Miracle-dz/UniFAR-FTUs huggingface dataset:
EP2/4 Receptors Promote the Synthesis of PGE2 Increasing Tissue Damage in Bovine Endometrial Explants Induced by Escherichia coli

The bovine uterine is easily contaminated with bacteria during coitus or parturition. A previous study suggested that prostaglandin E2 (PGE2) promoted Escherichia coli–infected bovine endometrial tissue inflammatory damage via cyclooxygenase-2 (COX-2) and microsomal prostaglandin E synthase-1 (mPGES-1). However, it remains unclear which PGE2 receptors regulate the proinflammatory effect of PGE2. In this study, we evaluated the effect of PGE2 and its mediated receptors on E. coli–infected endometrium explants isolated from the bovine uterus. The E. coli–infected bovine endometrial explants were cultured in vitro, and the study used EP2/4 receptor agonists to investigate the responses of COX-2, mPGES-1, PGE2, proinflammatory factors, and damage-associated molecular patterns (DAMPs). The expression of COX-2, mPGES-1, PGE2, proinflammatory factors, and DAMPs was significantly increased after infection with E. coli; however, the high expression levels caused by E. coli were reduced following treatment with COX-2 and mPGES-1 inhibitors. In addition, the expression levels of COX-2, mPGES-1, PGE2, proinflammatory factors, and DAMPs were higher in treatment with EP2/4 receptor agonists in E. coli–infected endometrium explants, and their promotable effects were effectively blocked by EP2/4 receptor antagonists. These findings provide evidence that PGE2 may promote the progress of inflammation in endometrial explants infected with E. coli in bovines. Furthermore, EP2/4 may be involved in a positive feedback loop for COX-2 and mPGES-1 expression, and this may be responsible for the proinflammatory reaction of PGE2 in E. coli–infected uteri of bovines. SIGNIFICANCE STATEMENT PGE2 promoted E. coli–infected bovine endometrial tissue damage via COX-2 and mPGES-1. However, this proinflammatory effect of PGE2 depends on which receptors are affected by PGE2, and this remains unclear. In this study, it was investigated that EP2 and EP4 may be involved in a positive feedback loop for COX-2 and mPGES-1 expression, and this may be responsible for the proinflammatory reaction of PGE2 in E. coli–infected uteri of bovines.
Persistent atrial fibrillation in heart failure with preserved ejection fraction: Prognostic relevance and association with clinical, imaging and invasive haemodynamic parameters

Atrial fibrillation (AF) is a frequent finding in HFpEF. However, its association with invasive haemodynamics, imaging parameters and outcome in HFpEF is not well established. Furthermore, the relevance of AF subtype with regard to outcome is unclear. This study sought to investigate the prognostic impact of paroxysmal and persistent AF in a well‐defined heart failure with preserved ejection fraction (HFpEF) population.
Carbonate production of Micronesian reefs suppressed by thermal anomalies and Acanthaster as sea-level rises

Coral reefs are essential to millions of island inhabitants. Yet, coral reefs are threatened by thermal anomalies associated with climate change and by local disturbances that include land-use change, pollution, and the coral-eating sea star Acanthaster solaris. In combination, these disturbances cause coral mortality that reduce the capacity of reefs to produce enough carbonate to keep up with sea-level rise. This study compared the reef-building capacity of shallow-water inner, patch, and outer reefs in the two islands of Pohnpei and Kosrae, Federated States of Micronesia. We identified which reefs were likely to keep up with sea-level rise under different climate-change scenarios, and estimated whether there were differences across habitats in the threshold of percentage coral cover at which net carbonate production becomes negative. We also quantified the influence of A. solaris on carbonate production. Whereas the northwestern outer reefs of Pohnpei and Kosrae had the highest net rates of carbonate production (18.5 and 16.4 kg CaCO3 m-2 yr-1, respectively), the southeastern outer reefs had the lowest rates of carbonate production (1.2–1.3 and 0.7 kg CaCO3 m-2 yr-1, respectively). The patch reefs of Pohnpei had on average higher net carbonate production rates (9.5 kg CaCO3 m-2 yr-1) than the inner reefs of both Pohnpei and Kosrae (7.0 and 7.8 kg CaCO3 m-2 yr-1, respectively). A. solaris were common on Kosrae and caused an average reduction in carbonate production of 0.6 kg CaCO3 m-2 yr-1 on Kosraean reefs. Northern outer reefs are the most likely habitats to keep up with sea-level rise in both Pohnpei and Kosrae. Overall, the inner reefs of Pohnpei and Kosrae need ~ 5.5% more coral cover to generate the same amount of carbonate as outer reefs. Therefore, inner reefs need special protection from land-use change and local pollution to keep pace with sea-level rise under all climate-change scenarios.
A novel patient-derived orthotopic xenograft model of esophageal adenocarcinoma provides a platform for translational discoveries

ABSTRACT Mouse models of gastroesophageal junction (GEJ) cancer strive to recapitulate the intratumoral heterogeneity and cellular crosstalk within patient tumors to improve clinical translation. GEJ cancers remain a therapeutic challenge due to the lack of a reliable mouse model for preclinical drug testing. In this study, a novel patient-derived orthotopic xenograft (PDOX) was established from GEJ cancer via transabdominal surgical implantation. Patient tumor was compared to subcutaneously implanted patient-derived tumor xenograft (PDX) and PDOX by Hematoxylin and Eosin staining, immunohistochemistry and next-generation sequencing. Treatment efficacy studies of radiotherapy were performed. We observed that mechanical abrasion of mouse GEJ prior to surgical implantation of a patient-derived tumor in situ promotes tumor engraftment (100%, n=6). Complete PDOX engraftment was observed with rapid intra- and extraluminal tumor growth, as evidenced by magnetic resonance imaging. PDOXs contain fibroblasts, tumor-associated macrophages, immune and inflammatory cells, vascular and lymphatic vessels. Stromal hallmarks of aggressive GEJ cancers are recapitulated in a GEJ PDOX mouse model. PDOXs demonstrate tumor invasion into vasculature and perineural space. Next-generation sequencing revealed loss of heterozygosity with very high allelic frequency in NOTCH3, TGFB1, EZH2 and KMT2C in the patient tumor, the subcutaneous PDX and the PDOX. Immunohistochemical analysis of Her2/neu (also known as ERBB2), p53 (also known as TP53) and p16 (also known as CDKN2A) in PDX and PDOX revealed maintenance of expression of proteins found in patient tumors, but membranous EGFR overexpression in patient tumor cells was absent in both xenografts. Targeted radiotherapy in this model suggested a decrease in size by 61% according to Response Evaluation Criteria in Solid Tumors (RECIST), indicating a partial response to radiation therapy. Our GEJ PDOX model exhibits remarkable fidelity to human disease and captures the precise tissue microenvironment present within the local GEJ architecture, providing a novel tool for translating findings from studies on human GEJ cancer. This model can be applied to study metastatic progression and to develop novel therapeutic approaches for the treatment of GEJ cancer. This article has an associated First Person interview with the first author of the paper. Editor's choice: The patient-derived orthotopic xenograft model of gastroesophageal adenocarcinoma maintains the morphological and molecular characteristics despite being highly heterogeneous, emphasizing its use as a powerful investigational platform to evaluate new therapies.
Pulmonary Hypertension Subtypes and Mortality in CKD.

RATIONALE & OBJECTIVE Pulmonary hypertension (PH) contributes to cardiovascular disease and mortality in patients with chronic kidney disease (CKD), but the pathophysiology is mostly unknown. This study sought to estimate the prevalence and consequences of PH subtypes in the setting of CKD. STUDY DESIGN Observational retrospective cohort study. SETTING & PARTICIPANTS We examined 12,618 patients with a right heart catheterization in the Duke Databank for Cardiovascular Disease from January 1, 2000, to December 31, 2014. EXPOSURES Baseline kidney function stratified by CKD glomerular filtration rate category and PH subtype. OUTCOMES All-cause mortality. ANALYTICAL APPROACH Multivariable Cox proportional hazards analysis. RESULTS In this cohort, 73.4% of patients with CKD had PH, compared with 56.9% of patients without CKD. Isolated postcapillary PH (39.0%) and combined pre- and postcapillary PH (38.3%) were the most common PH subtypes in CKD. Conversely, precapillary PH was the most common subtype in the non-CKD cohort (35.9%). The relationships between mean pulmonary artery pressure, pulmonary capillary wedge pressure, and right atrial pressure with mortality were similar in both the CKD and non-CKD cohorts. Compared with those without PH, precapillary PH conferred the highest mortality risk among patients without CKD (HR, 2.27; 95% CI, 2.00-2.57). By contrast, in those with CKD, combined pre- and postcapillary PH was associated with the highest risk for mortality in CKD in adjusted analyses (compared with no PH, HRs of 1.89 [95% CI, 1.57-2.28], 1.87 [95% CI, 1.52-2.31], 2.13 [95% CI, 1.52-2.97], and 1.63 [95% CI, 1.12-2.36] for glomerular filtration rate categories G3a, G3b, G4, and G5/G5D). LIMITATIONS The cohort referred for right heart catheterization may not be generalizable to the general population. Serum creatinine data in the 6 months preceding catheterization may not reflect true baseline CKD. Observational design precludes assumptions of causality. CONCLUSIONS In patients with CKD referred for right heart catheterization, PH is common and associated with poor survival. Combined pre- and postcapillary PH was common and portended the worst survival for patients with CKD.
Task Offloading Based on Lyapunov Optimization for MEC-Assisted Vehicular Platooning Networks

Due to limited computation resources of a vehicle terminal, it is impossible to meet the demands of some applications and services, especially for computation-intensive types, which not only results in computation burden and delay, but also consumes more energy. Mobile edge computing (MEC) is an emerging architecture in which computation and storage services are extended to the edge of a network, which is an advanced technology to support multiple applications and services that requires ultra-low latency. In this paper, a task offloading approach for an MEC-assisted vehicle platooning is proposed, where the Lyapunov optimization algorithm is employed to solve the optimization problem under the condition of stability of task queues. The proposed approach dynamically adjusts the offloading decisions for all tasks according to data parameters of current task, and judge whether it is executed locally, in other platooning member or at an MEC server. The simulation results show that the proposed algorithm can effectively reduce energy consumption of task execution and greatly improve the offloading efficiency compared with the shortest queue waiting time algorithm and the full offloading to an MEC algorithm.
Tacrolimus-Induced BMP/SMAD Signaling Associates With Metabolic Stress–Activated FOXO1 to Trigger β-Cell Failure

Active maintenance of β-cell identity through fine-tuned regulation of key transcription factors ensures β-cell function. Tacrolimus, a widely used immunosuppressant, accelerates onset of diabetes after organ transplantation, but underlying molecular mechanisms are unclear. Here we show that tacrolimus induces loss of human β-cell maturity and β-cell failure through activation of the BMP/SMAD signaling pathway when administered under mild metabolic stress conditions. Tacrolimus-induced phosphorylated SMAD1/5 acts in synergy with metabolic stress–activated FOXO1 through formation of a complex. This interaction is associated with reduced expression of the key β-cell transcription factor MAFA and abolished insulin secretion, both in vitro in primary human islets and in vivo in human islets transplanted into high-fat diet–fed mice. Pharmacological inhibition of BMP signaling protects human β-cells from tacrolimus-induced β-cell dysfunction in vitro. Furthermore, we confirm that BMP/SMAD signaling is activated in protocol pancreas allograft biopsies from recipients on tacrolimus. To conclude, we propose a novel mechanism underlying the diabetogenicity of tacrolimus in primary human β-cells. This insight could lead to new treatment strategies for new-onset diabetes and may have implications for other forms of diabetes.
Plasma Metabolic Profiling Analysis of Gout Party on Acute Gout Arthritis Rats Based on UHPLC–Q–TOF/MS Combined with Multivariate Statistical Analysis

Gout Party is a Chinese medicine prescription composed of Aconiti Lateralis Radix Praeparaia, Aconiti Radix Cocta, Cremastrae Pseudobulbus Pleiones Pseudobulbus, Smilacis Glabrae Rhizoma, Rehmanniae Radix, and Glycyrrhizae Radix et Rhizoma, which can relieve joint pain caused by gouty arthritis (GA) and rheumatoid, and has a therapeutic effect on acute gouty arthritis (AGA). However, little information is available on the molecular biological basis and therapeutic mechanism of Gout Party for the treatment of AGA. AGA model was established by injecting sodium urate, and colchicine served as a positive control drug. We established a metabolomic method based on ultra-high-performance liquid chromatography–tandem quadrupole/time-of-flight mass spectrometry (UHPLC–Q–TOF/MS) to analyze the plasma samples of model group rats and blank group rats. Multiple statistical analyses, including principal component analysis (PCA) and partial least square discrimination analysis (PLS-DA), were used to examine metabolite profile changes in plasma samples. Finally, we identified 2–ketobutyric acid, 3–hexenedioic acid, but–2–enoic acid, and so on; 22 endogenous metabolites associated with AGA. After successful molding, we found that 2–ketobutyric acid, 3–hexenedioic acid, but–2–enoic acid, argininic acid, galactonic acid, lactic acid, equol 4′–O–glucuronide, deoxycholic acid glycine conjugate, glycocholic acid, sphinganine 1–phosphate, LPE (0:0/20:3), LPE (0:0/16:0), LPC (15:0) decreased significantly (p < 0.05 or p < 0.01), alanine, erythrulose, 3–dehydrocarnitine, m–methylhippuric acid, 3–hydroxyoctanoic acid, p–cresol sulfate, estriol 3–sulfate 16–glucuronide, 10–hydroxy–9–(phosphonooxy)octadecenoate, docosahexaenoic acid increased significantly (p < 0.05 or p < 0.01). After Gout Party treatment, 14 biomarkers had a tendency to normal conditions. These above biomarkers were mainly involved in fatty acid metabolism, bile acid metabolism, amino acid metabolism, and energy metabolism pathways. These results suggested that Gout Party exerted therapeutic effects of treating AGA by improving energy metabolism disorder and amino acid metabolism dysfunction, and attenuating fatty acid metabolism abnormal and inflammation. The results of this experiment provided a reference for revealing the metabolic mechanism produced by Gout Party in the treatment of AGA, but the subsequent studies need to be further improved and supported by relevant cell experiments and clinical experiments.
THE IMPORTANCE OF ASSESING PSYCHOSOCIAL FUNCTIONS OF ASTHMATIC PATIENTS AND THEIR FAMILIES AS A COMPREHENSIVE ASTHMA CONTROL ASSESSMENT: A CASE CONTROL STUDY IN IRAN

The present study was conducted to compare the physical and psychosocial functions of asthmatic patients presenting at different levels of asthma control to that of healthy children in Iran. The aim was to determine if a correlation could be made between the two thus suggesting that the level of asthma control can be used as an indirect indicator for the level of psychosocial impact. A case-control study involving 160 asthmatic children aged between 8 to 12 years-old, in comparison to an age-sex matched healthy control group was thus conducted. The result demonstrates that asthmatic children are more likely to have emotional dysfunction associated with their disease. This in turn resulted in significantly negative effects on the parents’ daily working activities. The PedsQL scale which categorizes asthmatic children into three levels of asthma (controlled, partly-controlled and uncontrolled asthma) demonstrated significant differences in their Physical Function scale scores (p<0.05). However, no significant correlation between asthma control to Emotional, Social and School Functioning levels were found. In conclusion, the present study suggests that asthma not only impairs the Physical and Emotional functions of asthmatic children, but also affects their parents’ daily working activity. Tightening asthma control did not appear to improve the social functioning levels of these children although it does result in improved physical function. Therefore the level of asthma cannot be used as an indicator of heightened psychosocial impact. However, the authors of this paper would warrant that treating physicians should consider incorporating the psychosocial aspect of asthmatic children and their families in their treatment plan rather than aiming for only asthma control since this appears to be an important aspect of patient care.
The Newly Normed SKT Reveals Differences in Neuropsychological Profiles of Patients with MCI, Mild Dementia and Depression

The SKT (Syndrom-Kurztest) is a short cognitive performance test assessing deficits of memory and attention in the sense of speed of information processing. The new standardization of the SKT (2015) aimed at improving its sensitivity for early cognitive decline due to dementia in subjects aged 60 or older. The goal of this article is to demonstrate how the neuropsychological test profile of the SKT can be used to provide valuable information for a differential diagnosis between MCI (mild cognitive impairment), dementia and depression. n = 549 patients attending a memory clinic (Nuremberg, Germany) were diagnosed according to ICD-10 and tested with the SKT. The SKT consists of nine subtests, three for the assessment of memory and six for measuring attention in the sense of speed of information processing. The result of the SKT test procedure is a total score, which indicates the severity of overall cognitive impairment. Besides the summary score, two subscores for memory and attention can be interpreted. Using the level of depression as a covariate, statistical comparisons of SKT test profiles between the three patient groups revealed that depressed patients showed more pronounced deficits than MCI patients in all six attention subtests. On the other hand, MCI patients displayed significantly greater mnestic impairment than the depressed group, which was indicated by significant differences in the memory subscore. MCI and dementia patients showed similar deficit patterns dominated by impairment of memory (delayed recall) with MCI patients demonstrating less overall impairment. In sum, the SKT neuropsychological test profiles provided indicators for a differential diagnosis between MCI and beginning dementia vs. depression.
A robust multi-objective optimization framework to capture both cellular and intercellular properties in cardiac cellular model tuning: Analyzing different regions of membrane resistance profile in parameter fitting

Mathematical models of cardiac cells have been established to broaden understanding of cardiac function. In the process of developing electrophysiological models for cardiac myocytes, precise parameter tuning is a crucial step. The membrane resistance (Rm) is an essential feature obtained from cardiac myocytes. This feature reflects intercellular coupling and affects important phenomena, such as conduction velocity, and early after-depolarizations, but it is often overlooked during the phase of parameter fitting. Thus, the traditional parameter fitting that only includes action potential (AP) waveform may yield incorrect values for Rm. In this paper, a novel multi-objective parameter fitting formulation is proposed and tested that includes different regions of the Rm profile as additional objective functions for optimization. As Rm depends on the transmembrane voltage (Vm) and exhibits singularities for some specific values of Vm, analyses are conducted to carefully select the regions of interest for the proper characterization of Rm. Non-dominated sorting genetic algorithm II is utilized to solve the proposed multi-objective optimization problem. To verify the efficacy of the proposed problem formulation, case studies and comparisons are carried out using multiple models of human cardiac ventricular cells. Results demonstrate Rm is correctly reproduced by the tuned cell models after considering the curve of Rm obtained from the late phase of repolarization and Rm value calculated in the rest phase as additional objectives. However, relative deterioration of the AP fit is observed, demonstrating trade-off among the objectives. This framework can be useful for a wide range of applications, including the parameters fitting phase of the cardiac cell model development and investigation of normal and pathological scenarios in which reproducing both cellular and intercellular properties are of great importance.
Topping-off technique for stabilization of lumbar degenerative instabilities in 322 patients.

OBJECTIVE Semi-rigid instrumentation (SRI) was introduced to take advantage of the concept of load sharing in surgery for spinal stabilization. The authors investigated a topping-off technique in which interbody fusion is not performed in the uppermost motion segment, thus creating a smooth transition from stabilized to free motion segments. SRI using the topping-off technique also reduces the motion of the adjacent segments, which may reduce the risk of adjacent segment disease (ASD), a frequently observed sequela of instrumentation and fusion, but this technique may also increase the possibility of screw loosening (SL). In the present study the authors aimed to systematically evaluate reoperation rates, clinical outcomes, and potential risk factors and incidences of ASD and SL for this novel approach. METHODS The authors collected data for the first 322 patients enrolled at their institution from 2009 to 2015 who underwent surgery performed using the topping-off technique. Reoperation rates, patient satisfaction, and other outcome measures were evaluated. All patients underwent pedicle screw-based semi-rigid stabilization of the lumbar spine with a polyetheretherketone (PEEK) rod system. RESULTS Implantation of PEEK rods during revision surgery was performed in 59.9% of patients. A median of 3 motion segments (range 1-5 segments) were included and a median of 2 motion segments (range 0-4 segments) were fused. A total of 89.4% of patients underwent fusion, 73.3% by transforaminal lumbar interbody fusion (TLIF), 18.4% by anterior lumbar interbody fusion (ALIF), 3.1% by extreme lateral interbody fusion (XLIF), 0.3% by oblique lumbar interbody fusion (OLIF), and 4.9% by combined approaches in the same surgery. Combined radicular and lumbar pain according to a visual analog scale was reduced from 7.9 ± 1.0 to 4.0 ± 3.1, with 56.2% of patients indicating benefit from surgery. After maximum follow-up (4.3 ± 1.8 years), the reoperation rate was 16.4%. CONCLUSIONS The PEEK rod concept including the topping-off principle seems safe, with at least average patient satisfaction in this patient group. Considering the low rate of first-tier surgeries, the presented results seem at least comparable to those of most other series. Follow-up studies are needed to determine long-term outcomes, particularly with respect to ASD, which might be reduced by the presented approach.