Identification of the Novel HLA-C*01:257N Allele by Next-Generation Sequencing.
HLA-C*01:257N differs from the HLA-C*01:02:01:01 allele by one nucleotide substitution in exon 4.
Biomedical subjects
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HLA-C*01:257N differs from the HLA-C*01:02:01:01 allele by one nucleotide substitution in exon 4.
HLA-B*40:542 differs from the HLA-B*40:23 allele by two nucleotide substitutions in exon 3.
HLA-C*08:01:37 differs from HLA-C*08:01:01:01 by one single nucleotide substitution at position 927 G>A in exon 5.
Compared with HLA-C*01:02:01:01, HLA-C*01:254 and HLA-C*01:238Q show one and two nucleotide substitutions, respectively.
OBJECTIVE: Multiple sclerosis (MS) is an autoimmune disease of the central nervous system, and previous observational epidemiological studies have suggested an association between MS and male infertility; male infertility due to sperm abnormalities may result from a number of aetiological factors, such as genetics, autoimmune factors, etc., and there are currently no studies to assess whether MS is associated with sperm abnormalities in men. Therefore, we performed a Mendelian randomization (MR) analysis to assess the causal relationship between MS and abnormal spermatozoa. METHODS: In this study, independent single nucleotide polymorphisms (SNPs) strongly associated with multiple sclerosis (MS) were identified by mining public genome-wide association study repositories and used as instrumental variables to explore causality. The causal effect of MS on sperm abnormalities was systematically assessed using two-sample Mendelian randomization (MR) techniques, and various analytical models such as inverse variance weighting (IVW), MR-Egger and MR-PRESSO were implemented to dissect the association. In addition, a wide range of sensitivity tests, including Cochran's Q test to detect heterogeneity, MR-Egger intercept analysis to assess bias, leave-one-out to test model robustness, and funnel plot analysis to detect potential publication bias, were implemented to ensure the robustness and reliability of the causal inference results. RESULTS: There was a significant causal relationship between MS and abnormal sperm (OR 1.090, 95% CI [1.017-1.168], p = 0.014); The accuracy and robustness of the results were confirmed by sensitivity analysis. CONCLUSION: Here we show that there appears to be a causal relationship between multiple sclerosis and abnormal spermatozoa. MS as a chronic disease has a higher risk of concomitant sperm abnormalities in its male patients, and reproductive and fertility issues in men with MS should receive special attention from clinicians.
Pseudomonas plecoglossicida, a gram-negative bacterium, is the main pathogen of visceral white-point disease in marine fish, responsible for substantial economic losses in the aquaculture industry. The FliL protein, involved in torque production of the bacterial flagella motor, is essential for the pathogenicity of a variety of bacteria. In the current study, the fliL gene deletion strain (ΔfliL), fliL gene complement strain (C-ΔfliL), and wild-type strain (NZBD9) were compared to explore the influence of the fliL gene on P. plecoglossicida pathogenicity and its role in host immune response. Results showed that fliL gene deletion increased the survival rate (50%) and reduced white spot disease progression in the hybrid groupers. Moreover, compared to the NZBD9 strain, the ΔfliL strain was consistently associated with lower bacterial loads in the grouper spleen, head kidney, liver, and intestine, coupled with reduced tissue damage. Transcriptomic analysis identified 2 238 differentially expressed genes (DEGs) in the spleens of fish infected with the ΔfliL strain compared to the NZBD9 strain. Based on Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, the DEGs were significantly enriched in seven immune system-associated pathways and three signaling molecule and interaction pathways. Upon infection with the ΔfliL strain, the toll-like receptor (TLR) signaling pathway was activated in the hybrid groupers, leading to the activation of transcription factors (NF-κB and AP1) and cytokines. The expression levels of proinflammatory cytokine-related genes IL-1β, IL-12B, and IL-6 and chemokine-related genes CXCL9, CXCL10, and CCL4 were significantly up-regulated. In conclusion, the fliL gene markedly influenced the pathogenicity of P. plecoglossicida infection in the hybrid groupers. Notably, deletion of fliL gene in P. plecoglossicida induced a robust immune response in the groupers, promoting defense against and elimination of pathogens via an inflammatory response involving multiple cytokines.
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BACKGROUND: The integral synaptic vesicle protein and putative calcium sensor, synaptotagmin 1 (STG), has also been implicated in synaptic vesicle (SV) recovery. However, proteins with which STG interacts during SV endocytosis remain poorly understood. We have isolated an STG-associated endocytic complex (SAE) from presynaptic nerve terminals and have used a novel fractional recovery (FR) assay based on electrostatic dissociation to identify SAE components and map the complex structure. The location of SAE in the presynaptic terminal was determined by high-resolution quantitative immunocytochemistry at the chick ciliary ganglion giant calyx-type synapse. METHODOLOGY/PRINCIPLE FINDINGS: The first step in FR analysis was to immunoprecipitate (IP) the complex with an antibody against one protein component (the IP-protein). The immobilized complex was then exposed to a high salt (1150 mM) stress-test that caused shedding of co-immunoprecipitated proteins (co-IP-proteins). A Fractional Recovery ratio (FR: recovery after high salt/recovery with control salt as assayed by Western blot) was calculated for each co-IP-protein. These FR values reflect complex structure since an easily dissociated protein, with a low FR value, cannot be intermediary between the IP-protein and a salt-resistant protein. The structure of the complex was mapped and a blueprint generated with a pair of FR analyses generated using two different IP-proteins. The blueprint of SAE contains an AP180/X/STG/stonin 2/intersectin/epsin core (X is unknown and epsin is hypothesized), and an AP2 adaptor, H-/L-clathrin coat and dynamin scission protein perimeter. Quantitative immunocytochemistry (ICA/ICQ method) at an isolated calyx-type presynaptic terminal indicates that this complex is associated with STG at the presynaptic transmitter release face but not with STG on intracellular synaptic vesicles. CONCLUSIONS/SIGNIFICANCE: We hypothesize that the SAE serves as a recognition site and also as a seed complex for clathrin-mediated synaptic vesicle recovery. The combination of FR analysis with quantitative immunocytochemistry provides a novel and effective strategy for the identification and characterization of biologically-relevant multi-molecular complexes.
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The genetic relationship among the three color variants (Red, Green, and Black) of the Japanese sea cucumber, S. japonicus, was investigated using 11 microsatellite markers. Genetic differentiation testing among the three sympatric color types showed the strong heterogeneity of Red (p<0.001), while no significant difference was observed between Green and Black (p=0.301 to 0.961). UPGMA trees constructed from 10 sample lots from 5 localities showed two distinct clusters, one from the Red types and the other from the Green and Black types. In addition, the sympatric Green and Black formed one subcluster with strong bootstrap support at each locality. These results indicate the separate species status of Red and the other color types, and also support the population identity of sympatric Green and Black.
BACKGROUND: Leisure-time physical activity (LPA) has been associated with a reduced risk of type 2 diabetes. However, the potential effect of other types of physical activity on type 2 diabetes is still uncertain. The aim of this study was to examine the effect of occupational, commuting, daily living, and LPA on the incidence of type 2 diabetes in a cohort of middle-aged women. METHODS: We prospectively followed 70,658 women who had no prior history of diabetes at study recruitment for 4.6 years. Participants completed in-person interviews at baseline that collected information on diabetes risk factors including physical activity habits. Anthropometric measurements were taken by trained interviewers. Multivariate-adjusted hazard ratios were estimated by levels of occupational, commuting, daily living, and LPA. RESULTS: We documented 1973 incident cases of diabetes during 326,625 person-years of follow-up. LPA and daily living physical activity (DPA) were associated with a moderately reduced risk of type 2 diabetes. The relative risk for type 2 diabetes associated with LPA and DPA categories were 1.00, 0.89, 1.05, and 0.83, (P trend = 0.12) and 1.00, 0.98, 0.95, and 0.88, (P trend = 0.06) respectively. LPA was associated with lower risk of type 2 diabetes in employed participants (P trend = 0.09) while DPA was mainly associated with a reduction in risk in non-employed participants (P trend <0.01). While occupational physical activity was not associated with type 2 diabetes risk in this population, commuting to work was associated with a reduction in risk. A combination of DPA and LPA was associated with a reduced risk of type 2 diabetes. CONCLUSIONS: This study suggests that physical activity, either from leisure-time exercise or daily activity reduces the risk of type 2 diabetes in women, supporting the current health promotion efforts encouraging both exercise and non-exercise activity levels.
Chemoembolization has been found to be a potentially effective method of treating certain types of cancer. It involves arterial embolization of a tumor, in combination with simultaneous or subsequent local delivery of chemotherapeutic agents. In this study, PLGA-alginate microspheres were evaluated for their potential application in chemoembolization. Norcantharidin, which possesses anti-tumor properties, was used to investigate the application of drug-containing microspheres for chemoembolization. The release profiles of alginate, PLGA and PLGA-alginate microspheres were markedly different in phosphate buffered saline, with the composite microspheres showing the most appropriate release rate for chemoembolization. Burst effect decreased while particle size increased with increasing proportion of alginate in the PLGA-alginate microspheres. PLGA-alginate microspheres containing norcantharidin were effective in destroying the cancer cells used in this study. The growth inhibitory effect was concentration and time dependent. These microspheres also exhibited excellent embolization and therapeutic effects on rats with transplanted tumors.
This study investigates characteristics of aging in the central nervous system of the senescence accelerated prone mice (SAMP8). We examined 3 and 10-months old senescence-accelerated-prone mice (SAMP8) for functional and molecular changes in their brains, specifically in the hippocampus and somatosensory cortex. There was no statistically significant increase in the apoptosis indicators as revealed by Western Blotting for BAD and TUNEL experiments. However, the functional magnetic resonance imaging showed an increase in the area of BOLD images from the 3-month old to the 10-months old SAMP mice upon the application of tail stimulus. These results demonstrated a lack of neuronal deaths but an increase in the activated brain area with age.
OBJECTIVE: To evaluate the association of environmental exposure to tobacco smoke from husbands and from work, as well as from family members in early life, with all cause mortality and mortality due to cancer or cardiovascular disease in Chinese women. DESIGN: Ongoing prospective cohort study in Shanghai, China. PARTICIPANTS: Of 72,829 women who had never smoked, 65,180 women provided information on smoking by their husbands, and 66,520 women provided information on exposure to tobacco smoke at work and in early life from family members. MAIN OUTCOME MEASURES: All cause mortality and cause specific mortality with the main focus on cancer and cardiovascular disease. Cumulative mortality according to exposure status, and hazard ratios. RESULTS: Exposure to tobacco smoke from husbands (mainly current exposure) was significantly associated with increased all cause mortality (hazard ratio 1.15, 95% confidence interval 1.01 to 1.31) and with increased mortality due to cardiovascular disease (1.37, 1.06 to 1.78). Exposure to tobacco smoke at work was associated with increased mortality due to cancer (1.19, 0.94 to 1.50), especially lung cancer (1.79, 1.09 to 2.93). Exposure in early life was associated with increased mortality due to cardiovascular disease (1.26, 0.94 to 1.69). CONCLUSIONS: In Chinese women, exposure to environmental tobacco smoke is related to moderately increased risk of all cause mortality and mortality due to lung cancer and cardiovascular disease.
This study examined the heat shock protein 70 (HSP70) expression in hippocampal CA3 subfield of rats in different chronic stress models. The chronic restraint stress (CRS) and the chronic mild stress (CMS) models were used in this study. Observation of exploratory behavior in an open field test indicated stress level. The expression of HSP70 in hippocampal CA3 subfield was measured by immunohistochemical methods. The results showed that the number of quadrant crossing in both CRS and CMS groups decreased more than that of the control (P < 0.01). CRS group crossing decreased more than CMS group. Damage in the hippocampus of the CMS group occurred later and to a less extent than that of the CRS group. Compared with CMS group, the expression of HSP70 was greater in the CRS group. Moreover, increased stress duration enhanced these effects. These results show that the CRS model affects both exploratory behavior and HSP70 expression in the hippocampus more dramatically than the CMS model.
We report a large normal-state magnetoresistance with temperature-dependent anisotropy in very clean epitaxial MgB2 thin films (residual resistivity much smaller than 1 microOmega cm) grown by hybrid physical-chemical vapor deposition. The magnetoresistance shows a complex dependence on the orientation of the applied magnetic field, with a large magnetoresistance (Delta(rho)/(rho)0=136%) observed for the field H perpendicular ab plane. The angular dependence changes dramatically as the temperature is increased, and at high temperatures the magnetoresistance maximum changes to H||ab. We attribute the large magnetoresistance and the evolution of its angular dependence with temperature to the multiple bands with different Fermi surface topology in MgB2 and the relative scattering rates of the sigma and pi bands, which vary with temperature due to stronger electron-phonon coupling for the sigma bands.
The expression of the apoptosis-inducing ligands, TNF-alpha, FasL and TRAIL on peripheral blood mononuclear cells (PBMC) and the levels of their soluble form (TNF-alpha, sFasL and sTRAIL) in plasma from 40 hemorrhagic fever with renal syndrome (HFRS) patients as well as 26 healthy blood donors were determined by flow cytometry (FCM) analysis and sandwich ELISA, respectively. The status of Th1, Th2, Tc1 and Tc2 subsets in PBMC was evaluated by intracellular cytokine staining and FCM. Compared to controls, the expression of membrane bound FasL and TRAIL was up-regulated on surface of PBMC isolated from the HFRS patients, particularly on CD8+ T lymphocytes. The levels of TNF-alpha, sFasL and sTRAIL in plasma from the HFRS patients in the acute phase increase 4.7-fold, 6.0-fold and 1.8-fold, respectively, over those from the healthy donors. The percentage of Th1, Tc1 and Tc2 subsets in PBMC from the patients also increased significantly compared with those from healthy donors. These results indicate that dynamic changes occurred in both the membrane bound and soluble forms of apoptosis-inducing ligands (FasL, TRAIL and TNF-alpha) and proportions of Th1 and CTL in HFRS patients increased. Both factors may play an important role in the etiology of Hantaan virus infection in humans.
We employ experiment and theory to explore the nonlinear elasticity and yielding of concentrated suspensions of nanoparticles which interact via purely repulsive forces. These glassy suspensions are found to exhibit high exponent power law or simple exponential dependences of the shear elastic modulus and perturbative yield stress on nanoparticle volume fraction, as well as a monotonic decrease of the perturbative yield strain with increasing concentration. Our experimental observations are in good agreement with the predictions of a recently developed microscopic statistical mechanical theory, which describes glassy dynamics based on a nonequilibrium free energy that incorporates local cage correlations and activated barrier hopping processes [(1) Schweizer, K. S.; Saltzman, E. J. J. Chem. Phys. 2003, 119, 1181. (2) Saltzman, E. J.; Schweizer, K. S. J. Chem. Phys. 2003, 119, 1197. (3) Kobelev, V.; Schweizer, K. S. Phy. Rev. E 2005, 71, 021401].