Connexins in cancer: bridging the gap to the clinic.
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ABSTRACT:
SUBMITTER: Aasen T
PROVIDER: S-EPMC6555763 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Enhanced gap junctional communication (GJC) between neurons is considered a major factor underlying the neuronal synchrony driving seizure activity. In addition, the hippocampal sharp wave ripple complexes, associated with learning and seizures, are diminished by GJC blocking agents. Although gap junctional blocking drugs inhibit experimental seizures, they all have other non-specific actions. Besides interneuronal GJC between dendrites, inter-axonal and inter-glial GJC is also considered important for seizure generation. Interestingly, in most studies of cerebral tissue from animal seizure models and from human patients with epilepsy, there is up-regulation of glial, but not neuronal gap junctional mRNA and protein. Significant changes in the expression and post-translational modification of the astrocytic connexin Cx43, and Panx1 were observed in an in vitro Co(++) seizure model, further supporting a role for glia in seizure-genesis, although the reasons for this remain unclear. Further suggesting an involvement of astrocytic GJC in epilepsy, is the fact that the expression of astrocytic Cx mRNAs (Cxs 30 and 43) is several fold higher than that of neuronal Cx mRNAs (Cxs 36 and 45), and the number of glial cells outnumber neuronal cells in mammalian hippocampal and cortical tissue. Pannexin expression is also increased in both animal and human epileptic tissues. Specific Cx43 mimetic peptides, Gap 27 and SLS, inhibit the docking of astrocytic connexin Cx43 proteins from forming intercellular gap junctions (GJs), diminishing spontaneous seizures. Besides GJs, Cx membrane hemichannels in glia and Panx membrane channels in neurons and glia are also inhibited by traditional gap junctional pharmacological blockers. Although there is no doubt that connexin-based GJs and hemichannels, and pannexin-based membrane channels are related to epilepsy, the specific details of how they are involved and how we can modulate their function for therapeutic purposes remain to be elucidated.
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Project description:Atrial fibrillation (AF) represents the most common type of clinical cardiac arrhythmia worldwide and contributes to substantial morbidity, mortality and socioeconomic burden. Aggregating evidence highlights the strong genetic basis of AF. In addition to chromosomal abnormalities, pathogenic mutations in over 50 genes have been causally linked to AF, of which the majority encode ion channels, cardiac structural proteins, transcription factors and gap junction channels. In the heart, gap junctions comprised of connexins (Cxs) form intercellular pathways responsible for electrical coupling and rapid coordinated action potential propagation between adjacent cardiomyocytes. Among the 21 isoforms of connexins already identified in the mammal genomes, 5 isoforms (Cx37, Cx40, Cx43, Cx45 and Cx46) are expressed in human heart. Abnormal electrical coupling between cardiomyocytes caused by structural remodeling of gap junction channels (alterations in connexin distribution and protein levels) has been associated with enhanced susceptibility to AF and recent studies have revealed multiple causative mutations or polymorphisms in 4 isoforms of connexins predisposing to AF. In this review, an overview of the genetics of AF is made, with a focus on the roles of mutant myocardial connexins and gap junctions in the pathogenesis of AF, to underscore the hypothesis that cardiac connexins are a major molecular target in the management of AF.
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Project description:Glycomics@ExPASy (https://www.expasy.org/glycomics) is the glycomics tab of ExPASy, the server of SIB Swiss Institute of Bioinformatics. It was created in 2016 to centralize web-based glycoinformatics resources developed within an international network of glycoscientists. The hosted collection currently includes mainly databases and tools created and maintained at SIB but also links to a range of reference resources popular in the glycomics community. The philosophy of our toolbox is that it should be {glycoscientist AND protein scientist}-friendly with the aim of (1) popularizing the use of bioinformatics in glycobiology and (2) emphasizing the relationship between glycobiology and protein-oriented bioinformatics resources. The scarcity of data bridging these two disciplines led us to design tools as interactive as possible based on database connectivity to facilitate data exploration and support hypothesis building. Glycomics@ExPASy was designed, and is developed, with a long-term vision in close collaboration with glycoscientists to meet as closely as possible the growing needs of the community for glycoinformatics.
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Project description:Triple-negative breast cancer (TNBC) represents a challenge clinically due to a lack of response to hormonal and HER2-targeted agents coupled with an aggressive disease course. As the biology of this breast cancer subtype is better understood, it is clear that TNBC is a heterogeneous disease and one targeted therapy is unlikely to be active in all patients. Biomarkers predictive of response to treatment are thus of great importance in TNBC. This review outlines studies evaluating biomarkers predictive of response to neoadjuvant chemotherapy and to targeted therapies in the advanced setting. The development of validated biomarkers in conjunction with novel targeted therapies represents an opportunity to improve patient outcomes in TNBC.
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Project description:Since most cells in the heart co-express multiple connexins, we studied the possible heteromeric interactions between connexin30.2 and connexin40, connexin43 or connexin45 in transfected cells. Double-label immunofluorescence microscopy showed that connexin30.2 extensively co-localized with each co-expressed connexin at appositional membranes. When Triton X-100 solubilized connexons were affinity purified from co-expressing cells, connexin30.2 was isolated together with connexin40, connexin43, or connexin45. Co-expression of connexin30.2 with connexin40, connexin43, or connexin45 did not significantly reduce total junctional conductance. Gap junction channels in cells co-expressing connexin30.2 with connexin43 or connexin45 exhibited voltage-dependent gating intermediate between that of either connexin alone. In contrast, connexin30.2 dominated the voltage-dependence when co-expressed with connexin40. Our data suggest that connexin30.2 can form heteromers with the other cardiac connexins and that mixed channel formation will influence the gating properties of gap junctions in cardiac regions that co-express these connexins.
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Project description:Living art made with bacteria is gaining global attention, spreading from laboratories into the public domain: from school STEAM (Science, Technology, Engineering, the Arts, and Mathematics) events to art galleries, museums, community labs, and ultimately to the studios of microbial artists. Bacterial art is a synthesis of science and art that can lead to developments in both fields. Through the 'universal language of art', many social and preconceived ideas-including abstract scientific concepts-can be challenged and brought to the public attention in a unique way. By using bacteria to create publicly accessible art pieces, the barriers between humans and microbes can be lessened, and the artificial separation of the fields of science and art may be brought one step closer. Here, we document the history, impact, and current moment in the field of microbiologically inspired art for the benefit of educators, students, and the interested public. We provide a comprehensive historical background and examples of ancient bacterial art from cave paintings to uses in modern synthetic biology, a simple protocol for conducting bacterial art in a safe and responsible manner, a discussion of the artificial separation of science and art, and the future implications of art made from living microbes.
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Project description:Purpose of reviewThe purpose of this paper is to identify strategies for a successful transition to sports in patients following rehabilitation for ACL reconstruction surgery (ACLR).Recent findingsRecent research continues to demonstrate a relatively low rate of return to previous level of play among athletes following ACLR combined with a significant risk of injury to either the ipsi or the contralateral ACL. Recent research also demonstrates a growing use of a varied battery of assessments to determine readiness to return to sport as well as a lack of consensus on the ideal rehabilitation program, the criteria for clearance for return to play (both in time from surgery and functional milestones), and the nature of a conditioning program designed specifically for transitioning the cleared athlete back to competition. Due to the lack of consensus and consistency regarding rehabilitation protocols and criteria for clearance to play after ACLR, deficits in strength, neuromuscular control, and psychological readiness may exist in "cleared" athletes. These deficits may not only negatively impact sports performance but also raise the risk of re-injury. Programs designed to successfully return an athlete to previous level of play should include not only strength and conditioning aimed at restoring fitness that was compromised as a result of the injury but also include attention to psychological readiness and address deficits in neuromuscular control. Problems that exist following ACLR cannot be solved by one professional; successful rehabilitation and return to play require a coordinated effort among the surgeon, physical therapist, athletic trainer, and fitness professional. Future research is needed to determine the optimal strategy to restore the neuromuscular control, functional strength, and psychological readiness necessary for a successful return to competition following ACLR.
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Project description:Performing fundamental operando catalysis studies under realistic conditions is a key to further develop and increase the efficiency of industrial catalysts. Operando X-ray photoelectron spectroscopy (XPS) experiments have been limited to pressures, and the relevance for industrial applications has been questioned. Herein, we report on the CO oxidation experiment on Pd(100) performed at a total pressure of 1 bar using XPS. We investigate the light-off regime and the surface chemical composition at the atomistic level in the highly active phase. Furthermore, the observed gas-phase photoemission peaks of CO2, CO, and O2 indicate that the kinetics of the reaction during the light-off regime can be followed operando, and by studying the reaction rate of the reaction, the activation energy is calculated. The reaction was preceded by an in situ oxidation study in 7% O2 in He and a total pressure of 70 mbar to confirm the surface sensitivity and assignment of the oxygen-induced photoemission peaks. However, oxygen-induced photoemission peaks were not observed during the reaction studies, but instead, a metallic Pd phase is present in the highly active regime under the conditions applied. The novel XPS setup utilizes hard X-rays to enable high-pressure studies, combined with a grazing incident angle to increase the surface sensitivity of the measurement. Our findings demonstrate the possibilities of achieving chemical information of the catalyst, operando, on an atomistic level, under industrially relevant conditions.
| S-EPMC8397290 | biostudies-literature
Project description:Genetic diseases demonstrate that the normal function of CNS myelin depends on connexin32 (Cx32) and Cx47, gap junction (GJ) proteins expressed by oligodendrocytes. GJs couple oligodendrocytes and astrocytes (O/A channels) as well as astrocytes themselves (A/A channels). Because astrocytes express different connexins (Cx30 and Cx43), O/A channels must be heterotypic, whereas A/A channels may be homotypic or heterotypic. Using electrophysiological and immunocytochemical approaches, we found that Cx47/Cx43 and Cx32/Cx30 efficiently formed functional channels, but other potential heterotypic O/A and A/A pairs did not. These results suggest that Cx30/Cx30 and Cx43/Cx43 channels mediate A/A coupling, and Cx47/Cx43 and Cx32/Cx30 channels mediate O/A coupling. Furthermore, Cx47/Cx43 and Cx32/Cx30 channels have distinct macroscopic and single-channel properties and different dye permeabilities. Finally, Cx47 mutants that cause Pelizaeus-Merzbacher-like disease do not efficiently form functional channels with Cx43, indicating that disrupted Cx47/Cx43 channels cause this disease.
| S-EPMC6673504 | biostudies-literature
Project description:Background and aimsConnexins and their cell membrane channels contribute to the control of cell proliferation and compartmental functions in breast glands and their deregulation is linked to breast carcinogenesis. Our aim was to correlate connexin expression with tumor progression and prognosis in primary breast cancers.Materials and methodsMeta-analysis of connexin isotype expression data of 1809 and 1899 breast cancers from the Affymetrix and Illumina array platforms, respectively, was performed. Expressed connexins were also monitored at the protein level in tissue microarrays of 127 patients equally representing all tumor grades, using immunofluorescence and multilayer, multichannel digital microscopy. Prognostic correlations were plotted in Kaplan-Meier curves and tested using the log-rank test and cox-regression analysis in univariate and multivariate models.ResultsThe expression of GJA1/Cx43, GJA3/Cx46 and GJB2/Cx26 and, for the first time, GJA6/Cx30 and GJB1/Cx32 was revealed both in normal human mammary glands and breast carcinomas. Within their subfamilies these connexins can form homo- and heterocellular epithelial channels. In cancer, the array datasets cross-validated each other's prognostic results. In line with the significant correlations found at mRNA level, elevated Cx43 protein levels were linked with significantly improved breast cancer outcome, offering Cx43 protein detection as an independent prognostic marker stronger than vascular invasion or necrosis. As a contrary, elevated Cx30 mRNA and protein levels were associated with a reduced disease outcome offering Cx30 protein detection as an independent prognostic marker outperforming mitotic index and necrosis. Elevated versus low Cx43 protein levels allowed the stratification of grade 2 tumors into good and poor relapse free survival subgroups, respectively. Also, elevated versus low Cx30 levels stratified grade 3 patients into poor and good overall survival subgroups, respectively.ConclusionDifferential expression of Cx43 and Cx30 may serve as potential positive and negative prognostic markers, respectively, for a clinically relevant stratification of breast cancers.
| S-EPMC4226536 | biostudies-literature