bluuebunny/crossref_metadata_2025_split huggingface dataset:
Molecular dynamics and in silico mutagenesis on the reversible inhibitor-bound SARS-CoV-2 main protease complexes reveal the role of lateral pocket in enhancing the ligand affinity
Authors: Weng Ying Li , Naik Shiv Rakesh , Dingelstad Nadia , Lugo Miguel R. , Kalyaanamoorthy Subha , Ganesan Aravindhan 
Published: April 2021

AbstractThe 2019 novel coronavirus pandemic caused by SARS-CoV-2 remains a serious health threat to humans and there is an urgent need to develop therapeutics against this deadly virus. Recent scientific evidences have suggested that the main protease (Mpro) enzyme in SARS-CoV-2 can be an ideal drug target due to its crucial role in the viral replication and transcription processes. Therefore, there are ongoing research efforts to identify drug candidates against SARS-CoV-2 Mpro that resulted in hundreds of X-ray crystal structures of ligand-bound Mpro complexes in the Protein Data Bank (PDB) describing the interactions of different fragment chemotypes within different sites of the Mpro. In this work, we performed rigorous molecular dynamics (MD) simulation of 62 reversible ligand–Mpro complexes in the PDB to gain mechanistic insights about their interactions at the atomic level. Using a total of over 3 µs long MD trajectories, we characterized different pockets in the apo Mpro structure, and analyzed the dynamic interactions and binding affinity of ligands within those pockets. Our results identified the key residues that stabilize the ligands in the catalytic sites and other pockets of Mpro. Our analyses unraveled the role of a lateral pocket in the catalytic site in Mpro that is critical for enhancing the ligand binding to the enzyme. We also highlighted the important contribution from HIS163 in the lateral pocket towards ligand binding and affinity against Mpro through computational mutation analyses. Further, we revealed the effects of explicit water molecules and Mpro dimerization in the ligand association with the target. Thus, comprehensive molecular-level insights gained from this work can be useful to identify or design potent small molecule inhibitors against SARS-CoV-2 Mpro.
Complexed trace mineral supplementation alters antioxidant activities and expression in response to trailer stress in yearling horses in training
Authors: Latham Christine M. , Dickson Emily C. , Owen Randi N. , Larson Connie K. , White-Springer Sarah H. 
Published: April 2021

AbstractTo test the hypothesis that complexed trace mineral supplementation would increase antioxidant capacity and decrease muscle oxidative stress and damage in young horses entering an exercise training program, Quarter Horses (mean $$\pm$$
±
SD; 9.7 ± 0.7 mo) balanced by age, sex, and BW were assigned to receive complexed (CTM; n = 8) or inorganic (INORG; n = 8) trace minerals at -12 week relative to this study. Blood and muscle samples were collected before (week 0) and after 12 week of light exercise training surrounding a 1.5-h trailer stressor. Muscle glutathione peroxidase (GPx) activity was higher for CTM than INORG horses (P ≤ 0.0003) throughout the study. Following both trailer stressors, serum creatine kinase increased (P < 0.0001) and remained elevated through 24 h post-trailering (P < 0.0001). At week 0, muscle malondialdehyde, expression of superoxide dismutase 2, and whole blood GPx activity increased (P$$\le$$
≤
0.003) following trailering but trailering did not affect these measures at week 12. Young horses supplemented with CTM had higher muscle GPx activity than horses receiving INORG, but CTM did not affect damage markers following a stressor. Dietary CTM may be useful for improving antioxidant capacity during exercise training in young equine athletes.
Speciation of organosulfur compounds in carbonaceous chondrites
Authors: Zherebker Alexander , Kostyukevich Yury , Volkov Dmitry S. , Chumakov Ratibor G. , Friederici Lukas , Rüger Christopher P. , Kononikhin Alexey , Kharybin Oleg , Korochantsev Alexander , Zimmermann Ralf , Perminova Irina V. , Nikolaev Eugene 
Published: April 2021

AbstractDespite broad application of different analytical techniques for studies on organic matter of chondrite meteorites, information about composition and structure of individual compounds is still very limited due to extreme molecular diversity of extraterrestrial organic matter. Here we present the first application of isotopic exchange assisted Fourier transform ion cyclotron resonance mass spectrometry (FTICR MS) for analysis of alkali extractable fraction of insoluble organic matter (IOM) of the Murchison and Allende meteorites. This allowed us to determine the individual S-containing ions with different types of sulfur atoms in IOM. Thiols, thiophenes, sulfoxides, sulfonyls and sulfonates were identified in both samples but with different proportions, which contribution corroborated with the hydrothermal and thermal history of the meteorites. The results were supported by XPS and thermogravimetric analysis coupled to FTICR MS. The latter was applied for the first time for analysis of chondritic IOM. To emphasize the peculiar extraterrestrial origin of IOM we have compared it with coal kerogen, which is characterized by the comparable complexity of molecular composition but its aromatic nature and low oxygen content can be ascribed almost exclusively to degradation of biomacromolecules.
Reorganization of nurse scheduling reduces the risk of healthcare associated infections
Authors: Valdano Eugenio , Poletto Chiara , Boëlle Pierre-Yves , Colizza Vittoria 
Published: April 2021

AbstractEfficient prevention and control of healthcare associated infections (HAIs) is still an open problem. Using contact data from wearable sensors at a short-stay geriatric ward, we propose a proof-of-concept modeling study that reorganizes nurse schedules for efficient infection control. This strategy switches and reassigns nurses’ tasks through the optimization of shift timelines, while respecting feasibility constraints and satisfying patient-care requirements. Through a Susceptible-Colonized-Susceptible transmission model, we found that schedules reorganization reduced HAI risk by 27% (95% confidence interval [24, 29]%) while preserving timeliness, number, and duration of contacts. More than 30% nurse-nurse contacts should be avoided to achieve an equivalent reduction through simple contact removal. Nurse scheduling can be reorganized to break potential chains of transmission and substantially limit HAI risk, while ensuring the timeliness and quality of healthcare services. This calls for including optimization of nurse scheduling practices in programs for infection control in hospitals.
Photochemical efficiency correlated with candidate gene expression promote coffee drought tolerance
Authors: de Oliveira Santos Meline , Coelho Larissa Sousa , Carvalho Gladyston Rodrigues , Botelho Cesar Elias , Torres Luana Ferreira , Vilela Diego Júnior Martins , Andrade Alan Carvalho , Silva Vânia Aparecida 
Published: April 2021

AbstractThe aim of this study was to identify the correlation between photochemical efficiency and candidate genes expression to elucidate the drought tolerance mechanisms in coffee progenies (Icatu Vermelho IAC 3851-2 × Catimor UFV 1602-215) previously identified as tolerant in field conditions. Four progenies (2, 5, 12 and 15) were evaluated under water-deficit conditions (water deficit imposed 8 months after transplanting seedlings to the pots) and under irrigated system. Evaluations of physiological parameters and expression of candidate genes for drought tolerance were performed. Progeny 5 showed capacity to maintain water potential, which contributed to lower qP variation between irrigated and deficit conditions. However, the increases of qN and NPQ in response to stress indicate that this progeny is photochemically responsive to small variations of Ψam protecting the photosystem and maintaining qP. Data obtained for progeny 12 indicated a lower water status maintenance capacity, but with increased qN and NPQ providing maintenance of the ɸPSII and ETR parameters. A PCA analysis revealed that the genes coding regulatory proteins, ABA-synthesis, cellular protectors, isoforms of ascorbate peroxidase clearly displayed a major response to drought stress and discriminated the progenies 5 and 12 which showed a better photochemical response. The genes CaMYB1, CaERF017, CaEDR2, CaNCED, CaAPX1, CaAPX5, CaGolS3, CaDHN1 and CaPYL8a were up-regulated in the arabica coffee progenies with greater photochemical efficiency under deficit and therefore contributing to efficiency of the photosynthesis in drought tolerant progenies.
Signal quality as Achilles’ heel of graph theory in functional magnetic resonance imaging in multiple sclerosis
Authors: Baijot Johan , Denissen Stijn , Costers Lars , Gielen Jeroen , Cambron Melissa , D’Haeseleer Miguel , D’hooghe Marie B. , Vanbinst Anne-Marie , De Mey Johan , Nagels Guy , Van Schependom Jeroen 
Published: April 2021

AbstractGraph-theoretical analysis is a novel tool to understand the organisation of the brain.We assessed whether altered graph theoretical parameters, as observed in multiple sclerosis (MS), reflect pathology-induced restructuring of the brain's functioning or result from a reduced signal quality in functional MRI (fMRI). In a cohort of 49 people with MS and a matched group of 25 healthy subjects (HS), we performed a cognitive evaluation and acquired fMRI. From the fMRI measurement, Pearson correlation-based networks were calculated and graph theoretical parameters reflecting global and local brain organisation were obtained. Additionally, we assessed metrics of scanning quality (signal to noise ratio (SNR)) and fMRI signal quality (temporal SNR and contrast to noise ratio (CNR)). In accordance with the literature, we found that the network parameters were altered in MS compared to HS. However, no significant link was found with cognition. Scanning quality (SNR) did not differ between both cohorts. In contrast, measures of fMRI signal quality were significantly different and explained the observed differences in GTA parameters. Our results suggest that differences in network parameters between MS and HS in fMRI do not reflect a functional reorganisation of the brain, but rather occur due to reduced fMRI signal quality.
Investigating regions of shared genetic variation in attention deficit/hyperactivity disorder and major depressive disorder: a GWAS meta-analysis
Authors: Powell Victoria , Martin Joanna , Thapar Anita , Rice Frances , Anney Richard J. L. 
Published: April 2021

AbstractAttention deficit/hyperactivity disorder (ADHD) demonstrates a high level of comorbidity with major depressive disorder (MDD). One possible contributor to this is that the two disorders show high genetic correlation. However, the specific regions of the genome that may be responsible for this overlap are unclear. To identify variants associated with both ADHD and MDD, we performed a meta-analysis of GWAS of ADHD and MDD. All genome wide significant (p < 5 × 10–8) SNPs in the meta-analysis that were also strongly associated (p < 5 × 10–4) independently with each disorder were followed up. These putatively pleiotropic SNPs were tested for additional associations across a broad range of phenotypes. Fourteen linkage disequilibrium-independent SNPs were associated with each disorder separately (p < 5 × 10–4) and in the cross-disorder meta-analysis (p < 5 × 10–8). Nine of these SNPs had not been highlighted previously in either individual GWAS. Evidence supported nine of the fourteen SNPs acting as eQTL and two as brain eQTL. Index SNPs and their genomic regions demonstrated associations with other mental health phenotypes. Through conducting meta-analysis on ADHD and MDD only, our results build upon the previously observed genetic correlation between ADHD and MDD and reveal novel genomic regions that may be implicated in this overlap.
Association of pre- and early-pregnancy factors with the risk for gestational diabetes mellitus in a large Chinese population
Authors: Zhao Min , Yang Shuyu , Hung Tzu Chieh , Zheng Wenjie , Su Xiaojie 
Published: April 2021

AbstractGestational diabetes mellitus (GDM) has aroused wide public concern, as it affects approximately 1.8–25.1% of pregnancies worldwide. This study aimed to examine the association of pre-pregnancy demographic parameters and early-pregnancy laboratory biomarkers with later GDM risk, and further to establish a nomogram prediction model. This study is based on the big obstetric data from 10 “AAA” hospitals in Xiamen. GDM was diagnosed according to the International Association of Diabetes and Pregnancy Study Group (IADPSG) criteria. Data are analyzed using Stata (v14.1) and R (v3.5.2). Total 187,432 gestational women free of pre-pregnancy diabetes mellitus were eligible for analysis, including 49,611 women with GDM and 137,821 women without GDM. Irrespective of confounding adjustment, eight independent factors were consistently and significantly associated with GDM, including pre-pregnancy body mass index (BMI), pre-pregnancy intake of folic acid, white cell count, platelet count, alanine transaminase, albumin, direct bilirubin, and creatinine (p < 0.001). Notably, per 3 kg/m2 increment in pre-pregnancy BMI was associated with 22% increased risk [adjusted odds ratio (OR) 1.22, 95% confidence interval (CI) 1.21–1.24, p < 0.001], and pre-pregnancy intake of folic acid can reduce GDM risk by 27% (adjusted OR 0.73, 95% CI 0.69–0.79, p < 0.001). The eight significant factors exhibited decent prediction performance as reflected by calibration and discrimination statistics and decision curve analysis. To enhance clinical application, a nomogram model was established by incorporating age and above eight factors, and importantly this model had a prediction accuracy of 87%. Taken together, eight independent pre-/early-pregnancy predictors were identified in significant association with later GDM risk, and importantly a nomogram modeling these predictors has over 85% accuracy in early detecting pregnant women who will progress to GDM later.
Transcriptional perturbation of protein arginine methyltransferase-5 exhibits MTAP-selective oncosuppression
Authors: Busacca Sara , Zhang Qi , Sharkey Annabel , Dawson Alan G. , Moore David A. , Waller David A. , Nakas Apostolos , Jones Carolyn , Cain Kelvin , Luo Jin-li , Salcedo Adriana , Salaroglio Iris Chiara , Riganti Chiara , Le Quesne John , John Tom , Boutros Paul C. , Zhang Shu-Dong , Fennell Dean A. 
Published: April 2021

AbstractWe hypothesized that small molecule transcriptional perturbation could be harnessed to target a cellular dependency involving protein arginine methyltransferase 5 (PRMT5) in the context of methylthioadenosine phosphorylase (MTAP) deletion, seen frequently in malignant pleural mesothelioma (MPM). Here we show, that MTAP deletion is negatively prognostic in MPM. In vitro, the off-patent antibiotic Quinacrine efficiently suppressed PRMT5 transcription, causing chromatin remodelling with reduced global histone H4 symmetrical demethylation. Quinacrine phenocopied PRMT5 RNA interference and small molecule PRMT5 inhibition, reducing clonogenicity in an MTAP-dependent manner. This activity required a functional PRMT5 methyltransferase as MTAP negative cells were rescued by exogenous wild type PRMT5, but not a PRMT5E444Q methyltransferase-dead mutant. We identified c-jun as an essential PRMT5 transcription factor and a probable target for Quinacrine. Our results therefore suggest that small molecule-based transcriptional perturbation of PRMT5 can leverage a mutation-selective vulnerability, that is therapeutically tractable, and has relevance to 9p21 deleted cancers including MPM.
Identification of potential therapeutic antimicrobial peptides against Acinetobacter baumannii in a mouse model of pneumonia
Authors: Jung Chiau-Jing , Liao You-Di , Hsu Chih-Chieh , Huang Ting-Yu , Chuang Yu-Chung , Chen Jeng-Wei , Kuo Yu-Min , Chia Jean-San 
Published: April 2021

AbstractAcinetobacter baumannii-induced nosocomial pneumonia has become a serious clinical problem because of high antibiotic resistance rates. Antimicrobial peptides (AMP) are an ideal alternative strategy due to their broad-spectrum of antimicrobial activity and low incidence of bacterial resistance. However, their application is limited by toxicity and stability in vivo. The present study used a mouse model to directly identify potential AMPs effective for treatment of A. baumannii-induced pneumonia. Fifty-eight AMPs were screened and two identified (SMAP-29 and TP4) to have prophylactic effects which prevented the death of mice with pneumonia. Furthermore, two TP4 derivatives (dN4 and dC4) were found to have therapeutic activity in pneumonia mouse models by peritoneal or intravenous administration. Both dN4 and dC4 also inhibited and/or eliminated A. baumannii biofilms at higher doses. Taken together, these data suggest the AMP derivatives dN4 and dC4 represent a potential treatment strategy for A. baumannii-induced pneumonia.
Nationwide Glaucoma incidence in end stage renal disease patients and kidney transplant recipients
Authors: Moon Jong Joo , Kim Yong Woo , Oh Baek-Lok , Han Kyungdo , Kim Dong Ki , Joo Kwon Wook , Kim Yon Su , Park Ki Ho , Lee Hajeong , Kim Yong Chul , Jeoung Jin Wook 
Published: April 2021

AbstractGlaucoma shares common risk factors with chronic kidney disease (CKD) but previous cross-sectional studies have demonstrated discrepancies in the risk of glaucoma in CKD patients. This study enrolled kidney transplantation recipients (KTRs) (n = 10,955), end stage renal disease (ESRD) patients (n = 10,955) and healthy controls (n = 10,955) from National Health Insurance Service database of the Republic of Korea. A Cox proportional hazard regression model was used to calculate the hazard ratios (HR) for primary open-angle glaucoma (POAG) and primary angle-closure glaucoma (PACG) incidences. The incidence of POAG was higher in ESRD patients (3.36/1,000 person-years,P < 0.0001) and KTRs (3.22 /1,000 person-years,P < 0.0001), than in healthy controls (1.20/1,000 person-years). However, POAG risk showed no significant increase in either ESRD patients (P = 0.07) or KTRs (P = 0.08) when adjusted for the confounding factors. The incidence of PACG was significantly higher in ESRD patients (0.41/1,000 person-years) than in healthy controls (0.14/1,000 person-years,P = 0.008). The PACG incidence was significantly lower in KTRs than in ESRD patients (HR = 0.35,P = 0.015). In conclusion, this nationwide cohort study demonstrated that kidney transplantation can reduce the risk of PACG but not POAG in ESRD patients.
Network pharmacology and molecular docking study on the active ingredients of qidengmingmu capsule for the treatment of diabetic retinopathy
Authors: Zhang Mingxu , Yang Jiawei , Zhao Xiulan , Zhao Ying , Zhu Siquan 
Published: April 2021

AbstractDiabetic retinopathy (DR) is a leading cause of irreversible blindness globally. Qidengmingmu Capsule (QC) is a Chinese patent medicine used to treat DR, but the molecular mechanism of the treatment remains unknown. In this study, we identified and validated potential molecular mechanisms involved in the treatment of DR with QC via network pharmacology and molecular docking methods. The results of Ingredient-DR Target Network showed that 134 common targets and 20 active ingredients of QC were involved. According to the results of enrichment analysis, 2307 biological processes and 40 pathways were related to the treatment effects. Most of these processes and pathways were important for cell survival and were associated with many key factors in DR, such as vascular endothelial growth factor-A (VEGFA), hypoxia-inducible factor-1A (HIF-1Α), and tumor necrosis factor-α (TNFα). Based on the results of the PPI network and KEGG enrichment analyses, we selected AKT1, HIF-1α, VEGFA, TNFα and their corresponding active ingredients for molecular docking. According to the molecular docking results, several key targets of DR (including AKT1, HIF-1α, VEGFA, and TNFα) can form stable bonds with the corresponding active ingredients of QC. In conclusion, through network pharmacology methods, we found that potential biological mechanisms involved in the alleviation of DR by QC are related to multiple biological processes and signaling pathways. The molecular docking results also provide us with sound directions for further experiments.
The Hill We Climb
Authors: Holzhauer Peter 
Published: April 2021

„When day comes we ask ourselves, where can we find light in this never ending shade”?Die Welt ächzt unter einer nun schon einem Jahr andauernden Pandemie, die auch in unserem Land zahlreiche Opfer gefordert hat. Allein die Vereinigten Staaten von Amerika haben fast eine halbe Million Todesfälle als Opfer der Pandemie zu beklagen. Gleichzeitig gibt es neue Hoffnung auf Besserung durch politischen Wandel. Amerika, die ganze Welt und auch die Umwelt, der Garant für unser (Über)leben, waren in letzter Zeit nicht nur durch dieses Virus bedroht, sondern auch durch eine sich viral verbreitende Botschaft der Ignoranz, des Populismus und der Polemik sowie Rassismus und ökologischem Nihilismus.
Ein langer Weg: metastasierendes Pankreaskarzinom/COVID-19-Infektion und protrahiertes Fatigue-Syndrom
Authors: Holzhauer Peter 
Published: April 2021

ZusammenfassungDer lange Behandlungsverlauf einer 78-jährigen Patientin mit einem schon bei Erstdiagnose diffus hepatisch metastasierten Pankreaskarzinom wird – mit besonderem Fokus auf unerwünschte Begleiterscheinungen von Therapie und Krankheit – in dieser Kasuistik vorgestellt. Die Patientin leidet schon seit Diagnosestellung an einem ausgeprägten Fatigue-Syndrom, das den privaten als auch den selbstständigen beruflichen Alltag belastet. Im Vordergrund der klinischen Symptomatik stehen körperliche Erschöpfung und kognitive Einschränkungen wie Konzentrationsstörungen. Neben der Schilderung des Krankheits- und Behandlungsverlaufs werden begleitende supportive Behandlungselemente beschrieben.
Convergent Synthesis of Angiotensin II Receptor Blockers through C–H Arylation of 1-Benzyl-5-phenyl-1H-tetrazole with Functionalized Aryl Bromides
Authors: Seki Masahiko , Takahashi Yusuke 
Published: April 2021

AbstractHighly convergent synthesis of angiotensin II receptor blockers has been accomplished by means of late-stage C–H arylation using functionalized aryl bromides. C–H arylation of 1-benzyl-5-phenyl-1H-tetrazole with aryl bromides carrying methyl 2-ethoxybenzimidazole-7-carboxylate unexpectedly provided coupling products where ethyl group was migrated from oxygen to nitrogen atom. The O-to-N ethyl migration was completely suppressed by the use of N-pivaloyl-l-valine rather than the combined use of triphenylphosphine and sodium mesitylenesulfonate to result in the preferential formation of a key intermediate of candesartan cilexetil. In contrast, when an aryl bromide having ethyl 4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate was employed, the C–H arylation proceeded smoothly to provide a late-stage intermediate, which rapidly led to olmesartan medoxomil in 3 steps.
Minimally Invasive Triple Therapy of the Presurgical Neck
Authors: DeJoseph Louis , Hojjat Houmehr , Daraei Paul Pedram 
Published: April 2021

AbstractMinimally invasive in-office procedures are a fast growing field in plastic surgery. Patients often notice and complain about their neck at an earlier age. Modern treatments for the aging neck have continued to evolve over the past decade, with more options continuing to become available. In this article, we describe our noninvasive approach to the aging neck through the combination of submental liposuction, radiofrequency (RF) microneedling, and percutaneous RF as a safe and effective option. Through appropriate patient selection, preoperative counseling, and good surgical technique, appropriate results can be achieved with minimal downtime. Patient selection, counseling, appropriate anesthesia, procedure details, and results are discussed in this article.