GenVec

ABSTRACT Objective Our aim was to investigate the advantages of exome sequencing versus panel testing for patients with unexplained seizures. Methods We reviewed the diagnostic outcomes of exome sequencing by a commercial genetics laboratory for more than 16 000 individuals with a clinical history of seizures or suspected seizures. Results Exome sequencing identified diagnostic variants (pathogenic and/or likely pathogenic; L/PATH) in 778 seizure‐related genes, resulting in diagnoses in 4035 individuals (24.6% of the cohort). Of the 778 genes, 454 (58.4%) were not present on a comparison sample of six commercially available epilepsy panel tests. The analysis predicted that the epilepsy panels would have missed 52%–63% of diagnostic cases reported by exome sequencing. Nineteen percent (753/4035) of the cohort had a previous epilepsy panel. Exome sequencing added new diagnostic information in this panel‐tested sub‐cohort, including L/PATH variants not reported on the epilepsy panel (74.2% of patients) and L/PATH variants that were originally classified as variants of uncertain significance by the panel (11.2% of patients). Exome sequencing identified L/PATH variants likely to have immediate implications for clinical intervention in 17.9% of diagnostic cases and in 10.0% of cases with a previous nondiagnostic epilepsy panel. Significance The data demonstrated limitations of epilepsy panels and several advantages of exome sequencing over panels for patients with unexplained seizures. Exome sequencing offered a higher diagnostic rate than previously published for panels and the identification of variants with implications for clinical intervention among patients with prior nondiagnostic epilepsy panels. Another advantage of exome sequencing was the identification of clinically relevant findings unrelated to seizures. Together, these data further support the use of exome sequencing as a first‐tier test for patients with unexplained seizures and demonstrate the potential clinical benefits of comprehensive genetic testing. Trial Registration Not applicable

En el contexto del urgente desafío de la crisis ecosocial en el Antropoceno, este artículo explora la necesidad de trascender las estrategias convencionales de diseño sostenible. Se argumenta la importancia de adoptar visiones arquitectónicas alternativas y transformadoras, con un énfasis particular en la ética y la justicia socioecológica, especialmente desde la perspectiva del Sur Global. Tras una revisión de las limitaciones de los enfoques tradicionales, se presentan cinco propuestas disruptivas que buscan redefinir la práctica arquitectónica: diseño regenerativo, rehabilitación crítica, energías comunitarias, “sin espacio público no hay ciudad”, y tecnología ética. Estas visiones cuestionan la ‘sostenibilidad blanda’ y proponen modelos basados en la regeneración, la justicia y una profunda reconsideración del rol de la arquitectura en la construcción de futuros radicalmente justos y ecológicamente regenerativos.

Desde la aparición de las primeras edificaciones estables en el Neolítico, la relación entre construcción y naturaleza ha sido fundamental para el bienestar humano. A lo largo de los siglos, la arquitectura ha evolucionado significativamente, influyendo en el medio ambiente. En el siglo XX, la revolución industrial impulsó cambios tecnológicos que marcaron e internacionalizaron la arquitectura moderna, aunque también presentaron desafíos y problemas. Durante ese periodo, Venezuela experimentó un auge de la arquitectura influenciada por el modernismo europeo. En el siglo XXI, la tecnología ha jugado un papel crucial en la arquitectura, centrándose en la sostenibilidad, el cambio climático y la integración de la era digital. Desde su fundación en 1974 hasta el presente, el Instituto de Desarrollo Experimental de la Construcción-IDEC en la Facultad de Arquitectura y Urbanismo de la UCV, ejemplifica la importancia de la tecnología en arquitectura y su evolución hacia formas avanzadas y sustentables. Sin embargo, la investigación en el sector de las edificaciones se ha visto afectada por la falta de políticas estatales y la reducción de inversiones. Actualmente, se requieren estrategias claras que impulsen el desarrollo tecnológico en la construcción, fomentando la eficacia de las políticas y la gestión pública en el contexto de la modernización y descentralización del Estado.

Chronic progressive external ophthalmoplegia (CPEO), a genetic syndrome characterized by slowly progressive paresis of extraocular muscles, is often due to single large-scale deletions of the mitochondrial genome (mtDNA). Owing to heteroplasmy, mtDNA variants are often not uniformly expressed across tissues. This genetic variability affects clinical presentation and diagnostic testing. We report a case of a 34-year-old woman who presented with symptoms suspicious for a genetic myopathy: chronic asymmetric ptosis, slowly progressive asymmetric weakness, and external ophthalmoplegia. After initial nondiagnostic peripheral genetic testing, whole-exome and mitochondrial genome sequencing of muscle revealed a single large-scale mtDNA deletion, consistent with a diagnosis of mtDNA deletion-associated CPEO. Of interest, electrophysiologic studies showed myotonia in select muscles, a rarely reported finding. We discuss the clinical presentation and diagnostic approach in suspected CPEO, with an emphasis on common pitfalls in genetic testing for mitochondrial myopathies and the need for appropriate tissue and genetic testing modality selection.

Abstract Description CD19 CAR T-effector (CAR19Teff) therapy is promising in autoimmunity but limited by the inability to modulate pathogenic T cells and safety concerns like cytokine release syndrome and neurotoxicity. To address these limitations, we developed CD19 CAR engineered regulatory T cells (CAR19 EngTregs), which offer B cell depletion with the crucial capacity to suppress pathogenic T cells via bystander suppression and lower inflammatory cytokine secretion. We engineered human CAR19 EngTregs with stable FOXP3 and CAR expression and enriched edited cells to high purity using a chemically induced IL-2 signaling complex (CISC). CAR19 EngTregs exhibited stable core Treg markers upon CAR or TCR stimulation and mediated robust T cell suppression. In a human plasma B cell generation assay, CAR19 EngTregs showed antigen-dependent activation, and prevented B cell proliferation, differentiation to plasmablasts and long-lived plasma cells, and immunoglobulin (Ig) production. In both in vitro killing assays and adoptive transfer studies in humanized mice, CAR19 EngTregs mediated B cell depletion with lower cytotoxic and inflammatory cytokine levels than CAR19Teff. In pristane-treated humanized mice, human CAR19 EngTregs depleted B cells in vivo, elicited lower serum inflammatory cytokines, lower Ig titers, and reduced pathology versus CAR19Teff. These data demonstrate CAR19 EngTreg therapy could treat B and T cell-mediated autoimmunity with superior efficacy and safety than CAR19Teff therapy. Topic Categories Therapeutic Approaches to Autoimmunity (THER)

The Abelson-interactor 2 gene ( ABI2) encodes a protein that functions as a regulator of Rac-dependent actin cytoskeleton dynamics, a highly coordinated structural framework essential for maintaining intracellular homeostasis and vital in processes such as cell adhesion, communication, membrane transport, migration, cell growth, and development. As a component of the Rac-1 activated WAVE regulatory complex (WRC), ABI2 initiates the actin polymerization machinery Arp2/3 to drive lamellipodia formation, and underlying key cellular processes such as axonal guidance, cell motility, and cell adhesion. Additionally, ABI2 acts as a substrate for non-receptor tyrosine kinases ABL1 and ABL2, with downstream effects controlling neuronal differentiation and migration involved in neocortical development. Here, through exome sequencing and international collaborations, we identify eight unrelated individuals with severe neurodevelopmental delays linked to heterozygous ABI2 missense variants, including a recurrent p.Tyr491Cys in the highly conserved SH3 domain in six individuals. These variants arose de novo in cases where parental testing was available, and were associated with moderate to severe motor delay, absent or delayed expressive language, intellectual disability, seizures, autistic traits, as well as macrocephaly, thinning of the corpus callosum, and remarkable white matter signal abnormalities. This report adds ABI2 to the list of genes implicated in neurodevelopmental disorders, with an additional focus on epilepsy and brain malformations.