Miracle-dz/UniFAR-FTUs huggingface dataset:
Clinical and Technical Outcomes of patients undergoing EUS-Guided Gastroenterostomy using 20 mm vs 15 mm LAMS

Background/Aims: The majority of studies on EUS-guided gastroenterostomy (EUS-GE) for palliation of malignant gastric outlet obstruction (GOO) have utilized a 15mm lumen apposing metal stent (LAMS). More recently, a 20mm LAMS has become available. The aim of this study was to compare rates of technical and clinical success, and adverse events (AEs) in patients undergoing EUS-GE using a 20mm vs 15mm LAMS. Methods: Patients who underwent EUS-GE with 15mm or 20mm LAMS for malignant GOO during the period of 1/2018-10/2020 were included. The primary outcome was clinical success, defined as an increase in the gastric outlet obstruction score (GOOS) by at least 1 point during follow-up. Secondary outcomes were technical success, maximum tolerated diet, rate of reintervention, and the rate/severity of AEs. Results: A total of 267 patients (mean age 67yr, F 43%) with malignant GOO from 19 centers underwent EUS-GE. The rate of clinical success was similar between the 15mm and 20mm stents (89.2% [95% CI 84.2-94.2] vs 84.1% [95%CI 77.4-90.6]). However, a significantly higher proportion of patients in the 20mm group tolerated a soft solid/complete diet at the end of follow-up (91.2% [95%CI 84.4-95.7] vs 81.2% [95%CI 73.9-87.2] p=0.04). Overall, AEs occurred in 33 (12.4% [95%CI 8.4-16.3]) patients, with rates being similar between 15mm and 20mm stents (12.8% [95%CI 7.5-18.2] vs 11.8% [95%CI 6-17.6]), including incidence of severe/fatal AEs (2% [95%CI 0.4-5.8] vs 3.4% [95%CI 0.9-8.4]). Conclusions: The 20mm LAMS is similar to the 15mm LAMS in terms of safety and efficacy for patients undergoing EUS-GE for malignant GOO. The 20 mm LAMS allows a more advanced diet and is, thus, the preferred LAMS during EUS-GE.
A Novel Glutathione S-Transferase Gtt2 Class (VpGSTT2) Is Found in the Genome of the AHPND/EMS Vibrio parahaemolyticus Shrimp Pathogen

Glutathione S-transferases are a family of detoxifying enzymes that catalyze the conjugation of reduced glutathione (GSH) with different xenobiotic compounds using either Ser, Tyr, or Cys as a primary catalytic residue. We identified a novel GST in the genome of the shrimp pathogen V. parahaemolyticus FIM- S1708+, a bacterial strain associated with Acute Hepatopancreatic Necrosis Disease (AHPND)/Early Mortality Syndrome (EMS) in cultured shrimp. This new GST class was named Gtt2. It has an atypical catalytic mechanism in which a water molecule instead of Ser, Tyr, or Cys activates the sulfhydryl group of GSH. The biochemical properties of Gtt2 from Vibrio parahaemolyticus (VpGSTT2) were characterized using kinetic and crystallographic methods. Recombinant VpGSTT2 was enzymatically active using GSH and CDNB as substrates, with a specific activity of 5.7 units/mg. Low affinity for substrates was demonstrated using both Michaelis–Menten kinetics and isothermal titration calorimetry. The crystal structure showed a canonical two-domain structure comprising a glutathione binding G-domain and a hydrophobic ligand H domain. A water molecule was hydrogen-bonded to residues Thr9 and Ser 11, as reported for the yeast Gtt2, suggesting a primary role in the reaction. Molecular docking showed that GSH could bind at the G-site in the vicinity of Ser11. G-site mutationsT9A and S11A were analyzed. S11A retained 30% activity, while T9A/S11A showed no detectable activity. VpGSTT2 was the first bacterial Gtt2 characterized, in which residues Ser11 and Thr9 coordinated a water molecule as part of a catalytic mechanism that was characteristic of yeast GTT2. The GTT2 family has been shown to provide protection against metal toxicity; in some cases, excess heavy metals appear in shrimp ponds presenting AHPND/EMS. Further studies may address whether GTT2 in V. parahaemolyticus pathogenic strains may provide a competitive advantage as a novel detoxification mechanism.
Relative Effects of Dietary Administration of a Competitive Exclusion Culture and a Synbiotic Product, Age and Sampling Site on Intestinal Microbiota Maturation in Broiler Chickens

In this research, the effects of early post-hatch inoculation of a competitive exclusion product (Br) and the continuous feeding of a synbiotic supplement (Sy) containing probiotic bacteria, yeast, and inulin on the production traits and composition of ileal chymus (IC), ileal mucosa (IM), and caecal chymus (CC) microbiota of broiler chickens were evaluated. The dietary treatments had no significant effects on the pattern of intestinal microbiota or production traits. The digestive tract bacteriota composition was affected mostly by the sampling place and age of birds. The dominant family of IC was Lactobacillaceae, without change with the age. The abundance of the two other major families, Enterococcaceae and Lachnospiraceae decreased with the age of birds. In the IM, Clostridiaceae was the main family in the first three weeks. Its ratio decreased later and Lactobacillaceae became the dominant family. In the CC, Ruminococcaceae and Lachnospiraceae were the main families with decreasing tendency in the age. In IC, Br treatment decreased the abundance of genus Lactobacillus, and both Br and Sy increased the ratio of Enterococcus at day 7. In all gut segments, a negative correlation was found between the IBD antibody titer levels and the ratio of genus Leuconostoc in the first three weeks, and a positive correlation was found in the case of Bifidobacterium, Rombutsia, and Turicibacter between day 21 and 40.
How Positional Constraints Affect Footedness in Football: A Notational Analysis of Five Leagues in Europe

Abstract In elite-level soccer, the ability to take shots with both limbs from different positions in the pitch may be key to success. This research aimed to: 1) analyze footedness of elite-football players in European leagues during shooting by computing frequency of right- and left-foot use and accuracy; and 2) investigate whether an athlete’s distance from the target (goal, penalty, and outside penalty area) and pitch zone (center, left, or right from the goal) can constrain foot selection during shooting. We analyzed 1826 games from the 2017/18 season, divided between: Spanish LaLiga (380 matches); Italian Serie A (380 matches); English Premier League (380 matches); German Bundesliga (306 matches); and French Ligue 1 (380 matches). Results revealed asymmetrical proportions of foot selection, favoring the preferred foot for right- and left-footed athletes. Frequency of preferred foot selection increased as a function of distance from the target (i.e., the farther the athlete, higher the percentage of preferred foot selection). Shots taken from the left side were more often performed with the right foot and vice-versa, for both left- and right-footed athletes. Interestingly, asymmetries were observed only in foot selection, but not in performance, as success rate did not vary between limbs in any position.
MTF1 Is Essential for the Expression of MT1B, MT1F, MT1G, and MT1H Induced by PHMG, but Not CMIT, in the Human Pulmonary Alveolar Epithelial Cells

The inhalation of humidifier disinfectants (HDs) is linked to HD-associated lung injury (HDLI). Polyhexamethylene guanidine (PHMG) is significantly involved in HDLI, but the correlation between chloromethylisothiazolinone (CMIT) and HDLI remains ambiguous. Additionally, the differences in the molecular responses to PHMG and CMIT are poorly understood. In this study, RNA sequencing (RNA-seq) data showed that the expression levels of metallothionein-1 (MT1) isoforms, including MT1B, MT1E, MT1F, MT1G, MT1H, MT1M, and MT1X, were increased in human pulmonary alveolar epithelial cells (HPAEpiCs) that were treated with PHMG but not in those treated with CMIT. Moreover, upregulation of MT1B, MT1F, MT1G, and MT1H was observed only in PHMG-treated HPAEpiCs. The protein expression level of metal regulatory transcription factor 1 (MTF1), which binds to the promoters of MT1 isoforms, was increased in PHMG-treated HPAEpiCs but not in CMIT-treated HPAEpiCs. However, the expression of early growth response 1 (EGR1) and nuclear receptor superfamily 3, group C, member 1 (NR3C1), other transcriptional regulators involved in MT1 isomers, were increased regardless of treatment with PHMG or CMIT. These results suggest that MTF1 is an essential transcription factor for the induction of MT1B, MT1F, MT1G, and MT1H by PHMG but not by CMIT.
Trends in diagnosis, referral, red flag onset, patient profiles and natural outcome of de novo cardiac amyloidosis and their multidisciplinary implications

Abstract Background Cardiac amyloidosis (CA) is often overlooked or misdiagnosed. Effects of growing disease awareness, diagnostic ameliorations and novel treatment options on CA diagnosis and management are scarcely reported. Objective To report trends in diagnosis, referral routes, clinical presentation, early onset diagnostic red flags and outcome in de novo CA subjects. Methods An unselected cohort of 139 de novo CA patients over an 8-year period in a tertiary referral hospital was recruited. Results Transthyretin (ATTR, 82%, n = 114) was the most common CA form; Light-chain (AL, 15%, n = 21) and secondary (AA, 3%, n = 4) are less prevalent. Increased awareness over time led to a marked ATTR diagnostic surge, steep non-invasive diagnostic approach increment and increased nuclear medicine and external cardiologist referrals (all p < 0.001). A total of 41% (n = 57/139) of patients were referred by non-cardiology specialist disciplines. Specific referral to rule out CA (24–36%) and diagnostic time lag from symptom onset (9 ± 12 to 8 ± 14 months), however, did not improve (all p > 0.050). Multiple early red flag events preceded CA diagnose several years in ATTR: Left ventricular hypertrophy (LVH, 60%, 4.9 ± 4.3 y), heart failure (54%, 2.5 ± 3.5 y), atrial fibrillation (47%, 5.9 ± 6.7 y), bilateral carpal tunnel syndrome (43%, 9.5 ± 5.7 y) and spinal stenosis (40%, 7.4 ± 6.5 y). LVH ≥ 12 mm was absent in 11% ATTR (n = 13/114) and 5% AL (n = 1/21) patients. Hypertension was common in both ATTR (n = 70/114, 62%) and AL (n = 10/21, 48%). 56% (n = 78/139) of CA presented with heart failure. Cumulative 1 and 5-year mortality of 10%/66%, 40%/52% and 75%/75% for ATTR, AL, and AA, respectively, remains high. Conclusions Although CA diagnostic uptake and referral improve, specialist-specific disease and diagnostic red flag ignorance result in non-timely diagnosis and unfavourable outcome.
Inference for the treatment effect in longitudinal cluster randomized trials when treatment effect heterogeneity is ignored

In cluster-randomized trials, sometimes the effect of the intervention being studied differs between clusters, commonly referred to as treatment effect heterogeneity. In the analysis of stepped wedge and cluster-randomized crossover trials, it is possible to include terms in outcome regression models to allow for such treatment effect heterogeneity yet this is not frequently considered. Outside of some simulation studies of specific cases where the outcome is binary, the impact of failing to include terms for treatment effect heterogeneity on the variance of the treatment effect estimator is unknown. We analytically examine the impact of failing to include terms for treatment effect heterogeneity on the variance of the treatment effect estimator, when outcomes are continuous. Using analysis of variance and feasible generalized least squares we provide expressions for this variance. For both the cluster-randomized crossover design and the stepped wedge design, our analytic derivations indicate that failing to include treatment effect heterogeneity results in the estimates for variance of the treatment effect that are too small, leading to inflation of type I error rates. We therefore recommend assessing the sensitivity of sample size calculations and conclusions drawn from the analysis of cluster randomized trials to the inclusion of treatment effect heterogeneity.
Critical Conditions for Studying Interleukin‐11 Signaling In Vitro and Avoiding Experimental Artefacts

Interleukin (IL) 11 is a member of the IL6 family of cytokines which require the ubiquitous gp130 receptor to activate canonical (JAK/STAT) and non‐canonical (e.g., ERK) signaling pathways. The IL11 cytokine is upregulated in a number of fibro‐inflammatory diseases and cancer, where it binds the cognate IL11 receptor alpha subunit (IL11RA) to form a hexameric IL11:IL11RA:gp130 signaling complex. The specific IL11RA receptor is highly expressed on cells of the stromal and parenchymal niche but expressed at low levels on immune cells, highly passaged cells, or transformed cell lines. Consequently, primary cells such as hepatic stellate cells, fibroblasts, and hepatocytes are ideal experimental systems to study IL11 signaling in vitro. In contrast to immortalized cell lines, primary cells better display relevant cellular physiology and pathobiology. This collection of protocols details experimental and culturing conditions for primary cells that preserve meaningful cellular states and physiological responses ex vivo in conventional 2D cell culture systems. Readouts of cellular activity are chosen carefully to capture the non‐canonical, post‐transcriptional activity of IL11 signaling. Our data suggest that cell type, cell culture conditions, passage number, concentrations of stimuli, timing, and other factors have major implications for studies of IL11 signaling. In vitro experiments with primary cell material need to be planned and executed with great caution. Otherwise, physiologically relevant mechanisms may become dysfunctional and reproducible experimental artefacts can obscure our view of true cytokine biology. © 2021 The Authors. Current Protocols published by Wiley Periodicals LLC.
Bee Venom Acupuncture Effects on Pain and Its Mechanisms: An Updated Review

Bee venom (BV) is a complex natural toxin that contains various pharmaceutical compounds. Bee venom acupuncture (BVA), involving a BV injection into a certain acupuncture point, has been utilized to relieve a range of pain conditions. Regardless of whether pain is caused by disease or injury, if not effectively treated, pain can exert a detrimental effect on all aspects of life. In the past decade, many researchers have investigated the anti-nociceptive effects of BVA through clinical use and experimental evaluation. This report reviews the existing knowledge on the analgesic effects of BVA, focusing on musculoskeletal pain, inflammatory pain and neuropathic pain, and its analgesic mechanisms. Although further clinical trials are needed to clinical application of experimental results, this review will contribute to the standardization and generalization of BVA.
Insulin-Like Peptide and FoxO Mediate the Trehalose Catabolism Enhancement during the Diapause Termination Period in the Chinese Oak Silkworm (Antheraea pernyi)

Simple Summary In insects, the insulin/insulin-like growth factor signalling (IIS) pathway regulates the carbohydrate and lipid metabolisms, and plays important roles in diapause regulation. Trehalose accumulates in many diapausing insects, as it is a major carbohydrate reserve and a stress protectant. Because of metabolism depression, the trehalose concentration is maintained at relatively high levels over the diapause phase. In the present study, bovine insulin injection triggered diapause termination and synchronous eclosion in Antheraea pernyi pupae. Moreover, treatment with bovine insulin elevated the trehalose catabolism in diapausing pupae. As a homologue of vertebrate insulin, insulin-like peptide (ApILP) enhances the trehalose catabolism during the diapause termination process. The transcription factor forkhead box O (ApFoxO)—the downstream target of the IIS pathway—exhibited a contrasting effect on the trehalose catabolism to that of ApILP. These results suggest that ApILP and ApFoxO are involved in the regulation of trehalose catabolism during diapause termination in A. pernyi pupae. Abstract In insects, trehalose accumulation is associated with the insulin/insulin-like growth factor signalling (IIS) pathway. However, whether insulin-like peptide is involved in the regulation of the trehalose metabolism during diapause termination remains largely unknown. This study assessed whether insulin-like peptide (ApILP) enhances the trehalose catabolism in the pupae of Antheraea pernyi during their diapause termination process. Injection of 10 μg of bovine insulin triggered diapause termination and synchronous adult eclosion in diapausing pupae. Moreover, treatment with bovine insulin increased the expression of trehalase 1A (ApTre-1A) and trehalase 2 (ApTre-2), as well as the activity of soluble and membrane-bound trehalase, resulting in a decline in trehalose levels in the haemolymph. Silencing ApILP via RNA interference significantly suppressed the expression of ApTre-1A and ApTre-2, thus leading to an increase in the trehalose concentration during diapause termination. However, neither injection with bovine insulin nor ApILP knockdown directly affected trehalase 1B (ApTre-1B) expression. Moreover, overexpression of the transcription factor forkhead box O (ApFoxO) induced an increase in trehalose levels during diapause termination; however, depletion of ApFoxO accelerated the breakdown of trehalose in diapausing pupae by increasing the expression of ApTre-1A and ApTre-2. The results of this study help to understand the contributions of ApILP and ApFoxO to the trehalose metabolism during diapause termination.
Profoundly lower muscle mass and rate of contractile protein synthesis in boys with Duchenne muscular dystrophy

Boys with Duchenne muscular dystrophy (DMD) experience a progressive loss of functional muscle mass, with fibrosis and lipid accumulation. Accurate evaluation of whole‐body functional muscle mass (MM) in DMD patients has not previously been possible and the rate of synthesis of muscle proteins remains unexplored. We used non‐invasive, stable isotope‐based methods from plasma and urine to measure the fractional rate of muscle protein synthesis (FSR) functional muscle mass (MM), and fat free mass (FFM) in 10 DMD (6–17 years) and 9 age‐matched healthy subjects. An oral dose of D3creatine in 70% 2H2O was administered to determine MM and FFM followed by daily 70% 2H2O to measure protein FSR. Functional MM was profoundly reduced in DMD subjects compared to controls (17% vs. 41% of body weight, P < 0.0001), particularly in older, non‐ambulant patients in whom functional MM was extraordinarily low (<13% body weight). We explored the urine proteome to measure FSR of skeletal muscle‐derived proteins. Titin, myosin light chain and gelsolin FSRs were substantially lower in DMD subjects compared to controls (27%, 11% and 40% of control, respectively, P < 0.0001) and were strongly correlated. There were no differences in muscle‐derived sarcoplasmic proteins FSRs (creatine kinase M‐type and carbonic anhydrase‐3) measured in plasma. These data demonstrate that both functional MM, body composition and muscle protein synthesis rates can be quantified non‐invasively and are markedly different between DMD and control subjects and suggest that the rate of contractile but not sarcoplasmic protein synthesis is affected by a lack of dystrophin.
TP53 loss initiates chromosomal instability in fallopian tube epithelial cells

ABSTRACT High-grade serous ovarian cancer (HGSOC) originates in the fallopian tube epithelium and is characterized by ubiquitous TP53 mutation and extensive chromosomal instability (CIN). However, direct causes of CIN, such as mutations in DNA replication and mitosis genes, are rare in HGSOC. We therefore asked whether oncogenic mutations that are common in HGSOC can indirectly drive CIN in non-transformed human fallopian tube epithelial cells. To model homologous recombination deficient HGSOC, we sequentially mutated TP53 and BRCA1 then overexpressed MYC. Loss of p53 function alone was sufficient to drive the emergence of subclonal karyotype alterations. TP53 mutation also led to global gene expression changes, influencing modules involved in cell cycle commitment, DNA replication, G2/M checkpoint control and mitotic spindle function. Both transcriptional deregulation and karyotype diversity were exacerbated by loss of BRCA1 function, with whole-genome doubling events observed in independent p53/BRCA1-deficient lineages. Thus, our observations indicate that loss of the key tumour suppressor TP53 is sufficient to deregulate multiple cell cycle control networks and thereby initiate CIN in pre-malignant fallopian tube epithelial cells. This article has an associated First Person interview with the first author of the paper.
Fusaripyridines A and B; Highly Oxygenated Antimicrobial Alkaloid Dimers Featuring an Unprecedented 1,4-Bis(2-hydroxy-1,2-dihydropyridin-2-yl)butane-2,3-dione Core from the Marine Fungus Fusarium sp. LY019

The fungal strain, Fusarium sp. LY019, was obtained from the Red Sea sponge Suberea mollis. Bioassay-directed partition of the antimicrobial fraction of the extract of the culture of the fungus provided two dimeric alkaloids, fusaripyridines A and B (1 and 2). The compounds possess a previously unreported moiety, 1,4-bis(2-hydroxy-1,2-dihydropyridin-2-yl)butane-2,3-dione. Further, the compounds display a highly oxygenated substitution pattern on the dihydropyridine moieties, representing an additional feature of the fusaripyridines. Fusaripyridines A and B are the first examples of natural products possessing 1,4-bis(2-hydroxy-1,2-dihydropyridin-2-yl)butane-2,3-dione backbone. Careful analyses of the one- and two-dimensional NMR and HRESIMS spectra of the compounds secured their structural mapping, while their absolute stereochemistry was established by analyses of their ECD spectra. The production of such dimeric alkaloids with an unprecedented moiety in the culture of Fusarium sp. LY019 supports further understanding of the biosynthetic competences of the cultured marine-derived fungi. Fusaripyridines A and B selectively inhibited the growth of Candida albicans with MIC values down to 8.0 µM, while they are moderately active against S. aureus, E. coli and HeLa cells.
Phenotype and synthesis activity of joint chondrocytes extracted from newborn rats with prenatal ethanol exposure

Thirteen female Wistar rats were divided into two groups: one treated with ethanol and the other of untreated. Four newborns from each mother were selected and weighed, measured, and evaluated for physical characteristics. From these neonates, chondrocytes were extracted from the articular cartilages of the femur and tibia, and cultivated in a chondrogenic medium at 37oC and 5% CO2. At 7, 14, and 21 days of cultivation, alkaline phosphatase activity tests, MTT conversion to formazan, and percentage area covered by cells per field were performed. At 21 days, the percentage of PAS+ areas in 3D cultures was performed, as well as the evaluation of gene transcript expression for aggrecan, SOX-9, collagen type II, collagen X, Runx-2, and VEGF by real-time RT-PCR. The means were compared by Student’s t-test. The weight of the ethanol group neonates was significantly lower than that of the controls. Chondrocyte cultures from the ethanol group showed significantly higher AP activity, MTT conversion, and cell percentage. There was higher expression of collagen type II and lower expression of SOX-9 in the ethanol group. There was no difference in the percentage of PAS+ areas in pellets and in expression of aggrecan, collagen X, Runx-2, or VEGF between groups. In conclusion, prenatal exposure to ethanol alters the phenotype and activity of offspring chondrocytes, which may be mechanisms by which endochondral bone formation is compromised by maternal ethanol consumption.