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Facioscapulohumeral muscular dystrophy (FSHD) is linked to abnormal derepression of the transcription activator DUX4. This effect is localized to a low percentage of cells, requiring single-cell analysis. However, single-cell/nucleus RNA-seq cannot fully capture the transcriptome of multinucleated large myotubes. To circumvent these issues, we use multiplexed error-robust fluorescent in situ hybridization (MERFISH) spatial transcriptomics that allows profiling of RNA transcripts at a subcellular resolution. We simultaneously examined spatial distributions of 140 genes, including 24 direct DUX4 targets, in in vitro differentiated myotubes and unfused mononuclear cells (MNCs) of control, isogenic D4Z4 contraction mutant and FSHD patient samples, as well as the individual nuclei within them. We find myocyte nuclei segregate into two clusters defined by the expression of DUX4 target genes, which is exclusively found in patient/mutant nuclei, whereas MNCs cluster based on developmental states. Patient/mutant myotubes are found in FSHD-hi and FSHD-lo states with the former signified by high DUX4 target expression and decreased muscle gene expression. Pseudotime analyses reveal a clear bifurcation of myoblast differentiation into control and FSHD-hi myotube branches, with variable numbers of DUX4 target-expressing nuclei found in multinucleated FSHD-hi myotubes. Gene coexpression modules related to extracellular matrix and stress gene ontologies are significantly altered in patient/mutant myotubes compared with the control. We also identify distinct subpathways within the DUX4 gene network that may differentially contribute to the disease transcriptomic phenotype. Taken together, our MERFISH-based study provides effective gene network profiling of multinucleated cells and identifies FSHD-induced transcriptomic alterations during myoblast differentiation.

STUDY DESIGN: Systematic review. OBJECTIVE: Degenerative cervical myelopathy (DCM) is a common spinal cord disorder necessitating surgery. We aim to explore how effectively diffusion tensor imaging (DTI) can distinguish DCM from healthy individuals and assess the relationship between DTI metrics and symptom severity. METHODS: We included studies with adult DCM patients who had not undergone decompressive surgery and implemented correlation analyses between DTI parameters and severity, or compared healthy controls and DCM patients. RESULTS: 57 studies were included in our meta-analysis. At the maximal compression (MC) level, fractional anisotropy (FA) exhibited lower values in DCM patients, while apparent diffusion coefficient (ADC), mean diffusivity (MD), and radial diffusivity (RD) were notably higher in the DCM group. Moreover, our investigation into the diagnostic utility of DTI parameters disclosed high sensitivity, specificity, and area under the curve values for FA (.84, .80, .83 respectively) and ADC (.74, .84, .88 respectively). Additionally, we explored the correlation between DTI parameters and myelopathy severity, revealing a significant correlation of FA (.53, 95% CI:0.40 to .65) at MC level with JOA/mJOA scores. CONCLUSION: Current guidelines for DCM suggest decompressive surgery for both mild and severe cases. However, they lack clear recommendations on which mild DCM patients might benefit from conservative treatment vs immediate surgery. ADCs role here could be pivotal, potentially differentiating between healthy individuals and DCM. While it may not correlate with symptom severity, it might predict surgical outcomes, making it a valuable imaging biomarker for clearer management decisions in mild DCM.

IntroductionAlzheimer's disease (AD) is a neurodegenerative disorder with multifactorial etiology, including genetic factors that play a significant role in disease risk and resilience. However, the role of genetic diversity in preclinical AD studies has received limited attention.MethodsWe crossed five Collaborative Cross strains with 5xFAD C57BL/6J female mice to generate F1 mice with and without the 5xFAD transgene. Amyloid plaque pathology, microglial and astrocytic responses, neurofilament light chain levels, and gene expression were assessed at various ages.ResultsGenetic diversity significantly impacts AD-related pathology. Hybrid strains showed resistance to amyloid plaque formation and neuronal damage. Transcriptome diversity was maintained across ages and sexes, with observable strain-specific variations in AD-related phenotypes. Comparative gene expression analysis indicated correlations between mouse strains and human AD.DiscussionIncreasing genetic diversity promotes resilience to AD-related pathogenesis, relative to an inbred C57BL/6J background, reinforcing the importance of genetic diversity in uncovering resilience in the development of AD.HighlightsGenetic diversity's impact on AD in mice was explored. Diverse F1 mouse strains were used for AD study, via the Collaborative Cross. Strain-specific variations in AD pathology, glia, and transcription were found. Strains resilient to plaque formation and plasma neurofilament light chain (NfL) increases were identified. Correlations with human AD transcriptomics were observed.

IntroductionThe BIN1 coding variant rs138047593 (K358R) is linked to Late-Onset Alzheimer's Disease (LOAD) via targeted exome sequencing.MethodsTo elucidate the functional consequences of this rare coding variant on brain amyloidosis and neuroinflammation, we generated BIN1K358R knock-in mice using CRISPR/Cas9 technology. These mice were subsequently bred with 5xFAD transgenic mice, which serve as a model for Alzheimer's pathology.ResultsThe presence of the BIN1K358R variant leads to increased cerebral amyloid deposition, with a dampened response of astrocytes and oligodendrocytes, but not microglia, at both the cellular and transcriptional levels. This correlates with decreased neurofilament light chain in both plasma and brain tissue. Synaptic densities are significantly increased in both wild-type and 5xFAD backgrounds homozygous for the BIN1K358R variant.DiscussionThe BIN1 K358R variant modulates amyloid pathology in 5xFAD mice, attenuates the astrocytic and oligodendrocytic responses to amyloid plaques, decreases damage markers, and elevates synaptic densities.HighlightsBIN1 rs138047593 (K358R) coding variant is associated with increased risk of LOAD. BIN1 K358R variant increases amyloid plaque load in 12-month-old 5xFAD mice. BIN1 K358R variant dampens astrocytic and oligodendrocytic response to plaques. BIN1 K358R variant decreases neuronal damage in 5xFAD mice. BIN1 K358R upregulates synaptic densities and modulates synaptic transmission.

Facioscapulohumeral dystrophy (FSHD) is linked to contraction of D4Z4 repeats on chromosome 4q with SMCHD1 mutations acting as a disease modifier. D4Z4 heterochromatin disruption and abnormal upregulation of the transcription factor DUX4, encoded in the D4Z4 repeat, are the hallmarks of FSHD. However, defining the precise effect of D4Z4 contraction has been difficult because D4Z4 repeats are primate-specific and DUX4 expression is very rare in highly heterogeneous patient myocytes. We generated isogenic mutant cell lines harboring D4Z4 and/or SMCHD1 mutations in a healthy human skeletal myoblast line. We found that the mutations affect D4Z4 heterochromatin differently, and that SMCHD1 mutation or disruption of DNA methylation stabilizes otherwise variegated DUX4 target activation in D4Z4 contraction mutant cells, demonstrating the critical role of modifiers. Our study revealed amplification of the DUX4 signal through downstream targets, H3.X/Y and LEUTX. Our results provide important insights into how rare DUX4 expression leads to FSHD pathogenesis.

For the native people of northern Iran, the organization of the bloody battle of two bulls is called Varzajang. They insist on its continuation under titles such as safeguarding the local game, tradition, preservation of culture, and protection of identity. Although during the last few centuries, this unusual culture has undergone tremendous changes with the transformation of social structures, but its main core, "fighting two bulls", still remains. Recently, some university researchers also emphasized economic dimensions, its development to attract profit and financial income for the host, the attraction of tourism, and social cohesion. Although many tourists and historians in Iran have called this phenomenon a play since the past, but the ideal of the presence of wisdom in individual and social life makes us consider a play beautiful that accepts the equality of actors in its functions. This show, which has a kind of unconventional livelihood, denies half of its actors (women). Our intention to deal with this issue is not to try to bring women into this campaign, but to critically analyze it. Therefore, the central question is that the lack of presence of women in this ceremony indicates what kind of relationships? Therefore, the researcher tried to find an appropriate answer to the above questions with the bio-experiment among the mentioned activists and adopting the Moustakas strategy in phenomenology as a method as a result, Varzajang, in the continuation of the cultural tradition of the past in the society, despite the changes it has had, has not come close to the threshold of a cohesive social play.

Abstract Water splitting is a promising pathway for hydrogen production, providing an environmentally friendly fuel source. More recently, great attention has been given to transition metal dichalcogenides (TMDCs) because of their interesting chemical and physical properties. In particular, tungsten disulfide (WS2) has garnered significant attention as a catalyst for this application due to its unique layered 2D structure. In this study, few-layered WS2 and phosphorus-doped WS2 (WS2/P) nanoflakes are synthesized on SiO2/Si substrates as electrocatalysts for hydrogen evolution reactions (HER) in acidic conditions. Analyses of the synthesized WS2 and WS2/P films reveal that the few-layered WS2 is of high quality, exhibiting continuity and uniformity. The presence of a strong peak in the photoluminescence spectrum confirms the mono/few layer nature of the synthesized samples. In additionally, scanning force microscopy in quantitative imaging mode reveals that the thinnest layers observed on the substrate have a height of 1.35 nm, indicating the presence of double-layer WS2. The WS2/P electrocatalyst demonstrates superior HER performance compared to pristine WS2, showing a low overpotential of 245 mV at 10 mA.cm−2 and a small Tafel slope of 123 mV.dec−1. Furthermore, WS2/P exhibits a greater electrochemical surface area and excellent catalytic stability under acidic conditions. Consequently, few layer phosphorus-doped WS2 proves to be a highly suitable electrocatalyst for hydrogen production compared to the WS2.

Reevaluating the Paradox: Does Low-Dose Radiation from A-Bombs Affect Lifespan and Cancer Mortality?Reevaluating the Paradox: Does Low-Dose Radiation from A-Bombs Affect Lifespan and Cancer Mortality?Reevaluating the Paradox: Does Low-Dose Radiation from A-Bombs Affect Lifespan and Cancer Mortality?Reevaluating the Paradox: Does Low-Dose Radiation from A-Bombs Affect Lifespan and Cancer Mortality?Reevaluating the Paradox: Does Low-Dose Radiation from A-Bombs Affect Lifespan and Cancer Mortality?Reevaluating the Paradox: Does Low-Dose Radiation from A-Bombs Affect Lifespan and Cancer Mortality?Reevaluating the Paradox: Does Low-Dose Radiation from A-Bombs Affect Lifespan and Cancer Mortality?

Abstract Background Legg-Calve-Perthes Disease (LCPD) is described as idiopathic avascular osteonecrosis of the capital femoral epiphysis in pediatrics. LCPD is usually present in children between 2 and 15 years and happens more frequently in boys more than girls; this study aims to compare the outcome of two surgical methods in treating LCPD. Methods We included sixty patients with unilateral LCPD who underwent Salter or femoral varus osteotomy from 2007 to 2017. Patients were followed up for at least five years. Patients’ claudication, pain, leg circumference, range of motion, lever arm ratio (LAR), neck shaft angle (NSA), migration index, vertical distance, and the presence of teardrop sign, sagging rope sign, and Trendelenburg sign were evaluated five years after surgery. Results The mean neck shaft angle, the lever arm ratio, migration index and, sagging rope sign incidence in patients undergoing femoral varus osteotomy were significantly lower than those undergoing Salter surgery; the thigh circumference was higher in patients undergoing femoral varus osteotomy than those undergoing Salter osteotomy. Conclusion There were significant differences in biomechanical indices of hip and acetabulofemoral in salter and femoral varus osteotomy; the results of the current study are highly suggestive of prioritizing femoral varus osteotomy to Salter surgery.

Background: In Iran, marriages between Iranian women and Afghan immigrant men are on the rise; however, there is limited information available regarding domestic violence against Iranian women with Afghan immigrant spouses. Domestic violence is a serious social and public health issue that requires a precise understanding of the influential factors in this context. Aims: This study aimed to identify the factors influencing domestic violence against Iranian women with Afghan immigrant spouses. This study could contribute to improving policies and prevention programs aimed at addressing domestic violence in these communities. Methods: The present study utilized a descriptive phenomenological approach. The target population consisted of all Iranian women who were victims of domestic violence with Afghan immigrant spouses residing in Tehran province. The sampling method was a snowball technique, ultimately resulting in interviews conducted with 14 participants. Data collection utilized semi-structured, in-depth interviews, and the collected data were analyzed using a seven-step Colaizzi method. Results: The results indicated that factors such as personal characteristics of women (such as age, education, and economic status), characteristics of Afghan spouses (economic, cultural, and social), and family and social factors (such as cultural pressures and societal attitudes) play a role in increasing domestic violence against Iranian women with Afghan immigrant spouses. Conclusion: Given the findings of this study, it appears that a precise understanding of the factors influencing domestic violence in this community is crucial. This study can aid in formulating policies and prevention programs against domestic violence towards Iranian women with Afghan spouses, leading to improvements in their social and health-related conditions

Pragmatic competence entails awareness-raising of impoliteness. This paper delves into the pragmatics of impoliteness in online communication, focusing on X (Twitter) interactions, with a particular emphasis on 126 replies to Elon Musk's controversial tweet. Utilizing Culpeper's (2011) model of impoliteness formulae and implicational impoliteness, the study analyzes responses to this tweet, exploring the multifaceted dimensions of impoliteness. The research also investigates the moral order expectations expressed by the repliers, shedding light on the factors influencing their reactions and responses. By employing qualitative content analysis and thematic analysis, the study reveals the nuanced forms of impoliteness and the underlying moral order themes inherent in these online exchanges. "Responsible wealth behavior," "appropriate and non-offensive language," "respect and decency," "refraining from political narratives," "engaging in social responsibility," and "showing transparency, accountability, and ethics" were the identified moral order expectations. The findings underscore the relevance of examining impoliteness in the digital age, where public figures' tweets can have far-reaching consequences and provoke diverse reactions from the online community. This research contributes to a deeper understanding of impoliteness in online discourse and its implications for social media interactions by language learners, which are currently lacking in language classrooms.

The search for extraterrestrial intelligence is a fascinating and important endeavor, but it raises significant ethical and safety concerns. In the search for extraterrestrial intelligence, scientists use knowledge of physics to identify potential communication methods and signals that may be used by extraterrestrial civilizations. One of the most notable scientists to highlight these concerns was the late physicist Stephen Hawking, who cautioned that actively attempting to communicate with extraterrestrial civilizations could harm humanity. While it is true that we cannot predict the intentions of any potential extraterrestrial civilizations, some scientists argue that the potential advantages of seeking contact outweigh the potential risks. Deciding to initiate contact with extraterrestrial civilizations is a complex issue that requires balancing scientific curiosity with concerns for our own safety. The “Intelligence Trap” is a concept in psychology that suggests that highly intelligent people are more susceptible to cognitive biases and flawed thinking than less intelligent people. It can be argued that Hawking’s warnings may be an example of the so-called intelligence trap, as some evidence from the field of physics suggests. Nonetheless, Hawking emphasized that it is crucial for scientists and policymakers to carefully weigh the potential risks and benefits of such efforts and proceed with caution.

PurposeGiven the emergence of PSMA-targeted diagnostic agents and therapeutics, we sought to investigate patterns of FOLH1 expression in RCC and their impacts on RCC outcomes.MethodsWe conducted a pooled multi-institutional analysis of patients with RCC having undergone DNA and RNA next-generation sequencing. FOLH1-high/low expression was defined as the ≥75th/

Alzheimer's disease (AD) is the leading cause of dementia in older adults, and the need for effective, sustainable therapeutic targets is imperative. The complement pathway has been proposed as a therapeutic target. C5aR1 inhibition reduces plaque load, gliosis, and memory deficits in animal models, however, the cellular bases underlying this neuroprotection were unclear. Here, we show that the C5aR1 antagonist PMX205 improves outcomes in the Arctic48 mouse model of AD. A combination of single cell and single nucleus RNA-seq analysis of hippocampi derived from males and females identified neurotoxic disease-associated microglia clusters in Arctic mice that are C5aR1-dependent, while microglial genes associated with synapse organization and transmission and learning were overrepresented in PMX205-treated mice. PMX205 also reduced neurotoxic astrocyte gene expression, but clusters associated with protective responses to injury were unchanged. C5aR1 inhibition promoted mRNA-predicted signaling pathways between brain cell types associated with cell growth and repair, while suppressing inflammatory pathways. Finally, although hippocampal plaque load was unaffected, PMX205 prevented deficits in short-term memory in female Arctic mice. In conclusion, C5aR1 inhibition prevents cognitive loss, limits detrimental glial polarization while permitting neuroprotective responses, as well as leaving most protective functions of complement intact, making C5aR1 antagonism an attractive therapeutic strategy for AD.

During the early days of the COVID-19 pandemic, low dose radiation therapy (LDRT) was proposed as a potentially effective treatment method. To minimize potential toxicity, the initial treatment approach involved a few mGy of adapting radiation followed by a single 250 mGy whole lung challenging dose. However, antiviral drugs were also introduced as a promising treatment option, which were thought to have the potential to revolutionize the management of the crisis. Despite early warnings, many physicians did not fully consider the key point that, in contrast with LDRT, antiviral drug treatments can result in strong selective pressure on the virus. This can lead to the emergence of new SARS-CoV-2 variants, a phenomenon that can have serious global consequences. After more than two years, the truth has been revealed: the WHO Guideline Development Group has advised against the use of remdesivir, a widely used antiviral medication, for COVID-19. Meanwhile, a growing body of evidence suggests that LDRT can be a promising, low-risk approach for avoiding or delaying invasive respiratory support in COVID-19 patients. Although there is substantial supporting documentation, more high-quality, controlled, and randomized double-blind clinical trials are needed to further investigate the efficacy and potential therapeutic mechanisms of LDRT for COVID-19.

Abstract Previous studies have suggested that choroid plexus (ChP) enlargement occurs in individuals with schizophrenia-spectrum disorders (SSD) and is associated with peripheral inflammation. However, it is unclear whether such an enlargement delineates a biologically defined subgroup of SSD. Moreover, it remains elusive how ChP is linked to brain regions associated with peripheral inflammation in SSD. A cross-sectional cohort of 132 individuals with SSD and 107 age-matched healthy controls (HC) underwent cerebral magnetic resonance imaging (MRI) and clinical phenotyping to investigate the ChP and associated regions. A case-control comparison of ChP volumes was conducted, and structural variance was analyzed by employing the variability ratio (VR). K-means clustering analysis was used to identify subgroups with distinct patterns of the ventricular system, and the clusters were compared in terms of demographic, clinical, and immunological measures. The relationship between ChP volumes and brain regions, previously associated with peripheral inflammation, was investigated. We did not find a significant enlargement of the ChP in SSD compared to HC but detected an increased VR of ChP and lateral ventricle volumes. Based on these regions, we identified 3 clusters with differences in cognitive measures and possibly inflammatory markers. Larger ChP volume was associated with higher volumes of hippocampus, putamen, and thalamus in SSD but not in HC. This study suggests that ChP variability, but not mean volume, is increased in individuals with SSD, compared to HC. Larger ChP volumes in SSD were associated with higher volumes of regions previously associated with peripheral inflammation.

This paper presents a novel multi-stereo camera system for robust indoor localization, leveraging point cloud data and temporal fusion techniques. The system integrates three synchronized stereo cameras to capture point clouds from multiple angles, enhancing coverage and improving point cloud density in complex indoor environments. By combining data from different perspectives and accumulating point clouds over time, the method mitigates the limitations in the short range of point clouds derived from stereo cameras, ensuring broader coverage for effective localization. To manage the computational complexity of large-scale point clouds and reduce noise in accumulated data, voxelization is applied to downsample the point clouds while preserving key geometric features. The localization process is driven by a predictive point cloud odometry method, refined through the Iterative Closest Point (ICP) algorithm. Experimental results demonstrate the system’s ability to achieve accurate localization within a pre-built LiDAR map. This study highlights the feasibility of using low-cost stereo camera systems as an alternative to LiDAR-based solutions for indoor localization.

Abstract The intricate cellular process, known as the epithelial-mesenchymal transition (EMT), significantly influences solid tumors development. Changes in cell shape, metabolism, and gene expression linked to EMT facilitate tumor cell invasion, metastasis, drug resistance, and recurrence. So, a better understanding of the intricate processes underlying EMT and its role in tumor growth may lead to the development of novel therapeutic approaches for the treatment of solid tumors. This review article focuses on the signals that promote EMT and metabolism, the intracellular signaling pathways leading to EMT, and the network of interactions between EMT and cancer cell metabolism. Furthermore, the functions of EMT in treatment resistance, recurrence, and metastasis of solid cancers are covered. Lastly, treatment approaches that focus on intracellular signaling networks and metabolic alterations brought on by EMT will be discussed.

This report focuses on the multifaceted approach to dam construction in Iran, considering the significance and role of dams in water storage, flood control, hydropower generation, and agricultural advancement. The construction of each dam must take into account its environmental, economic, social, cultural, and security impacts, and it should be technically justifiable. This inquiry aims to examine the role of dam construction in the development of water resources based on the assigned functions of dams. It seeks to answer the question, from the perspective of experts and stakeholders in the field of dam construction: Have the dams that have been built or are currently under construction and design in Iran met the primary criteria for construction and design to achieve this goal? The response to this question is provided through an evaluation of various expert opinions and an analysis of discourses, presented in a comprehensive volume for those interested in the subject.