3 track album

Researchers found that the gap junction protein Cx26 relocates to mitochondria in metastatic colorectal cancer, driving EMT and calcium signaling, and that the myeloma drug bortezomib exploits this

Age-related hearing loss (ARHL) represents a progressive auditory disorder. Growing evidence indicates that degradation of connexin 26 (Cx26) in cochlear may constitute one of the pathogenic mechanism...

Design of the Cx34.7 and Cx35 mutant library A semi-rational design approach was used to design the mutant library. Sequence alignments between the M. americana connexins and the connexins for which the most structure–function data existed (Cx26, Cx32, Cx36, Cx40 and Cx43) were performed in ClustalW. Sites identified by previous studies as conferring specificity for docking were used, as well as those identified by homology modelling from the structures of Cx26 (ref. 56). Specifically, we primarily focused on residues in the extracellular loops: four residues at the interface in EL2, KEVE/KDVE (M. americana Cx34.7 and Cx35), and one residue in EL1. The homologous residues in other connexins had been demonstrated to be highly tolerant to mutations and critical for docking specificity57. Mutations were modelled in Swiss PDB Viewer using homology models of Cx34.7 and Cx35 from a Cx26 and Cx32 interface structure so as not to create mutations with obvious steric hindrance. A wide range of substitutions were made for these five residues of interest, including those intended to introduce compatible electrostatic interactions, as well as less likely candidates. Mutations were also created that targeted other residues nearby and/or adjacent to these five for which there was some published evidence...

Un hallazgo clave revela cómo ciertos tumores de cuerdas vocales se vuelven más invasivos y por qué esa pista puede cambiar la oncología Un equipo del Ifom y de la Universidad de Milán ha identificado...

Mutations in the GJB2 gene, which encodes Connexin 26 (Cx26), are responsible for the majority of cases of non-syndromic congenital hearing loss in humans. While murine GJB2 knockout models have provided mechanistic insight, anatomical and physiological differences limit their translational relevance. Pigs represent a valuable large-animal model because their auditory anatomy and maturation closely resemble those of humans. This study compared two genome-editing approaches to disrupt GJB2 in porcine oocytes before fertilization: (1) electroporation with CRISPR/Cas9 ribonucleoprotein and (2) microinjection with cytosine base editor (BE3) and single-guide RNAs (sgRNAs). Electroporation produced high mutation rates (70–90%) across three concentrations of Cas9/sgRNA but yielded mostly heterozygous or mosaic blastocysts, with limited homozygous knockouts (< 4%). BE3 achieved precise cytosine-to-thymine conversions that introduced premature stop codons, reaching up to 47% total editing and 20% homozygous nonsense alleles. However, blastocyst formation declined at higher component concentrations. Overall, BE3 produced more predictable mutations than conventional CRISPR/Cas9, although embryo developmental competence was dose-dependent. Both methods effectively targeted GJB2 and demonstrated feasibility of pre-fertilization genome editing in porcine oocytes. These findings establish the groundwork for generating GJB2-deficient pigs as translational models of Cx26-related congenital deafness and for future evaluation of gene-therapy strategies in a large-animal system.

Docket Nos. RM26-7-000 & CX26-1-000 The Federal Energy Regulatory Commission voted unanimously today to streamline its National Environmental Policy Act (NEPA) review for water power actions, that hav...

日本の南を流れる世界的な海流「黒潮（日本海流）」。ミネラルに富み、多くの海の幸を育む黒潮の水は果たしてどんな味がするのか？　どうしても気になった野食ハンター、黒潮がぶち当たる高知まで汲みに行ってきました。美味しいとはいえ海水、そのまま飲むわけにもいかず、どう調理するか迷った挙げ句ふざけて「茶碗蒸し」にしてみたので...

EGF-induced de novo transcription of connexins Cx26 and Cx31 promotes flocking behavior that fluidizes epithelia and enables coordinated collective migration. Connexin-driven cytoplasmic exchange mechanistically links growth-factor signaling to invasive dynamics. These results uncover how flocking underpins early cancer dissemination and position connexins as essential regulators and promising therapeutic targets. Abstract The initial invasion of tumors requires a transition from a solid, jammed state to a fluid-like, flocking, unjammed state that enables collective migration. Here, we show that de novo gene transcription is essential for the emergence of flocking in epithelial tissues and identify connexins (Cx) as key mediators of this transition. Using quiescent HaCaT keratinocytes, tumorigenic A431 epidermoid carcinoma cells, primary bronchial epithelial explants, and vocal fold carcinoma (VFC) cells, we find that flocking induction depends on transcriptional programs activated downstream of epidermal growth factor (EGF). EGF stimulation upregulates Cx26 and Cx31 and enhances gap-junctional intercellular communication (GJIC), which is necessary—though not sufficient—to generate the large-scale cell-volume fluctuations and density heterogeneity that accompany unjamming. Sustained signaling through extracellular signal-regulated kinase 1/2 (ERK1/2) and AKT serine/threonine kinase (AKT) downstream of the EGF receptor (EGFR) is required for connexin induction, linking mechanical state transitions to extracellular cues. Pharmacological inhibition and CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats–CRISPR associated protein 9) knockout of connexins block unjamming and collective motility. VFC cells display constitutively elevated connexins and persistent flocking that is highly sensitive to connexin inhibition. Consistently, high Cx26 expression correlates with reduced survival across carcinomas. These findings reveal a transcriptionally controlled, connexin-dependent mechanism that enables tissue fluidization and collective invasion.

Connexin26 can not only form intercellular channels that mediate rapid communication on the cell membrane, but also enter the nucleus as a transcription factor to directly regulate the transcription of nuclear genes. In the developing cochlea, Cx26 can control the maturation of the molecular scissor ADAM10 by regulating the transcription of TspanC8, ultimately affecting the formation of the tunnel of Corti. ABSTRACT Gap junction Beta 2 Protein (GJB2, Connexin26, Cx26), the primary genetic cause of hereditary hearing loss (25%–50% of cases), has been exclusively regarded as forming an intercellular channel that mediates rapid communication. Here, we redefine its biological role by discovering its nuclear localization and direct transcriptional regulatory function in cochlear structure development. We demonstrate that Cx26 could aggregate in the nucleus of cochlear support cell and cell lines. Cx26 can bind to the promoter transcription start point of genomic DNA and directly regulate gene transcription, thus controlling the structural development of the tunnel of Corti during cochlear development. Further, we provide strategies based on mechanisms to promote the TC development and hearing rescue in Cx26 deficient cochlea, which has important implications for the discovery and development of treatment strategies for hearing loss caused by Cx26 deficiency.

https://trt.world/cx26