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Neurobiology of Disease Aug 2024Huntington's disease (HD) is a neurodegenerative disorder that severely affects the basal ganglia and regions of the cerebral cortex. While astrocytosis and microgliosis...
Huntington's disease (HD) is a neurodegenerative disorder that severely affects the basal ganglia and regions of the cerebral cortex. While astrocytosis and microgliosis both contribute to basal ganglia pathology, the contribution of gliosis and potential factors driving glial activity in the human HD cerebral cortex is less understood. Our study aims to identify nuanced indicators of gliosis in HD which is challenging to identify in the severely degenerated basal ganglia, by investigating the middle temporal gyrus (MTG), a cortical region previously documented to demonstrate milder neuronal loss. Immunohistochemistry was conducted on MTG paraffin-embedded tissue microarrays (TMAs) comprising 29 HD and 35 neurologically normal cases to compare the immunoreactivity patterns of key astrocytic proteins (glial fibrillary acidic protein, GFAP; inwardly rectifying potassium channel 4.1, Kir4.1; glutamate transporter-1, GLT-1; aquaporin-4, AQP4), key microglial proteins (ionised calcium-binding adapter molecule-1, IBA-1; human leukocyte antigen (HLA)-DR; transmembrane protein 119, TMEM119; purinergic receptor P2RY12, P2RY12), and indicators of proliferation (Ki-67; proliferative cell nuclear antigen, PCNA). Our findings demonstrate an upregulation of GFAP protein expression attributed to the presence of more GFAP expressing cells in HD, which correlated with greater cortical mutant huntingtin (mHTT) deposition. In contrast, Kir4.1, GLT-1, and AQP4 immunoreactivity levels were unchanged in HD. We also demonstrate an increased number of IBA-1 and TMEM119 microglia with somal enlargement. IBA-1, TMEM119, and P2RY12 reactive microglia immunophenotypes were also identified in HD, evidenced by the presence of rod-shaped, hypertrophic, and dystrophic microglia. In HD cases, IBA-1 cells contained either Ki-67 or PCNA, whereas GFAP astrocytes were devoid of proliferative nuclei. These findings suggest cortical microgliosis may be driven by proliferation in HD, supporting the hypothesis of microglial proliferation as a feature of HD pathophysiology. In contrast, astrocytes in HD demonstrate an altered GFAP expression profile that is associated with the degree of mHTT deposition.
Topics: Humans; Huntington Disease; Microglia; Astrocytes; Male; Female; Middle Aged; Cell Proliferation; Adult; Aged; Cerebral Cortex; Calcium-Binding Proteins; Gliosis; Glial Fibrillary Acidic Protein; Membrane Proteins; Microfilament Proteins
PubMed: 38844243
DOI: 10.1016/j.nbd.2024.106554 -
Circulation Research Jun 2024Autoimmunity significantly contributes to the pathogenesis of myocarditis, underscored by its increased frequency in autoimmune diseases such as systemic lupus... (Review)
Review
Autoimmunity significantly contributes to the pathogenesis of myocarditis, underscored by its increased frequency in autoimmune diseases such as systemic lupus erythematosus and polymyositis. Even in cases of myocarditis caused by viral infections, dysregulated immune responses contribute to pathogenesis. However, whether triggered by existing autoimmune conditions or viral infections, the precise antigens and immunologic pathways driving myocarditis remain incompletely understood. The emergence of myocarditis associated with immune checkpoint inhibitor therapy, commonly used for treating cancer, has afforded an opportunity to understand autoimmune mechanisms in myocarditis, with autoreactive T cells specific for cardiac myosin playing a pivotal role. Despite their self-antigen recognition, cardiac myosin-specific T cells can be present in healthy individuals due to bypassing the thymic selection stage. In recent studies, novel modalities in suppressing the activity of pathogenic T cells including cardiac myosin-specific T cells have proven effective in treating autoimmune myocarditis. This review offers an overview of the current understanding of heart antigens, autoantibodies, and immune cells as the autoimmune mechanisms underlying various forms of myocarditis, along with the latest updates on clinical management and prospects for future research.
Topics: Myocarditis; Humans; Autoimmune Diseases; Animals; Autoantibodies; Autoimmunity; T-Lymphocytes; Autoantigens; Cardiac Myosins
PubMed: 38843292
DOI: 10.1161/CIRCRESAHA.124.323816 -
Journal of the American Heart... Jul 2024High-sensitivity troponin I (hs-cTnI) and T (hs-cTnT) provide complementary information regarding cardiovascular disease risk. The explanation for their distinct risk...
Individual and Joint Associations of High-Sensitivity Troponin I and High-Sensitivity Troponin T with Cardiac Phenotypes and Outcomes in the General Population: An Analysis From the Dallas Heart Study.
BACKGROUND
High-sensitivity troponin I (hs-cTnI) and T (hs-cTnT) provide complementary information regarding cardiovascular disease risk. The explanation for their distinct risk profiles is incompletely understood.
METHODS AND RESULTS
hs-cTnI and hs-cTnT were measured in Dallas Heart Study participants. Associations of hs-cTnI and hs-cTnT with demographics and phenotypes were assessed using linear regression. Associations with incident heart failure, atherosclerotic cardiovascular disease, global cardiovascular disease, and cardiovascular and all-cause mortality were assessed using Cox models. Among 3276 participants (56% women, 50% Black persons, median age 43 years), the correlation between hs-cTnI and hs-cTnT was modest (Spearman rho=0.35). Variables associated with hs-cTnI but not hs-cTnT included hypertension, higher body mass index and total cholesterol, and lower high-density lipoprotein and cholesterol efflux capacity. Older age, male sex, and diabetes were positively associated, and smoking was negatively associated, with hs-cTnT but not hs-cTnI. Hs-cTnI and hs-cTnT were associated with heart failure (hazard ratio [HR] per SD log hs-cTnI 1.53 [95% CI, 1.30-1.81] and HR per SD log hs-cTnT 1.65 [95% CI, 1.40-1.95]), global cardiovascular disease (HR, 1.22 [95% CI, 1.10-1.34] and HR, 1.27 [95% CI, 1.15-1.32]), and all-cause mortality (HR, 1.12 [95% CI, 1.01-1.25], and HR, 1.17 [95% CI, 1.06-1.29]). After adjustment for N-terminal pro-B-type natriuretic peptide and the alternative troponin, both remained associated with heart failure (HR per SD log hs-cTnI 1.32 [95% CI, 1.1-1.58] and HR per log hs-cTnT 1.27 [95% CI, 1.06-1.51]).
CONCLUSIONS
Hs-cTnI and hs-cTnT are modestly correlated, demonstrate differential associations with cardiac and metabolic phenotypes, and provide complementary information regarding heart failure risk.
Topics: Humans; Female; Male; Troponin I; Troponin T; Middle Aged; Adult; Biomarkers; Phenotype; Cardiovascular Diseases; Texas; Heart Failure; Risk Assessment; Prognosis; Incidence; Risk Factors; Predictive Value of Tests
PubMed: 38842289
DOI: 10.1161/JAHA.124.034549 -
Journal of the American Heart... Jun 2024
Topics: Adolescent; Child; Child, Preschool; Female; Humans; Male; Age Factors; Biomarkers; Troponin I; Troponin T; United States
PubMed: 38842269
DOI: 10.1161/JAHA.123.035142 -
Langmuir : the ACS Journal of Surfaces... Jun 2024Actin, found in all eukaryotic cells as globular (G) or filamentous (F) actin, undergoes polymerization, with G-actin units changing shape to become F-actin. Thermal...
Actin, found in all eukaryotic cells as globular (G) or filamentous (F) actin, undergoes polymerization, with G-actin units changing shape to become F-actin. Thermal proteins, or proteinoids, are created by heating amino acids (160-200 °C), forming polymeric chains. These proteinoids can swell in an aqueous solution at around 50 °C, producing hollow microspheres filled with a solution, exhibiting voltage spikes. Our research explores the signaling properties of proteinoids, actin filaments, and hybrid networks combining actin and proteinoids. Proteinoids replicate brain excitation dynamics despite lacking specific membranes or ion channels. We investigate enhancing conductivity and spiking by using pure actin, yielding improved coordination in networks compared with individual filaments or proteinoids. Temperature changes (20 short-peptide supramolecular C to 80 °C) regulate conduction states, demonstrating external control over emergent excitability in protobrain systems. Adding actin to proteinoids reduces spike timing variability, providing a more uniform feature distribution. These findings support theoretical models proposing cytoskeletal matrices for functional specification in synthetic protocell brains, promoting stable interaction complexity. The study concludes that life-like signal encoding can emerge spontaneously within biological polymer scaffolds, incorporating abiotic chemistry.
Topics: Actin Cytoskeleton; Microspheres; Actins; Temperature; Animals
PubMed: 38837748
DOI: 10.1021/acs.langmuir.4c01107 -
BMB Reports Jun 2024T-plastin (PLST), a member of the actin-bundling protein family, plays crucial roles in cytoskeletal structure, regulation, and motility. Studies have shown that the...
T-plastin (PLST), a member of the actin-bundling protein family, plays crucial roles in cytoskeletal structure, regulation, and motility. Studies have shown that the plastin family is associated with the malignant characteristics of cancer, such as circulating tumor cells and metastasis, by inducing epithelialmesenchymal transition (EMT) in various cancer cells. However, the role of PLST in the EMT of human lung cancer cells remains unclear. In this study, we observed that PLST overexpression enhanced cell migratory and invasive abilities, whereas its downregulation resulted in their suppression. Moreover, PLST expression levels were associated with the expression patterns of EMT markers, including E-cadherin, vimentin, and Slug. Furthermore, the phosphorylation levels of focal adhesion kinase (FAK) and AKT serine/threonine kinase (AKT) were dependent on PLST expression levels. These findings indicate that PLST induces the migration and invasion of human lung cancer cells by promoting Slug-mediated EMT via the FAK/AKT signaling pathway. [BMB Reports 2024; 57(6): 305-310].
Topics: Humans; Epithelial-Mesenchymal Transition; Lung Neoplasms; Proto-Oncogene Proteins c-akt; Snail Family Transcription Factors; Signal Transduction; Cell Movement; Cell Line, Tumor; Microfilament Proteins; Membrane Glycoproteins; Focal Adhesion Protein-Tyrosine Kinases; Focal Adhesion Kinase 1; Phosphorylation; Neoplasm Invasiveness; Cadherins
PubMed: 38835117
DOI: 10.5483/BMBRep.2024-0040 -
The Journal of Cell Biology Jul 2024Profilin binds microtubules in vitro. However, a new study by Vitriol and colleagues (https://doi.org/10.1083/jcb.202309097) now suggests that effects of profilin on...
Profilin binds microtubules in vitro. However, a new study by Vitriol and colleagues (https://doi.org/10.1083/jcb.202309097) now suggests that effects of profilin on microtubule dynamics in cells are indirect and result from its impact on actin dynamics rather than its direct binding to microtubules.
Topics: Actins; Microtubules; Profilins; Protein Binding
PubMed: 38832903
DOI: 10.1083/jcb.202404112 -
Molecules and Cells Jun 2024The actin-based cytoskeleton is considered a fundamental driving force for cell differentiation and development. Destrin (Dstn), a member of the actin-depolymerizing...
The actin-based cytoskeleton is considered a fundamental driving force for cell differentiation and development. Destrin (Dstn), a member of the actin-depolymerizing factor family, regulates actin dynamics by treadmilling actin filaments and increasing globular actin pools. However, the specific developmental roles of dstn have yet to be fully elucidated. Here, we investigated the physiological functions of dstn during early embryonic development using Xenopus laevis as an experimental model organism. dstn is expressed in anterior neural tissue and neural plate during Xenopus embryogenesis. Depleting dstn promoted morphants with short body axes and small heads. Moreover, dstn inhibition extended the neural plate region, impairing cell migration and distribution during neurulation. In addition to the neural plate, dstn knockdown perturbed neural crest cell migration. Our data suggest new insights for understanding the roles of actin dynamics in embryonic neural development, simultaneously presenting a new challenge for studying the complex networks governing cell migration involving actin dynamics.
Topics: Animals; Cell Movement; Xenopus laevis; Destrin; Embryonic Development; Xenopus Proteins; Neural Crest; Neurogenesis; Neural Plate; Actins; Gene Expression Regulation, Developmental
PubMed: 38825188
DOI: 10.1016/j.mocell.2024.100076 -
European Journal of Cell Biology Jun 2024Actin is a central mediator of the chondrocyte phenotype. Monolayer expansion of articular chondrocytes on tissue culture polystyrene, for cell-based repair therapies,...
Actin is a central mediator of the chondrocyte phenotype. Monolayer expansion of articular chondrocytes on tissue culture polystyrene, for cell-based repair therapies, leads to chondrocyte dedifferentiation. During dedifferentiation, chondrocytes spread and filamentous (F-)actin reorganizes from a cortical to a stress fiber arrangement causing a reduction in cartilage matrix expression and an increase in fibroblastic matrix and contractile molecule expression. While the downstream mechanisms regulating chondrocyte molecular expression by alterations in F-actin organization have become elucidated, the critical upstream regulators of F-actin networks in chondrocytes are not completely known. Tropomyosin (TPM) and the RhoGTPases are known regulators of F-actin networks. The main purpose of this study is to elucidate the regulation of passaged chondrocyte F-actin stress fiber networks and cell phenotype by the specific TPM, TPM3.1, and the RhoGTPase, CDC42. Our results demonstrated that TPM3.1 associates with cortical F-actin and stress fiber F-actin in primary and passaged chondrocytes, respectively. In passaged cells, we found that pharmacological TPM3.1 inhibition or siRNA knockdown causes F-actin reorganization from stress fibers back to cortical F-actin and causes an increase in G/F-actin. CDC42 inhibition also causes formation of cortical F-actin. However, pharmacological CDC42 inhibition, but not TPM3.1 inhibition, leads to the re-association of TPM3.1 with cortical F-actin. Both TPM3.1 and CDC42 inhibition, as well as TPM3.1 knockdown, reduces nuclear localization of myocardin related transcription factor, which suppresses dedifferentiated molecule expression. We confirmed that TPM3.1 or CDC42 inhibition partially redifferentiates passaged cells by reducing fibroblast matrix and contractile expression, and increasing chondrogenic SOX9 expression. A further understanding on the regulation of F-actin in passaged cells may lead into new insights to stimulate cartilage matrix expression in cells for regenerative therapies.
Topics: Chondrocytes; Stress Fibers; Animals; Actins; Cell Dedifferentiation; Tropomyosin; Phenotype; Cells, Cultured; cdc42 GTP-Binding Protein; SOX9 Transcription Factor; Trans-Activators
PubMed: 38823166
DOI: 10.1016/j.ejcb.2024.151424 -
Cell Reports Jun 2024The epithelial adaptations to mechanical stress are facilitated by molecular and tissue-scale changes that include the strengthening of junctions, cytoskeletal...
The epithelial adaptations to mechanical stress are facilitated by molecular and tissue-scale changes that include the strengthening of junctions, cytoskeletal reorganization, and cell-proliferation-mediated changes in tissue rheology. However, the role of cell size in controlling these properties remains underexplored. Our experiments in the zebrafish embryonic epidermis, guided by theoretical estimations, reveal a link between epithelial mechanics and cell size, demonstrating that an increase in cell size compromises the tissue fracture strength and compliance. We show that an increase in E-cadherin levels in the proliferation-deficient epidermis restores epidermal compliance but not the fracture strength, which is largely regulated by Ezrin-an apical membrane-cytoskeleton crosslinker. We show that Ezrin fortifies the epithelium in a cell-size-dependent manner by countering non-muscle myosin-II-mediated contractility. This work uncovers the importance of cell size maintenance in regulating the mechanical properties of the epithelium and fostering protection against future mechanical stresses.
Topics: Animals; Zebrafish; Cytoskeletal Proteins; Cell Size; Myosin Type II; Zebrafish Proteins; Stress, Mechanical; Epithelial Cells; Cadherins; Epidermis; Epithelium; Cell Proliferation
PubMed: 38823013
DOI: 10.1016/j.celrep.2024.114271