Miracle-dz/UniFAR-FTUs huggingface dataset:
Efficacy and Effectiveness Too Trials: Clinical Trial Designs to Generate Evidence on Efficacy and on Effectiveness in Wide Practice

Efficacy trials, designed to gain regulatory marketing approval, evaluate drugs in optimally selected patients under advantageous conditions for relatively short time periods. Effectiveness trials, designed to evaluate use in usual practice, assess treatments among more typical patients in real‐world conditions with longer follow‐up periods. In “efficacy‐to‐effectiveness (E2E) trials,” if the initial efficacy trial component is positive, the trial seamlessly transitions to an effectiveness trial component to efficiently yield both types of evidence. Yet more time could be saved by simultaneously addressing efficacy and effectiveness in an “efficacy and effectiveness too (EE2) trial. ” Additionally, hybrids of the E2E and EE2 approaches with differing degrees of overlap of the two components could allow flexibility for specific drug development needs. In planning EE2 trials, each stakeholder's current and future needs, incentives, and perspective must be considered. Although challenging, the ultimate benefits to stakeholders, the health system, and the public should justify this effort.
Inflammasome and Caspase-1 Activity Characterization and Evaluation: An Imaging Flow Cytometer–Based Detection and Assessment of Inflammasome Specks and Caspase-1 Activation

Inflammasome dysregulation is a hallmark of various inflammatory diseases. Evaluating inflammasome-associated structures (ASC specks) and caspase-1 activity by microscopy is time consuming and limited by small sample size. The current flow cytometric method, time of flight inflammasome evaluation (TOFIE), cannot visualize ASC specks or caspase-1 activity, making colocalization studies of inflammasome components and enzymatic activity impossible. We describe a rapid, high-throughput, single-cell, fluorescence-based image analysis method utilizing the Amnis ImageStreamX instrument that quantitatively and qualitatively characterizes the frequency, area, and cellular distribution of ASC specks and caspase-1 activity in mouse and human cells. Unlike TOFIE, this method differentiates between singular perinuclear specks and false positives. With our technique we also show that the presence of NLRP3 reduces the size of ASC specks, which is further reduced by the presence of active caspase-1. The capacity of our approach to simultaneously detect and quantify ASC specks and caspase-1 activity, both at the population and single-cell level, renders it the most powerful tool available for visualizing and quantifying the impact of mutations on inflammasome assembly and activity.
Four decades of functional community change reveals gradual trends and low interlinkage across trophic groups in a large marine ecosystem

The rate at which biological diversity is altered on both land and in the sea, makes temporal community development a critical and fundamental part of understanding global change. With advancements in trait‐based approaches, the focus on the impact of temporal change has shifted towards its potential effects on the functioning of the ecosystems. Our mechanistic understanding of and ability to predict community change is still impeded by the lack of knowledge in long‐term functional dynamics that span several trophic levels. To address this, we assessed species richness and multiple dimensions of functional diversity and dynamics of two interacting key organism groups in the marine food web: fish and zoobenthos. We utilized unique time series‐data spanning four decades, from three environmentally distinct coastal areas in the Baltic Sea, and assembled trait information on six traits per organism group covering aspects of feeding, living habit, reproduction and life history. We identified gradual long‐term trends, rather than abrupt changes in functional diversity (trait richness, evenness, dispersion) trait turnover, and overall multi‐trait community composition. The linkage between fish and zoobenthic functional community change, in terms of correlation in long‐term trends, was weak, with timing of changes being area and trophic group specific. Developments of fish and zoobenthos traits, particularly size (increase in small size for both groups) and feeding habits (e.g. increase in generalist feeding for fish and scavenging or predation for zoobenthos), suggest changes in trophic pathways. We summarize our findings by highlighting three key aspects for understanding functional change across trophic groups: (a) decoupling of species from trait richness, (b) decoupling of richness from density and (c) determining of turnover and multi‐trait dynamics. We therefore argue for quantifying change in multiple functional measures to help assessments of biodiversity change move beyond taxonomy and single trophic groups.
Liquid Chromatography Analysis of Common Nutritional Components, in Feed and Food

Food and feed laboratories share several similarities when facing the implementation of liquid-chromatographic analysis. Using the experience acquired over the years, through application chemistry in food and feed research, selected analytes of relevance for both areas were discussed. This review focused on the common obstacles and peculiarities that each analyte offers (during the sample treatment or the chromatographic separation) throughout the implementation of said methods. A brief description of the techniques which we considered to be more pertinent, commonly used to assay such analytes is provided, including approaches using commonly available detectors (especially in starter labs) as well as mass detection. This manuscript consists of three sections: feed analysis (as the start of the food chain); food destined for human consumption determinations (the end of the food chain); and finally, assays shared by either matrices or laboratories. Analytes discussed consist of both those considered undesirable substances, contaminants, additives, and those related to nutritional quality. Our review is comprised of the examination of polyphenols, capsaicinoids, theobromine and caffeine, cholesterol, mycotoxins, antibiotics, amino acids, triphenylmethane dyes, nitrates/nitrites, ethanol soluble carbohydrates/sugars, organic acids, carotenoids, hydro and liposoluble vitamins. All analytes are currently assayed in our laboratories.
[Macrophage migration inhibitory factor (MIF) gene -173 G>C polymorphism and its relationship to coronary artery disease and type 2 diabetes].

OBJECTIVE Recent studies indicate that macrophage migration inhibitory factor (MIF) is a potent proinflammatory cytokine which mediates the inflammatory process during atherosclerosis. The purpose of the study was to investigate an association between MIF gene polymorphism and type 2 diabetes mellitus (T2DM) and coronary artery disease (CAD) in the Turkish population. METHODS A total of 139 unselected Turkish patients with significant CAD (coronary lesion with 50-100% stenosis) and 120 control participants (coronary lesion with <30% stenosis) were genotyped for MIF rs755622 polymorphisms using hybridization probes in a Roche LightCycler 480 Real-Time Polymerase Chain Reaction 480 device. Blood samples were drawn before coronary angiography. Gensini and SYNTAX scores were used to determine the angiographic extent and severity of CAD. RESULTS When the groups were stratified according to T2DM, polymorphism of MIF was not associated with T2DM in CAD patients (p>0.05). In the same subgroups, carriers of the MIF common allele in the control group demonstrated a protection against developing T2DM compared with noncarriers (p<0.05). In addition, MIF C allele carriage was associated with higher glycated hemoglobin (HbA1c) in the T2DM group (p=0.038). CONCLUSION The MIF rs755622 polymorphism was associated with HbA1c. This result suggests that the MIF gene variant may contribute to CAD risk through diabetes in the Turkish population.
La sclérose latérale amyotrophique : une maladie d'origine génétique et environnementale

■ La sclerose laterale amyotrophique (SLA) peut etre consideree cote une affection multifactorielle dans laquelle interviennent a la fois des facteurs environnementaux et genetiques. ■ De nombreuses etudes ont cherche a isoler des facteurs environnementaux, d'habitudes de vie et traumatiques, mais aucun n'a pu etre individuellement confirme. L'interpretation des etudes epidemiologiques cas-controles reste limitee par leur manque de puissance lie a la relative rarete de la pathologie. ■ Les formes monogeniques de SLA sont maintenant mieux caracterisees et les genes responsables sont connus pour certaines d'entre elles. ■ Plusieurs genes de susceptibilite ont ete incrimines dans les formes sporadiques de SLA, mais aucun d'entre eux n'a pu etre entierement valide.
RNA-Binding Motif Protein 24 (RBM24) Is Involved in Pregenomic RNA Packaging by Mediating Interaction between Hepatitis B Virus Polymerase and the Epsilon Element

Hepatitis B virus (HBV) is a ubiquitous human pathogen, and HBV infection is a major global health burden. Chronic HBV infection is associated with the development of liver diseases, including fulminant hepatitis, hepatic fibrosis, cirrhosis, and hepatocellular carcinoma. A currently approved vaccine can prevent HBV infection, and medications are able to reduce viral loads and prevent liver disease progression. However, current treatments rarely achieve a cure for chronic infection. Thus, it is important to gain insight into the mechanisms of HBV replication. In this study, we found that the host factor RBM24 is involved in pregenomic RNA (pgRNA) packaging and regulates HBV replication. These findings highlight a potential target for antiviral therapeutics of HBV infection. ABSTRACT Encapsidation of pregenomic RNA (pgRNA) is a crucial step in hepatitis B virus (HBV) replication. Binding by viral polymerase (Pol) to the epsilon stem-loop (ε) on the 5′-terminal region (TR) of pgRNA is required for pgRNA packaging. However, the detailed mechanism is not well understood. RNA-binding motif protein 24 (RBM24) inhibits core translation by binding to the 5′-TR of pgRNA. Here, we demonstrate that RBM24 is also involved in pgRNA packaging. RBM24 directly binds to the lower bulge of ε via RNA recognition submotifs (RNPs). RBM24 also interacts with Pol in an RNA-independent manner. The alanine-rich domain (ARD) of RBM24 and the reverse transcriptase (RT) domain of Pol are essential for binding between RBM24 and Pol. In addition, overexpression of RBM24 increases Pol-ε interaction, whereas RBM24 knockdown decreases the interaction. RBM24 was able to rescue binding between ε and mutant Pol lacking ε-binding activity, further showing that RBM24 mediates the interaction between Pol and ε by forming a Pol-RBM24-ε complex. Finally, RBM24 significantly promotes the packaging efficiency of pgRNA. In conclusion, RBM24 mediates Pol-ε interaction and formation of a Pol-RBM24-ε complex, which inhibits translation of pgRNA and results in pgRNA packing into capsids/virions for reverse transcription and DNA synthesis. IMPORTANCE Hepatitis B virus (HBV) is a ubiquitous human pathogen, and HBV infection is a major global health burden. Chronic HBV infection is associated with the development of liver diseases, including fulminant hepatitis, hepatic fibrosis, cirrhosis, and hepatocellular carcinoma. A currently approved vaccine can prevent HBV infection, and medications are able to reduce viral loads and prevent liver disease progression. However, current treatments rarely achieve a cure for chronic infection. Thus, it is important to gain insight into the mechanisms of HBV replication. In this study, we found that the host factor RBM24 is involved in pregenomic RNA (pgRNA) packaging and regulates HBV replication. These findings highlight a potential target for antiviral therapeutics of HBV infection.
Marka Sevgisinin Marka Güveni, Olumsuz Bilgiye Karşı Direnç ve Tekrar Satın Alma Niyeti Çerçevesinde İncelenmesi

Bu calismanin amaci, marka guveninin marka sevgisine dogrudan etkisi, marka guveni ve marka sevgisinin olumsuz bilgiye karsi direnc ve tekrar satin alma niyetine dogrudan etkileri ile marka sevgisinin marka guveninin olumsuz bilgiye karsi direnc ve tekrar satin alma niyetine etkisindeki aracilik rollerinin belirlenmesidir. Bu amacla, olusturulan hipotezlerin test edilmesi icin anket yoluyla Ankara da yasayan 400 hane halkindan veri toplanmistir. Arastirmada kullanilan marka sevgisi ve marka guveni olceklerinin veri ile uyumunu test etmek amaciyla kesifsel ve dogrulayici faktor analizleri uygulanmistir. Olusturulan hipotezler dogrusal ve coklu regresyon ile bootstrapping yontemi kullanilarak test edilmistir. Buna gore, marka guveni marka sevgisi, olumsuz bilgiye karsi direnc ve tekrar satin alma niyetini olumlu yonde etkilemektedir. Ayrica, marka sevgisinin olumsuz bilgiye karsi dirence ve tekrar satin alma niyetine olumlu yonde etkisi bulunmaktadir.
Risk Factors Associated With Altered Circulating MicroRNA‐125b and Their Influences on Uremic Vascular Calcification Among Patients With End‐Stage Renal Disease

Background MicroRNA‐125b (miR‐125b) has been shown to regulate vascular calcification (VC), and serum miR‐125b levels are a potential biomarker for estimating the risk of uremic VC status. However, it is unknown whether clinical features, including chronic kidney disease–mineral bone disorder molecules, affect serum miR‐125b levels. Methods and Results Patients receiving chronic dialysis for ≥3 months were recruited from different institutes. Serum miR‐125b and chronic kidney disease–mineral bone disorder effectors, including intact parathyroid hormone, 25‐OH‐D, fibroblast growth factor‐23, osteoprotegerin, and fetuin‐A, were quantified. We used multivariate regression analyses to identify factors associated with low serum miR‐125b levels and an area under receiver operating characteristic curve curve to derive optimal cutoffs for factors exhibiting close associations. Further regression analyses evaluated the influence of miR‐125b on VC risk. Among 223 patients receiving chronic dialysis (mean age, 67.3 years; mean years of dialysis, 5.2), 54 (24.2%) had high serum miR‐125b levels. Osteoprotegerin (P=0.013), fibroblast growth factor‐23 (P=0.006), and fetuin‐A (P=0.036) were linearly associated with serum miR‐125b levels. High osteoprotegerin levels independently correlated with high serum miR‐125 levels. Adding serum miR‐125b levels and serum osteoprotegerin levels (≥400 pg/mL) into models estimating the risk of uremic VC increased the area under receiver operating characteristic curve values (for models without miR‐125b/osteoprotegerin, with miR‐125b, and both: 0.74, 0.79, and 0.81, respectively). Conclusions Serum osteoprotegerin levels ≥400 pg/mL and serum miR‐125b levels synergistically increased the accuracy of estimating VC risk among patients receiving chronic dialysis. Taking miR‐125b and osteoprotegerin levels into consideration when estimating VC risk may be recommended.
H-NS uses an autoinhibitory conformational switch for environment-controlled gene silencing

Abstract As an environment-dependent pleiotropic gene regulator in Gram-negative bacteria, the H-NS protein is crucial for adaptation and toxicity control of human pathogens such as Salmonella, Vibrio cholerae or enterohaemorrhagic Escherichia coli. Changes in temperature affect the capacity of H-NS to form multimers that condense DNA and restrict gene expression. However, the molecular mechanism through which H-NS senses temperature and other physiochemical parameters remains unclear and controversial. Combining structural, biophysical and computational analyses, we show that human body temperature promotes unfolding of the central dimerization domain, breaking up H-NS multimers. This unfolding event enables an autoinhibitory compact H-NS conformation that blocks DNA binding. Our integrative approach provides the molecular basis for H-NS–mediated environment-sensing and may open new avenues for the control of pathogenic multi-drug resistant bacteria.
Heterogeneity of transposon expression and activation of the repressive network in human fetal germ cells

ABSTRACT Epigenetic resetting in germ cells during development de-represses transposable elements (TEs). piRNAs protect fetal germ cells by targeted mRNA destruction and deposition of repressive epigenetic marks. Here, we provide the first evidence for an active piRNA pathway and TE repression in germ cells of human fetal testis. We identify pre-pachytene piRNAs with features of secondary amplification that map most abundantly to the long interspersed element type 1 (L1) family of TEs. L1-ORF1p expression is heterogeneous in fetal germ cells, peaks at mid-gestation and declines concomitantly with increases in piRNAs, nuclear localization of HIWI2 and an increase in H3K9me3. Surprisingly, the same cells with accumulation of L1-ORF1p display highest levels of HIWI2 and H3K9me3. Conversely, the earliest germ cells with high levels of L1-ORF1p express low levels of the chaperone HSP90α. We propose that a subset of germ cells resists L1 expression, whereas L1-expressing germ cells activate the repression pathway that leads to epigenetic silencing of L1 via H3K9me3. Summary: Expression of L1 transposons in germ cells of the human fetal testis is developmentally regulated and heterogeneous, and corresponds with upregulation of PIWI/piRNA repression machinery and accumulation of H3K9me3.
PENINGKATAN KEMAMPUAN MENGENAL ANGKA MELALUI PERMAINAN BOWLING ANAK KELOMPOK A DI PAUD KASIH IBU BANDA ACEH

Penelitian berlatar belakang pada kemampuan anak kelompok A di PAUD Kasih Ibu Kota Banda Aceh yang masih rendah tentang kemampuan mengenal angka, Adapun rumusan masalah pada penelitian ini apakah permainan bowling dapat meningkatkan kemampuan mengenal angka anak kelompok A di PAUD Kasih Ibu Banda Aceh. Metode yang digunakan pada penelitian ini adalah Penelitian Tindakan Kelas. Tehnik pengumpulan data melalui observasi dan analisis data menggunakan deskriptif kuantitatif. Subjek penelitian 10 orang, 7 perempuan dan 3 laki-laki. Hasil penelitian pra siklus menunjukkan “berkembang sangat baik” yaitu 15%, “berkembang sesuai harapan” 42,5%, “mulai berkembang” 32,5%, dan “belum berkembang” 10%. Pada siklus I “berkembang sangat baik” yaitu 55%, “berkembang sesuai harapan” 30%, “mulai berkembang” 7,5%, dan“belum berkembang yaitu 10%”. Dapat disimpulkan bahwa permainan bowling dapat meningkatkan kemampuan mengenal angka pada anak kelompok A di PAUD Kasih Ibu Kota Banda Aceh. Kata Kunci : Permainan Bowling, Kemampuan Mengenal Angka, Usia 4-5 Tahun
Comparison of quality of life of patients on treatment with cisplatin and gemcitabine, carboplatin and gemcitabine, carboplatin and paclitaxel, carboplatin and pemetrexed for non-small cell lung cancer

Non-small cell lung cancer is a fatal disease associated with high morbidity. It is important to evaluate the effects of treatment on patient's quality of life. Quality of life can be assessed by using EORTC QLQ - C30 and EORTC QLQ - LC 13. Eighty-six patients were enrolled in the study. The patients were divided into four arms as follows: Patients in arm 1 received cisplatin 80 mg/m 2 and gemcitabine 1.25 g/m 2 as infusion separately in isotonic normal saline. Arm 2 received carboplatin 300 mg/m 2 and gemcitabine 1.2 mg/m 2 as infusion separately in 5% dextrose injection. Arm 3 received paclitaxel 100 mg/m 2 as infusion in isotonic normal saline and carboplatin 300 mg/m 2 as infusion in 5% dextrose injection. Arm 4 received pemetrexed 500 mg/m 2 as infusion in isotonic normal saline and carboplatin 300 mg/m 2 as infusion in 5% dextrose injection. The quality of life of the enrolled patients is based on EORTC QLQ - C30 and EORTC QLQ - LC 13 questionnaire. Prevalence of non-small cell lung cancer is more in males, 60–70 years of age. Most of the subjects were from rural areas and had only school-level education. The prevalence of non-small cell lung cancer was more with smokers, ex-smokers and patients with multiple social habits. Comorbidities also increase the risk of non-small cell lung cancer. By analyzing EORTC QLQ - C30 and EORTC QLQ - LC 13 questionnaires, it was found that diarrhea was found to be significant between the groups. Global health status and quality of life are distributed equally among each group. Quality of life and global health status are distributed equally among each sub groups.
Epigenetically modulated FOXM1 suppresses dendritic cell maturation in pancreatic cancer and colon cancer

Forkhead box transcription factor M1 (FOXM1) is a proliferation‐associated transcription factor involved in tumorigenesis through transcriptional regulation of its target genes in various cells, including dendritic cells (DCs). Although previous work has shown that FOXM1 enhances DC maturation in response to house dust mite allergens, it is not known whether FOXM1 affects DC maturation in the context of tumor‐specific immunity. In this study, we examined the central role of FOXM1 in regulating bone marrow‐derived dendritic cell (BMDC) maturation phenotypes and function in pancreatic cancer and colon cancer. FOXM1 retarded maturation phenotypes of BMDCs, inhibited promotion of T‐cell proliferation, and decreased interleukin‐12 (IL‐12) p70 in tumor‐bearing mice (TBM). Notably, FOXM1 expression was epigenetically regulated by dimethylation on H3 lysine 79 (H3K79me2), a modification present in both tumor cells and BMDCs. Increased H3K79me2 enrichment was observed at the FOXM1 promoter in both BMDCs from TBM, and in BMDCs from wild‐type mice cultured with tumor‐conditioned medium that mimics the tumor microenvironment (TME). Furthermore, inhibition of the H3K79 methyltransferase DOT1L not only decreased enrichment of H3K79me2, but also downregulated expression of FOXM1 and partially reversed its immunosuppressive effects on BMDCs. Furthermore, we found that FOXM1 upregulated transcription of Wnt family number 5A (Wnt5a) in BMDCs in vitro; we also observed that exogenous Wnt5a expression abrogated BMDC maturation phenotypes by inhibiting FOXM1 and H3K79me2 modification. Therefore, our results reveal that upregulation of FOXM1 by H3K79me2 in pancreatic cancer and colon cancer significantly inhibits maturation phenotypes and function of BMDCs through the Wnt5a signaling pathway, and thus provide novel insights into FOXM1‐based antitumor immunotherapy.
Biosynthetic Gene Content of the ‘Perfume Lichens’ Evernia prunastri and Pseudevernia furfuracea

Lichen-forming fungi produce a vast number of unique natural products with a wide variety of biological activities and human uses. Although lichens have remarkable potential in natural product research and industry, the molecular mechanisms underlying the biosynthesis of lichen metabolites are poorly understood. Here we use genome mining and comparative genomics to assess biosynthetic gene clusters and their putative regulators in the genomes of two lichen-forming fungi, which have substantial commercial value in the perfume industry, Evernia prunastri and Pseudevernia furfuracea. We report a total of 80 biosynthetic gene clusters (polyketide synthases (PKS), non-ribosomal peptide synthetases and terpene synthases) in E. prunastri and 51 in P. furfuracea. We present an in-depth comparison of 11 clusters, which show high homology between the two species. A ketosynthase (KS) phylogeny shows that biosynthetic gene clusters from E. prunastri and P. furfuracea are widespread across the Fungi. The phylogeny includes 15 genomes of lichenized fungi and all fungal PKSs with known functions from the MIBiG database. Phylogenetically closely related KS domains predict not only similar PKS architecture but also similar cluster architecture. Our study highlights the untapped biosynthetic richness of lichen-forming fungi, provides new insights into lichen biosynthetic pathways and facilitates heterologous expression of lichen biosynthetic gene clusters.