Miracle-dz/UniFAR-FTUs huggingface dataset:
An “Outside-In” and “Inside-Out” Consideration of Complement in the Multiple Sclerosis Brain: Lessons From Development and Neurodegenerative Diseases

The last 15 years have seen an explosion of new findings on the role of complement, a major arm of the immune system, in the central nervous system (CNS) compartment including contributions to cell migration, elimination of synapse during development, aberrant synapse pruning in neurologic disorders, damage to nerve cells in autoimmune diseases, and traumatic injury. Activation of the complement system in multiple sclerosis (MS) is typically thought to occur as part of a primary (auto)immune response from the periphery (the outside) against CNS antigens (the inside). However, evidence of local complement production from CNS-resident cells, intracellular complement functions, and the more recently discovered role of early complement components in shaping synaptic circuits in the absence of inflammation opens up the possibility that complement-related sequelae may start and finish within the brain itself. In this review, the complement system will be introduced, followed by evidence that implicates complement in shaping the developing, adult, and normal aging CNS as well as its contribution to pathology in neurodegenerative conditions. Discussion of data supporting “outside-in” vs. “inside-out” roles of complement in MS will be presented, concluded by thoughts on potential approaches to therapies targeting specific elements of the complement system.
The IL-17/IL-23 Axis and Its Genetic Contribution to Psoriatic Arthritis

Psoriatic arthritis (PsA) is a chronic inflammatory disease belonging to the family of spondyloarthropathies (SpA). PsA commonly aggravates psoriasis of the skin and frequently manifests as an oligoarthritis with axial skeletal involvement and extraarticular manifestations including dactylitis, enthesitis, and uveitis. The weight of genetic predisposition to psoriasis and PsA is illustrated by the concordance rates in monozygotic twins which clearly demonstrate that genomics is insufficient to induce the clinical phenotype. The association of PsA with several single nucleotide polymorphisms (SNPs) at the IL23R locus and the involvement of Th17 cells in the immunopathogenesis of PsA clearly put the IL-23/IL-17 axis in the spotlight. The IL-23 and IL-17 cytokines have a pivotal role in the chronic inflammation of the synovium in PsA and are also prominent in the skin lesions of those with PsA. In this review, we focus on the genetic association of the IL-23/IL-17 axis with PsA and the contribution of these master cytokines in the pathophysiology of the disease, highlighting the main cell types incriminated in PsA and their specific role in the peripheral blood, lesional skin and joints of patients. We then provide an overview of the approved biologic drugs targeting the IL-23/IL-17 axis and discuss the advantages of genetic stratification to enhance personalized therapies in PsA.
DYNAMICS OF NITROGEN AND CARBON IN SOIL DURING PAPERMILL SLUDGE DECOMPOSITION1

A fertile agricultural soil was amended with primary papermill sludge at rates from 0 to 267 g/kg soil. Samples incubated at 12 and 25°C displayed N immobilization proportional to the rates of sludge addition. Prior to 50 d of incubation, N immobilization was pronounced at both temperatures. Between 50 and 100 d, net mineralization began in the 33-g/kg treatment at 12°C and in the 33-g/kg and 67-g/kg treatments at 25°C. By day 150, net mineralization was evident in the 67-g/kg rate at 12°C and in the 133-g/kg treatment at 25°C. By the end of the incubation, extractable N levels were reduced from approximately 3 to 80% of the controls incubated at 12°C and from approximately 1 to 84% of the controls incubated at 25°C. A highly significant negative relationship between extractable N and sludge addition was determined at day 250. Statistical analyses indicated significant differences in the polynomial regression equations for each temperature. Total carbon mineralized was significantly increased with incremental sludge addition. Mineralized Carbon (as a percentage of added sludge C) ranged from approximately 7% in the 267-g/kg rate to approximately 24% in the 17-g/kg rate incubated at 12°C, and from 17% in the 267-g/kg rate to 65% in the 17-g/kg rate incubated at 25°C. Organic matter determined on day 250 indicated that the 133− and 267-g/kg rates significantly increased organic matter content at both incubation temperatures. Results suggest that, with proper management, papermill sludge could be useful in conservation of soil N and organic matter.
Personality, Coping Strategies, and Mental Health in High-Performance Athletes During Confinement Derived From the COVID-19 Pandemic

The COVID-19 outbreak has affected the sports field unprecedentedly. The emergency alert has deprived athletes of training in a suitable environment, as they are faced with cancellations of relevant events in their sports careers. This situation can cause stress levels and other emotional disorders similar to those experienced by athletes during periods of injury. Since the relationship between psychological factors and sports injuries is well-studied, the Global Psychological Model of Sports Injury (MGPLD) is applied to this historical situation for athletes. The purpose of this study was to analyze the relationships between perfectionism and trait anxiety with indicators of mental health (mood, depression, state anxiety, and stress) in high-performance athletes during confinement due to the COVID-19 pandemic, as well as to explore the coping strategies that athletes have applied and whether they are perceived as useful for managing negative emotional states. A cross-sectional study was conducted through online questionnaires during April 2020, adapting the Psychological Assessment Protocol of the High-Performance Sports Center of Murcia (Spain), to assess the psychological effects of confinement in a cross-cultural sample of 310 athletes (141 women and 169 men) from different countries in Europe, Asia, and America, and from diverse sports disciplines. The protocol comprised six instruments that test perfectionism, trait anxiety, mood states, stress, depression, coping strategies, and sleep. It was answered online via Google Forms. The results show that maladaptive perfectionism was related to all the indicators of athletes' mental health. However, athletes' levels of anxiety, stress, and depressive symptoms are relatively low, and the use of coping strategies such as cognitive restructuring and emotional calm was associated with lower levels of negative emotional states. Besides, the Iceberg Profile, a suitable fit for the mental health model, is observed in the mood of athletes, both in men and in women, although women showed higher levels of anxiety, stress, and depression than men. A strong relationship was observed between maladaptive perfectionism and martial arts sports discipline, superior to other sports. In short, it can be concluded that high-performance athletes in the studied sample showed negative emotional state values below the expected average. Finally, the proposals for practical applications of the results collected are discussed.
Destabilizing Different Strengths of Fear Memories Requires Different Degrees of Prediction Error During Retrieval

Reactivation of consolidated memories can induce a labile period, in which these reactivated memories might be susceptible to change and need reconsolidation. Prediction error (PE) has been recognized as a necessary boundary condition for memory destabilization. Moreover, memory strength is also widely accepted as an essential boundary condition to destabilize fear memory. This study investigated whether different strengths of conditioned fear memories require different degrees of PE during memory reactivation in order for the memories to become destabilized. Here, we assessed the fear-potentiated startle and skin conductance response, using the post-retrieval extinction procedure. A violation of expectancy (PE) was induced during retrieval to reactivate enhanced (unpredictable-shock) or ordinary (predictable-shock) fear memories that were established the day before. Results showed that a PE retrieval before extinction can prevent the return of predictable-shock fear memory but cannot prevent the return of unpredictable-shock fear memory, indicating that a single PE is insufficient to destabilize enhanced fear memory. Therefore, we further investigated whether increasing the degree of PE could destabilize enhanced fear memory using different retrieval strategies (multiple PE retrieval and unreinforced CS retrieval). We found that spontaneous recovery of enhanced fear memory was prevented in both retrieval strategies, but reinstatement was only prevented in the multiple PE retrieval group, suggesting that a larger amount of PE is needed to destabilize enhanced fear memory. The findings suggest that behavioral updating during destabilization requires PE, and the degree of PE needed to induce memory destabilization during memory retrieval depends on the strength of fear memory. The study indicates that memory reconsolidation inference can be used to destabilize stronger memories, and the findings shed lights on the treatment of posttraumatic stress disorders and anxiety disorders.
Peptide-Based Targeting of the L-Type Calcium Channel Corrects the Loss-of-Function Phenotype of Two Novel Mutations of the CACNA1 Gene Associated With Brugada Syndrome

Brugada syndrome (BrS) is an inherited arrhythmogenic disease that may lead to sudden cardiac death in young adults with structurally normal hearts. No pharmacological therapy is available for BrS patients. This situation highlights the urgent need to overcome current difficulties by developing novel groundbreaking curative strategies. BrS has been associated with mutations in 18 different genes of which loss-of-function (LoF) CACNA1C mutations constitute the second most common cause. Here we tested the hypothesis that BrS associated with mutations in the CACNA1C gene encoding the L-type calcium channel (LTCC) pore-forming unit (Cavα1.2) is functionally reverted by administration of a mimetic peptide (MP), which through binding to the LTCC chaperone beta subunit (Cavβ2) restores the physiological life cycle of aberrant LTCCs. Two novel Cavα1. 2 mutations associated with BrS were identified in young individuals. Transient transfection in heterologous and cardiac cells showed LoF phenotypes with reduced Ca2+ current (ICa). In HEK293 cells overexpressing the two novel Cavα1. 2 mutations, Western blot analysis and cell surface biotinylation assays revealed reduced Cavα1. 2 protein levels at the plasma membrane for both mutants. Nano-BRET, Nano-Luciferase assays, and confocal microscopy analyses showed (i) reduced affinity of Cavα1. 2 for its Cavβ2 chaperone, (ii) shortened Cavα1. 2 half-life in the membrane, and (iii) impaired subcellular localization. Treatment of Cavα1. 2 mutant-transfected cells with a cell permeant MP restored channel trafficking and physiologic channel half-life, thereby resulting in ICa similar to wild type. These results represent the first step towards the development of a gene-specific treatment for BrS due to defective trafficking of mutant LTCC.
The Association of Early Electrocardiographic Abnormalities With Brain Injury Severity and Outcome in Severe Traumatic Brain Injury

The aim of this study was to evaluate the frequency of electrocardiographic (ECG) abnormalities in the acute phase of severe traumatic brain injury (TBI) and the association with brain injury severity and outcome. In contrast to neurovascular diseases, sparse information is available on this issue. Data of adult patients with severe TBI admitted to the Intensive Care Unit (ICU) for intracranial pressure monitoring of a level-1 trauma center from 2002 till 2018 were analyzed. Patients with a cardiac history were excluded. An ECG recording was obtained within 24 h after ICU admission. Admission brain computerized tomography (CT)-scans were categorized by Marshall-criteria (diffuse vs. mass lesions) and for location of traumatic lesions. CT-characteristics and maximum Therapy Intensity Level (TILmax) were used as indicators for brain injury severity. We analyzed data of 198 patients, mean (SD) age of 40 ± 19 years, median GCS score 3 [interquartile range (IQR) 3–6], and 105 patients (53%) had thoracic injury. In-hospital mortality was 30%, with sudden death by cardiac arrest in four patients. The incidence of ECG abnormalities was 88% comprising ventricular repolarization disorders (57%) mostly with ST-segment abnormalities, conduction disorders (45%) mostly with QTc-prolongation, and arrhythmias (38%) mostly of supraventricular origin. More cardiac arrhythmias were observed with increased grading of diffuse brain injury (p = 0.042) or in patients treated with hyperosmolar therapy (TILmax) (65%, p = 0.022). No association was found between ECG abnormalities and location of brain lesions nor with thoracic injury. Multivariate analysis with baseline outcome predictors showed that cardiac arrhythmias were not independently associated with in-hospital mortality (p = 0.097). Only hypotension (p = 0.029) and diffuse brain injury (p = 0.017) were associated with in-hospital mortality. In conclusion, a high incidence of ECG abnormalities was observed in patients with severe TBI in the acute phase after injury. No association between ECG abnormalities and location of brain lesions or presence of thoracic injury was present. Cardiac arrhythmias were indicative for brain injury severity but not independently associated with in-hospital mortality. Therefore, our findings likely suggest that ECG abnormalities should be considered as cardiac mimicry representing the secondary effect of traumatic brain injury allowing for a more rationale use of neuroprotective measures.
TSPAN7 Exerts Anti-Tumor Effects in Bladder Cancer Through the PTEN/PI3K/AKT Pathway

The tetraspanin protein superfamily participate in the dynamic regulation of cellular membrane compartments expressed in a variety of tumor types, which may alter the biological properties of cancer cells such as cell development, activation, growth and motility. The role of tetraspanin 7 (TSPAN7) has never been investigated in bladder cancer (BCa). In this study, we aimed to investigate the biological function of TSPAN7 and its therapeutic potential in human BCa. First, via reverse transcription and quantitative real-time PCR (qRT-PCR), we observed downregulation of TSPAN7 in BCa tissues samples and cell lines and found that this downregulation was associated with a relatively high tumor stage and tumor grade. Low expression of TSPAN7 was significantly correlated with a much poorer prognosis for BCa patients than was high expression. Immunohistochemistry (IHC) showed that low TSPAN7 expression was a high-risk predictor of BCa patient overall survival. Furthermore, the inhibitory effects of TSPAN7 on the proliferation and migration of BCa cell lines were detected by CCK-8, wound-healing, colony formation and transwell assays in vitro. Flow cytometry analysis revealed that TSPAN7 induced BCa cell lines apoptosis and cell cycle arrest. In vivo, tumor growth in nude mice bearing tumor xenografts could be obviously affected by overexpression of TSPAN7. Western blotting showed that overexpression of TSPAN7 activated Bax, cleaved caspase-3 and PTEN but inactivated Bcl-2, p-PI3K, and p-AKT to inhibit BCa cell growth via the PTEN/PI3K/AKT pathway. Taken together, our study will help identify a potential marker for BCa diagnosis and supply a target molecule for BCa treatment.
PEIERLS INSTABILITY AND VIBRATIONAL SPECTRA OF POLYACETYLENE

It is shown that the Peierls instability in conjugated polymers is modified by the interaction of π electrons. This modification gives rise to the absence of a soft mode of stretching CC vibrations. Taking into account electron correlations we obtain reasonable agreement between the calculated and measured frequencies of the carbon skeleton of polyacetylene with all the CC bonds being equal in length. It is shown that the conclusion for the bond length alternation in polyacetylene does not follow from the experimental data on the vibrations of polyacetylene.
How Well Do Commonly Used Co-contraction Indices Approximate Lower Limb Joint Stiffness Trends During Gait for Individuals Post-stroke?

Muscle co-contraction generates joint stiffness to improve stability and accuracy during limb movement but at the expense of higher energetic cost. The quantification of joint stiffness generated from muscle co-contraction is difficult through both experimental and computational means for its benefit and cost to be assessed. Quantification of muscle co-contraction may offer an alternative path for estimating joint stiffness. By choosing the commonly used Co-Contraction Indices (CCIs) to represent muscle co-contraction, this study investigated the feasibility of using CCI to approximate lower limb joint stiffness trends during gait. A calibrated EMG-driven musculoskeletal model of a hemiparetic individual post-stroke from a previous study was used to generate the quantities required for CCI calculation and model-based estimation of joint stiffness. A total of 14 classes of CCIs for various combinations of antagonistic muscle pairs were calculated based on two common CCI formulations, each with 7 types of quantities that included variations of electromyography (EMG) signals and joint moments from the muscles. Correlations between CCIs and model-based estimates of sagittal plane stiffness of the lower extremity joints (hip, knee, ankle) were computed. Although moderate to strong correlation was observed between some CCI formulations and the corresponding joint stiffness, these associations were highly dependent on the methodological choices made for CCI computation. The overall findings of this study were the following: (1) the formulation proposed by Rudolph et al. (2000), CCI1, was more correlated with joint stiffness than that of Falconer and Winter (1985); (2) Moment-based CCI1 from individual antagonistic muscle pairs was more correlated than EMG-based CCI1; (3) EMG signals with calibrated electromechanical delay and joint moment generated by individual muscle without normalization to a reference value were the most correlated for EMG-based CCI1 and moment-based CCI1, respectively. The combination of antagonistic muscle pairs for most correlated within each CCI class was also identified. By using CCI to approximate joint stiffness trends, this study may open an alternative path to studying joint stiffness.
Long-Term Survival in Nonsurgical Esophageal Cancer Patients Who Received Consolidation Chemotherapy Compared With Patients Who Received Concurrent Chemoradiotherapy Alone: A Systematic Review and Meta-Analysis

Background Concurrent chemoradiotherapy (CCRT) is the standard treatment for nonsurgical esophageal cancer (EC). However, esophageal cancer patients receiving CCRT alone are still unsatisfactory in terms of local control and overall survival (OS) benefit. Clinicians generally add consolidation chemotherapy (CCT) after CCRT. It remains controversial whether CCT following CCRT is beneficial for esophageal cancer. We, therefore, undertook a meta-analysis to assess the need for CCT in inoperable esophageal cancer. Materials and Methods We combed PubMed, Embase, Cochrane Library, Web of Science, and CNKI for relevant published articles up to July 2020 that compared CCRT plus CCT to CCRT alone for patients with nonsurgical EC. Our primary endpoint was OS and progression-free survival (PFS), and the secondary endpoint was treatment toxicity. We analyzed the hazard ratio (HR) to estimate the time-to-event data and the odds ratio (OR) to compare the treatment-related effect. To assess heterogeneity, we performed the I2 test and examined publication bias using funnel plots analysis. Results The 11 retrospective studies involved 2008 patients. Of these 2008 patients, 1018 received CCRT plus CCT, and 990 received CCRT. Compared to CCRT alone, CCT after CCRT did not improve disease control rate (DCR) (OR 1.66; 95% CI 0.53–5.15, p=0.384) and objective response rate (ORR) (OR 1.44; 95% CI 0.62–3.35, p=0.393). However, OS (HR 0.72; 95% CI 0.59–0.86, p < 0.001) and PFS (HR 0.61; 95% CI 0.44–0.84, p=0.003) did increase. Our results show that CCT plus CCRT had a clear survival advantage over CCRT alone. The risk of treatment toxicity did not increase for EC patients who received CCT. Conclusion CCT after CCRT significantly increases OS and PFS in patients with nonsurgical EC and could provide them remarkable survival benefits. The results provide an evidence-based framework for the use of CCT after CCRT.
Rapid GMP-Compliant Expansion of SARS-CoV-2–Specific T Cells From Convalescent Donors for Use as an Allogeneic Cell Therapy for COVID-19

COVID-19 disease caused by the SARS-CoV-2 virus is characterized by dysregulation of effector T cells and accumulation of exhausted T cells. T cell responses to viruses can be corrected by adoptive cellular therapy using donor-derived virus-specific T cells. One approach is the establishment of banks of HLA-typed virus-specific T cells for rapid deployment to patients. Here we show that SARS-CoV-2–exposed blood donations contain CD4 and CD8 memory T cells which recognize SARS-CoV-2 spike, nucleocapsid and membrane antigens. Peptides of these antigens can be used to isolate virus-specific T cells in a GMP-compliant process. The isolated T cells can be rapidly expanded using GMP-compliant reagents for use as an allogeneic therapy. Memory and effector phenotypes are present in the selected virus-specific T cells, but our method rapidly expands the desirable central memory phenotype. A manufacturing yield ranging from 1010 to 1011 T cells can be obtained within 21 days culture. Thus, multiple therapeutic doses of virus-specific T cells can be rapidly generated from convalescent donors for potential treatment of COVID-19 patients.
Effect of Induction Chemotherapy in Nasopharyngeal Carcinoma: An Updated Meta-Analysis

Background Previous meta-analysis had evaluated the effect of induction chemotherapy in nasopharyngeal carcinoma. But two trials with opposite findings were not included and the long-term result of another trial significantly differed from the preliminary report. This updated meta-analysis was thus warranted. Methods Literature search was conducted to identify randomized controlled trials focusing on the additional efficacy of induction chemotherapy in nasopharyngeal carcinoma. Trial-level pooled analysis of hazard ratio (HR) for progression free survival and overall survival and risk ratio (RR) for locoregional control rate and distant control rate were performed. Results Twelve trials were eligible. The addition of induction chemotherapy significantly prolonged both progression free survival (HR=0.68, 95% confidence interval [CI] 0.60–0.76, p<0.001) and overall survival (HR=0.67, 95% CI 0.54–0.80, p<0.001), with 5-year absolute benefit of 11.31% and 8.95%, respectively. Locoregional (RR=0.80, 95% CI 0.70–0.92, p=0.002) and distant control (RR=0.70, 95% CI 0.62–0.80) rates were significantly improved as well. The incidence of grade 3–4 adverse events during the concurrent chemoradiotherapy was higher in leukopenia (p=0.028), thrombocytopenia (p<0.001), and fatigue (p=0.038) in the induction chemotherapy group. Conclusions This meta-analysis supported that induction chemotherapy could benefit patients with nasopharyngeal carcinoma in progression free survival, overall survival, locoregional, and distant control rate.