ABSTRACT
BACKGROUND: Monkeypox is an emerging infectious disease with confirmed cases and deaths in several parts of the world. In light of this crisis, this study aims to analyze the global knowledge pattern of monkeypox-related patents and explore current trends and future technical directions in the medical development of monkeypox to inform research and policy. METHODS: A comprehensive study of 1,791 monkeypox-related patents worldwide was conducted using the Derwent patent database by descriptive statistics, social network method and linear regression analysis. RESULTS: Since the 21st century, the number of monkeypox-related patents has increased rapidly, accompanied by increases in collaboration between commercial and academic patentees. Enterprises contributed the most in patent quantity, whereas the initial milestone patent was filed by academia. The core developments of technology related to the monkeypox include biological and chemical medicine. The innovations of vaccines and virus testing lack sufficient patent support in portfolios. CONCLUSIONS: Monkeypox-related therapeutic innovation is geographically limited with strong international intellectual property right barriers though it has increased rapidly in recent years. The transparent licensing of patent knowledge is driven by the merger and acquisition model, and the venture capital, intellectual property and contract research organization model. Currently, the patent thicket phenomenon in the monkeypox field may slow the progress of efforts to combat monkeypox. Enterprises should pay more attention to the sharing of technical knowledge, make full use of drug repurposing strategies, and promote innovation of monkeypox-related technology in hotspots of antivirals (such as tecovirimat, cidofovir, brincidofovir), vaccines (JYNNEOS, ACAM2000), herbal medicine and gene therapy.
Subject(s)
Communicable Diseases, Emerging , Mpox (monkeypox) , Vaccines , Humans , Communicable Diseases, Emerging/drug therapy , Communicable Diseases, Emerging/epidemiology , Mpox (monkeypox)/drug therapy , Mpox (monkeypox)/epidemiology , TechnologyABSTRACT
Up to date, the reported fucosidases generally show poor activities toward the IgG core-fucose, which limits the efficiency of ENGase-catalyzed glycoengineering process. However, EndoS or EndoS2 owns excellent activity and great selectivity towards the N-glycosylation of IgGs, and their non-catalytic domains are deduced to have specific interactions to IgG Fc domain that result in the great activity and selectivity. Herein, we constructed a series fusion protein of AlfC (an α-l-fucosidase from Lactobacillus casei BL23) with EndoS/S2 non-catalytic domain by replacing the catalytic GH (glycan hydrolase) domain of EndoS/S2 with the AlfC. We found that all these fused AlfCs showed significantly enhanced defucosylation activity toward the deglycosylated IgGs (Fucα1,6GlcNAc-IgG). We also performed the kinetic study of these fusion enzymes, and our results tend to tell that the EndoS-based fusion proteins have higher kcat values while the EndoS2-based ones possess lower Km values other than higher kcat. Conclusively, our research provides an effective approach to improve the activity of AlfC and remarkably shortened the defucosylation process within several minutes, which will significantly promote the development of glycoengineered antibodies in the future.
Subject(s)
Polysaccharides , alpha-L-Fucosidase , alpha-L-Fucosidase/genetics , alpha-L-Fucosidase/metabolism , Polysaccharides/metabolism , Antibodies, Monoclonal , Immunoglobulin G/metabolismABSTRACT
PURPOSE OF REVIEW: Eosinophilic gastritis/gastroenteritis (EG/EGE) are rare eosinophilic infiltrative disorders in children and adults that fall under the umbrella term eosinophilic gastrointestinal disorders (EGIDs). EGIDs also include eosinophilic esophagitis (EoE) and eosinophilic colitis. In this article, we present the current literature regarding the clinical presentation, diagnostic criteria, and management of EG/EGE. RECENT FINDINGS: The underlying complex pathophysiology remains unknown, yet hypersensitivity response is a central component. Unlike EoE, standardized diagnostic criteria are lacking but, promising research employing tissue-based and blood-based methods of diagnosis have been reported. Non-EoE EGIDs are more challenging to treat than EoE. More than a third of patients may achieve spontaneous remission. Still, most will require dietary elimination and/or pharmaceutical interventions, mainly corticosteroids, but also biologics (monoclonal antibodies against IL-4, IL-5, TNFα, integrin α4ß7, and IgE), mast-cell stabilizers, leukotriene (LT)-receptor antagonists, and antihistamines. Promising research suggests the role of AK002, an anti-siglec antibody, in clinical and histological improvement. Given the rarity and underdiagnosis of EG/EGE, different natural progression compared to EoE, heterogeneous clinical manifestations, and probable normal endoscopic appearance, it is vital to maintain a high suspicion index in atopic patients, obtain at least 5-6 random biopsies from each site for gastro/duodenal eosinophilic infiltrate with the subsequent exclusion of inflammatory, allergic and infectious differential diagnoses to increase the yield of an accurate diagnosis. Corticosteroids remain the mainstay of treatment, often requiring long-term use. Steroid-sparing agents remain experimental. Goals of therapy move beyond clinical remission but lack evidence to support histological remission.
Subject(s)
Enteritis , Eosinophilic Esophagitis , Gastroenteritis , Antibodies, Monoclonal, Humanized , Enteritis/diagnosis , Enteritis/drug therapy , Eosinophilia , Eosinophilic Esophagitis/diagnosis , Eosinophilic Esophagitis/drug therapy , Gastritis , HumansABSTRACT
Chromogranins are pro-hormone secretory proteins released from neuroendocrine cells, with effects on control of blood pressure. We conducted a genome-wide association study for plasma catestatin, the catecholamine release inhibitory peptide derived from chromogranin A (CHGA), and other CHGA- or chromogranin B (CHGB)-related peptides, in 545 US and 1252 Australian subjects. This identified loci on chromosomes 4q35 and 5q34 affecting catestatin concentration (P = 3.40 × 10-30 for rs4253311 and 1.85 × 10-19 for rs2731672, respectively). Genes in these regions include the proteolytic enzymes kallikrein (KLKB1) and Factor XII (F12). In chromaffin cells, CHGA and KLKB1 proteins co-localized in catecholamine storage granules. In vitro, kallikrein cleaved recombinant human CHGA to catestatin, verified by mass spectrometry. The peptide identified from this digestion (CHGA360-373) selectively inhibited nicotinic cholinergic stimulated catecholamine release from chromaffin cells. A proteolytic cascade involving kallikrein and Factor XII cleaves chromogranins to active compounds both in vivo and in vitro.
Subject(s)
Biomarkers/metabolism , Catecholamines/metabolism , Chromaffin Cells/metabolism , Chromogranin A/blood , Genetic Loci/genetics , Hypertension/genetics , Peptide Fragments/blood , Adolescent , Adrenal Glands/metabolism , Adult , Aged , Animals , Australia , Biomarkers/analysis , Cells, Cultured , Factor XII/genetics , Factor XII/metabolism , Female , Genome-Wide Association Study , Humans , Hypertension/blood , Kallikreins/genetics , Kallikreins/metabolism , Male , Mice , Middle Aged , Rats , United States , Young AdultABSTRACT
Goblet cell carcinoid (GCC) or goblet cell carcinoma is a unique mixed endocrine-exocrine neoplasm that is almost exclusively seen in the appendix. The hallmark of GCC is the concentric infiltration of the appendiceal wall by small tight clusters, nests or cords of tumor cells that exhibit a goblet cell morphology with a small compressed nucleus and conspicuous intracytoplasmic mucin. The coexistence of high-grade adenocarcinoma with GCC has been increasingly recognized as a common finding, which has been called adenocarcinoma ex GCC or mixed GCC-adenocarcinoma. A number of studies have shown that it is the high-grade adenocarcinomatous component that dictates the prognosis. Several histologic classification/grading systems have been proposed, which correlate with overall patient survival. Treatment options are primarily based on tumor stage and the presence or absence of a high-grade adenocarcinomatous component.
Subject(s)
Adenocarcinoma/pathology , Appendiceal Neoplasms/pathology , Carcinoid Tumor/pathology , Goblet Cells/pathology , Neoplasms, Complex and Mixed/pathology , Adenocarcinoma/chemistry , Adenocarcinoma/mortality , Adenocarcinoma/therapy , Appendiceal Neoplasms/chemistry , Appendiceal Neoplasms/mortality , Appendiceal Neoplasms/therapy , Biomarkers, Tumor/analysis , Biomarkers, Tumor/genetics , Biopsy , Carcinoid Tumor/chemistry , Carcinoid Tumor/mortality , Carcinoid Tumor/therapy , Goblet Cells/chemistry , Humans , Immunohistochemistry , Molecular Diagnostic Techniques , Neoplasm Grading , Neoplasm Staging , Neoplasms, Complex and Mixed/chemistry , Neoplasms, Complex and Mixed/mortality , Neoplasms, Complex and Mixed/therapy , Treatment OutcomeABSTRACT
Acute hepatitis and acute liver failure are severe medical conditions that require early clinical intervention. Histopathologic findings on a liver biopsy or a liver explant may help identify the underlying etiology or provide an important direction for further clinical, laboratory and radiographical investigation. This review is divided into two main portions. The first portion concentrates on various etiologies and discusses unique histologic features that can be associated with specific etiologies. The second portion describes the general morphologic features based on which the diagnosis of acute hepatitis and acute liver failure are made. Histopathologic distinction between collapse and cirrhosis and limitations of histopathologic assessment for underlying etiologies are addressed in this portion. Another focus of this review is non-necrotic acute liver failure, which typically features diffuse microvesicular steatosis secondary to various etiologies causing mitochondrial dysfunction. Molecular testing serves an increasingly important role in the diagnosis and management of this group of disorders.
Subject(s)
Hepatitis/pathology , Liver Failure, Acute/pathology , Mitochondrial Diseases/pathology , Acute Disease , Biopsy , HumansABSTRACT
BACKGROUND: Plasma coagulation Factor XIIa (Hageman factor; encoded by F12) and kallikrein (KAL or Fletcher factor; encoded by KLKB1) are proteases of the kallikerin-kinin system involved in converting the inactive circulating prorenin to renin. Renin is a key enzyme in the formation of angiotensin II, which regulates blood pressure, fluid and electrolyte balance and is a biomarker for cardiovascular, metabolic and renal function. The renin-angiotensin system is implicated in extinction learning in posttraumatic stress disorder. METHODS & RESULTS: Active plasma renin was measured from two independent cohorts- civilian twins and siblings, as well as U.S. Marines, for a total of 1,180 subjects. Genotyping these subjects revealed that the carriers of the minor alleles at the two loci- F12 and KLKB1 had a significant association with reduced levels of active plasma renin. Meta-analyses confirmed the association across cohorts. In vitro studies verified digestion of human recombinant pro-renin by kallikrein (KAL) to generate active renin. Subsequently, the active renin was able to digest the synthetic substrate angiotensinogen to angiotensin-I. Examination of mouse juxtaglomerular cell line and mouse kidney sections showed co-localization of KAL with renin. Expression of either REN or KLKB1 was regulated in cell line and rodent models of hypertension in response to oxidative stress, interleukin or arterial blood pressure changes. CONCLUSIONS: The functional variants of KLKB1 (rs3733402) and F12 (rs1801020) disrupted the cascade of enzymatic events, resulting in diminished formation of active renin. Using genetic, cellular and molecular approaches we found that conversion of zymogen prorenin to renin was influenced by these polymorphisms. The study suggests that the variant version of protease factor XIIa due to the amino acid substitution had reduced ability to activate prekallikrein to KAL. As a result KAL has reduced efficacy in converting prorenin to renin and this step of the pathway leading to activation of renin affords a potential therapeutic target.
Subject(s)
Factor XIIa/genetics , Kallikreins/genetics , Polymorphism, Single Nucleotide , Renin-Angiotensin System/genetics , Renin/blood , Adolescent , Adult , Aged , Alleles , Angiotensin I/blood , Angiotensinogen/blood , Animals , Blood Pressure , Cell Cycle Proteins , Cell Line , Gene Expression Regulation , Genetic Loci , Genome-Wide Association Study , Genotyping Techniques , Humans , Hypertension/genetics , Juxtaglomerular Apparatus/cytology , Kallikreins/blood , Male , Mice , Middle Aged , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Prekallikrein/metabolism , Renin/genetics , Serine Endopeptidases/metabolism , Transferases , Young AdultABSTRACT
Chromogranin A (CHGA) is coreleased with catecholamines from secretory vesicles in adrenal medulla and sympathetic axons. Genetic variation in the CHGA 3'-region has been associated with autonomic control of circulation, hypertension, and hypertensive nephropathy, and the CHGA 3'-untranslated region (3'-UTR) variant C+87T (rs7610) displayed peak associations with these traits in humans. Here, we explored the molecular mechanisms underlying these associations. C+87T occurred in a microRNA-107 (miR-107) motif (match: T>C), and CHGA mRNA expression varied inversely with miR-107 abundance. In cells transfected with chimeric luciferase/CHGA 3'-UTR reporters encoding either the T allele or the C allele, changes in miR-107 expression levels had much greater effects on expression of the T allele. Cotransfection experiments with hsa-miR-107 oligonucleotides and eukaryotic CHGA plasmids produced similar results. Notably, an in vitro CHGA transcription/translation experiment revealed that changes in hsa-miR-107 expression altered expression of the T allele variant only. Mice with targeted ablation of Chga exhibited greater eGFR. Using BAC transgenesis, we created a mouse model with a humanized CHGA locus (T/T genotype at C+87T), in which treatment with a hsa-miR-107 inhibitor yielded prolonged falls in SBP/DBP compared with wild-type mice. We conclude that the CHGA 3'-UTR C+87T disrupts an miR-107 motif, with differential effects on CHGA expression, and that a cis:trans (mRNA:miR) interaction regulates the association of CHGA with BP and hypertensive nephropathy. These results indicate new strategies for probing autonomic circulatory control and ultimately, susceptibility to hypertensive renal sequelae.
Subject(s)
Chromogranin A/genetics , Hypertension, Renal/genetics , MicroRNAs/genetics , 3' Untranslated Regions , Alleles , Animals , Blood Pressure , Chromogranin A/metabolism , Glomerular Filtration Rate , HEK293 Cells , Humans , Hypertension, Renal/metabolism , Luciferases , Male , Mice , Mice, Transgenic , PC12 Cells , Polymorphism, Genetic , RatsABSTRACT
Hypertension is a common hereditary syndrome with unclear pathogenesis. Chromogranin A (Chga), which catalyzes formation and cargo storage of regulated secretory granules in neuroendocrine cells, contributes to blood pressure homeostasis centrally and peripherally. Elevated Chga occurs in spontaneously hypertensive rat (SHR) adrenal glands and plasma, but central expression is unexplored. In this report, we measured SHR and Wistar-Kyoto rat (control) Chga expression in central and peripheral nervous systems, and found Chga protein to be decreased in the SHR brainstem, yet increased in the adrenal and the plasma. By re-sequencing, we systematically identified five promoter, two coding and one 3'-untranslated region (3'-UTR) polymorphism at the SHR (versus WKY or BN) Chga locus. Using HXB/BXH recombinant inbred (RI) strain linkage and correlations, we demonstrated genetic determination of Chga expression in SHR, including a cis-quantitative trait loci (QTLs) (i.e. at the Chga locus), and such expression influenced biochemical determinants of blood pressure, including a cascade of catecholamine biosynthetic enzymes, catecholamines themselves and steroids. Luciferase reporter assays demonstrated that the 3'-UTR polymorphism (which disrupts a microRNA miR-22 motif) and promoter polymorphisms altered gene expression consistent with the decline in SHR central Chga expression. Coding region polymorphisms did not account for changes in Chga expression or function. Thus, we hypothesized that the 3'-UTR and promoter mutations lead to dysregulation (diminution) of Chga in brainstem cardiovascular control nuclei, ultimately contributing to the pathogenesis of hypertension in SHR. Accordingly, we demonstrated that in vivo administration of miR-22 antagomir to SHR causes substantial (â¼18 mmHg) reductions in blood pressure, opening a novel therapeutic avenue for hypertension.
Subject(s)
Chromogranin A/genetics , Chromogranin A/metabolism , Hypertension/genetics , MicroRNAs/genetics , Promoter Regions, Genetic , 3' Untranslated Regions , Adrenal Glands/metabolism , Animals , Blood Pressure/genetics , Brain Stem/metabolism , Cell Line, Tumor , Chromogranin A/blood , Chromogranin A/chemistry , DNA-Binding Proteins/genetics , Gene Expression Regulation , Genetic Linkage , Humans , Hypertension/drug therapy , Hypertension/metabolism , Hypertension/physiopathology , Male , MicroRNAs/metabolism , PC12 Cells , Polymorphism, Genetic , Protein Structure, Secondary , Quantitative Trait Loci , Rats , Rats, Inbred SHR , Rats, Inbred WKY , Sequence Alignment , Transcription, GeneticABSTRACT
Chromogranin B (CHGB) is the major matrix protein in human catecholamine storage vesicles. CHGB genetic variation alters catecholamine secretion and blood pressure. Here, effective Chgb protein under-expression was achieved by siRNA in PC12 cells, resulting in ~ 48% fewer secretory granules on electron microscopy, diminished capacity for catecholamine uptake (by ~ 79%), and a ~ 73% decline in stores available for nicotinic cholinergic-stimulated secretion. In vivo, loss of Chgb in knockout mice resulted in a ~ 35% decline in chromaffin granule abundance and ~ 44% decline in granule diameter, accompanied by unregulated catecholamine release into plasma. Over-expression of CHGB was achieved by transduction of a CHGB-expressing lentivirus, resulting in ~ 127% elevation in CHGB protein, with ~ 122% greater abundance of secretory granules, but only ~ 14% increased uptake of catecholamines, and no effect on nicotinic-triggered secretion. Human CHGB protein and its proteolytic fragments inhibited nicotinic-stimulated catecholamine release by ~ 72%. One conserved-region CHGB peptide inhibited nicotinic-triggered secretion by up to ~ 41%, with partial blockade of cationic signal transduction. We conclude that bi-directional quantitative derangements in CHGB abundance result in profound changes in vesicular storage and release of catecholamines. When processed and released extra-cellularly, CHGB proteolytic fragments exert a feedback effect to inhibit catecholamine secretion, especially during nicotinic cholinergic stimulation.
Subject(s)
Catecholamines/metabolism , Chromaffin Granules/metabolism , Chromogranin B/physiology , Extracellular Fluid/physiology , Intracellular Fluid/physiology , Amino Acid Sequence , Animals , Catecholamines/genetics , Chromaffin Granules/genetics , Humans , Mice , Mice, Knockout , Molecular Sequence Data , RatsABSTRACT
The Syrian Cardiomyopathic Hamster (BIO-14.6/53.58 strains) model of cardiac failure, resulting from naturally occurring deletion at the SGCD (delta-sarcoglycan) locus, displays widespread disturbances in catecholamine metabolism. Rare Mendelian myopathy disorders of human SGCD occur, although common naturally occurring SGCD genetic variation has not been evaluated for effects on human norepinephrine (NE) secretion. This study investigated the effect of SGCD genetic variation on control of NE secretion in healthy twin pairs. Genetic associations profiled SNPs across the SGCD locus. Trait heritability (h(2)) and genetic covariance (pleiotropy; shared h(2)) were evaluated. Sympathochromaffin exocytosis in vivo was probed in plasma by both catecholamines and Chromogranin B (CHGB). Plasma NE is substantially heritable (p = 3.19E-16, at 65.2 ± 5.0% of trait variance), sharing significant (p < 0.05) genetic determination with circulating and urinary catecholamines, CHGB, eGFR, and several cardio-metabolic traits. Participants with higher pNE showed significant (p < 0.05) differences in several traits, including increased BP and hypertension risk factors. Peak SGCD variant rs1835919 predicted elevated systemic vascular compliance, without changes in specifically myocardial traits. We used a chimeric-regulated secretory pathway photoprotein (CHGA-EAP) to evaluate the effect of SGCD on the exocytotic pathway in transfected PC12 cells; in transfected cells, expression of SGCD augmented CHGA trafficking into the exocytotic regulated secretory pathway. Thus, our investigation determined human NE secretion to be a highly heritable trait, influenced by common genetic variation within the SGCD locus. Circulating NE aggregates with BP and hypertension risk factors. In addition, coordinate NE and CHGB elevation by rs1835919 implicates exocytosis as the mechanism of release.
Subject(s)
Genetic Loci , Inheritance Patterns , Polymorphism, Single Nucleotide , Sarcoglycans/genetics , Sympathetic Nervous System/physiology , Adolescent , Adult , Aged , Animals , Chromogranin A/metabolism , Exocytosis , Genetic Pleiotropy , Humans , Middle Aged , Norepinephrine/blood , Norepinephrine/metabolism , PC12 Cells , Protein Transport , Quantitative Trait Loci , Quantitative Trait, Heritable , Rats , Sarcoglycans/metabolism , Young AdultABSTRACT
Automatic segmentation of tumor-infiltrating lymphocytes (TILs) from pathological images is essential for the prognosis and treatment of cancer. Deep learning technology has achieved great success in the segmentation task. It is still a challenge to realize accurate segmentation of TILs due to the phenomenon of blurred edges and adhesion of cells. To alleviate these problems, a squeeze-and-attention and multi-scale feature fusion network (SAMS-Net) based on codec structure, namely SAMS-Net, is proposed for the segmentation of TILs. Specifically, SAMS-Net utilizes the squeeze-and-attention module with the residual structure to fuse local and global context features and boost the spatial relevance of TILs images. Besides, a multi-scale feature fusion module is designed to capture TILs with large size differences by combining context information. The residual structure module integrates feature maps from different resolutions to strengthen the spatial resolution and offset the loss of spatial details. SAMS-Net is evaluated on the public TILs dataset and achieved dice similarity coefficient (DSC) of 87.2% and Intersection of Union (IoU) of 77.5%, which improved by 2.5% and 3.8% compared with UNet. These results demonstrate the great potential of SAMS-Net in TILs analysis and can further provide important evidence for the prognosis and treatment of cancer.
Subject(s)
Lymphocytes, Tumor-Infiltrating , Humans , Computational BiologyABSTRACT
Composite lymphoma implies the presence of two or more morphological and immunophenotypical subtypes of lymphoma in a single tissue or organ. Composite lymphoma with concurrent mantle cell lymphoma (MCL) and classical Hodgkin lymphoma is extremely rare. In this case report, we present the case of a 70-year-old male who was diagnosed with a composite of MCL and classical Hodgkin lymphoma (cHL) and achieved near-complete resolution with chemoimmunotherapy. To the best of our knowledge, this is the first case of this kind demonstrating the effectiveness of a combination chemoimmunotherapy regimen leading to complete remission in composite lymphoma involving MCL and cHL. We report the history, imaging findings, and pathology and illustrate the challenges in therapeutic decision-making in managing composite lymphoma patients involving MCL and cHL. We also review the literature on this rare entity and discuss its clinical implications.
ABSTRACT
Hypertensive disorder in pregnancy (HDP) remains a major health burden, and it is associated with systemic cardiovascular adaptation. The pulse wave is an important basis for evaluating the status of the human cardiovascular system. This research aims to evaluate the application value of pulse waves in the diagnosis of hypertensive disorder in pregnancy.This research a retrospective study of pregnant women who attended prenatal care and labored at Beijing Haidian District Maternal and Child Health Hospital. We extracted maternal hemodynamic factors and measured the pulse wave of the pregnant women. We developed an HDP predictive model by using support vector machine algorithms at five-gestational-week stages.At five-gestational-week stages, the area under the receiver operating characteristic curve (AUC) of the predictive model with pulse wave parameters was higher than that of the predictive model with hemodynamic factors. The AUC values of the predictive model with pulse wave parameters were 0.77 (95% CI 0.64 to 0.9), 0.83 (95% CI 0.77 to 0.9), 0.85 (95% CI 0.81 to 0.9), 0.93 (95% CI 0.9 to 0.96) and 0.88 (95% CI 0.8 to 0.95) at five-gestational-week stages, respectively. Compared to the predictive models with hemodynamic factors, the predictive model with pulse wave parameters had better prediction effects on HDP.Pulse waves had good predictive effects for HDP and provided appropriate guidance and a basis for non-invasive detection of HDP.
Subject(s)
Algorithms , Machine Learning , Pregnancy , Child , Humans , Female , Retrospective Studies , Heart Rate , BeijingABSTRACT
PURPOSE OF REVIEW: Essential hypertension has long been considered to be primarily 'genetic,' though recent studies have only revealed minor contributions to blood pressure. Technology has advanced tremendously in the recent years, with much focus on DNA studies utilizing both candidate gene and genome-wide association studies. However, many new areas that need continued investigation have arisen. RECENT FINDINGS: In addition to DNA studies, genetic studies are actively pursuing previously unexplored areas of potential variation, such as that which occurs posttranscriptionally in RNA and posttranslationally in protein structure. Advances have also been made in animal models and systems biology for large-scale integrative approaches. However, many other areas need continued investigation in the genetics of hypertension, including improved phenotyping and trait definition, gene-by-gene interactions (epistasis), and gene-by-environment interactions. 'Next generation' sequencing will assist researchers in performing more extensive genetic studies even more quickly, especially on unusual (rare) genetic variants. SUMMARY: Hypertension appears to have many genetic contributions from each regulatory area ranging from DNA to RNA to protein to postprotein to interactive influences of the environment on genes. New technologies have enabled such research to advance in the recent years. However, for this complex trait of hypertension, continued efforts must progress in all of these areas as well as in increased modeling and sequencing, so that the knowledge may be united for a comprehensive understanding of this common disease, such that diagnosis and treatment options in hypertensive patients and those at risk are facilitated.
Subject(s)
Hypertension/genetics , Animals , Disease Models, Animal , Epigenesis, Genetic , Epistasis, Genetic , Gene Dosage , Genetic Linkage , Genome-Wide Association Study , Humans , MicroRNAs/physiology , Phenotype , Proteomics , Sequence Analysis, DNA , Systems BiologyABSTRACT
Hypertension is a complex trait with deranged autonomic control of the circulation. The sympathoadrenal system exerts minute-to-minute control over cardiac output and vascular tone. Catecholamine storage vesicles (or chromaffin granules) of the adrenal medulla contain remarkably high concentrations of chromogranins/secretogranins (or "granins"), catecholamines, neuropeptide Y, adenosine triphosphate (ATP), and Ca(2+). Within secretory granules, granins are co-stored with catecholamine neurotransmitters and co-released upon stimulation of the regulated secretory pathway. The principal granin family members, chromogranin A (CHGA), chromogranin B (CHGB), and secretogranin II (SCG2), may have evolved from shared ancestral exons by gene duplication. This article reviews human genetic variation at loci encoding the major granins and probes the effects of such polymorphisms on blood pressure, using twin pairs to probe heritability and individuals with the most extreme blood pressure values in the population to study hypertension.
Subject(s)
Catecholamines/metabolism , Chromogranin A/genetics , Chromogranin B/genetics , Hypertension/genetics , Polymorphism, Genetic/genetics , Secretogranin II/genetics , Analysis of Variance , Catecholamines/genetics , Chi-Square Distribution , Chromogranins/genetics , Chromogranins/metabolism , Confidence Intervals , Disease Progression , Female , Genetic Variation , Genotype , Humans , Hypertension/metabolism , Hypertension/pathology , Male , Odds Ratio , Risk FactorsABSTRACT
BACKGROUND: Malignant lymphoma is a type of tumor that originated from the lymphohematopoietic system, with complex etiology, diverse pathological morphology, and classification. It takes a lot of time and energy for doctors to accurately determine the type of lymphoma by observing pathological images. OBJECTIVE: At present, an automatic classification technology is urgently needed to assist doctors in analyzing the type of lymphoma. METHODS: In this paper, by comparing the training results of the BP neural network and BP neural network optimized by genetic algorithm (GA-BP), adopts a deep residual neural network model (ResNet-50), with 374 lymphoma pathology images as the experimental data set. After preprocessing the dataset by image flipping, color transformation, and other data enhancement methods, the data set is input into the ResNet-50 network model, and finally classified by the softmax layer. RESULTS: The training results showed that the classification accuracy was 98.63%. By comparing the classification effect of GA-BP and BP neural network, the accuracy of the network model proposed in this paper is improved. CONCLUSIONS: The network model can provide an objective basis for doctors to diagnose lymphoma types.
Subject(s)
Lymphoma , Physicians , Disease Progression , Humans , Lymphoma/diagnosis , Neural Networks, ComputerABSTRACT
Purpose The automatic analysis of ultrasound images facilitates the diagnosis of breast cancer effectively and objectively. However, due to the characteristics of ultrasound images, it is still a challenging task to achieve analyzation automatically. We suppose that the algorithm will extract lesion regions and distinguish categories easily if it is guided to focus on the lesion regions.Method We propose a multi-task learning (SHA-MTL) model based on soft and hard attention mechanisms for breast ultrasound (BUS) image simultaneous segmentation and binary classification. The SHA-MTL model consists of a dense CNN encoder and an upsampling decoder, which are connected by attention-gated (AG) units with soft attention mechanism. Cross-validation experiments are performed on BUS datasets with category and mask labels, and multiple comprehensive analyses are performed on the two tasks.Results We assess the SHA-MTL model on a public BUS image dataset. For the segmentation task, the sensitivity and DICE of the SHA-MTL model to the lesion regions increased by 2.27% and 1.19% compared with the single task model, respectively. The classification accuracy and F1 score increased by 2.45% and 3.82%, respectively.Conclusion The results validate the effectiveness of our model and indicate that the SHA-MTL model requires less a priori knowledge to achieve better results by comparing with other recent models. Therefore, we can draw the conclusion that paying more attention to the lesion region of BUS is conducive to the discrimination of lesion types.
Subject(s)
Breast Neoplasms , Algorithms , Breast Neoplasms/diagnostic imaging , Female , Humans , Image Processing, Computer-Assisted , Ultrasonography , Ultrasonography, MammaryABSTRACT
GTP cyclohydrolase 1 (GCH1) is rate limiting in the provision of the cofactor tetrahydrobiopterin for biosynthesis of catecholamines and NO. We asked whether common genetic variation at GCH1 alters transmitter synthesis and predisposes to disease. Here we undertook a systematic search for polymorphisms in GCH1, then tested variants' contributions to NO and catecholamine release as well as autonomic function in twin pairs. Renal NO and neopterin excretions were significantly heritable, as were baroreceptor coupling (heart rate response to BP fluctuation) and pulse interval (1/heart rate). Common GCH1 variant C+243T in the 3'-untranslated region (3'-UTRs) predicted NO excretion, as well as autonomic traits: baroreceptor coupling, maximum pulse interval, and pulse interval variability, though not catecholamine secretion. In individuals with the most extreme BP values in the population, C+243T affected both diastolic and systolic BP, principally in females. In functional studies, C+243T decreased reporter expression in transfected 3'-UTRs plasmids. We conclude that human NO secretion traits are heritable, displaying joint genetic determination with autonomic activity by functional polymorphism at GCH1. Our results document novel pathophysiological links between a key biosynthetic locus and NO metabolism and suggest new strategies for approaching the mechanism, diagnosis, and treatment of risk predictors for cardiovascular diseases such as hypertension.
Subject(s)
Cardiovascular Diseases/metabolism , Cardiovascular Diseases/pathology , GTP Cyclohydrolase/genetics , GTP Cyclohydrolase/metabolism , Genetic Predisposition to Disease , Nitric Oxide/metabolism , Polymorphism, Genetic/genetics , Adult , Animals , Cardiovascular Diseases/epidemiology , Cardiovascular Diseases/genetics , Female , Genome, Human/genetics , Genotype , Haplotypes , Humans , Hypertension/enzymology , Hypertension/genetics , Male , Middle Aged , Phenotype , Phylogeny , RNA/genetics , Twins/geneticsABSTRACT
BACKGROUND: Approximately 90% of persons with amyotrophic lateral sclerosis (ALS) have the sporadic form, which may be caused by the interaction of multiple environmental factors and previously unknown genes. METHODS: We performed a genomewide association analysis using 766,955 single-nucleotide polymorphisms (SNPs) found in 386 white patients with sporadic ALS and 542 neurologically normal white controls (the discovery series). Associations of SNPs with sporadic ALS were confirmed in two independent replication populations: replication series 1, with 766 case patients with the disease and 750 neurologically normal controls, and replication series 2, with 135 case patients and 275 controls. RESULTS: We identified 10 genetic loci that are significantly associated (P<0.05) with sporadic ALS in three independent series of case patients and controls and an additional 41 loci that had significant associations in two of the three series. The most significant association with disease in white case patients as compared with controls was found for a SNP near an uncharacterized gene known as FLJ10986 (P=3.0x10(-4); odds ratio for having the genotype in patients vs. controls, 1.35; 95% confidence interval, 1.13 to 1.62). The FLJ10986 protein was found to be expressed in the spinal cord and cerebrospinal fluid of patients and of controls. Specific SNPs seem to be associated with sex, age at onset, and site of onset of sporadic ALS. CONCLUSIONS: Variants of FLJ10986 may confer susceptibility to sporadic ALS. FLJ10986 and 50 other candidate loci warrant further investigation for their potential role in conferring susceptibility to the disease.