Genetic analysis of a family affected by congenital myasthenic syndrome due to a Novel mutation in the SLC5A7 gene.

BACKGROUND: Mutations in the SLC5A7 gene cause congenital myasthenia, a rare genetic disorder. Mutation points in the SLC5A7 gene differ among individuals and encompass various genetic variations; however, exon deletion variants have yet to be reported in related cases. This study aims to explore the clinical phenotype and genetic traits of a patient with congenital myasthenic syndrome due to SLC5A7 gene variation and those of their family members. CASE PRESENTATION: We describe a case of a Chinese male with congenital myasthenic syndrome presenting fluctuating limb weakness. Genetic testing revealed a heterozygous deletion mutation spanning exons 1-9 in the SLC5A7 gene. QPCR confirmed a deletion in exon 9 of the SLC5A7 gene in the patient's mother and brother. Clinical symptoms of myasthenia improved following treatment with pyridostigmine. CONCLUSION: Exons 1, 5, and 9 of the SLC5A7 gene encode the choline transporter's transmembrane region. Mutations in these exons can impact the stability and plasma membrane levels of the choline transporter. Thus, a heterozygous deletion in exons 1-9 of the SLC5A7 gene could be the pathogenic cause for this patient. In patients exhibiting fluctuating weakness, positive RNS, and seronegativity for myasthenia gravis antibodies, a detailed family history should be considered, and enhanced genetic testing is recommended to determine the cause.

Association of triglyceride-glucose index with myocardial injury post-stroke in older patients with first-ever ischemic stroke.

BACKGROUND: Myocardial injury post-stroke is a common sequela of acute stroke. Triglyceride-glucose index (TyG index), a valuable surrogate indicator of insulin resistance, has been suggested to be closely related to cardiovascular outcomes. However, it is unknown whether the TyG index is independently associated with a higher risk of myocardial injury post-stroke. We therefore investigated the longitudinal association between TyG index and risk of myocardial injury post-stroke in older patients with first-ever ischemic stroke and no prior cardiovascular comorbidities. METHODS: We included older patients with first-ever ischemic stroke and no prior cardiovascular comorbidities between January 2021 to December 2021. The individuals were stratified into low and high TyG index groups according to the optimal cutoff value with TyG index. We performed logistic regression analysis, propensity score matching (PSM) analysis, restricted cubic spline analysis, and subgroup analyses to explore the longitudinal association between TyG index and risk of myocardial injury post-stroke. RESULTS: We included 386 individuals with a median age of 69.8 years (interquartile range: 66.6, 75.3). The optimal TyG index cut-off for predicting myocardial injury post-stroke was 8.9 (sensitivity 67.8%; specificity 75.5%; area under curve 0.701). Multivariate logistic regression analysis revealed that the risk of genesis of myocardial injury post-stroke increased with elevated TyG index (odds ratio [OR], 2.333; 95% confidence interval [CI], 1.201-4.585; P = 0.013). Furthermore, all covariates were well balanced between the two groups. The longitudinal association between TyG index and myocardial injury post-stroke remained significantly robust (OR: 2.196; 95% CI: 1.416-3.478; P < 0.001) after PSM adjustment. CONCLUSION: Individuals with an elevated TyG index were more susceptible to having an increased risk of myocardial injury post-stroke. TyG index thus might be served as a complementary approach for optimized-for-risk stratification in older patients with first-ever ischemic stroke and no prior cardiovascular comorbidities.

The immunometabolite S-2-hydroxyglutarate exacerbates perioperative ischemic brain injury and cognitive dysfunction by enhancing CD8+ T lymphocyte-mediated neurotoxicity.

BACKGROUND: Metabolic dysregulation and disruption of immune homeostasis have been widely associated with perioperative complications including perioperative ischemic stroke. Although immunometabolite S-2-hydroxyglutarate (S-2HG) is an emerging regulator of immune cells and thus triggers the immune response, it is unclear whether and how S-2HG elicits perioperative ischemic brain injury and exacerbates post-stroke cognitive dysfunction. METHODS: Perioperative ischemic stroke was induced by transient middle cerebral artery occlusion for 60 min in C57BL/6 mice 1 day after ileocecal resection. CD8+ T lymphocyte activation and invasion of the cerebrovascular compartment were measured using flow cytometry. Untargeted metabolomic profiling was performed to detect metabolic changes in sorted CD8+ T lymphocytes after ischemia. CD8+ T lymphocytes were transfected with lentivirus ex vivo to mobilize cell proliferation and differentiation before being transferred into recombination activating gene 1 (Rag1-/-) stroke mice. RESULTS: The perioperative stroke mice exhibit more severe cerebral ischemic injury and neurological dysfunction than the stroke-only mice. CD8+ T lymphocyte invasion of brain parenchyma and neurotoxicity augment cerebral ischemic injury in the perioperative stroke mice. CD8+ T lymphocyte depletion reverses exacerbated immune-mediated cerebral ischemic brain injury in perioperative stroke mice. Perioperative ischemic stroke triggers aberrant metabolic alterations in peripheral CD8+ T cells, in which S-2HG is more abundant. S-2HG alters CD8+ T lymphocyte proliferation and differentiation ex vivo and modulates the immune-mediated ischemic brain injury and post-stroke cognitive dysfunction by enhancing CD8+ T lymphocyte-mediated neurotoxicity. CONCLUSION: Our study establishes that S-2HG signaling-mediated activation and neurotoxicity of CD8+ T lymphocytes might exacerbate perioperative ischemic brain injury and may represent a promising immunotherapy target in perioperative ischemic stroke.

Modelling group movement with behaviour switching in continuous time.

This article presents a new method for modelling collective movement in continuous time with behavioural switching, motivated by simultaneous tracking of wild or semi-domesticated animals. Each individual in the group is at times attracted to a unobserved leading point. However, the behavioural state of each individual can switch between 'following' and 'independent'. The 'following' movement is modelled through a linear stochastic differential equation, while the 'independent' movement is modelled as Brownian motion. The movement of the leading point is modelled either as an Ornstein-Uhlenbeck (OU) process or as Brownian motion (BM), which makes the whole system a higher-dimensional Ornstein-Uhlenbeck process, possibly an intrinsic non-stationary version. An inhomogeneous Kalman filter Markov chain Monte Carlo algorithm is developed to estimate the diffusion and switching parameters and the behaviour states of each individual at a given time point. The method successfully recovers the true behavioural states in simulated data sets , and is also applied to model a group of simultaneously tracked reindeer (Rangifer tarandus).

ShinyKGode: an interactive application for ODE parameter inference using gradient matching.

Motivation: Mathematical modelling based on ordinary differential equations (ODEs) is widely used to describe the dynamics of biological systems, particularly in systems and pathway biology. Often the kinetic parameters of these ODE systems are unknown and have to be inferred from the data. Approximate parameter inference methods based on gradient matching (which do not require performing computationally expensive numerical integration of the ODEs) have been getting popular in recent years, but many implementations are difficult to run without expert knowledge. Here, we introduce ShinyKGode, an interactive web application to perform fast parameter inference on ODEs using gradient matching. Results: ShinyKGode can be used to infer ODE parameters on simulated and observed data using gradient matching. Users can easily load their own models in Systems Biology Markup Language format, and a set of pre-defined ODE benchmark models are provided in the application. Inferred parameters are visualized alongside diagnostic plots to assess convergence. Availability and implementation: The R package for ShinyKGode can be installed through the Comprehensive R Archive Network (CRAN). Installation instructions, as well as tutorial videos and source code are available at https://joewandy.github.io/shinyKGode. Supplementary information: Supplementary data are available at Bioinformatics online.

Statistical inference in mechanistic models: time warping for improved gradient matching.

Inference in mechanistic models of non-linear differential equations is a challenging problem in current computational statistics. Due to the high computational costs of numerically solving the differential equations in every step of an iterative parameter adaptation scheme, approximate methods based on gradient matching have become popular. However, these methods critically depend on the smoothing scheme for function interpolation. The present article adapts an idea from manifold learning and demonstrates that a time warping approach aiming to homogenize intrinsic length scales can lead to a significant improvement in parameter estimation accuracy. We demonstrate the effectiveness of this scheme on noisy data from two dynamical systems with periodic limit cycle, a biopathway, and an application from soft-tissue mechanics. Our study also provides a comparative evaluation on a wide range of signal-to-noise ratios.

Modeling interdependent animal movement in continuous time.

This article presents a new approach to modeling group animal movement in continuous time. The movement of a group of animals is modeled as a multivariate Ornstein Uhlenbeck diffusion process in a high-dimensional space. Each individual of the group is attracted to a leading point which is generally unobserved, and the movement of the leading point is also an Ornstein Uhlenbeck process attracted to an unknown attractor. The Ornstein Uhlenbeck bridge is applied to reconstruct the location of the leading point. All movement parameters are estimated using Markov chain Monte Carlo sampling, specifically a Metropolis Hastings algorithm. We apply the method to a small group of simultaneously tracked reindeer, Rangifer tarandus tarandus, showing that the method detects dependency in movement between individuals.

Approximate parameter inference in systems biology using gradient matching: a comparative evaluation.

BACKGROUND: A challenging problem in current systems biology is that of parameter inference in biological pathways expressed as coupled ordinary differential equations (ODEs). Conventional methods that repeatedly numerically solve the ODEs have large associated computational costs. Aimed at reducing this cost, new concepts using gradient matching have been proposed, which bypass the need for numerical integration. This paper presents a recently established adaptive gradient matching approach, using Gaussian processes (GPs), combined with a parallel tempering scheme, and conducts a comparative evaluation with current state-of-the-art methods used for parameter inference in ODEs. Among these contemporary methods is a technique based on reproducing kernel Hilbert spaces (RKHS). This has previously shown promising results for parameter estimation, but under lax experimental settings. We look at a range of scenarios to test the robustness of this method. We also change the approach of inferring the penalty parameter from AIC to cross validation to improve the stability of the method. METHODS: Methodology for the recently proposed adaptive gradient matching method using GPs, upon which we build our new method, is provided. Details of a competing method using RKHS are also described here. RESULTS: We conduct a comparative analysis for the methods described in this paper, using two benchmark ODE systems. The analyses are repeated under different experimental settings, to observe the sensitivity of the techniques. CONCLUSIONS: Our study reveals that for known noise variance, our proposed method based on GPs and parallel tempering achieves overall the best performance. When the noise variance is unknown, the RKHS method proves to be more robust.

Up-regulation of Glis2 involves in neuronal apoptosis after intracerebral hemorrhage in adult rats.

The novel Krüppel-like zinc finger protein Gli-similar 2 (Glis2), one member of the transcription factors, is involved in controlling the flow of genetic information and the modulation of diverse cellular activities. Accumulating evidence has demonstrated its important roles in adult development and several diseases. However, information regarding the regulation and possible function of Glis2 in the central nervous system is still limited. In this study, we explored the roles of Glis2 during the pathophysiological process of intracerebral hemorrhage (ICH). An ICH rat model was established and assessed by behavioral tests. Expression of Glis2 was significantly up-regulated in brain areas surrounding the hematoma following ICH. Immunofluorescence showed that Glis2 was strikingly increased in neurons, but not astrocytes or microglia. Up-regulation of Glis2 was found to be accompanied by the increased expression of active caspase-3 and Bax and decreased expression of Bcl-2 in vivo and vitro studies. Moreover, knocking down Glis2 by RNA-interference in PC12 cells reduced active caspase-3 and Bax expression while increased Bcl-2. Collectively, we speculated that Glis2 might exert pro-apoptotic function in neurons following ICH.

Nrdp1 is Associated with Neuronal Apoptosis in Lipopolysaccharide-Induced Neuroinflammation.

Neuregulin receptor degradation protein-1 (Nrdp1), a kind of ring finger E3 ubiquitin ligase, is expressed in several adult tissues, including the heart, testis, prostate and brain. Studies of this molecule have demonstrated its great importance in regulating cell growth, apoptosis and oxidative stress in various cell types. However, information regarding its expression and possible function in the central nervous system is still limited. In this study, we performed a neuroinflammation model by lipopolysaccharide (LPS) lateral ventral injection in adult rats. It was found that the expression of Nrdp1 was significantly increased in cerebral cortex after LPS injection. Immunofluorescence indicated that Nrdp1 was located in the neurons, but not astrocytes or microglia. Furthermore, there was a concomitant up-regulation of active caspase-3 and decreased expression of BRUCE (an inhibitor of apoptosis protein). In addition, decreasing Nrdp1 levels by RNA interference in cortical primary neurons reduced active caspase-3 expression but induced up-regulation of BRUCE. Collectively, all these results suggested that Nrdp1 might play a role in neuronal apoptosis by reducing the expression of BRUCE in neuroinflammation after LPS injection.

Solution-grown 3D Cu2O networks for efficient solar water splitting.

We report a facile and large-scale solution fabrication of cuprous oxide (Cu2O) nanowires/nanorods and 3D porous Cu2O networks and their application as photocathodes for efficient solar water splitting. The growth mechanism and structural characterization of 3D porous Cu2O networks are studied in detail. The photocathodic performance of Cu2O electrodes prepared under different growth conditions is investigated in a pH-neutral medium. The porous Cu2O network photocathodes exhibit large photocurrent, high spectral photoresponse, and incident photon-to-current efficiency compared with Cu2O nanowire/nanorod photoelectrodes. The photoelectrochemical stability of the 3D Cu2O network is significantly improved by applying multi-layer metal oxide protection.

Dermoscopy and Histopathology of Hyperkeratosis of Nipple and Areola: A Case Report.

We describe a case involving a 19-year-old female with who presented with bilateral nipple-areola brown patches persisting for five years. The diagnosis of hyperkeratosis of the nipple and areola (HNA) was established through dermoscopy and histopathology. The findings highlight the value of dermoscopy in the diagnosis and differentiation of HNA.

Superficial Acral Fibromyxoma: A Report of Two Cases with CD68 Expression.

Superficial Acral fibroma (SAF), also known as osteofibroma, is a rare fibromatous tumor primarily involving superficial soft tissues. Clinically, SAF typically manifests as a slow-growing, solitary, well-defined nodule or mass. Although these lesions are generally asymptomatic, some cases may present with associated pain, often linked to a history of trauma. SAF lesions commonly exhibit hemispherical, polypoid, or warty growths, with occasional occurrences of ulceration and bleeding.The majority of SAFs express CD34 and CD99, but in the two cases we report, there was diffuse expression of CD34 and focal positive expression of CD68. CD68 positivity suggests a propensity for tumor cells to metastasize to secondary sites. Notably, previously reported cases of single SAF did not display positive CD68 expression, indicating a potential association with other aggressive tumors. However, the current clinical and pathological manifestations do not clarify the diagnosis of additional malignant tumors. Consequently, regular postoperative monitoring of the patient from the aforementioned two cases is essential to detect the presence of other malignant tumors. The significance of CD68-positive expression in this case lies in its potential association with such tumors.

Nodular Elastoidosis with Cysts and Acne: A Case Report.

A 53-year-old male presented to the clinic for "bilateral temporal dark yellow plaques with pruritus for 8 years." The patient had bilateral temporal dark yellow plaques without obvious inducement 8 years ago and did not see doctors at that time. Five years ago, bilateral temporal skin lesions gradually increased and were accompanied by severe itching. On top of them, there were several blackheads and pimples with the size of needle tips up to the size of rice grains. After compression, lipid substances could be excreted and there was a clear odor. The patient sought medical attention at a local hospital, but the diagnosis and medication were unknown, and the symptoms did not improve. In the past month, due to the aggravation of skin lesions and itching that affected sleep, he visited the outpatient clinic of our hospital again. The patient was diagnosed with nodular elastoidosis with cysts and acne and was given 5% peroxybenzoyl gel and 0.1% tretinoin cream for topical use. After 2 weeks, the itching symptoms of the patient were significantly reduced.

Prurigo Pigmentosa Successfully Treated with Oral Minocycline: A Case Report.

Purpose: We aimed to report a case of prurigo pigmentosa (PP) with blisters. Patients and Methods: A 21-year-old male patient presented to our hospital with erythema, papules, and blisters all over the front chest and back. Densely distributed round and oval edematous erythema was noted on the neck, front chest, and back of the patient. Histopathologic examination of the skin lesions (blisters) on the chest revealed epidermal cell hyperkeratosis. He was diagnosed with PP and was treated with oral minocycline. Results: After 1-week minocycline administration, the patient's itching was relieved, and the blisters dried up. His skin lesions recurred following self-withdrawal from the medication; subsequently, the patient was administered oral minocycline treatment again. After 1-month continuous oral treatment, the drug was discontinued. No recurrence of symptoms was noted. Conclusion: Oral minocycline is effective for the treatment of PP.

A Case of Coma Bullae Associated with Brachioradial Artery.

We present the first case of coma bullae observed in a 67-year-old woman due to pressure and ischemia associated with brachioradial artery. A skin biopsy taken from the ulcer border revealed extensive loss of the epidermis, fibrosis of dermis, mild infiltration by lymphocytes and neutrophils, and necrosis of the focal eccrine ducts. CT angiography of the right upper limb showed a high origin of the radial artery, meanwhile both high originating radial artery and the anastomoses were tortuous and were of relatively small caliber. The diagnosis of coma bullae was made. After tissue debridement, the skin lesions gradually recovered, leaving atrophic scars.

Reflectance Confocal Microscopy and Dermoscopy For the Diagnosis and Treatment of Cutaneous Larva Migrans.

We describe a 39-year-old woman with a 1-month-old linear erythema diagnosed with cutaneous larva migrans by reflectance confocal microscopy (RCM). This case reveals that the great significance of diagnosing and treating cutaneous larva migrans (CLM) by RCM and dermoscopy, which might provide novel insights into dermatological clinical practice.

Simple Lymphangioma of the Scrotum: A Case Report.

As scrotal simple lymphangioma is a rare benign proliferation of lymphatic vessels in the scrotum, a few reports were documented. A 68-year-old man gradually developed vesicles on the scrotum for ten years and easily ruptured due to friction. Physical examination showed diffuse millet-sized vesicles on the scrotum with milky white fluids and chyle-like exudates. Histopathological examination revealed proliferating and dilated lymphatic vessels with various sizes of lumens in the dermis. An immunohistochemical study showed positive staining for D2-40 and CD31. Therefore, the patient was diagnosed with scrotal lymphangioma and received carbon dioxide laser therapy. After the treatment, the vesicles markedly decreased, and no apparent exudates were observed. During one year of the follow-up, no relapse, scars, or other complications occurred.

Systemic-Immune-Inflammation Index as a Promising Biomarker for Predicting Perioperative Ischemic Stroke in Older Patients Who Underwent Non-cardiac Surgery.

Objective: This study aimed to investigate the clinical prognostic values of the preoperative systemic-immune-inflammation index (SII) in older patients undergoing non-cardiac surgery, using perioperative ischemic stroke as the primary outcome. Methods: This retrospective cohort study included older patients who underwent non-cardiac surgery between January 2008 and August 2019. The patients were divided into SII < 583 and SII ≥ 583 group according to the optimal SII cut-off value. The outcome of interest was ischemic stroke within 30 days after surgery. Primary, sensitivity, and subgroup analyses were performed to confirm that preoperative SII qualifies as a promising, independent prognostic indicator. Propensity score matching (PSM) analysis was further applied to address the potential residual confounding effect of covariates to examine the robustness of our results. Results: Among the 40,670 included patients with a median age of 70 years (interquartile range: 67, 74), 237 (0.58%) experienced an ischemic stroke within 30 days after surgery. SII ≥ 583 was associated with an increased risk of perioperative ischemic stroke in multivariate regression analysis [odds ratio (OR), 1.843; 95% confidence interval (CI), 1.369-2.480; P < 0.001]. After PSM adjustment, all covariates were well balanced between the two groups. The correlation between the SII and perioperative ischemic stroke remained significantly robust (OR: 2.195; 95% CI: 1.574-3.106; P < 0.001) in the PSM analysis. Conclusion: Preoperative SII, which includes neutrophil, platelet, and lymphocyte counts obtained from routine blood analysis, was a potential prognostic biomarker for predicting perioperative ischemic stroke after non-cardiac surgery in elderly older patients. An elevated SII, based on an optimal cut-off value of 583, was an independent risk factor for perioperative ischemic stroke.

Corrigendum: Type 2 diabetes increases risk of unfavorable survival outcome for postoperative ischemic stroke in patients who underwent non-cardiac surgery: A retrospective cohort study.

[This corrects the article DOI: 10.3389/fnagi.2021.810050.].