Miracle-dz/UniFAR-FTUs huggingface dataset:
How subtle differences in polymer molecular weight affect doxorubicin-loaded PLGA nanoparticles degradation and drug release

Abstract Aims: To evaluate the influence of minor differences in molecular weights of commercially available low molecular weight PLGA grades on the kinetics of doxorubicin release from the nanoparticles. Methods: Three low-molecular weight 50/50 PLGA polymers were thoroughly characterised concerning intrinsic viscosity, molecular weight (Mw), acid value, and residual monomer content. The doxorubicin-loaded nanoparticles prepared using these polymers were evaluated concerning the kinetics of drug release and hydrolytic degradation. Results: The Mw of the polymers were slightly different: 10.2, 10.3, and 4.7 kDa. The nanoparticles obtained from the polymer with Mw of 4.7 kDa exhibited considerably higher rates of drug release and polymer degradation. Conclusion: In the case of low molecular weight PLGA grades even a few kilodaltons could be important for the batch-to-batch reproducibility of the nanoformulation parameters. These results bring forward the importance of in-house characterisation of the polymers to be used for the nanoparticle preparation.
Molecular Profile of Gastrointestinal Stromal Tumors in Sixty-Eight Patients from a Single Swiss Institution

Introduction: Gastrointestinal stromal tumor (GIST) is the most common mesenchymal neoplasm of the gastrointestinal tract. It has distinct molecular features and primarily affects the KIT and PDGFRA genes. Objective: We wanted to assess the molecular profile of 68 GIST patients who were sequenced consecutively between 2014 and 2019 at our institute of pathology. Methods: Our cohort comprised 60 primary and 8 metastatic GIST patients; 43 and 57% of the cases, respectively, were analyzed by Sanger sequencing or next-generation sequencing (NGS). Results: Of the 60 primary GIST patients, 47 (78%) showed a KIT mutation; 2 cases showed a double KIT mutation, and 1 of these was a therapy-naive GIST. Nine (15%) patients harbored a PDGFRA mutation, 2 (3%) had a BRAF mutation, 1 (2%) had a PIK3CA mutation, and 1 (2%) did not show any mutation. One BRAF and the PIK3CA mutation have not been described in GIST before. All metastatic GIST harbored exclusively KIT mutations. Conclusion: A retrospective analysis of GIST sequenced at our institute revealed incidences of KIT and PDGFRA mutations comparable to those in other cohorts from Europe. Interestingly, we found 2 previously undescribed mutations in the BRAF and PIK3CA genes as well as 1 treatment-naive case with a double KIT mutation in exon 11.
Initial high-dose corticosteroids and renal impairment are risk factors for early severe infections in elderly patients with antineutrophil cytoplasmic autoantibody-associated vasculitis

Supplemental Digital Content is available in the text Abstract Recent large observational studies of antineutrophil cytoplasmic autoantibody-associated vasculitis (AAV) show that severe infection is a major cause of death and that the majority of infections occur during the early phase of initiating remission-induction therapy. Many risk factors for severe infection have been suggested, but these have been inconsistent. Nevertheless, infectious risk factors in elderly patients with AAV have not been adequately investigated in previous studies. In this retrospective observational study, we examined potential predictors of severe infection within 90 days (early severe infections) after remission-induction therapy in patients with AAV aged 65 years or older. We included 167 consecutive elderly patients with AAV admitted to our hospital. Data from medical history and remission-induction therapy were analyzed for predictive risk factors associated with early severe infections. The relationship between initial doses of corticosteroids and cumulative incidence of severe infections was also analyzed. A multivariate analysis of risk factors for early severe infections was performed using logistic regression analysis. The Kaplan–Meier method was used to estimate the overall survival, and the log-rank test was used to evaluate the differences between patients with and without early severe infections. Gray method was used to compare the cumulative incidence of severe infections in patients who did and did not receive initial high-dose corticosteroids. Logistic regression analysis showed that initial high-dose corticosteroid administration (prednisolone ≥0.8 mg/kg/d) (odds ratio [OR] 3.86, P = .030) and serum creatinine levels at diagnosis ≥1.5 mg/dL (OR 5.13, P = .003) were independent predictors of early severe infection although administration of cyclophosphamide or rituximab was not. The cumulative incidence of severe infections was also significantly higher in patients who received initial high-dose corticosteroids (P = .042), and patients with early severe infections exhibited a high mortality rate within 6 months (P < .001). Our findings suggest that initial high-dose corticosteroids and renal impairment at diagnosis are associated with a higher risk of early severe infections and early death in elderly patients with AAV.
Enrichment of nitrogen fixing bacteria in a nitrogen deficient wastewater treatment system.

Anthropogenic nitrogen fixation is essential to sustain a global population of 7.7 billion. However, there has been a long-standing desire to find cheaper and more environmentally friendly alternatives to the Haber Bosch process. In this study, we developed a new strategy of nitrogen fixation by enriching free-living N2 fixing bacteria (NFB) in reactors fed with low nitrogen wastewater, analogous to those usually found in certain industrial effluents such as paper mills. Our reactors fixed appreciable quantities of nitrogen with a rate of 11.8 mg of N per litre per day. This rate is comparable to recent "breakthrough" nitrogen fixing technologies and far higher than observed in low C:N reactors (fed with organic matter and nitrogen). NFB were quantified using qPCR of the nifH (marker gene used to identify biological nitrogen fixation) and 16S rRNA genes. The nifH gene was enriched by a factor of ten in the nitrogen fixing reactors (compared to controls) attaining 13% of the bacterial population (1:4.2 copies of nifH to 16S rRNA). Illumina MiSeq 16S rRNA gene amplicon sequencing of reactors showed that the microbial community was dominated (19%) by Clostridium pasteurianum. We envisage that nitrogen enriched biomass could potentially be used as a biofertiliser and that the treated wastewater could be released to the environment with very little post treatment.
Angiotensin and biased analogs induce structurally distinct active conformations within a GPCR

Choosing the drug to fit the protein Many approved drugs bind to G protein–coupled receptors (GPCRs). A challenge in targeting GPCRs is that different ligands preferentially activate different signaling pathways. Two papers show how biased signaling arises for the angiotensin II type 1 receptor that couples to two signaling partners (G proteins and arrestins). Suomivuori et al. used large-scale atomistic simulations to show that coupling to the two pathways is through two distinct GPCR conformations and that extracellular ligands favor one or the other conformation. Wingler et al. present crystal structures of the same receptor bound to ligands with different bias profiles. These structures show conformational changes in and around the binding pocket that match those observed in simulations. This work could provide a framework for the rational design of drugs that are more effective and have fewer side effects. Science, this issue p. 881, p. 888 Crystal structures elucidate how ligands select among signaling conformations of a G protein–coupled receptor. Biased agonists of G protein–coupled receptors (GPCRs) preferentially activate a subset of downstream signaling pathways. In this work, we present crystal structures of angiotensin II type 1 receptor (AT1R) (2.7 to 2.9 angstroms) bound to three ligands with divergent bias profiles: the balanced endogenous agonist angiotensin II (AngII) and two strongly β-arrestin–biased analogs. Compared with other ligands, AngII promotes more-substantial rearrangements not only at the bottom of the ligand-binding pocket but also in a key polar network in the receptor core, which forms a sodium-binding site in most GPCRs. Divergences from the family consensus in this region, which appears to act as a biased signaling switch, may predispose the AT1R and certain other GPCRs (such as chemokine receptors) to adopt conformations that are capable of activating β-arrestin but not heterotrimeric Gq protein signaling.
Molecular Heterogeneity of β-Thalassemia in the Kohat Region, Khyber Pakhtunkhwa Province, Pakistan

Abstract The present study was intended to report the incidence of the most frequently occurring β-thalassemia (β-thal) mutations in the Kohat region [Khyber Pakhtunkhwa (KP) Province, Pakistan], their inheritance pattern in patients, and consanguinity in the parents. Moreover, this study could provide valuable information regarding thalassemia diagnoses such as prenatal diagnosis (PND), genetic counseling and carrier screening for controlling the affected births in the population. During this study, 160 peripheral blood samples of affected patients, their parents and siblings were collected from 25 discrete families having at least one child needing regular blood transfusions from different areas of the Kohat region. β-Thalassemia mutations found in the population were screened via the amplification refractory mutation system-polymerase chain reaction (ARMS-PCR). A total of 320 alleles was evaluated for the presence of six β-thal mutations. Of these six β-thal mutations, the frameshift codons (FSC) 8/9 (+G) (HBB: c.27_28insG) was found to be the most frequent in the studied population, and more interestingly, followed by IVS-I-5 (G>C) (HBB: c.92+5G>C) and FSC 5 (–CT) (HBB: c.17_18delCT). The findings of the present study show differences with previous results from other regions of the Pashtun population, which demarcates the heterogeneity in mutations found in the Pashtun ethnicity. These observations may help in implementing parental meetings about disease recurrence in future, large scale mutation screening and PND for the population of the Kohat region and also the whole Pashtun ethnicity.
The comparative efficacy of supervised- versus home-based exercise programs in patients with ankylosing spondylitis

Abstract Objectives: The aim of this meta-analysis is to investigate the comparative efficacy between supervised- and home-based programs in patients with ankylosing spondylitis (AS). Method: A systematic search in PubMed, Web of Science, EMBASE, and the Cochrane Library was electronically performed by 2 independent investigators in order to capture all potential studies comparing supervised- with home-based in patients with AS from inception to April 2018. After extracted essential information, apprised risk of bias, statistical analysis was performed with Review Manager (RevMan) software (version 5.3.0). The protocol was registered at PROSPERO platform with an identifier of CRD42018097046. Results: A total of 7 studies comprising 271 patients were included finally. Meta-analyses showed that, compared to home-based program, supervised-based program was associated with reduced bath ankylosing spondylitis metrology index (BASMI) scores (mean difference [MD], -0.45; 95% confidence interval [CI], -0.73, -0.17), bath ankylosing spondylitis disease activity index (BASDAI) scores (MD, -0.48; 95% CI, -0.88, -0.08), and bath ankylosing spondylitis functional index (BASFI) scores (MD, -0.78; 95% CI, -1.19, -0.37). However, depression scores (standard mean difference, -0.22; 95% CI, -0.58, 0.14) between the 2 groups showed no significant defference. Conclusions: Both supervised- and home-based programs can benefit to reduce BASMI, BASDAI, and BASFI scores in AS patients. However, short-term, supervised exercise program may be more effective than home-based exercises at decreasing disease activity with AS.
A pilot study to investigate the measurement of immunoglobulin A in Welsh Cob and Welsh Pony foals’ faeces and their dam’s milk

ABSTRACT Aims: To determine if an ELISA for measurement of IgA in equine serum could be used to measure concentrations of IgA in foal faeces and to determine correlations with concentrations in the milk of the dam. Methods: Faeces from 20 Welsh Cob and Welsh Pony foals and milk from their dams were collected within 12 hours (Day 0) and at 6 days after parturition (Day 6). On Day 6, faeces could not be collected from 2/20 foals, and milk samples could not be collected from 3/20 mares. An equine IgA ELISA validated for serum and plasma was used to measure concentrations of IgA in all samples in triplicate. The precision of the assay for each sample type was determined using modified CV. Results: IgA was not detectable in 7/20 Day 0 faecal samples and in 2/18 Day 6 faecal samples. For samples with detectable IgA, the mean modified CV was 10.5 (95% CI = 6.0–15.0)% for Day 0 faecal samples, and was 6.8 (95% CI = 4.3–9.4)% for Day 6 faecal samples. Median concentrations of IgA in faeces on Day 0 were lower than concentrations on Day 6 (0.7 mg/g vs. 37 mg/g dry matter; p = 0.003). Concentrations of IgA in milk and faeces on Day 6 were statistically correlated (r = 0.59; p = 0.006). Conclusions and clinical relevance: The IgA ELISA showed acceptable precision when used to estimate concentrations of IgA in foal faeces during the first week of life, but IgA could not be detected in 37% of meconium samples collected on Day 0. This assay may be useful for investigation of the role of maternal milk IgA in the gastrointestinal tract of neonatal foals, but further assessment of both accuracy and precision of the ELISA is required.
Left ventricular myocardial crypts: morphological patterns and prognostic implications.

AIMS Left ventricular (LV) myocardial crypts are considered a subtle marker of hypertrophic cardiomyopathy. However, crypts have also been observed in seemingly healthy individuals and it is unknown whether myocardial crypts are associated with adverse outcome. METHODS AND RESULTS Myocardial crypts were defined as invaginations traversing >50% of the myocardial wall and assessed using contrast-enhanced cardiac computed tomography in 10 097 individuals from the Copenhagen General Population Study. Number of crypts, location, shape, penetrance, and volume were assessed. The endpoint was a composite of major adverse cardiovascular events and defined as death, myocardial infarction, heart failure, or stroke. Cox regression models were adjusted for clinical variables, medical history, electrocardiographic parameters, and cardiac chamber sizes. A total of 1199 LV myocardial crypts were identified in 915 (9.1%) individuals. Seven hundred (6.9%) had one crypt and 215 (2.1%) had multiple crypts. During a median follow-up of 4.0 years (interquartile range 1.5-6.7), major adverse cardiovascular events occurred in 619 individuals. Individuals with one or multiple crypts had a hazard ratio for major adverse cardiovascular events of 1.00 [95% confidence interval (CI): 0.72-1.40; P = 0.98] and 0.90 (95% CI: 0.47-1.75; P = 0.76), respectively, compared with those with no crypts. No specific pattern of crypt location, shape, penetrance, or volume was associated to an increased hazard ratio for major adverse cardiovascular events. CONCLUSION LV myocardial crypts are frequent in the general population and are not associated with intermediate-term major adverse cardiovascular events.
Validity and reliability of a computer-vision-based smartphone app for measuring barbell trajectory during the snatch

ABSTRACT The purpose of this study was to investigate the validity of a smartphone app to measure biomechanical barbell parameters during the snatch. Ten collegiate NCAA division I athletes performed two repetitions each at 40, 50, 60, 70, and 80% of their 1-repetition maximum snatch. Barbell motions were simultaneously recorded with a motion capture system and the smartphone app. The motion capture system recorded the 3-D position of a reflective marker attached to the end of the barbell while the smartphone app was used to record sagittal plane video and track the shape of the weight plate from which the barbell center was derived. Peak forward (PFD) and backward (PBD) displacements and peak vertical displacement (PVD) and velocity (PVV) were calculated from both sets of data. Significant, strong to very strong Pearson’s product-moment correlation coefficients between both systems were noted for all parameters (r = 0.729–0.902, all p < 0.001). Small significant biases between systems were observed for PVD (ES = 0.284, p < 0.001) and PFD (ES=0.340, p < 0.01), while trivial to small, non-significant biases were observed for PBD (ES = 0.143) and PVV (ES = –0.100). Collectively, the results suggest that the app can provide biomechanical data of barbell motions similar to a 3-D motion capture system.
The CO2 stimulus duration and steady‐state time point used for data extraction alters the cerebrovascular reactivity outcome measure

What is the central question of this study? Cerebrovascular reactivity (CVR) is a common functional test to assess brain health, and impaired CVR has been associated with all‐cause cardiovascular mortality: does the duration of the CO2 stimulus and the time point used for data extraction alter the CVR outcome measure? What is the main finding and its importance? This study demonstrated CVR measures calculated from 1 and 2 min CO2 stimulus durations were significantly higher than CVR calculated from a 4 min CO2 stimulus. CVRs calculated from the first 2 min of the CO2 stimulus were significantly higher than CVR values calculated from the final minute if the duration was ≥4 min. This study highlights the need for consistent methodological approaches.
Acute effect of concurrent exercise on serum leptin and resistance insulin response in sedentary men

Aim: This study aimed to determine the delayed effect of one session of concurrent exercise on serum leptin and resistance insulin levels of sedentary men. Materials and Methods: Fifteen healthy young men with a mean age of 22.9 ± 1.7 years and a body mass index of 23.3 ± 1 kg/m2 voluntarily participated in this experimental research. They participated in one session of concurrent exercise including 20 min of aerobic running on a treadmill at 60%–70% maximum oxygen uptake plus a resistance exercise at the intensity of 70% of 1-repetition maximum with ten repetitions per set to second round. Blood serum leptin, glucose, insulin, and insulin resistance index were assessed before, 24, 48, and 72 h after the exercise program.Results: The results showed that leptin level did not change statistically significantly immediately and 72 h after the exercise termination (P > 0.05) but did decrease statistically significantly 24 and 48 h after the exercise program (P ≤ 0.05). The result also showed that insulin and insulin resistance levels decreased statistically significantly immediately after the exercise and lasted for up to 48 h postexercise (P ≤ 0.05); however, it returned to its initial value after 72 h of recovery (P > 0.05). Conclusions: It was concluded that energy use in one session of concurrent exercise might reduce leptin levels up to 48 h of recovery. In addition, a decrease in insulin, a known inducer of leptin expression in adipocytes, occurs before the decrease in leptin. This change may mediate the decrease of leptin concentration.
Accuracy of Refractive Outcome Using Optical Low Coherence Reflectometry in Silicone Oil-Filled Eyes Undergoing Intraocular Lens Implantation with Silicone Oil Removal

Aim: To assess the accuracy and consistency of intraocular lens (IOL) power calculation using optical low coherence reflectometry device (OLCR), LENSTAR LS-900, in silicone oil-filled eyes undergoing combined IOL implantation and silicone oil removal (SOR). Setting: Sankara Eye Hospital, Bangalore, Karnataka, India. Design: Retrospective study. Method: This study comprised 49 silicone oil-filled eyes of 47 patients who underwent combined IOL implantation with SOR. All patients were measured with OLCR before performing phacoemulsification and IOL implantation in silicone oil mode. The predicted refraction as calculated with OLCR was correlated with the postoperative spherical equivalent. Results: The mean deviation of the spherical equivalent was −0.74 diopters (D). The mean difference between predicted refraction and postoperative spherical equivalent was −0.34 D. The mean axial length of the eyes was 23.53+1.86 (range 21.49–30.03 mm). Conclusion: OLCR is a safe device that provides precise biometry and accurate IOL power calculation in silicone oil-filled eyes.
Mayaro fever: A brief review on the immune profile

Mayaro virus is an emergent alphavirus that infects humans, leading to Mayaro fever. Approximately fifty percent of infected patients develop arthritis symptoms in the recovery phase, a phase that can last up to a year. The literature about Mayaro virus infection and its immune response is scarce, which may hamper the development of treatment strategies. We summarize changes in cytokines and chemokines in the acute and recovery phase in Mayaro virus infected patients, and relate this molecular characterization with the immune response. VEGF and IL-12/p70 show pronounced changes in patients in the acute phase, suggesting the development of cellular immunity and Th1 response. IL-6, IL-7, CXCL8/IL-8, IL-13, IL-17, and IFN-γ are elevated in patients with arthritis symptoms in the long-term recovery phase, which may be related to the continuous inflammatory process, a possible Th2 inhibiting and promoting Th17 process. Although few studies discuss the issue, with a small number of patients and different backgrounds, inflammatory and immune response and manifestations seem to be closely linked. This information may help to develop the appropriate treatment strategies in Mayaro virus infection. Therefore, we analyzed and summarized data available in literature.