ABSTRACT
Human genetic variation associates with the composition of the gut microbiome, yet its influence on clinical traits remains largely unknown. We analyzed the consequences of nearly a thousand gut microbiome-associated variants (MAVs) on phenotypes reported in electronic health records from tens of thousands of individuals. We discovered and replicated associations of MAVs with neurological, metabolic, digestive, and circulatory diseases. Five significant MAVs in these categories correlate with the relative abundance of microbes down to the strain level. We also demonstrate that these relationships are independently observed and concordant with microbe by disease associations reported in case-control studies. Moreover, a selective sweep and population differentiation impacted some disease-linked MAVs. Combined, these findings establish triad relationships among the human genome, microbiome, and disease. Consequently, human genetic influences may offer opportunities for precision diagnostics of microbiome-associated diseases but also highlight the relevance of genetic background for microbiome modulation and therapeutics.
Subject(s)
Disease , Gastrointestinal Microbiome , Genetic Variation , Disease/genetics , Genome, Human , Humans , Phenomics , PhenotypeABSTRACT
Heparin-induced thrombocytopenia (HIT) is an unpredictable, potentially catastrophic adverse effect resulting from an immune response to platelet factor 4 (PF4)/heparin complexes. We performed a genome-wide association study (GWAS) with positive functional assay as the outcome in a large discovery cohort of patients divided into 3 groups: (1) functional assay-positive cases (n = 1269), (2) antibody-positive (functional assay-negative) controls (n = 1131), and (3) antibody-negative controls (n = 1766). Significant associations (α = 5 × 10-8) were investigated in a replication cohort (α = 0.05) of functional assay-confirmed HIT cases (n = 177), antibody-positive (function assay-negative) controls (n = 258), and antibody-negative controls (n = 351). We observed a strong association for positive functional assay with increasing PF4/heparin immunoglobulin-G (IgG) level (odds ratio [OR], 16.53; 95% confidence interval [CI], 13.83-19.74; P = 1.51 × 10-209) and female sex (OR, 1.15; 95% CI, 1.01-1.32; P = .034). The rs8176719 C insertion variant in ABO was significantly associated with positive functional assay status in the discovery cohort (frequency = 0.41; OR, 0.751; 95% CI, 0.682-0.828; P = 7.80 × 10-9) and in the replication cohort (OR, 0.467; 95% CI, 0.228-0.954; P = .0367). The rs8176719 C insertion, which encodes all non-O blood group alleles, had a protective effect, indicating that the rs8176719 C deletion and the O blood group were risk factors for HIT (O blood group OR, 1.42; 95% CI, 1.26-1.61; P = 3.09 × 10-8). Meta-analyses indicated that the ABO association was independent of PF4/heparin IgG levels and was stronger when functional assay-positive cases were compared with antibody-positive (functional assay-negative) controls than with antibody-negative controls. Sequencing and fine-mapping of ABO demonstrated that rs8176719 was the causal single nucleotide polymorphism (SNP). Our results clarify the biology underlying HIT pathogenesis with ramifications for prediction and may have important implications for related conditions, such as vaccine-induced thrombotic thrombocytopenia.
Subject(s)
Genome-Wide Association Study , Thrombocytopenia , ABO Blood-Group System/genetics , Anticoagulants/adverse effects , Female , Heparin/adverse effects , Humans , Immunoglobulin G , Male , Platelet Factor 4/genetics , Risk Factors , Thrombocytopenia/chemically induced , Thrombocytopenia/geneticsABSTRACT
OBJECTIVES: To test the hypothesis that genetic predisposition to systemic lupus erythematosus (SLE) increases the risk of cardiometabolic disorders. METHODS: Using 41 single nucleotide polymorphisms (SNPs) associated with SLE, we calculated a weighted genetic risk score (wGRS) for SLE. In a large biobank we tested the association between this wGRS and 9 cardiometabolic phenotypes previously associated with SLE: atrial fibrillation, ischemic stroke, coronary artery disease, type 1 and type 2 diabetes, obesity, chronic kidney disease, hypertension, and hypercholesterolemia. Additionally, we performed a phenome-wide association analysis (pheWAS) to discover novel clinical associations with a genetic predisposition to SLE. Findings were replicated in the Electronic Medical Records and Genomics (eMERGE) Network. To further define the association between SLE-related risk alleles and the selected cardiometabolic phenotypes, we performed an inverse variance weighted regression (IVWR) meta-analysis. RESULTS: The wGRS for SLE was calculated in 74,759 individuals of European ancestry. Among the pre-selected phenotypes, the wGRS was significantly associated with type 1 diabetes (OR [95%CI] =1.11 [1.06, 1.17], P-value = 1.05x10-5). In the PheWAS, the wGRS was associated with several autoimmune phenotypes, kidney disorders, and skin neoplasm; but only the associations with autoimmune phenotypes were replicated. In the IVWR meta-analysis, SLE-related risk alleles were nominally associated with type 1 diabetes (P = 0.048) but the associations were heterogeneous and did not meet the adjusted significance threshold. CONCLUSION: A weighted GRS for SLE was associated with an increased risk of several autoimmune-related phenotypes including type I diabetes but not with cardiometabolic disorders.
Subject(s)
Cardiovascular Diseases , Lupus Erythematosus, Systemic , Metabolic Diseases , Alleles , Cardiovascular Diseases/genetics , Diabetes Mellitus, Type 1/genetics , Diabetes Mellitus, Type 2 , Genetic Predisposition to Disease , Humans , Lupus Erythematosus, Systemic/genetics , Polymorphism, Single NucleotideABSTRACT
The complex neuronal circuitry connected by submicron synapses in our brain calls for technologies that can map neural networks with ultrahigh spatiotemporal resolution to decipher the underlying mechanisms for multiple aspects of neuroscience. Here we show that, through combining graphene transistor arrays with scanning photocurrent microscopy, we can detect the electrical activities of individual synapses of primary hippocampal neurons. Through measuring the local conductance change of graphene optoelectronic probes directly underneath neuronal processes, we are able to estimate millivolt extracellular potential variations of individual synapses during depolarization. The ultrafast nature of graphene photocurrent response allows for decoding of activity patterns of individual synapses with a sub-millisecond temporal resolution. This new neurotechnology provides promising potentials for recording of electrophysiological outcomes of individual synapses in neural networks.
Subject(s)
Graphite/chemistry , Lab-On-A-Chip Devices , Neurons/metabolism , Synapses/metabolism , Transistors, Electronic , Animals , Cells, Cultured , Coculture Techniques , Electrophysiological Phenomena , Equipment Design , Hippocampus/cytology , Hippocampus/metabolism , Microscopy, Fluorescence , Nerve Net/cytology , Nerve Net/metabolism , Neurons/cytology , RatsABSTRACT
Dendritic spines are actin-rich protrusions that establish excitatory synaptic contacts with surrounding neurons. Reorganization of the actin cytoskeleton is critical for the development and plasticity of dendritic spines, which is the basis for learning and memory. Rho family GTPases are emerging as important modulators of spines and synapses, predominantly through their ability to regulate actin dynamics. Much less is known, however, about the function of guanine nucleotide exchange factors (GEFs), which activate these GTPases, in spine and synapse development. In this study we show that the Rho family GEF Asef2 is found at synaptic sites, where it promotes dendritic spine and synapse formation. Knockdown of endogenous Asef2 with shRNAs impairs spine and synapse formation, whereas exogenous expression of Asef2 causes an increase in spine and synapse density. This effect of Asef2 on spines and synapses is abrogated by expression of GEF activity-deficient Asef2 mutants or by knockdown of Rac, suggesting that Asef2-Rac signaling mediates spine development. Because Asef2 interacts with the F-actin-binding protein spinophilin, which localizes to spines, we investigated the role of spinophilin in Asef2-promoted spine formation. Spinophilin recruits Asef2 to spines, and knockdown of spinophilin hinders spine and synapse formation in Asef2-expressing neurons. Furthermore, inhibition of N-methyl-d-aspartate receptor (NMDA) activity blocks spinophilin-mediated localization of Asef2 to spines. These results collectively point to spinophilin-Asef2-Rac signaling as a novel mechanism for the development of dendritic spines and synapses.
Subject(s)
Dendritic Spines/metabolism , Guanine Nucleotide Exchange Factors/genetics , Hippocampus/metabolism , Microfilament Proteins/genetics , Nerve Tissue Proteins/genetics , Neurogenesis/genetics , Proto-Oncogene Proteins c-akt/genetics , Actin Cytoskeleton/chemistry , Actin Cytoskeleton/genetics , Actin Cytoskeleton/metabolism , Amino Acid Sequence , Animals , Dendritic Spines/ultrastructure , Embryo, Mammalian , Gene Expression Regulation, Developmental , Guanine Nucleotide Exchange Factors/antagonists & inhibitors , Guanine Nucleotide Exchange Factors/metabolism , Hippocampus/growth & development , Hippocampus/ultrastructure , Microfilament Proteins/metabolism , Molecular Sequence Data , Nerve Tissue Proteins/metabolism , Primary Cell Culture , Proto-Oncogene Proteins c-akt/agonists , Proto-Oncogene Proteins c-akt/metabolism , RNA, Small Interfering/genetics , RNA, Small Interfering/metabolism , Rats , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Receptors, N-Methyl-D-Aspartate/genetics , Receptors, N-Methyl-D-Aspartate/metabolism , Signal Transduction , Synapses/genetics , Synapses/metabolism , Synapses/ultrastructureABSTRACT
BACKGROUND: Understanding blood-brain barrier responses to inflammatory stimulation (such as lipopolysaccharide mimicking a systemic infection or a cytokine cocktail that could be the result of local or systemic inflammation) is essential to understanding the effect of inflammatory stimulation on the brain. It is through the filter of the blood-brain barrier that the brain responds to outside influences, and the blood-brain barrier is a critical point of failure in neuroinflammation. It is important to note that this interaction is not a static response, but one that evolves over time. While current models have provided invaluable information regarding the interaction between cytokine stimulation, the blood-brain barrier, and the brain, these approaches-whether in vivo or in vitro-have often been only snapshots of this complex web of interactions. METHODS: We utilize new advances in microfluidics, organs-on-chips, and metabolomics to examine the complex relationship of inflammation and its effects on blood-brain barrier function ex vivo and the metabolic consequences of these responses and repair mechanisms. In this study, we pair a novel dual-chamber, organ-on-chip microfluidic device, the NeuroVascular Unit, with small-volume cytokine detection and mass spectrometry analysis to investigate how the blood-brain barrier responds to two different but overlapping drivers of neuroinflammation, lipopolysaccharide and a cytokine cocktail of IL-1ß, TNF-α, and MCP1,2. RESULTS: In this study, we show that (1) during initial exposure to lipopolysaccharide, the blood-brain barrier is compromised as expected, with increased diffusion and reduced presence of tight junctions, but that over time, the barrier is capable of at least partial recovery; (2) a cytokine cocktail also contributes to a loss of barrier function; (3) from this time-dependent cytokine activation, metabolic signature profiles can be obtained for both the brain and vascular sides of the blood-brain barrier model; and (4) collectively, we can use metabolite analysis to identify critical pathways in inflammatory response. CONCLUSIONS: Taken together, these findings present new data that allow us to study the initial effects of inflammatory stimulation on blood-brain barrier disruption, cytokine activation, and metabolic pathway changes that drive the response and recovery of the barrier during continued inflammatory exposure.
Subject(s)
Blood-Brain Barrier/immunology , Blood-Brain Barrier/metabolism , Brain/immunology , Brain/metabolism , Cytokines/metabolism , Blood-Brain Barrier/drug effects , Brain/drug effects , Claudin-5/metabolism , Cytokines/pharmacology , Dose-Response Relationship, Drug , Humans , Interleukin-1beta/pharmacology , Lab-On-A-Chip Devices , Lipopolysaccharides/pharmacology , Metabolic Networks and Pathways/drug effects , Metabolic Networks and Pathways/genetics , Models, Biological , Protein Transport/drug effects , Tight Junctions/drug effects , Time Factors , Tumor Necrosis Factor-alpha/pharmacology , Zonula Occludens-1 Protein/metabolismABSTRACT
Non-muscle myosin II (MyoII) contractility is central to the regulation of numerous cellular processes, including migration. Rho is a well-characterized modulator of actomyosin contractility, but the function of other GTPases, such as Rac, in regulating contractility is currently not well understood. Here, we show that activation of Rac by the guanine nucleotide exchange factor Asef2 (also known as SPATA13) impairs migration on type I collagen through a MyoII-dependent mechanism that enhances contractility. Knockdown of endogenous Rac or treatment of cells with a Rac-specific inhibitor decreases the amount of active MyoII, as determined by serine 19 (S19) phosphorylation, and negates the Asef2-promoted increase in contractility. Moreover, treatment of cells with blebbistatin, which inhibits MyoII activity, abolishes the Asef2-mediated effect on migration. In addition, Asef2 slows the turnover of adhesions in protrusive regions of cells by promoting large mature adhesions, which has been linked to actomyosin contractility, with increased amounts of active ß1 integrin. Hence, our data reveal a new role for Rac activation, promoted by Asef2, in modulating actomyosin contractility, which is important for regulating cell migration and adhesion dynamics.
Subject(s)
Cell Movement , Collagen Type I/metabolism , Guanine Nucleotide Exchange Factors/physiology , Myosin Type II/metabolism , rac GTP-Binding Proteins/metabolism , Cell Adhesion , Cell Line, Tumor , Humans , Integrin beta1/metabolism , cdc42 GTP-Binding Protein/metabolismABSTRACT
Asef2, a 652-amino acid protein, is a guanine nucleotide exchange factor (GEF) that regulates cell migration and other processes via activation of Rho family GTPases, including Rac. Binding of the tumor suppressor adenomatous polyposis coli (APC) to Asef2 is known to induce its GEF activity; however, little is currently known about other modes of Asef2 regulation. Here, we investigated the role of phosphorylation in regulating Asef2 activity and function. Using high-resolution mass spectrometry (MS) and tandem mass spectrometry (MS/MS), we obtained complete coverage of all phosphorylatable residues and identified six phosphorylation sites. One of these, serine 106 (S106), was particularly intriguing as a potential regulator of Asef2 activity because of its location within the APC-binding domain. Interestingly, mutation of this serine to alanine (S106A), a non-phosphorylatable analogue, greatly diminished the ability of Asef2 to activate Rac, while a phosphomimetic mutation (serine to aspartic acid, S106D) enhanced Rac activation. Furthermore, expression of these mutants in HT1080 cells demonstrated that phosphorylation of S106 is critical for Asef2-promoted migration and for cell-matrix adhesion assembly and disassembly (adhesion turnover), which is a process that facilitates efficient migration. Collectively, our results show that phosphorylation of S106 modulates Asef2 GEF activity and Asef2-mediated cell migration and adhesion turnover.
Subject(s)
Cell Adhesion , Cell Movement , Guanine Nucleotide Exchange Factors/metabolism , Protein Processing, Post-Translational , Amino Acid Sequence , Cell Line, Tumor , Guanine Nucleotide Exchange Factors/chemistry , HEK293 Cells , Humans , Molecular Sequence Data , Phosphorylation , Serine/chemistryABSTRACT
A microfluidic cell co-culture platform that uses a liquid fluorocarbon oil barrier to separate cells into different culture chambers has been developed. Characterization indicates that the oil barrier could be effective for multiple days, and a maximum pressure difference between the oil barrier and aqueous media in the cell culture chamber could be as large as ~3.43 kPa before the oil barrier fails. Biological applications have been demonstrated with the separate transfection of two groups of primary hippocampal neurons with two different fluorescent proteins and subsequent observation of synaptic contacts between the neurons. In addition, the quality of the fluidic seal provided by the oil barrier is shown to be greater than that of an alternative solid-PDMS valve barrier design by testing the ability of each device to block low molecular weight CellTracker dyes used to stain cells in the culture chambers.
Subject(s)
Cell Tracking , Fluorocarbons/chemistry , Hippocampus/cytology , Microfluidic Analytical Techniques , Neurons/cytology , Animals , Cell Tracking/instrumentation , Cell Tracking/methods , Cells, Cultured , Microfluidic Analytical Techniques/instrumentation , Microfluidic Analytical Techniques/methods , RatsABSTRACT
Introduction: Circulating metabolites act as biomarkers of dysregulated metabolism and may inform disease pathophysiology. A portion of the inter-individual variability in circulating metabolites is influenced by common genetic variation. We evaluated whether a genetics-based "virtual" metabolomics approach can identify novel metabolite-disease associations. Methods: We examined the association between polygenic scores for 724 metabolites with 1,247 clinical phenotypes in the BioVU DNA biobank, comprising 57,735 European ancestry and 15,754 African ancestry participants. We applied Mendelian randomization (MR) to probe significant relationships and validated significant MR associations using independent GWAS of candidate phenotypes. Results and Discussion: We found significant associations between 336 metabolites and 168 phenotypes in European ancestry and 107 metabolites and 56 phenotypes in African ancestry. Of these metabolite-disease pairs, MR analyses confirmed associations between 73 metabolites and 53 phenotypes in European ancestry. Of 22 metabolitephenotype pairs evaluated for replication in independent GWAS, 16 were significant (false discovery rate p < 0.05). These included associations between bilirubin and X-21796 with cholelithiasis, phosphatidylcholine (16:0/22:5n3,18:1/20:4) and arachidonate with inflammatory bowel disease and Crohn's disease, and campesterol with coronary artery disease and myocardial infarction. These associations may represent biomarkers or potentially targetable mediators of disease risk.
ABSTRACT
The temperature-dependent thermal conductivity of violet phosphorus on a perforated SiO2/Si substrate has been investigated via optothermal Raman spectroscopy. The obtained temperature coefficients of the Tg mode and Ptub mode of the violet phosphorus sample are -0.01268 and -0.01789 cm-1 K-1, respectively. On the basis of the temperature coefficients and power coefficients, the thermal conductivity of the violet phosphorus has been calculated to be 44.642 ± 4.995 W/mK at room temperature, which is higher than that of other two-dimensional materials such as black phosphorus and MoS2 due to the effect of boundary scattering and the phonon mean free path. Additionally, the thermal conductivity of violet phosphorus decreases as a power exponential function of the temperature, which is primarily associated with the phonon mean free path and phonon group velocity. This work provides a scientific foundation for thermal management and heat dissipation in designing micro-nano devices with violet phosphorus.
ABSTRACT
OBJECTIVE: Genetic studies have suggested that the branched-chain amino acids (BCAAs) valine, leucine, and isoleucine have a causal association with type 2 diabetes (T2D). However, inferences are based on a limited number of genetic loci associated with BCAAs. METHODS: Instrumental variables (IVs) for each BCAA were constructed and validated using large well-powered data sets and their association with T2D was tested using a two-sample inverse-variance weighted Mendelian randomization approach. Sensitivity analyses were performed to ensure the accuracy of the findings. A reverse association was assessed using instrumental variables for T2D. RESULTS: Estimated effect sizes between BCAA IVs and T2D, excluding outliers, were as follows: valine (ß = 0.14 change in log-odds per SD change in valine, 95% CI: -0.06 to 0.33, p = 0.17), leucine (ß = 0.15, 95% CI: -0.02 to 0.32, p = 0.09), and isoleucine (ß = 0.13, 95% CI: -0.08 to 0.34, p = 0.24). In contrast, T2D IVs were positively associated with each BCAA, i.e., valine (ß = 0.08 per SD change in levels per log-odds change in T2D, 95% CI: 0.05 to 0.10, p = 1.8 × 10-9 ), leucine (ß = 0.06, 95% CI: 0.04 to 0.09, p = 4.5 × 10-8 ), and isoleucine (ß = 0.06, 95% CI: 0.04 to 0.08, p = 2.8 × 10-8 ). CONCLUSIONS: These data suggest that the BCAAs are not mediators of T2D risk but are biomarkers of diabetes.
Subject(s)
Amino Acids, Branched-Chain , Diabetes Mellitus, Type 2 , Humans , Diabetes Mellitus, Type 2/genetics , Mendelian Randomization Analysis , Isoleucine/genetics , Leucine/genetics , Valine/geneticsABSTRACT
Composite structures integrated with metasurfaces and nonlinear films have emerged as alternative candidates to enhance nonlinear response. The cooperative interaction between the two components is complicated. Herein, a split-ring resonator (SRR)-type metasurface was fabricated on a free-standing nanocrystal diamond (NCD) film utilizing electron beam lithography, electron beam evaporation, and a lift-off process. The terahertz (THz) radiation from the SRR-NCD under normal incidence originates from the high-order magnetic resonance of SRR because the NCD film cannot produce detectable THz radiation at this incident angle. As increasing the incident angle, the contribution of the THz radiation from the NCD film gradually increases until reaching 40° incident angle limitation. The results indicate that this angular-dependent THz radiation is induced by the interplay between the NCD film and SRR. This study offers a new approach to investigate nonlinear processes in composite structures.
ABSTRACT
BACKGROUND: Greater left atrial size is associated with a higher incidence of cardiovascular disease and mortality, but the full spectrum of diagnoses associated with left atrial enlargement in sex-stratified clinical populations is not well known. Our study sought to identify genetic risk mechanisms affecting left atrial diameter (LAD) in a clinical cohort. METHODS: Using Vanderbilt deidentified electronic health record, we studied 6163 females and 5993 males of European ancestry who had at least 1 LAD measure and available genotyping. A sex-stratified polygenic score was constructed for LAD variation and tested for association against 1680 International Classification of Diseases code-based phenotypes. Two-sample univariable and multivariable Mendelian randomization approaches were used to assess etiologic relationships between candidate associations and LAD. RESULTS: A phenome-wide association study identified 25 International Classification of Diseases code-based diagnoses in females and 11 in males associated with a polygenic score of LAD (false discovery rate q<0.01), 5 of which were further evaluated by Mendelian randomization (waist circumference [WC], atrial fibrillation, heart failure, systolic blood pressure, and coronary artery disease). Sex-stratified differences in the genetic associations between risk factors and a polygenic score for LAD were observed (WC for females; heart failure, systolic blood pressure, atrial fibrillation, and WC for males). By multivariable Mendelian randomization, higher WC remained significantly associated with larger LAD in females, whereas coronary artery disease, WC, and atrial fibrillation remained significantly associated with larger LAD in males. CONCLUSIONS: In a clinical population, we identified, by genomic approaches, potential etiologic risk factors for larger LAD. Further studies are needed to confirm the extent to which these risk factors may be modified to prevent or reverse adverse left atrial remodeling and the extent to which sex modifies these risk factors.
Subject(s)
Atrial Fibrillation , Coronary Artery Disease , Heart Failure, Systolic , Female , Humans , Male , Atrial Fibrillation/diagnosis , Atrial Fibrillation/genetics , Atrial Fibrillation/complications , Genomics , Heart Atria/diagnostic imaging , Risk Factors , Mendelian Randomization AnalysisABSTRACT
OBJECTIVE: The objective of this study was to identify the transcriptional landscape of insulin resistance (IR) in subcutaneous adipose tissue (SAT) in humans across the spectrum of obesity. METHODS: We used SAT RNA sequencing in 220 individuals with metabolic phenotyping. RESULTS: We identified a 35-gene signature with high predictive accuracy for homeostatic model of IR that was expressed across a variety of non-immune cell populations. We observed primarily "protective" IR associations for adipocyte transcripts and "deleterious" associations for macrophage transcripts, as well as a high concordance between SAT and visceral adipose tissue (VAT). Multiple SAT genes exhibited dynamic expression 5 years after weight loss surgery and with insulin stimulation. Using available expression quantitative trait loci in SAT and/or VAT, we demonstrated similar genetic effect sizes of SAT and VAT on type 2 diabetes and BMI. CONCLUSIONS: SAT is conventionally viewed as a metabolic buffer for lipid deposition during positive energy balance, whereas VAT is viewed as a dominant contributor to and prime mediator of IR and cardiometabolic disease risk. Our results implicate a dynamic transcriptional architecture of IR that resides in both immune and non-immune populations in SAT and is shared with VAT, nuancing the current VAT-centric concept of IR in humans.
Subject(s)
Insulin Resistance , Intra-Abdominal Fat , Obesity , Subcutaneous Fat , Transcriptome , Humans , Intra-Abdominal Fat/metabolism , Male , Subcutaneous Fat/metabolism , Female , Middle Aged , Adult , Obesity/genetics , Obesity/metabolism , Diabetes Mellitus, Type 2/metabolism , Diabetes Mellitus, Type 2/genetics , Body Mass Index , Adipocytes/metabolism , Quantitative Trait LociABSTRACT
Polygenic variation unrelated to disease contributes to interindividual variation in baseline white blood cell (WBC) counts, but its clinical significance is uncharacterized. We investigated the clinical consequences of a genetic predisposition toward lower WBC counts among 89,559 biobank participants from tertiary care centers using a polygenic score for WBC count (PGSWBC) comprising single nucleotide polymorphisms not associated with disease. A predisposition to lower WBC counts was associated with a decreased risk of identifying pathology on a bone marrow biopsy performed for a low WBC count (odds-ratio = 0.55 per standard deviation increase in PGSWBC [95%CI, 0.30-0.94], p = 0.04), an increased risk of leukopenia (a low WBC count) when treated with a chemotherapeutic (n = 1724, hazard ratio [HR] = 0.78 [0.69-0.88], p = 4.0 × 10-5) or immunosuppressant (n = 354, HR = 0.61 [0.38-0.99], p = 0.04). A predisposition to benign lower WBC counts was associated with an increased risk of discontinuing azathioprine treatment (n = 1,466, HR = 0.62 [0.44-0.87], p = 0.006). Collectively, these findings suggest that there are genetically predisposed individuals who are susceptible to escalations or alterations in clinical care that may be harmful or of little benefit.
Subject(s)
Genetic Predisposition to Disease , Leukopenia , Multifactorial Inheritance , Polymorphism, Single Nucleotide , Humans , Leukocyte Count , Male , Female , Leukopenia/genetics , Leukopenia/blood , Middle Aged , Aged , Adult , Immunosuppressive Agents/therapeutic useABSTRACT
Integrin α1ß1 binding to collagen IV, which is mediated by the α1-inserted (I) domain, down-regulates collagen synthesis. When unligated, a salt bridge between Arg(287) and Glu(317) is thought to keep this domain in a low affinity conformation. Ligand binding opens the salt bridge leading to a high-affinity conformation. How modulating integrin α1ß1 affinity alters collagen homeostasis is unknown. To address this question, we utilized a thermolysin-derived product of the α1α2α1 network of collagen IV (α1α2α1(IV) truncated protomer) that selectively binds integrin α1ß1. We show that an E317A substitution enhanced binding to the truncated protomer, consistent with a previous finding that this substitution eliminates the salt bridge. Surprisingly, we show that an R287A substitution did not alter binding, whereas R287E/E317R substitutions enhanced binding to the truncated protomer. NMR spectroscopy and molecular modeling suggested that eliminating the Glu(317) negative charge is sufficient to induce a conformational change toward the open state. Thus, the role played by Glu(317) is largely independent of the salt bridge. We further show that cells expressing E317A or R287E/E317R substitutions have enhanced down-regulation of collagen IV synthesis, which is mediated by the ERK/MAPK pathway. In conclusion, we have demonstrated that modulating the affinity of the extracellular α1 I domain to collagen IV enhances outside-in signaling by potentiating ERK activation and enhancing the down-regulation of collagen synthesis.
Subject(s)
Collagen Type IV/biosynthesis , Down-Regulation , Integrin alpha1beta1/metabolism , Laminin/metabolism , MAP Kinase Signaling System , Models, Molecular , Protein Biosynthesis , Amino Acid Substitution , Animals , Cell Line, Transformed , Collagen Type IV/genetics , Enzyme Activation/genetics , Extracellular Signal-Regulated MAP Kinases/chemistry , Extracellular Signal-Regulated MAP Kinases/genetics , Extracellular Signal-Regulated MAP Kinases/metabolism , Humans , Integrin alpha1beta1/chemistry , Integrin alpha1beta1/genetics , Laminin/chemistry , Laminin/genetics , Ligands , Mice , Mice, Mutant Strains , Mutation, Missense , Nuclear Magnetic Resonance, Biomolecular , Protein Binding , Protein Structure, TertiaryABSTRACT
There have been many reports of mitochondrial DNA (mtDNA) mutations associated with human malignancies. We have observed allelic instability in UV-induced cutaneous tumors at the mt-Tr locus encoding the mitochondrial tRNA for arginine. We examined the effects of somatic alterations at this locus by modeling the change in a uniform nuclear background by generating cybrids harboring allelic variation at mt-Tr. We utilized the naturally occurring mtDNA variation at mt-Tr within the BALB/cJ (BALB) and C57BL/6J (B6) strains of Mus musculus to transfer their mitochondria into a mouse ρ(0) cell line that lacked its own mtDNA. The BALB haplotype containing the mt-Tr 9821insA allele produced significant changes in cellular respiration (resulting in lowered ATP production), but increased rates of cellular proliferation in cybrid cells. Furthermore, the mtDNA genotype associated with UV-induced tumors endowed the cybrid cells with a phenotype of resistance to UV-induced apoptosis and enhanced migration and invasion capabilities. These studies support a role for mtDNA changes in cancer.
Subject(s)
Allelic Imbalance , Cell Transformation, Neoplastic/genetics , DNA, Mitochondrial/genetics , Mitochondria/genetics , Alleles , Animals , Antioxidants/metabolism , Apoptosis/genetics , Arginine/genetics , Arginine/metabolism , Cell Line , Cell Movement/genetics , Cell Nucleus/genetics , Cell Proliferation , Cell Respiration/genetics , Cell Transformation, Neoplastic/metabolism , Cell Transformation, Neoplastic/pathology , Genetic Loci , Genetic Variation , Haplotypes/genetics , Hybrid Cells/metabolism , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mitochondria/metabolism , Mutation/genetics , Neoplasm Invasiveness/genetics , Phenotype , RNA, Transfer/geneticsABSTRACT
Background: Short-form videos have become one of the most popular ways for people to entertain and relax. However, the intense interest in short-form videos has given rise to short-video addiction, which poses risks to both physical and mental health of individuals. Undergraduates are one of the important users for short-form videos, and the influence of short-form video addiction calls for more attention. This study aimed to investigate the association between short-form video addiction and academic procrastination among undergraduates, exploring the role of executive functions (i.e., attentional control) and personality traits (i.e., boredom proneness) in the association. Methods: Using stratified random cluster sampling method, the data of 1,047 college students were used in the study. All variables were measured by empirical instruments, and all instruments were highly reliable. Mediation and moderation analysis was conducted using Model 4 and 7 in PROCESS macro powered by SPSS. Results: Results revealed that short-form video addiction not only directly impacted academic procrastination but also placed indirect effect on academic procrastination through attentional control. Furthermore, the mediating effect of attentional control was contingent upon individuals' boredom proneness. Higher levels of boredom proneness weakened the impact of short-form video addiction on attentional control. Conclusion: The findings expand our knowledge of the negative effects of short-form video addiction and the underlying mechanisms, providing implications for mitigating undergraduates' academic procrastination.
ABSTRACT
All-optical terahertz (THz) modulators have received tremendous attention due to their significant role in developing future sixth-generation technology and all-optical networks. Herein, the THz modulation performance of the Bi2Te3/Si heterostructure is investigated via THz time-domain spectroscopy under the control of continuous wave lasers at 532 nm and 405 nm. Broadband-sensitive modulation is observed at 532 nm and 405 nm within the experimental frequency range from 0.8 to 2.4 THz. The modulation depth reaches 80% under the 532 nm laser illumination with a maximum power of 250 mW and 96% under 405 nm illumination with a high power of 550 mW. The mechanism of the largely enhanced modulation depth is attributed to the construction of a type-II Bi2Te3/Si heterostructure, which could promote photogenerated electron and hole separation and increase carrier density dramatically. This work proves that a high photon energy laser can also achieve high-efficiency modulation based on the Bi2Te3/Si heterostructure, and the UV-Visible control laser may be more suitable for designing advanced all-optical THz modulators with micro-level sizes.