Miracle-dz/UniFAR-FTUs huggingface dataset:
A Novel Missense Mutation in Peripheral Myelin Protein-22 Causes Charcot-Marie-Tooth Disease

Background: Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral neuropathy. A great number of causative genes have been described in CMT, and among them, the heterozygous duplication of peripheral myelin protein-22 (PMP22) is the major cause. Although the missense mutation in PMP22 is rarely reported, it has been demonstrated to be associated with CMT. This study described a novel missense mutation of PMP22 in a Chinese family with CMT phenotype. Methods: Targeted next-generation sequencing (NGS) was used to screen the causative genes in a family featured with an autosomal dominant demyelinating form of CMT. The potential variants identified by targeted NGS were verified by Sanger sequencing and classified according to the American College of Medical Genetics and Genomics standards and guidelines. Further cell transfection studies were performed to characterize the function of the novel variant. Results: Using targeted NGS, a novel heterozygous missense variant in PMP22 (c.320G>A, p.G107D) was identified. In vitro cell functional studies revealed that mutant PMP22 protein carrying p.G107D mutation lost the ability to reach the plasma membrane, was mainly retained in the endoplasmic reticulum, and induced cell apoptosis. Conclusions: This study supported the notion that missense mutations in PMP22 give rise to a CMT phenotype, possibly through a toxic gain-of-function mechanism.
Large Artery Atherosclerotic Occlusive Disease

ABSTRACT Purpose of Review: Extracranial or intracranial large artery atherosclerosis is often identified as a potential etiologic cause for ischemic stroke and transient ischemic attack. Given the high prevalence of large artery atherosclerosis in the general population, determining whether an identified atherosclerotic lesion is truly the cause of a patient’s symptomatology can be difficult. In all cases, optimally treating each patient to minimize future stroke risk is paramount. Extracranial or intracranial large artery atherosclerosis can be broadly compartmentalized into four distinct clinical scenarios based upon the individual patient’s history, examination, and anatomic imaging findings: asymptomatic and symptomatic extracranial carotid stenosis, intracranial atherosclerosis, and extracranial vertebral artery atherosclerotic disease. This review provides a framework for clinicians evaluating and treating such patients. Recent Findings: Intensive medical therapy achieves low rates of stroke and death in asymptomatic carotid stenosis. Evidence indicates that patients with severe symptomatic carotid stenosis should undergo carotid revascularization sooner rather than later and that the risk of stroke or death is lower using carotid endarterectomy than with carotid stenting. Specific to stenting, the risk of stroke or death is greatest among older patients and women. Continuous vascular risk factor optimization via sustained behavioral modifications and intensive medical therapy is the mainstay for stroke prevention in the setting of intracranial and vertebral artery origin atherosclerosis. Summary: Lifelong vascular risk factor optimization via sustained behavioral modifications and intensive medical therapy are the key elements to reduce future stroke risk in the setting of large artery atherosclerosis. When considering a revascularization procedure for carotid stenosis, patient demographics, comorbidities, and the periprocedural risks of stroke and death should be carefully considered.
Assessment of the antioxidant activity of an olive oil total polyphenolic fraction and hydroxytyrosol from a Greek Olea europea variety in endothelial cells and myoblasts

Olive oil (OO) constitutes the basis of the Mediterranean diet, and it seems that its biophenols, such as hydroxytyrosol (HT) may scavenge free radicals, attracting distinct attention due to their beneficial effects in many pathological conditions, such as cancer. To the best of our knowedge, this is the first study in which the functional properties of an OO total polyphenolic fraction (TPF) and pure HT were examined in order to determine their antioxidant effects at a cellular level in endothelial cells and myoblasts. The test compounds were isolated using a green gradient-elution centrifugal partition chromatography-based method that allows the isolation of large volumes of OO in a continuous extraction procedure and with extremely low solvent consumption. For the isolation of HT, a combination of two chromatographic techniques was used, which is effective for the recovery of pure compounds from complex natural extracts. Moreover, TPF and HT exhibited potent free radical scavenging activity in vitro. The cells were treated with non-cytotoxic concentrations and their redox status [in terms of glutathione (GSH) and reactive oxygen species (ROS) levels] was assessed. TPF extract was less cytotoxic than HT, and the observed differences between the two cell lines used suggest a tissue-specific activity. Finally, flow cytometric analysis revealed that both TPF and HT improved the redox status by increasing the levels of GSH, one of the most important antioxidant molecules, in both endothelial cells and myoblasts, while the ROS levels were not significantly affected.
Wet lay-up technique for manufacturing of advanced laminated composites

Incorporation of nanofillers into laminated composites is expected to produce a material with improved performance for many potential industrial applications. The focus of this work is to produce advanced composites by simple wet lay-up technique. The impact of adding three different nanofillers (multi-wall carbon nanotubes (MWCNT), silicon carbide (SiC) and aluminum oxide (Al2O3),) on the thermal and mechanical stability of woven Kevlar KM2Plus/epoxy composites was investigated. Silicon carbide and aluminum oxide were added at different weight percentages up to 3wt%, whereas the addition of multiwall carbon nanotubes was limited to 1wt%. The mechanical behavior was evaluated through three-point bending tests. The thermal stability was examined using differential scanning calorimetry (DSC) and thermo-gravimetric analysis (TGA) techniques. The results revealed that simple wet lay-up technique is a recommended alternative method for production of thermostable composites with improved thermomechanical performance. The improvement in thermomechanical stability increases with the nanofiller content. However, MWCNT composites showed an optimum content value of 0.5wt % after which the mechanical performance starts to degrade due to agglomeration.
Cyclooxygenase-2 (COX-2) polymorphism rs689466 may contribute to the increased susceptibility to post-traumatic osteomyelitis in Chinese population

Abstract Background: Cyclooxygenase-2 (COX-2) enzyme is one of the major mediators during inflammation reactions, and COX-2 gene polymorphisms of rs20417 and rs689466 have been reported to be associated with several inflammatory diseases. However, potential links between the two polymorphisms and risk of developing post-traumatic osteomyelitis remain unclear. The present study aimed to investigate associations between the rs20417 and rs689466 polymorphisms and susceptibility to post-traumatic osteomyelitis in Chinese population. Methods: A total of 189 patients with definite diagnosis of post-traumatic osteomyelitis and 220 healthy controls were genotyped for rs20417 and rs689466 using the SNaPshot genotyping method. Chi-square test was used to compare differences of genotype distributions as well as outcomes of five different genetic models between the two groups. Results: Significant association was found between rs689466 and post-traumatic osteomyelitis by recessive model (GG vs. AA + AG) (OR = 1.74, 95% CI: 1.098–2.755, p = .018). Although no statistical differences were identified of rs689466 between the two groups by allele model (p = .098) or homozygous model (p = .084), outcomes revealed a tendency that allele G may be a risk factor and people of GG genotype may be in a higher risk to develop post-traumatic osteomyelitis in Chinese population. However, no significant link was found between rs20417 and susceptibility to post-traumatic osteomyelitis in this Chinese cohort. Conclusions: To our knowledge, we reported for the first time that COX-2 gene polymorphism rs689466 may contribute to the increased susceptibility to post-traumatic osteomyelitis in Chinese population.
A wearable resistive robot facilitates locomotor adaptations during gait.

BACKGROUND Robotic-resisted treadmill walking is a form of task-specific training that has been used to improve gait function in individuals with neurological injury, such as stroke, spinal cord injury, or cerebral palsy. Traditionally, these devices use active elements (e.g., motors or actuators) to provide resistance during walking, making them bulky, expensive, and less suitable for overground or in-home rehabilitation. We recently developed a low-cost, wearable robotic brace that generates resistive torques across the knee joint using a simple magnetic brake. However, the possible effects of training with this device on gait function in a clinical population are currently unknown. OBJECTIVE The purpose of this study was to test the acute effects of resisted walking with this device on kinematics, muscle activation patterns, and gait velocity in chronic stroke survivors. METHODS Six stroke survivors wore the resistive brace and walked on a treadmill for 20 minutes (4×5 minutes) at their self-selected walking speed while simultaneously performing a foot trajectory-tracking task to minimize stiff-knee gait. Electromyography, sagittal plane gait kinematics, and overground gait velocity were collected to evaluate the acute effects of the device on gait function. RESULTS Robotic-resisted treadmill training resulted in a significant increase in quadriceps and hamstring EMG activity during walking. Significant aftereffects (i.e., improved joint excursions) were also observed on the hip and knee kinematics, which persisted for several steps after training. More importantly, training resulted in significant improvements in overground gait velocity. These results were consistent in all the subjects tested. CONCLUSION This study provides preliminary evidence indicating that robotic-resisted treadmill walking using our knee brace can result in meaningful biomechanical aftereffects that translate to overground walking.
Hybrid CMOS-Graphene Sensor Array for Subsecond Dopamine Detection

We introduce a hybrid CMOS-graphene sensor array for subsecond measurement of dopamine via fast-scan cyclic voltammetry (FSCV). The prototype chip has four independent CMOS readout channels, fabricated in a 65-nm process. Using planar multilayer graphene as biologically compatible sensing material enables integration of miniaturized sensing electrodes directly above the readout channels. Taking advantage of the chemical specificity of FSCV, we introduce a region of interest technique, which subtracts a large portion of the background current using a programmable low-noise constant current at about the redox potentials. We demonstrate the utility of this feature for enhancing the sensitivity by measuring the sensor response to a known dopamine concentration in vitro at three different scan rates. This strategy further allows us to significantly reduce the dynamic range requirements of the analog-to-digital converter (ADC) without compromising the measurement accuracy. We show that an integrating dual-slope ADC is adequate for digitizing the background-subtracted current. The ADC operates at a sampling frequency of 5–10 kHz and has an effective resolution of about 60 pA, which corresponds to a theoretical dopamine detection limit of about 6 nM. Our hybrid sensing platform offers an effective solution for implementing next-generation FSCV devices that can enable precise recording of dopamine signaling in vivo on a large scale.
Effect of Polymorphisms on the Pharmacokinetics, Pharmacodynamics and Safety of Sertraline in Healthy Volunteers

Sertraline is a selective serotonin reuptake inhibitor widely metabolized in the liver by cytochrome P450 (CYP) enzymes. Besides, it is a P‐glycoprotein substrate. Moreover, serotonin transporters and serotonin receptors are involved in its efficacy and safety. The aim of this study was to evaluate the role of polymorphisms of metabolizing enzymes, transporters and receptors on the pharmacokinetics, pharmacodynamics and tolerability of sertraline in healthy volunteers. Forty‐six healthy volunteers (24 men and 22 women) receiving a 100‐mg single oral dose of sertraline were genotyped for 17 genetic variants of CYP enzymes (CYP2B6, CYP2C9, CYP2C19, CYP2D6), ATP‐binding cassette subfamily B member 1 (ABCB1), solute carrier family 6 member 4 (SLC6A4), 5‐hydroxytryptamine receptor 2A (HTR2A) and 5‐hydroxytryptamine receptor 2C (HTR2C) genes. Pharmacokinetic and pharmacodynamic parameters were similar in men and women. Polymorphisms in CYP2C19 and CYP2B6 genes influenced sertraline pharmacokinetics, with a greater effect of CYP2C19. Individuals carrying defective alleles for CYP2C19 and CYP2B6 showed higher area under the curve (AUC) and half‐life (T1/2). Moreover, CYP2C19*17 was related to a decreased AUC and T1/2. No significant effect was found for polymorphisms in CYP2C9, CYP2D6 and ABCB1 on sertraline pharmacokinetics. Sertraline had a small heart rate‐lowering effect, directly related to maximum concentration (Cmax) and the presence of ABCB1 minor alleles. Sertraline had no significant effect on blood pressure and QTc. There was a tendency to present more adverse drug reactions in women and individuals with higher AUC of sertraline, such as CYP2C19 intermediate metabolizers and CYP2B6 G516T T/T individuals.
Trypanosomatid Infections: How Do Parasites and Their Excreted–Secreted Factors Modulate the Inducible Metabolism of l-Arginine in Macrophages?

Mononuclear phagocytes (monocytes, dendritic cells, and macrophages) are among the first host cells to face intra- and extracellular protozoan parasites such as trypanosomatids, and significant expansion of macrophages has been observed in infected hosts. They play essential roles in the outcome of infections caused by trypanosomatids, as they can not only exert a powerful antimicrobial activity but also promote parasite proliferation. These varied functions, linked to their phenotypic and metabolic plasticity, are exerted via distinct activation states, in which l-arginine metabolism plays a pivotal role. Depending on the environmental factors and immune response elements, l-arginine metabolites contribute to parasite elimination, mainly through nitric oxide (NO) synthesis, or to parasite proliferation, through l-ornithine and polyamine production. To survive and adapt to their hosts, parasites such as trypanosomatids developed mechanisms of interaction to modulate macrophage activation in their favor, by manipulating several cellular metabolic pathways. Recent reports emphasize that some excreted–secreted (ES) molecules from parasites and sugar-binding host receptors play a major role in this dialog, particularly in the modulation of the macrophage’s inducible l-arginine metabolism. Preventing l-arginine dysregulation by drugs or by immunization against trypanosomatid ES molecules or by blocking partner host molecules may control early infection and is a promising way to tackle neglected diseases including Chagas disease, leishmaniases, and African trypanosomiases. The present review summarizes recent knowledge on trypanosomatids and their ES factors with regard to their influence on macrophage activation pathways, mainly the NO synthase/arginase balance. The review ends with prospects for the use of biological knowledge to develop new strategies of interference in the infectious processes used by trypanosomatids, in particular for the development of vaccines or immunotherapeutic approaches.
Safe, Efficient, and Robust SDN Updates by Combining Rule Replacements and Additions

Disruption-free updates are a key primitive to effectively operate SDN networks and maximize the benefits of their programmability. In this paper, we study how to implement this primitive safely (with respect to forwarding correctness and policies), efficiently (in terms of consumed network resources) and robustly to unpredictable factors, such as delayed message delivery and processing. First, we analyze the fundamental limitations of prior proposals, which either: 1) progressively replace initial flow rules with new ones or 2) instruct switches to maintain both initial and final rules. Second, we show that safe, efficient, and robust updates can be achieved by leveraging a more general approach. We indeed unveil a dualism between rule replacements and additions that opens new degrees of freedom for supporting SDN updates. Third, we demonstrate how to build upon this dualism. We propose FLIP, an algorithm that computes operational sequences combining the efficiency of rule replacements with the applicability of rule additions. FLIP identifies constraints on rule replacements and additions that independently prevent safety violations from occurring during the update. Then, it explores the solution space by swapping constraints that prevent the same safety violations, until it reaches a satisfiable set of constraints. Fourth, we perform extensive simulations, showing that FLIP can significantly outperform prior work. In the average case, it guarantees a much higher success rate than algorithms only based on rule replacements, and massively reduces the memory overhead needed by techniques solely using rule additions.
The delta opioid peptide D‐Alanine 2, Leucine 5 Enkephaline (DADLE)‐induces neuroprotection through cross‐talk between the UPR and pro‐survival MAPK‐NGF‐Bcl2 signaling pathways via modulation of several micro‐RNAs in SH‐SY5Y cells subjected to ER stress

Parkinson's disease (PD) is the second most progressive neurodegenerative disease characterized by the loss of dopaminergic neurons and accumulation of misfolded proteins in endoplasmic reticulum (ER) leading to activation of the unfolded protein response (UPR). In the present study, we aimed to determine the potential survival effect of the delta opioid neuro‐peptide D‐Alanine 2, Leucine 5 Enkephaline (DADLE), and its mechanism in dopaminergic SH‐SY5Y cells which were subjected to ER stress. In this cellular model of PD, enhanced cell survivability was observed on DADLE treatment (but not with μ and κ opioid agonists) along with concomitant down regulation of the UPR stress sensors and protein aggregates. The study found increased phosphorylation of MEK‐1, which leads to activation of MAP kinase as well as enhanced expression of the pro‐survival gene nerve growth factor and anti‐apoptotic marker Bcl2. DADLE treatment could also significantly inhibit expression of the pro‐apoptotic marker BIM. Next‐generation sequence analysis revealed 93 micro (mi) RNAs to be differentially regulated following DADLE treatment in cells subjected to ER stress. Pathway prediction and previously published reports revealed that out of these 93 miRNAs, 34 can play a role in promoting cell survival. Specific modulation of two such miRNAs, namely miR‐30c‐2‐3p and miR‐200c, could partially reverse the positive survival effect induced by DADLE. Apart from the known miRNAs, various novel miRNAs were also observed following DADLE treatment which could also play a role in enhancing the survival of SH‐SY5Y cells under ER stress.
Mechanisms underlying capsaicin effects in canine coronary artery: implications for coronary spasm.

AIMS The TRPV1, transient receptor potential vanilloid type 1, agonist capsaicin is considered to be beneficial for cardiovascular health because it dilates coronary arteries through an endothelial-dependent mechanism and may slow atheroma progression. However, recent reports indicate that high doses of capsaicin may constrict coronary arterioles and even provoke myocardial infarction. Thus far, the mechanisms by which TRPV1 activation modulates coronary vascular tone remain poorly understood. This investigation examined whether there is a synergistic interplay between locally acting vasoconstrictive pro-inflammatory hormones (autacoids) and capsaicin effects in the coronary circulation. METHODS AND RESULTS Experiments were performed in canine conduit coronary artery rings and isolated smooth muscle cells (CASMCs). Isometric tension measurements revealed that 1-10 μM capsaicin alone did not affect resting tension of coronary artery rings. In contrast, in endothelium-intact rings pre-contracted with a Gq/11-coupled FP/TP (prostaglandin F/thromboxane) receptor agonist, prostaglandin F2α (PGF2α; 10 μM), capsaicin first induced transient dilation that was followed by sustained contraction. In endothelium-denuded rings pre-contracted with PGF2α or thromboxane analogue U46619 (1 μM, a TP receptor agonist), capsaicin induced only sustained contraction. Blockers of the TP receptor or TRPV1 significantly inhibited capsaicin effects, but these were still observed in the presence of 50 μM nifedipine and 70 mM KCl. Capsaicin also potentiated 20 mM KCl-induced contractions. Fluorescence imaging experiments in CASMCs revealed that the Gq/11-phospholipase C (PLC)-protein kinase C (PKC) and Ca(2+)-PLC-PKC pathways are likely involved in sensitizing CASMC TRPV1 channels. CONCLUSION Capsaicin alone does not cause contractions in conduit canine coronary artery; however, pre-treatment with pro-inflammatory prostaglandin-thromboxane agonists may unmask capsaicin's vasoconstrictive potential.
Association Control for Vehicular WiFi Access: Pursuing Efficiency and Fairness

Deploying road-side WiFi access points has made possible internet access in a vehicle, nevertheless it is challenging to maintain client performance at vehicular speed especially when multiple mobile users exist. This paper considers the association control problem for vehicular WiFi access in the Drive-thru Internet scenario. In particular, we aim to improve the efficiency and fairness for all users. We design efficient algorithms to achieve these objectives through several techniques including approximation. Our simulation results demonstrate that our algorithms can achieve significantly better performance than conventional approaches.
Differential effects of circadian typology on sleep-related symptoms, physical fatigue and psychological well-being in relation to resilience

ABSTRACT Various physiological and psychological functions are influenced by circadian typology (CT), which was reported to be related to resilience. However, few studies have assessed the effects of CT in relation to resilience. The aim of the present study was to assess the influence of CT on sleep-related symptoms, physical fatigue and psychological well-being in relation to resilience. The present study included a total of 1794 healthy hospital employees, and they completed the Morningness–Eveningness Questionnaire, Connor–Davidson Resilience Scale, Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale, Fatigue Severity Scale, Hospital Anxiety and Depression Scale and World Health Organization Quality of Life Scale Abbreviated Version. Subjects with evening type showed lower sleep quality, more daytime sleepiness and physical fatigue than neither types and morning types. Additionally, evening types were more depressed and anxious and reported a poorer quality of life. CT was found to be a significant predictor of sleep quality, but CT was minimally associated with physical fatigue and psychological well-being in the regression analysis. Instead, resilience was substantially related to all of the variables measured. In conclusion, CT independently predicts sleep quality, but the effects of CT on physical fatigue and psychological well-being are negligible compared to those of resilience.