InferLoop: leveraging single-cell chromatin accessibility for the signal of chromatin loop.

Deciphering cell-type-specific 3D structures of chromatin is challenging. Here, we present InferLoop, a novel method for inferring the strength of chromatin interaction using single-cell chromatin accessibility data. The workflow of InferLoop is, first, to conduct signal enhancement by grouping nearby cells into bins, and then, for each bin, leverage accessibility signals for loop signals using a newly constructed metric that is similar to the perturbation of the Pearson correlation coefficient. In this study, we have described three application scenarios of InferLoop, including the inference of cell-type-specific loop signals, the prediction of gene expression levels and the interpretation of intergenic loci. The effectiveness and superiority of InferLoop over other methods in those three scenarios are rigorously validated by using the single-cell 3D genome structure data of human brain cortex and human blood, the single-cell multi-omics data of human blood and mouse brain cortex, and the intergenic loci in the GWAS Catalog database as well as the GTEx database, respectively. In addition, InferLoop can be applied to predict loop signals of individual spots using the spatial chromatin accessibility data of mouse embryo. InferLoop is available at https://github.com/jumphone/inferloop.

Liver regeneration and ethanol detoxification: A new link in YAP regulation of ALDH1A1 during alcohol-related hepatocyte damage.

Yes-associated protein (YAP), a central effector in the Hippo pathway, is involved in the regulation of organ size, stem cell self-renewal, and tissue regeneration. In this study, we observed YAP activation in patients with alcoholic steatosis, hepatitis, and cirrhosis. Accumulation of this protein in the nucleus was also observed in murine livers that were damaged after chronic-plus-single binge or moderate ethanol ingestion combined with carbon tetrachloride intoxication (ethanol/CCl4 ). To understand the role of this transcriptional coactivator in alcohol-related liver injury, we knocked out the Yap1 gene in hepatocytes of floxed homozygotes through adeno-associated virus (AAV8)-mediated deletion utilizing Cre recombinase. Yap1 hepatocyte-specific knockouts (KO) exhibited hemorrhage, massive hepatic necrosis, enhanced oxidative stress, elevated hypoxia, and extensive infiltration of CD11b+ inflammatory cells into hepatic microenvironments rich for connective tissue growth factor (Ctgf) during ethanol/CCl4 -induced liver damage. Analysis of whole-genome transcriptomics indicated upregulation of genes involved in hypoxia and extracellular matrix (ECM) remodeling, whereas genes related to hepatocyte proliferation, progenitor cell activation, and ethanol detoxification were downregulated in the damaged livers of Yap1 KO. Acetaldehyde dehydrogenase (Aldh)1a1, a gene that encodes a detoxification enzyme for aldehyde substrates, was identified as a potential YAP target because this gene could be transcriptionally activated by a hyperactive YAP mutant. The ectopic expression of the human ALDH1A1 gene caused increase in hepatocyte proliferation and decrease in hepatic necrosis, oxidative stress, ECM remodeling, and inflammation during ethanol/CCl4 -induced liver damage. Taken together, these observations indicated that YAP was crucial for liver repair during alcohol-associated injury. Its regulation of ALDH1A1 represents a new link in liver regeneration and detoxification.

Revealing modifier variations characterizations for elucidating the genetic basis of human phenotypic variations.

Epistatic interactions complicate the identification of variants involved in phenotypic effect. In-depth knowledge in modifiers and in pathogenic variants would benefit the mechanistic studies on the genetic basis of complex traits. We systematically compared the modifier variants which have evidence of modifier effect with the pathogenic variants from multiple angles. Our study found that genomic loci of modifier variations differ from pathogenic loci in many aspects, such as population genetics statistics, epigenetic features, evolutionary characteristics and functional properties of the variations. Genes containing modifier variation(s) exhibit higher probability of being haploinsufficient and higher probability of recessive disease causation, and they are relatively more important in network communication. Furthermore, we reinforced that co-expression analysis is an effective methodology to predict functional associations between modifier genes and their potential target genes. In many aspects, we detected statistically significant differences between modifier variants/genes and pathogenic variants/genes, and investigated relationships between modifiers and their potential targets. Our results offer some actionable insights that may provide appropriate guidelines to clinical genetics and researchers to elucidate the molecular mechanism underlying the human phenotypic variation.

Antibody-dependent enhancement (ADE) of dengue virus: Identification of the key amino acid that is vital in DENV vaccine research.

BACKGROUND: The antibody-dependent enhancement (ADE) of dengue virus (DENV) has critically restricted vaccine development. Prior research suggested pr4 as the probable ADE epitope of DENV. METHODS: Chimeric DENV was constructed by replacing the DENV pr4 gene with the corresponding Japanese encephalitis virus (JEV) gene to determine whether it can reduce ADE activities. An alanine scanning method and bioinformatics analysis were utilized to identify the amino acid of pr4 that was crucial as an ADE epitope. RESULTS: Chimeric virus reduced ADE and virulence. The amino acids at the following locations on the mutant peptides showed significantly reduced binding ability to prM antibody: pr4.5 (position 5 - leucine), pr4.6 (position 6 - leucine), pr4.7 (position 7 - phenyalanine) and pr4.16 (position 16 - cysteine). The four amino acids had formed a pocket-like structure, which could increase the possibility of binding to an antibody. CONCLUSIONS: ADE activities could be reduced by replacing the DENV pr4 gene with the corresponding JEV gene. Leucine at position 5, leucine at position 6, phenyalanine at position 7 and cysteine at position 16 were the key amino acid sites in the ADE response of DENV. The occurrence of ADE can potentially be reduced by the replacement of key amino acids, hence highlighting its possible contribution to dengue vaccine design, paving a way for future vaccine research.

Hepatocyte nuclear factor 4α negatively regulates connective tissue growth factor during liver regeneration.

Liver regeneration after injury requires fine-tune regulation of connective tissue growth factor (Ctgf). It also involves dynamic expression of hepatocyte nuclear factor (Hnf)4α, Yes-associated protein (Yap), and transforming growth factor (Tgf)-ß. The upstream inducers of Ctgf, such as Yap, etc, are well-known. However, the negative regulator of Ctgf remains unclear. Here, we investigated the Hnf4α regulation of Ctgf post-various types of liver injury. Both wild-type animals and animals contained siRNA-mediated Hnf4α knockdown and Cre-mediated Ctgf conditional deletion were used. We observed that Ctgf induction was associated with Hnf4α decline, nuclear Yap accumulation, and Tgf-ß upregulation during early stage of liver regeneration. The Ctgf promoter contained an Hnf4α binding sequence that overlapped with the cis-regulatory element for Yap and Tgf-ß. Ctgf loss attenuated inflammation, hepatocyte proliferation, and collagen synthesis, whereas Hnf4α knockdown enhanced Ctgf induction and liver fibrogenesis. These findings provided a new mechanism about fine-tuned regulation of Ctgf through Hnf4α antagonism of Yap and Tgf-ß activities to balance regenerative and fibrotic signals.

Transcriptional regulation of plant seed development.

Plant seeds, which are unique reproductive organs of gymnosperms and angiosperms, are used for edible, medicinal, and industrial purposes. Transcription factors (TFs) are master regulators of plant growth, development, and stress responses. This review describes, in detail, the functions of TFs in regulating seed development. Different TFs, or even different TF families, may have similar functions in seed development. For example, WUSCHEL-related homeobox, LEC2/FUS3/ABI3, and HEME ACTIVATOR PROTEIN3 families can control plant seed embryonic initiation and development. In contrast, some members of the same TF family may have completely opposite roles. For instance, AtMYB76 and AtMYB89 inhibit the accumulation of seed oil, whereas AtMYB96 promotes seed fatty acid accumulation in Arabidopsis thaliana. Compared with the number of studies that have addressed regulation by single TFs, only a few have focused on multiple-TF regulatory networks. This review should be useful as a reference for future studies on regulatory networks of TF complexes.

Sex-Specific Association of Blood Pressure Categories With All-Cause Mortality: The Rural Chinese Cohort Study.

INTRODUCTION: The relationship between blood pressure categories and all-cause mortality has not been fully addressed in cohort studies, especially in the general Chinese population. Our study aimed to assess the sex-specific association of systolic blood pressure (SBP), diastolic blood pressure (DBP), and 2017 United States hypertension guidelines with all-cause mortality in China. METHODS: We conducted a prospective study of 13,760 rural Chinese adults aged 18 or older (41.1% men). Mean age overall was 49.4, 51.0 for men, and 48.3 for women. We analyzed the blood pressure-mortality relationship by using restricted cubic splines and Cox proportional-hazards regression analysis, estimating hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: During a mean follow-up of 5.95 years, 710 people died (60.3% men) from any cause. We found a U-shaped SBP-mortality or DBP-mortality relationship for both sexes. Mortality risk was increased for men with SBP 120-139 mm Hg (adjusted HR [aHR], 1.42; 95% CI, 1.10-1.82) or ≥140 mm Hg (aHR, 2.05; 95% CI, 1.54-2.72), and for DBP ≥90 mm Hg (aHR, 1.53; 95% CI, 1.10-2.13) as compared with SBP 100-119 mm Hg or DBP 70-79 mm Hg. Mortality risk also was increased for men with blood pressure status defined according to 2017 US hypertension guidelines as elevated, SBP 120-129 and DBP >80 mm Hg (aHR 1.48; 95% CI,1.11-1.98); stage 1 hypertension, SBP/DBP 130-139/80-89 mm Hg (aHR 1.53; CI, 1.19-1.97); and stage 2 hypertension, SBP/DBP ≥140/90 mm Hg (aHR 1.83; CI, 1.33-2.51). No significant relationship was observed for women. CONCLUSION: Elevated blood pressure and stages 1 and 2 hypertension were positively associated with all-cause mortality for men but not women in rural China.

Spinal IL-36γ/IL-36R participates in the maintenance of chronic inflammatory pain through astroglial JNK pathway.

Emerging evidence indicates that spinal neuroinflammation contributes to the maintenance of chronic inflammatory pain. IL-36, as a novel member of the interleukin (IL)-1 super-family cytokines, plays an important role in inflammatory responses. The present study aimed to investigate the role of spinal IL-36 and IL-36 receptor (IL-36R) signaling in the pathology of chronic inflammatory pain. IL-36γ and IL-36R, but not IL-36α and IL-36ß, were persistently upregulated in the spinal cord of mice with intraplantar injections of complete Freund's adjuvant (CFA). Intrathecal administration of both IL-36R antagonist (IL-36Ra) and IL-36γ siRNA significantly attenuated CFA-induced chronic inflammatory pain behaviors. Furthermore, CFA-induced IL-36γ expression was mainly observed in spinal neurons whereas IL-36R was primarily expressed in spinal astrocytes. Additionally, the intrathecal injection of IL-36γ was sufficient to induce pain hypersensitivity and astrocyte activation in naive mice, and these effects could be inhibited by blocking c-Jun N-terminal kinase (JNK) phosphorylation. In vitro experiments also demonstrated that the IL-36γ could induce astrocytic JNK activation and inflammatory cytokines release, which was mediated by IL-36R. Finally, intrathecal injection of IL-36γ-activated astrocytes in a pJNK-dependent manner induced mechanical allodynia and thermal hyperalgesia in naive mice. Collectively, these findings reveal that the neuronal/astrocytic interaction in the spinal cord by which neuronally produced IL-36γ activates astrocytes via IL-36R-mediated JNK pathway is crucial for the maintenance of chronic inflammatory pain. Thus, IL-36γ/IL-36R-mediated astrocyte signaling may be a suitable therapeutic target for chronic inflammatory pain.

The association between fasting plasma glucose and all-cause and cause-specific mortality by gender: The rural Chinese cohort study.

BACKGROUND: To evaluate the association between fasting plasma glucose (FPG) and mortality by gender. METHODS: A total of 17 248 eligible participants from a rural Chinese prospective cohort population were included. The same questionnaire interview and anthropometric and laboratory measurements were performed at both baseline (2007-2008) and follow-up (2013-2014). Participants were classified according to baseline FPG and diabetic status by sex. Restricted cubic splines and Cox proportional-hazards regression models, estimating hazard ratio (HR) and 95% confidence interval (CI), were used to assess the FPG-mortality relation. RESULTS: During the 6-year follow-up, 618 men and 489 women died. The FPG-mortality relation was J shaped for both sexes. For men, risk of all-cause and noncardiovascular disease (CVD)/noncancer mortality was greater with low fasting glucose (LFG) than with normal fasting glucose (adjusted HR [aHR] 1.60; 95% CI, 1.05-2.43; and aHR 2.16; 95% CI, 1.15-4.05). Men with diabetes mellitus (DM) showed increased risk of all-cause (aHR 2.04; 95% CI, 1.60-2.60), CVD (aHR 1.98; 95% CI, 1.36-2.89), and non-CVD/noncancer mortality (aHR 2.62; 95% CI, 1.76-3.91). Men with impaired fasting glucose (IFG) had borderline risk of CVD mortality (aHR 1.34; 95% CI, 1.00-1.79). Women with LFG had increased risk of non-CVD/noncancer mortality (aHR 2.27; 95% CI, 1.04-4.95), and women with DM had increased risk of all-cause (aHR 1.73; 95% CI, 1.35-2.23), CVD (aHR 1.76; 95% CI, 1.24-2.50), and non-CVD/noncancer mortality (aHR 1.97; 95% CI, 1.27-3.08). CONCLUSIONS: LFG is positively associated with all-cause mortality risk in rural Chinese men but not in women.

Ablation of Ggnbp2 impairs meiotic DNA double-strand break repair during spermatogenesis in mice.

Gametogenetin (GGN) binding protein 2 (GGNBP2) is a zinc finger protein expressed abundantly in spermatocytes and spermatids. We previously discovered that Ggnbp2 resection caused metamorphotic defects during spermatid differentiation and resulted in an absence of mature spermatozoa in mice. However, whether GGNBP2 affects meiotic progression of spermatocytes remains to be established. In this study, flow cytometric analyses showed a decrease in haploid, while an increase in tetraploid spermatogenic cells in both 30- and 60-day-old Ggnbp2 knockout testes. In spread spermatocyte nuclei, Ggnbp2 loss increased DNA double-strand breaks (DSB), compromised DSB repair and reduced crossovers. Further investigations demonstrated that GGNBP2 co-immunoprecipitated with a testis-enriched protein GGN1. Immunofluorescent staining revealed that both GGNBP2 and GGN1 had the same subcellular localizations in spermatocyte, spermatid and spermatozoa. Ggnbp2 loss suppressed Ggn expression and nuclear accumulation. Furthermore, deletion of either Ggnbp2 or Ggn in GC-2spd cells inhibited their differentiation into haploid cells in vitro. Overexpression of Ggnbp2 in Ggnbp2 null but not in Ggn null GC-2spd cells partially rescued the defect coinciding with a restoration of Ggn expression. Together, these data suggest that GGNBP2, likely mediated by its interaction with GGN1, plays a role in DSB repair during meiotic progression of spermatocytes.

Ggnbp2-Null Mutation in Mice Leads to Male Infertility due to a Defect at the Spermiogenesis Stage.

Gametogenetin binding protein 2 (GGNBP2) is an evolutionarily conserved zinc finger protein. Although Ggnbp2-null embryos in the B6 background died because of a defective placenta, 6.8% of Ggnbp2-null mice in the B6/129 mixed background were viable and continued to adulthood. Adult Ggnbp2-null males were sterile, with smaller testes and an azoospermic phenotype, whereas mutant females were fertile. Histopathological analysis of 2-month-old Ggnbp2-null testes revealed absence of mature spermatozoa in the seminiferous tubules and epididymides and reduction of the number of spermatids. Ultrastructural analysis indicated dramatic morphological defects of developing spermatids in the Ggnbp2-null testes, including irregularly shaped acrosomes, acrosome detachment, cytoplasmic remnant, ectopic manchette, and ill-formed head shape in both elongating and elongated spermatids. However, the numbers of spermatogonia, spermatocytes, Leydig cells, and Sertoli cells in Ggnbp2-null testes did not significantly differ from the wild-type siblings. Gonadotropins, testosterone, and the blood-testis barrier were essentially unaffected. Western blot analyses showed increases in α-E-catenin, ß-catenin, and N-cadherin, decreases in E-cadherin, afadin, and nectin-3, and no changes in vinculin, nectin-2, focal adhesion kinase, and integrin-ß1 protein levels in Ggnbp2-null testes compared to wild-type siblings. Together, this study demonstrates that GGNBP2 is critically required for maintenance of the adhesion integrity of the adlumenal germ epithelium and is indispensable for normal spermatid transformation into mature spermatozoa in mice.

Association of change in waist circumference and dyslipidaemia risk: The rural Chinese cohort study.

OBJECTIVE: To investigate the association of change in waist circumference (WC) and incidence of dyslipidaemia in a cohort study of a rural Chinese population. METHODS: Change in WC (ΔWC) was defined as the value at follow-up minus the corresponding value at baseline. Risk of dyslipidaemia associated with ΔWC was assessed by odds ratios and 95% confidence intervals in a logistic regression model, and the odds ratios were transformed to relative risks (RRs). RESULTS: Among 7691 participants without dyslipidaemia at baseline, 3213 (41.78%) showed dyslipidaemia at 6 year follow-up. Risk of dyslipidaemia was decreased for participants with the first quartile of ΔWC and normal baseline WC (adjusted RR [aRR] = 0.79 [95% confidence interval: 0.64-0.98]) and was increased with the fourth quartile of ΔWC and male gender, age 18 to 30 years, age 31 to 50 years, or normal baseline WC (aRR = 1.55 [1.19-2.03], 2.40 [1.16-4.95], 1.32 [1.06-1.64], and 1.66 [1.35-2.04], respectively). The risk of dyslipidaemia increased with change in WC from normal at baseline to abnormal at follow-up for both genders (aRR = 1.88 [1.39-2.55] for men and 1.60 [1.30-1.97] for women) and decreased with abnormal baseline WC changed to normal WC for women (aRR = 0.61 [0.45-0.83]). CONCLUSIONS: Dynamic change in waist circumference was closely related to the incidence of dyslipidaemia in a rural Chinese population. Waist circumference reduction could decrease dyslipidaemia risk, whereas WC increase may increase the risk. Interventions to control or reduce WC to within the normal range are important for early prevention of dyslipidaemia.

Cohort study to determine the waist circumference cutoffs for predicting type 2 diabetes mellitus in rural China.

BACKGROUND: Limited information is available on the cutoffs of waist circumference (WC) for predicting type 2 diabetes mellitus (T2DM). We aimed to define the optimal WC cutoffs for predicting T2DM among rural Chinese people. METHODS: A cohort of 11 968 participants (732 new-onset T2DM) from a rural area in China with age 18 to 87 years was established at baseline during July to August of 2007 and 2008 and followed up during July to August of 2013 and 2014. Scatterplot, X-tile plot, and receiver operating characteristic (ROC) curve analyses were used to determine WC cutoffs for predicting T2DM. RESULTS: The WC cutoffs for males and females were 84 and 86 cm (scatterplot), 83 and 88 cm (X-tile plot), and 87 and 88 cm (ROC curve). According to the highest risk score, the optimal WC cutoffs were 87 cm for males and 88 cm for females. With the optimal WC cutoffs, the sensitivity, specificity, positive likelihood ratio, area under the ROC curve, and population-attributable risk proportions were 67.9%, 67.0%, 2.06%, 0.70%, and 46%, respectively, for males and 52.5%, 75.0%, 2.10%, 0.69%, and 34%, respectively, for females; the corresponding adjusted hazard ratio for WC predicting T2DM was 3.66 (95% confidence interval 2.80-4.78) for males and 2.55 (2.08-3.12) for females. CONCLUSIONS: The optimal WC cutoffs for predicting T2DM were similar between males and females. As well, the criteria of WC for central obesity are no longer practical for predicting T2DM.

Identification of an obesity index for predicting metabolic syndrome by gender: the rural Chinese cohort study.

BACKGROUND: To compare the accuracy of different obesity indexes, including waist circumference (WC), weight-to-height ratio (WHtR), body mass index (BMI), and lipid accumulation product (LAP), in predicting metabolic syndrome (MetS) and to estimate the optimal cutoffs of these indexes in a rural Chinese adult population. METHODS: This prospective cohort involved 8468 participants who were followed up for 6 years. MetS was defined by the International Diabetes Federation, American Heart Association, and National Heart, Lung, and Blood Institute criteria. The power of the 4 indexes for predicting MetS was estimated by receiver operating characteristic (ROC) curve analysis and optimal cutoffs were determined by the maximum of Youden's index. RESULTS: As compared with WHtR, BMI, and LAP, WC had the largest area under the ROC curve (AUC) for predicting MetS after adjusting for age, smoking, drinking, physical activity, and education level. The AUCs (95% CIs) for WC, WHtR, BMI, and LAP for men and women were 0.862 (0.851-0.873) and 0.806 (0.794-0.817), 0.832 (0.820-0.843) and 0.789 (0.777-0.801), 0.824 (0.812-0.835) and 0.790 (0.778-0.802), and 0.798 (0.785-0.810) and 0.771 (0.759-0.784), respectively. The optimal cutoffs of WC for men and women were 83.30 and 76.80 cm. Those of WHtR, BMI, and LAP were approximately 0.51 and 0.50, 23.90 and 23.00 kg/m2, and 19.23 and 20.48 cm.mmol/L, respectively. CONCLUSIONS: WC as a preferred index over WHtR, BMI, and LAP for predicting MetS in rural Chinese adults of both genders; the optimal cutoffs for men and women were 83.30 and 76.80 cm.

An X-linked Myh11-CreERT2 mouse line resulting from Y to X chromosome-translocation of the Cre allele.

The Myh11-CreERT2 mouse line (Cre+ ) has gained increasing application because of its high lineage specificity relative to other Cre drivers targeting smooth muscle cells (SMCs). This Cre allele, however, was initially inserted into the Y chromosome (X/YCre+ ), which excluded its application in female mice. Our group established a Cre+ colony from male ancestors. Surprisingly, genotype screening identified female carriers that stably transmitted the Cre allele to the following generations. Crossbreeding experiments revealed a pattern of X-linked inheritance for the transgene (k > 1000), indicating that these female carries acquired the Cre allele through a mechanism of Y to X chromosome translocation. Further characterization demonstrated that in hemizygous X/XCre+ mice Cre activity was restricted to a subset arterial SMCs, with Cre expression in arteries decreased by 50% compared to X/YCre+ mice. This mosaicism, however, diminished in homozygous XCre+ /XCre+ mice. In a model of aortic aneurysm induced by a SMC-specific Tgfbr1 deletion, the homozygous XCre+ /XCre+ Cre driver unmasked the aortic phenotype that is otherwise subclinical when driven by the hemizygous X/XCre+ Cre line. In conclusion, the Cre allele carried by this female mouse line is located on the X chromosome and subjected to X-inactivation. The homozygous XCre+ /XCre+ mice produce uniform Cre activity in arterial SMCs.

Cumulative increased risk of incident type 2 diabetes mellitus with increasing triglyceride glucose index in normal-weight people: The Rural Chinese Cohort Study.

BACKGROUND: Risk of type 2 diabetes mellitus (T2DM) is increased in metabolically obese but normal-weight people. However, we have limited knowledge of how to prevent T2DM in normal-weight people. We aimed to evaluate the association between triglyceride glucose (TyG) index and incident T2DM among normal-weight people in rural China. METHODS: We included data from 5706 people with normal body mass index (BMI) (18.5-23.9 kg/m2) without baseline T2DM in a rural Chinese cohort followed for a median of 6.0 years. A Cox proportional-hazard model was used to assess the risk of incident T2DM by quartiles of TyG index and difference in TyG index between follow-up and baseline (TyG-D), estimating hazard ratios (HRs) and 95% confidence intervals (CIs). A generalized additive plot was used to show the nonparametric smoothed exposure-response association between risk of T2DM and TyG index as a continuous variable. TyG was calculated as ln [fasting triglyceride level (mg/dl) × fasting plasma glucose level (mg/dl)/2]. RESULTS: Risk of incident T2DM was increased with quartiles 2, 3 and 4 versus quartile 1 of TyG index (adjusted HR [aHR] 2.48 [95% CI 1.20-5.11], 3.77 [1.83-7.79], and 5.30 [2.21-12.71], P trend < 0.001 across quartiles of TyG index). Risk of incident T2DM was increased with quartile 4 versus quartile 1 of TyG-D (aHR 3.91 [2.22-6.87]). The results were consistent when analyses were restricted to participants without baseline metabolic syndrome and impaired fasting glucose level. The generalized additive plot showed cumulative increased risk of T2DM with increasing TyG index. CONCLUSIONS: Risk of incident T2DM is increased with increasing TyG index among rural Chinese people, so the index might be an important indicator for identifying people at high risk of T2DM.

Avian Influenza A (H7N9) viruses isolated from patients with mild and fatal infection differ in pathogenicity and induction of cytokines.

Since 2013, a novel Influenza A (H7N9) virus strain has continued to circulate within poultry and causing human disease. Influenza A (H7N9) virus results in two types of infection: mild and severe. The different results of clinical findings may be related with host susceptibility and characteristics of the virus itself. In order to investigate potential pathogenesis of Influenza A (H7N9) virus, we performed pathogenecity and cytokines analysis of two isolates, A/Guangdong/6/2013 H7N9 virus (GD-6) from a patient with a mild infection, and A/Guangdong/7/2013 H7N9 virus (GD-7) from a patient with a fatal infection. We found that GD-7 replicated to higher levels than GD-6 in human peripheral blood mononuclear cells (PBMCs), lung tissues, and mice. Furthermore, GD-7 infection resulted in more severe lung damage in mice lung tissues than GD-6 infection. GD-7 elicited higher levels of interleukin-6 (IL-6) and tumor necrosis factor-α(TNF-α) than GD-6 did. In conclusion, GD-7 was more pathogenic and induced higher levels of proinflammatory cytokines than GD-6 did.

A risk-score model for predicting risk of type 2 diabetes mellitus in a rural Chinese adult population: A cohort study with a 6-year follow-up.

BACKGROUND: Several prediction tools have been developed to identify people with type 2 diabetes mellitus (T2DM) and to quantify the probability of developing T2DM. However, most of the risk models were constructed based on cross-sectional studies and tea-drinking was not included. METHODS: A total of 15 768 participants without known T2DM were followed up from 2007-2008 to 2013-2014; 12 654 were randomly assigned to the derivation dataset and 3114 to the validation dataset. We constructed a risk-score model for T2DM by using a Cox proportional-hazards model. Risk scores were calculated by multiplying ß by 10 in the derivation cohort and were verified in the validation dataset. The model's accuracy was assessed by the area under the receiver operating characteristic curve (AUC). RESULTS: Predictors for T2DM risk in the derivation dataset were drinking tea frequently, body mass index ≥28.0 kg/m2 , waist to height ratio ≥ 0.5, triglycerides level 1.70 to 2.25 and ≥2.26 mmol/L, and fasting plasma glucose 5.6 to 6.0 and ≥6.1 mmol/L. The corresponding scores were -2, 7, 7, 4, 6, 11, and 25, respectively. The sensitivity, specificity, and AUC (95% confidence interval) for this full model were 69.63%, 75.56%, and 0.791 (0.783-0.799), respectively. The ability of the non-invasive models to predict T2DM was not superior to that of the full model. With the validation dataset, the predictive performance was better for our full model than the Framingham risk-score model (AUC 0.731 vs 0.525, P < .001). CONCLUSIONS: Our risk-score model has fair efficacy for predicting 6-year risk of T2DM in a rural adult Chinese population.

Prediction of a new body shape index and body adiposity estimator for development of type 2 diabetes mellitus: The Rural Chinese Cohort Study.

To compare the ability of a body shape index (ABSI) and body adiposity estimator (BAE) to BMI, waist circumference (WC) and waist:height ratio (WHtR) for predicting development of type 2 diabetes mellitus (T2DM) in rural adult Chinese. The prospective cohort study included 11 687 eligible participants who were free of T2DM at baseline. The risk of new-onset T2DM for ABSI, BAE, BMI, WC and WHtR quintiles was estimated by Cox proportional-hazards regression at follow-up. We also compared the power of ABSI and BAE to BMI, WC and WHtR for predicting the development of T2DM. With increasing ABSI, BAE, BMI, WC and WHtR, T2DM incidence was substantially increased (P trend<0·0001). After adjustment for multi-covariates, risk of T2DM was increased from the second to fifth quintile as compared with first quintile for ABSI (1·27; 95 % CI 0·95, 1·69; 1·35; 95 % CI 1·00, 1·82; 1·75; 95 % CI 1·33, 2·32 and 1·87; 95 % CI 1·40, 2·49; P trend<0·0001); BAE (1·82; 95 % CI 1·38, 2·41; 1·93; 95 % CI 1·38, 2·68; 2·73; 95 % CI 1·94, 3·84 and 4·18; 95 % CI 2·98, 5·87; P trend<0·0001); BMI (1·42; 95 % CI 1·03, 1·97; 1·62; 95 % CI 1·18, 2·23; 2·59; 95 % CI 1·92, 3·50 and 3·90; 95 % CI 2·90, 5·26; P trend<0·0001); WC (1·53; 95 % CI 1·08, 2·17; 1·66; 95 % CI 1·18, 2·33; 2·72; 1·97, 3·76 and 4·09; 95 % CI 2·97, 5·62; P trend<0·0001); and WHtR (1·40; 95 % CI 0·98, 1·99; 2·06; 95 % CI 1·47, 2·88; 2·90; 95 % CI 2·10, 4·01 and 4·22; 95 % CI 3·05, 5·85; P trend<0·0001). ABSI, BAE, BMI, WC and WHR were effective and comparable in discriminating cases from non-cases of T2DM. Risk of T2DM was increased with elevated ABSI and BAE, but the predictive ability for T2DM did not differ than that of BMI, WC and WHtR in a rural Chinese population.