Plasma water T2 detects age-stratified differences in cardiometabolic health among familial CCM patients with Hispanic CCM1 mutation.

Cerebral cavernous malformations (CCMs) are abnormal clusters of capillaries in the nervous system. This pilot study analyzed the cardiometabolic health status of individuals with familial CCMs caused by a rare mutation in the CCM1 gene (fCCM1). The aim was to compare plasma water T2 values from individuals with fCCM1 with values from metabolically unhealthy and healthy individuals with no known CCM mutations. This observational, cross-sectional study included 75 participants: 11 fCCM1 patients, 24 metabolically unhealthy and 40 metabolically healthy individuals. Plasma water T2, an early, global and practical marker of cardiometabolic health, was measured in the time domain using benchtop magnetic resonance relaxometry. The results were stratified by age (equal to or less than 45 vs. older than 45 years). Group means were compared using Welch's one-way ANOVA and post hoc Tukey-Kramer tests. Multivariable linear regression, with T2 as the outcome variable, was used to explore associations with age, gender, Hispanic ethnicity and fCCM1 status. In the younger age stratum, the fCCM1 group had a mean plasma water T2 value comparable to the metabolically healthy group (p = 0.6388), but higher than the unhealthy group (p < 0.0001). By contrast, in the older stratum, the mean plasma water T2 value for the fCCM1 group was comparable to the metabolically unhealthy group (p = 0.7819) and lower than the healthy group (p = 0.0005). Multivariable linear regression revealed that age and the interaction between age and fCCM1 status were significant predictors of T2, even after adjusting for gender and Hispanic ethnicity. Plasma water T2 shows potential as a biomarker for assessing the health status of individuals with fCCM1. Further research is needed to validate these preliminary observations and elucidate the association between CCMs and cardiometabolic health.

Circulating Blood Prognostic Biomarker Signatures for Hemorrhagic Cerebral Cavernous Malformations (CCMs).

Cerebral cavernous malformations (CCMs) are a neurological disorder characterized by enlarged intracranial capillaries in the brain, increasing the susceptibility to hemorrhagic strokes, a major cause of death and disability worldwide. The limited treatment options for CCMs underscore the importance of prognostic biomarkers to predict the likelihood of hemorrhagic events, aiding in treatment decisions and identifying potential pharmacological targets. This study aimed to identify blood biomarkers capable of diagnosing and predicting the risk of hemorrhage in CCM1 patients, establishing an initial set of circulating biomarker signatures. By analyzing proteomic profiles from both human and mouse CCM models and conducting pathway enrichment analyses, we compared groups to identify potential blood biomarkers with statistical significance. Specific candidate biomarkers primarily associated with metabolism and blood clotting pathways were identified. These biomarkers show promise as prognostic indicators for CCM1 deficiency and the risk of hemorrhagic stroke, strongly correlating with the likelihood of hemorrhagic cerebral cavernous malformations (CCMs). This lays the groundwork for further investigation into blood biomarkers to assess the risk of hemorrhagic CCMs.

Deep-Learning Uncovers certain CCM Isoforms as Transcription Factors.

BACKGROUND: Cerebral Cavernous Malformations (CCMs) are brain vascular abnormalities associated with an increased risk of hemorrhagic strokes. Familial CCMs result from autosomal dominant inheritance involving three genes: KRIT1 (CCM1), MGC4607 (CCM2), and PDCD10 (CCM3). CCM1 and CCM3 form the CCM Signal Complex (CSC) by binding to CCM2. Both CCM1 and CCM2 exhibit cellular heterogeneity through multiple alternative spliced isoforms, where exons from the same gene combine in diverse ways, leading to varied mRNA transcripts. Additionally, both demonstrate nucleocytoplasmic shuttling between the nucleus and cytoplasm, suggesting their potential role in gene expression regulation as transcription factors (TFs). Due to the accumulated data indicating the cellular localization of CSC proteins in the nucleus and their interaction with progesterone receptors, which serve dual roles as both cellular signaling components and TFs, a question has arisen regarding whether CCMs could also function in both capacities like progesterone receptors. METHODS: To investigate this potential, we employed our proprietary deep-learning (DL)-based algorithm, specifically utilizing a biased-Support Vector Machine (SVM) model, to explore the plausible cellular function of any of the CSC proteins, particularly focusing on CCM gene isoforms with nucleocytoplasmic shuttling, acting as TFs in gene expression regulation. RESULTS: Through a comparative DL-based predictive analysis, we have effectively discerned a collective of 11 isoforms across all CCM proteins (CCM1-3). Additionally, we have substantiated the TF functionality of 8 isoforms derived from CCM1 and CCM2 proteins, marking the inaugural identification of CCM isoforms in the role of TFs. CONCLUSIONS: This groundbreaking discovery directly challenges the prevailing paradigm, which predominantly emphasizes the involvement of CSC solely in endothelial cellular functions amid various potential cellular signal cascades during angiogenesis.

Familial CCM Genes Might Not Be Main Drivers for Pathogenesis of Sporadic CCMs-Genetic Similarity between Cancers and Vascular Malformations.

Cerebral cavernous malformations (CCMs) are abnormally dilated intracranial capillaries that form cerebrovascular lesions with a high risk of hemorrhagic stroke. Recently, several somatic "activating" gain-of-function (GOF) point mutations in PIK3CA (phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit p110α) were discovered as a dominant mutation in the lesions of sporadic forms of cerebral cavernous malformation (sCCM), raising the possibility that CCMs, like other types of vascular malformations, fall in the PIK3CA-related overgrowth spectrum (PROS). However, this possibility has been challenged with different interpretations. In this review, we will continue our efforts to expound the phenomenon of the coexistence of gain-of-function (GOF) point mutations in the PIK3CA gene and loss-of-function (LOF) mutations in CCM genes in the CCM lesions of sCCM and try to delineate the relationship between mutagenic events with CCM lesions in a temporospatial manner. Since GOF PIK3CA point mutations have been well studied in reproductive cancers, especially breast cancer as a driver oncogene, we will perform a comparative meta-analysis for GOF PIK3CA point mutations in an attempt to demonstrate the genetic similarities shared by both cancers and vascular anomalies.

Key Members of the CmPn as Biomarkers Distinguish Histological and Immune Subtypes of Hepatic Cancers.

Liver cancer, comprising hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), is a leading cause of cancer-related deaths worldwide. The liver is a primary metabolic organ for progesterone (PRG) and PRG exerts its effects through classic nuclear PRG receptors (nPRs) and non-classic membrane PRG receptors (mPRs) or a combination of both. Previous studies have shown that the CCM signaling complex (CSC) couples both nPRs and mPRs to form the CmPn (CSC-mPR-PRG-nPR) signaling network, which is involved in multiple cellular signaling pathways, including tumorigenesis of various cancers. Despite advances in treatment, 5-year survival rates for liver cancer patients remain low, largely due to the chemoresistant nature of HCCs. The lack of sensitive and specific biomarkers for liver cancer diagnosis and prognosis emphasizes the need for identifying new potential biomarkers. We propose the potential use of CmPn members' expression data as prognostic biomarkers or biomarker signatures for the major types of hepatic cancer, including HCCs and CCAs, as well as rare subtypes such as undifferentiated pleomorphic sarcoma (UPS) and hepatic angiosarcoma (HAS). In this study, we investigated the CmPn network through RNAseq data and immunofluorescence techniques to measure alterations to key cancer pathways during liver tumorigenesis. Our findings reveal significant differential expression of multiple CmPn members, including CCM1, PAQR7, PGRMC1, and nPRs, in both HCCs and CCAs, highlighting the crucial roles of mPRs, nPRs, and CSC signaling during liver tumorigenesis. These key members of the CmPn network may serve as potential biomarkers for the diagnosis and prognosis of liver cancer subtypes, including rare subtypes.

Biomarkers derived from CmP signal network in triple negative breast cancers.

Breast cancer is the most commonly diagnosed cancer and the second leading cause of cancer-related death in women, accounting for approximately 30% of all new cancer cases. The prognosis of breast cancer heavily depends on the stage of diagnosis, with early detection resulting in higher survival rates. Various risk factors, including family history, alcohol consumption and hormone exposure, contribute to breast cancer development. Triple-negative breast cancer (TNBC), characterized by the absence of certain receptors, is particularly aggressive and heterogeneous. Cerebral cavernous malformations (CCMs), abnormal dilations of small blood vessels in the brain, is contributed by mutated genes like CCM1, CCM2, and CCM3 through the perturbed formation of the CCM signaling complex (CSC). The CSC-non-classic membrane progesterone receptors (mPRs)-progesterone (PRG) (CmP)/CSC-mPRs-PRG-classic nuclear progesterone receptors (nPRs) (CmPn) signaling network, which integrates the CSC with mPRs and nPRs, plays a role in breast cancer tumorigenesis. Understanding these pathways can provide insights into potential treatments. This paper focuses on the emerging field of CmPn/CmP signal networks, which involve PRG, its receptors (nPRs and mPRs), and the CSC. These networks play a role in tumorigenesis, particularly in TNBCs. Aims to deliver a thorough examination of the CmP/CmPn pathways concerning TNBCs, this paper provides a comprehensive overview of these pathways, explores their applications and highlights their significance in the context of TNBCs.

Cryo-ET of Env on intact HIV virions reveals structural variation and positioning on the Gag lattice.

HIV-1 Env mediates viral entry into host cells and is the sole target for neutralizing antibodies. However, Env structure and organization in its native virion context has eluded detailed characterization. Here, we used cryo-electron tomography to analyze Env in mature and immature HIV-1 particles. Immature particles showed distinct Env positioning relative to the underlying Gag lattice, providing insights into long-standing questions about Env incorporation. A 9.1-Å sub-tomogram-averaged reconstruction of virion-bound Env in conjunction with structural mass spectrometry revealed unexpected features, including a variable central core of the gp41 subunit, heterogeneous glycosylation between protomers, and a flexible stalk that allows Env tilting and variable exposure of neutralizing epitopes. Together, our results provide an integrative understanding of HIV assembly and structural variation in Env antigen presentation.

Instability in a coiled-coil signaling helix is conserved for signal transduction in soluble guanylyl cyclase.

How nitric oxide (NO) activates its primary receptor, α1/ß1 soluble guanylyl cyclase (sGC or GC-1), remains unknown. Likewise, how stimulatory compounds enhance sGC activity is poorly understood, hampering development of new treatments for cardiovascular disease. NO binding to ferrous heme near the N-terminus in sGC activates cyclase activity near the C-terminus, yielding cGMP production and physiological response. CO binding can also stimulate sGC, but only weakly in the absence of stimulatory small-molecule compounds, which together lead to full activation. How ligand binding enhances catalysis, however, has yet to be discovered. Here, using a truncated version of sGC from Manduca sexta, we demonstrate that the central coiled-coil domain, the most highly conserved region of the ~150,000 Da protein, not only provides stability to the heterodimer but is also conformationally active in signal transduction. Sequence conservation in the coiled coil includes the expected heptad-repeating pattern for coiled-coil motifs, but also invariant positions that disfavor coiled-coil stability. Full-length coiled coil dampens CO affinity for heme, while shortening of the coiled coil leads to enhanced CO binding. Introducing double mutation αE447L/ßE377L, predicted to replace two destabilizing glutamates with leucines, lowers CO binding affinity while increasing overall protein stability. Likewise, introduction of a disulfide bond into the coiled coil results in reduced CO affinity. Taken together, we demonstrate that the heme domain is greatly influenced by coiled-coil conformation, suggesting communication between heme and catalytic domains is through the coiled coil. Highly conserved structural imperfections in the coiled coil provide needed flexibility for signal transduction.