Miracle-dz/UniFAR-FTUs huggingface dataset:
Significant role of long non-coding RNA MALAT1 in deep vein thrombosis via the regulation of vascular endothelial cell physiology through the microRNA-383-5p/BCL2L11 axis

ABSTRACT Deep vein thrombosis (DVT) is a vascular disease. The long non-coding RNA (lncRNA), metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), is positively expressed in DVT tissues, and regulates the biological behavior of endothelial progenitor cells. Here, we explored whether MALAT1 affected the physiology of human vascular endothelial cells (HUVECs) and analyzed its underlying mechanism. To overexpress/silence the expression of MALAT1 in HUVECs, MALAT1-plasmid/MALAT1-small interfering RNA (siRNA) was used. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide and flow cytometry analyses were performed to observe the cell viability and apoptosis. Reverse transcription-quantitative polymerase chain reaction and western blotting were used to determine the apoptosis-related protein and gene expression levels. We used Starbase software to predict the associations among MALAT1, microRNA (miR)-383-5p, and BCL2-like 11 (BCL2L11). Luciferase reporter assay was used to validate their relationship. Compared to the control vector group, MALAT1-plasmid suppressed the viability and induced apoptosis of HUVECs, while improving Bcl-2-associated X protein (Bax) expression and decreasing Bcl-2 expression. There was an interaction between MALAT1 and miR-383-5p. Compared to the control siRNA group, MALAT1-siRNA increased the cell viability, reduced cell apoptosis, upregulated Bcl-2 expression, and suppressed Bax expression. These changes were reversed by the miR-383-5p inhibitor. Additionally, we verified that BCL2L11 is a target of miR-383-5p. miR-383-5p improved the cell proliferation, while decreasing cell apoptosis in HUVECs by targeting BCL2L11. Therefore, the lncRNA-MALAT1/miR-383-5p/BCL2L11 axis may be effective for DVT treatment. Graphical Abstract
N‐of‐1 trials to facilitate evidence‐based deprescribing: Rationale and case study

Deprescribing has emerged as an important aspect of patient‐centred medication management but is vastly underutilized in clinical practice. The current narrative review will describe an innovative patient‐centred approach to deprescribing—N‐of‐1 trials. N‐of‐1 trials involve multiple‐period crossover design experiments conducted within individual patients. They enable patients to compare the effects of two or more treatments or, in the case of deprescribing N‐of‐1 trials, continuation with a current treatment versus no treatment or placebo. N‐of‐1 trials are distinct from traditional between‐patient studies such as parallel‐group or crossover designs which provide an average effect across a group of patients and obscure differences between individuals. By generating data on the effect of an intervention for the individual rather than the population, N‐of‐1 trials can promote therapeutic precision. N‐of‐1 trials are a particularly appealing strategy to inform deprescribing because they can generate individual‐level evidence for deprescribing when evidence is uncertain, and can thus allay patient and physician concerns about discontinuing medications. To illustrate the use of deprescribing N‐of‐1 trials, we share a case example of an ongoing series of N‐of‐1 trials that compare maintenance versus deprescribing of beta‐blockers in patients with heart failure with preserved ejection fraction. By providing quantifiable data on patient‐reported outcomes, promoting personalized pharmacotherapy, and facilitating shared decision making, N‐of‐1 trials represent a potentially transformative strategy to address polypharmacy.
Impact of allogeneic stem cell transplantation in childhood and adolescence on quality of adulthood life: A case–control study

Allogeneic hematopoietic stem cell transplantation (allo‐HSCT) is associated with late complications that can impair the quality of life (QoL) of patients for years after transplant. The purpose of the present study was to determine the difference in the QoL of adults that underwent allo‐HSCT in childhood and adolescence compared with not transplanted adults.
Delay discounting and alcohol consumption correlate with dorsal anterior insula activation during choice in nontreatment‐seeking heavy drinkers

Abstract Background The anterior insular cortex (AIC), a prominent salience network node, integrates interoceptive information and emotional states into decision making. While AIC activation during delay discounting (DD) in alcohol use disorder (AUD) has been previously reported, the associations between AIC activation, impulsive choice, alcohol consumption, and connectivity remain unknown. We therefore tested AIC brain responses during DD in heavy drinkers and their association with DD performance, alcohol drinking, and task‐based connectivity. Methods Twenty‐nine heavy drinkers (12 females; mean (SD) age=31.5 ± 6.1 years; mean (SD)=40.8 ± 23.4 drinks/week) completed a DD task during functional MRI. Regions activated during DD decision making were tested for correlation with DD behavior and alcohol drinking. Psychophysiological interaction (PPI) models assessed the task‐dependent functional connectivity (FC) of activation during choice. Results Delay discounting choice activated bilateral anterior insular cortex, anterior cingulate cortex, and left precentral gyrus. Right dorsal (d) AIC activation during choice negatively correlated withdiscounting of delayed rewards and alcohol consumption. PPI analysis revealed FC of the right dAIC to both the anterior and posterior cingulate cortices—key nodes in the midline default mode network. Conclusions Greater dAIC involvement in intertemporal choice may confer more adaptive behavior (lower impulsivity and alcohol consumption). Moreover, salience network processes governing discounting may require midline default mode (precuneus/posterior cingulate cortex) recruitment. These findings supporta key adaptive role for right dAIC in decision making involving future rewards and risky drinking.
Identifying connectivity for two sympatric carnivores in human-dominated landscapes in central Iran

Central Iran supports a diversity of carnivores, most of which are threatened by habitat loss and fragmentation. Carnivore conservation requires the identification and preservation of core habitats and ensuring connectivity between them. In the present study, we used species distribution modeling to predict habitat suitability and connectivity modeling to predict linkage (resistant kernel and factorial least-cost path analyses) for grey wolf and golden jackal in central Iran. For grey wolf, elevation, topographic ruggedness, and distance to Conservation Areas (CAs) were the strongest predictors; for golden jackal, distance to human settlements, dump sites and topographic ruggedness were the most influential variables in predicting the occurrence of this species. Our results also indicated a high potential for large parts of the landscape to support the occurrence of these two canid species. The largest and the most crucial core habitats and corridor paths for the conservation of both species are located in the southern part of the study landscape. We found a small overlap between golden jackal corridor paths and core habitats with CAs, which has important implications for conservation and future viability of the golden jackal populations. Some sections of core areas are bisected by roads, where most vehicle collisions with grey wolf and golden jackal occurred. To minimize mortality risk, we propose that successful conservation of both species will necessitate integrated landscape-level management, as well as conservation of core areas and corridors and development of mitigation strategies to reduce vehicle collisions.
An umbrella review on the use of antipsychotics in anxiety disorders: A registered report protocol

Anxiety disorders, including panic disorder (PD), generalized anxiety disorder (GAD), social anxiety disorder (SAD), agoraphobia, and specific phobia, are among the most common psychiatric disorders. Although the traditional pharmacologic treatments for anxiety included barbiturates and then benzodiazepines, the introduction of tricyclic antidepressants, followed by the selective serotonin reuptake inhibitors (SSRIs), marked a tidal shift in the treatment of anxiety. Although not approved for treatment of anxiety disorders (with the exception of trifluoperazine) there is ongoing off-label, unapproved use of both first-generation “typical” antipsychotics (FGAs) and second-generation or “atypical” antipsychotics (SGAs) for anxiety. Although there have been systematic reviews and meta-analyses on the use of antipsychotics in anxiety disorders, most of these reviews focused on SGAs, primarily the use of quetiapine in GAD. Given that there is little known about the potential benefits and short-and long-term risks of using antipsychotics in anxiety, there is a need for an umbrella review of systematic reviews and meta-analyses of the use of both FGAs and SGAs in anxiety disorders. The specific aims of this study are as follows: (1) Evaluate the evidence of efficacy of FGAs and SGAs in anxiety disorders as an adjunctive treatment to SSRIs, serotonin norepinephrine reuptake inhibitors (SNRIs) and other non-antipsychotic medications; (2) Compare monotherapy with antipsychotics to first-line treatments for anxiety disorders in terms of effectiveness, risks, and side effects; and (3) Evaluate the short- and long-term risks and side effects of prescribing antipsychotics in anxiety disorders. The review is registered on PROSPERO (CRD42021237436). Since data extraction has not begun, there is not preliminary data to share.
Exploring the Insecticidal Potential of Gaseous and Aqueous Ozone to Control Spotted-Wing Drosophila, Drosophila suzukii (Diptera: Drosophilidae)

Abstract Over the last decade, numerous companies have marketed aqueous ozone sprayers for insect and disease management, but little to no data has been published on their efficacy. Thus, we evaluated the potential of both gaseous and aqueous ozone as a potential preharvest insecticide against the adult life stage of the invasive fruit pest, spotted-wing drosophila, Drosophila suzukii (Matsumura). Gaseous ozone was applied at two dosages, 14,600 and 30,100 ppmv, for varying durations and the respective concentration-time (CT) exposure responses were modeled for sex-specific mortalities recorded at 0, 24, 48, and 72 h following treatment. We found that gaseous ozone primarily caused mortality immediately following exposure, with slight increases 72 h following ozone treatments. The female and male lethal concentration-time (LCT) 50 estimates were significantly different at 0, 24, 48, and 72 h after 30,100 ppmv treatments, where males observed an increased mortality response. However, the LCT 99 estimates confidence intervals (95%) of adult female and male D. suzukii were similar at 0, 24, 48, and 72 h after 14,600 or 30,100 ppmv ozone treatments. In contrast, ozone dissolved in distilled water at 18.52 ppm (mg/L) did not provide any mortality after total immersion of subjects for 30 s. While gaseous ozone may have some utility as a fumigant for D. suzukii in closed vessels where concentrations could be maintained, we did not identify any insecticidal potential for ozone dissolved in aqueous solution when simulating a preharvest treatment under optimal laboratory conditions.
The impact of apical periodontitis, non‐surgical root canal retreatment and periapical surgery on serum inflammatory biomarkers

Abstract Aim The aim of the study was to measure serum levels of molecular markers of inflammation in patients undergoing non‐surgical root canal retreatment (Re‐RCT) and periapical surgery (PS) for the treatment of apical periodontitis and to establish if such levels are influenced by the size of apical radiolucencies at baseline and by the treatment outcome. Methodology A total of 115 participants were recruited (n = 50 Controls, n = 35 Re‐RCT, n = 30 PS). Preoperative periapical radiographs and cone beam CT (CBCT) scans of teeth were taken. Blood was collected from treatment groups at baseline, 3‐, 6‐, and 12‐month post‐treatment and from controls at baseline and 12 months. Serum levels of IL‐1β, IL‐6, IL‐8, TNF‐α, Pentraxin 3, ICAM‐1, VCAM‐1, hs‐CRP, FGF‐23, MMP‐2, MMP‐8, MMP‐9, C3 and ADMA were analysed using multiplex immunoassay and enzyme‐linked immunosorbent assay. Different time points within the same group were compared using Wilcoxon signed‐rank test, and differences between groups were analysed using the Mann–Whitney test. Non‐linear association between different factors was assessed using Spearman's correlation. Results Preoperative serum levels of FGF‐23, IL‐1β, hs‐CRP and ADMA were significantly higher in the diseased groups compared with controls (p < .001; p = .008; p < .001; p = .013, respectively). The preoperative size of the radiolucency was associated with increased levels of FGF‐23, IL‐1β and IL‐6. At 3‐months following treatment, IL‐1β, IL‐8, hs‐CRP, C3, MMP‐2 and MMP‐9 levels increased compared with baseline in treatment groups. IL‐1β and IL‐8 further increased at 6 months, whereas FGF‐23, hs‐CRP, C3, MMP2 and MMP‐9 decreased. One‐year post‐treatment, FGF‐23, pentraxin‐3 and ADMA were significantly reduced below baseline levels. At the 1‐year review, CBCT revealed that 25.9% of treated cases completely healed, while 63% were healing, and 11.1% failed. Treatment outcome was found to be influenced by preoperative levels of ADMA and IL‐8 levels at 6 months. Conclusions Both symptomatic and asymptomatic apical periodontitis (AP) can contribute to increased levels of molecular markers of inflammation. A further transient inflammatory markers rise after root canal retreatment and apical surgery were demonstrated. Successful endodontic treatment and periapical surgery result in a long‐term reduction in inflammatory marker levels.
Preferences and User Experiences of Wearable Devices in Epilepsy

Background and Objectives To examine the preferences and user experiences of people with epilepsy and caregivers regarding automated wearable seizure detection devices. Methods We performed a mixed-methods systematic review. We searched electronic databases for original peer-reviewed publications between January 1, 2000, and May 26, 2021. Key search terms included “epilepsy,” “seizure,” “wearable,” and “non-invasive. ” We performed a descriptive and qualitative thematic analysis of the studies included according to the technology acceptance model. Full texts of the discussion sections were further analyzed to identify word frequency and word mapping. Results Twenty-two observational studies were identified. Collectively, they comprised responses from 3,299 participants including patients with epilepsy, caregivers, and healthcare workers. Sixteen studies examined user preferences, 5 examined user experiences, and 1 examined both experiences and preferences. Important preferences for wearables included improving care, cost, accuracy, and design. Patients desired real-time detection with a latency of ≤15 minutes from seizure occurrence, along with high sensitivity (≥90%) and low false alarm rates. Device-related costs were a major factor for device acceptance, where device costs of <$300 USD and a monthly subscription fee of <$20 USD were preferred. Despite being a major driver of wearable-based technologies, sudden unexpected death in epilepsy was rarely discussed. Among studies evaluating user experiences, there was a greater acceptance toward wristwatches. Thematic coding analysis showed that attitudes toward device use and perceived usefulness were reported consistently. Word mapping identified “specificity,” “cost,” and “battery” as key single terms and “battery life,” “insurance coverage,” “prediction/detection quality,” and the effect of devices on “daily life” as key bigrams. Discussion User acceptance of wearable technology for seizure detection was strongly influenced by accuracy, design, comfort, and cost. Our findings emphasize the need for standardized and validated tools to comprehensively examine preferences and user experiences of wearable devices in this population using the themes identified in this study. Greater efforts to incorporate perspectives and user experiences in developing wearables for seizure detection, particularly in community-based settings, are needed. Trial Registration Information PROSPERO Registration CRD42020193565.
Figure-ground responsive fields of monkey V4 neurons estimated from natural image patches

Neurons in visual area V4 modulate their responses depending on the figure-ground (FG) organization in natural images containing a variety of shapes and textures. To clarify whether the responses depend on the extents of the figure and ground regions in and around the classical receptive fields (CRFs) of the neurons, we estimated the spatial extent of local figure and ground regions that evoked FG-dependent responses (RF-FGs) in natural images and their variants. Specifically, we applied the framework of spike triggered averaging (STA) to the combinations of neural responses and human-marked segmentation images (FG labels) that represent the extents of the figure and ground regions in the corresponding natural image stimuli. FG labels were weighted by the spike counts in response to the corresponding stimuli and averaged over. The bias due to the nonuniformity of FG labels was compensated by subtracting the ensemble average of FG labels from the weighted average. Approximately 50% of the neurons showed effective RF-FGs, and a large number exhibited structures that were similar to those observed in virtual neurons with ideal FG-dependent responses. The structures of the RF-FGs exhibited a subregion responsive to a preferred side (figure or ground) around the CRF center and a subregion responsive to a non-preferred side in the surroundings. The extents of the subregions responsive to figure were smaller than those responsive to ground in agreement with the Gestalt rule. We also estimated RF-FG by an adaptive filtering (AF) method, which does not require spherical symmetry (whiteness) in stimuli. RF-FGs estimated by AF and STA exhibited similar structures, supporting the veridicality of the proposed STA. To estimate the contribution of nonlinear processing in addition to linear processing, we estimated nonlinear RF-FGs based on the framework of spike triggered covariance (STC). The analyses of the models based on STA and STC did not show inconsiderable contribution of nonlinearity, suggesting spatial variance of FG regions. The results lead to an understanding of the neural responses that underlie the segregation of figures and the construction of surfaces in intermediate-level visual areas.
Lymphatic function and anatomy in early stages of lipedema

Lipedema is an inflammatory subcutaneous adipose tissue disease that develops in women and may progress to lipolymphedema, a condition similar to lymphedema, in which lymphatic dysfunction results in irresolvable edema. Because it has been shown that dilated lymphatic vessels, impaired pumping, and dermal backflow are associated with presymptomatic, cancer‐acquired lymphedema, this study sought to understand whether these abnormal lymphatic characteristics also characterize early stages of lipedema prior to lipolymphedema development.
Confirmatory efficacy testing for individual dose–placebo comparisons using serial gatekeeping procedure in dose‐finding trials with multiple comparison procedures–modeling

Dose‐finding trials play a key role in the entire drug development process to determine optimal doses for regulatory approval. We address confirmatory efficacy testing for individual dose–placebo comparisons in the context of a dose‐finding trial designed with multiple comparison procedures–modeling (MCP–Mod). An extension of the MCP–Mod, called closed MCP–Mod, has been proposed to carry out the MCP–Mod in conjunction with pairwise dose‐placebo comparisons; however, an issue associated with the misspecification of candidate dose–response models remains. We consider another way to combine the MCP–Mod and the individual dose‐placebo comparisons using serial gatekeeping procedures with fixed sequence, Holm, Hochberg, and step‐down Dunnett procedure. The method controls the family‐wise error rate in the strong sense and is simple enough to be implemented by existing software. Simulation studies suggested that the serial gatekeeping procedure was comparable with the closed MCP–Mod in terms of statistical power to detect the efficacy of at least one dose, and both methods were capable of pursuing the efficacy claim rather than just establishing the dose–response signal with less than a 20% increase in sample size when assuming monotonic dose–response shapes. The serial gatekeeping procedure would have advantages in the simplicity of implementation and ease of interpretation. The dose‐finding trials aiming to declare the dose–response signal, as well as the efficacy of individual doses, would be worth considering as an option to accelerate the drug development program in certain situations.
Pyrone Derivatives from a Mangrove Endophytic Fungus Phomopsis asparagi LSLYZ‐87

Chemical investigation of the endophytic fungus Phomopsis asparagi LSLYZ‐87 cultured on PDB medium led to the isolation of two new pyrone derivatives, phomasparapyrone A (1), and phomasparapyrone B (2), together with the known kojic acid (3). Their planar structures were connected through 1D and 2D NMR spectroscopic data. And the stereo structures of 1 and 2 were defined by comparison of the experimental ECD spectra to calculated one. All isolates were evaluated for their anti‐neuroinflammatory activities. Among them, compound 2 showed moderate inhibition on NO accumulation induced by LPS on BV‐2 cells in a dose dependent manner at 30, 40 and 50 μM, and without cytotoxicity in a concentration of 50.0 μM.
JAML promotes acute kidney injury mainly through a macrophage-dependent mechanism

Although macrophages are undoubtedly attractive therapeutic targets for acute kidney injury (AKI) because of their critical roles in renal inflammation and repair, the underlying mechanisms of macrophage phenotype switching and efferocytosis in the regulation of inflammatory responses during AKI are still largely unclear. The present study elucidated the role of junctional adhesion molecule–like protein (JAML) in the pathogenesis of AKI. We found that JAML was significantly upregulated in kidneys from 2 different murine AKI models including renal ischemia/reperfusion injury (IRI) and cisplatin-induced AKI. By generation of bone marrow chimeric mice, macrophage-specific and tubular cell–specific Jaml conditional knockout mice, we demonstrated JAML promoted AKI mainly via a macrophage-dependent mechanism and found that JAML-mediated macrophage phenotype polarization and efferocytosis is one of the critical signal transduction pathways linking inflammatory responses to AKI. Mechanistically, the effects of JAML on the regulation of macrophages were, at least in part, associated with a macrophage-inducible C-type lectin–dependent mechanism. Collectively, our studies explore for the first time to our knowledge new biological functions of JAML in macrophages and conclude that JAML is an important mediator and biomarker of AKI. Pharmacological targeting of JAML-mediated signaling pathways at multiple levels may provide a novel therapeutic strategy for patients with AKI.