bluuebunny/crossref_metadata_2025_split huggingface dataset:
Solution NMR Studies of CYP121 of Mycobacterium tuberculosis; Evidence that Ligand Binding is Bi‐modal
Authors: Estrada D. Fernando , Campomizzi Christopher , Ferguson Shaun , Scheffler Emelie-Jo , Jay Natalie , Lioi James , Kumar Amit 
Published: April 2020

Mycobacterium tuberculosis (Mtb) is the causative pathogen in the development of tuberculosis (TB). The rise of multi‐drug resistant forms of TB, combined with the fact that one third of the world’s population are carriers of latent TB, underscores the need for the development of novel anti‐TB agents. A current drug target is the cytochrome P450 (CYP) 121 of Mtb; an essential enzyme that mediates an unusual phenol coupling reaction of the dipeptide di‐cyclotyrosine (cYY). Our current understanding of atomic level active site/inhibitor interactions in CYP121 stems primarily from co‐crystallization of drug fragments or cYY with the enzyme. However, these studies result in protein structures that reflect the same unchanging conformation, thus resulting in a gap in our understanding of dynamic active site/ligand interactions that would otherwise help inform specificity in the design of novel CYP121 inhibitors.In this preliminary work, we’ve begun to address this gap by adapting CYP121 for analysis by solution NMR. The enzyme produces a well‐dispersed, resolvable 1H‐15N HSQC spectrum. We have acquired 2D spectra of the enzyme while bound to a variety of azoles representing a range of ligand sizes and chemistry. We report that, while ligands with a similar overall structure (econazole and miconazole) produce similar perturbations of the NMR spectra, other ligands with distinct overall structures (ketoconazole and fluconazole) produce chemical shift perturbations that are unexpectedly similar to each other, yet can be categorized separately from other ligand‐induced changes. These preliminary studies suggest that ligand binding in CYP121 is partially bi‐modal, indicative of a structure that retains a semi‐rigid backbone in solution. This work lays the foundation for understanding CYP121 dynamics that will be a critical component of future drug design of novel anti‐TB agents.Support or Funding InformationResearch supported by start‐up funds at SUNY BuffaloA backbone amide resonance of CYP121 in response to azole bindingFigure 1
Is There a Role for Compression Socks in Basketball? Potential Impact on Performance.
Authors: KANTOURIS NIKOLAOS , STEWART CLAIRE 
Published: April 2020

PurposeThe aim of this study was to examine the effects of wearing compression socks (CS) on perceived exertion, biochemical parameters and performance parameters in untrained females after a basketball‐simulating exercise.MethodsSeven untrained females (age 24.9 ± 0.4 years, height 161.7 ± 4.3 cm and weight 56.2 ± 7.0 kg) completed a basketball‐simulating exercise protocol on two occasions, in a random, counter‐balanced order: wearing either CS or placebo socks (PL) during exercise and recovery. Participants were requested to perform up to 6 circuits within 28 s each. Simulated basketball exercise included jogging, running, sprints, jumps, shuffles, all performed on a basketball court. Capillary blood samples were collected pre‐exercise and 1, 3, 5, 7, 9, 15, and 20 min post‐exercise for lactate determination. Three counter‐movement jumps (CMJ) were performed pre‐, 20 min post‐ and 72 h postexercise. Rating of perceived exertion (RPE) was obtained pre‐ and immediately postexercise. Three capillary blood samples were obtained pre‐, 20 min post‐ and 72 h postexercise for the determination of creatine kinase (CK) concentration. Data were analyzed by two‐way ANOVA with repeated measures for CK and CMJ and by paired t tests for RPE, lactate, comfort and tight scales.ResultsNo differences were found between CS and PL for CMJ (Figure
1, p = 0.11), CK (p = 0.31), peak postexercise lactate (p = 0.21), 20 min post‐exercise lactate (p = 0.88), RPE (p = 0.52) and comfort (p = 0.36). However, tight feeling of socks was higher in CS when compared with PL (Figure
2, p < 0.001).ConclusionDespite increased compression, CS did not exert a positive impact on RPE, lactate peak and clearance, performance or a muscle damage marker after a basketball‐simulating exercise protocol in untrained female individuals.Support or Funding InformationThe authors received no specific funding for this work.Counter‐movement jump height in compression and control groups. Values are mean ± SD.Figure 1Perceptual scales of comfort and tight feeling of socks prior to exercise between compression and control groups. Values are mean ± SD.Figure 2
Tibetan and Han Chinese oxygen transport at 2200 m and simulated 4200 m during peak exercise
Authors: Gu Wanjun , Wuren Tana , Xu Ian , Qin Ga , Yan Ma , Wei Guan , Wagner Harrieth , Ge Ri-Li , Wagner Peter , Simonson Tatum 
Published: April 2020

Despite lower Hb concentration, Tibetans resident at 4200m exhibit greater exercise capacity than do Han Chinese also resident at 4200m. Whether these adaptations are maintained at intermediate altitude and/or acute hypobaric hypoxia are unknown.Thirty‐seven healthy, non‐smoking subjects, all resident for at least six months at ~2200 m, of Tibetan (NMale = 10; NFemale = 9) or Han Chinese (NMale = 8; NFemale = 10) ancestries were studied at 2200 m and then during acutely simulated altitude (4200 m in a hypobaric chamber). Subjects performed an incremental cycle test to exhaustion. At peak exercise, oxygen consumption (VO2max), cardiac output (QTmax), ventilation (VE), hemoglobin ([Hb]), blood oxygen saturation (SaO2), and arterial blood gases were measured and diffusing capacity in lung (DL) and muscle (DM) were calculated.At peak exercise at 2200 m, Tibetan males had 1.23 g/dL less [Hb] compared to their Han Chinese male counterparts (p = 0.03). Tibetan females had 1.05 g/dL less [Hb] then Han Chinese females, but the result is not statistically significant (p = 0.064)Compared to Han Chinese, Tibetan females tended to have 4.85 and 2.72 mLmin−1Kg−1 higher VO2max at 2200 m and 4200 m (both p = 0.03). For males, Tibetans tended to have 6.90 and 2.78 mLmin−1Kg−1 higher VO2max than Han Chinese. However, the difference in VO2max was not significant in males at 2200 m or 4200 m (p = 0.095, p = 0.306, respectively).Tibetan males, but not females, had a significantly higher lung O2 diffusing capacity (DL) compared to Han Chinese (p = 0.028 for males; p = 0.192 for females). Tibetans also tended to have increased muscle O2 diffusing capacity (DM), but the difference was not statistically significant.Tibetan compared to Han Chinese females exhibited higher VE during maximal exercise at both 2200 m and 4200 m (p < 0.03, p < 0.02, respectively). The differences were not significant in males (p > 0.54 for 2200 m, p > 0.20 for 4200 m).In addition, Tibetans had 0.53 g/dL higher carboxyhemoglobin compared to Han Chinese at 2200 m (p = 0.005) independent of sex. Considering Tibetans had lower [Hb] than Han Chinese, higher CO content might suggest increased red blood cell destruction in Tibetans.In summary, among Tibetans, who exhibit significantly lower [Hb] and elevated COHb, females exhibit increased exercise capacity and ventilation compared to Han Chinese females at 2200m, and similar trends were exhibited in males acutely exposed to simulated 4200 m. Male Tibetans exhibited greater DL than Han Chinese counterparts. Trends were further noted for greater QT and DM in Tibetans, which is consistent with our previous studies of Tibetans residents at 4200 m. Therefore, it is evident that unique traits of high‐altitude adaptation of Tibetans are retained at intermediate altitude. Such differences between hypoxic‐exercise responses of Tibetans and Han Chinese are likely innate and may be attributed to genetics.Table 1
Tibetans and Han Chinese residents at intermediate altitude respond differently to chronic and simulated altitude‐induced hypoxia
Authors: Gu Wanjun , Wuren Tana , Qin Ga , Yan Ma , Wei Guan , Wagner Harrieth , Ge Ri-Li , Wagner Peter , Simonson Tatum 
Published: April 2020

It has previously been shown that Tibetans residents at high altitude (> 4000m), have higher resting ventilation, lower heart rate, and higher blood‐oxygen saturation compared to Han Chinese residents at the same altitude. However, the extent to which these findings are due to differences in acclimatization versus innate variation between populations is unclear.Thirty‐seven healthy, non‐smoking subjects, all resident at intermediate altitude (2200m) were studied. The subjects were of Tibetan (NMale = 10; NFemale = 9) and Han Chinese (NMale = 8; NFemale = 10) ancestries between ages of twenty to twenty‐five. The study was carried out under ambient conditions at 2200m and during acutely simulated altitude at 4200m in a hypobaric chamber. For each subject at rest, oxygen consumption (VO2), heart rate (HR), ventilation (VE), hemoglobin concentration ([Hb]), blood oxygen saturation (SaO2), and arterial blood gases were measured at both altitudes.Tibetans males, compared to Han Chinese, tend to have 1.2 g/dl lower [Hb] at 4200 m and 0.89 g/dl lower [Hb] at 2200 m. However, the difference is only significant at 2200 m (p = 0.036), and no difference in [Hb] is found in females.At 2200 m, Tibetan males have significantly lower resting heart rate compared to Han Chinese males (p = 0.0062). At 4200 m, this difference persists: both Tibetan males and females have lower resting heart rates than their Han Chinese counterparts (p = 0.042, p = 0.043).At both 2200 m and 4200 m, Tibetan females tend to have significantly higher VO2 (both p = 0.043), higher VCO2 (p = 0.027, p = 0.033) and higher VE (p = 0.018, p = 0.019) compared to Han Chinese females, suggesting increased ventilation. In males, no differences in VO2 or VCO2 were observed at 2200 m and 4200 m, and Tibetan males tend to have higher VE only at 4200 m, though the result is not statistically significant (p = 0.12).At 2200 m, there is no difference of SaO2 between Tibetans and Han Chinese; all groups have SaO2 well above ninety percent. However, the difference of SaO2 is more pronounced at 4200 m. Both Tibetan males and females have higher SaO2 compared to Han Chinese, although the result is only significant in the males (p = 0.045) and exhibits a trend in females (p = 0.15).In conclusion, Tibetans, whose ancestors lived at ~4200m, retain certain physiological traits when resident at 2200m. These include lower resting [Hb], higher VO2, VCO2 and VE. When acutely exposed to altitude‐induced hypoxia, Tibetans tend to maintain higher resting SaO2 and VO2. Therefore, the differences we found between Tibetans and Han Chinese are likely due more to innate differences, such as genetic and epigenetic programs.Table 1
Differential ventilation using flow control valves as a potential bridge to full ventilatory support during the COVID-19 crisis: From bench to bedside
Authors: Levin Matthew A. , Chen Martin D. , Shah Anjan , Shah Ronak , Zhou George , Kane Erica , Burnett Garrett , Ranginwala Shams , Madek Jonathan , Gidicsin Christopher , Park Chang , Katz Daniel , Salter Benjamin , Kohli-Seth Roopa , Lin Hung-Mo , Eisenkraft James B. , Uysal Suzan , McCarry Michael , Reich David L. , Leibowitz Andrew B. 
Published: April 2020

ABSTRACTBackgroundIt has been projected that there will be too few ventilators to meet demand during the COVID-19 (SARS CoV-2) pandemic. Ventilator sharing has been suggested as a crisis standard of care strategy to increase availability of mechanical ventilation. The safety and practicality of shared ventilation in patients is unknown. We designed and evaluated a system whereby one mechanical ventilator can be used to simultaneously ventilate two patients who have different lung compliances using a custom manufactured flow control valve to allow for individual adjustment of tidal volume and airway pressure for each patient.MethodsThe system was first evaluated in a simulation lab using two human patient simulators under expected clinical conditions. It was then tested in an observational study of four patients with acute respiratory failure due to COVID-19. Two separately ventilated COVID-19 patients were connected to a single ventilator for one hour. This intervention was repeated in a second pair of patients. Ventilatory parameters (tidal volume, peak airway pressures, compliance) were recorded at five minute intervals during both studys. Arterial blood gases were taken at zero, thirty, and sixty minutes. The primary outcome was maintenance of stable acid-base status and oxygenation during shared ventilation.ResultsTwo male and two female patients, age range 32-56 yrs, participated. Ideal body weight and driving pressure were markedly different among patients. All patients demonstrated stable physiology and ventilation for the duration of shared ventilation. In one patient tidal volume was increased after 30 minutes to correct a respiratory acidosis.ConclusionsDifferential ventilation using a single ventilator and a split breathing circuit with flow control valves is possible. A single ventilator could feasibly be used to safely ventilate two COVID-19 patients simultaneously as a bridge to full ventilatory support.Summary StatementNot applicable.
Outcomes of hydroxychloroquine usage in United States veterans hospitalized with Covid-19
Authors: Magagnoli Joseph , Narendran Siddharth , Pereira Felipe , Cummings Tammy , Hardin James W. , Sutton S. Scott , Ambati Jayakrishna 
Published: April 2020

ABSTRACTBACKGROUNDDespite limited and conflicting data on the use of hydroxychloroquine in patients with Covid-19, the U.S. Food and Drug Administration has authorized the emergency use of this drug when clinical trials are unavailable or infeasible. Hydroxychloroquine, alone or in combination with azithromycin, is being widely used in Covid-19 therapy based on anecdotal and limited observational evidence.METHODSWe performed a retrospective analysis of data from patients hospitalized with confirmed SARS-CoV-2 infection in all United States Veterans Health Administration medical centers until April 11, 2020. Patients were categorized based on their exposure to hydroxychloroquine alone (HC) or with azithromycin (HC+AZ) as treatments in addition to standard supportive management for Covid-19. The two primary outcomes were death and the need for mechanical ventilation. We determined the association between treatment and the primary outcomes using competing risk hazard regression adjusting for clinical characteristics via propensity scores. Discharge and death were taken into account as competing risks and subdistribution hazard ratios are presented.RESULTSA total of 368 patients were evaluated (HC, n=97; HC+AZ, n=113; no HC, n=158). Rates of death in the HC, HC+AZ, and no HC groups were 27.8%, 22.1%, 11.4%, respectively. Rates of ventilation in the HC, HC+AZ, and no HC groups were 13.3%, 6.9%, 14.1%, respectively. Compared to the no HC group, the risk of death from any cause was higher in the HC group (adjusted hazard ratio, 2.61; 95% CI, 1.10 to 6.17; P=0.03) but not in the HC+AZ group (adjusted hazard ratio, 1.14; 95% CI, 0.56 to 2.32; P=0.72). The risk of ventilation was similar in the HC group (adjusted hazard ratio, 1.43; 95% CI, 0.53 to 3.79; P=0.48) and in the HC+AZ group (adjusted hazard ratio, 0.43; 95% CI, 0.16 to 1.12; P=0.09), compared to the no HC group.CONCLUSIONSIn this study, we found no evidence that use of hydroxychloroquine, either with or without azithromycin, reduced the risk of mechanical ventilation in patients hospitalized with Covid-19. An association of increased overall mortality was identified in patients treated with hydroxychloroquine alone. These findings highlight the importance of awaiting the results of ongoing prospective, randomized, controlled studies before widespread adoption of these drugs.
Two patients with acute meningo-encephalitis concomitant to SARS-CoV-2 infection
Authors: Bernard-Valnet Raphaël , Pizzarotti Beatrice , Anichini Angelica , Demars Yoris , Russo Enrico , Schmidhauser Marie , Cerutti-Sola Jonathan , Rossetti Andrea O. , Pasquier Renaud Du 
Published: April 2020

AbstractHuman coronaviruses are known for their tropism for central nervous system and to be associated with neurological complications. SARS-CoV-2 pandemy represent a major health issue and if respiratory symptoms are at the forefront, neurological symptoms should be expected. Here we report the case of two patient that developed encephalitic symptoms with neuropsychological impairment and pathologic cerebrospinal fluid features concomitantly to SARS-CoV-2 documented infection. Both patient recovered promptly without treatment. This report raises the question of central nervous system involvement in SARS-CoV-2 infection and the need for investigation of neuropsychological complications in infected patient.
Leveraging Deep Learning to Simulate Coronavirus Spike proteins has the potential to predict future Zoonotic sequences
Authors: Crossman Lisa C 
Published: April 2020

AbstractMotivationCoronaviridae are a family of positive-sense RNA viruses capable of infecting humans and animals. These viruses usually cause a mild to moderate upper respiratory tract infection, however, they can also cause more severe symptoms, gastrointestinal and central nervous system diseases. These viruses are capable of flexibly adapting to new environments, hence health threats from coronavirus are constant and long-term. Immunogenic spike proteins are glyco-proteins found on the surface of Coronaviridae particles that mediate entry to host cells. The aim of this study was to train deep learning neural networks to produce simulated spike protein sequences, which may be able to aid in knowledge and/or vaccine design by creating alternative possible spike sequences that could arise from zoonotic sources in future.ResultsHere we have trained deep learning recurrent neural networks (RNN) to provide computer-simulated coronavirus spike protein sequences in the style of previously known sequences and examine their characteristics. Training used a dataset of alpha, beta, gamma and delta coronavirus spike sequences. In a test set of 100 simulated sequences, all 100 had most significant BLAST matches to Spike proteins in searches against NCBI non-redundant dataset (NR) and also possessed concomitant Pfam domain matches.ConclusionsSimulated sequences from the neural network may be able to guide us in future with prospective targets for vaccine discovery in advance of a potential novel zoonosis. We may effectively be able to fast-forward through evolution using neural networks to investigate sequences that could arise.
Affinity proteomic dissection of the human nuclear cap-binding complex interactome
Authors: Dou Yuhui , Kalmykova Svetlana , Pashkova Maria , Oghbaie Mehrnoosh , Jiang Hua , Molloy Kelly R. , Chait Brian T. , Rout Michael P. , Fenyö David , Jensen Torben Heick , Altukhov Ilya , LaCava John 
Published: April 2020

ABSTRACTA 5’, 7-methylguanosine cap is a quintessential feature of RNA polymerase II-transcribed RNAs, and a textbook aspect of co-transcriptional RNA processing. The cap is bound by the cap-binding complex (CBC), canonically consisting of nuclear cap-binding proteins 1 and 2 (NCBP1/2). The CBC has come under renewed investigative interest in recent years due to its participation in RNA-fate decisions via interactions with RNA productive factors as well as with adapters of the degradative RNA exosome - including the proteins SRRT (a.k.a. ARS2) and ZC3H18, and macromolecular assemblies such as the nuclear exosome targeting (NEXT) complex and the poly(A) exosome targeting (PAXT) connection. A novel cap-binding protein, NCBP3, was recently proposed to form an alternative, non-canonical CBC together with NCBP1, and to interact with the canonical CBC along with the protein SRRT. The theme of post-transcriptional RNA fate, and how it relates to co-transcriptional ribonucleoprotein assembly is abundant with complicated, ambiguous, and likely incomplete models. In an effort to clarify the compositions of NCBP1-, 2-, and 3-related macromolecular assemblies, including their intersections and differences, we have applied an affinity capture-based interactome screening approach, where the experimental design and data processing have been modified and updated to identify interactome differences between targets under a range of experimental conditions, in the context of label-free quantitative mass spectrometry. This study generated a comprehensive view of NCBP-protein interactions in the ribonucleoprotein context and demonstrates the potential of our approach to benefit the interpretation of complex biological pathways.
Sequence determinants and evolution of constitutive and alternative splicing in yeast species
Authors: Schirman Dvir , Yakhini Zohar , Dahan Orna , Pilpel Yitzhak 
Published: April 2020

AbstractRNA splicing is a key process in eukaryotic gene expression. Most Intron-containing genes are constitutively spliced, hence efficient splicing of an intron is crucial for efficient gene expression. Here we use a large synthetic oligo library of ~20,000 variants to explore how different intronic sequence features affect splicing efficiency and mRNA expression levels inS. cerevisiae. Using a combinatorial design of synthetic introns we demonstrate how non-consensus splice site sequences affect splicing efficiency in each of the three splice sites. We then show thatS. cerevisiaesplicing machinery tends to select alternative 3’ splice sites downstream of the original site, and we suggest that this tendency created a selective pressure, leading to the avoidance of cryptic splice site motifs near introns’ 3’ ends. We further use natural intronic sequences from other yeast species, whose splicing machineries have diverged to various extents, to show how intron architectures in the various species have been adapted to the organism’s splicing machinery. We suggest that the observed tendency for cryptic splicing is a result of a loss of a specific splicing factor, U2AF1. Lastly, we show that synthetic sequences containing two introns give rise to alternative RNA isoforms inS. cerevisiae, exposing intronic features that control and facilitate alternative splicing. Our study reveals novel mechanisms by which introns are shaped in evolution to allow cells to regulate their transcriptome.
Characterizing the frequency of non-allelic homologous recombination (NAHR) on the human X chromosome (Xq28) using digital inverted PCR
Authors: Bierwert Lou Ann , Bryce Samantha , Merritt Robert B. 
Published: April 2020

AbstractLittle is currently known about the rates at which non-allelic homologous recombination (NAHR) occurs. However, most current research suggests that NAHR is rare. Previous work by Small, et al (1998), examined an inversion polymorphism on the long arm of the X-chromosome, involving two genes (FLNAandEMD), and determined the frequency of the two gene arrangements in a group of European individuals. Here we quantify the rate at which the causal NAHR, in inverted repeats flanking theFLNAandEMDgenes, occurs in meiosis using digital PCR of sperm samples, with male cheek cells as controls. NAHR was documented in all samples, including the cheek cell samples at a mean recombination rate of 1.8%, indicating that NAHR occurs much more frequently than initially believed, and appears to be occurring in mitosis. The increase in NAHR frequency in spermatogenesis is not significant leaving in question NAHR occurrence in meiosis. This study reveals a more accurate way to quantitate NAHR, serving as an important first step in better understanding various NAHR-associated diseases.Author SummaryWe sought to more accurately quantitate and characterize NAHR at a site at the end of the long arm of the X chromosome that contains a set of inverted repeats flanking two genes,filaminandemerin. We determined that NAHR is happening far more frequently than previously thought, and in this case unequally, depending on the direction of the inversion. We speculate on the possibility of local adaptation playing a role in this. These high-resolution results were obtained by modifying a previously published assay which can be easily adapted to other inversions. This could be especially helpful in studying those NAHR inversions related to disease.