Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease leading to motor neuron loss. Currently mutations in > 40 genes have been linked to ALS, but the contribution of many genes and genetic mutations to the ALS pathogenic process remains poorly understood. Therefore, we first performed comparative interactome analyses of five recently discovered ALS-associated proteins (C21ORF2, KIF5A, NEK1, TBK1, and TUBA4A) which highlighted many novel binding partners, and both unique and shared interactors. The analysis further identified C21ORF2 as a strongly connected protein. The role of C21ORF2 in neurons and in the nervous system, and of ALS-associated C21ORF2 variants is largely unknown. Therefore, we combined human iPSC-derived motor neurons with other models and different molecular cell biological approaches to characterize the potential pathogenic effects of C21ORF2 mutations in ALS. First, our data show C21ORF2 expression in ALS-relevant mouse and human neurons, such as spinal and cortical motor neurons. Further, the prominent ALS-associated variant C21ORF2-V58L caused increased apoptosis in mouse neurons and movement defects in zebrafish embryos. iPSC-derived motor neurons from C21ORF2-V58L-ALS patients, but not isogenic controls, show increased apoptosis, and changes in DNA damage response, mitochondria and neuronal excitability. In addition, C21ORF2-V58L induced post-transcriptional downregulation of NEK1, an ALS-associated protein implicated in apoptosis and DDR. In all, our study defines the pathogenic molecular and cellular effects of ALS-associated C21ORF2 mutations and implicates impaired post-transcriptional regulation of NEK1 downstream of mutant C21ORF72 in ALS.

UNASSIGNED: Cytomegalovirus (CMV) is a classic opportunistic infection in transplant recipients. Treatment-refractory CMV infections are of concern, with growing identification of strains that have developed genetic mutations which confer resistance to standard antiviral therapy. Resistant and refractory CMV infections are associated with worse patient outcomes, prolonged hospitalization, and increased healthcare costs.
UNASSIGNED: This article provides a comprehensive practical overview of resistant and refractory CMV infections in transplant recipients. We review the updated definitions for these infections, antiviral pharmacology, mechanisms of drug resistance, diagnostic workup, management strategies, and host-related factors including immune optimization.
UNASSIGNED: Resistant and refractory CMV infections are a significant contributor to post-transplant morbidity and mortality. This is likely the result of a combination of prolonged antiviral exposure and active viral replication in the setting of intensive pharmacologic immunosuppression. Successful control of resistant and refractory infections in transplant recipients requires a combination of immunomodulatory optimization and appropriate antiviral drug choice with sufficient treatment duration.

Hyperekplexia is a neurologic disorder characterized by an exaggerated startle reflex in response to different types of stimuli. Hyperekplexia is defined by the triad of neonatal hypertonia, excessive startle reflexes, and generalized stiffness following the startle. Although uncommon, hyperekplexia can lead to serious consequences such as falls, brain injury, or sudden infant death syndrome.Aim of this study was to identify cases of neonatal hyperekplexia with a confirmed genetic diagnosis and to establish the genotype-phenotype correlation at onset. Articles were selected from 1993 to 2024 and PRISMA Statement was applied including newborns within 28 days of life. So, we retrieved from literature 14 cases of genetically confirmed neonatal hyperekplexia. The onset of clinical manifestations occurred in the first day of life in 8 of 14 patients (57.14%). Clinical findings were muscle stiffness (100%), startle reflex (66.66%), apnea/cyanosis (41.66%), positive nose-tapping test (33.33%), jerks (33.33%), jitteriness (25%), and ictal blinking (25%). Genes involved were GLRA1 in 9 of 14 (64.28%), SLC6A5 in 2 of 14 (14.28%), GPHN in 1 of 14 (7.14%), and GLRB in 2 of 14 (14.28%). Patients showed heterozygous (66.66%) or homozygous (33.33%) status. In 7 of 14 cases (50%), the condition occurred in other family members. A genotype-phenotype correlation was not achievable.Timely diagnosis is crucial to improve the natural history of hyperekplexia avoiding/reducing possible major complications such as sudden infant death syndrome, brain injury, and serious falls. Early differentiation from epilepsy minimizes treatment cost and improves the quality of life of patients.

BACKGROUND: Research is needed to understand and address barriers to risk management for women at high (≥20% lifetime) risk for breast cancer, but recruiting this population for research studies is challenging.
OBJECTIVE: This paper compares a variety of recruitment strategies used for a cross-sectional, observational study of high-risk women.
METHODS: Eligible participants were assigned female at birth, aged 25-85 years, English-speaking, living in the United States, and at high risk for breast cancer as defined by the American College of Radiology. Individuals were excluded if they had a personal history of breast cancer, prior bilateral mastectomy, medical contraindications for magnetic resonance imaging, or were not up-to-date on screening mammography per American College of Radiology guidelines. Participants were recruited from August 2020 to January 2021 using the following mechanisms: targeted Facebook advertisements, Twitter posts, ResearchMatch (a web-based research recruitment database), community partner promotions, paper flyers, and community outreach events. Interested individuals were directed to a secure website with eligibility screening questions. Participants self-reported method of recruitment during the eligibility screening. For each recruitment strategy, we calculated the rate of eligible respondents and completed surveys, costs per eligible participant, and participant demographics.
RESULTS: We received 1566 unique responses to the eligibility screener. Participants most often reported recruitment via Facebook advertisements (724/1566, 46%) and ResearchMatch (646/1566, 41%). Community partner promotions resulted in the highest proportion of eligible respondents (24/46, 52%), while ResearchMatch had the lowest proportion of eligible respondents (73/646, 11%). Word of mouth was the most cost-effective recruitment strategy (US $4.66 per completed survey response) and paper flyers were the least cost-effective (US $1448.13 per completed survey response). The demographic characteristics of eligible respondents varied by recruitment strategy: Twitter posts and community outreach events resulted in the highest proportion of Hispanic or Latina women (1/4, 25% and 2/6, 33%, respectively), and community partner promotions resulted in the highest proportion of non-Hispanic Black women (4/24, 17%).
CONCLUSIONS: Although recruitment strategies varied in their yield of study participants, results overall support the feasibility of identifying and recruiting women at high risk for breast cancer outside of clinical settings. Researchers must balance the associated costs and participant yield of various recruitment strategies in planning future studies focused on high-risk women.

The neurotoxin β-N-methylamino-L-alanine (BMAA) produced by marine diatoms has been implicated as an important environmental trigger of neurodegenerative diseases in humans. However, the biosynthesis mechanism of BMAA in marine diatoms is still unknown. In the present study, the strain of diatom Thalassiosira minima almost lost the biosynthesis ability for BMAA after a long-term subculture in our laboratory. The production of BMAA-containing proteins in the mutant strain of T. minima reduced to 18.2 % of that in the wild strain, meanwhile the cell size decreased but pigment content increased in the mutant strain. Take consideration of our previous transcriptional data on the mixed diatom and cyanobacterium cultures, the current transcriptome analysis showed four identical and highly correlated KEGG pathways associated with the accumulation of misfolded proteins in diatom, including ribosome, proteasome, SNARE interactions in vesicle transport, and protein processing in the endoplasmic reticulum. Analysis of amino acids and transcriptional information suggested that amino acid synthesis and degradation are associated with the biosynthesis of BMAA-containing proteins. In addition, a reduction in the precision of ubiquitination-mediated protein hydrolysis and vesicular transport by the COPII system will exacerbate the accumulation of BMAA-containing proteins in diatoms.

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Histiocytic neoplasms are rare diseases involving macrophages, dendritic cells, and monocytes. They include Langerhans cell histiocytosis (LCH), Erdheim-Chester disease (ECD), Rosai-Dorfman disease (RDD), juvenile xanthogranuloma (JXG), and histiocytic sarcoma. Histiocytic neoplasms are characterized by varied clinical courses and prognoses, necessitating a nuanced understanding of their classification, epidemiology, and clinical manifestations. Genetic studies have revealed somatic mutations, predominantly in the MAPK pathway, suggesting a clonal neoplastic nature. This review covers the current understanding of histiocytic neoplasms, molecular pathophysiology, with a particular focus on mutations in genes such as BRAF, MAP2K1, and the PI3K-AKT signaling pathways, and evolving treatment strategies, especially focusing on LCH, ECD, RDD, and JXG. The treatment landscape has evolved with advancements in targeted therapies. BRAF inhibitors, such as vemurafenib and dabrafenib, have shown efficacy, especially in high-risk LCH cases; however, challenges remain, including relapse post-treatment discontinuation, and adverse effects. MEK inhibitors have also demonstrated effectiveness, and cobimetinib has recently been approved for use in adults. Further research is required to determine the optimal treatment duration and strategies for managing therapy interruptions. Advancements in molecular genetics and targeted therapies have revolutionized the management of histiocytic neoplasms. However, ongoing research is crucial for optimizing patient outcomes.

Galectins are innate immune system regulators associated with disease progression in cancer. This paper aims to investigate the correlation between mutated cancer-critical genes and galectin levels in breast cancer patients to determine whether galectins and genetic profiles can be used as biomarkers for disease and potential therapy targets. Prisma Health Cancer Institute\'s Biorepository provided seventy-one breast cancer samples, including all four stages spanning the major molecular subtypes and histologies. Hotspot mutation statuses of cancer-critical genes were determined using multiplex PCR in tumor samples from the same patients by Precision Genetics and the University of South Carolina Functional Genomics Core Facility. The galectin-1, -3, and -9 levels in patients\' sera were analyzed using Enzyme-linked Immunosorbent Assay (ELISA). An analysis was performed using JMP software to compare mean and median serum galectin levels between samples with and without specific cancer-critical genes, including pooled t-test, Wilcoxon Rank Sum Test, ANOVA, and Steel Dwass Test (α=0.05). Our analysis indicates that KIT mutations correlate with elevated serum levels of galectin-9 in patients with breast cancer. In patients with Luminal A subtype, FLT3 mutation correlates with lower serum galectin-1 and -9 levels and TP53 mutations correlate with higher serum galectin-3 levels. Patients with invasive ductal carcinoma had significantly higher serum galectin-3 levels than patients with ductal carcinoma in situ. Patients with both TP53 and PIK3CA mutations exhibit elevated serum galectin-3 levels, while patients with one or neither mutation show no significant difference in serum galectin-3 levels. In addition, metastatic breast cancer samples were more likely to have a KIT or PIK3CA mutation compared to primary breast cancer samples. The relationship between genetic mutations and galectin levels has the potential to identify appropriate candidates for combined therapy, targeting genetic mutations and galectins. Further understanding of the effect of genetic mutations and galectin levels on cancer progression and metastasis could aid in the search for biomarkers for breast cancer diagnosis, disease progression, and prognosis.

Early cancer detection and treatment depend on the discovery of specific genes that cause cancer. The classification of genetic mutations was initially done manually. However, this process relies on pathologists and can be a time-consuming task. Therefore, to improve the precision of clinical interpretation, researchers have developed computational algorithms that leverage next-generation sequencing technologies for automated mutation analysis. This paper utilized four deep learning classification models with training collections of biomedical texts. These models comprise bidirectional encoder representations from transformers for Biomedical text mining (BioBERT), a specialized language model implemented for biological contexts. Impressive results in multiple tasks, including text classification, language inference, and question answering, can be obtained by simply adding an extra layer to the BioBERT model. Moreover, bidirectional encoder representations from transformers (BERT), long short-term memory (LSTM), and bidirectional LSTM (BiLSTM) have been leveraged to produce very good results in categorizing genetic mutations based on textual evidence. The dataset used in the work was created by Memorial Sloan Kettering Cancer Center (MSKCC), which contains several mutations. Furthermore, this dataset poses a major classification challenge in the Kaggle research prediction competitions. In carrying out the work, three challenges were identified: enormous text length, biased representation of the data, and repeated data instances. Based on the commonly used evaluation metrics, the experimental results show that the BioBERT model outperforms other models with an F1 score of 0.87 and 0.850 MCC, which can be considered as improved performance compared to similar results in the literature that have an F1 score of 0.70 achieved with the BERT model.

Spastic paraplegia and psychomotor retardation with or without seizures (SPPRS) is a rare neurodevelopmental disorder associated with autosomal recessive mutations in the HACE1 gene. This case report presents the clinical features and genetic analysis of an 11-month-old girl and her sister with SPPRS, making it the third reported case in the Middle East and the second in Saudi Arabia. The patient exhibited hypotonia, global developmental delay, speech delay, swallowing difficulties, and recurrent respiratory infections. A homozygous pathogenic variant in the HACE1 gene (p.R664*) was identified through genetic analysis, confirming the diagnosis of SPPRS. This case report emphasizes the importance of considering variations in clinical presentation, especially in rare disorders where only a few cases are reported. Further research and case studies are needed to better understand the complete phenotypic spectrum of SPPRS and its complications.