Gynesonics, Inc.’s Post

https://lnkd.in/grqHjMys Article title: Flies to Humans - Humans to Flies: A Virtuous Circle of Colorectal Cancer Prevention   Author(s): Elena Kamilari; Yiorgos Apidianakis; Myrofora Panagi   Journal: Archives of Clinical Gastroenterology   Journal ISSN: 2455-2283 Abstract   The two Nobel prizes in physiology or medicine of 1995 and 2011 establish Drosophila genetics as a significant contributor of genes and signaling pathways relevant to human disease, including innate immunity and cancer. Other than providing clues on mammalian gene homologue function, relatively little attention has been paid on the translational aspect of Drosophila genes, microbes and environmental factors that influence homeostasis and disease. #Biomarkers #Drosophila #Human #ModelHost #ColorectalCancer #Inflammation #InflammatoryBowelDisease #FunctionalGIDisorders #GastrointestinalAndLiverDisease #DigestiveOncology #GastrointestinalSurgery #PediatricGastroenterology #ColorectalCancer #PancreaticCancer #HepatocellularCarcinoma #GastrointestinalBleeding #Endoscopy #Peertechz #PeertechzPublications #SurgicalGastroenterology #StomachUlcers #VirtualColonoscopy #GastricUlceration #RouxenYGastricBypass #GastricAcidSecretion #GastricMucosa #GastricUlcerHealing #GastricCardiaCancer #ReproductiveEndocrinology #EndocrineDisorders #Hepatology #AlimentaryCanal #PancreasCancer

Discovery of a potential shared therapeutic option for Lysosomal storage disorders: Lysosomal storage disorders (LSDs) are devastating diseases with limited treatment options. Researchers demonstrated that LSD-causing mutations in Hexb, Gla, Npc1, Ctsd, and Gba1 genes converge on the accumulation of the cytoplasmatic dsDNA and DNA sensor cGAS, leading to autoactivation of the cGAS–STING innate immune pathway in neurons, driving neurodegeneration. Notably, genetic or pharmacological targeting of cGAS–STING, digestion of neuronal cytosolic dsDNA by DNase, or lysosomal dysfunction correction alleviates pathology in models of Sandhoff, Fabry, and Niemann–Pick diseases. These findings unveil a common therapeutic target for LSDs, linking lysosomal defects to innate immunity and facilitating the development of a unified treatment strategy. https://lnkd.in/eWCkizHd #genetics #genomics #precisionmedicine #genomicmedicine #brain #neurology #neuroscience #neurodegeneration #raredisease #pathology #sandhoff #fabry #gaucher #niemannpick #immunity #immunology #autoimmune #metabolism #drugdevelopment #drugdiscovery #biotechnology #innovation #research #science #sciencecommunication

The Critical Role of Cytosine Stability in DNA Integrity and Fetal Development: During pregnancy, the embryo undergoes rapid cellular proliferation and differentiation to develop into a fully formed fetus. This intense cellular activity poses a significant challenge: ensuring the fidelity of DNA replication and preserving genomic integrity. Cytosine, one of the four principal nucleotides in DNA, is integral to this process. Cytosine is inherently susceptible to a spontaneous chemical reaction known as deamination, which transforms it into uracil—a nucleotide typically exclusive to RNA. If this conversion remains uncorrected, it can introduce mutations during DNA replication, potentially leading to developmental abnormalities or complications in pregnancy. The implications of such mutations are profound. Genes regulating critical developmental pathways—such as those involved in cell differentiation and tissue growth—are essential for proper fetal development. A mutation in these regulatory genes can lead to congenital abnormalities or jeopardize pregnancy viability. Moreover, cytosine plays a pivotal role in epigenetic regulation through methylation, impacting gene expression at critical developmental stages. Recent research published in PLOS Biology and Epigenetics & Chromatin explores how cytosine deamination contributes to increased mutation rates. The findings emphasize the need for robust DNA repair mechanisms, such as base excision repair, to preserve genomic stability during critical periods of development. Although these studies do not specifically focus on pregnancy, they underscore the importance of cytosine stability in safeguarding DNA integrity, which is essential for healthy fetal development. How can we leverage our understanding of cytosine stability to improve prenatal health outcomes? I welcome your thoughts and insights! #Bioinformatics #cytosine #Biology #MolecularBiology https://lnkd.in/gmfGh552

🔬Scientists have discovered that as mammals age, their guts experience an imbalance and buildup of faulty🧬mitochondrial DNA (mtDNA), but we don't fully understand how this affects gut health. They studied this in older male mice👴🐁and found that their small intestines had more mtDNA mutations, suggesting a link to aging. By comparing mice bred to accumulate these mutations with regular mice, they found that increasing mtDNA mutations led to poorer gut function, including reduced ability for intestinal stem cells to regenerate. They discovered that a specific response called the mitochondrial unfolded protein response (UPRmt), triggered by these mutations, worsens gut aging. However, when they supplemented the mice with NMN💊, a substance that boosts NAD+ levels, the aging process in the gut reversed. This research shows that by understanding and targeting these molecular pathways, scientists might be able to slow down gut aging in mammals. #longevity #newresearch #antiaging #NAD+ #GutHealth #MitochondrialDNA #ScienceNews #NMN #AgingResearch https://lnkd.in/ePXin8et

The article titled "Congenital hydrocephalus: new Mendelian mutations and evidence for oligogenic inheritance" explores the genetic basis of primary congenital hydrocephalus (PCH), a condition characterized by ventriculomegaly due to impaired cerebrospinal fluid homeostasis. The study aims to identify novel causal genes and investigate the possibility of oligogenic inheritance for PCH. 𝐊𝐞𝐲 𝐅𝐢𝐧𝐝𝐢𝐧𝐠𝐬: 𝐆𝐞𝐧𝐞𝐭𝐢𝐜 𝐀𝐧𝐚𝐥𝐲𝐬𝐢𝐬: Whole-exome sequencing (WES) was performed on 28 unrelated probands, identifying pathogenic or likely pathogenic variants in 18% of cases, including genes not previously linked to isolated PCH. Novel mutations were found in known hydrocephalus genes, and three novel candidate genes (RNPC3, TIE1, and DNAH2) were identified in 11% of the cohort. 𝐎𝐥𝐢𝐠𝐨𝐠𝐞𝐧𝐢𝐜 𝐈𝐧𝐡𝐞𝐫𝐢𝐭𝐚𝐧𝐜𝐞: The study found a significant burden of genetic variants in primary ciliary genes in PCH patients compared to controls, supporting the hypothesis of oligogenic inheritance. This suggests that PCH could involve multiple gene mutations, rather than being purely Mendelian. Digenic Combinations: A candidate digenic pair involving genes IFT172 and TTC21B, both implicated in intraflagellar transport, was predicted to have a digenic effect, meaning that mutations in both genes together contribute to the disease. 𝐂𝐥𝐢𝐧𝐢𝐜𝐚𝐥 𝐈𝐦𝐩𝐥𝐢𝐜𝐚𝐭𝐢𝐨𝐧𝐬: The findings highlight the need to include these novel genes in diagnostic panels for PCH and provide insight into the genetic complexity underlying the condition. 𝐂𝐨𝐧𝐜𝐥𝐮𝐬𝐢𝐨𝐧: The study demonstrates the low contribution of Mendelian mutations in PCH and suggests that oligogenic inheritance involving primary ciliary genes may play a significant role. This research advances the understanding of PCH's genetic landscape, potentially aiding in better diagnosis and management of the condition. #clinicalgenetics #healthcare #humangenetics #medicalgenetics #medicine #molecularmedicine #neurogenetics #neurology #neuroscience

When my PI first described this project to me, he said "Deleting Alk5 in Pdgfrb+ cells results in this severe phenotype of gross brain hemorrhage in utero, and we have no idea why??" 9 years, several hypotheses and hundreds of experiments later, we now know exactly why! Check out this latest publication which describes how the TGFb pathway in pericytes plays an indispensable role during blood-brain-barrier development by epigenetic repression of Angiopoetin-2 (ANGPT2). Excessive production of this angiogenic ligand disturbs cerebrovascular quiescence by inducing hyperactive TIE2 signaling, endothelial hyperproliferation, vessel distension and barrier disruption culminating in germinal matrix hemorrhage - intraventricular hemorrhage (GMH-IVH). While pharmacological targeting ANGPT2 reduces disease severity, its genetic ablation results in a nearly complete rescue of the phenotype and extensively prolongs survival! The study identifies pericyte-derived ANGPT2 as a promising therapeutic target for GMH-IVH, a devastating cerebrovascular disease in premies lacking treatment and further uncovers elegant molecular mechanisms of ANGPT2 repression via epigenetic remodeling which may be relevant for adult hemorrhagic stroke. Huge thanks to all colleagues and collaborators who supported me through this super exciting scientific endeavor, it was totally worth it 😇 Raja Chakraborty Kathleen Martin, Lina Ntokou, MSc, PhD, Junichi Saito, Praveen Ballabh, Alex Agyemang and Daniel Greif.

In celebration of #worldkidneyday, I am excited to share that our study is now published in the American Journal of Physiology - Renal Physiology (AJP-Renal)! https://lnkd.in/e3jwb6r5 Focal Segmental Glomerulosclerosis (FSGS) is a severe form of chronic kidney disease that attacks the blood-filtering cells of the kidney and often leads to kidney failure. Development of treatments for FSGS has been stagnant for decades, and kidney failure is irreversible and can only be managed by highly invasive procedures including dialysis and kidney transplant. A major gap in knowledge in FSGS pathogenesis and treatment is that it has been generally accepted that the kidney has a very limited capability to regenerate after an injury such as in FSGS. However, more recent studies have challenged this view and showed that some kidney cells have stem cell-like properties and are capable of regeneration. Our team led by Dr. Moumita Barua previously found that mutations in a gene called PAX2 account for 4% of adults with FSGS. PAX2 regulates cell differentiation and cell fate specification during kidney development, and recent studies suggest PAX2-expressing cells in the adult kidney may have stem cell-like properties. Here, we investigated cellular mechanisms by which PAX2 mutations lead to FSGS. We found that PAX2 mutant mice experience a more severe kidney disease after experimentally-induced FSGS when compared to normal mice, including worsened kidney tissue damage and increased mortality when compared to mice without the PAX2 mutation. We also presented findings suggesting kidney cells expressing the mutant form of PAX2 are compromised in their ability to regenerate the injured and lost cells after kidney injury, therefore further worsening FSGS and likely contributes to progression to kidney failure, hence the increased mortality in this group. These findings provide an important framework for future studies to more comprehensively understand the underlying cellular and molecular mechanisms by which PAX2 mutations drive FSGS, with the overall goal of harnessing identified disease pathways and impaired signalling mechanisms towards advancing therapeutic development in FSGS and preventing its further progression to kidney failure. Please check out our article here and feel free to message me for any questions/insights! https://lnkd.in/e3jwb6r5

Ok, hear me out, my mind is blown 🤯    Let me walk you through this awesome article that I just read in 🦠 Cell Immunity. So basically I will highlight some of the main points, coupled with my take on the potential explanation it may have in the psychosomatics of the body. Because, #psychoneuroendocrinoimmunology #PNEI #psychosomatics Points: - Mast cells are considered one of the most ancient immune cells originating nearly 500 million years ago from primitive test cells of urochordates. Mast cells are a versatile component of innate immunity, and they essentially populate all organs. - Mas-related G protein-coupled receptors (MRGPRs) opened a new chapter in the understanding of immunity and sensory biology. They have been discovered in 2001 by Dong, Anderson, and colleagues - The main mechanisms for MRGPRs is facilitating the crosstalk between sensory nerves (dorsal root ganglia) and immune cells (predominantly mast cells). - The origin of mast cells is important! Mast cells with embryonic origins (i.e., yolk sac) are found in connective tissues, fat, and sub-mucosa of the skin, in proximity to blood and lymphatic vessels, and neurons. Mast cells that develop from the bone marrow are predominantly found in respiratory and gastrointestinal mucosal tissues and they both contain different granule molecules. - Besides the activation of mast cells through the well-established IgE-dependent fashion, they can also be triggered in an IgE-independent fashion - hence, MRGPRs (especially the MRGPR2)! - MRGPR may be responsible for adverse drug reactions (eg. red man syndrome) - (thinking about make-up triggered eczema flare-ups 💅 ) - But, there is a balance ⚖ Unlike MRGPR2s there are MRGPRDs which are maintained by Langerhans cells and promote homeostasis, protecting against aberrant mast cell activation in response to chemical irritants via their glutamate release.  - MRGPRD ligand is Beta-alanine (Food for thought, pun intended: Beta-alanine (carnosine) can only be obtained by consuming animal products 🍖 .) - The genes encoding MGRPRs are highly polymorphic; how do these mutations impact immune cell function and disease state, is not yet known. Why is this mind blowing to me? Because, ▶our pyschological state are basically emotions ▶ which involve muscle activity (eg. facial expression, tensing of the body) ▶ muscle activity is the proprioceptive input that feeds into the dorsal root ganglia ▶ they in turn release neuropeptides which are ligands to potential MRGPRs on the mast cell surface ▶ causing the IgE-independent response ▶ and potential skin reactions and itching. So, the idiom "to give someone an itch" might be freakishly accurate. The language explains more of the body than we realize. https://lnkd.in/dz7tE472

🎉New Paper🥳 Excited to share the first Corresponding and Lead Author paper from #Salman_Lab. Great team effort from everyone, and a big shout-out to the fantastic and relentless Gizem O., this work wasn't to be done without all her hard work and dedication 🙌 In this paper, we investigated the role of variant-specific effects of GBA1 mutations on iPSC-derived dopaminergic neuron proteostasis. We report that severe GBA1 mutations were found to trigger the accumulation and release of oligomeric α-synuclein in iPSC-derived dopaminergic neurons, primarily as a result of increased ER stress and defective macroautophagy, while mild GBA1 mutations affected chaperone-mediated autophagy , which is mainly responsible for the degradation of the monomeric form of α-synuclein. https://lnkd.in/exv28m-r Department of Physiology, Anatomy & Genetics - University of Oxford Kavli Institute for Nanoscience Discovery, University of Oxford

#PediatricCancers are #RareDiseases, with over 100 subtypes and varying contributing genetic factors. Research into the #genomic factors that contribute to these diseases means early detection and the development of novel and targeted therapeutic methods. PhenoTips' founder and CEO Pawel Buczkowicz, PhD's research focuses on identifying the genomic causes and potential therapeutic targets of high-risk childhood cancer such as #pediatric #BrainstemGliomas. Read the 2014 Nature Portfolio paper by Buczkowicz et al., "Genomic analysis of diffuse intrinsic pontine gliomas identifies three molecular subgroups and recurrent activating ACVR1 mutations". https://lnkd.in/eQFm3w7R