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Glucose-regulated protein 78 (GRP78) binds to and stabilizes melanocortin 4 receptor (MC4R), which activates protein kinase A (PKA) by regulating G proteins. GRP78 is primarily used as a marker for endoplasmic reticulum stress; however, its other functions have not been well studied. Therefore, in this study, we aimed to investigate the function of GRP78 during porcine embryonic development. The developmental quality of porcine embryos, expression of cell cycle proteins, and function of mitochondria were evaluated by inhibiting the function of GRP78. Porcine oocytes were activated to undergo parthenogenesis, and blastocysts were obtained after 7 days of in vitro culture. GRP78 function was inhibited by adding 20 μM HA15 to the in vitro culture medium. The inhibition in GRP78 function led to a decrease in G proteins release, which subsequently downregulated the cyclic adenosine monophosphate (cAMP)/PKA pathway. Ultimately, inhibition of GRP78 function induced the inhibition of CDK1 and cyclin B expression and disruption of the cell cycle. In addition, inhibition of GRP78 function regulated DRP1 and SIRT1 expression, resulting in mitochondrial dysfunction. This study provides new insights into the role of GRP78 in porcine embryonic development, particularly its involvement in the regulation of the MC4R pathway and downstream cAMP/PKA signaling. The results suggest that the inhibition of GRP78 function in porcine embryos by HA15 treatment may have negative effects on embryo quality and development. This study also demonstrated that GRP78 plays a crucial role in the functioning of MC4R, which releases the G protein during porcine embryonic development. Show less

We showed previously that inhibition of KIT signaling in GISTs activates FGFR-signaling pathway rendering cancer cells resistant to receptor tyrosine kinase inhibitor (RTKi) imatinib mesylate (IM) (Gleevec) despite of absence of secondary Show less

Proline-rich coiled-coil 2C ( The Cancer Genome Atlas (TCGA) RNA-sequencing datasets of 371 cases of primary liver cancer and 50 normal liver tissue specimens were obtained to analyze correlation between Analysis of TCGA data sets revealed that patients with high Show less

Mitochondrial degeneration in various neurodegenerative diseases, specifically in Alzheimer's disease, involves excessive mitochondrial fission and reduced fusion, leading to cell damage. P110 is a seven-amino acid peptide that restores mitochondrial dynamics by acting as an inhibitor of mitochondrial fission. However, the role of P110 as a neuroprotective agent in AD remains unclear. Therefore, we performed cell culture studies to evaluate the neuroprotective effect of P110 on amyloid-β accumulation and mitochondrial functioning. Human SH-SY5Y neuronal cells were incubated with 1 µM and 10 µM of P110, and Real-Time PCR and Western blot analysis were done to quantify the expression of genes pertaining to AD and neuronal health. Exposure of SH-SY5Y cells to P110 significantly increased APP mRNA levels at 1 µM, while BACE1 mRNA levels were increased at both 1 µM and 10 µM. However, protein levels of both APP and BACE1 were significantly reduced at 10 µM of P110. Further, P110 treatment significantly increased ADAM10 and Klotho protein levels at 10 µM. In addition, P110 exposure significantly increased active mitochondria and reduced ROS in live SH-SY5Y cells at both 1 µM and 10 µM concentrations. Taken together, our results indicate that P110 might be useful in attenuating amyloid-β generation and improving neuronal health by maintaining mitochondrial function in neurons. Show less

Emerging evidence indicates that the interactions and dynamic changes among tumor-associated macrophages (TAMs) are pivotal in molding the tumor microenvironment (TME), thereby influencing diverse clinical outcomes. However, the potential clinical ramifications of these evolutionary shifts in tumor-associated macrophages within pancreatic adenocarcinoma (PAAD) remain largely unexamined. Single-cell RNA sequencing (scRNA-seq) data were retrieved from the Tumor Immune Single-cell Hub. The Seurat and Monocle algorithms were employed to elucidate the progression of TAMs, using non-negative matrix factorization (NMF) to determine molecular classifications. Subsequently, the prognosis, biological characteristics, genomic modifications, and immune landscape across various clusters were interpreted. Furthermore, the sensitivity of potential therapeutic drugs between subtypes was predicted. Cellular experiments were conducted to explore the function of the NR1H3 gene in pancreatic cancer. These experiments encompassed gene knockdown, proliferation assessment, clone formation evaluation, transwell examination, and apoptosis analysis. Trajectory gene expression analysis of tumor-associated macrophages identified three disparate clusters, each associated with different clinical outcomes Compared to clusters C1 and C2, cluster C3 is seemingly at a less advanced pathological stage and associates with a relatively favorable prognosis. Further investigation revealed pronounced genetic instability in cluster C2, whereas cluster C3 demonstrated notable genetic stability. Cluster C1, characterized as "immune-hot," exhibits an abundance of immune cells and elevated immune checkpoint expression, suggesting its suitability for immunotherapy. Furthermore, several potential therapeutic agents have been pinpointed, potentially facilitating the clinical application of these insights. Cell assays indicated that NR1H3 knockdown markedly induced apoptosis and suppressed clonogenesis, migration, and proliferation of pancreatic cancer cells in the PTAU-8988 and PANC-1 cell lines. Overall, our study discerned three clusters with unique characteristics, defined by the evolution of TAMs. We propose customized therapeutic strategies for patients within these specific clusters to improve clinical outcomes and optimize clinical management. Show less

Periodontitis is one of the most common oral diseases and has been shown to be a risk factor for systemic diseases. Our aim was to investigate the relationship between periodontitis and cognitive impairment and to explore the role of the P38 MAPK signaling pathway in this process. We established a periodontitis model by ligating the first molars of SD rats with silk thread and injecting We demonstrated that silk ligature-induced periodontitis plus injection of Our findings strongly suggest that topical application of Show less

Ovarian cancer remains the most lethal gynecologic malignancy in the USA. For over twenty years, epithelial-mesenchymal transition (EMT) has been characterized extensively in development and disease. The dysregulation of this process in cancer has been identified as a mechanism by which epithelial tumors become more aggressive, allowing them to survive and invade distant tissues. This occurs in part due to the increased expression of the EMT transcription factor, Show less

Melanocortin 4 receptor (MC4R), the most important monogenetic cause of human metabolic disorders, has been of great interest to many researchers in the field of energy homeostasis and public health. Because MC4R is a vital pharmaceutical target for maintaining controllable appetite and body weight for professional athletes, previous studies have mainly focused on the central, rather than the peripheral, roles of MC4R. Thus, the local expression of MC4R and its behavioral regulation remain unclear. In an attempt to shed light on different directions for future studies of MC4R signaling, we review a series of recent and important studies exploring the peripheral functions of MC4R and the direct physiological interaction between peripheral organs and central MC4R neurons in this article. Show less

Atrophic gastritis, one of the processes leading to gastric cancer (GC), is closely related to Helicobacter pylori (HP) infection. This study aimed to understand how HP causes chronic inflammation that leads to ulcers and stomach problems. Twenty-eight CAG patients were included in the study (9 HP-infected and 19 HP-uninfected). Endoscopy, histopathology, and high-throughput mRNA sequencing were performed. Differentially expressed genes (DEGs) were validated via qRT-PCR. Principal component analysis (PCA) results showed that more than 88.9 ​% of the samples were classified into the HP (+) group. A total of 157 DEGs were identified, of which 38 were up-regulated and 119 were down-regulated. The DEGs were mainly enriched in the biological process (BP) terms associated with immune system process, adaptive immune response, G protein-coupled receptor signaling pathway, as well as point to numerous key pathways, including fat digestion and absorption, retinol metabolism, steroid hormone biosynthesis, ascorbate and aldarate metabolism, and chemical carcinogenesis. APOA1, APOA4, FOXP3, NR1H4, ABCG5, ACTA1, CCL19, CCR7, CYP3A4, and PDCD had the highest degrees in protein-protein interaction network as the hub genes; they were also included into the transcription factor (TF)-target network except for PDCD. APOA1 and CYP3A4 were extremely significantly up-regulated in HP (+) CAG patients compared with the HP (-) CAG patients, while FOXP3, CCR7 and CCL19 were significantly down-regulated. The expression of APOA1, CYP3A4, FOXP3, CCR7, and CCL19 are the potential indicators for CAG to GC development, being the biomarkers to predict progression of CAG and poor prognosis of GC. Show less

The occurrence and progression of lung cancer are correlated with telomeres and telomerase. Telomere length is reduced in the majority of tumors, including lung cancers. Telomere length variations have been associated with lung cancer risk and may serve as therapeutic targets as well as predictive biomarkers for lung cancer. Nevertheless, the effects of telomere-associated genes on lung cancer prognosis have not been thoroughly studied. We aim to investigate the relationship between telomere-associated genes and lung cancer prognosis. The Cancer Genome Atlas and Genotype-Tissue Expression databases were used as training sets to build a predictive model. Three integrated Gene Expression Omnibus datasets served as validation sets. Using cluster consistency analysis and regression with the least absolute shrinkage and selection operator, we developed a telomere-related gene risk signature (TMGsig) based on 11 overall survival-related genes ( The results indicated a negative outcome for the high-risk score group. Immunological microenvironment and somatic mutations differed between the high- and low-risk groups. A statistically significant difference existed between the low-risk and high-risk groups in terms of the expression levels of B cells and CD4 cells, and the risk score was essentially inversely linked with immune cell expression. TMGsig can predict outcomes in patients with lung adenocarcinoma. Show less

Acute cardiomyopathy is a significant global health concern and one of the leading causes of death in developed countries. Prior studies have shown an association between acute cardiomyopathy and low vitamin D levels. Although paricalcitol, a vitamin D receptor (VDR) activator, has demonstrated clinical benefits in patients with advanced kidney disease, its effect on cardiac remodeling in cardiomyopathy is unknown. This study aimed to investigate the relative effects of paricalcitol on cardiomyopathy in rats. Wistar-Kyoto rats were administered vehicle (sham control group) or isoproterenol to induce cardiomyopathy. Rats administered isoproterenol were subsequently treated with paricalcitol (experimental group) or vehicle (isoproterenol group). Picrosirius red and immunofluorescence staining were used to analyze cardiac fibrosis and hypertrophy. Immunohistochemistry staining was used to confirm the molecular mechanisms involved in isoproterenol-induced cardiomyopathy in rats. Injection of paricalcitol could reduce collagen and transforming growth factor-beta 1 (TGF-β1) levels while activating fibroblast growth factor receptor 1 (FGFR1) and fibroblast growth factor-23 (FGF23) without the help of Klotho, thereby reducing myocardial hypertrophy and fibrosis. As a VDR activator, paricalcitol reduces isoproterenol-induced cardiac fibrosis and hypertrophy by reducing the expression of TGF-β1 and enhancing the expression of VDR, FGFR1, and FGF23. Show less

Deoxynivalenol (DON) is a trichothecene toxin that mainly produced by strains of Fusarium spp. DON contamination is widely distributed and is a global food safety threat. Existing studies have expounded its harmful effects on growth inhibition, endocrine disruption, immune function impairment, and reproductive toxicity. In energy metabolism, DON suppresses appetite, reduces body weight, triggers lipid oxidation, and negatively affects cholesterol and fatty acid homeostasis. In this study, high-fat diet (HFD) induced obese C57BL/6J mice were orally treated with 0.1 mg/kg bw/d and 1.0 mg/kg bw/d DON for 4 weeks. The lipid metabolism of mice and the molecular mechanisms were explored. The data showed that although DON reduced body weight and fat mass in HFD mice, it significantly increased their serum triglyceride concentrations, disturbance of serum lipid metabolites, impaired glucose, and resulted in insulin intolerance in mice. In addition, the transcriptional and expression changes of lipid metabolism genes in the liver and epididymis (EP) adipose indicate that the DON-mediated increase in serum triglycerides is caused by lipoprotein lipase (LPL) inhibition in EP adipose. Furthermore, DON down-regulates the expression of LPL through the PPARγ signaling pathway in EP adipose. These results are further confirmed by the serum lipidomics analysis. In conclusion, DON acts on the PPARγ pathway of white adipose to inhibit the expression of LPL, mediate the increase of serum triglyceride in obese mice, disturb the homeostasis of lipid metabolism, and increase the risk of cardiovascular disease. This study reveals the interference mechanism of DON on lipid metabolism in obese mice and provides a theoretical basis for its toxic effect in obese individuals. Show less

The decline of endothelial autophagy is closely related to vascular senescence and disease, although the molecular mechanisms connecting these outcomes in vascular endothelial cells (VECs) remain unclear. Here, we identify a crucial role for CD44, a multifunctional adhesion molecule, in controlling autophagy and ageing in VECs. The CD44 intercellular domain (CD44ICD) negatively regulates autophagy by reducing PIK3R4 and PIK3C3 levels and disrupting STAT3-dependent PtdIns3K complexes. CD44 and its homologue clec-31 are increased in ageing vascular endothelium and Caenorhabditis elegans, respectively, suggesting that an age-dependent increase in CD44 induces autophagy decline and ageing phenotypes. Accordingly, CD44 knockdown ameliorates age-associated phenotypes in VECs. The endothelium-specific CD44ICD knock-in mouse is shorter-lived, with VECs exhibiting obvious premature ageing characteristics associated with decreased basal autophagy. Autophagy activation suppresses the premature ageing of human and mouse VECs overexpressing CD44ICD, function conserved in the CD44 homologue clec-31 in C. elegans. Our work describes a mechanism coordinated by CD44 function bridging autophagy decline and ageing. Show less

Acute pancreatitis results in high morbidity and mortality. Gallstones and alcoholism are considered leading causes of acute pancreatitis. However, increasing prevalence of obesity, diabetes and lifestyle choices has resulted in Hypertriglyceridaemia induced pancreatitis (HTAP) becoming more common. HTAP is said to be more severe than other causes. The treatment options available vary including intravenous (IV) insulin, heparin, plasma exchange, fibrates, niacin, omega three fatty acids and dietary restrictions. This is a case report of a patient presenting with HTAP and the dilemma treating physicians faced in trying to balance the need for urgent treatment with invasiveness of procedure and paucity of evidence. Show less

In rheumatoid arthritis (RA), hyperproliferative fibroblast-like synoviocytes (FLS) can secrete a variety of tissue hydrolases, such as matrix metalloproteinases (MMPs), causing the destruction of chondrocytes. Mesenchymal stem cells (MSCs) can directly affect FLS through extracellular vesicles (EVs). Interleukin-27 (IL-27) is a pleiotropic immune regulator frequently overexpressed in RA. The study intended to examine the effects of IL-27-induced exosomes from bone-marrow mesenchymal stem cells (BM-MSCs) and to determine if they promote the secretion of MMP3 in synovial cells. The research team performed a genetic study. The study took place at the First Affiliated Hospital of Hainan Medical University in Haikou City, Hainan, China. The research team: (1) determined if IL-27 expression had occurred in the synovial fluid; (2) co-cultured IL-27-induced MSCs with FLS to detect the expression of MMP3 in the FLS; (3) Under IL-27 induction, MSC-derived exosomes with IL-27R knockdown were collected to detect the expression of microRNAs(miRNAs) associated with RA; (4) screened the miRNAs to determine the most significant differences in expression; (5) determined the miRNA target genes in arthritis, using Western blot (WB) and qRT-PCR; and (6) Dual luciferase and ChIP experiments confirm regulation of MMP3 by L3MBTL4. IL-27 was highly expressed in RA, and the IL-27-induced, MSC-derived exosomes promoted the expression of MMP3 in FLS. The IL-27-induced MSC-derived exosomes significantly upregulated the expression of miR-206-3p, and the miR-206-3p target, miR-206/ lethal(3) malignant brain tumor-like protein 4 (L3MBTL4), regulated the MMP3 transcription. The IL-27-induced, MSC-derived exosomes promoted MMP3 expression in the FLS through the miR-206-3p/L3MBTL4 axis, thereby promoting chondrocyte degradation and aggravating RA. IL-27 can induce the expression of miR-206 in MSCs, and miR-206 can be transported into FLS through MSC-EVs to promote FLS migration and MMP3 expression and aggravate articular cartilage damage. Patients with RA who have a high IL-27 expression may not be suitable to receive treatment with MSCs, and clinicians can use MSCs that knock down or delete IL-27R to treat RA patients who have a high IL-27 expression. Show less

Heterosis, also known as hybrid vigor, is widely used in aquaculture, but the molecular causes for this phenomenon remain obscure. Here, we conducted a transcriptome analysis to unveil the gene expression patterns and molecular bases underlying thermo-resistant heterosis in Crassostrea gigas ♀ × Crassostrea angulata ♂ (GA) and C. angulata ♀ × C. gigas ♂ (AG). About 505 million clean reads were obtained, and 38,210 genes were identified, of which 3779 genes were differentially expressed between the reciprocal hybrids and purebreds. The global gene expression levels were toward the C. gigas genome in the reciprocal hybrids. In GA and AG, 95.69% and 92.00% of the differentially expressed genes (DEGs) exhibited a non-additive expression pattern, respectively. We observed all gene expression modes, including additive, partial dominance, high and low dominance, and under- and over-dominance. Of these, 77.52% and 50.00% of the DEGs exhibited under- or over-dominance in GA and AG, respectively. The over-dominance DEGs common to reciprocal hybrids were significantly enriched in protein folding, protein refolding, and intrinsic apoptotic signaling pathway, while the under-dominance DEGs were significantly enriched in cell cycle. As possible candidate genes for thermo-resistant heterosis, GRP78, major egg antigen, BAG, Hsp70, and Hsp27 were over-dominantly expressed, while MCM6 and ANAPC4 were under-dominantly expressed. This study extends our understanding of the thermo-resistant heterosis in oysters. Show less

Overweight/obesity (OW/OB) is associated with modifications in lipoprotein (Lp)-associated enzymes and proteins, such as cholesteryl ester transfer protein (CETP), Lp-associated phospholipase A To analyze the presence of alterations in Lp-associated enzymes and proteins in children and adolescents with UW and OW/OB and their relation to novel cardiometabolic indexes. Thirty male children and adolescents with UW, 66 with normal weight (NW) and 30 with OW/OB were included. Anthropometric parameters, glucose, Lp profile and the activities of CETP, LpPLA Both UW and OW/OB showed impaired antioxidant PON1 activity. Moreover, TyG, VAI and HLAP were all capable of predicting alterations in crucial modulators of Lp metabolism and vascular inflammation in children and adolescents with varying degrees of alterations in body weight. Show less

MicroRNA-9-5p (miR-9-5p) is highly expressed in the brain and has been implicated in the risk of schizophrenia. We compared the expression levels of miR-9-5p in schizophrenia cases and healthy controls and evaluated whether regulatory targets of miR-9-5p are enriched in schizophrenia genome-wide risk genes. Literature-based analysis was conducted to construct molecular pathways connecting miR-9-5p and schizophrenia. We found that the expression levels of miR-9-5p were down-regulated in the peripheral blood of schizophrenia patients compared with those in healthy controls. miR-9-5p can regulate 24 out of the 1136 genome-wide risk genes of schizophrenia, which was higher than by chance (hypergeometric test P = 4.09E-06). The literature-based analysis showed that quantitative genetic changes driven by miR-9 exert more inhibitory (the IL1B, ABCB1, FGFR1 genes) than promoting (the INS gene) effects on schizophrenia, suggesting that miR-9 may protect against schizophrenia. Our results suggest that miR-9-5p deficiency may contribute to the development of schizophrenia. Show less

The melanocortin-3 receptor (MC3R) is a negative regulator of the central melanocortin circuitry via presynaptic expression on agouti-related protein (AgRP) nerve terminals, from where it regulates GABA release onto secondary MC4R-expressing neurons. However, MC3R knockout (KO) mice also exhibit defective behavioral and neuroendocrine responses to fasting. Here, we demonstrate that MC3R KO mice exhibit defective activation of AgRP neurons in response to fasting, cold exposure, or ghrelin while exhibiting normal inhibition of AgRP neurons by sensory detection of food in the ad libitum-fed state. Using a conditional MC3R KO model, we show that the control of AgRP neuron activation by fasting and ghrelin requires the specific presence of MC3R within AgRP neurons. Thus, MC3R is a crucial player in the responsiveness of the AgRP soma to both hormonal and neuronal signals of energy need. Show less

Despite available targeted treatments for the disease, drug-resistant chronic lymphocytic leukemia (CLL) poses a clinical challenge. The objective of this study is to examine whether the dual-specific phosphatases DUSP1 and DUSP6 are required to negatively regulate mitogen-activated protein kinases (MAPKs) and thus counterbalance excessive MAPK activity. We show that high expression of DUSP6 in CLL correlates with poor clinical prognosis. Importantly, genetic deletion of the inhibitory phosphatase DUSP1 or DUSP6 and blocking DUSP1/6 function using a small-molecule inhibitor reduces CLL cell survival in vitro and in vivo. Using global phospho-proteome approaches, we observe acute activation of MAPK signaling by DUSP1/6 inhibition. This promotes accumulation of mitochondrial reactive oxygen species and, thereby, DNA damage and apoptotic cell death in CLL cells. Finally, we observe that DUSP1/6 inhibition is particularly effective against treatment-resistant CLL and therefore suggest transient DUSP1/6 inhibition as a promising treatment concept to eliminate drug-resistant CLL cells. Show less

Glucose-dependent insulinotropic polypeptide receptor (GIPR) is a potential drug target for metabolic disorders. It works with glucagon-like peptide-1 receptor and glucagon receptor in humans to maintain glucose homeostasis. Unlike the other two receptors, GIPR has at least 13 reported splice variants (SVs), more than half of which have sequence variations at either C or N terminus. To explore their roles in endogenous peptide-mediated GIPR signaling, we determined the cryoelectron microscopy (cryo-EM) structures of the two N terminus-altered SVs (referred as GIPR-202 and GIPR-209 in the Ensembl database, SV1 and SV2 here, respectively) and investigated the outcome of coexpressing each of them in question with GIPR in HEK293T cells with respect to ligand binding, receptor expression, cAMP (adenosine 3,5-cyclic monophosphate) accumulation, β-arrestin recruitment, and cell surface localization. It was found that while both N terminus-altered SVs of GIPR neither bound to the hormone nor elicited signal transduction per se, they suppressed ligand binding and cAMP accumulation of GIPR. Meanwhile, SV1 reduced GIPR-mediated β-arrestin 2 responses. The cryo-EM structures of SV1 and SV2 showed that they reorganized the extracellular halves of transmembrane helices 1, 6, and 7 and extracellular loops 2 and 3 to adopt a ligand-binding pocket-occupied conformation, thereby losing binding ability to the peptide. The results suggest a form of signal bias that is constitutive and ligand-independent, thus expanding our knowledge of biased signaling beyond pharmacological manipulation (i.e., ligand specific) as well as constitutive and ligand-independent (e.g., SV1 of the growth hormone-releasing hormone receptor). Show less

Lymphoplasmacytic lymphoma (LPL) is an incurable low-grade B-cell lymphoma of the bone marrow. Despite a cumulative risk of progression, there is no approved therapy for patients in the asymptomatic phase. We conducted a first-in-human clinical trial of a novel therapeutic DNA idiotype neoantigen vaccine in nine patients with asymptomatic LPL. Treatment was well tolerated with no dose limiting toxicities. One patient achieved a minor response, and all remaining patients experienced stable disease, with median time to disease progression of 61+ months. Direct interrogation of the tumor microenvironment by single-cell transcriptome analysis revealed an unexpected dichotomous antitumor response, with significantly reduced numbers of clonal tumor mature B-cells, tracked by their unique BCR, and downregulation of genes involved in signaling pathways critical for B-cell survival post-vaccine, but no change in clonal plasma cell subpopulations. Downregulation of HLA class II molecule expression suggested intrinsic resistance by tumor plasma cell subpopulations and cell-cell interaction analyses predicted paradoxical upregulation of IGF signaling post vaccine by plasma cell, but not mature B-cell subpopulations, suggesting a potential mechanism of acquired resistance. Vaccine therapy induced dynamic changes in bone marrow T-cells, including upregulation of signaling pathways involved in T-cell activation, expansion of T-cell clonotypes, increased T-cell clonal diversity, and functional tumor antigen-specific cytokine production, with little change in co-inhibitory pathways or Treg. Vaccine therapy also globally altered cell-cell communication networks across various bone marrow cell types and was associated with reduction of protumoral signaling by myeloid cells, principally non-classical monocytes. These results suggest that this prototype neoantigen vaccine favorably perturbed the tumor immune microenvironment, resulting in reduction of clonal tumor mature B-cell, but not plasma cell subpopulations. Future strategies to improve clinical efficacy may require combinations of neoantigen vaccines with agents which specifically target LPL plasma cell subpopulations, or enable blockade of IGF-1 signaling or myeloid cell checkpoints. Show less

Immunophenotyping by flow cytometry (FCM) is a useful diagnostic tool for the evaluation of mature B-cell neoplasms (MBN). Here, CD200 expression may play a significant role and improve the distinction between various MBNs, but any potential as a prognostic marker is yet to be established. The present prospective study was conducted on all the suspected cases of MBNs. Immunophenotyping was done using a BD FACS Canto FCM using a panel of 4 to 6 color combinations of monoclonal antibodies; CD45, CD34, CD5, CD19, CD20, CD22, CD23, CD79b, FMC7, CD10, CD38, ZAP70, CD200, IgG, IgM, CD25, CD103, CD2, CD3, CD11c as well as κ and λ light chains. CD200 expression was compared in different subgroups. Of the total of 130 cases included in the study, CD200 was positive in 118 cases (90%). CD200 was expressed in 100% of the cases of CLL(86 cases), atypical CLL(06 cases), HCL(14 cases), FL(02 cases), SMZL(04 cases), LPL (01 case), and low-grade NHL (05 cases), with the highest intensity of fluorescence in HCL followed by CLL. All the cases of MCL and PLL were exclusively negative for CD200. In conclusion, the results of the present study support inclusion of this marker in the flow cytometric panels for the differential diagnosis of MBNs. Show less

Hypertrophic cardiomyopathy (HCM) is a genetic heart muscle disease that frequently causes sudden cardiac death (SCD) among young adults. Several pathogenic mutations in genes encoding the cardiac sarcomere have been identified as diagnostic factors for HCM and proposed as prognostic markers for SCD. The objective of this review was to determine the scope of available literature on the variants encoding sarcomere proteins associated with SCD reported among Indian patients with HCM. The eligibility criteria for the scoping review included full text articles that reported the results of genetic screening for sarcomeric gene mutations in HCM patients of Indian south Asian ancestry. We systematically reviewed studies from the databases of Medline, Scopus, Web of Science core collection and Google Scholar. The electronic search strategy included a combination of generic terms related to genetics, disease and population. The protocol of the study was registered with Open Science Framework (https://osf.io/53gde/). A total of 19 articles were identified that reported pathogenic or likely pathogenic (P/LP) variants within MYH7, MYBPC3, TNNT2, TNNI3 and TPM1 genes, that included 16 singletons, one de novo and one digenic mutation (MYH7/ TPM1) associated with SCD among Indian patients. Evidence from functional studies and familial segregation implied a plausible mechanistic role of these P/LP variants in HCM pathology. This scoping review has compiled all the P/LP variants reported to-date among Indian patients and summarized their association with SCD. Single homozygous, de novo and digenic mutations were observed to be associated with severe phenotypes compared to single heterozygous mutations. The abstracted genetic information was updated with reference sequence ID (rsIDs) and compiled into freely accessible HCMvar database, available at https://hcmvar.heartfailure.org.in/. This can be used as a population specific genetic database for reference by clinicians and researchers involved in the identification of diagnostic and prognostic markers for HCM. Show less

The activation loop (A-loop) of kinases, a key regulatory region, is recurrently mutated in several kinase proteins in cancer resulting in dysregulated kinase activity and response to kinase inhibitors. FGFR1 receptor tyrosine kinase represents an important oncogene and therapeutic target for solid and hematological tumors. Here we investigate the biochemical and molecular effects of D647N mutation lying in the A-loop of FGFR1. When expressed in normal and tumoral in vitro cell models, FGFR1 Show less

The promotion of intersystem crossing (ISC) is critical for achieving a high-efficiency long-persistent luminescence (LPL) from organic materials. However, the use of a transition-metal complex for LPL materials has not been explored because it can also shorten the emission lifetime by accelerating the phosphorescence decay. Here, we report a new class of LPL materials by doping a monovalent Au-carbene complex into a boron-embedded molecular host. The donor-acceptor systems exhibit photoluminescence with both high efficiencies (>57 %) and long lifetimes (ca. 40 ms) at room temperature. It is revealed that the Au atom promotes the population of low-lying triplet excited states of the host aggregate (T Show less