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We quantified and determined for the first time the distribution pattern of the neuropeptide NPFF in the human cerebral cortex and subjacent white matter. To do so, we studied n = 9 cases without neurological disorders and n = 22 cases with neurodegenerative diseases, including sporadic amyotrophic lateral sclerosis (ALS, n = 8), Alzheimer's disease (AD, n = 8), Pick's disease (PiD, n = 3), and schizophrenia (n = 3). NPFF-immunopositive cells were located chiefly, but not exclusively, in the superficial white matter and constituted there a subpopulation of white matter interstitial cells (WMIC): Pyramidal-like and multipolar somata predominated in the gyral crowns, whereas bipolar and ovoid somata predominated in the cortex surrounding the sulci. Their sparsely ramified axons were unmyelinated and exhibited NPFF-positive bead-like varicosities. We found significantly fewer NPFF-immunopositive cells in the gray matter of the frontal, cingulate, and superior temporal gyri of both sporadic ALS and late-stage AD patients than in controls, and significantly fewer NPFF-positive cells in the subjacent as well as deep white matter of the frontal gyrus of these patients compared to controls. Notably, the number of NPFF-positive cells was also significantly lower in the hippocampal formation in AD compared to controls. In PiD, NPFF-positive cells were present in significantly lower numbers in the gray and white matter of the cingulate and frontal gyrii in comparison to controls. In schizophrenic patients, lower wNPFF cell counts in the neocortex were significant and global (cingulate, frontal, superior temporal gyrus, medial, and inferior gyri). The precise functions of NPFF-positive cells and their relationship to the superficial corticocortical white matter U-fibers are currently unknown. Here, NPFF immunohistochemistry and expression characterize a previously unrecognized population of cells in the human brain, thereby providing a new entry-point for investigating their physiological and pathophysiological roles. [ABSTRACT FROM AUTHOR]

There is a well-established link between physical activity and brain health. As such, the effectiveness of physical exercise as a therapeutic strategy has been explored in a variety of neurological contexts. To determine the extent to which physical exercise could be most beneficial under different circumstances, studies are needed to uncover the underlying mechanisms behind the benefits of physical activity. Interest has grown in understanding how physical activity can regulate microglia, the resident immune cells of the central nervous system. Microglia are key mediators of neuroinflammatory processes and play a role in maintaining brain homeostasis in healthy and pathological settings. Here, we explore the evidence suggesting that physical activity has the potential to regulate microglia activity in various animal models. We emphasize key areas where future research could contribute to uncovering the therapeutic benefits of engaging in physical exercise. [ABSTRACT FROM AUTHOR]

Background: Recent research has indicated the significance of immune activation in amyotrophic lateral sclerosis (ALS). However, the impact of peripheral immunity on cognitive impairment in sporadic ALS remains poorly characterized. Therefore, we aim to assess the relationship between peripheral immune parameters and cognitive impairment in patients with sporadic ALS. Methods: A case–control study involving 289 patients with sporadic ALS was conducted. All participants underwent cognitive assessment and measurements of blood immune parameters. The main outcomes included adjusted odds ratios (ORs) in multivariate logistic regression analysis and adjusted coefficients in a multivariate linear regression model. Sensitivity analysis was performed with stratification by the King’s clinical stage. Results: Cognitive impairment was observed in 98 (33.9%) patients. Higher counts of leukocyte (OR, 0.53; 95% CI, 0.29 to 0.95; p  =  0.03), neutrophil (OR, 0.48; 95% CI, 0.26 to 0.88; p  =  0.02), and monocyte (OR, 0.33; 95% CI, 0.18 to 0.60; p  <  0.001) were significantly associated with better cognitive preformence in sporadic ALS, particularly among patients in King’s clinical stages 1 and 2. Conversely, a higher percentage of CD4+ T cells was linked to an increased risk of cognitive impairment (OR, 2.79; 95% CI, 1.52 to 5.09; p  =  0.001), particularly evident in patients in King’s clinical stage 3. Conclusion: These results highlight the involvement of peripheral immunity in the cognitive impairment of sporadic ALS and suggest dynamic and intricate roles that vary across disease stages. Elucidating the links between immunity and ALS sheds light on the pathophysiological mechanisms underlying this fatal neurodegenerative disorder and informs potential immunotherapeutic strategies. [ABSTRACT FROM AUTHOR]

The etiology of the neurodegenerative disease amyotrophic lateral sclerosis (ALS) is complex and considered multifactorial. The majority of ALS cases are sporadic, but familial cases also exist. Estimates of heritability range from 8% to 61%, indicating that additional factors beyond genetics likely contribute to ALS. Numerous environmental factors are considered, which may add up and synergize throughout an individual's lifetime building its unique exposome. One level of integration between genetic and environmental factors is epigenetics, which results in alterations in gene expression without modification of the genome sequence. Methylation reactions, targeting DNA or histones, represent a large proportion of epigenetic regulations and strongly depend on the availability of methyl donors provided by the ubiquitous one-carbon (1C) metabolism. Thus, understanding the interplay between exposome, 1C metabolism, and epigenetic modifications will likely contribute to elucidating the mechanisms underlying altered gene expression related to ALS and to developing targeted therapeutic interventions. Here, we review evidence for 1C metabolism alterations and epigenetic methylation dysregulations in ALS, with a focus on the impairments reported in neural tissues, and discuss these environmentally driven mechanisms as the consequences of cumulative exposome or late environmental hits, but also as the possible result of early developmental defects. [ABSTRACT FROM AUTHOR]

Background: Caveolae are essential in regulating signal transduction mechanisms of ion channels in vascular tissue, including BKCa channels (maxi-K). The current study investigated the localization of maxi-K channels within caveolae. Methods: Sixteen rats were divided into two groups: A control group and a treated group, where arteries in the treated group were incubated with methyl-ß-cyclodextrin (MßCD) to disassemble caveolae from artery tissue. Immunohistochemistry (IHC), immunocytochemistry (ICC), transmission electron microscopy (TEM) and Western blot techniques were used in this study. Result: IHC of intact arteries showed colocalization of maxi-K channels with caveolin-1 in smooth muscle and endothelial cells and colocalized of maxi-K channels with caveolin-3 in smooth muscle cells only. These findings were also corroborated with ICC in a single smooth muscle cell. TEM revealed caveolae covering most plasma membranes of smooth muscle and endothelial cells and showed that caveolae sit close to the sarcoplasmic reticulum only in smooth muscle cells. TEM showed incubating arteries with MßCD led to the disassembly of caveolae from artery tissue. This study concluded that maxi-K channels localize to caveolae and that caveolae abolishment by MßCD led to the abolition of the coupling of caveolae and the sarcoplasmic reticulum. [ABSTRACT FROM AUTHOR]

Together, lower back and neck pain are among the leading causes of acquired disability worldwide and have experienced a marked increase over the past 25 years. Paralleled with the increasing aging population and the rise in chronic disease, this trend is only predicted to contribute to the growing global burden. In the context of cervical neck pain, this symptom is most often a manifestation of cervical degenerative disc disease (DDD). Traditionally, multilevel neck pain related to DDD that is recalcitrant to both physical and medical therapy can be treated with a procedure known as cervical corpectomy. Presently, there are many flavors of cervical corpectomy; however, the overarching goal is the removal of the pain-generating disc via the employment of the modern anterior approach. In this review, we will briefly detail the pathophysiological mechanism behind DDD, overview the development of the anterior approach, and discuss the current state of treatment options for said pathology. Furthermore, this review will also add to the current body of literature surrounding updated indications, surgical techniques, and patient outcomes related to cervical corpectomy. Finally, our discussion ends with highlighting the future direction of cervical corpectomy through the introduction of the "skip corpectomy" and distractable mesh cages. [ABSTRACT FROM AUTHOR]

Background: Rare diseases, predominantly caused by genetic factors and often presenting neurological manifestations, are significantly underrepresented in research. This review addresses the urgent need for advanced research in rare neurological diseases (RNDs), which suffer from a data scarcity and diagnostic challenges. Bridging the gap in RND research is the integration of machine learning (ML) and omics technologies, offering potential insights into the genetic and molecular complexities of these conditions. Methods: We employed a structured search strategy, using a combination of machine learning and omics-related keywords, alongside the names and synonyms of 1840 RNDs as identified by Orphanet. Our inclusion criteria were limited to English language articles that utilized specific ML algorithms in the analysis of omics data related to RNDs. We excluded reviews and animal studies, focusing solely on studies with the clear application of ML in omics data to ensure the relevance and specificity of our research corpus. Results: The structured search revealed the growing use of machine learning algorithms for the discovery of biomarkers and diagnosis of rare neurological diseases (RNDs), with a primary focus on genomics and radiomics because genetic factors and imaging techniques play a crucial role in determining the severity of these diseases. With AI, we can improve diagnosis and mutation detection and develop personalized treatment plans. There are, however, several challenges, including small sample sizes, data heterogeneity, model interpretability, and the need for external validation studies. Conclusions: The sparse knowledge of valid biomarkers, disease pathogenesis, and treatments for rare diseases presents a significant challenge for RND research. The integration of omics and machine learning technologies, coupled with collaboration among stakeholders, is essential to develop personalized treatment plans and improve patient outcomes in this critical medical domain. [ABSTRACT FROM AUTHOR]

The connection between body weight alterations and Alzheimer's disease highlights the intricate relationship between the brain and adipose tissue in the context of neurological disorders. During midlife, weight gain increases the risk of cognitive decline and dementia, whereas in late life, weight gain becomes a protective factor. Despite their substantial impact on metabolism, the role of adipokines in the transition from healthy aging to neurological disorders remains largely unexplored. We aim to investigate how the adipose tissue milieu and the secreted adipokines are involved in the transition between biological and pathological aging, highlighting the bidirectional relationship between the brain and systemic metabolism. Understanding the function of these adipokines will allow us to identify biomarkers for early detection of Alzheimer's disease and uncover novel therapeutic options. [ABSTRACT FROM AUTHOR]

Purpose of Review: Atypical parkinsonism is a term usually used to describe three neurodegenerative parkinsonian disorders: progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and multiple system atrophy (MSA). In contrast to Parkinson's disease, these disorders have a poor prognosis and present with a multitude of diverse symptoms, including parkinsonism, dystonia, myoclonus, gait disorders, dysarthria, dysphagia, sleep, cognitive, and behavioral disorders. In the absence of an approved disease-modifying treatment, symptomatic treatment is the mainstay of management. The purpose of this review is to present an overview of the management of these complex disorders, with a particular focus on a holistic and multidisciplinary approach. Recent Findings: In addition to presenting the most significant pharmacological interventions for symptom management, data regarding non-pharmacological interventions are analyzed. Important non-pharmacological clinical practice questions such as breaking the news, palliative care, and end-of-life issues are discussed, in an effort to present an overview of the management of atypical parkinsonism from diagnosis to the most advanced stages of these diseases. Summary: Management of atypical parkinsonian disorders includes symptomatic pharmacological and non-pharmacological interventions, in addition to addressing issues such as informing the patient of the diagnosis, palliative care, and end-of-life issues, which require a multidisciplinary approach. [ABSTRACT FROM AUTHOR]

The disease-specific accumulation of pathological proteins has long been the major focus of research in neurodegenerative diseases (ND), including Alzheimer's disease (AD) and related dementias (RD), but the recent identification of a multitude of genetic risk factors for ND in immune-associated genes highlights the importance of immune processes in disease pathogenesis and progression. Studies in animal models have characterized the local immune response to disease-specific proteins in AD and ADRD, but due to the complexity of disease processes and the co-existence of multiple protein pathologies in human donor brains, the precise role of immune processes in ND is far from understood. To better characterize the interplay between different extracellular and intracellular protein pathologies and the brain's intrinsic immune system in ND, we set out to comprehensively profile the local immune response in postmortem brain samples of individuals with "pure" beta-Amyloid and tau pathology (AD), "pure" α-Synuclein pathology in Lewy body diseases (LBD), as well as cases with Alzheimer's disease neuropathological changes (ADNC) and Lewy body pathology (MIX). Combining immunohistochemical profiling of microglia and digital image analysis, along with deep immunophenotyping using gene expression profiling on the NanoString nCounter® platform and digital spatial profiling on the NanoString GeoMx® platform we identified a robust immune activation signature in AD brain samples. This signature is maintained in persons with mixed pathologies, irrespective of co-existence of AD pathology and Lewy body (LB) pathology, while LBD brain samples with "pure" LB pathology exhibit an attenuated and distinct immune signature. Our studies highlight disease- and brain region-specific immune response profiles to intracellular and extracellular protein pathologies and further underscore the complexity of neuroimmune interactions in ND. [ABSTRACT FROM AUTHOR]

Background: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that is now recognized to involve autonomic dysfunction. The burden of autonomic dysfunction is an important factor in the quality of life and prognosis of ALS patients. This article presents the clinical characteristics of a young female ALS patient with a fused in sarcoma (FUS) gene mutation and notable hyperhidrosis. Method: Detailed clinical characteristics of the patients were collected, and comprehensive examinations such as electrophysiological assessment, neuro-ultrasound, genetic testing, and relevant blood tests were conducted. Result: A 24-year-old female experienced progressive weakness in both lower limbs for over 5 months, along with excessive sweating on both palms and feet. A positive skin iodine-starch test was observed. Electromyography revealed extensive neurogenic damage and prolonged sympathetic skin response (SSR) latency in both lower limbs. Full exon gene sequencing showed a heterozygous mutation c.1574C>T (p.Pro525Leu) in the FUS gene. Conclusion: The pathogenesis of ALS remains unclear at present. This case underscores the presence of autonomic nervous symptoms in ALS associated with FUS mutation and highlights the importance of early diagnosis and timely treatment intervention to enhance patient prognosis. [ABSTRACT FROM AUTHOR]

The e4 allele of the apolipoprotein E gene is the strongest genetic risk factor for sporadic Alzheimer's disease. Nevertheless, how APOE is regulated is still elusive. In a trans-eQTL analysis, we found a genome-wide significant association between transmembrane protein 106B (TMEM106B) genetic variants and cortical APOE mRNA levels in human brains. The goal of this study is to determine whether TMEM106B is mis-regulated in Alzheimer's disease or in other neurodegenerative conditions. Available genomic, transcriptomic and proteomic data from human brains were downloaded from the Mayo Clinic Brain Bank and the Religious Orders Study and Memory and Aging Project. An in-house mouse model of the hippocampal deafferentation/reinnervation was achieved via a stereotaxic lesioning surgery to the entorhinal cortex, and mRNA levels were measured using RNAseq technology. In human temporal cortices, the mean TMEM106B expression was significantly higher in Alzheimer's disease compared to cognitively unimpaired individuals. In the mouse model, hippocampal Tmem106b reached maximum levels during the early phase of reinnervation. These results suggest an active response to tissue damage that is consistent with compensatory synaptic and terminal remodeling. [ABSTRACT FROM AUTHOR]

Phishing, a well-known cyberattack that cannot be completely eradicated from the Internet, has increased dramatically since the COVID-19 pandemic. Despite previous efforts to reduce this prevalent Internet threat, constantly changing attacks make phishing detection a difficult task. The lack of continuous learning support provided by existing solutions and the lack of a systematic knowledge acquisition process make its detection more difficult. SmartiPhish is introduced in this context as the first anti-phishing solution with integrated continuous learning support with an innovative knowledge acquisition process. SmartiPhish combines deep learning and reinforcement learning to have a successful phishing detection solution. The deep learning model predicts a phishing probability for a given web page based on the URL and HTML content, and the probability is then passed to a reinforcement learning environment to make a decision based on the popularity of the web page and prior knowledge of it. SmartiPhish has a detection accuracy of 96.40% and a detection time of 4.3 s. SmartiPhish performs well in an imbalanced environment, and zero-day attack detection is also interesting. Furthermore, SmartiPhish demonstrated a 5.65% performance improvement in just six weeks, in contrast to the existing anti-phishing tools' declining performance trend over time. [ABSTRACT FROM AUTHOR]

The recent surge in phishing incidents in the post-COVID era poses a serious threat towards the social and economic well-being of users. The escalation in dependency upon the internet for meeting daily chores has made them vulnerable to falling prey to the ever-evolving menace of phishing. The objective of this article is: to explore different tactics and motivational factors behind phishing, identify the communication mediums through which phishing is circulated and perform a detailed review along with a comparison of the various surveys in this domain. Another objective is to determine the open research challenges in this genre and to identify the scope of research in the future. An extensive literature survey is performed, which includes articles from eminent online research databases. Barring a few initial articles related to phishing, the articles published in Science Citation/Scopus-indexed journals and survey/review articles published in the last ten years are considered. Highly cited works are given preference. The search query returned numerous articles, which were narrowed by title screening. Further screening of articles was performed by reading the abstract and eliminating the articles related to user-oriented phishing interventions. Eventually, 25 survey articles were shortlisted to be surveyed. This article is an effort to provide a novel taxonomy of phishing to academia that would assist in identifying the sections where phishing countermeasures are inadequate. [ABSTRACT FROM AUTHOR]

Background: Tear fluid (TF) production is an important component of normal ocular function. It is regulated by parasympathetic and sympathetic innervation. Because parasympathetic nerve fibers originate in the brainstem, pathology in this brain region may affect TF production. For example, a reduction in TF production has been described in patients with Parkinson's disease (PD). Methods: TF was collected at one center from 772 individuals, 708 of which were patients with different neurological diseases, and 64 healthy controls. Wetting lengths (WL) were recorded using Schirmer test strips with a collection time of 10 min. Results: WL correlated negatively with age and was significantly reduced in subgroups of patients with neurodegenerative diseases (NDDs) (PD, Amyotrophic lateral sclerosis (ALS), other motor neuron diseases (MNDs)), as well as inflammatory/autoimmune/infectious central nervous system (CNS) diseases and vascular CNS diseases (VCDs), even if corrected for age or sex. While temperature had a significant negative effect on TF production, other environmental factors, such as hours of sunlight and humidity, did not. Conclusion: WL was altered in many neurological diseases compared to healthy controls. Most importantly, we observed a reduction of WL in NDDs, independent of age or sex. This study highlights the potential of WL as an easily obtainable parameter and suggests functional alterations in the autonomic innervation in various neurological disorders. [ABSTRACT FROM AUTHOR]

Neurons are the primary cells responsible for information processing in the central nervous system (CNS). However, they are vulnerable to damage and insult in a variety of neurological disorders. As the most abundant glial cells in the brain, astrocytes provide crucial support to neurons and participate in synapse formation, synaptic transmission, neurotransmitter recycling, regulation of metabolic processes, and the maintenance of the blood-brain barrier integrity. Though astrocytes play a significant role in the manifestation of injury and disease, they do not work in isolation. Cellular interactions between astrocytes and neurons are essential for maintaining the homeostasis of the CNS under both physiological and pathological conditions. In this review, we explore the diverse interactions between astrocytes and neurons under physiological conditions, including the exchange of neurotrophic factors, gliotransmitters, and energy substrates, and different CNS diseases such as Alzheimer's disease, Parkinson's disease, stroke, traumatic brain injury, and multiple sclerosis. This review sheds light on the contribution of astrocyte-neuron crosstalk to the progression of neurological diseases to provide potential therapeutic targets for the treatment of neurological diseases., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Ga-doped zinc oxide (ZnO) microwires hold great promise for developing highly efficient light sources because of the wide bandgap with proper exciton binding energy. However, most microwires grown from one mainstream approach, i.e., chemical vapor deposition (CVD), are morphologically and crystallographically defective, exhibiting limited photoluminescence performances. Herein, a simple and effective X-ray irradiation strategy is demonstrated for enhancing the photoluminescence of Ga-doped ZnO microwire in ambient conditions. Under moderate doses (≤ 150 Gy), the photoluminescence monotonically rockets up with X-ray dose increment and achieves nine-fold enhancement at a dose of ≈150 Gy, recording high photoluminescence improvement of ZnO microwires to date. The elemental characteristics under different controlled irradiation atmospheres suggest the elimination of surface oxygen vacancy and the cross-section transmission electron microscope reveals prominent lattice relaxations after mild X-ray irradiation. In addition, the X-ray irradiated microwires further exhibit elevated electroluminescence by over three times. The enhanced photoluminescence and electroluminescence as well as long-term stability enable us to imagine the super-rapid applications of ZnO microwires in modern optoelectronic devices., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

From the day we are born, the nervous system is subject to insult, disease and degeneration. Aberrant phosphorylation states in neurofilaments, the major intermediate filaments of the neuronal cytoskeleton, accompany and mediate many pathological processes in degenerative disease. Neuronal damage, degeneration and death can release these internal components to the extracellular space and eventually the cerebrospinal fluid and blood. Sophisticated assay techniques are increasingly able to detect their presence and phosphorylation states at very low levels, increasing their utility as biomarkers and providing insights and differential diagnosis for the earliest stages of disease. Although a variety of studies focus on single or small clusters of neurofilament phosphorylated epitopes, this review offers a wider perspective of the phosphorylation landscape of the neurofilament heavy subunit, a major intermediate filament component in both ageing and disease., (© 2024 International Society for Neurochemistry.)

Subunit vaccines, significant in next-generation vaccine development, offer precise targeting of immune responses by focusing on specific antigens. However, this precision often comes at the cost of eliciting strong and durable immunity, posing a great challenge to vaccine design. To address this limitation, recent advancements in nanoparticles (NPs) are utilized to enhance antigen delivery efficiency and boost vaccine efficacy. This review examines how the physicochemical properties of NPs influence various stages of the immune response during vaccine delivery and analyzes how different NP types contribute to immune activation and enhance vaccine performance. It then explores the unique characteristics and immune activation mechanisms of these NPs, along with their recent advancements, and highlights their application in subunit vaccines targeting infectious diseases and cancer. Finally, it discusses the challenges in NP-based vaccine development and proposes future directions for innovation in this promising field., (© 2024 Wiley‐VCH GmbH.)

Background: Cerebrospinal fluid (CSF) and serum tau (t-tau, p-tau) are potential biomarkers for neurodegeneration in Alzheimer disease (AD), but their role in amyotrophic lateral sclerosis (ALS) is unclear. Objectives: The aim of our study was to evaluate CSF and serum p-tau and t-tau in patients with ALS and to analyze the correlation and clinical parameters between them. Methods: CSF and serum samples were obtained from 90 patients with ALS, 48 other neurological disease (OND), and 20 with AM (ALS mimic, AM) diseases. The levels of p-tau and t-tau in the CSF and serum were assessed with an enzyme-linked immunosorbent assay, and disease progression parameters, including the duration, the ALSFRS-R score, disease progression rate (DPR), the upper motor neuron (UMN) score, the Mini-mental State Examination (MMSE) score, the Montreal Cognitive Assessment (MoCA) score, and the Edinburgh Cognitive and Behavioral ALS Screen (ECAS) results, were analyzed by registered neurologists. Statistical analyses were performed using Prism software. Results: Compared with controls, patients with ALS displayed significantly lower levels of CSF p-tau and p-tau:t-tau ratio. The CSF p-tau level in patients with ALS and cognition impairment was higher than that in patients with ALS who did not have cognition impairment. CSF p-tau level was negatively correlated with MMSE, MoCA, and ECAS total score and the specific score of ECAS in patients with ALS and cognition impairment. Conclusions: The CSF p-tau level and p-tau:t-tau ratio were lower in patients with ALS than patients with OND and AM. Results suggest that CSF p-tau may be used as an index of cognition impairment in patients with ALS. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is the most frequent neurodegenerative disease of the motor system that affects upper and lower motor neurons, leading to progressive muscle weakness, spasticity, atrophy, and respiratory failure, with a life expectancy of 2–5 years after symptom onset. In addition to motor symptoms, patients with ALS have a multitude of nonmotor symptoms; in fact, it is currently considered a multisystem disease. The purpose of our narrative review is to evaluate the different types of pain, the correlation between pain and the disease's stages, the pain assessment tools in ALS patients, and the available therapies focusing above all on the benefits of cannabis use. Pain is an underestimated and undertreated symptom that, in the last few years, has received more attention from research because it has a strong impact on the quality of life of these patients. The prevalence of pain is between 15% and 85% of ALS patients, and the studies on the type and intensity of pain are controversial. The absence of pain assessment tools validated in the ALS population and the dissimilar study designs influence the knowledge of ALS pain and consequently the pharmacological therapy. Several studies suggest that ALS is associated with changes in the endocannabinoid system, and the use of cannabis could slow the disease progression due to its neuroprotective action and act on pain, spasticity, cramps, sialorrhea, and depression. Our research has shown high patients' satisfaction with the use of cannabis for the treatment of spasticity and related pain. However, especially due to the ethical problems and the lack of interest of pharmaceutical companies, further studies are needed to ensure the most appropriate care for ALS patients. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease, characterized by the death of upper (UMN) and lower motor neurons (LMN) in the motor cortex, brainstem, and spinal cord. Despite decades of research, ALS remains incurable, challenging to diagnose, and of extremely rapid progression. A unifying feature of sporadic and familial forms of ALS is cortical hyperexcitability, which precedes symptom onset, negatively correlates with survival, and is sufficient to trigger neurodegeneration in rodents. Using electrocorticography in the Sod1G86R and FusΔNLS/+ ALS mouse models and standard electroencephalography recordings in patients with sporadic ALS, we demonstrate a deficit in theta-gamma phase-amplitude coupling (PAC) in ALS. In mice, PAC deficits started before symptom onset, and in patients, PAC deficits correlated with the rate of disease progression. Using mass spectrometry analyses of CNS neuropeptides, we identified a presymptomatic reduction of noradrenaline (NA) in the motor cortex of ALS mouse models, further validated by in vivo two-photon imaging in behaving SOD1G93A and FusΔNLS/+ mice, that revealed pronounced reduction of locomotion-associated NA release. NA deficits were also detected in postmortem tissues from patients with ALS, along with transcriptomic alterations of noradrenergic signaling pathways. Pharmacological ablation of noradrenergic neurons with DSP-4 reduced theta-gamma PAC in wild-type mice and administration of a synthetic precursor of NA augmented theta-gamma PAC in ALS mice. Our findings suggest theta-gamma PAC as means to assess and monitor cortical dysfunction in ALS and warrant further investigation of the NA system as a potential therapeutic target. Editor's summary: Cortical hyperexcitability in amyotrophic lateral sclerosis (ALS) is commonly assessed by transcranial magnetic stimulation combined with electromyogram recordings, but this approach requires functional nerve-to-muscle connections. Scekic-Zahirovic et al. show that cortical hyperexcitability was associated with early deficits in theta-gamma phase-amplitude coupling (PAC) and decreased noradrenaline (NA) in the motor cortex of patients with ALS and mouse models. PAC deficits could be ameliorated by administration of a synthetic NA precursor in mice. These results suggest that PAC could serve as an alternative, muscle-independent readout for cortical hyperexcitability in ALS and warrant further studies into NA signaling as a potential molecular culprit driving this hyperexcitability. —Daniela Neuhofer [ABSTRACT FROM AUTHOR]

The individual and global burden of migraine is of such significance that there are accelerated efforts to develop new therapies. New migraine therapeutics are needed to address the current deficiencies that exist in the efficacy and adherence rate of approved anti-migraine medications. The recent discovery of the calcitonin gene related peptide as an add-on to the role of serotonin has markedly increased the range of new treatment options for acute and chronic migraine. Despite this, tackling the complexity of migraine disorders requires a complete understanding of its pathophysiology. Preclinical animal models can shed light on disease-related pathophysiology, including migraine. Indeed, the use of animal models has been instrumental in developing many therapeutics. However, an animal model is limited by the predictive and face validity of that model, and this extends to preclinical migraine models. In this review, a summary of the current understanding of the pathophysiology of migraine is given from both a preclinical and clinical perspective, and an emphasis is placed on the animal models of migraine. We will discuss the strengths and pitfalls of common preclinical migraine models as well as experimental research areas to explore further. [ABSTRACT FROM AUTHOR]

Neurodegenerative diseases are often referred to as diseases of old age, and with the aging population, they are gaining scientific and medical interest. Environmental stressors, most notably traffic noise and air pollution, have recently come to the forefront, and have emerged as disease risk factors. The evidence for a connection between environmental risk factors and neurodegenerative disease is growing. In this review, the most common neurodegenerative diseases and their epidemiological association with traffic noise and air pollution are presented. Also, the most important mechanisms involved in neurodegenerative disease development, oxidative stress, and neuroinflammation are highlighted. An overview of the in vivo findings will provide a mechanistic link between noise, air pollution, and neurodegenerative pathology. Finally, the importance of the direct and indirect pathways, by which noise and air pollution cause cerebral damage, is discussed. More high-quality data are still needed from both epidemiological and basic science studies in order to better understand the causal connection between neurodegenerative diseases and environmental risk factors. [ABSTRACT FROM AUTHOR]

Despite tremendous efforts in basic research and a growing number of clinical trials aiming to find effective treatments, amyotrophic lateral sclerosis (ALS) remains an incurable disease. One possible reason for the lack of effective causative treatment options is that ALS may not be a single disease entity but rather may represent a clinical syndrome, with diverse genetic and molecular causes, histopathological alterations, and subsequent clinical presentations contributing to its complexity and variability among individuals. Defining a way to subcluster ALS patients is becoming a central endeavor in the field. Identifying specific clusters and applying them in clinical trials could enable the development of more effective treatments. This review aims to summarize the available data on heterogeneity in ALS with regard to various aspects, e.g., clinical, genetic, and molecular. [ABSTRACT FROM AUTHOR]

Purpose of review: To describe the clinical presentation, diagnosis, and treatment options of vasculitic neuropathies. Overall, vasculitic neuropathies can be divided into systemic and nonsystemic. Systemic vasculitic neuropathies form part of rheumatological diseases, where in some cases, the vasculitic is the predominant feature, and these are called primary vasculitis, while in others, the vasculitis is secondary to a connective tissue disease. Nonsystemic vasculitic neuropathies involve only the peripheral nervous system, and thus, diagnosis is more challenging as it requires a high degree of suspicion and confirmation with nerve biopsy results. Recent findings: Over the past few years, rituximab has been increasingly used for induction and maintenance treatment of vasculitis due to a more favorable side effect profile and similar efficacy when compared to cyclophosphamide. Summary: Herein, we describe the different types of vasculitic neuropathies. Regarding their treatment, have focused on the indications, dosing, and side effects for the most common options for primary systemic vasculitic neuropathies, as these tend to be similar for the classical nonsystemic vasculitic neuropathy phenotype. [ABSTRACT FROM AUTHOR]

In recent years, security incidents of website occur increasingly frequently, and this motivates us to study websites' security. Although there are many phishing detection approaches to detect phishing websites, the detection accuracy has not been desirable. In this paper, we propose a novel phishing detection model based on a novel neural network classification method. This detection model can achieve high accu-racy and has good generalization ability by design risk minimization principle. Furthermore, the training process of the novel detection model is simple and stable by Monte Carlo algorithm. Based on testing of a set of phishing and benign websites, we have noted that this novel phishing detection model achieves the best Accuracy, True-positive rate (TPR), False-positive rate (FPR), Precision, Recall, F-measure and Matthews Correlation Coefficient(MCC) comparable to other models as Naive Bayes (NB), Logistic Regression(LR), K-Nearest Neighbor (KNN), Decision Tree (DT), Linear Support Vector Machine (LSVM), Radial-Basis Support Vector Machine (RSVM) and Linear Discriminant Analysis (LDA). Furthermore, based upon experiments, we find that the proposed detection model can achieve a high Accuracy of 97.71% and a low FPR of 1.7%. It indicates that the proposed detection model is promising and can be effectively applied to phishing detection. [ABSTRACT FROM AUTHOR]

In real-world anomaly detection tasks such as Credit Card Fraud Detection, Cancer Patients Detection, Phishing Website Detection, etc., the training datasets often suffer from skewed class distribution. But the traditional Machine Learning (ML) classification algorithms assume balanced class distribution and equal misclassification costs. As a result, when class-imbalanced data are presented to the traditional ML algorithms they tend to produce biased and inaccurate predictive ML models. In this study, we propose four novel Phishing Website Classification models namely, SMOTEENN-XGB, SMOTEENN-RF, SMOTEENN-LR, and SMOTEENN-SVM by combining SMOTEENN (SMOTE + ENN) hybrid sampling technique with eXtreme Gradient Boosting (XGB), Random Forest (RF), Logistic Regression (LR), and Support Vector Machine (SVM) classifiers respectively. We propose the use of SMOTEENN hybrid sampling as the novel approach to address the problem of class imbalance in Phishing Website datasets prior to building classification models. To the best of our knowledge and belief, our novel proposed four models SMOTEENN-XGB, SMOTEENN-RF, SMOTEEEN-LR, and SMOTEENN-SVM for Phishing Website Detection based on SMOTEENN hybrid sampling approach have not been published in the existing studies as of now. [ABSTRACT FROM AUTHOR]

Large Language Models (LLMs) are reshaping the landscape of Machine Learning (ML) application development. The emergence of versatile LLMs capable of undertaking a wide array of tasks has reduced the necessity for intensive human involvement in training and maintaining ML models. Despite these advancements, a pivotal question emerges: can these generalized models negate the need for task-specific models? This study addresses this question by comparing the effectiveness of LLMs in detecting phishing URLs when utilized with prompt-engineering techniques versus when fine-tuned. Notably, we explore multiple prompt-engineering strategies for phishing URL detection and apply them to two chat models, GPT-3.5-turbo and Claude 2. In this context, the maximum result achieved was an F1-score of 92.74% by using a test set of 1000 samples. Following this, we fine-tune a range of base LLMs, including GPT-2, Bloom, Baby LLaMA, and DistilGPT-2—all primarily developed for text generation—exclusively for phishing URL detection. The fine-tuning approach culminated in a peak performance, achieving an F1-score of 97.29% and an AUC of 99.56% on the same test set, thereby outperforming existing state-of-the-art methods. These results highlight that while LLMs harnessed through prompt engineering can expedite application development processes, achieving a decent performance, they are not as effective as dedicated, task-specific LLMs. [ABSTRACT FROM AUTHOR]

Water polo is a team sport in which anaerobic capacity plays a significant role, but there is a lack of ecologically valid tests of water polo-specific anaerobic capacity. Therefore, the purpose of this study was to design and validate a method for evaluating the anaerobic capacity of water polo players. The sample of participants included 10 male junior water polo players (16.70 ± 1.06 years, 186.11 ± 6.06 cm, 81.18 ± 6.88 kg). Measurements included power output in the Wingate anaerobic test (WAnT) and the newly designed eggbeater kick anaerobic test (EKAT). WAnT included peak power (PP), average power (AP), minimal power (MP), and power drop (PD), and EKAT included the same four parameters as well as anaerobic capacity (AC). The results of this study show a significant correlation between test and retest values of power output (Pearson's correlation: 0.63, 0.87, 0.85, and 0.90 for PP, AP, MP, and AC, respectively). T-test calculation showed no significant differences between test and retest values for EKAT. Correlation analysis between EKAT and WAnT showed no significant correlation between corresponding power outputs. In conclusion, our results suggest that EKAT has proper metric characteristics, indicating the practical applicability of this test for male water polo players. Further studies on older players and female players are warranted. [ABSTRACT FROM AUTHOR]

The objective was to develop an interdisciplinary weaning protocol (IWP) for patients with tracheostomy tubes due to acquired brain injury, and to effect evaluate implementation of the IWP on decannulation rates and weaning duration. An expert panel completed a literature review in 2018 to identify essential criteria in the weaning process. Based on consensus and availability in clinical practice, criteria for guiding the weaning process were included in the protocol. Using the IWP, dysphagia is graded as either severe, moderate, or mild. The weaning process is guided through a protocol which specified the daily duration of cuff deflation until decannulation, along with recommendations for treatment and rehabilitation interventions. Data from 337 patient records (161 before and 176 after implementation) were included for effect evaluation. Decannulation rate during hospitalization was unchanged at 91% vs. 90% before and after implementation (decannulation rate at 60 days was 68% vs. 74%). After implementation, the weaning duration had decreased compared to before implementation, hazard ratio 1.309 (95%CI: 1.013; 1.693), without any increased risk of tube-reinsertion or pneumonia. Furthermore, a tendency toward decreased length of stay was seen with median 102 days (IQR: 73–138) and median 90 days (IQR: 58–119) (p = 0.061) before and after implementation, respectively. Scientific debate on weaning protocols for tracheostomy tubes are encouraged. [ABSTRACT FROM AUTHOR]

Background: Cerebral microbleeds (CMB) play an important role in neurodegenerative pathology. Objective: The present study aims to test whether cerebrospinal fluid (CSF) growth-associated protein 43 (GAP-43) level is linked to CMBs in elderly people. Methods: A total of 750 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) who had measurements of GAP-43 and CMBs were included in the study. According to the presence and extent of CMBs, participants were stratified into different groups. Regression analyses were used to assess cross-sectional and longitudinal associations between GAP-43 and CMBs. Results: Participants with CMB were slightly older and had higher concentrations of CSF GAP43. In multivariable adjusted analyses for age, gender, APOEɛ4 status, and cognitive diagnoses, higher CSF GAP-43 concentrations were modestly associated with CMB presence (OR = 1.169, 95% CI = 1.001–1.365) and number (β= 0.020, SE = 0.009, p = 0.027). Similarly, higher CSF GAP43 concentrations were accrual of CMB lesions, associated with higher CMB progression (OR = 1.231, 95% CI = 1.044–1.448) and number (β= 0.017, SE = 0.005, p = 0.001) in the follow up scan. In stratified analyses, slightly stronger associations were noted in male participants, those 65 years and older, carriers of APOEɛ4 alleles, and with more advanced cognitive disorders. Conclusions: CSF GAP-43 was cross-sectionally associated with the presence and extent of CMBs. GAP-43 might be used as a biomarker to track the dynamic changes of CMBs in elderly persons. [ABSTRACT FROM AUTHOR]

Background: Classifications of AAFD/PCFD have evolved with an increased understanding of the pathology involved. A review of classification systems helps identify deficiencies and respective contributions to the evolution in understanding the classification of AAFD/PCFD. Methods: Using multiple electronic database searches (Medline, PubMed) and Google search, original papers classifying AAFD/PCFD were identified. Nine original papers were identified that met the inclusion criteria. Results: Johnson's original classification and multiple variants provided a significant leap in understanding and communicating the pathology but remained tibialis posterior tendon-focused. Drawbacks of these classifications include the implication of causality, linearity of progression through stages, an oversimplification of stage 2 deformity, and a failure to understand that multiple tendons react, not just tibialis posterior. Later classifications, such as the PCFD classification, are deformity-centric. Early ligament laxity/instability in normal attitude feet and all stages of cavus feet can present with pain and instability with minor/no deformity. These may not be captured in deformity-based classifications. The authors developed the 'Triple Classification' (TC) understanding that primary pathology is a progressive ligament failure/laxity that presents as tendon reactivity, deformity, and painful impingement, variably manifested depending on starting foot morphology. In this classification, starting foot morphology is typed, ligament laxities are staged, and deformity is zoned. Conclusions: This review has used identified deficiencies within classification systems for AAFD/PCFD to delink ligament laxity, deformity, and foot type and develop the 'Triple classification'. Advantages of the TC may include representing foot types with no deformity, defining complex secondary instabilities, delinking foot types, tendon reactivity/ligament instability, and deformity to represent these independently in a new classification system. Level of Evidence: Level V. [ABSTRACT FROM AUTHOR]

Mouse models are crucial for neuroscience research, yet discrepancies arise between macro- and meso-scales due to sample preparation altering brain morphology. The absence of an accessible toolbox for magnetic resonance imaging (MRI) data processing presents a challenge for assessing morphological changes in the mouse brain. To address this, we developed the MBV-Pipe (Mouse Brain Volumetric Statistics-Pipeline) toolbox, integrating the methods of Diffeomorphic Anatomical Registration Through Exponentiated Lie Algebra (DARTEL)-Voxel-based morphometry (VBM) and Tract-Based Spatial Statistics (TBSS) to evaluate brain tissue volume and white matter integrity. To validate the reliability of MBV-Pipe, brain MRI data from seven mice at three time points (in vivo, post-perfusion, and post-fixation) were acquired using a 9.4T ultra-high MRI system. Employing the MBV-Pipe toolbox, we discerned substantial volumetric changes in the mouse brain following perfusion relative to the in vivo condition, with the fixation process inducing only negligible variations. Importantly, the white matter integrity was found to be largely stable throughout the sample preparation procedures. The MBV-Pipe source code is publicly available and includes a user-friendly GUI for facilitating quality control and experimental protocol optimization, which holds promise for advancing mouse brain research in the future., Competing Interests: Declarations. Competing Interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Tumor vaccines stand at the vanguard of tumor immunotherapy, demonstrating significant potential and promise in recent years. While tumor vaccines have achieved breakthroughs in the treatment of cancer, they still encounter numerous challenges, including improving the immunogenicity of vaccines and expanding the scope of vaccine application. As natural immune activators, bacterial components offer inherent advantages in tumor vaccines. Bacterial membrane components, with their safer profile, easy extraction, purification, and engineering, along with their diverse array of immune components, activate the immune system and improve tumor vaccine efficacy. This review systematically summarizes the mechanism of action and therapeutic effects of bacterial membranes and its derivatives (including bacterial membrane vesicles and hybrid membrane biomaterials) in tumor vaccines. Subsequently, the authors delve into the preparation and advantages of tumor vaccines based on bacterial membranes and hybrid membrane biomaterials. Following this, the immune effects of tumor vaccines based on bacterial outer membrane vesicles are elucidated, and their mechanisms are explained. Moreover, their advantages in tumor combination therapy are analyzed. Last, the challenges and trends in this field are discussed. This comprehensive analysis aims to offer a more informed reference and scientific foundation for the design and implementation of bacterial membrane-based tumor vaccines., (© 2024 Wiley‐VCH GmbH.)

The railway industry forecasts growth in passenger and freight traffic over the next 30 years. This places additional demands on rolling stock depot facilities, many of which were designed and built before the modern age of information technology. This paper explores the potential of improving the efficiency and effectiveness of rolling stock maintenance management to meet the challenges of the near future, by utilising advanced computing techniques. The objective of the work is to create optimised maintenance plans for a fleet of trains, considering optimal use of resources. As a "glue" for joining up functions and operations, a generic Depot and Vehicle ontology (called the Virtual Depot) is introduced. The ontology captures the structures, relationships, and attributes of objects in the Depot (rolling stock, sensors, depot assets, tools, resources, and staff). The ontology is populated with example company and fleet-specific knowledge using an automated knowledge acquisition method. This paper describes the systematic method for the creation of a Virtual Depot. Two particular aspects are discussed in detail—knowledge acquisition of fleet-specific information obtained from a manufacturer's Vehicle Maintenance Instruction manuals and the construction of a short-term scheduling process within the Virtual Depot. Our evaluation considers the integrative aspects of the method, demonstrating how the ontological structure and its acquired specific information informs and benefits the scheduling process, in particular with respect to schedule optimisation. Results from an initial case study show there is significant potential to optimise short-term maintenance schedules, and the ability to automatically consider resource availability in short-term scheduling is demonstrated. [ABSTRACT FROM AUTHOR]

High dietary intake of saturated fatty acids is a suspected risk factor for neurodegenerative diseases, including Alzheimer's disease (AD). To decipher the causal link behind these associations, high-fat diets (HFD) have been repeatedly investigated in animal models. Preclinical studies allow full control over dietary composition, avoiding ethical concerns in clinical trials. The goal of the present article is to provide a narrative review of reports on HFD in animal models of AD. Eligibility criteria included mouse models of AD fed a HFD defined as > 35% of fat/weight and western diets containing > 1% cholesterol or > 15% sugar. MEDLINE and Embase databases were searched from 1946 to August 2022, and 32 preclinical studies were included in the review. HFD-induced obesity and metabolic disturbances such as insulin resistance and glucose intolerance have been replicated in most studies, but with methodological variability. Most studies have found an aggravating effect of HFD on brain Aβ pathology, whereas tau pathology has been much less studied, and results are more equivocal. While most reports show HFD-induced impairment on cognitive behavior, confounding factors may blur their interpretation. In summary, despite conflicting results, exposing rodents to diets highly enriched in saturated fat induces not only metabolic defects, but also cognitive impairment often accompanied by aggravated neuropathological markers, most notably Aβ burden. Although there are important variations between methods, particularly the lack of diet characterization, these studies collectively suggest that excessive intake of saturated fat should be avoided in order to lower the incidence of AD. [ABSTRACT FROM AUTHOR]

Purpose: We aimed to quantify oropharyngeal swallowing physiology in amyotrophic lateral sclerosis (ALS) and examine relationships between swallowing impairments and ratings of pulmonary function (forced vital capacity percent predicted, FVC % pre) and functional status (ALS Functional Rating Scale-- Revised, ALSFRS-R). Method: A retrospective analysis of swallowing-related data of persons with ALS (PALS) was completed. Their Modified Barium Swallow Impairment Profile component, Oral Total (OT), and Pharyngeal Total (PT) scores were compared with data from age- (±1 year) and sex-matched healthy controls retrieved from an archival normative data set using Mann--Whitney U tests. Relationships between PALS' OT and PT scores, FVC % pre, and ALSFRS-R were examined using Pearson product--moment correlations and multiple linear regression modeling. Results: Twenty-one PALS (12 women), with a mean age of 62.2 ± 9.9 years, were included in the analyses. Compared to healthy controls, PALS exhibited significantly worse function across 13 (76%) physiological swallowing components (all p < .05). OT and PT scores significantly differed between PALS and healthy controls (each p < .001), with higher scores (worse impairment) observed in the former. When adjusting for age and sex, FVC % pre was a significant predictor of OT score (p = .045). An inverse relationship was found with ALSFRS-R and OT score (p = .052). FVC % pre (p = .061) and ALSFRS-R (p = .54) did not significantly predict PT score. Conclusions: PALS demonstrated swallowing impairments across oropharyngeal domains and the esophageal component. In our PALS cohort, FVC % pre was a useful clinical indicator of oral swallowing impairment. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that has a complex genetic basis. Through advancements in genetic screening, researchers have identified more than 40 mutant genes associated with ALS, some of which impact immune function. Neuroinflammation, with abnormal activation of immune cells and excessive production of inflammatory cytokines in the central nervous system, significantly contributes to the pathophysiology of ALS. In this review, we examine recent evidence on the involvement of ALS-associated mutant genes in immune dysregulation, with a specific focus on the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway and N6-methyladenosine (m6A)-mediated immune regulation in the context of neurodegeneration. We also discuss the perturbation of immune cell homeostasis in both the central nervous system and peripheral tissues in ALS. Furthermore, we explore the advancements made in the emerging genetic and cell-based therapies for ALS. This review underscores the complex relationship between ALS and neuroinflammation, highlighting the potential to identify modifiable factors for therapeutic intervention. A deeper understanding of the connection between neuroinflammation and the risk of ALS is crucial for advancing effective treatments for this debilitating disorder. [ABSTRACT FROM AUTHOR]

A mutation in C9ORF72 is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Patients with ALS or FTD often develop autoimmunity and inflammation that precedes or coincides with the onset of neurological symptoms, but the underlying mechanisms are poorly understood. Here, we knocked out murine C9orf72 in seven hematopoietic progenitor compartments by conditional mutagenesis and found that myeloid lineage C9orf72 prevents splenomegaly, loss of tolerance, and premature mortality. Furthermore, we demonstrated that C9orf72 plays a role in lymphoid cells to prevent interleukin-17A (IL-17A) production and neutrophilia. Mass cytometry identified early and sustained elevation of the costimulatory molecule CD80 expressed on C9orf72-deficient mouse macrophages, monocytes, and microglia. Enrichment of CD80 was similarly observed in human spinal cord microglia from patients with C9ORF72-mediated ALS compared with non-ALS controls. Single-cell RNA sequencing of murine spinal cord, brain cortex, and spleen demonstrated coordinated induction of gene modules related to antigen processing and presentation and antiviral immunity in C9orf72-deficient endothelial cells, microglia, and macrophages. Mechanistically, C9ORF72 repressed the trafficking of CD80 to the cell surface in response to Toll-like receptor agonists, interferon-γ, and IL-17A. Deletion of Il17a in C9orf72-deficient mice prevented CD80 enrichment in the spinal cord, reduced neutrophilia, and reduced gut T helper type 17 cells. Last, systemic delivery of an IL-17A neutralizing antibody augmented motor performance and suppressed neuroinflammation in C9orf72-deficient mice. Altogether, we show that C9orf72 orchestrates myeloid costimulatory potency and provide support for IL-17A as a therapeutic target for neuroinflammation associated with ALS or FTD. Editor's summary: Patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) often exhibit autoimmune inflammation before neurological symptoms. Although mutated C9ORF72 has been linked to ALS and FTD, its role in neuroinflammation is unclear. Limone et al. found that hematopoietic loss of C9orf72 expression drove excess IL-17A inflammation. Myeloid-specific loss of C9orf72 was sufficient to cause severe autoimmunity. C9orf72-deficient mice had more myeloid cells with higher surface expression of costimulatory molecule CD80, which was potentiated by IL-17A. Patients with C9ORF72-related ALS similarly showed CD80 enrichment in spinal cord microglia. IL-17A neutralizing antibody reduced neuroinflammation in C9orf72-deficient mice, supporting further investigation of IL-17A–based therapies for ALS- and FTD-associated neuroinflammation. —Molly Ogle [ABSTRACT FROM AUTHOR]

Website Uniform Resource Locator (URL) spoofing remains one of the ways of perpetrating phishing attacks in the twenty-first century. Hackers continue to employ URL spoofing to deceive naïve and unsuspecting consumers into releasing important personal details in malicious websites. Blacklists and rule-based filters that were once effective at reducing the risks and sophistication of phishing are no longer effective as there are over 1.5 million new phishing websites created monthly. Therefore, research aimed at unveiling new techniques for detecting phishing websites has sparked a lot of interest in both academics and business with machine and deep learning techniques being at the forefront. Among the deep learning techniques that have been employed, Convolutional Neural Network (CNN) remains one of the most widely used with high performance in feature learning. However, CNN has a problem of memorizing contextual relationships in URL text, which makes it challenging to efficiently detect sophisticated malicious URLs in real-time applications. On the contrary, Long Short-Term Memory (LSTM) deep learning model has been successfully employed in complex real-time problems because of its ability to store inputs for a long period of time. This study experiments with the use of hybrid CNN and LSTM deep learning models for spoofing website URL detection in order to exploit the combined strengths of the two approaches for a more sophisticated spoofing URL detection. Two publicly available datasets (UCL spoofing Website and PhishTank Datasets) were used to evaluate the performance of the proposed hybrid model against other models in the literature. The hybrid CNN-LSTM model achieved accuracies of 98.9% and 96.8%, respectively, when evaluated using the UCL and PhishTank datasets. On the other hand, the standalone CNN and LSTM achieved accuracies of 90.4% and 94.6% on the UCL dataset, while their accuracies on the PhishTank dataset were 89.3% and 92.6%, respectively. The results show that the hybrid CNN-LSTM algorithm largely outperformed the standalone CNN and LSTM models, which demonstrates a much better performance. Therefore, the hybrid deep learning technique is recommended for detecting spoofing website URL thereby reducing losses attributed to such attacks. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder which is characterized by the loss of both upper and lower motor neurons in the central nervous system. In a significant fraction of ALS cases - irrespective of family history- a genetic background may be identified. The genetic background of ALS shows a high variability from one ethnicity to another. The most frequent genetic cause of ALS is the repeat expansion of the C9orf72 gene. With the emergence of next-generation sequencing techniques and copy number alteration calling tools the focus in ALS genetics has shifted from disease causing genes and mutations towards genetic susceptibility and risk factors. In this review we aimed to summarize the most widely recognized and studied ALS linked repeat expansions and copy number variations other than the hexanucleotide repeat expansion in the C9orf72 gene. We compare and contrast their involvement and phenotype modifying roles in ALS among different populations. [ABSTRACT FROM AUTHOR]

Background: Increasing evidence has highlighted retinal impairments in neurodegenerative diseases. Dominant mutations in TAR DNA-binding protein 43 (TDP-43) cause amyotrophic lateral sclerosis (ALS), and the accumulation of TDP-43 in the cytoplasm is a pathological hallmark of ALS, frontotemporal dementia (FTD), and many other neurodegenerative diseases. Objective: While homozygous transgenic mice expressing the disease-causing human TDP-43 M337V mutant (TDP-43M337V mice) experience premature death, hemizygous TDP-43M337V mice do not suffer sudden death, but they exhibit age-dependent motor-coordinative and cognitive deficits. This study aims to leverage the hemizygous TDP-43M337V mice as a valuable ALS/FTD disease model for the assessment also of retinal changes during the disease progression. Methods: We evaluated the retinal function of young TDP-43M337V mice by full field electroretinogram (ERG) recordings. Results: At 3–4 months of age, well before the onset of brain dysfunction at 8 months, the ERG responses were notably impaired in the retinas of young female TDP-43M337V mice in contrast to their male counterparts and age-matched non-transgenic mice. Mitochondria have been implicated as critical targets of TDP-43. Further investigation revealed that significant changes in the key regulators of mitochondrial dynamics and bioenergetics were only observed in the retinas of young female TDP-43M337V mice, while these alterations were not present in the brains of either gender. Conclusions: Together our findings suggest a sex-specific vulnerability within the retina in the early disease stage, and highlight the importance of retinal changes and mitochondrial markers as potential early diagnostic indicators for ALS, FTD, and other TDP-43 related neurodegenerative conditions. [ABSTRACT FROM AUTHOR]

Background: Blood-brain barrier (BBB) dysfunction could favor the pathogenesis and progression of Alzheimer's disease (AD). Vascular risk factors (VRF) could worsen BBB integrity, thus promoting neurode generation. Objective: To investigate BBB permeability and its relation with VRF along the AD continuum (ADc). Cerebrospinal fluid (CSF) Amyloid (A) and p-tau (T) levels were used to stratify patients. Methods: We compared CSF/plasma albumin ratio (QAlb) of 131 AD patients and 24 healthy controls (HC). APOE genotype and VRF were evaluated for each patient. Spearman's Rho correlation was used to investigate the associations between Qalb and CSF AD biomarkers. Multivariate regression analyses were conducted to explore the relationship between Qalb and AD biomarkers, sex, age, cognitive status, and VRF. Results: QAlb levels did not show significant difference between ADc patients and HC (p = 0.984). However, QAlb was significantly higher in A + T–compared to A + T+ (p = 0.021). In ADc, CSF p-tau demonstrated an inverse correlation with QAlb, a finding confirmed in APOE4 carriers (p = 0.002), but not in APOE3. Furthermore, in APOE4 carriers, sex, hypertension, and hypercholesterolemia were associated with QAlb (p = 0.004, p = 0.038, p = 0.038, respectively), whereas only sex showed an association in APOE3 carriers (p = 0.026). Conclusions: BBB integrity is preserved in ADc. Among AT categories, A + T–have a more permeable BBB than A + T+. In APOE4 carriers, CSF p-tau levels display an inverse association with BBB permeability, which in turn, seems to be affected by VRF. These data suggest a possible relationship between BBB efficiency, VRF and CSF p-tau levels depending on APOE genotype. [ABSTRACT FROM AUTHOR]

Every evolution, rooted in its principles, presents a time-relevant paradigm shift. In the regards, technological evolution has been a significant milestone in the journey of educational contributions. It has today become an integral part of the education eco-system. While generation-z students are characteristically tech-savvy, at the same time it questions the caliber of the faculty to address the needs of these students. To understand the evolution of teaching pedagogies of the classroom, a qualitative study was conducted with Connectivism as the underlying theoretical framework. Through the semi-structured interviews, twenty seven faculty were interviewed with five questions. The first round of coding was carried out using the descriptive and vivo methods and second was carried out using the focused coding. Five themes have been discussed from the round one coding and summarized using the round two. The paper presents the results and discussion of this qualitative study and opens the potential space for future technology-related research questions. Writing learning outcomes, evolving classrooms and selecting technology have been discussed with respect to technological implications. The study concludes that the research groups need to develop philosophies by integrating the technology into the learning styles. [ABSTRACT FROM AUTHOR]

Mucosal-associated invariant T (MAIT) cells are innate-like T cells that recognize bacterial riboflavin–based metabolites as activating antigens. Although MAIT cells are found in tissues, it is unknown whether any host tissue–derived antigens exist. Here, we report that a sulfated bile acid, cholic acid 7-sulfate (CA7S), binds the nonclassical MHC class I protein MR1 and is recognized by MAIT cells. CA7S is a host-derived metabolite whose levels were reduced by more than 98% in germ-free mice. Deletion of the sulfotransferase 2a family of enzymes (Sult2a1-8) responsible for CA7S synthesis reduced the number of thymic MAIT cells in mice. Moreover, recognition of CA7S induced MAIT cell survival and the expression of a homeostatic gene signature. By contrast, recognition of a previously described foreign antigen, 5-(2-oxopropylideneamino)-6-d-ribitylaminouracil (5-OP-RU), drove MAIT cell proliferation and the expression of inflammatory genes. Thus, CA7S is an endogenous antigen for MAIT cells, which promotes their development and function. Editor's summary: Mucosal-associated invariant T (MAIT) cells are an innate-like T cell subset important for mucosal homeostasis, which recognize microbiota-derived vitamin B metabolites presented by the MHC-Ib molecule MR1. It is unclear, however, whether any host-derived ligands are also important for MAIT cell function and survival. Ito et al. report that the host-derived bile acid metabolite cholic acid 7-sulfate (CA7S) binds MR1 and is recognized by MAIT cells in mice. Moreover, genetic deletion of sulfotransferase 2a enzymes (Sult2a1-8) needed for its synthesis in mice reduced thymic MAIT cell numbers. A previously characterized vitamin B metabolite, 5-OP-RU, triggered human MAIT cell proliferation and the expression of inflammatory genes. By contrast, CA7S promoted human MAIT cell survival and a gene program associated with wound healing and immunoregulation. —Seth Thomas Scanlon [ABSTRACT FROM AUTHOR]