Miracle-dz/UniFAR-FTUs huggingface dataset:
Thiopurine Derivative-Induced Fpg/Nei DNA Glycosylase Inhibition: Structural, Dynamic and Functional Insights

DNA glycosylases are emerging as relevant pharmacological targets in inflammation, cancer and neurodegenerative diseases. Consequently, the search for inhibitors of these enzymes has become a very active research field. As a continuation of previous work that showed that 2-thioxanthine (2TX) is an irreversible inhibitor of zinc finger (ZnF)-containing Fpg/Nei DNA glycosylases, we designed and synthesized a mini-library of 2TX-derivatives (TXn) and evaluated their ability to inhibit Fpg/Nei enzymes. Among forty compounds, four TXn were better inhibitors than 2TX for Fpg. Unexpectedly, but very interestingly, two dithiolated derivatives more selectively and efficiently inhibit the zincless finger (ZnLF)-containing enzymes (human and mimivirus Neil1 DNA glycosylases hNeil1 and MvNei1, respectively). By combining chemistry, biochemistry, mass spectrometry, blind and flexible docking and X-ray structure analysis, we localized new TXn binding sites on Fpg/Nei enzymes. This endeavor allowed us to decipher at the atomic level the mode of action for the best TXn inhibitors on the ZnF-containing enzymes. We discovered an original inhibition mechanism for the ZnLF-containing Fpg/Nei DNA glycosylases by disulfide cyclic trimeric forms of dithiopurines. This work paves the way for the design and synthesis of a new structural class of inhibitors for selective pharmacological targeting of hNeil1 in cancer and neurodegenerative diseases.
A service evaluation and stakeholder perspectives of an innovative digital minor illness referral service from NHS 111 to community pharmacy

Introduction The management of minor conditions represents a significant burden for urgent and emergency care services and reduces the capacity to provide specialist care for higher acuity healthcare need. A pilot Digital Minor Illness Service (DMIRS) was commenced in the North East of England in December 2017 to feasibility test the NHS 111 referral to community pharmacy for patients presenting with minor conditions. Objectives A formative evaluation of the service activity data and qualitative investigation of stakeholders involved in the service design, management, delivery and use, aims to present and investigate the service outcomes. Method Routine service activity data was evaluated during Jan–Dec 2018 to investigate the demographics of patients included in the service; the presenting conditions; and how those referrals were managed by community pharmacies. Semi-structured interviews with NHS 111 call handlers, project team members, community pharmacists and patients were undertaken to investigate the design, management, implementation and delivery of the service. Results 13,246 NHS 111 patient calls were referred to community pharmacy during the evaluative period. The most common presenting conditions were acute pain (n = 1144, 8.6%) and cough (n = 887, 6.7%). A large volume of complaints (47.1%, 6233) were resolved in community pharmacy. Stakeholders explained the structured approach to service design, organisation and implementation facilitated successful delivery and management. Patients reported positive experiences with accessing care via DMIRS. Conclusions DMIRS demonstrated that patients could be referred to community pharmacy for the management of minor conditions, shifting a burden away from urgent and emergency care. The service data provides key information for further optimisation of service design, and stakeholder training and awareness. The service was acceptable and valued by patients. Evidence from the DMIRS pilot has been utilised to inform recent national healthcare policy and practice around the management of minor conditions within the urgent and emergency care setting.
Histone deacetylase 6 inhibition improves survival in a swine model of lethal hemorrhage, polytrauma, and bacteremia

Supplemental digital content is available in the text. BACKGROUND Trauma is the leading cause of death for young Americans. Nonspecific histone deacetylase inhibitors, such as valproic acid, have been shown to improve survival in preclinical models of lethal trauma, hemorrhage, and sepsis. The doses needed to achieve a survival benefit are higher than Food and Drug Administration–approved doses, and the nonspecificity raises concerns about unintended adverse effects. The isoform-specific histone deacetylase 6 inhibitor, ACY-1083, has been found to be as efficacious as valproic acid in a rodent model of hemorrhagic shock. We hypothesized that ACY-1083 treatment would improve survival in a swine model of lethal hemorrhage, polytrauma, and bacteremia. METHODS Swine were subjected to 45% blood volume hemorrhage, brain injury, femur fracture, rectus crush, splenic and liver lacerations, and colon injury. After 1 hour of shock (mean arterial pressure, 30–35 mm Hg), animals were randomized to normal saline resuscitation (control) or normal saline plus ACY-1083 30 mg/kg treatment (n = 5/group). After 3 hours (simulating delayed evacuation), packed red blood cells and antibiotics were administered, the colon injury was repaired, and the abdomen was closed. Animals were then monitored for another 4 hours. Survival was assessed using Kaplan-Meier and log-rank test. RESULTS This combination of injuries was lethal. All animals became bacteremic, in addition to the severe hemorrhagic shock. Survival in the control group was 0%, and ACY-1083 treatment increased survival to 80% (p = 0.019). There was no difference in the brain lesion size between the groups. CONCLUSION A single dose of ACY-1083 markedly improves survival in an otherwise lethal model of polytrauma, hemorrhagic shock, and bacteremia.
Revisiting Aldehyde Oxidase Mediated Metabolism in Drug-like Molecules: An Improved Computational Model.

Aldehyde oxidase (AOX) is a drug metabolizing molydbo-flavoenzyme that has gained increasing attention because of contribution to the biotransformation in phase I metabolism of xenobiotics. Unfortunately, the intra- and inter-species variations in AOX activity and lack of reliable and predictive animal models make evaluation of AOX-catalyzed metabolism prone to be misleading. In this study, we developed an improved computational model integrating both atom-level and molecule-level features to predict whether a drug-like molecule is a potential human AOX (hAOX) substrate and to identify the corresponding sites of metabolism. Additionally, we combined the proposed computational strategy and in vitro experiments for evaluating the metabolic property of a series of epigenetic-related drug candidates still in early stage of development. In summary, this study provides an improved strategy to evaluate the liability of molecules toward hAOX and offers useful information for accelerating the drug design and optimization stage.
Inflammation and Vascular Calcification Causing Effects of Oxidized HDL are Attenuated by Adiponectin in Human Vascular Smooth Muscle Cells

The role of oxidized high- density lipoprotein (oxHDL) and the protective effects of adiponectin in terms of vascular calcification is not well-established. This study was conducted to investigate the effects of oxHDL with regard to inflammation and vascular calcification and to determine the protective role of adiponectin in attenuating the detrimental effects of oxHDL. Cell viability, mineralization, and calcification assays were conducted to optimize the concentration of oxHDL. Then, human vascular smooth muscle cells (HAoVSMCs) were incubated with β-glycerophosphate, HDL, oxHDL, adiponectin, or the combination of oxHDL with adiponectin for 24 h. Protein expression of IL-6, TNF-α, osterix, RUNX2, ALP, type 1 collagen, osteopontin, osteocalcin, WNT-5a, NF-ĸβ(p65), cAMP and STAT-3 were measured by ELISA kits. OxHDL induced vascular calcification by promoting the formation of mineralization nodules and calcium deposits in HAoVSMCs. This was accompanied by an increased secretion of IL-6, osterix, WNT-5a and NF-ĸβ (p65). Interestingly, these detrimental effects of oxHDL were suppressed by adiponectin. Besides, incubation of adiponectin alone on HAoVSMCs showed a reduction of inflammatory cytokines, osteoblastic markers (RUNX2, osterix and osteopontin), WNT-5a and NF-ĸβ (p65). This study exhibits the ability of oxHDL in inducing inflammation and vascular calcification and these detrimental effects of oxHDL can be attenuated by adiponectin.
Interaction between Amorphous Zirconia Nanoparticles and Graphite: Electrochemical Applications for Gallic Acid Sensing Using Carbon Paste Electrodes in Wine

Amorphous zirconium oxide nanoparticles (ZrO2) have been used for the first time, to modify carbon paste electrode (CPE) and used as a sensor for the electrochemical determination of gallic acid (GA). The voltammetric results of the ZrO2 nanoparticles-modified CPE showed efficient electrochemical oxidation of gallic acid, with a significantly enhanced peak current from 261 µA ± 3 to about 451 µA ± 1. The modified surface of the electrode and the synthesised zirconia nanoparticles were characterised by scanning electrode microscopy (SEM), Energy-dispersive x-ray spectroscopy (EDXA), X-ray powdered diffraction (XRD) and Fourier-transform infrared spectroscopy (FTIR). Meanwhile, the electrochemical behaviour of GA on the surface of the modified electrode was studied using differential pulse voltammetry (DPV), showing a sensitivity of the electrode for GA determination, within a concentration range of 1 × 10−6 mol L−1 to 1 × 10−3 mol L−1 with a correlation coefficient of R2 of 0.9945 and a limit of detection of 1.24 × 10−7 mol L−1 (S/N = 3). The proposed ZrO2 nanoparticles modified CPE was successfully used for the determination of GA in red and white wine, with concentrations of 0.103 mmol L−1 and 0.049 mmol L−1 respectively.
Validation of the Clinical Global Impression—Corrections Scale (CGI-C) by Equipercentile Linking to the BPRS-E

Background: The Clinical Global Impression—Corrections (CGI-C) is an adaptation of the severity scale of the Clinical Global Impression for use in correctional facilities. Although it has been shown to have good inter-rater reliability, there have been no validation studies of this instrument. Method: We analyzed data from 726 initial assessments of persons detained in two correctional facilities and compared clinician's ratings for the CGI-C and modified Brief Psychiatric Rating Scale-Expanded (BPRS-E). We used equipercentile linkage and Spearman correlations to investigate concordance in the total sample, by diagnostic groups, and by gender. Results: We found that the CGI-C scores and BPRS-E scores among persons in remand settings were significantly correlated (ρ = 0.51, p < 0.001) and that correlations were the same for men and women. We found that points of equivalence can be reliably found between the two scales using equipercentile linkage, and that those with psychotic disorders had lower BPRS-E scores than those with mood/anxiety/situational stress for equivalent CGI-C scores. Conclusion: Overall, CGI-C ratings correspond well to BPRS-E ratings for both men and women remand prisoners across diagnoses, and the CGI-C appears to be a valid tool for the assessment of severity of symptoms in this setting.
Steady-State Kinetics of Enzyme-Catalyzed Hydrolysis of Echothiophate, a P–S Bonded Organophosphorus as Monitored by Spectrofluorimetry

Enzyme-catalyzed hydrolysis of echothiophate, a P–S bonded organophosphorus (OP) model, was spectrofluorimetrically monitored, using Calbiochem Probe IV as the thiol reagent. OP hydrolases were: the G117H mutant of human butyrylcholinesterase capable of hydrolyzing OPs, and a multiple mutant of Brevundimonas diminuta phosphotriesterase, GG1, designed to hydrolyze a large spectrum of OPs at high rate, including V agents. Molecular modeling of interaction between Probe IV and OP hydrolases (G117H butyrylcholinesterase, GG1, wild types of Brevundimonas diminuta and Sulfolobus solfataricus phosphotriesterases, and human paraoxonase-1) was performed. The high sensitivity of the method allowed steady-state kinetic analysis of echothiophate hydrolysis by highly purified G117H butyrylcholinesterase concentration as low as 0.85 nM. Hydrolysis was michaelian with Km = 0.20 ± 0.03 mM and kcat = 5.4 ± 1.6 min−1. The GG1 phosphotriesterase hydrolyzed echothiophate with a high efficiency (Km = 2.6 ± 0.2 mM; kcat = 53400 min−1). With a kcat/Km = (2.6 ± 1.6) × 107 M−1min−1, GG1 fulfills the required condition of potential catalytic bioscavengers. quantum mechanics/molecular mechanics (QM/MM) and molecular docking indicate that Probe IV does not interact significantly with the selected phosphotriesterases. Moreover, results on G117H mutant show that Probe IV does not inhibit butyrylcholinesterase. Therefore, Probe IV can be recommended for monitoring hydrolysis of P–S bonded OPs by thiol-free OP hydrolases.
South African Trends in Health Outcomes and Health-Related Behaviour: Evidence from Repeated Cross-Sectional Surveys

This study examines trends in ill-health status, medical aid coverage and public health care facility utilisation across a spectrum of socio-demographic variables, using population- weighted General Household Surveys (GHS) covering the years 2004-2014. As there are few obvious patterns in the raw health variables' time series, the analysis, which is descriptive in nature, relies upon both parametric and nonparametric analysis to smooth the time series in order to outline a few general trends. Over time, medical aid coverage and the general population's `preference' for public health care decreased by 0.2% and 0.1% per year, respectively, while reports of ill-health status increased by 0.4% annually. Moreover, the probability that an individual, who is covered by a medical aid scheme, would utilize public health care decreased by 44%.
Coxsackievirus B3 Infection of Human Neural Progenitor Cells Results in Distinct Expression Patterns of Innate Immune Genes

Coxsackievirus B3 (CVB3), a member of Picornaviridae family, is an important human pathogen that causes a wide range of diseases, including myocarditis, pancreatitis, and meningitis. Although CVB3 has been well demonstrated to target murine neural progenitor cells (NPCs), gene expression profiles of CVB3-infected human NPCs (hNPCs) has not been fully explored. To characterize the molecular signatures and complexity of CVB3-mediated host cellular responses in hNPCs, we performed QuantSeq 3′ mRNA sequencing. Increased expression levels of viral RNA sensors (RIG-I, MDA5) and interferon-stimulated genes, such as IFN-β, IP-10, ISG15, OAS1, OAS2, Mx2, were detected in response to CVB3 infection, while IFN-γ expression level was significantly downregulated in hNPCs. Consistent with the gene expression profile, CVB3 infection led to enhanced secretion of inflammatory cytokines and chemokines, such as interleukin-6 (IL-6), interleukin-8 (IL-8), and monocyte chemoattractant protein-1 (MCP-1). Furthermore, we show that type I interferon (IFN) treatment in hNPCs leads to significant attenuation of CVB3 RNA copy numbers, whereas, type II IFN (IFN-γ) treatment enhances CVB3 replication and upregulates suppressor of cytokine signaling 1/3 (SOCS) expression levels. Taken together, our results demonstrate the distinct molecular patterns of cellular responses to CVB3 infection in hNPCs and the pro-viral function of IFN-γ via the modulation of SOCS expression.
Influence of competition on performance factors in under-19 soccer players at national league level

The aim of this study was to analyse and quantify the acute effects of competition on several performance factors in under-19 male soccer players. To this end, 198 national league players (17.56 ± 0.78 years) performed various tests to measure jump capacity, kicking velocity and sprint times immediately pre-match (T1), at half-time (T2) and post-match (T3). Tests included kicking the ball to measure ball velocity (KICK), sprinting for 40 meters, timing the first 30 meters (30mACCEL), the last 10 meters (10mACCEL) and the total distance (40mACCEL), and performing countermovement jumps (CMJ). For subsequent analysis, the sample was divided into 5 playing positions: goalkeepers (n = 24), defenders (n = 51), midfielders (n = 36), wingers (n = 54) and forwards (n = 33). For all positions, we found a significant decline in performance (p<0.05) for kicking velocity (2.91% - 6.51%) and sprinting (0.44%-5.85%). For the CMJ, all positions except defenders presented a significant decline in performance that ranged from 1.5% to 4.56%. These findings highlight the need to individualise fitness training, taking into account the match needs and demands of the different playing positions in order to minimise the effects of match fatigue and accelerate post-match recovery.
Virion-incorporated PSGL-1 and CD43 inhibit both cell-free infection and transinfection of HIV-1 by preventing virus–cell binding

Significance No host-encoded restriction factor identified thus far inhibits the first step of HIV-1 infection: virus–cell attachment. Here we demonstrate that virion-incorporated host transmembrane proteins PSGL-1 and CD43 inhibit attachment of HIV-1 particles to target cells. This inhibition of virus attachment occurs regardless of molecules mediating virus–cell binding and leads to inhibition of both cell-free infection and bystander cell-mediated transinfection. We also show that coclustering of HIV-1 structural protein Gag with PSGL-1 and subsequent progeny virion release contribute to depletion of PSGL-1 from an infected cell surface. Our study reveals an anti–HIV-1 mechanism in which virion-incorporated host transmembrane proteins block virus attachment. In addition, we report a previously unidentified role for Gag in viral down-regulation of antiviral proteins. HIV-1 particles incorporate various host transmembrane proteins in addition to viral Env glycoprotein during assembly at the plasma membrane. In polarized T cells, HIV-1 structural protein Gag localizes to the plasma membrane of uropod, a rear-end protrusion. Notably, uropod transmembrane proteins PSGL-1 and CD43 cocluster specifically with Gag assembling at the plasma membrane even in cells that do not form uropods. Recent reports have shown that expression of either PSGL-1 or CD43 in virus-producing cells reduces the infectivity of progeny virions and that HIV-1 infection reduces the cell surface expression of these proteins. However, the mechanisms for both processes remain to be determined. In this study, we found that virion incorporation of PSGL-1 and CD43 closely correlates with diminished virion infectivity. PSGL-1 and CD43 inhibited virus attachment to CD4+ cells irrespective of the presence of Env. These proteins also inhibited virion attachment to CD4− lymphoid organ fibroblastic reticular cells that mediate transinfection of CD4+ T cells. Consistent with the possibility that highly extended extracellular domains of these proteins physically block virus–cell attachment, the inhibitory effect of PSGL-1 required its full-length ectodomain. HIV-1 encoding Gag mutants that are defective in either coclustering with these host proteins or ESCRT-dependent particle release failed to reduce PSGL-1 on surface of infected cells. This study reveals an anti–HIV-1 mechanism that suppresses virus–cell attachment and a previously unappreciated process of HIV-1-mediated down-regulation of host antiviral proteins, both of which likely require virion incorporation of these proteins.
The roles of first phase, second phase insulin secretion, insulin resistance, and glucose effectiveness of having prediabetes in nonobese old Chinese women

Abstract It has been established that prediabetes can causes significant comorbidities, particularly in the elderly. The deterioration of glucose metabolism are generally considered to be results of the impairment of the 4 factors: first, second insulin secretion (FPIS, SPIS, respectively), glucose effectiveness (GE), and insulin resistance. In this study, we enrolled older women to investigate their relationships with prediabetes. Five thousand four hundred eighty-two nonobese, nondiabetic women were included. They were divided into normal glucose tolerance and prediabetes groups. Receiver operating characteristic curve was performed to investigate the effects on whether to have prediabetes for each factors. Two models were built: Model 1: FPIS + SPIS, and Model 2: model 1 + GE. The area under the receiver operating characteristic (aROC) curve was used to determine the predictive power of these models. The aROC curve of GE was significantly higher than the diagonal line followed by SPIS and FPIS accordingly. The aROC curve of Model 1 (0.611) was not different from GE. However, Model 2 improved significantly up to 0.663. Based on this model, an equation was built (−0.003 × GE − 212.6 × SPIS − 17.9 × insulin resistance + 4.8). If the calculated value is equal or higher than 0 (≥0), then the subject has higher chance to have prediabetes (sensitivity = 0.607, specificity = 0.635). Among the 4 factors, GE is the most important contributor for prediabetes in older women. By building a model composed of FPIS, SPIS, and GE, the aROC curve increased significantly. The equation built from this model could predict prediabetes precisely.
Pharmacokinetic evaluation of MFF in combinations with tacrolimus and cyclosporine. Findings of C0 and AUC

Abstract We hypothesized that area under the concentration time curve (AUC(0-12)) is more accurate pharmacokinetic predictor vs trough level of mycophenolic acid (C0). Study was performed at the University Hospital of Limoges (France) and included 238 renal recipients aged 22 to 82 years. Risk of nephropathy was evaluated by analyzing data of protocol biopsies according to the Banff 97 classification. Assessment of immunosuppressants’ exposures was based on the calculation of the mean of AUC(0-12). The AUC(0-12) was estimated using a Bayesian estimator and a 3-point limited sampling strategy. Cyclosporine and tacrolimus analyses were performed using liquid chromatography–mass spectrometry method. The measurement of total mycophenolic acid was performed using a validated high-performance liquid chromatography method with ultraviolet detection. IBM SPSS 20.0 was used for statistical analysis. The most accurate dosing of mycophenolate mofetil (MMF) was observed in patients receiving MMF with tacrolimus, 70.6% of patients’ AUC(0-12) exposures were within the therapeutic range. The highest rates of low dosing were observed in patients receiving MMF with cyclosporine, 30.9% of patients had AUC(0-12) exposures below the therapeutic range. The assessment of AUC(0-12) revealed 38% of chronic nephropathy cases, while C0 enables to identify only 20% of chronic nephropathy cases. Probability test results showed that more likely AUC(0-12) and C0 will be maintained within the therapeutic width if patients receive MMF with tacrolimus vs MMF with cyclosporine: 0.6320 vs 0.6410 for AUC(0-12) determination and 0.8415 vs 0.4827 for C0 determination. Combination of MMF with tacrolimus is dosed more precisely vs dosing of MMF with cyclosporine. 72 (70.6%) patients AUC(0-12) and 79 (77.5%) patients C0 out of 102 patients were within the therapeutic range. The AUC(0-12) monitoring of mycophenolic acid in patients receiving MMF with tacrolimus or in patients receiving MMF with cyclosporine enabled to identify more overdosing and possible risky cases. Study results show that standard MMF dosing without monitoring and with mycophenolic acid level within the therapeutic width is possible and demonstrates less risky cases in patients receiving MMF with tacrolimus, while patients receiving MMF with cyclosporine should be intensively monitored to achieve the highest safety. However, AUC(0-12) monitoring is advised showing better compliance vs C0 monitoring.