Miracle-dz/UniFAR-FTUs huggingface dataset:
Design and implementation of active learning strategies to enhance student understanding of foundational concepts in biochemistry

For many students biochemistry is a demanding course because they are expected to apply previously learned foundational concepts to new biological contexts. These foundational concepts serve as a scaffold onto which to build threshold concepts such as the physical basis of interactions. Unfortunately, many students possess misconceptions or gaps in knowledge of these foundational concepts which hinder their understanding of new information. This paper describes the implementation of an iterative process to improve student foundational concept learning in an introductory biochemistry course. The process includes pre‐assessment of foundational concept knowledge, introduction of interventions targeting low performing concepts and re‐assessment of student learning gains. Diverse active learning strategies such as problem‐based worksheets, tactile learning activities, review activities and learning cycle activities were introduced to target concepts including hydrogen bonding, pH/pKa, bond energy and chemical equilibrium. While all active learning strategies resulted in improved posttest scores compared to pretest scores, no one strategy appears to be more beneficial than another. Survey results suggest students recognized the value of utilizing the various active learning strategies in the classroom to enhance critical thinking skills, engagement during class time, and collaboration skills. The process allows instructors the breadth and flexibility to introduce diverse active learning strategies tailored to their specific student needs in an effort to improve student foundational concept learning.
Prevalence of Missing Data in the National Cancer Database and Association With Overall Survival

Key Points Question What is the prevalence of missing data in the medical record, and is this prevalence associated with outcome estimation for patients with cancer? Findings In this cohort study of more than 4 million patients with cancer using abstracted medical records from the National Cancer Database, a high prevalence of missing data for patients with the 3 most common cancers in the US was found. Patients with missing data had worse overall survival than those with complete data. Meaning The study’s findings suggest substantial gaps in documentation and data capture via the medical record for patients with cancer.
Global Epidemiology of End-Stage Kidney Disease and Disparities in Kidney Replacement Therapy

Background: The global epidemiology of end-stage kidney disease (ESKD) reflects each nation’s unique genetic, environmental, lifestyle, and sociodemographic characteristics. The response to ESKD, particularly regarding kidney replacement therapy (KRT), depends on local disease burden, culture, and socioeconomics. Here, we explore geographic variation and global trends in ESKD incidence and prevalence and examine variations in KRT modality, practice patterns, and mortality. We conclude with a discussion on disparities in access to KRT and strategies to reduce ESKD global burden and to improve access to treatment in low- and middle-income countries (LMICs). Summary: From 2003 to 2016, incidence rates of treated ESKD were relatively stable in many higher income countries but rose substantially predominantly in East and Southeast Asia. The prevalence of treated ESKD has increased worldwide, likely due to improving ESKD survival, population demographic shifts, higher prevalence of ESKD risk factors, and increasing KRT access in countries with growing economies. Unadjusted 5-year survival of ESKD patients on KRT was 41% in the USA, 48% in Europe, and 60% in Japan. Dialysis is the predominant KRT in most countries, with hemodialysis being the most common modality. Variations in dialysis practice patterns account for some of the differences in survival outcomes globally. Worldwide, there is a greater prevalence of KRT at higher income levels, and the number of people who die prematurely because of lack of KRT access is estimated at up to 3 times higher than the number who receive treatment. Key Messages: Many people worldwide in need of KRT as a life-sustaining treatment do not receive it, mostly in LMICs where health care resources are severely limited. This large treatment gap demands a focus on population-based prevention strategies and development of affordable and cost-effective KRT. Achieving global equity in KRT access will require concerted efforts in advocating effective public policy, health care delivery, workforce capacity, education, research, and support from the government, private sector, nongovernmental, and professional organizations.
Risk of venous thromboembolism associated with tofacitinib in patients with rheumatoid arthritis: a population-based cohort study.

OBJECTIVE To evaluate the risk of venous thromboembolism (VTE) with tofacitinib compared to tumor necrosis factor inhibitors (TNFIs) in patients with rheumatoid arthritis (RA). METHODS RA patients initiating tofacitinib or a TNFI without use of any biologic or tofacitinib any time prior were identified from IBM 'MarketScan' (2012-2018), Medicare (parts A, B, and D, 2012-2017), or 'Optum'Clinformatics (2012-2019) and followed until treatment discontinuation, treatment switch, insurance disenrollment, or administrative censoring. The primary outcome, VTE, was identified using inpatient claims for pulmonary embolism or deep vein thrombosis. A Cox proportional hazards model provided hazard ratio (HR) and 95% confidence intervals (CI) after accounting for confounding through propensity score (PS) fine-stratification weighting. HRs were pooled across databases with inverse variance meta-analytic method. RESULTS A total of 42,201, 25,078, and 20,374 RA patients were identified from MarketScan, Medicare, and Optum, respectively; of whom 7.1%, 7.1%, and 9.7% were tofacitinib initiators. The crude incidence rates (IRs)/100 person-years (95% CI) were 0.42 (0.20-0.77) and 0.35 (0.29-0.42) in MarketScan, 1.18 (0.68-1.92) and 0.83 (0.71-0.97) in Medicare, and 0.19 (0.04-0.57) and 0.34 (0.26-0.44) in Optum for tofacitinib and TNFIs, respectively. PS-weighted HRs showed no significant differences in the risk of VTE between tofacitinib and TNFIs in any database with a pooled HR (95% CI) of 1.13 (0.77-1.65). CONCLUSION Overall, VTE occurred infrequently (<1 per 100) in a total of 87,653 RA patients initiating tofacitinib or a TNFI. We observed no evidence for an increased risk of VTE for tofacitinib versus TNFIs in RA patients.
Chemical and biochemical control of skin pigmentation with special emphasis on mixed melanogenesis

Melanins are widely distributed in animals and plants; in vertebrates, most melanins are present on the body surface. The diversity of pigmentation in vertebrates is mainly attributed to the quantity and ratio of eumelanin and pheomelanin synthesis. Most natural melanin pigments in animals consist of both eumelanin and pheomelanin in varying ratios, and thus, their combined synthesis is called “mixed melanogenesis. ” Gene expression is an established mechanism for controlling melanin synthesis; however, there are multiple factors that affect melanin synthesis besides gene expression. Due to the differential sensitivity of the eumelanin and pheomelanin synthetic pathways to pH, melanosomal pH likely plays a major role in mixed melanogenesis. Here, we focused on various factors affecting mixed melanogenesis including (1) chemical regulation of melanin synthesis, (2) melanosomal pH regulation during normal melanogenesis and effect on mixed melanogenesis, and (3) mechanisms of melanosomal pH control (proton pumps, channels, transporters, and signaling pathways).
Long-term prognosis following hospitalization for acute myocarditis – a matched nationwide cohort study

Abstract Objective The aim of this study was to examine the long-term risk of heart failure (HF) and all-cause mortality, in patients discharged alive following hospitalization for myocarditis. Background. Prognosis in patients with apparently uncomplicated myocarditis is in general perceived as good, but data on long-term outcomes are sparse. Methods. From nationwide Danish registries we included patients without prior cardiac disease, discharged alive with a first-time diagnosis of myocarditis 1996–2016. Patients were matched 1:10 by age- and sex, with controls from the general population. Risk of HF hospitalization and death in cases and controls was compared by use of adjusted Cox regression analyses. Results. We identified 1557 patients with a first-time diagnosis of myocarditis, 72% men, median age 39 years. Patients with myocarditis had more hypertension, diabetes, and cancer, and received more pharmacotherapy prior to hospitalization compared to matched controls. During a mean follow-up of 8.5 years, the event rate of HF hospitalization was 8.7 vs. 2.2 per 1000 patient-years (py) in cases and controls; HR 4.59 (95% CI; 3.58–5.88) and for all-cause mortality, event rate 21.9 vs 11.2 per 1000 py; HR 2.10 (95% CI; 1.82–2.43). Among 784 patients with no events or HF medication one year after diagnosis, risk of HF hospitalization (HR 2.15; 95% CI; 1.18–3.92), and all-cause mortality (HR 1.62; 95% CI; 1.21–2.16) remained elevated compared to matched controls. Conclusion. Myocarditis in younger patients without prior cardiac disease was associated with a long-term excess risk of HF hospitalization, and death, even in patients free of events and HF medication 1 year after discharge. Highlights Myocarditis ranges from chest discomfort to severe heart failure. In most patients, left ventricular ejection fraction recovers but the long-term adverse cardiac risk is unknown. Patients with myocarditis and no prior cardiac disease were at higher risk of death and heart failure Routine follow-up may be warranted following an episode of acute myocarditis.
Fitness effects of spontaneous mutations in a warming world

Spontaneous mutations fuel evolutionary processes and differ in consequence, but the consequences depend on the environment. Biophysical considerations of protein thermostability predict that warm temperatures may systematically increase the deleteriousness of mutation. We sought to test whether mutation reduced fitness more when measured in an environment that reflected climate change projections for temperature. We investigated the effects of spontaneous mutations on life history, size, and fitness in 21 mutation accumulation lines and 12 control lines of Daphnia pulex at standard and elevated (+4℃) temperatures. Warmer temperature accelerated life history and reduced body length and clutch sizes. Mutation led to reduced mean clutch sizes and fitness estimates at both temperatures. We found no evidence of a systematic temperature–mutation interaction on trait means, although some lines showed evidence of beneficial mutation at one temperature and deleterious mutation at the other. However, trait variances are also influenced by mutation, and we observed increased variances due to mutation for most traits. For variance of the intrinsic rate of increase and some reproductive traits, we found significant temperature–mutation interactions, with a larger increase due to mutation in the warmer environment. This suggests that selection on new mutations will be more efficient at elevated temperatures.
Expression profiling of Echinococcus multilocularis miRNAs throughout metacestode development in vitro

The neglected zoonotic disease alveolar echinococcosis (AE) is caused by the metacestode stage of the tapeworm parasite Echinococcus multilocularis. MicroRNAs (miRNAs) are small non-coding RNAs with a major role in regulating gene expression in key biological processes. We analyzed the expression profile of E. multilocularis miRNAs throughout metacestode development in vitro, determined the spatial expression of miR-71 in metacestodes cultured in vitro and predicted miRNA targets. Small cDNA libraries from different samples of E. multilocularis were sequenced. We confirmed the expression of 37 miRNAs in E. multilocularis being some of them absent in the host, such as miR-71. We found a few miRNAs highly expressed in all life cycle stages and conditions analyzed, whereas most miRNAs showed very low expression. The most expressed miRNAs were miR-71, miR-9, let-7, miR-10, miR-4989 and miR-1. The high expression of these miRNAs was conserved in other tapeworms, suggesting essential roles in development, survival, or host-parasite interaction. We found highly regulated miRNAs during the different transitions or cultured conditions analyzed, which might suggest a role in the regulation of developmental timing, host-parasite interaction, and/or in maintaining the unique developmental features of each developmental stage or condition. We determined that miR-71 is expressed in germinative cells and in other cell types of the germinal layer in E. multilocularis metacestodes cultured in vitro. MiRNA target prediction of the most highly expressed miRNAs and in silico functional analysis suggested conserved and essential roles for these miRNAs in parasite biology. We found relevant targets potentially involved in development, cell growth and death, lifespan regulation, transcription, signal transduction and cell motility. The evolutionary conservation and expression analyses of E. multilocularis miRNAs throughout metacestode development along with the in silico functional analyses of their predicted targets might help to identify selective therapeutic targets for treatment and control of AE.
Assembly of a dsRNA synthesizing complex: RNA-DEPENDENT RNA POLYMERASE 2 contacts the largest subunit of NUCLEAR RNA POLYMERASE IV

Significance Short interfering RNAs (siRNAs) can inhibit mRNA translation or guide chromatin modifications that inhibit transcription, thus impacting gene regulation. In plants, transcriptional gene silencing involves siRNAs whose double-stranded (ds) precursors are generated by the coupled activities of NUCLEAR RNA POLYMERASE IV and RNA-DEPENDENT RNA POLYMERASE 2. We present evidence that Pol IV-RDR2 association involves contact between RDR2 and NRPD1, Pol IV’s largest catalytic subunit. As the only subunit never shared by Pol II or Pol IV, NRPD1 interaction accounts for RDR2's specific association with Pol IV. The positions of the protein docking sites suggest that Pol IV transcripts are generated in close proximity to RDR2’s catalytic site, enabling RDR2 to efficiently engage Pol IV transcripts and convert them into dsRNAs. In plants, transcription of selfish genetic elements such as transposons and DNA viruses is suppressed by RNA-directed DNA methylation. This process is guided by 24-nt short-interfering RNAs (siRNAs) whose double-stranded precursors are synthesized by DNA-dependent NUCLEAR RNA POLYMERASE IV (Pol IV) and RNA-DEPENDENT RNA POLYMERASE 2 (RDR2). Pol IV and RDR2 coimmunoprecipitate, and their activities are tightly coupled, yet the basis for their association is unknown. Here, we show that an interval near the RDR2 active site contacts the Pol IV catalytic subunit, NRPD1, the largest of Pol IV’s 12 subunits. Contacts between the catalytic regions of the two enzymes suggests that RDR2 is positioned to rapidly engage the free 3′ ends of Pol IV transcripts and convert these single-stranded transcripts into double-stranded RNAs (dsRNAs).
The number of catalytic cycles in an enzyme’s lifetime and why it matters to metabolic engineering

Significance The continuous replacement of enzymes and other proteins appropriates up to half the maintenance energy budget in microorganisms and plants. High enzyme replacement rates therefore cut the productivity of biosystems ranging from microbial fermentations to crops. However, yardsticks to assess what drives enzyme protein replacement and guidelines on how to reduce it are lacking. Accordingly, we compared enzymes’ life spans across kingdoms using a new yardstick (catalytic cycles until replacement [CCR]) and related CCR to enzyme reaction chemistry. We concluded that 1) many enzymes fail due to collateral damage from the reaction they catalyze, and 2) such damage and its attendant enzyme replacement costs are mitigable by engineering and are therefore promising targets for synthetic biology. Metabolic engineering uses enzymes as parts to build biosystems for specified tasks. Although a part’s working life and failure modes are key engineering performance indicators, this is not yet so in metabolic engineering because it is not known how long enzymes remain functional in vivo or whether cumulative deterioration (wear-out), sudden random failure, or other causes drive replacement. Consequently, enzymes cannot be engineered to extend life and cut the high energy costs of replacement. Guided by catalyst engineering, we adopted catalytic cycles until replacement (CCR) as a metric for enzyme functional life span in vivo. CCR is the number of catalytic cycles that an enzyme mediates in vivo before failure or replacement, i.e., metabolic flux rate/protein turnover rate. We used estimated fluxes and measured protein turnover rates to calculate CCRs for ∼100–200 enzymes each from Lactococcus lactis, yeast, and Arabidopsis. CCRs in these organisms had similar ranges (<103 to >107) but different median values (3–4 × 104 in L. lactis and yeast versus 4 × 105 in Arabidopsis). In all organisms, enzymes whose substrates, products, or mechanisms can attack reactive amino acid residues had significantly lower median CCR values than other enzymes. Taken with literature on mechanism-based inactivation, the latter finding supports the proposal that 1) random active-site damage by reaction chemistry is an important cause of enzyme failure, and 2) reactive noncatalytic residues in the active-site region are likely contributors to damage susceptibility. Enzyme engineering to raise CCRs and lower replacement costs may thus be both beneficial and feasible.
GRAS-domain transcription factor PAT1 regulates jasmonic acid biosynthesis in grape cold stress response.

Cultivated grapevine (Vitis) is a highly valued horticultural crop, and cold stress affects its growth and productivity. Wild Amur grape (Vitis amurensis) PAT1 (Phytochrome A signal transduction 1, VaPAT1) is induced by low temperature, and ectopic expression of VaPAT1 enhances cold tolerance in Arabidopsis (Arabidopsis thaliana). However, little is known about the molecular mechanism of VaPAT1 during the cold stress response in grapevine. Here, we confirmed overexpression of VaPAT1 in transformed grape calli enhanced cold tolerance. Yeast two-hybrid and bimolecular fluorescence complementation assays highlighted an interaction between VaPAT1 with INDETERMINATE-DOMAIN 3 (VaIDD3). A role of VaIDD3 in cold tolerance was also indicated. Transcriptome analysis revealed VaPAT1 and VaIDD3 overexpression and cold treatment coordinately modulate the expression of stress-related genes including lipoxygenase 3 (LOX3), a gene encoding a key jasmonate biosynthesis enzyme. Co-expression network analysis indicated LOX3 might be a downstream target of VaPAT1. Both electrophoretic mobility shift and dual luciferase reporter assays showed the VaPAT1-IDD3 complex binds to the IDD-box (AGACAAA) in the VaLOX3 promoter to activate its expression. Overexpression of both VaPAT1 and VaIDD3 increased the transcription of VaLOX3 and JA levels in transgenic grape calli. Conversely, VaPAT1-SRDX (dominant repression) and CRISPR/Cas9-mediated mutagenesis of PAT1-ED causing the loss of the C-terminus in grape calli dramatically prohibited the accumulation of VaLOX3 and JA levels during cold treatment. Together, these findings point to a pivotal role of VaPAT1 in the cold stress response in grape by regulating JA biosynthesis.
Evaluation of seroprevalence and clinical and laboratory findings of patients admitted to health institutions in Gümüşhane with suspicion of Crimean-Congo hemorrhagic fever

Background/aim To determine the seroprevalence and evaluate clinical findings and laboratory results of patients prediagnosed with Crimean-Congo hemorrhagic fever (CCHF) in Gümüşhane. Materials and methods Included in the cross-sectional study were 362 patients (162 female, 200 male) between 0 and 94 years of age, who were followed up after receiving a preliminary diagnosis of CCHF between January 2011 and December 2019. Anamnesis, age, sex, clinical findings, laboratory results, epidemiological and clinical evaluations, severity criteria, risk factor reviews, and a comparison of the suspected negative cases with positive cases were analyzed retrospectively. Patients included in the study were evaluated as RNA-positive by polymerase chain reaction (PCR) or IgM-positive by ELISA. Results Of the 362 patients admitted to health institutions with a preliminary diagnosis of CCHF, 242 were diagnosed as CCHF-positive (66.9%). Moreover, 196 of those CCHF-positive patients (81%) were admitted to health institutions during the summer months. Statistical analyses revealed a significant relationship between the incidence of CCHF and patients who had been in contact with animals, lived in rural areas, and had engaged in farming and animal husbandry. In addition, fever, headache, diffuse bodily pain, nausea and vomiting, diarrhea, fever of 38 °C or higher, tachycardia, elevated ALT/AST, creatine kinase (CK), and lactate dehydrogenase (LDH) levels, leukopenia, and thrombocytopenia were detected in the CCHF-positive patients. Significant relations were found between this disease and these symptoms. However, there was no significant relationship between the statistical evaluation of the disease and bloody diarrhea, bodily bruises, rash, unconsciousness, gingival bleeding, hypotension, epistaxis, petechiae, splenomegaly, ecchymosis, hematuria, maculopapular rash, gastrointestinal system complaints, anemia, or elevation of the international normalized ratio and activated partial thromboplastin time duration, separately. Conclusion Of the 362 patients, 66.9% (242) of those who received a preliminary diagnosis of CCHF were indeed CCHF-positive in Gümüşhane. It was concluded that CCHF remains an important endemic disease in Gümüşhane. In addition, elevated ALT/AST, CK, and LDH levels, leukopenia, and thrombocytopenia in patients presenting with headache, fever, fever of 38 °C or higher, generalized body pain, nausea/vomiting, diarrhea, and tachycardia will play a pivotal role in the preliminary diagnosis of CCHF.