Miracle-dz/UniFAR-FTUs huggingface dataset:
RhoA as a Signaling Hub Controlling Glucagon Secretion from Pancreatic α-Cells.

Glucagon hypersecretion from pancreatic islet α-cells exacerbates hyperglycemia in type 1 (T1D) and type 2 (T2D) diabetes. Still, the underlying mechanistic pathways that regulate glucagon secretion remain controversial. Among the three complementary main mechanisms (intrinsic, paracrine and juxtacrine) proposed to regulate glucagon release from α-cells, juxtacrine interactions are the least studied. It is known that tonic stimulation of α-cell EphA receptors by ephrinA ligands (EphA forward signaling) inhibits glucagon secretion in mouse and human islets and restores glucose inhibition of glucagon secretion in sorted mouse α-cells, and these effects correlate with increased F-actin density. Here, we elucidate the downstream target of EphA signaling in α-cells. We demonstrate that RhoA, a Rho family GTPase, plays a key role in this pathway. Pharmacological inhibition of RhoA disrupts glucose inhibition of glucagon secretion in islets and decreases cortical F-actin density in dispersed α-cells and α-cells in intact islets. Quantitative FRET biosensor imaging shows that increased RhoA activity follows directly from EphA stimulation. In addition to modulating F-actin density, we show that EphA forward signaling and RhoA activity affects α-cell Ca2+ activity in a novel mechanistic pathway. Finally, we show that stimulating EphA forward signaling restores glucose inhibition of glucagon secretion from human T1D donor islets.
SpatialRank: Urban Event Ranking with NDCG Optimization on Spatiotemporal Data

The problem of urban event ranking aims at predicting the top-k most risky locations of future events such as traffic accidents and crimes. This problem is of fundamental importance to public safety and urban administration especially when limited resources are available. The problem is, however, challenging due to complex and dynamic spatio-temporal correlations between locations, uneven distribution of urban events in space, and the difficulty to correctly rank nearby locations with similar features. Prior works on event forecasting mostly aim at accurately predicting the actual risk score or counts of events for all the locations. Rankings obtained as such usually have low quality due to prediction errors. Learning-to-rank methods directly optimize measures such as Normalized Discounted Cumulative Gain (NDCG), but cannot handle the spatiotemporal autocorrelation existing among locations. In this paper, we bridge the gap by proposing a novel spatial event ranking approach named SpatialRank. SpatialRank features adaptive graph convolution layers that dynamically learn the spatiotemporal dependencies across locations from data. In addition, the model optimizes through surrogates a hybrid NDCG loss with a spatial component to better rank neighboring spatial locations. We design an importance-sampling with a spatial filtering algorithm to effectively evaluate the loss during training. Comprehensive experiments on three real-world datasets demonstrate that SpatialRank can effectively identify the top riskiest locations of crimes and traffic accidents and outperform state-of-art methods in terms of NDCG by up to 12.7%.
Assessment of patient perception of treatment assignment and patient-reported outcomes in a cannabis use disorder trial

ABSTRACT Background: Blinding is a cornerstone of trial methodology. Prior work indicates participant-perceived assignment may be associated with trial outcomes. Less is known about how perception changes over time and if this is associated with outcomes. Objectives: To evaluate if participants change their perception of assignment over time in a blinded trial, and if perception is associated with different types of patient-reported outcomes (PROs). Methods: This was a secondary analysis of data from the Achieving Cannabis Cessation-Evaluating N-Acetylcysteine Treatment (ACCENT) trial, which evaluated the efficacy of N-acetylcysteine (NAC) relative to placebo for treating cannabis use disorder. Participants (N = 234; 164 men, 70 women) were asked at weeks 5 and 9 what treatment (placebo or NAC) they believed they were receiving. We included PROs proximal (cannabis-associated problems, craving) and distal (anxiety) to the intervention. Analysis was by multiple linear regression and mixed models. Results: Approximately 20% of participants in both arms changed their perception over time. Relative to participants who consistently perceived assignment to placebo, participants who consistently perceived assignment to NAC did not always have comparatively better average scores (coefficient −3.3 [95% CI: −7.0, 0.5]). In some analyses, participants who switched to guessing NAC from placebo had comparatively better average scores (coefficient −3.0 [95% CI: −9.3, 3.4]), but this was inconsistent across outcomes or strata defined by actual assignment or guess accuracy. Conclusion: The study suggests that the proportion of individuals who switch their perception over time is modest. However, this group may influence the estimates of intervention effects on some PROs.
Plasma Levels of Advanced Glycation Endproducts and Risk of Cardiovascular Events: Findings From 2 Prospective Cohorts

Background Advanced glycation endproducts (AGEs) have been linked to cardiovascular disease (CVD) in cohorts with and without diabetes. Data are lacking on prospective associations of various α‐dicarbonyl‐derived AGEs and incident CVD in the general population. We tested the hypothesis that major plasma AGEs are associated with new‐onset CVD in 2 population‐based cohorts of differing age and comorbidities. Methods and Results Analyses involved a random subcohort (n=466) from the Cardiovascular Health Study and a case‐cohort sample (n=1631) from the Multi‐Ethnic Study of Atherosclerosis. Five AGEs and 2 oxidative products were measured by liquid chromatography tandem mass spectrometry. Associations with CVD (myocardial infarction and stroke) were evaluated with Cox regression. Participants in the Cardiovascular Health Study were older than the Multi‐Ethnic Study of Atherosclerosis, and had more comorbidities, along with higher levels of all AGEs. During median follow‐up of 11 years, 439 participants in the Multi‐Ethnic Study of Atherosclerosis and 200 in the Cardiovascular Health Study developed CVD. After multivariable adjustment, carboxymethyl‐lysine, 3‐deoxyglucosone hydroimidazolones and a summary variable of all measured AGEs (principal component 1) were significantly associated with incident CVD in the Cardiovascular Health Study (HRs [95% CI]: 1.20 [1.01, 1.42], 1.45 [1.23, 1.72], and 1.29 [1.06, 1.56], respectively), but not the Multi‐Ethnic Study of Atherosclerosis. Oxidative products were not associated with CVD in either cohort. Conclusions We found α‐dicarbonyl‐derived AGEs to be associated with CVD in an older cohort, but not in a healthier middle‐aged/older cohort. Our results suggest that AGEs may exert detrimental cardiovascular effects only under conditions of marked dicarbonyl and oxidative stress. Further investigation of α‐dicarbonyl derivatives could lead to potential new strategies for CVD prevention in high‐risk older populations.
Finite Element Analysis of the Stresses Induced by One-Piece and Two-Piece Dental Implants Supporting All-on-4 Implant-Supported Prostheses.

PURPOSE To find out the difference in the stresses induced by one-piece monophasic and two-piece dental implants supporting All-on-4 implant-supported prostheses using finite element analysis. MATERIALS AND METHODS Two finite element maxillary models were designed: In the two-piece model, two-piece dental implants were used, and in the one-piece model, one-piece dental implants were used. The dental implants were placed according to the All-on-4 treatment concept. The anterior implants were axially placed; however, the posterior implants were placed with a distal inclination of 15 degrees. In each model, the prosthetic superstructure was designed to be a titanium implant prosthesis with zirconia crowns. Three loading scenarios were applied in this study. The first scenario simulated biting function with a total load of 250 N. The second scenario simulated incision function in which 90-N horizontal static load was applied to the palatal surface of central incisors. The third scenario simulated biting in the presence of a cantilever. RESULTS In the three loading scenarios, the stresses were higher in the two-piece model. Higher stress values were recorded posteriorly rather than anteriorly in both models. CONCLUSION One-piece dental implants induce lower stress values compared with two-piece dental implants when used in All-on-4 implant-supported prostheses.
Dysregulated MAPK signaling pathway in acute myeloid leukemia with RUNX1 mutations

ABSTRACT Background Acute myeloid leukemia (AML) is a hematologic malignancy with genetic alterations. RUNX1, which is an essential transcription factor for hematopoiesis, is frequently mutated in AML. Loss-of-function mutation of RUNX1 is correlated with poor prognosis of AML patients. It is urgent to reveal the underlying mechanism. Research design and methods TCGA AML, GSE106291, GSE142700, and GSE67609 datasets were used. R package was used to define differentially expressed miRNAs, miRNA target genes, RUNX1-related gene, RUNX directly regulating genes, and so on. The relationship of gene expression with overall survival was analyzed by Cox regression. KEGG and GO analyses were applied to the above-mentioned genesets and overlapped genes. Alteration and importance of MAPK pathway were validated in K562 cells by Western blotting and apoptosis assay in vitro. Results RUNX1 regulated MAPK pathway indirectly and directly. MAPK pathway was altered in K562-cell-induced mutated RUNX1, and these cells were more sensitive to AraC after p38 was inhibited. Conclusions RUNX1 could modulate MAPK pathway, which may provide a potential therapeutic target for AML patients with RUNX1 mutations.
Depressive symptoms before and after Parkinson’s diagnosis—A longitudinal analysis

Background Depression is common in Parkinson’s disease (PD). It is however unclear when and how depressive symptoms develop and progress in the course of PD development. Objective To assess how depressive symptoms evolve in PD, using repeated measures. Methods In 2994 older adults, ages 70–79 years, depressive symptoms were assessed 8 times over 11 years using the 10-item Center for Epidemiologic Studies Depression Scale (CESD-10). For each PD patient at each time point, we calculated the difference between CESD-10 score and its expected value estimated based on data from individuals without PD, and then realigned the time scale in reference to the year of PD diagnosis. We examined longitudinal changes in CESD-10 scores before and after PD diagnosis using a joint modeling approach to account for competing risks of non-participation and death. Results A total of 79 PD patients were identified at enrollment or during the follow-up, with repeatedly assessed depressive symptom data up to 9 years before and after PD diagnosis. We found a monotonic trend of increasing CESD-10 score in PD patients throughout the observational period (p = 0.002). The observed scores became higher than expected approximately 7 years before PD diagnosis and significantly different 1 year before PD diagnosis. Conclusions Increasing depressive symptomatology appears to precede PD diagnosis by a few years.
Momomycin, an Antiproliferative Cryptic Metabolite from the Oxytetracycline Producer Streptomyces rimosus.

Natural products provide an important source of pharmaceuticals and chemical tools. Traditionally, assessment of unexplored microbial phyla has led to new natural products. However, with every new microbe, the number of orphan biosynthetic gene clusters (BGC) grows. As such, the more difficult proposition is finding new molecules from well-studied strains. Herein, we targeted Streptomyces rimosus, the widely-used oxytetracycline producer, for the discovery of new natural products. Using MALDI-MS-guided high-throughput elicitor screening (HiTES), we mapped the global secondary metabolome of S. rimosus and structurally characterized products of three cryptic BGCs, including momomycin, an unusual cyclic peptide natural product with back-bone modifications and several non-canonical amino acids. We elucidated important aspects of its biosynthesis and evaluated its bioactivity. Our studies showcase HiTES as an effective approach for unearthing new chemical matter from "drained" strains.
Treatment of severe coronary artery calcification with intravascular lithotripsy: Initial experience of a prospective single centre registry.

INTRODUCTION Coronary artery calcification can lead to suboptimal results when performing coronary angioplasty with conventional techniques. Shockwave intravascular lithotripsy (IVL) has recently been introduced as a new modality to treat heavily calcified coronary arteries. The purpose of this study was to determine the procedural success and safety of IVL in calcified lesions. MATERIALS AND METHODS This was a prospective single-centre study regarding the utility of IVL in treatment of calcified coronary arteries. Intravascular ultrasound (IVUS) was used in all cases to characterise the lesions pre procedure and to assess procedural success post procedure. The primary end point was procedural success, defined by IVL treatment and successful stent implantation. The secondary end point was in-hospital and 30-day major adverse cardiovascular event (MACE). RESULTS Five patients with severely calcified lesions were successfully treated with IVL. The primary end point was achieved in all patients. All of the lesions were severely calcified with concentric calcium. Multiple calcium fractures were identified on IVUS after IVL in all cases. None of the patients suffered in-hospital or 30-day MACE. The average diameter stenosis at baseline was 1.8±0.4mm and the post PCI diameter stenosis was 2.9±0.1mm, with significant acute luminal gain of 1.2±0.3mm (p<0.01). There were no complications of coronary dissection, slow or no reflow, stent thrombosis, or vessel perforation. CONCLUSION Our initial experience demonstrates the feasibility and safety of IVL in the management of calcified coronary stenosis. The shockwave IVL is an effective treatment approach to disrupt coronary calcification, facilitating stent implantation with optimal results. It is a safe procedure with a good success rate and low rate of complications.
Time trends of coronary procedures, guideline-based drugs and all-cause mortality following acute coronary syndrome in patients with bipolar disorder

Abstract Aim This study analyzed time trends in the use of coronary procedures, guideline-based drugs, and 1-year all-cause and presumed cardiovascular mortality (CV) following acute coronary syndrome (ACS) in patients with and without bipolar disorder (BD). Method Using Danish registries 497 patients with ACS and BD in the period 1996–2016 were matched 1:2 on age, sex and year of ACS to patients without preexisting psychiatric disease. Results Patients with BD and ACS received fewer coronary angiography (CAG) compared to psychiatric healthy controls (PHC). However, the difference between the populations decreased over time. For percutaneous coronary intervention (PCI) and coronary artery bypass (CABG) no differences in trend over time were found. In general patients with BD redeemed fewer prescriptions of guideline-based tertiary prophylactic drugs compared to PHCs. The difference remains constant over time for all drugs except for acetylsalicylic acid, lipid-lowering drugs and beta blockers, where the difference decreased. The 1-year all-cause mortality gap and the presumed CV mortality gap remained unchanged. Conclusion Despite improvements in treatment disparities regarding CAG, acetylsalicylic acid, lipid-lowering drugs and beta-blockers, the treatment gap remained unchanged concerning PCI and CABG. Likewise, patients with BD experienced a lower rate of the remaining redeemed prescriptions. The overall crude mortality risk ratio for patients with BD experiencing ACS remained unchanged over the study period compared to PHC.
基于Naive Bayes Classifiers的航空影像纹理分类

在Naive Bayes Classifiers模型中，要求父节点下的子节点（特征变量）之间相对独立，然而在现实世界中，特征与特征之间是非独立的、相关的。 提出一种预处理方法，实验结果表明，该方法明显地提高了分类精度。
Complex resonance frequencies of a finite, circular radiating duct with an infinite flange

Radiation by solid or fluid bodies can be characterized by resonance modes. They are complex, as well as resonance frequencies, because of the energy loss due to radiation. For ducts, they can be computed from the knowledge of the radiation impedance matrix. For the case of a flanged duct of finite length radiating on one side in an infinite medium, the expression of this matrix was given by Zorumski, using a decomposition in duct modes. In order to calculate the resonance frequencies, the formulation used in Zorumski's theory must be modified as it is not valid for complex frequencies. The analytical development of the Green's function in free space used by Zorumski depends on the integrals of Bessel functions which become divergent for complex frequencies. This paper proposes first a development of the Green's function which is valid for all frequencies. Results are applied to the calculation of the complex resonance frequencies of a flanged duct, by using a formulation of the internal pressure based upon cascade impedance matrices. Several series of resonance modes are found, each series being shown to be related to a dominant duct mode. Influence of higher order duct modes and the results for several fluid densities is presented and discussed.
Impact of clozapine on the expression of miR-675-3p in plasma exosomes derived from patients with schizophrenia

Abstract Objectives Recently, the expression changes of microRNAs (miRNAs) in the serum exosomes (EXO) of schizophrenia (SCZ) have been reported. The aim of this study was to investigate the global expression changes of miRNA derived from the plasma EXO of patients with treatment-resistant schizophrenia (TRS) and the effects of clozapine on miRNA expression. Methods Global miRNA expression changes in plasma EXO between TRS and controls were studied using microarray analysis. Then, miRNA expressions among TRS, non-TRS, and controls were confirmed with quantitative qPCR experiments. We also studied changes in EXO miRNA expression with in-vitro SH-SY5Y cells. Results A microarray for miRNA expression analysis (nine controls vs. nine patients with TRS) revealed 13 up- and 18 downregulated miRNAs that were relevant to neuronal and brain development based on gene ontology analysis. Of those, upregulated miR-675-3p expression was successfully validated in the same cohort by qPCR experiments. Conversely, miR-675-3p expression levels were significantly decreased in the non-TRS cohort (50 controls vs. 50 patients without TRS without clozapine treatment). Conclusions We identified global miRNA changes in plasma EXO derived from patients with SCZ that were relevant to neuronal functions, among which, hsa-miR-675-3p expression was upregulated by clozapine treatment.
Efficacy and safety of ruxolitinib for steroid-refractory graft-versus-host disease: Systematic review and meta-analysis of randomised and non-randomised studies

Background Hematopoietic stem cell transplantation (HSCT) for haematological disorders. Graft-versus-host disease (GVHD), a cause of morbidity and mortality is treated with corticosteroids. However, patients with steroid-refractory GVHD after HSCT have a poor prognosis. Ruxolitinib, a selective Janus kinase inhibitor, is a novel treatment strategy for steroid-refractory GVHD. Objectives To assess the efficacy of ruxolitinib for the treatment of steroid-refractory GVHD and analyse its adverse effects. Study design Meta-analysis. Search methods Randomised controlled trials (RCTs) and non-RCTs of ruxolitinib-based therapy in patients with steroid-refractory GVHD were found in the Cochrane Central Register of Controlled Trials, EMBASE, PubMed, and Web of Science in March 2021. Outcomes included overall response rate, survival, and adverse effects. The Methodological Index for Non-randomised Studies (MINORS) and the Cochrane collaboration risk-of-bias tool were used to assess methodological quality. Funnel plots, Egger’s test, and the trim and fill method were used to assess publication bias. Results In total, 1470 studies were identified; 19 studies (17 non-RCTs, 2 RCTs) involving 1358 patients met our inclusion criteria. Survival rates at the longest follow-up in non-RCTs, were 57.5% (95% CI 46.9–67.4) and 80.3% (95% CI 69.7–87.9) for acute GVHD (aGVHD) and chronic GVHD (cGVHD), respectively. In non-RCTs, the overall response was 74.9% (95% CI 66.6–81.8, I2 = 49%) in aGVHD and 73.1% (95% CI 62.5–81.6, I2 = 49%) in cGVHD. In aGVHD, the response rates were gastrointestinal, 61.4–90.2%; skin, 52.5–80.6%; and liver, 41.8–71.8%. In cGVHD, the response rates were gastrointestinal, 30.1–70.4%; skin, 30.1–84.4%; lung, 27.0–83.0%; and mouth 3.5–98.1%. In addition, a lower aGVHD grade and moderate cGVHD were associated with a better clinical response. Common adverse events were cytopenia and infectious complications. Conclusions Our systematic review and meta-analysis indicated that ruxolitinib therapy could be a potentially effective and safe treatment for patients with steroid-refractory GVHD.
Epidemiology of rheumatoid arthritis: genetic and environmental influences

ABSTRACT Introduction Rheumatoid arthritis (RA) is a chronic systemic disease characterized by articular involvement and extra-articular manifestations. The incidence and prevalence of the disease vary across populations, and there is an ongoing debate on whether a change of RA occurrence over time exists or is due to methodological issues and other biases. Moreover, the disease’s onset is related to an interaction of genetic and environmental factors that influence its expression. Areas covered This review explores the latest knowledge on RA epidemiology and the possible risk factors associated with its presentation to identify potential warning signs that may in the future help disease management. Expert opinion Current epidemiological evidence suggests a significant impact of smoking, sex hormones, and lifestyle status in RA occurrence. However, the association between these variables has not yet been thoroughly studied. Still, their effect must be interpreted as they may present subsequently integral indicators for a more rational approach of the disease.