Miracle-dz/UniFAR-FTUs huggingface dataset:
MiR-4729 regulates TIE1 mRNA m6A modification and angiogenesis in hemorrhoids by targeting METTL14

Background Hemorrhoids are a frequently-occurring disease of the anorectal system that is often accompanied by vascular hyperplasia and edema. A METTL14-mediated RNA N-6 methyladenosine (m6A) modification can improve mRNA stability and increase its transcriptional and translational activities, closely related to the occurrence of many diseases. Methods Western blot, qPCR, and immunofluorescence staining were used to detect the levels of gene and protein expression. Haematoxylin and eosin staining was used for histopathological examination. RNA immunoprecipitation-PCR and RNA dot blotting were used to detect mRNA m6A modification. Results Obvious signs of angiogenesis (CD31+/vWF+) were identified in the hemorrhoids. High levels of METTL14 expression on vascular endothelial cells (CD31+) suggested that angiogenesis was accompanied by differential modification of m6A RNA. It was subsequently found that the level of miR-4729 expression was significantly decreased in hemorrhoid tissues. The luciferase reporter enzyme assay results suggested that miR-4729 silenced its expression by targeting the 3'UTR of METTL14 mRNA. MiR-4729 overexpression in human umbilical vein endothelial cells (HUVECs) inhibited the proliferation and migration of HUVECs in vitro and vascular structure formation in the outer matrix. MiR-4729 overexpression significantly inhibited endogenous METTL14 expression in HUVECs and reduced the entire m6A RNA modification, especially the level of m6A methylation at the specific site of the 3' UTR of TIE1 mRNA. Moreover, miR-4729 overexpression significantly inhibited the molecular loop of the TIE1/VEGFA signaling pathway in HUVECs. Conclusions Our findings confirmed that the down-regulation of miR-4729 in hemorrhoid vascular endothelial cells was one of the main reasons for vascular proliferation. The overexpression of miR-4729 in vascular endothelial cells decreased the global mRNA methylation and TIE1 mRNA 3'UTR-specific site methylation by silencing METTL14 expression, reducing TIE1 mRNA stability, down-regulating the TIE1/VEGFA signal molecular loop expression, and weakening angiogenesis ability.
Score for predicting overall survival in pancreatic adenocarcinoma patients with positive lymph nodes after surgery: a novel nomogram-based risk assessment.

Background Pancreatic adenocarcinoma (PaC) patients with positive lymph nodes (PLNs) have a dismal prognosis and lack a specific prognostic stage. This study aimed to construct a nomogram for the prediction of overall survival (OS) in these patients. Methods A total of 1,340 patients screened from the Surveillance, Epidemiology, and End Results database were included and randomly divided at a ratio of 7:3 into a training set (n=940) and an internal validation set (n=400). Cox regression analyses were conducted to select independent predictors in the training set, and a nomogram was constructed. The model was verified in the internal validation set and in an external validation set, which comprised 64 patients from a Chinese institute. Results Six independent prognostic factors (age at diagnosis, tumor grade, lymph node ratio, T stage, radiotherapy, and chemotherapy) were identified in PaC patients with PLNs and were entered into the nomogram. The final model had a higher C-index for predicting OS than the American Joint Committee on Cancer-8th edition staging system (training set: 0.658 vs. 0.546; internal validation set: 0.661 vs. 0.546; external validation set: 0.691 vs. 0.581). The 1-, 2-, and 3-year area under the receiver operating characteristic curve values indicated better discrimination power for the established nomogram with respect to the prediction of OS in the training, internal validation, and external validation sets than for the American Joint Committee on Cancer-8th edition staging system. Furthermore, the nomogram performed well in both calibration and decision curve analyses (DCA) of clinical applicability. OS in PaC patients with PLNs was significantly distinguished among the three risk groups stratified according to the nomogram score (P<0.001). Conclusions The well-calibrated nomogram was determined to be extremely efficient in predicting survival, and defining a high-risk population based on the nomogram score among PaC patients with PLNs after surgery.
Progesterone receptor isoform B regulates the Oxtr-Plcl2-Trpc3 pathway to suppress uterine contractility

Significance Preterm birth affects 10 to 12% of all pregnancies and is the primary cause of neonatal morbidity and mortality worldwide, while prolonged labor increases the risks of infection, uterine rupture, and neonatal distress. Progesterone suppresses uterine contractions. As humans maintain high levels of progesterone throughout parturition, a “functional progesterone withdrawal” hypothesis suggests that switching between myometrial PGR-A and PGR-B isoform activities is crucial for transitioning into the parturition mode. Our mouse models provide evidence in support of this hypothesis. These findings also demonstrate a significant difference in downstream transcriptomic landscapes between the two PGR isoforms. Therefore, this work opens a venue to investigate the PGR isoform interacting signaling for parturition control, providing a possible pathway for developing clinical therapies. Uterine contractile dysfunction leads to pregnancy complications such as preterm birth and labor dystocia. In humans, it is hypothesized that progesterone receptor isoform PGR-B promotes a relaxed state of the myometrium, and PGR-A facilitates uterine contraction. This hypothesis was tested in vivo using transgenic mouse models that overexpress PGR-A or PGR-B in smooth muscle cells. Elevated PGR-B abundance results in a marked increase in gestational length compared to control mice (21.1 versus 19.1 d respectively, P < 0.05). In both ex vivo and in vivo experiments, PGR-B overexpression leads to prolonged labor, a significant decrease in uterine contractility, and a high incidence of labor dystocia. Conversely, PGR-A overexpression leads to an increase in uterine contractility without a change in gestational length. Uterine RNA sequencing at midpregnancy identified 1,174 isoform-specific downstream targets and 424 genes that are commonly regulated by both PGR isoforms. Gene signature analyses further reveal PGR-B for muscle relaxation and PGR-A being proinflammatory. Elevated PGR-B abundance reduces Oxtr and Trpc3 and increases Plcl2 expression, which manifests a genetic profile of compromised oxytocin signaling. Functionally, both endogenous PLCL2 and its paralog PLCL1 can attenuate uterine muscle cell contraction in a CRISPRa-based assay system. These findings provide in vivo support that PGR isoform levels determine distinct transcriptomic landscapes and pathways in myometrial function and labor, which may help further the understanding of abnormal uterine function in the clinical setting.
The functional polymorphisms linked with interleukin-1β gene expression are associated with bipolar disorder

Supplemental Digital Content is available in the text. Background Bipolar disorder (BD) is a severe psychiatric illness attributable to multifactorial risk components (e.g. environmental stimuli, neuroinflammation, etc.), and genetic variations affecting these risk components are considered pivotal predisposing factors. The interleukin-1β (IL-1β) gene and its protein product have been repeatedly highlighted in the pathogenesis of BD. As functional polymorphisms and haplotypes linked with IL-1β mRNA expression have been reported, whether they are correlated with the risk of developing BD remains to be tested. Methods To examine whether variations in the IL-1β gene locus confer genetic risk of BD, we recruited 930 BD patients and 912 healthy controls for the current study. All subjects were Han Chinese, and were age- and gender-matched. We tested seven functional single nucleotide polymorphisms (SNPs) spanning the IL-1β gene and one haplotype composed of three SNPs for their associations with risk of BD. Results We found that the functional SNPs in the promoter region of IL-1β gene were significantly associated with risk of BD. The haplotype analyses further supported the involvement of IL-1β promoter SNPs in BD. The BD risk SNPs in our study have been previously reported to predict higher IL-1β levels in the brain and peripheral blood, which is consistent with the clinical observation of elevated IL-1β levels in the lymphocytes or peripheral blood of patients with BD compared with healthy subjects. Conclusion Our results support the contention that IL-1β is likely a risk gene for BD, and further investigations on this gene may promote our understanding and clinical management of this illness.
Prognostic role of the ascending aorta dilatation in patients with arterial hypertension

Supplemental Digital Content is available in the text Background: Ascending aorta (ASC) dilatation (AAD) is a common finding in arterial hypertension, affecting about 15% of hypertensive patients. AAD is associated with an increase in cardiac and vascular hypertension-related organ damage, but its prognostic role is unknown. The aim of the study was to evaluate the prognostic value of AAD as predictor of cardiovascular events in essential hypertensive patients. Methods: Recruited patients underwent two-dimensional transthoracic echocardiography from 2007 to 2013 and followed-up for cardiovascular events until November 2018 by phone call and hospital information system check. ASC diameter and AAD were defined using both absolute and scaled definitions. Four hundred and twenty-three hypertensive patients were included in our study. Results: During a median follow-up of 7.4 years (interquartile range 5.6–9.1 years), 52 events were observed. After adjusting for age, sex and BSA, both ASC diameter and AAD definition, according to ARGO-SIIA project, resulted associated with a greater risk of cardiovascular event (both P < 0.010), even after adjusting for major confounders (both P < 0.010). Moreover, we observed that the assessment of ASC improves risk stratification compared with pulse wave velocity alone, and that in absence of AAD, sinus of valsalva dilatation lost any prognostic value (P = 0.262). Conclusions: ASC diameter and AAD are both associated with a greater risk of cardiovascular events. ASC should be assessed to optimize risk stratification in hypertensive patients and its dilatation may be considered as a surrogate for vascular organ damage.
Estimation of atmospheric emissions from maritime activity in the Veracruz port, Mexico

ABSTRACT The port of Veracruz is one of the most important ports in Mexico and is currently in the process of a major expansion. The new port area, “Bahía Norte”, will be three times larger than the current port, “Bahía Sur”. Atmospheric emissions from the Veracruz port system, specifically from the engines of ships undergoing maneuvering and hotelling operations, were determined on a daily basis from 2018 to 2019 for sulfur dioxide (SO2), nitrogen oxides (NOx), carbon monoxide (CO), non-methane volatile organic compounds (NMVOC), particles (PM), particles smaller than 10 micrometers (PM10), particles smaller than 2.5 micrometers (PM2.5) and carbon dioxide (CO2). A bottom-up method was used to estimate the atmospheric emissions, based on official data from the European Environment Agency. The method utilizes on technical information on the type of ship, the power of the main engine (ME) and auxiliary engine (AE), load factor, specific fuel consumption, and spent time in the maneuvering and hotelling phases. The highest atmospheric emissions occurred in the hotelling phase. For the “Bahía Sur” emissions (Mg/year) were 328.6, 993.3, 122.3, 30.6, 22.9, 19.1, 18.5 and 52,723.4 for SO2, NOx, CO, NMVOC, PM, PM10, PM2.5 and CO2, respectively. For “Bahía Norte” the corresponding emissions were 43.9, 132.7, 16.3, 4.1, 3.1, 2.5, 2.3 and 7,040.9, also in the hotelling phase. The average combined of the atmospheric emissions from maneuvering and hotelling phases (Mg/year) were 1.18, 3.49, 0.44, 0.13, 0.09, 0.08, 0.07, and 189.23 for SO2, NOx, CO, NMVOC, PM, PM10, PM2.5 and CO2, respectively. During the 2018–2019 period of the study the “Bahía Sur” contributed ~87% and the “Bahía Norte” ~13% of the atmospheric emissions. Implications: The atmospheric emissions reported in this study can be used for the simulation of air quality considering environmental or photochemical pollution models, since atmospheric emissions are reported on a daily basis and compliance with air quality can be monitored considering the reference-concentration established by the Official Mexican Standards in order to propose prevention, minimization and control measures. In addition, the analysis of the information that was carried out in this study may be applied to other port systems in Mexico that are located on the Pacific coast and the Gulf-Caribbean.
The analysis of models for indirect measurement of surface temperatures in massive charge

2Analýza modelu pre nepriame meranie povrchovej teploty v masivnej vsadzke In this article are described the models for indirect measurement of the surface temperatures in the steel coil. The indirect measurement of surface temperatures is part of intelligent system of indirect temperature measurement in the steel coil. The major task of this system is to measure massive charge temperatures in the annealing process continuously in time. In the design and creation of these models we used the fact that only one direct measured temperature of the atmosphere was at our disposal – the one under the protection cover. The created and verified models are in the form of difference equations and the surface temperatures depend on the atmospheric temperature only. The system of indirect temperature measurement The task of the system of indirect temperature measurement in massive charge is the indirect measurement of internal temperatures during heat treatment. The system goes out the direct measured quantities and then it provides information about the temperature inside the charge. It’s impossible to obtain this information without destructive measurement. Nowadays we can divide the system of indirect temperature measurement into two basic models (Fig. 1): 1. The model for indirect measurement of surface temperatures, 2. The model for indirect measurement of internal temperatures. Both models are very important in the whole system of the indirect temperatures measurement. The internal temperatures inside the charge are calculated by the elementary balance method, following the surface temperatures. It was necessary to assemble models for indirect measurement of surface temperatures, because these temperatures are not measured directly. The model for indirect temperature measurement of the surface in massive charge calculates surface temperatures (Tsurface). These temperatures are calculated from directly measured temperature of the atmosphere (Tatm) and directly measured temperatures of the etalon (Tetal). The internal temperatures (Tinternal) inside the charge are calculated from indirectly measured temperatures of the surface (Kostur, 2005; Pastor, 2006).
Safety of concomitant therapy with radium‐223 and abiraterone or enzalutamide in a real‐world population

Real‐world utilization and outcomes of combination therapy for men with metastatic castrate‐resistant prostate cancer (mCRPC) are largely unknown. We evaluated the overall survival (OS) and skeletal‐related events (SREs) among men who received radium‐223 with or without concomitant abiraterone or enzalutamide in the Veterans Affairs (VA) Health System.
Antihypertensive treatment decrease stroke occurrence: a prospective cohort study

Supplemental Digital Content is available in the text Objective: Among the risk factors of stroke, hypertension was one of the most important and modifiable factors. The current study aimed to assess whether antihypertensive treatment to ideal levels of blood pressure can eliminate stroke risk in a prospective cohort study. Methods: The Kailuan study was a prospective longitudinal cohort study on stroke risk factors and events. We analyzed association of baseline antihypertensive treatment efficacy with the risk of stroke during 11.0-year follow-up, and further evaluated association of newly antihypertensive treatment efficacy at 4-year follow-up with subsequent stroke. Multivariate Cox proportion models were used to calculated hazard ratios and their 95% confidence intervals (CIs) for stroke. Results: A total of 97 772 participants (median age: 51.65 years) without previous stroke were included. At baseline, 55 518 participants had normotension, 2339 treated and controlled, 32 331 untreated hypertension and 7584 treated but uncontrolled. Compared with normotension, individuals with treated and controlled, untreated hypertension and treated but uncontrolled, had 83, 97 and 162% higher risk of developing total stroke after adjusting for potential stroke risk factors, respectively (hazard ratio 1.83 [95% CI 1.56–2.15], 1.97 [95% CI 1.85–2.11] and 2.62 [95% CI 2.40–2.86]; all P < 0.05). Whereas, normotension at baseline, who were newly normotension with antihypertensives at 4-year follow-up, exhibited no elevated total stroke risk (hazard ratio, 1.41 [95% CI 0.87–2.30]). Similar results existed for stroke subtypes (ischemic stroke and hemorrhagic stroke). Conclusion: The data suggest that, antihypertensive treatment to normotensive individuals can reduce stroke risk in a short time.
Transplantation of GMP-grade human iPSC-derived retinal pigment epithelial cells in rodent model: the first pre-clinical study for safety and efficacy in China

Background Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly due in large part to age-dependent atrophy of retinal pigment epithelium (RPE) cells. RPE cells form a monolayer located between the choroid and the outer segments of photoreceptors, playing multifarious roles in maintenance of visual function. Allogeneically induced pluripotent stem cell-derived RPE (iPSC-RPE or iRPE) has become a potential approach for providing an abundant source of donors for clinical cell products. Transplantation of iRPE has been proven effective in rescuing impaired retinas in Royal College of Surgeons (RCS) rats after approximately 5 to 6 weeks. Here, we explore the long-term (19 weeks) safety and efficacy of human iRPE cell transplantation in pre-clinical animal models. Methods The expression of human RPE-specific markers in iRPE cells was determined using immunofluorescence staining. For the proliferative test, Ki-67 expression was also verified by immunofluorescence and flow cytometric analysis. Then, iRPE cells were transplanted into the subretinal space of immune-deficient NOD/SCID/IL-2Rgcnull (NSG) mice to assess their safety. To evaluate whether the transplanted cells could survive and rescue visual function, we performed color fundus photography, focal electroretinogram and immunostaining after delivering iRPE cells into the subretinal space of RCS rats. Results Human iRPE cells expressed native RPE-specific markers, such as microphthalmia-associated transcription factor (MiTF), retinal pigment epithelium-specific 65-kDa protein (RPE65) and tight-junction associated structural protein (ZO-1), and their proliferative capacity (Ki-67 expression) was poor after 25 days of induction. A tumorigenicity test revealed no tumor formation or abnormal proliferation in the immunodeficient mice after subretinal injection of 5×105 iRPE cells. The transplanted iRPE cells survived for at least 19 weeks and maintained visual function for 15 weeks. Conclusions In the present study, we provided further evidence for the use of human iRPE transplantation to treat retinal degenerative disease in pre-clinical animal models. Therefore, we consider human iRPE cells a promising source of cell replacement therapy for AMD.
Towards a better integration of emotional factors in autobiographical memory

ABSTRACT While the role of emotion in autobiographical memory (ABM) is acknowledged in some models, its specific effects are blurred by narrow approaches towards emotion that are often limited to a distinction between intensity and valence. After presenting a critical review of the role assigned to emotion for the development of ABM, this paper surveys current perspectives which encourage a broader approach to emotion in the development of ABM. Research on Flashbulb memories provides an important context where the role of emotion has been the most extensively investigated. This paper makes three important recommendations for future research, which are to (1) provide an assessment of emotional responses that includes appraisals, action tendencies, bodily sensations, and emotion intensity; (2) investigate the role of specific emotional states; and (3) adopt systematically a multi-component approach of ABM measurement, which takes accuracy, consistency, vividness, degree of details, and confidence into account.
GABAergic cortical network physiology in frontotemporal lobar degeneration

Abstract The clinical syndromes caused by frontotemporal lobar degeneration are heterogeneous, including the behavioural variant frontotemporal dementia (bvFTD) and progressive supranuclear palsy. Although pathologically distinct, they share many behavioural, cognitive and physiological features, which may in part arise from common deficits of major neurotransmitters such as γ-aminobutyric acid (GABA). Here, we quantify the GABAergic impairment and its restoration with dynamic causal modelling of a double-blind placebo-controlled crossover pharmaco-magnetoencephalography study. We analysed 17 patients with bvFTD, 15 patients with progressive supranuclear palsy, and 20 healthy age- and gender-matched controls. In addition to neuropsychological assessment and structural MRI, participants undertook two magnetoencephalography sessions using a roving auditory oddball paradigm: once on placebo and once on 10 mg of the oral GABA reuptake inhibitor tiagabine. A subgroup underwent ultrahigh-field magnetic resonance spectroscopy measurement of GABA concentration, which was reduced among patients. We identified deficits in frontotemporal processing using conductance-based biophysical models of local and global neuronal networks. The clinical relevance of this physiological deficit is indicated by the correlation between top-down connectivity from frontal to temporal cortex and clinical measures of cognitive and behavioural change. A critical validation of the biophysical modelling approach was evidence from parametric empirical Bayes analysis that GABA levels in patients, measured by spectroscopy, were related to posterior estimates of patients’ GABAergic synaptic connectivity. Further evidence for the role of GABA in frontotemporal lobar degeneration came from confirmation that the effects of tiagabine on local circuits depended not only on participant group, but also on individual baseline GABA levels. Specifically, the phasic inhibition of deep cortico-cortical pyramidal neurons following tiagabine, but not placebo, was a function of GABA concentration. The study provides proof-of-concept for the potential of dynamic causal modelling to elucidate mechanisms of human neurodegenerative disease, and explains the variation in response to candidate therapies among patients. The laminar- and neurotransmitter-specific features of the modelling framework, can be used to study other treatment approaches and disorders. In the context of frontotemporal lobar degeneration, we suggest that neurophysiological restoration in selected patients, by targeting neurotransmitter deficits, could be used to bridge between clinical and preclinical models of disease, and inform the personalized selection of drugs and stratification of patients for future clinical trials.