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Age-related disorders, such as Alzheimer’s disease (AD) and age-related macular degeneration (AMD) share common features such as amyloid-β (Aβ) protein accumulation. Retinal deposition of Aβ aggregates in AMD patients has suggested a potential link between AMD and AD. In the present study, we analyzed the expression pattern of a focused set of miRNAs, previously found to be involved in both AD and AMD, in the retina of a triple transgenic mouse model of AD (3xTg-AD) at different time-points. Several miRNAs were differentially expressed in the retina of 3xTg-AD mice, compared to the retina of age-matched wild-type (WT) mice. In particular, bioinformatic analysis revealed that miR-155 had a central role in miRNA-gene network stability, regulating several pathways, including apoptotic and inflammatory signaling pathways modulated by TNF-related apoptosis-inducing ligand (TNFSF10). We showed that chronic treatment of 3xTg-AD mice with an anti-TNFSF10 monoclonal antibody was able to inhibit the retinal expression of miR-155, which inversely correlated with the expression of its molecular target SOCS-1. Moreover, the fine-tuned mechanism related to TNFSF10 immunoneutralization was tightly linked to modulation of TNFSF10 itself and its death receptor TNFRSF10B, along with cytokine production by microglia, reactive gliosis, and specific AD-related neuropathological hallmarks (i.e., Aβ deposition and Tau phosphorylation) in the retina of 3xTg-AD mice. In conclusion, immunoneutralization of TNFSF10 significantly preserved the retinal tissue in 3xTg-AD mice, suggesting its potential therapeutic application in retinal degenerative disorders.

Breast cancer (BC) remains a leading cause of cancer-related mortality among women, with therapeutic resistance posing significant challenges. This study explores haloperidol (Halo), a clinically approved antipsychotic drug, for its potential antitumoral effects and ability to induce ferroptosis, a non-apoptotic programmed cell death linked to oxidative stress and lipid peroxidation. Halo’s activity, partially mediated by sigma (σ) receptors, may enhance chemotherapy efficacy. This investigation delves into the role of heme oxygenase (HO), which was demonstrated to exhibit dual effects in ferroptosis as it’s crucial for the modulation of iron intracellular levels and redox balance. Analysis of main related indicators depict a clear activation of ferroptotic cell death following Halo treatment evidenced by heightened oxidative stress conditions, as indicated by increased lipid peroxidation, elevated reactive oxygen species levels, significant glutathione depletion and mitochondrial membrane potential impairment. Further investigation revealed a protective role of HO-1 and the involvement of ferritinophagic process in MCF-7 BC cells. Additionally, it was evaluated whether Halo effect could be strictly dependent on its activity towards σ receptors and its efficacy in a 3D spheroid model. Data herein reported allow to elucidate Halo triggering of so-called non-canonical ferroptotic pathway suggesting its potential as a candidate for BC treatment.

E3 ubiquitin protein ligase encoded by ARIH2 gene catalyses the ubiquitination of target proteins and plays a crucial role in posttranslational modifications across various cellular processes. As prior documented, mutations in genes involved in the ubiquitination process are often associated with autism spectrum disorder (ASD) and/or intellectual disability (ID). In the current study, a de novo heterozygous mutation was identified in the splicing intronic region adjacent to the last exon of the ARIH2 gene using whole exome sequencing (WES). We hypothesize that this mutation, found in an ASD/ID patient, disrupts the protein Ariadne domain which is involved in the autoinhibition of ARIH2 enzyme. Predictive analyses elucidated the implications of the novel mutation in the splicing process and confirmed its autosomal dominant inheritance model. Nevertheless, we cannot exclude the possibility that other genetic factors, undetectable by WES, such as mutations in non-coding regions and polygenic risk in inter-allelic complementation, may contribute to the patient's phenotype. This work aims to suggest potential relationship between the detected mutation in ARIH2 gene and both ASD and ID, even though functional studies combined with new sequencing approaches will be necessary to validate this hypothesis.

Global warming and air pollution affect the transmission pathway and the survival of viruses, altering the human immune system as well. The first wave of the COVID-19 pandemic dramatically highlights the key roles of climate and air chemistry in viral epidemics. The elongated form of the Italian peninsula and the two major islands (the largest in Europe) is a perfect case study to assess some of these key roles, as the fate of the virus is mirroring the industrialization in the continental part of our country. Fine particulate matter (PM 2.5 ), geography, and climate explain what is happening in Italy and support cleaner air actions to address efficiently other outbreaks. Besides the environmental factors, future works should also address the genetic difference among individuals to explain the spatial variability of the human response to viral infections.

Next-Generation Sequencing (NGS) techniques have become a cornerstone of molecular diagnostics, enabling high-throughput, parallel analysis of multiple disease-associated genes. Their targeted design allows streamlined interpretation and optimised diagnostic yield, especially in disorders with known genetic heterogeneity. In this review, we provide a comprehensive overview of the clinical application of NGS techniques—targeted gene panels, whole exome sequencing (WES) and whole genome sequencing (WGS)—detailing the methodological workflow and the critical steps involved in their implementation. Particular emphasis is placed on the genes identified through NGS that are implicated in neurodevelopmental, neurodegenerative, psychiatric, neuromuscular, cardiovascular, and metabolic disorders. We also compare the advantages and limitations of panel-based diagnostics versus WES and WGS, and discuss future directions, including the integration of long-read sequencing technologies into multidisciplinary clinical practice. Finally, we consider how these advances may ultimately bridge biomedical research and clinical practise to improve the diagnosis and management of multifactorial diseases.

CSMD1 is a gene involved in various biological processes and is highly expressed in the central nervous system, where it plays a key role in complement activity, brain circuit development, and cognitive function. It has been implicated as a susceptibility gene for schizophrenia and a causative factor in developmental epileptic encephalopathy, neurodevelopmental disorders, and intellectual disability. However, no MIM phenotype number has been assigned to CSMD1 for a specific disorder. Here, we report an individual presenting with moderate intellectual disability, anxiety disorder, obsessive–compulsive personality traits, and facial dysmorphisms. Trio-based whole-exome sequencing (WES) identified two heterozygous CSMD1 variants, c.8095A>G and c.5315T>C, both classified as variants of uncertain significance (VUS) according to ACMG criteria. Computational analysis using the DOMINO tool supported an autosomal recessive inheritance model for CSMD1. This study contributes to the growing evidence linking CSMD1 to neurodevelopmental phenotypes, highlighting the need for further investigations to clarify its pathogenic role.

The 26S proteasome is a large, ATP-dependent proteolytic complex responsible for degrading ubiquitinated proteins in eukaryotic cells. It plays a crucial role in maintaining cellular protein homeostasis by selectively eliminating misfolded, damaged, or regulatory proteins marked for degradation. In this study, whole-exome sequencing (WES) was performed on an individual presenting with developmental delay and mild intellectual disability, as well as on both of his unaffected parents. This analysis identified a de novo variant, c.959C>G (p.Pro320Arg), in the PSMC5 gene. As predicted, this gene shows a very likely autosomal dominant inheritance pattern. Notably, PSMC5 has not previously been associated with any phenotype in the OMIM database. This variant was recently submitted to the ClinVar database as a variant of uncertain significance (VUS) and remains absent in both gnomAD and dbSNP. Notably, it has been identified in six unrelated individuals presenting with clinical features comparable to those observed in the patient described in this study. Multiple in silico prediction tools classified the variant as pathogenic, and a PhyloP conservation score supports strong evolutionary conservation of the mutated nucleotide. Protein structure predictions using the AlphaFold3 algorithm revealed notable structural differences between the mutant and wild-type PSMC5 proteins. We hypothesize that the p.Pro320Arg substitution alters the structure and function of PSMC5 as a regulatory subunit of the 26S proteasome, potentially impairing the stability and activity of the entire complex. Although functional studies are imperative, this study contributes to a deeper understanding of PSMC5, expands the spectrum of associated neurodevelopmental phenotypes, and highlights its potential as a therapeutic target. Furthermore, this study resulted in the submission of the identified variant to the ClinVar database (SCV006083352), where it was classified as pathogenic.

Background and Objectives: Zinc finger proteins are important transcription factors that regulate gene expression and play a critical role in neurodevelopment including autism spectrum disorders (ASDs). They are involved in a variety of cellular processes, including cell proliferation, differentiation, and apoptosis. Materials and Methods: Whole-exome sequencing (WES) analysis on a patient diagnosed with ASD. Results: Sequencing identified a homozygous insertion causing a stop codon, resulting in the removal of several functional domains including the zinc finger C2HC/C3H type of the ZC2HC1C protein. To date, no MIM entry has been assigned to the detected gene. In silico predictions described the variant as likely pathogenic, indicating an autosomal recessive inheritance pattern. In this study, we hypothesize that this homozygous mutation disrupts protein function and may represent a susceptibility gene for autism. The parents and the patient’s sister were healthy and carry the variant in the heterozygous condition. This gene is expressed in brain tissues showing high expression in both the choroid plexus (ChP) and midbrain, whose dysfunctions, as reported, may lead to ASD. Moreover, predictive pathway analyses indicated the probable involvement of this gene in primary cilia development. This process has been frequently linked to neurodevelopmental impairments, such as autism, as documented in previous studies. Conclusions: Further analyses are needed via in vitro functional assays or by ZC2HC1C gene knockout to validate its functional role.

The origin and evolution of genes are central themes in evolutionary biology and genomics, shedding light on how molecular innovations shape biological complexity and adaptation. This review explores the principal mechanisms underlying gene emergence in eukaryotes, including gene duplication, de novo gene birth, horizontal gene transfer, viral gene domestication, and exon shuffling. We examine the population dynamics that govern the fixation of new genes, their functional integration, and the selective forces acting upon them—from purifying selection to adaptive innovation. Examples such as NOTCH2NL and SRGAP2C, which originated through recent segmental duplications followed by neofunctionalization, illustrate how duplicate-derived de novo genes can play a key role in human brain development. In addition, we highlight the emerging relevance of nuclear architecture in determining the evolutionary fate of new genes, offering a spatial dimension to gene innovation. We also discuss methodological approaches for detecting new genes and inferring selection, and finally, we highlight the emerging role of the human pangenome in revealing hidden gene diversity and its implications for evolutionary and biomedical research. Understanding gene innovation not only enhances our grasp of evolutionary processes but also informs clinical studies on disease susceptibility and human uniqueness.

Zinc finger proteins are frequently implicated in a wide range of neurodevelopmental disorders (NDDs). In this study, we report a case of mild intellectual disability (ID), global developmental delay (GDD), and developmental coordination disorder (DCD) in an individual with unaffected parents. Trio-based whole-exome sequencing (WES) identified a de novo variant (c.1530dup, p.Glu511ArgfsTer16) in the ZNF496 gene of the proband. According to ACMG guidelines, this novel variant is classified as pathogenic. It creates a frameshift that introduces a premature stop codon, resulting in a truncated protein of 525 amino acids (compared to the wild-type 587 residues). Notably, NMDEscPredictor analysis predicted that the transcript escapes nonsense-mediated decay (NMD) despite the frameshift. Computational analyses suggest the potential pathogenetic effects of the identified variant. As documented, ZNF496 interacts with JARID2, a gene associated with NDDs, ID and facial dysmorphism (MIM: #620098). In silico analyses suggest that the identified mutation disrupts this interaction by deleting ZNF496’s C2H2 domain, potentially dysregulating JARID2 target genes. To our knowledge, this is the first reported association between ZNF496 and NDDs, and the variant has been submitted to the ClinVar database (SCV006100880). Functional studies are imperative to validate ZNF496’s role in NDDs and confirm the mutation’s impact on ZNF496-JARID2 interactions.