Miracle-dz/UniFAR-FTUs huggingface dataset:
The effect of Mg2+ on Ca2+ binding to cardiac troponin C in hypertrophic cardiomyopathy associated TNNC1 variants

Cardiac troponin C (cTnC) is the critical Ca2+‐sensing component of the troponin complex. Binding of Ca2+ to cTnC triggers a cascade of conformational changes within the myofilament that culminate in force production. Hypertrophic cardiomyopathy (HCM)‐associated TNNC1 variants generally induce a greater degree and duration of Ca2+ binding, which may underly the hypertrophic phenotype. Regulation of contraction has long been thought to occur exclusively through Ca2+ binding to site II of cTnC. However, work by several groups including ours suggest that Mg2+, which is several orders of magnitude more abundant in the cell than Ca2+, may compete for binding to the same cTnC regulatory site. We previously used isothermal titration calorimetry (ITC) to demonstrate that physiological concentrations of Mg2+ may decrease site II Ca2+‐binding in both N‐terminal and full‐length cTnC. Here, we explore the binding of Ca2+ and Mg2+ to cTnC harbouring a series of TNNC1 variants thought to be causal in HCM. ITC and thermodynamic integration (TI) simulations show that A8V, L29Q and A31S elevate the affinity for both Ca2+ and Mg2+. Further, L48Q, Q50R and C84Y that are adjacent to the EF hand binding motif of site II have a more significant effect on affinity and the thermodynamics of the binding interaction. To the best of our knowledge, this work is the first to explore the role of Mg2+ in modifying the Ca2+ affinity of cTnC mutations linked to HCM. Our results indicate a physiologically significant role for cellular Mg2+ both at baseline and when elevated on modifying the Ca2+ binding properties of cTnC and the subsequent conformational changes which precede cardiac contraction.
Identification and characterization of the key volatile flavor compounds in black teas from distinct regions worldwide.

Volatile flavor compounds in 112 black teas from seven countries were analyzed by untargeted metabolomics using headspace solid-phase microextraction and gas chromatography-mass spectrometry (HS-SPME/GC-MS). Multivariate statistical analysis and odor activity values (OAVs) were used to classify these samples and identify key odorants. A total of 140 volatile flavor compounds (VFCs), including 12 different groups, were identified, and alcohols were prevalent in China and India samples, accounting for 40.83% and 34.96% of the total VFCs, respectively. Eight volatile compounds with OAVs > 1 were identified as key active differential odorants in Chinese, Indian, and Sri Lankan samples, including linalool, pentanoic acid, methyl salicylate, hexanoic acid, 1-methyl-naphthalene, phenylethyl alcohol, geraniol, and β-ionone. Linalool, pentanoic acid, and hexanoic acid in Indian black teas, phenylethyl alcohol in Chinese black teas, and 1-methyl-naphthalene, β-ionone in Sri Lankan black teas could be used to discriminate different black tea groups. A total of 12-14 VFCs with OAVs > 1 were identified as key active aromatics in Chinese black tea sample. Linalool and benzeneacetaldehyde in Yingde (Guangdong) black tea, methyl salicylate in Taiwanese samples, and benzeneacetic acid in Anhui black tea could be used as biomarkers to distinguish them from other Chinese samples. Sensory evaluation results showed that most black teas presented the common sweet, floral odors, which were consistent with GC-MS analysis. These results will contribute to characterize the odor metabolome of black teas and provide biochemical basis for identifying the authenticity of different black teas. PRACTICAL APPLICATION: Linalool, pentanoic acid, and hexanoic acid in Indian black teas, phenylethyl alcohol in Chinese black teas, 1-methyl-naphthalene, β-ionone, and methyl salicylate in Sri Lankan black teas could be used to discriminate black teas from the three countries. Linalool and benzeneacetaldehyde in Yingde black teas, methyl salicylate in Taiwanese black teas, and benzeneacetic acid in Anhui black tea are the potential biomarkers to distinguish these teas from other Chinese black teas.
Ventral onlay glanuloplasty for treatment of fossa navicularis strictures

ABSTRACT Purpose: Management of fossa navicularis (FN) strictures balances restoring urethral patency with adequate cosmesis. Historically, FN strictures are managed via glans cap or glans wings, and in severe cases, multi-stage procedures. Ventral onlay glanuloplasty (VOG) is an easily reproducible technique that involves a single-stage augmentation with buccal mucosal graft. We have been applying this technique for several years and present early promising outcomes of this novel approach. Materials and Methods: We retrospectively reviewed all patients with FN strictures who underwent VOG at our institution. Treatment success was designated by the absence of extravasation on voiding cystourethrogram and no need for further urethral instrumentation on follow up. Glans cosmesis was assessed by patients providing binary (yes/no) response to the satisfaction in their appearance. We also noted stricture length, stricture etiology, demographic characteristics and any post-operative complications and reported median, interquartile range (IQR) and count, frequency (%), accordingly. Results: Ten patients underwent VOG and fit our inclusion criteria. Median stricture length was 2.0 cm (IQR 1.6 -2). Success rate was 90% (9/10) with a median follow up of 30 months (IQR 24.3 – 36.8). The one recurrence was treated by dilation combined with triamcinolone injection at 419 days post-op. Stricture etiology included primarily iatrogenic causes such as transurethral prostate resection (4/10), greenlight laser vaporization (2/10), cystolitholapaxy (1/10), and traumatic catheterization (3/10). All patients were satisfied with penile cosmesis. Conclusion: VOG is a simple technique for treating FN strictures. Based on our preliminary series, VOG provides sustained distal urethral patency and patients are pleased with the appearance.
Effects of telecardiac rehabilitation on coronary heart disease: A PRISMA-compliant systematic review and meta-analysis

Background: We performed a meta-analysis to investigate the effectiveness of telecardiac rehabilitation compared to center-based rehabilitation on cardiorespiratory fitness, blood pressure, blood lipids, body composition, and quality of life in patients with coronary heart disease. Methods: We searched the Medical Literature Analysis and Retrieval System Online, Cumulative Index to Nursing and Allied Health Literature, Cochrane, Embase, and Scopus databases and retrieved studies published until October 8, 2021. Randomized controlled trials were included to evaluate cardiorespiratory fitness, blood pressure, blood lipids, body composition, and quality of life after telecardiac rehabilitation and center-based rehabilitation in patients with coronary heart disease. The criteria of the Cochrane Handbook for Systematic Reviews of Interventions were used to evaluate the methodological quality of the studies. Funnel plot analysis and Egger test were performed to confirm the publication bias. Results: A total of 8 studies, including 750 participants, reported the effectiveness of the telecardiac rehabilitation and center-based rehabilitation included in the analysis. Except for total cholesterol and mental quality of life (P < .05), all parameters were not significantly different between telecardiac rehabilitation and center-based rehabilitation (P > .05). Conclusion: Telecardiac rehabilitation was similar to the effects of center-based rehabilitation. The overall prognosis of patients with coronary heart disease can be improved by increasing patients’ participation in cardiac rehabilitation through telerehabilitation.
Kinetic Equation for High-Energy Particles of Axisymmetric Tokamaks in Terms of Constants of Motion

In this paper, it is shown that the distribution function of high-energy particles satisfies the three-dimensional Fokker-Planck equation for constants of motion. Transport coefficients of this equation are calculated for the axisymmetric tokamak with a circular cross section. The collisional transport of the marginally circulating fast particles is found to be enhanced more than that of the other particles.
Pulmonary adverse events following immune checkpoint inhibitors

Purpose of review Immune checkpoint inhibitors (ICIs) have rapidly become a mainstay of cancer treatment. However, immune modulation resulting from checkpoint inhibition can cause inflammation in any organ system, with pneumonitis being one of the most severe immune-related adverse events (irAEs). Here, we review the most recent literature on pulmonary adverse events following ICIs. Recent findings Several systematic reviews and meta-analyses of data from trials of antiprogrammed death-1 (PD-1; nivolumab, pembrolizumab), anti-PD-ligand-1 (PD-L1; atezolizumab, avelumab, durvalumab) and anticytotoxic T lymphocyte antigen-4 (CTLA-4; ipilimumab or tremelimumab) in patients with advanced cancer have explored the relative risk and incidence of lung toxicity among different tumor types and therapeutic regimens. They have showed that the incidence of all-grade (1–4) and high-grade (3–4) pneumonitis is significantly higher in nonsmall cell lung cancer (NSCLC) compared with other tumor types. In addition, they have demonstrated that immunotherapy, especially monoimmunotherapy, has a significantly lower risk of irAEs compared to immune-chemotherapy. Treatment for lung cancer, preexisting interstitial lung disease, smoking history and male sex appear to increase the risk for ICI-related pneumonitis. Summary Lung toxicity is an uncommon but potentially severe and even fatal complication of ICIs. Timely recognition is critically important but challenging, particularly in patients with lung cancer wherein drug toxicity can mimic disease progression or recurrence.
Optimal growth temperature of Arctic soil bacterial communities increases under experimental warming

Future climate warming in the Arctic will likely increase the vulnerability of soil carbon stocks to microbial decomposition. However, it remains uncertain to what extent decomposition rates will change in a warmer Arctic, because extended soil warming could induce temperature adaptation of bacterial communities. Here we show that experimental warming induces shifts in the temperature–growth relationships of bacterial communities, which is driven by community turnover and is common across a diverse set of 8 (sub) Arctic soils. The optimal growth temperature (Topt) of the soil bacterial communities increased 0.27 ± 0.039 (SE) and 0.07 ± 0.028°C per °C of warming over a 0–30°C gradient, depending on the sampling moment. We identify a potential role for substrate depletion and time‐lag effects as drivers of temperature adaption in soil bacterial communities, which possibly explain discrepancies between earlier incubation and field studies. The changes in Topt were accompanied by species‐level shifts in bacterial community composition, which were mostly soil specific. Despite the clear physiological responses to warming, there was no evidence for a common set of temperature‐responsive bacterial amplicon sequence variants. This implies that community composition data without accompanying physiological measurements may have limited utility for the identification of (potential) temperature adaption of soil bacterial communities in the Arctic. Since bacterial communities in Arctic soils are likely to adapt to increasing soil temperature under future climate change, this adaptation to higher temperature should be implemented in soil organic carbon modeling for accurate predictions of the dynamics of Arctic soil carbon stocks.
Neurochemical classification of serotonin‐immunoreactive neurons co‐innervating motor endplates in the mouse esophagus

Serotonin immunoreactivity was previously found in myenteric neurons co‐innervating motor endplates in the mouse esophagus striated muscle and an involvement in motility control was suggested. However, it is not known if other neuroactive substances are present in these neurons and to what extent they co‐localize. First, vasoactive intestinal peptide (VIP) was established as a bona fide marker for putative inhibitory myenteric neurons by evaluating co‐localization with neuronal nitric oxide synthase (nNOS) and neuropeptide Y (NPY). Then, co‐localization of serotonin and VIP was tested in co‐innervating axons on motor endplates, which were visualized with α‐bungarotoxin (α‐BT) by multilabel immunofluorescence. Myenteric ganglia were also surveyed for co‐localization in neuronal perikarya and varicosities. nNOS, NPY, and VIP were completely co‐localized in enteric co‐innervating nerve terminals on motor endplates. After co‐staining with VIP, we found (a) serotonin (5‐HT)‐positive nerve endings without VIP (44% of 5‐HT‐positively innervated endplates), (b) 5‐HT‐ and VIP‐positive endings without co‐localization (35%), and (c) 5‐HT‐ and VIP‐positive endings with co‐localization (21%). About one‐fifth of nerve terminals on motor endplates containing 5‐HT originate from putative inhibitory peptidegic nitrergic neurons. However, the majority represents a different population presumably subserving different functions.
Radiotherapy or Autologous Stem-Cell Transplantation for Primary CNS Lymphoma in Patients Age 60 Years and Younger: Long-Term Results of the Randomized Phase II PRECIS Study

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. We previously reported the results of a randomized phase II study in patients with newly diagnosed primary CNS lymphoma (age 18-60 years). Patients were treated with high-dose methotrexate-based induction chemotherapy followed by whole-brain radiotherapy (WBRT) or high-dose chemotherapy (thiotepa-busulfan-cyclophosphamide) with autologous stem-cell transplantation (ASCT). The median follow-up was 33 months. In this report, we provide long-term data (median follow-up, 8 years) regarding the outcomes and toxicities. Fifty-three and 44 patients received induction chemotherapy followed by WBRT or ASCT, respectively. Their 8-year event-free survival from random assignment was 67% and 39% in the ASCT and WBRT arms, respectively (P = .03), with a significantly lower risk of relapse after ASCT (hazard ratio, 0.13; P < .001). One third of patients who relapsed after WBRT were alive after salvage treatment. Five and four patients died of ASCT and WBRT-related toxicities, respectively. The 8-year overall survival was 69% and 65% in the ASCT and WBRT arms, respectively (not significant). Balance (52% v 10%, P ≤ 0.001) and neurocognition (64% v 13%, P < .001) significantly deteriorated after WBRT compared with ASCT during the follow-up. This study shows that 40 Gy WBRT should be avoided in first-line treatment because of its neurotoxicity and suboptimal efficacy in reducing relapses while ASCT appears to be highly efficient in preventing relapses.
Cooperative Learning of Deep Generative Models with Application in Sound Synthesis

Fires, rainstorms or insect swarms produce natural sounds made up of rapidly occurringacoustic events. which we call ”sound textures”. This kind of phenomena have been studiedby computational audio community [MS11] and neural science people for a long time. Fromprevious studies, it has been verified that sound textures can be schematically synthesizedfrom statistical models fairly well. Here we take a novel approach involving neural networksor deep learning methods. Specifically, we use cooperative training of a descriptor and agenerator network, modeled as a convolutional neural network(ConvNet) and a deconvolu-tional neural network(DeconvNet) respectively. From several experiments, we proved thatour framework can capture the essence of sound textures and synthesize identifiable naturalsound
What psychological interventions are effective for the management of persistent physical symptoms (PPS)? A systematic review and meta‐analysis

Abstract Objectives Presentation of persistent physical symptoms is associated with increased health care utilization, yet clinical outcomes often remain suboptimal. This systematic review aimed to determine whether psychological interventions are effective for the management of PPS and if so, what are the features of the interventions and at what level of care are they delivered. The review also set out to establish which symptoms in those diagnosed with PPS can be effectively managed with psychological intervention. Methods Studies were included if they clearly reported a psychological intervention, specified the study sample as adults with a diagnosis of persistent physical symptoms, included a comparator and as a minimum an outcome measure of somatic symptoms. Risk of bias was assessed using the EPHPP. Meta‐analysis was conducted to estimate the overall effect of interventions on somatic symptoms (the primary outcome), anxiety and depression (secondary outcomes). Results Seventeen papers of varying quality indicated that psychological interventions can be effective for the management of somatic symptoms reported by individuals with PPS within a primary care setting. Psychological interventions were also found to be effective at reducing depression symptoms in individuals with PPS in twelve of the included studies. However, the meta‐analysis results suggest that the psychological interventions utilized within eleven of the included studies did not significantly impact anxiety symptoms. Conclusions Psychological interventions have some success in managing somatic symptoms in PPS patients within primary care settings although their effects on other psychological symptoms is more mixed. The review highlights the importance of establishing a clearer diagnostic classification to inform treatment trajectories and the need for appropriate training and support within a multi‐disciplinary team to enable the provision of such therapies.
Creatine riboside is a cancer cell–derived metabolite associated with arginine auxotrophy

The metabolic dependencies of cancer cells have substantial potential to be exploited to improve the diagnosis and treatment of cancer. Creatine riboside (CR) is identified as a urinary metabolite associated with risk and prognosis in lung and liver cancer. However, the source of high CR levels in patients with cancer as well as their implications for the treatment of these aggressive cancers remain unclear. By integrating multiomics data on lung and liver cancer, we have shown that CR is a cancer cell–derived metabolite. Global metabolomics and gene expression analysis of human tumors and matched liquid biopsies, together with functional studies, revealed that dysregulation of the mitochondrial urea cycle and a nucleotide imbalance were associated with high CR levels and indicators of a poor prognosis. This metabolic phenotype was associated with reduced immune infiltration and supported rapid cancer cell proliferation that drove aggressive tumor growth. CRhi cancer cells were auxotrophic for arginine, revealing a metabolic vulnerability that may be exploited therapeutically. This highlights the potential of CR not only as a poor-prognosis biomarker but also as a companion biomarker to inform the administration of arginine-targeted therapies in precision medicine strategies to improve survival for patients with cancer.
Gap Analysis of Organizational Project Management Practices in Engineering Company - A Study of an Organization in Sweden, Finland and Abu-Dhabi

In an attempt to manage increasing cost and complexity of engineering projects, companies are emphasising on developing and applying good project management practices. Project management practices help organizations and practitioners to identify their priorities and develop related competencies to achieve their project targets. The main purpose of this study is to evaluate organizational project management practices at three different project offices, located in Sweden Finland and Abu-Dhabi, in an Engineering company to find out the best practices in order to deliver projects while focusing on the customer requirements and company’s internal processes. Project management theory offers a number of maturity assessment and evaluation techniques to analyse the implemented project management practices and process within an organization and help improving these processes to consistently achieve the organizational objectives. This study consists of interviews conducted with the senior project management, questionnaire distributed among the project team and study of internal processes in the studied company. The analysis revealed number of gaps in standard documentation and different project management practices associated to project execution which shows lack of company provided standards and best practices. Company provided systems to allocate resources and manage lessons learned for projects are not effectively managed which results in excessive use of external resources and repetition of mistakes. Furthermore, recommendations are provided to develop and implement company provided standards, with flexibility of accommodating local requirements of each office, guidelines and templates with the responsibility of each project individual to practice and improve those standards. Additionally, a new role of supportive PMO is recommended to introduce, who would support project managers in creating and developing project standards and to ensure same standards are implemented and continuously monitored in all three offices.
Fibrinogen supplementation for the trauma patient: Should you choose fibrinogen concentrate over cryoprecipitate?

Fibrinogen supplementation for bleeding trauma patients using fibrinogen concentrate instead of cryoprecipitate is associated with earlier fibrinogen administration and improved outcomes. BACKGROUND Trauma-induced coagulopathy is frequently associated with hypofibrinogenemia. Cryoprecipitate (Cryo), and fibrinogen concentrate (FC) are both potential means of fibrinogen supplementation. The aim of this study was to compare the outcomes of traumatic hemorrhagic patients who received fibrinogen supplementation using FC versus Cryo. METHODS We performed a 2-year (2016–2017) retrospective cohort analysis of the American College of Surgeons Trauma Quality Improvement Program database. All adult trauma patients (≥18 years) who received FC or Cryo as an adjunct to resuscitation were included. Patients with bleeding disorders, chronic liver disease, and those on preinjury anticoagulants were excluded. Patients were stratified into those who received FC, and those who received Cryo. Propensity score matching (1:2) was performed. Outcome measures were transfusion requirements, major complications, hospital, and intensive care unit lengths of stay, and mortality. RESULTS A matched cohort of 255 patients who received fibrinogen supplementation (85 in FC, 170 in Cryo) was analyzed. Overall, the mean age was 41 ± 19 years, 74% were male, 74% were white and median Injury Severity Score was 26 (22–30). Compared with the Cryo group, the FC group required less units of packed red blood cells, fresh frozen plasma, and platelets, and had shorter in-hospital and intensive care unit length of stay. There were no significant differences between the two groups in terms of major in-hospital complications and mortality. CONCLUSION Fibrinogen supplementation in the form of FC for the traumatic hemorrhagic patient is associated with improved outcomes and reduced transfusion requirements as compared with Cryo. Further studies are required to evaluate the optimal method of fibrinogen supplementation in the resuscitation of trauma patients. LEVEL OF EVIDENCE Therapeutic/Care Management; Level III.