Miracle-dz/UniFAR-FTUs huggingface dataset:
Effect of external electric fields on the potential energy profile of K+ ions in selective filter of the KcsA potassium channel

In this study, the potential energy profile of potassium ions in the selective filter part of a KcsA channel was investigated via the application of the molecular simulation method. For this purpose, using the molecular dynamics simulation, the effect of an applied electric field, either constant or oscillating, was studied on the dynamics of K ions in the filter. It was found that when the channel is exposed to a constant electric field of strength 0.03 V/nm, the ions experience a hopping motion. Furthermore, it was shown that the application of oscillating electric fields of 1 and 2.5 GHz, can increase the rigidity of the filter atomic bonds. By computing the potential energy of K ion in the filter, it was shown that the depth of the potential wells, corresponding to the filter sites, increased when an alternative field was applied. Therefore, exposing the channel to the GHz oscillating electric field could disturb the passing rate of ions through the filter, which in turn may affect the operation of these kinds of channels.
Systematic analysis of protein targets associated with adverse events of drugs from clinical trials and post-marketing reports

Adverse drug reactions (ADRs) are undesired effects of medicines that can harm patients and are a significant source of attrition in drug development. ADRs are anticipated by routinely screening drugs against secondary pharmacology protein panels. However, there is still a lack of quantitative information on the links between these off-target proteins and the risk of ADRs in humans. Here, we present a systematic analysis of associations between measured and predicted in vitro bioactivities of drugs, and adverse events (AEs) in humans from two sources of data: the Side Effect Resource (SIDER), derived from clinical trials, and the Food and Drug Administration Adverse Event Reporting System (FAERS), derived from post-marketing surveillance. The ratio of a drug’s in vitro potency against a given protein relative to its therapeutic unbound drug plasma concentration was used to select proteins most likely to be relevant to in vivo effects. In examining individual target bioactivities as predictors of AEs, we found a trade-off between the Positive Predictive Value and the fraction of drugs with AEs that can be detected, however considering sets of multiple targets for the same AE can help identify a greater fraction of AE-associated drugs. Of the 45 targets with statistically significant associations to AEs, 30 are included on existing safety target panels. The remaining 15 targets include 8 carbonic anhydrases, of which CA5B was significantly associated with cholestatic jaundice. We include the full quantitative data on associations between in vitro bioactivities and AEs in humans in this work, which can be used to make a more informed selection of safety profiling targets.
Biochemical and crystallographic investigations into isonitrile formation by a nonheme iron-dependent oxidase/decarboxylase

The isonitrile moiety is found in marine sponges and some microbes, where it plays a role in processes such as virulence and metal acquisition. Until recently only one route was known for isonitrile biosynthesis, a condensation reaction that brings together a nitrogen atom of l-Trp/l-Tyr with a carbon atom from ribulose-5-phosphate. With the discovery of ScoE, a mononuclear Fe(II) α-ketoglutarate-dependent dioxygenase from Streptomyces coeruleorubidus, a second route was identified. ScoE forms isonitrile from a glycine adduct, with both the nitrogen and carbon atoms coming from the same glycyl moiety. This reaction is part of the nonribosomal biosynthetic pathway of isonitrile lipopeptides. Here, we present structural, biochemical, and computational investigations of the mechanism of isonitrile formation by ScoE, an unprecedented reaction in the mononuclear Fe(II) α-ketoglutarate-dependent dioxygenase superfamily. The stoichiometry of this enzymatic reaction is measured, and multiple high-resolution (1.45–1.96 Å resolution) crystal structures of Fe(II)-bound ScoE are presented, providing insight into the binding of substrate, (R)-3-((carboxylmethyl)amino)butanoic acid (CABA), cosubstrate α-ketoglutarate, and an Fe(IV)=O mimic oxovanadium. Comparison to a previously published crystal structure of ScoE suggests that ScoE has an “inducible” α-ketoglutarate binding site, in which two residues arginine-157 and histidine-299 move by approximately 10 Å from the surface of the protein into the active site to create a transient α-ketoglutarate binding pocket. Together, data from structural analyses, site-directed mutagenesis, and computation provide insight into the mode of α-ketoglutarate binding, the mechanism of isonitrile formation, and how the structure of ScoE has been adapted to perform this unusual chemical reaction.
Soft tissue vibration: a biologically-inspired mechanism for stabilizing bipedal locomotion

Humans are made up of mostly soft tissue that vibrates during locomotion. This vibration has been shown to store and dissipate energy during locomotion. However, the effects of soft tissue vibration (wobbling masses) on the dynamics of bipedal walking have not been assessed in terms of stability. Given that much of the human body is vibrating just following foot-ground contact, it may have dynamic implications on the stability of walking. A rigid bipedal walker and a bipedal walker with soft tissue were simulated to quantify the effects of soft tissue vibration on gait periodicity, orbital stability, global stability, and robustness to uneven terrain. It was found that moderate amounts of energy dissipation resulted in much more stable walking dynamics relative to that of a rigid bipedal walker.
Patients With a History of Oronasal Fistula Repair Exhibit Lower Oral Health Measured With Patient-Centric Outcomes Measures

Introduction: Oronasal fistulae following palatoplasty may affect patients’ quality of life by impacting their ability to eat, speak, and maintain oral hygiene. We aimed to quantify the impact of previous oronasal fistula repair on patients’ quality of life using patient-reported outcome psychometric tools. Methods: A cross-sectional study of 8- to 9-year-old patients with cleft palate and/or lip was completed. Patients who had a cleft team clinic between September 2018 and August 2019 were recruited. Participants were divided into 2 groups (no fistula, prior fistula repair). Differences in the individual CLEFT-Q and Child Oral Health Impact Profile-Short Form 19 (COHIP-SF 19) Oral Health scores between the 2 groups were evaluated using a multivariate analysis controlling for Veau classification and syndromic diagnosis. Results: Sixty patients with a history of cleft palate were included. Forty-two (70%) patients had an associated cleft lip. Thirty-two (53.3%) patients had no history of fistula and 28 (46.7%) patients had undergone a fistula repair. CLEFT-Q Dental, Jaw, and Speech Function were all higher in patients without a history of a fistula repair; however, none of these differences were statistically significant. The COHIP-SF 19 Oral Health score demonstrated a significantly lower score in the fistula group, indicating poorer oral health (P = .05). Conclusions: One would expect that successful repair of a fistula would result in improved function and patient satisfaction, but the consistent trend toward lower CLEFT-Q scores and significantly increased COHIP-SF 19 Oral Health scores in our study group suggests that residual effects linger and that the morbidity of a fistula may not be completely treated with a secondary correction.
Impact of a single non-sex-related stroke risk factor on atrial fibrillation and oral anticoagulant outcomes: a systematic review and meta-analysis

Aims Oral anticoagulants (OACs) are crucial for treating atrial fibrillation (AF) patients at high thromboembolic risk. However, in AF patients at intermediate thromboembolic risk with a single non-sex-related stroke risk factor (CHA2DS2-VASc score 1 in men, 2 in women), guidelines advise to consider starting anticoagulation, which may result in OAC non-initiation due to underestimation of the thromboembolic risk of a single stroke risk factor and overestimation of the OAC-related bleeding risk. A critical appraisal of the role of OACs and the benefit–risk profile of non-vitamin K antagonist oral anticoagulants (NOACs) compared with vitamin K antagonists (VKAs) in this patient subgroup are needed. Methods and results This systematic review provides an overview of literature on the effectiveness and safety of OACs in AF patients with a single non-sex-related stroke risk factor after searching Medline and Embase. Differences between individual stroke risk factors regarding the ischaemic stroke risk in non-anticoagulated AF patients are identified in a meta-analysis, demonstrating the highest increased risk in patients aged 65–74 years old or with diabetes mellitus, followed by heart failure, hypertension and vascular disease. Furthermore, meta-analysis results favour NOACs over VKAs, given their equal effectiveness and superior safety in AF patients at intermediate thromboembolic risk (HR 0.93, 95% CI 0.65 to 1.34 for stroke or systemic embolism; HR 0.60, 95% CI 0.45 to 0.80 for major bleeding; HR 0.48, 95% CI 0.14 to 1.59 for intracranial bleeding; HR 0.58, 95% CI 0.47 to 0.71 for mortality). Conclusion Our systematic review with meta-analysis favours the use of anticoagulation in AF patients with a single non-sex-related stroke risk factor, especially when age ≥65 years or diabetes mellitus is present, with a preference for NOACs over VKAs.
Calcification of the thoracic aorta on low-dose chest CT predicts severe COVID-19.

BACKGROUND Cardiovascular comorbidity anticipates poor prognosis of SARS-CoV-2 disease (COVID-19) and correlates with the systemic atherosclerotic transformation of the arterial vessels. The amount of aortic wall calcification (AWC) can be estimated on low-dose chest CT. We suggest quantification of AWC on the low-dose chest CT, which is initially performed for the diagnosis of COVID-19, to screen for patients at risk of severe COVID-19. METHODS Seventy consecutive patients (46 in center 1, 24 in center 2) with parallel low-dose chest CT and positive RT-PCR for SARS-CoV-2 were included in our multi-center, multi-vendor study. The outcome was rated moderate (no hospitalization, hospitalization) and severe (ICU, tracheal intubation, death), the latter implying a requirement for intensive care treatment. The amount of AWC was quantified with the CT vendor's software. RESULTS Of 70 included patients, 38 developed a moderate, and 32 a severe COVID-19. The average volume of AWC was significantly higher throughout the subgroup with severe COVID-19, when compared to moderate cases (771.7 mm3 (Q1 = 49.8 mm3, Q3 = 3065.5 mm3) vs. 0 mm3 (Q1 = 0 mm3, Q3 = 57.3 mm3)). Within multivariate regression analysis, including AWC, patient age and sex, as well as a cardiovascular comorbidity score, the volume of AWC was the only significant regressor for severe COVID-19 (p = 0.004). For AWC > 3000 mm3, the logistic regression predicts risk for a severe progression of 0.78. If there are no visually detectable AWC risk for severe progression is 0.13, only. CONCLUSION AWC seems to be an independent biomarker for the prediction of severe progression and intensive care treatment of COVID-19 already at the time of patient admission to the hospital; verification in a larger multi-center, multi-vendor study is desired.
De novo assembly, annotation, marker discovery, and genetic diversity of the Stipa breviflora Griseb. (Poaceae) response to grazing

Grassland is one of the most widely-distributed ecosystems on Earth and provides a variety of ecosystem services. Grasslands, however, currently suffer from severe degradation induced by human activities, overgrazing pressure and climate change. In the present study, we explored the transcriptome response of Stipa breviflora, a dominant species in the desert steppe, to grazing through transcriptome sequencing, the development of simple sequence repeat (SSR) markers, and analysis of genetic diversity. De novo assembly produced 111,018 unigenes, of which 88,164 (79.41%) unigenes were annotated. A total of 686 unigenes showed significantly different expression under grazing, including 304 and 382 that were upregulated and downregulated, respectively. These differentially expressed genes (DEGs) were significantly enriched in the “alpha-linolenic acid metabolism” and “plant-pathogen interaction” pathways. Based on transcriptome sequencing data, we developed eight SSR molecular markers and investigated the genetic diversity of S. breviflora in grazed and ungrazed sites. We found that a relatively high level of S. breviflora genetic diversity occurred under grazing. The findings of genes that improve resistance to grazing are helpful for the restoration, conservation, and management of desert steppe.
Placebo Surgery Controlled Trials

Supplemental Digital Content is available in the text Objective: To explore whether placebo surgery controlled trials achieve what they set out to do by investigating discrepancy between projected and actual design aspects of trials identified through systematic review methods. Summary Background: Interest in placebo surgery controlled trials is growing in response to concerns regarding unnecessary surgery and the societal cost of low-value healthcare. As questions about the justifiability of using placebo controls in surgery have been addressed, attention is now being paid to more practical concerns. Methods: Six databases were searched from inception - May 2020 (MEDLINE, Embase, Emcare, APA PsycInfo, CINAHL, Cochrane Library). Placebo surgery controlled trials with a published protocol were included. Three authors extracted “projected” design aspects from protocols and “actual” design aspects from main findings papers. Absolute and relative difference between projected and actual design aspects were presented for each trial. Trials were grouped according to whether they met their target sample size (“completed”) and were concluded in a timely fashion. Pairs of authors assessed risk of bias. Results: Of 24 trials with data available to analyse; 3 were completed and concluded within target timeframe; 10 were completed and concluded outside the target timeline; 4 were completed without clear target timeframes; 2 were incomplete and concluded within the target framework; 5 were incomplete and concluded outside the target timeline. Trials which reached the recruitment target underestimated trial duration by 88% and number of recruitment sites by 87%. Conclusions: Trialists need to factor additional time and sites into future placebo surgery controlled trials. A robust reporting framework of projected and actual trial design is imperative for trialists to learn from their predecessors. Review Registration: PROSPERO (CRD42019133296)
Characterization of a highly stable mixed‐mode reversed‐phase/weak anion‐exchange stationary phase based on hybrid organic/inorganic particles

Abstract We have characterized Atlantis ethylene‐bridged hybrid C18 anion‐exchange, a mixed‐mode reversed‐phase/weak anion‐exchange stationary phase designed to give greater retention for anions (e.g., ionized acids) compared to conventional reversed‐phase materials. The retention and selectivity of this stationary phase were compared to that of three benchmark materials, using a mixture of six polar compounds that includes an acid, two bases, and three neutrals. The compatibility of the ethylene‐bridged hybrid C18 anion‐exchange material with 100% aqueous mobile phases was also evaluated. We investigated the batch‐to‐batch reproducibility of the ethylene‐bridged hybrid C18 anion‐exchange stationary phase for 27 batches across three different particle sizes (1.7, 2.5, and 5 μm) and found it to be comparable to that of one of the most reproducible C18 stationary phases. We also characterized the acid and base stability of the ethylene‐bridged hybrid C18 anion‐exchange stationary phase and the results show it to be usable over a wide pH range, from 2 to 10. The extended upper pH limit relative to silica‐based reversed‐phase/weak anion‐exchange materials is enabled by the use of ethylene‐bridged hybrid organic/inorganic particles. The improved base stability allows Atlantis ethylene‐bridged hybrid C18 anion‐exchange to be used with a wider range of mobile phase pH values, opening up a greater range of selectivity options.
Factors Affecting Nitrate Concentrations in Stream Base Flow.

Land use, geology, and riparian canopy are indicated as factors affecting nitrate concentrations in stream base flow. Much of this nitrogen is derived as nitrate from groundwater that discharges to streams as base flow. In this study, boosted regression trees (BRTs) were used to relate nitrate concentrations in base flow (n = 156) to explanatory variables describing nitrogen sources, geology, and soil and catchment characteristics. From these relations, a BRT model was developed to predict base flow nitrate concentrations in streams throughout the Chesapeake Bay watershed. The highest base flow nitrate concentrations were associated with intensive agricultural land use, carbonate geology, and sparse riparian canopy, which suggested that reduced nitrogen inputs, particularly over carbonate terrane, are critical for limiting nitrate concentrations. The lowest nitrate concentrations in the BRT model were associated with extensive riparian canopy, high levels of organic carbon in soils, and suboxic conditions at shallow depths, which suggested that denitrification in the subsurface, particularly in the riparian zone, is limiting base flow nitrate concentrations. Nitrate transport from aquifers to streams can take decades to occur, resulting in decades-long lag times between the time when a land-use activity is implemented and when its effects are fully observed in streams. Predictive models of base flow nitrate concentrations in streams will help identify which portions of a watershed are likely to have large fractions of total stream nitrogen load derived from pathways with significant lag times.
Application of Quality Risk Assessment and DoE-Based Enhanced Analytical Quality by Design Approach to Development of Chromatography Method for Estimation of Combined Pharmaceutical Dosage Form of Five Drugs.

The high-performance liquid chromatography method was only reported for simultaneous estimation of aspirin, simvastatin, ramipril, atenolol and hydrochlorothiazide in polycap capsule. High-performance thin-layer chromatography (HPTLC) method is now accepted as a method of analysis by many pharmaceutical industries and included as an official method in monographs of pharmacopeias of many countries. Hence, HPTLC method was developed and validated for the estimation of polycap capsule using enhanced analytical quality by design based on principles of quality risk management and design of experiment (DOE). Quality risk management was performed by the identification and assessment of risky method parameters. DoE was carried out by Placket-Burman screening design and Box-Behnken response surface methodology using resolution and tailing factor as critical method attributes. Method operable design region was navigated for optimization and development of the method. The developed method was validated as per ICH Q2 (R1) guideline. The method was found accurate, specific, precise and sensitive for the said estimation. The developed method was applied for the assay of polycap capsule and results were found in good agreement with the labeled claim. The developed method can be used as an alternative to reported HPLC methods for quality control of polycap capsule.
Use of spin traps in the study of silyl radicals in the gas phase

The aim of this study was to probe the utility of the spin-trapping technique for the identification and estimation of radicals derived from organosilicon compounds in the gas phase. The methods of generation comprised electric discharge and mercury-sensitized photolysis; the traps were Me3 C—NO and PhCNN(O)CMe3. After establishing that the procedures were satisfactory, using toluene and n-hexane as radical sources, a range of monosilanes was studied. Several systems gave reasonable yields of spin-trap radicals. For example, SiMe4 gave H2CSiMe3 adducts, Me3SiH gave H2CSi(H)Me2 and Me3Si· adducts and PhSiH3 gave PhSiH2 adducts. Certain chlorosilanes gave chlorine atom adducts using electric-discharge generation, but only very weak signals from unknown radical derivatives using the photolytic method.In many other cases, such as Me2SiH2 and MeSiH3, we were unable to detect any radical products despite extensive attempts under a wide range of conditions. We conclude that the technique is quite satisfactory for the detection of carbon-centred radicals, but is less reliable for the study of silyl radicals. In a few cases, we also used 2,6-di-t-butylquinone as a trap, but the results were less satisfactory than with the nitrone trap.
The Effects of Dissolved Oxygen Concentration, Fractional Oxygen Consumption, and Additives on JP-8 Thermal Stability

Since dissolved oxygen participates in fuel deposit formation, knowledge of the effects of dissolved oxygen concentration on fuel thermal stability is critical for fuel system design. In this work, the combined effects of dissolved oxygen availability and additives on jet fuel thermal stability are studied. Experiments with JP-8 jet fuel were conducted in a three-part heat exchanger which simulated a complex thermal and flow environment. The dissolved oxygen content at the flow inlet was varied, and deposition was studied under conditions of either fractional or complete oxygen consumption. The effects of a thermal stability additive package were also studied. An intriguing result found with JP-8 fuels is an increase in deposits formed in heated regions for decreased oxygen consumption, but inverse behavior with the additive package.
Role of Thr199 residue in human β-carbonic anhydrase-II pH-dependent activity elucidated by microsecond simulation analysis

Abstract Carbonic anhydrases catalyze the reversible hydration of carbon dioxide to form bicarbonate, a reaction required for many functions such as carbon assimilation, pH acid–base homeostasis, respiration and photosynthesis via a zinc-hydroxide mechanism for carbon dioxide hydration. In earlier studies, it was revealed that Carbonic anhydrases are inactive at pH 7.5 and active at pH 8.4. This steep pH dependence for its activity led us to design this work to understand its mode of action at atomic level detail. In our microsecond simulation based analysis, it was revealed that the interaction between Glu106 and Thr199 plays a critically important role in its activity. Thr199 co-ordinated loop movement was observed to be acting as a lid, with ‘open’ and ‘close’ mechanism for substrate entry to the core of the catalytic site, where Zn-ion resides and executes its carbon dioxide hydration mechanism. On the other hand, decline in the total secondary structural elements percentage in the protein was observed in correspondence to the pH condition change. The α-helices between Thr125-Gly145 and Val150-Lys170 residues were especially noticed to be losing their structural integrity responsible for formation of dimer and tetramers. In conclusion, our analysis showed that the interaction between Glu106 and Thr199 is crucial for maintaining the structural integrity of the Thr199 coordinated loop, responsible for allowing substrate towards the catalytic site. Communicated by Ramaswamy H. Sarma