Miracle-dz/UniFAR-FTUs huggingface dataset:
Efficacy and safety of ticagrelor and clopidogrel in East Asian patients with coronary artery disease undergoing percutaneous coronary intervention

Abstract Aims The efficacy and safety of ticagrelor and clopidogrel in East Asian patients with coronary artery disease (CAD) undergoing percutaneous coronary intervention (PCI) remains uncertain. The purpose of this study was to compare the efficacy and safety of ticagrelor and clopidogrel in East Asian patients with CAD treated with PCI. Methods A total of 12383 patients with CAD undergoing PCI who received dual antiplatelet therapy (DAPT) were consecutively enrolled in the ticagrelor group (n = 1321) and the clopidogrel group (n = 11062). Major adverse cardiovascular and cerebrovascular events (MACCEs) and thrombolysis in myocardial infarction (TIMI) bleeding events were compared according to ticagrelor or clopidogrel use were compared. Results After propensity matching (n = 1321 in each group), ticagrelor was associated with lower incidence of MACCEs compared with clopidogrel (3.9 vs. 5.9%, hazard ratio [HR] = 0.65, 95% confidence interval [CI] 0.45–0.92, p = .015). The incidence of TIMI bleeding events was higher in the ticagrelor group than in the clopidogrel group (4.5 vs. 2.9%, HR = 1.90, 95% CI 1.25–2.88, p = .024). The difference between ticagrelor and clopidogrel for net adverse clinical events was nonsignificant (4.3 vs. 4.9%, HR = 0.88, 95% CI 0.61–1.27, p = .458). Conclusions Ticagrelor was associated with a lower incidence of MACCEs and an increased risk of TIMI bleeding events in East Asian patients with CAD receiving PCI.
CH7233163 Overcomes Osimertinib-Resistant EGFR-Del19/T790M/C797S Mutation

Osimertinib is the only EGFR-tyrosine kinase inhibitor (TKI) capable of overcoming EGFR-T790M–mutated NSCLC, but osimertinib-resistant EGFR triple mutations (Del19/T790M/C797S or L858R/T790M/C797S) have been reported. Although allosteric EGFR TKIs (e.g., EAI-045) that potentially overcome L858R/T790M/C797S have been identified, there are no effective inhibitors against Del19/T790M/C797S. In this study, we identified CH7233163 as having the potential to overcome EGFR-Del19/T790M/C797S. CH7233163 showed potent antitumor activities against tumor with EGFR-Del19/T790M/C797S in vitro and in vivo. In addition to EGFR-Del19/T790M/C797S, the characterization assays showed that CH7233163 more selectively inhibits various types of EGFR mutants (e.g., L858R/T790M/C797S, L858R/T790M, Del19/T790M, Del19, and L858R) over wild type. Furthermore, crystal structure analysis suggested that CH7233163 is a noncovalent ATP-competitive inhibitor for EGFR-Del19/T790M/C797S that utilizes multiple interactions with the EGFR's αC-helix-in conformation to achieve potent inhibitory activity and mutant selectivity. Therefore, we conclude that CH7233163 is a potentially effective therapy for osimertinib-resistant patients, especially in cases of EGFR-Del19/T790M/C797S.
Sexual violence against migrants and asylum seekers. The experience of the MSF clinic on Lesvos Island, Greece

Objectives Sexual violence can have a destructive impact on the lives of people. It is more common in unstable conditions such as during displacement or migration of people. On the Greek island of Lesvos, Médecins Sans Frontières provided medical care to survivors of sexual violence among the population of asylum seekers. This study describes the patterns of sexual violence reported by migrants and asylum seekers and the clinical care provided to them. Methods This is a descriptive study, using routine program data. The study population consisted of migrants and asylum seekers treated for conditions related to sexual violence at the Médecins Sans Frontières clinic on Lesvos Island (September 2017-January 2018). Results There were 215 survivors of sexual violence who presented for care, of whom 60 (28%) were male. The majority of incidents reported (94%) were cases of rape; 174 (81%) of survivors were from Africa and 185 (86%) of the incidents occurred over a month before presentation. Half the incidents (118) occurred in transit, mainly in Turkey, and 76 (35%) in the country of origin; 10 cases (5%) occurred on Lesvos. The perpetrator was known to the survivor in 23% of the cases. The need for mental health care exceeded the capacity of available mental care services. Conclusion Even though the majority of cases delayed seeking medical care after the incident, it is crucial that access to mental health services is guaranteed for those in need. Such access and security measures for people in transit need to be put in place along migration routes, including in countries nominally considered safe, and secure routes need to be developed.
Differences and Similarities in the Peptide Profile of Preterm and Term Mother’s Milk, and Preterm and Term Infant Gastric Samples

Our previous studies revealed that milk proteases begin to hydrolyze proteins in the mammary gland and that proteolytic digestion continues within the infant stomach. No research has measured how the release of milk peptides differs between the gastric aspirates of term and premature infants. This study examined the presence of milk peptides in milk and gastric samples from term and preterm infants using an Orbitrap Fusion Lumos mass spectrometer. Samples were collected from nine preterm-delivering and four term-delivering mother–infant pairs. Our study reveals an increased count and ion abundance of peptides and decreased peptide length from mother’s milk to the infant stomach, confirming that additional break-down of the milk proteins occurred in both preterm and term infants’ stomachs. Protein digestion occurred at a higher level in the gastric contents of term infants than in gastric contents of preterm infants. An amino acid cleavage site-based enzyme analysis suggested that the observed higher proteolysis in the term infants was due to higher pepsin/cathepsin D activity in the stomach. Additionally, there was a higher quantity of antimicrobial peptides in term infant gastric contents than in those of preterm infants, which could indicate that preterm infants benefit less from bioactive peptides in the gut.
Genetic variability, heritability and genetic advance for leaf, pod and seed protein content in cowpea {Vigna unguiculata (L.) Walp.}

Genetic variability, heritability and genetic advance for leaf. pod and seed protein content were studied in F2 generation of five inter-varietal crosses of cowpea viz., (1) COVU 623 x CO2 (2) COVU 623 xCO3 COVU 623 x CO4 (4) COVU 623 x PAlYUR 1 (5) COVU 623 x KM 1. Of the five crosses studied, crosses 3, 4 and 5 recorded high heritability coupled with moderate genetic ad vance indicating that both additive as well as dominant gene action might be involved in controlling these traits.
The effects of pre-intervention mindset induction on a brief intervention to increase risk perception and reduce alcohol use among university students: A pilot randomized controlled trial

Objective Brief interventions based on personalized feedback have shown promising results in reducing risky alcohol use among university students. We investigated the effects of activating deliberative (predecisional) or implemental (postdecisional) mindsets on the effectiveness of a standardized brief intervention, the ASSIST-linked Brief Intervention. This intervention comprises a personalized feedback and a decisional balance exercise. We hypothesized that participants in a deliberative mindset should show better outcomes related to risk perception and behavior than participants in an implemental mindset. Methods A sample of 257 students provided baseline measures on risk perception, readiness to change, and alcohol use. Of those, 64 students with risky alcohol use were randomly allocated to one of two mindset induction conditions–deliberative or implemental mindset. Thereafter, they received the ASSIST-linked Brief Intervention and completed self-report questionnaires on changes in risk perception, alcohol use, and readiness to change at post-intervention and four-week follow-up. Results In contrast to our hypotheses, the four-weeks follow-up revealed that participants in the implemental mindset consumed significantly less alcohol than participants in a deliberative mindset did. The former decreased and the latter increased their alcohol intake; resistance to the brief intervention was stronger in the latter condition. However, neither deliberative nor implemental mindset participants showed any changes in risk perceptions or in their readiness to change alcohol consumption. Conclusions These findings suggest that mindset induction is a powerful moderator of the effects of the ASSIST-linked Brief Intervention. We argue that systematic research on mindset effects on brief intervention techniques aimed to reduce risky alcohol use is highly needed in order to identify the processes involved with commitment and resistance being the main candidates.
Transcriptomic analysis of cyanobacterial alkane overproduction reveals stress-related genes and inhibitors of lipid droplet formation

The cyanobacterium Nostoc punctiforme can form lipid droplets (LDs), internal inclusions containing triacylglycerols, carotenoids and alkanes. LDs are enriched for a 17 carbon-long alkane in N. punctiforme , and it has been shown that the overexpression of the aar and ado genes results in increased LD and alkane production. To identify transcriptional adaptations associated with increased alkane production, we performed comparative transcriptomic analysis of an alkane overproduction strain. RNA-seq data identified a large number of highly upregulated genes in the overproduction strain, including genes potentially involved in rRNA processing, mycosporine-glycine production and synthesis of non-ribosomal peptides, including nostopeptolide A. Other genes encoding helical carotenoid proteins, stress-induced proteins and those for microviridin synthesis were also upregulated. Construction of N. punctiforme strains with several upregulated genes or operons on multi-copy plasmids resulted in reduced alkane accumulation, indicating possible negative regulators of alkane production. A strain containing four genes for microviridin biosynthesis completely lost the ability to synthesize LDs. This strain exhibited wild-type growth and lag phase recovery under standard conditions, and slightly faster growth under high light. The transcriptional changes associated with increased alkane production identified in this work will provide the basis for future experiments designed to use cyanobacteria as a production platform for biofuel or high-value hydrophobic products.
Establishment of a highly precise multi-attribute method for the characterization and quality control of therapeutic monoclonal antibodies

ABSTRACT The multi-attribute method (MAM) has garnered attention as a new quality control method of therapeutic monoclonal antibodies (mAbs). MAM analysis allows multiple relative quantifications of several structural attributes of therapeutic mAbs; however, some issues remain to be addressed in its procedures especially for sample preparation. The goal of this study was to optimize the sample preparation method for MAM analysis of mAbs. Using a model mAb, we compared five sample preparation methods based on sequence coverage, peptide redundancy, missed cleavage and chemical deamidation. It was found that low pH buffer and short digestion time reduced artificial deamidation. The desalting process after carboxymethylation was essential to obtaining high sequence coverage by a short digestion time. The generation of missed cleavage peptides was also improved by using a trypsin/lysyl endopeptidase (Lys-C) mixture. Next, we evaluated the usefulness of our method as a part of MAM analysis. Finally, 17 glycopeptides, 2 deamidated peptides and N- and C-terminal peptides of the heavy chain were successfully monitored with acceptable mass accuracy and coefﬁcient of variation (CV, %) of the relative peak area. On the other hand, 4 oxidated peptides indicated the unavoidable slightly higher inter-assay CV (%) of the peak area ratio due to the instability in the MS sample solution. Collectively, we demonstrated that our method was applicable as an easy and reliable sample preparation method for MAM analysis, and the variation in the relative peak area could be influenced by the modification type rather than by the amount of each peptide. Graphical Abstract
In vivo demonstration of pulmonary microvascular involvement in COVID-19 using dual-energy computed tomography

Vascular involvement in coronavirus disease 2019 (COVID-19) has been suggested by several observations, such as the high rate of pulmonary embolism [1], the prothrombotic state and the proinflammatory biological profile [2, 3], as well as the pathological findings of severe endothelial injury and diffuse thrombosis [4]. Dual-energy computed tomography (DECT) allows specific imaging of the iodinated contrast agent distribution within the lung, which has been demonstrated as a surrogate marker of lung perfusion [5, 6]. Therefore, our goal was to assess in vivo pulmonary microvascular involvement in patients with COVID-19 pneumonia by using DECT and to determine whether vascular changes vary during the course of the disease. In COVID-19 pneumonia, dual-energy computed tomography has shown two patterns of lung perfusion along the course of the disease: an increase in perfusion blood volume (PBV) with ground-glass opacities and a decrease in PBV with consolidation https://bit.ly/2Zh0XcI
De Novo Protein Design for Novel Folds Using Guided Conditional Wasserstein Generative Adversarial Networks

Although massive data is quickly accumulating on protein sequence and structure, there is a small and limited number of protein architectural types (or structural folds). This study is addressing the following question: how well could one reveal underlying sequence-structure relationships and design protein sequences for an arbitrary, potentially novel, structural fold? In response to the question, we have developed novel deep generative models, namely, semi-supervised gcWGAN (guided, conditional, Wasserstein Generative Adversarial Networks). To overcome training difficulties and improve design qualities, we build our models on conditional Wasserstein GAN (WGAN) that uses Wasserstein distance in the loss function. Our major contributions include (1) constructing a low-dimensional and generalizable representation of the fold space for the conditional input; (2) developing an ultra-fast sequence-to-fold predictor (or oracle) and incorporating its feedback into WGAN as a loss to guide model training; and (3) exploiting sequence data with and without paired structures to enable a semi-supervised training strategy. Assessed by the oracle over 100 novel folds not in the training set, gcWGAN generates successful designs and covers 3.5 times more target folds compared to a competing data-driven method (cVAE). Assessed by sequence- and structure-based predictors, gcWGAN designs are physically and biologically sound. Assessed by a structure predictor over representative novel folds, including one not even part of basis folds, gcWGAN designs have comparable or better fold accuracy yet much more sequence diversity and novelty than cVAE. The ultra fast data-driven model is further shown to boost the success of a principle-driven de novo method (RosettaDesign), through generating design seeds and tailoring design space. In conclusion, gcWGAN explores uncharted sequence space to design proteins by learning generalizable principles from current sequence-structure data. Data, source codes, and trained models are available at https://github.com/Shen-Lab/gcWGAN.
Rescuing AAV gene transfer from neutralizing antibodies with an IgG-degrading enzyme

Preexisting humoral immunity to recombinant adeno-associated virus (AAV) vectors restricts the treatable patient population and efficacy of human gene therapies. Approaches to clear neutralizing antibodies (NAbs), such as plasmapheresis and immunosuppression, are either ineffective or cause undesirable side effects. Here, we describe a clinically relevant strategy to rapidly and transiently degrade NAbs before AAV administration using an IgG-degrading enzyme (IdeZ). We demonstrate that recombinant IdeZ efficiently cleaved IgG in dog, monkey, and human antisera. Prophylactically administered IdeZ cleaved circulating human IgG in mice and prevented AAV neutralization in vivo. In macaques, a single intravenous dose of IdeZ rescued AAV transduction by transiently reversing seropositivity. Importantly, IdeZ efficiently cleaved NAbs and rescued AAV transduction in mice passively immunized with individual human donor sera representing a diverse population. Our antibody clearance approach presents a potentially new paradigm for expanding the prospective patient cohort and improving efficacy of AAV gene therapy.
Periprocedural Euglycemic Diabetic Ketoacidosis Associated With Sodium–Glucose Cotransporter 2 Inhibitor Therapy During Colonoscopy

More than 10% of adults undergoing colonoscopy have type 2 diabetes (T2D) (1). The use of sodium–glucose cotransporter 2 inhibitors (SGLT2i) has increased due to their glycemic control and benefits of lowering cardiovascular morbidity and mortality as well as reducing diabetic nephropathy (2,3). Diabetic ketoacidosis (DKA) is a rare complication associated with SGLT2i. Precipitating factors include fasting, dietary modifications, intercurrent illnesses, surgical stress, insulin insufficiency, and inappropriate management of SGLT2i in the periprocedural period. SGLT2i-induced ketoacidosis can present either with elevated blood glucose levels (BGL) or with near-normal BGL (<250 mg/dL), termed euglycemic diabetic ketoacidosis (EDKA) (4). Interventional gastroenterology procedures, in particular colonoscopy, pose risk for EDKA with SGLT2i use due to cathartic bowel preparation, fluid-only dietary restriction, and fasting. We present a series of cases of EDKA in the setting of colonoscopy and discuss its procedure-specific implications. Eight cases of SGLT2i-associated EDKA in the setting of colonoscopy were identified between August 2019 and February 2020 across three centers. Five cases were identified through the Central Adelaide Local Health Network (CALHN), South Australia, and three were identified at the Royal Brisbane and Women’s Hospital (RBWH), Queensland. Ethical approval was obtained from the CALHN (13194) and RBWH (LNR/2020/QRBW/61873) Human Research Ethics Committees. All patients had T2D and were aged between 45 and 75 years (Table 1). One patient was on a very-low-calorie diet, which may have been a contributory …
Mesenchymal Stromal-Like Cells in the Glioma Microenvironment: What Are These Cells?

Simple Summary We review here what is currently known about the role of mesenchymal stromal-like cells, which complicate our understanding of the glioma microenvironment. We provide an overview of the major studies on these cells, highlighting their role in tumor progression and prognosis. Researchers and clinicians should consider these cells to be an integral component of the glioma microenvironment, and of considerable potential value for future prognostic and therapeutic perspectives. Abstract The glioma microenvironment is a critical regulator of tumor progression. It contains different cellular components such as blood vessels, immune cells, and neuroglial cells. It also contains non-cellular components, such as the extracellular matrix, extracellular vesicles, and cytokines, and has certain physicochemical properties, such as low pH, hypoxia, elevated interstitial pressure, and impaired perfusion. This review focuses on a particular type of cells recently identified in the glioma microenvironment: glioma-associated stromal cells (GASCs). This is just one of a number of names given to these mesenchymal stromal-like cells, which have phenotypic and functional properties similar to those of mesenchymal stem cells and cancer-associated fibroblasts. Their close proximity to blood vessels may provide a permissive environment, facilitating angiogenesis, invasion, and tumor growth. Additional studies are required to characterize these cells further and to analyze their role in tumor resistance and recurrence.
Social Media Use and Mental Health during the COVID‐19 Pandemic: Moderator Role of Disaster Stressor and Mediator Role of Negative Affect

Background Informed by the differential susceptibility to media effects model (DSMM), the current study aims to investigate associations of COVID‐19‐related social media use with mental health outcomes and to uncover potential mechanisms underlying the links. Methods A sample of 512 (62.5% women; M age = 22.12 years, SD = 2.47) Chinese college students participated in this study from 24 March to 1 April 2020 via online questionnaire. They completed measures of social media use, the COVID‐19 stressor, negative affect, secondary traumatic stress (STS), depression, and anxiety as well as covariates. Results As expected, results from regression analyses indicated that a higher level of social media use was associated with worse mental health. More exposure to disaster news via social media was associated with greater depression for participants with high (but not low) levels of the disaster stressor. Moreover, path analysis showed negative affect mediated the relationship of social media use and mental health. Conclusions These findings suggest that the disaster stressor may be a risk factor that amplifies the deleterious impact of social media use on depression. In addition, excessive exposure to disaster on social media may trigger negative affect, which may in turn contribute to mental health problems. Future interventions to improve mental health should consider elements of both disaster stressor and negative affect.
Seizure‐onset regions demonstrate high inward directed connectivity during resting‐state: An SEEG study in focal epilepsy

In patients with medically refractory focal epilepsy, stereotactic‐electroencephalography (SEEG) can aid in localizing epileptogenic regions for surgical treatment. SEEG, however, requires long hospitalizations to record seizures, and ictal interpretation can be incomplete or inaccurate. Our recent work showed that non‐directed resting‐state analyses may identify brain regions as epileptogenic or uninvolved. Our present objective is to map epileptogenic networks in greater detail and more accurately identify seizure‐onset regions using directed resting‐state SEEG connectivity.
Synthesis, extracorporeal nephrotoxicity, and 3D‐QSAR of andrographolide derivatives

Andrographolide is a traditional Chinese medicine monomer with many pharmacological activities, but has potential nephrotoxicity. Here, we aim to investigate the relationship between modification of andrographolide structure and its nephrotoxicity. Twenty‐three andrographolide derivatives were synthesized, and their structures were confirmed by 1H‐NMR and HRMS. Nephrotoxicity of these compounds against human renal tubular epithelial (HK‐2) cells was evaluated using the MTT assay. The results indicated that most of them had significantly reduced nephrotoxicity, especially compounds III, V, and IXc, with IC50 values of 1,985, 1,300, and 806.9 μmol/L, respectively, which were obviously superior to andrographolide (IC50 30.60 μmol/L). However, compounds Ia–If (IC50 values < 30 μmol/L), the 14‐OH derivatives of andrographolide, showed higher nephrotoxicity than that of andrographolide. Three‐dimensional quantitative structure‐activity relationship (3D‐QSAR) models of COMFA and COMSIA were established (COMFA: q2 = 0.639, r2 = 0.951; COMSIA: q2 = 0.569, r2 = 0.857). This model allowed proposing five new compounds with lower theoretical nephrotoxicity, which would be worthwhile to synthesize and evaluate. We believe that predicted models will help us to understand the structural modification requirements of andrographolide to reduce the nephrotoxicity, and further investigations will be needed to determine the mechanism involved in the effect of less nephrotoxic compounds.