between bacterial vertical and horizontal antibiotic resistance propagation

Plasmid-mediated horizontal gene transfer of antibiotic resistance and virulence in pathogenic bacteria underlies a major public health issue. Understanding how, in the absence of antibiotic-mediated selection, plasmid-bearing cells avoid being outnumbered by plasmid-free cells is key to developing counterstrategies. Here, we quantified the induction of the plasmidial sex pheromone pathway of Enterococcus faecalis to show that the integration of the stimulatory (mate-sensing) and inhibitory (self-sensing) signaling modules from the pCF10 conjugative plasmid provides a precise measure of the recipient-to-donor ratio, agnostic to variations in population size. Such ratiometric control of conjugation favors vertical plasmid transfer under low mating likelihood and allows activation of conjugation functions only under high mating likelihood. We further show that this strategy constitutes a cost-effective investment into mating effort because overstimulation produces unproductive self-aggregation and growth rate reduction. A mathematical model suggests that ratiometric control of conjugation increases plasmid fitness and predicts a robust long-term, stable coexistence of donors and recipients. Our results demonstrate how population-level parameters can control transfer of antibiotic resistance in bacteria, opening the door for biotic control strategies.
An Optimization of Liquid–Liquid Extraction of Urinary Volatile and Semi-Volatile Compounds and Its Application for Gas Chromatography-Mass Spectrometry and Proton Nuclear Magnetic Resonance Spectroscopy

Urinary volatile compounds (VCs) have been recently assessed for disease diagnoses. They belong to very diverse chemical classes, and they are characterized by different volatilities, polarities and concentrations, complicating their analysis via a single analytical procedure. There remains a need for better, lower-cost methods for VC biomarker discovery. Thus, there is a strong need for alternative methods, enabling the detection of a broader range of VCs. Therefore, the main aim of this study was to optimize a simple and reliable liquid–liquid extraction (LLE) procedure for the analysis of VCs in urine using gas chromatography-mass spectrometry (GC-MS), in order to obtain the maximum number of responses. Extraction parameters such as pH, type of solvent and ionic strength were optimized. Moreover, the same extracts were analyzed using Proton Nuclear Magnetic Resonance Spectroscopy (1H-NMR), to evaluate the applicability of a single urine extraction for multiplatform purposes. After the evaluation of experimental conditions, an LLE protocol using 2 mL of urine in the presence of 2 mL of 1 M sulfuric acid and sodium sulphate extracted with dichloromethane was found to be optimal. The optimized method was validated with the external standards and was found to be precise and linear, and allowed for detection of >400 peaks in a single run present in at least 50% of six samples—considerably more than the number of peaks detected by solid-phase microextracton fiber pre-concentration-GC-MS (328 ± 6 vs. 234 ± 4). 1H-NMR spectroscopy of the polar and non-polar extracts extended the range to >40 more (mainly low volatility compounds) metabolites (non-destructively), the majority of which were different from GC-MS. The more peaks detectable, the greater the opportunity of assessing a fingerprint of several compounds to aid biomarker discovery. In summary, we have successfully demonstrated the potential of LLE as a cheap and simple alternative for the analysis of VCs in urine, and for the first time the applicability of a single urine solvent extraction procedure for detecting a wide range of analytes using both GC-MS and 1H-NMR analysis to enhance putative biomarker detection. The proposed method will simplify the transport between laboratories and storage of samples, as compared to intact urine samples.