Miracle-dz/UniFAR-FTUs huggingface dataset:
NMDA receptors in axons: there's no coincidence

In the textbook view, N‐methyl‐d‐aspartate (NMDA) receptors are postsynaptically located detectors of coincident activity in Hebbian learning. However, controversial presynaptically located NMDA receptors (preNMDARs) have for decades been repeatedly reported in the literature. These preNMDARs have typically been implicated in the regulation of short‐term and long‐term plasticity, but precisely how they signal and what their functional roles are have been poorly understood. The functional roles of preNMDARs across several brain regions and different forms of plasticity can differ vastly, with recent discoveries showing key involvement of unusual subunit composition. Increasing evidence shows preNMDAR can signal through both ionotropic action by fluxing calcium and in metabotropic mode even in the presence of magnesium blockade. We argue that these unusual properties may explain why controversy has surrounded this receptor type. In addition, the expression of preNMDARs at some synapse types but not others can underlie synapse‐type‐specific plasticity. Last but not least, preNMDARs are emerging therapeutic targets in disease states such as neuropathic pain. We conclude that axonally located preNMDARs are required for specific purposes and do not end up there by accident.
Preferences on the Timing of Initiating Advance Care Planning and Withdrawing Life-Sustaining Treatment between Terminally-Ill Cancer Patients and Their Main Family Caregivers: A Prospective Study

Background: The Western individualistic understanding of autonomy for advance care planning is considered not to reflect the Asian family-centered approach in medical decision-making. The study aim is to compare preferences on timing for advance care planning initiatives and life-sustaining treatment withdrawal between terminally-ill cancer patients and their family caregivers in Taiwan. Methods: A prospective study using questionnaire survey was conducted with both terminally-ill cancer patient and their family caregiver dyads independently in inpatient and outpatient palliative care settings in a tertiary hospital in Northern Taiwan. Self-reported questionnaire using clinical scenario of incurable lung cancer was employed. Descriptive analysis was used for data analysis. Results: Fifty-four patients and family dyads were recruited from 1 August 2019 to 15 January 2020. Nearly 80% of patients and caregivers agreed that advance care planning should be conducted when the patient was at a non-frail stage of disease. Patients’ frail stage of disease was considered the indicator for life-sustaining treatments withdrawal except for nutrition and fluid supplements, antibiotics or blood transfusions. Patient dyads considered that advance care planning discussions were meaningful without arousing emotional distress. Conclusion: Patient dyads’ preferences on the timing of initiating advance care planning and life-sustaining treatments withdrawal were found to be consistent. Taiwanese people’s medical decision-making is heavily influenced by cultural characteristics including relational autonomy and filial piety. The findings could inform the clinical practice and policy in the wider Asia–Pacific region.
Eating Habits and Lifestyle during COVID-19 Lockdown in the United Arab Emirates: A Cross-Sectional Study

The coronavirus disease is still spreading in the United Arab Emirates (UAE) with subsequent lockdowns and social distancing measures being enforced by the government. The purpose of this study was to assess the effect of the lockdown on eating habits and lifestyle behaviors among residents of the UAE. A cross-sectional study among adults in the UAE was conducted using an online questionnaire between April and May 2020. A total of 1012 subjects participated in the study. During the pandemic, 31% reported weight gain and 72.2% had less than eight cups of water per day. Furthermore, the dietary habits of the participants were distanced from the Mediterranean diet principles and closer to “unhealthy” dietary patterns. Moreover, 38.5% did not engage in physical activity and 36.2% spent over five hours per day on screens for entertainment. A significantly higher percentage of participants reported physical exhaustion, emotional exhaustion, irritability, and tension “all the time” during the pandemic compared to before the pandemic (p < 0.001). Sleep disturbances were prevalent among 60.8% of the participants during the pandemic. Although lockdowns are an important safety measure to protect public health, results indicate that they might cause a variety of lifestyle changes, physical inactivity, and psychological problems among adults in the UAE.
Pre-commercial thinning in naturally regenerated stands of European beech (Fagus sylvaticaL.): effects of thinning pattern, stand density and pruning on tree growth and stem quality

Pre-commercial thinning in naturally regenerated stands of European beech is often expensive and must be justified by improved development of the remaining crop. Based on a field experiment established in two 14-year-old naturally regenerated beech stands in Denmark, we investigated some effects of pre-commercial thinning and pruning on future crop tree growth and stem quality. The treatments included (1) no thinning, (2) moderate to heavy strip thinning, with or without subsequent selective thinning, and (3) extremely heavy strip thinning in two perpendicular directions (checkerboard thinning), with or without subsequent selective thinning and with or without pruning. The resulting residual stand densities ranged from 10⁵ to only 200 ha⁻¹. Treatment effects were evaluated on one potential future crop tree for every 100 m². Potential future crop trees were selected 32 years after germination based on spatial distribution, growth potential and stem quality. Total crop tree height was unaffected by strip thinning, but reduced by checkerboard thinning. Stem diameter at 1.30 m above ground level increased with decreasing stand density but, for checkerboard thinning, was reduced by pruning. The lower live branch was located at a lower position with heavy strip thinning and with checkerboard thinning without pruning. The frequency of crop trees with a forked stem was largest with checkerboard thinning and these forks were located at a lower position. Stem tilt and stem bend (stem straightness) were essentially unaffected by thinning practice. However, pruned trees tilted less and had straighter stems. The initial formation of epicormic branches on crop trees was unrelated to thinning and pruning practice, but crop trees that had been pruned for these were less prone to subsequently develop epicormic branches. In summary, moderate to heavy pre-commercial thinning had no effect on stem quality, while extremely heavy thinning without pruning resulted in unacceptably low stem quality. The no-thinning option resulted in acceptable growth and stem quality of the crop trees and this remains a viable management alternative for young beech.
Diagnosis and Treatment of Lower Extremity Venous Thromboembolism: A Review.

Importance Incidence rates for lower extremity deep vein thrombosis (DVT) range from 88 to 112 per 100 000 person-years and increase with age. Rates of recurrent VTE range from 20% to 36% during the 10 years after an initial event. Observations PubMed and Cochrane databases were searched for English-language studies published from January 2015 through June 2020 for randomized clinical trials, meta-analyses, systematic reviews, and observational studies. Risk factors for venous thromboembolism (VTE), such as older age, malignancy (cumulative incidence of 7.4% after a median of 19 months), inflammatory disorders (VTE risk is 4.7% in patients with rheumatoid arthritis and 2.5% in those without), and inherited thrombophilia (factor V Leiden carriers with a 10-year cumulative incidence of 10.9%), are associated with higher risk of VTE. Patients with signs or symptoms of lower extremity DVT, such as swelling (71%) or a cramping or pulling discomfort in the thigh or calf (53%), should undergo assessment of pretest probability followed by D-dimer testing and imaging with venous ultrasonography. A normal D-dimer level (ie, D-dimer <500 ng/mL) excludes acute VTE when combined with a low pretest probability (ie, Wells DVT score ≤1). In patients with a high pretest probability, the negative predictive value of a D-dimer less than 500 ng/mL is 92%. Consequently, D-dimer cannot be used to exclude DVT without an assessment of pretest probability. Postthrombotic syndrome, defined as persistent symptoms, signs of chronic venous insufficiency, or both, occurs in 25% to 50% of patients 3 to 6 months after DVT diagnosis. Catheter-directed fibrinolysis with or without mechanical thrombectomy is appropriate in those with iliofemoral obstruction, severe symptoms, and a low risk of bleeding. The efficacy of direct oral anticoagulants-rivaroxaban, apixaban, dabigatran, and edoxaban-is noninferior to warfarin (absolute rate of recurrent VTE or VTE-related death, 2.0% vs 2.2%). Major bleeding occurs in 1.1% of patients treated with direct oral anticoagulants vs 1.8% treated with warfarin. Conclusions and Relevance Greater recognition of VTE risk factors and advances in anticoagulation have facilitated the clinical evaluation and treatment of patients with DVT. Direct oral anticoagulants are noninferior to warfarin with regard to efficacy and are associated with lower rates of bleeding, but costs limit use for some patients.
Measurable residual disease in hematopoietic stem cell transplantation-eligible patients with acute myeloid leukemia: clinical significance and promising therapeutic strategies

Abstract Allogeneic hematopoietic stem cell transplantation (alloHCT) results in improved outcomes for acute myeloid leukemia (AML) patients compared to consolidation chemotherapy in transplant-eligible patients with adverse-risk disease. Despite achieving a complete remission (CR) to initial therapy, defined as <5% bone marrow blasts with recovery of peripheral blood elements, a large number of patients suffer disease relapse following alloHCT. There is a growing focus on minimal or measurable residual disease (MRD) in patients with AML, variably defined using multiparametric flow cytometry and nucleic acid sequencing techniques, to detect levels of disease not included in current CR terminology. MRD has emerged as an important prognostic tool in AML and may improve risk stratification, further refine selection of post-remission treatment, and provide an opportunity for therapeutic intervention. Herein, we review MRD detection methods, timing of measurement, prognostic implications, and MRD-directed therapy in AML patients undergoing alloHCT.
Disentangling the Roles of RIM and Munc13 in Synaptic Vesicle Localization and Neurotransmission

Efficient neurotransmitter release at the presynaptic terminal requires docking of synaptic vesicles to the active zone membrane and formation of fusion-competent synaptic vesicles near voltage-gated Ca2+ channels. Rab3-interacting molecule (RIM) is a critical active zone organizer, as it recruits Ca2+ channels and activates synaptic vesicle docking and priming via Munc13-1. However, our knowledge about Munc13-independent contributions of RIM to active zone functions is limited. To identify the functions that are solely mediated by RIM, we used genetic manipulations to control RIM and Munc13-1 activity in cultured hippocampal neurons from mice of either sex and compared synaptic ultrastructure and neurotransmission. We found that RIM modulates synaptic vesicle localization in the proximity of the active zone membrane independent of Munc13-1. In another step, both RIM and Munc13 mediate synaptic vesicle docking and priming. In addition, while the activity of both RIM and Munc13-1 is required for Ca2+-evoked release, RIM uniquely controls neurotransmitter release efficiency. However, activity-dependent augmentation of synaptic vesicle pool size relies exclusively on the action of Munc13s. Based on our results, we extend previous findings and propose a refined model in which RIM and Munc13-1 act in overlapping and independent stages of synaptic vesicle localization and release. SIGNIFICANCE STATEMENT The presynaptic active zone is composed of scaffolding proteins that functionally interact to localize synaptic vesicles to release sites, ensuring neurotransmission. Our current knowledge of the presynaptic active zone function relies on structure-function analysis, which has provided detailed information on the network of interactions and the impact of active zone proteins. Yet, the hierarchical, redundant, or independent cooperation of each active zone protein to synapse functions is not fully understood. Rab3-interacting molecule and Munc13 are the two key functionally interacting active zone proteins. Here, we dissected the distinct actions of Rab3-interacting molecule and Munc13-1 from both ultrastructural and physiological aspects. Our findings provide a more detailed view of how these two presynaptic proteins orchestrate their functions to achieve synaptic transmission.
Chorioretinal Side Effects of Therapeutic Ocular Irradiation: A Multimodal Imaging Approach

Radiation chorioretinopathy, radiation maculopathy, and radiation optic neuropathy are the major complications of ophthalmic radiotherapy. Optical coherence tomography (OCT) and OCT angiography (OCTA) are revolutionary imaging methods, allowing the visualization of the retinal cellular architecture and the retinal vascular system, respectively. In recent years this multimodal imaging approach has been applied to several retinal disease, but its role in the clinical characterization of retinal complications secondary to ophthalmic radiotherapy has not yet been defined. The purpose of this review is to critically evaluate the role of OCT and OCTA in the clinical assessment of radiation-induced chorioretinopathy, maculopathy, and optic neuropathy.
Usefulness of Tranexamic Acid Administration During Sagittal Split Ramus Osteotomy

Abstract Tranexamic acid has been used to reduce intraoperative bleeding; however, its effect on anti-inflammation and the amount of drainage after orthognathic surgery is yet to be determined. Therefore, we aimed to examine the effect of tranexamic acid on intraoperative bleeding volume and operation time, amount of drainage, and anti-inflammation after orthognathic surgery. Forty healthy women who underwent bilateral sagittal split ramus osteotomy under general anesthesia participated in this study. The amount of intraoperative bleeding, the operation time, the amount of drainage, and the C-reactive protein level were compared between patients intravenously administered with tranexamic acid before surgery (before-surgery group) and those administered with the drug after surgery (after-surgery group). All data were analyzed using the Student t-test. Results were considered to be statistically significant when P < 0.05. Although no significant difference was found in the amount of drainage between the groups (P > 0.05), significant variations were detected in the amount of bleeding during surgery (before-surgery group: 161.7 ± 45.3 mL versus after-surgery group: 270.2 ± 24.0 mL; P = 0.0009), operation time (before-surgery group: 141.3 ± 16.8 min versus after-surgery group: 166.8 ± 24.9 min; P = 0.03), and postoperative C-reactive protein level (before-surgery group: 3.77 ± 0.40 mg/dL versus after-surgery group: 5.02 ± 0.75 mg/dL; P = 0.012) between the groups. In conclusion, administering tranexamic acid before surgery was found to significantly decrease bleeding, reduce operation time, and suppress postoperative inflammation.
Low-Level Vagus Nerve Stimulation Reverses Obstructive Sleep Apnea-Related Atrial Fibrillation by Ameliorating Sympathetic Hyperactivity and Atrial Myocyte Injury

Background: Previous studies have proved that low-level vagus nerve stimulation (LLVS) could suppress acute obstructive sleep apnea (OSA), which is associated with atrial fibrillation (AF). Objective: This study investigates the underlying electrophysiological, neural, and cardiomyocyte injury mechanisms on acute OSA-induced AF, examining whether LLVS can attenuate or reverse this remodeling. Methods and Results: Eighteen mongrel dogs received endotracheal intubation under general anesthesia and were randomly divided into three groups: the OSA group (simulated OSA with clamping of the trachea cannula at the end of expiration for 2min followed ventilation 8min, lasting 6h, n=6), the OSA+LLVS group (simulated OSA plus LLVS, n=6), and a control group (sham clamping the trachea cannula without stimulation, n=6). In the OSA+LLVS group, the atrial effective refractory period was significantly lengthened while the sinus node recovery time and AF duration decreased after the 4th hour, and the expression level of Cx40 and Cx43 was significantly increased compared to the OSA group. Norepinephrine, TH, and ChAT were significantly decreased in the OSA+LLVS group compared with the OSA group. Mitochondrial swelling, cardiomyocyte apoptosis, and glycogen deposition, along with a higher concentration of TNF-α, IL-6 were observed in the OSA group, and the LLVS inhibited the structural remodeling and expression of inflammatory cytokines. Conclusion: LLVS decreased the inducibility of AF partly by ameliorating sympathetic hyperactivity and atrial myocyte injury after acute OSA-induced AF.
Drug Repurposing for Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) is the most aggressive type of breast cancer which presents a high rate of relapse, metastasis, and mortality. Nowadays, the absence of approved specific targeted therapies to eradicate TNBC remains one of the main challenges in clinical practice. Drug discovery is a long and costly process that can be dramatically improved by drug repurposing, which identifies new uses for existing drugs, both approved and investigational. Drug repositioning benefits from improvements in computational methods related to chemoinformatics, genomics, and systems biology. To the best of our knowledge, we propose a novel and inclusive classification of those approaches whereby drug repurposing can be achieved in silico: structure-based, transcriptional signatures-based, biological networks-based, and data-mining-based drug repositioning. This review specially emphasizes the most relevant research, both at preclinical and clinical settings, aimed at repurposing pre-existing drugs to treat TNBC on the basis of molecular mechanisms and signaling pathways such as androgen receptor, adrenergic receptor, STAT3, nitric oxide synthase, or AXL. Finally, because of the ability and relevance of cancer stem cells (CSCs) to drive tumor aggressiveness and poor clinical outcome, we also focus on those molecules repurposed to specifically target this cell population to tackle recurrence and metastases associated with the progression of TNBC.
Nipah virus dynamics in bats and implications for spillover to humans

Significance Nipah virus (NiV) is a zoonotic virus and World Health Organization (WHO) priority pathogen that causes near-annual outbreaks in Bangladesh and India with >75% mortality. This work advances our understanding of transmission of NiV in its natural bat reservoir by analyzing data from a 6-y multidisciplinary study of serology, viral phylogenetics, bat ecology, and immunology. We show that outbreaks in Pteropus bats are driven by increased population density, loss of immunity over time, and viral recrudescence, resulting in multiyear interepizootic periods. Incidence is low, but bats carry NiV across Bangladesh and can shed virus at any time of year, highlighting the importance of routes of transmission to the timing and location of human NiV outbreaks. Nipah virus (NiV) is an emerging bat-borne zoonotic virus that causes near-annual outbreaks of fatal encephalitis in South Asia—one of the most populous regions on Earth. In Bangladesh, infection occurs when people drink date-palm sap contaminated with bat excreta. Outbreaks are sporadic, and the influence of viral dynamics in bats on their temporal and spatial distribution is poorly understood. We analyzed data on host ecology, molecular epidemiology, serological dynamics, and viral genetics to characterize spatiotemporal patterns of NiV dynamics in its wildlife reservoir, Pteropus medius bats, in Bangladesh. We found that NiV transmission occurred throughout the country and throughout the year. Model results indicated that local transmission dynamics were modulated by density-dependent transmission, acquired immunity that is lost over time, and recrudescence. Increased transmission followed multiyear periods of declining seroprevalence due to bat-population turnover and individual loss of humoral immunity. Individual bats had smaller host ranges than other Pteropus species (spp.), although movement data and the discovery of a Malaysia-clade NiV strain in eastern Bangladesh suggest connectivity with bats east of Bangladesh. These data suggest that discrete multiannual local epizootics in bat populations contribute to the sporadic nature of NiV outbreaks in South Asia. At the same time, the broad spatial and temporal extent of NiV transmission, including the recent outbreak in Kerala, India, highlights the continued risk of spillover to humans wherever they may interact with pteropid bats and the importance of limiting opportunities for spillover throughout Pteropus’s range.
Development of lipL32 real-time PCR combined with an internal and extraction control for pathogenic Leptospira detection

At least two real-time PCRs for the early diagnosis of leptospirosis have been described, evaluated and validated. However, at least one other report suggested adaptation and modification of primers and probes used in these assays since additional Leptospira species have been described and the primers and probe in use possess a serious mismatch to corresponding target sequence. In this study we developed a real-time PCR for detection of pathogenic Leptospira based on the lipL32 gene. The present method consists of generic primers and probes based on target sequence of 10 pathogenic Leptospira species including Leptospira interrogans. The hybridization, annealing and extension temperature (60°C) were optimized as the optimal temperature of the DNA polymerase enzyme which is used in the amplification reaction. The present assay has a high analytical sensitivity and specificity; the calculated diagnostic sensitivity and specificity were 93.0% and 98.3% respectively. Moreover, the present method includes an internal control which enables easy detection of false negative results and an optional extraction control which enables the estimation of the DNA extraction efficiency.