Meet the authors: Yu Zhou, Ting Shan, and Feiyan Liu.

We talk to authors Yu Zhou, Ting Shan, and Feiyan Liu about their paper "m6A modification negatively regulates translation by switching mRNA from polysome to P-body via IGF2BP3" (in this issue of Molecular Cell), their passion for RNA biology, and what it's like leading a "wet and dry" lab.

m6A modification negatively regulates translation by switching mRNA from polysome to P-body via IGF2BP3.

In the cytoplasm, mRNAs are dynamically partitioned into translating and non-translating pools, but the mechanism for this regulation has largely remained elusive. Here, we report that m6A regulates mRNA partitioning between polysome and P-body where a pool of non-translating mRNAs resides. By quantifying the m6A level of polysomal and cytoplasmic mRNAs with m6A-LAIC-seq and m6A-LC-MS/MS in HeLa cells, we observed that polysome-associated mRNAs are hypo-m6A-methylated, whereas those enriched in P-body are hyper-m6A-methylated. Downregulation of the m6A writer METTL14 enhances translation by switching originally hyper-m6A-modified mRNAs from P-body to polysome. Conversely, by proteomic analysis, we identify a specific m6A reader IGF2BP3 enriched in P-body, and via knockdown and molecular tethering assays, we demonstrate that IGF2BP3 is both necessary and sufficient to switch target mRNAs from polysome to P-body. These findings suggest a model for the dynamic regulation of mRNA partitioning between the translating and non-translating pools in an m6A-dependent manner.

The SARS-CoV-2 subgenome landscape and its novel regulatory features.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is currently a global pandemic. CoVs are known to generate negative subgenomes (subgenomic RNAs [sgRNAs]) through transcription-regulating sequence (TRS)-dependent template switching, but the global dynamic landscapes of coronaviral subgenomes and regulatory rules remain unclear. Here, using next-generation sequencing (NGS) short-read and Nanopore long-read poly(A) RNA sequencing in two cell types at multiple time points after infection with SARS-CoV-2, we identified hundreds of template switches and constructed the dynamic landscapes of SARS-CoV-2 subgenomes. Interestingly, template switching could occur in a bidirectional manner, with diverse SARS-CoV-2 subgenomes generated from successive template-switching events. The majority of template switches result from RNA-RNA interactions, including seed and compensatory modes, with terminal pairing status as a key determinant. Two TRS-independent template switch modes are also responsible for subgenome biogenesis. Our findings reveal the subgenome landscape of SARS-CoV-2 and its regulatory features, providing a molecular basis for understanding subgenome biogenesis and developing novel anti-viral strategies.

Optical nondegenerate solitons in a birefringent fiber with a 35 degree elliptical angle.

In this paper, we investigate the optical nondegenerate solitons in a birefringent fiber with a 35 degree elliptical angle. We derive the nondegenerate bright one- and two-soliton solutions by solving the coupled Schrödinger equation. The formation of nondegenerate solitons is related to the wave numbers of the solitons, and we further demonstrate that it is caused by the incoherent addition of different components. We note that the interaction between two degenerate solitons or a nondegenerate soliton and a degenerate soliton is usually inelastic. This is led to the incoherent interaction between solitons of different components and the coherent interaction between solitons of the same component. Through the asymptotic analysis, we find that the two degenerate solitons are elastic interactions under certain conditions, and analyzed the influence of the Kerr nonlinear intensity coefficient γ and the second-order group velocity dispersion ß2 in this system on solitons: the velocity and amplitude of the solitons are proportional to |ß2|, while the amplitude of the solitons is inversely proportional to γ. Two nondegenerate solitons are elastic interactions, but the phase of the soliton can be adjusted to make it inelastic. Furthermore, regardless of the situation mentioned above, total intensities of the solitons before the interaction are equal to that after the soliton interaction.

Nonlinear Pharmacokinetics of Topical Flurbiprofen Gel in a Phase I Study Among Chinese Healthy Adults.

INTRODUCTION: PDX-02 (Flurbiprofen sodium) is a topical nonsteroidal anti-inflammatory drug in gel formulation for local analgesia and anti-inflammation. A Phase I clinical trial was conducted to assess the safety, tolerability, and pharmacokinetics of single and multiple doses of PDX-02 gel in Chinese healthy adults. METHODS: The trial comprised three parts: (1) a single-dose ascending study with three dose levels (0.5%, 1% to 2% PDX-02 gel) applied on a 136 cm2 skin area; (2) a multiple-dose study with either 1% or 2% PDX-02 gel applied on a 136 cm2 skin area for 7 consecutive days; and (3) a high dose group with 2% PDX-02 gel on an 816 cm2 skin area and a frequent multiple dose group with 2% PDX-02 gel on a 272 cm2 skin area four times a day for 7 consecutive days. The safety, tolerability and pharmacokinetics of the PDX-02 gel were evaluated in each part. RESULTS: A total of sixty participants completed the trial, with all adverse events recovered and all positive skin reaction being transient and recovered. The overall absorption of topical PDX-02 gel was slow with a mean peak time exceeding 9 h. The elimination rate remained consistent between dose groups. A less-than-dose-proportional nonlinear pharmacokinetics relationship was observed within the studied dose range, and this is likely due to the autoinduction of skin first-pass metabolism. CONCLUSION: The topical PDX-02 gel showed favorable safety and tolerability in both single and multiple dosing studies, with a less-than-dose-proportional nonlinear pharmacokinetics observed.

Peroxynitrite-activated fluorescent probe with two reaction triggers for pathological diagnosis and therapeutic evaluation of inflammation.

Excessive peroxynitrite (ONOO-) is closely related to the occurrence and progression of inflammation. Therefore, the development of an efficacious ONOO- activatable probe holds great potential for the early diagnosis of pathological inflammation, and the direct evaluation of the therapeutic efficacy of active protectants. In this work, a new ONOO--activated fluorescent probe (SZP) which greatly improved the specificity and sensitivity (LOD = 8.03 nM) with large Stokes shift (150 nm) through introducing two reaction triggers (diphenyl phosphinate moiety, CC unsaturated bond) was rationally designed for rapid detecting ONOO- (within 2 min). The excellent properties of probe SZP enable it to realize the fluorescence-guided diagnosis of inflammation. More importantly, probe SZP has also been utilized to assess the anti-inflammatory efficacy of traditional Chinese medicines (TCMs) active ingredients for the remediation of inflammation by monitoring ONOO- fluctuation for the first time.

γ-Glutamyltranspeptidase-Activated Near-Infrared fluorescent probe for visualization of Drug-Induced liver injury.

Drug-induced liver injury (DILI), induced by overdose or chronic administration of drugs, has become the leading cause of acute liver failure. Therefore, an accurate diagnostic method for DILI is critical to improve treatment efficiency. The production of γ-glutamyltranspeptidase (GGT) is closely related to the progression of drug-induced hepatotoxicity. KL-Glu exhibits a prominent GGT-activated NIR fluorescence (734 nm) with a large Stokes shift (137 nm) and good sensitivity/selectivity, making it favorable for real-time detection of endogenous GGT activity. Using this probe, we evaluated the GGT up-regulation under the acetaminophen-induced liver injury model. Moreover, KL-Glu was successfully used to assess liver injury induced by the natural active ingredient triptolide and the effective amelioration upon treatment with N-acetyl cysteine (NAC) or Glutathione (GSH) in cells and in vivo by fluorescent trapping the fluctuation of GGT for the first time. Therefore, the fluorescent probe KL-Glu can be used as a potential tool to explore the function of GGT in the progression of DILI and for the early diagnosis and prognostic evaluation of DILI.

Ceramide Analog 5cc Overcomes TRAIL Resistance by Enhancing JNK Activation and Repressing XIAP Expression in Metastatic Colon Cancer Cells.

INTRODUCTION: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is considered to be an effective apoptosis inducer due to its selectivity for tumor cells. However, many cancer cells, especially metastatic cancer cells, often exhibit resistance to TRAIL because their apoptotic pathway is impaired or their pro-survival pathway is overactivated. TRAIL resistance is the main obstacle to current TRAIL therapy. Nowadays, ceramide analogs represent a new class of potential anticancer agents. Therefore, we hypothesized that disrupting pro-survival signaling with ceramide analogs would increase TRAIL-mediated apoptosis. METHODS: MTT assay and flow cytometry were conducted to evaluate the synergistic effect of ceramide analog 5cc on TRAIL in metastatic colon cancer cells. Western blot was used to detect signaling proteins affected by 5cc. RNA interference was performed to analyze the effects of specific gene on 5cc-enhanced apoptosis. RESULTS: Ceramide analog 5cc markedly enhanced TRAIL-induced apoptosis evidenced by increased propidium iodide/annexin V double-positive cells and PARP cleavage in SW620 and LS411N cells. At the molecular level, 5cc significantly reduced the expression of anti-apoptotic protein X-linked inhibitor of apoptosis protein (XIAP) through the activation of the c-Jun n-terminal kinase (JNK) pathway which is critically involved in sensitizing tumor cells to TRAIL/5cc combination. JNK-silenced cells exhibited a significant reversal of TRAIL/5cc-mediated apoptosis. CONCLUSION: Our data demonstrated that ceramide analog 5cc overcomes TRAIL resistance by enhancing JNK activation and repressing XIAP expression in metastatic colon cancer cells.

Modelling inflammatory biomarker dynamics in a human lipopolysaccharide (LPS) challenge study using delay differential equations.

Clinical studies in healthy volunteers challenged with lipopolysaccharide (LPS), a constituent of the cell wall of Gram-negative bacteria, represent a key model to characterize the Toll-like receptor 4 (TLR4)-mediated inflammatory response. Here, we developed a mathematical modelling framework to quantitatively characterize the dynamics and inter-individual variability of multiple inflammatory biomarkers in healthy volunteer LPS challenge studies. Data from previously reported LPS challenge studies were used, which included individual-level time-course data for tumour necrosis factor α (TNF-α), interleukin 6 (IL-6), interleukin 8 (IL-8) and C-reactive protein (CRP). A one-compartment model with first-order elimination was used to capture the LPS kinetics. The relationships between LPS and inflammatory markers was characterized using indirect response (IDR) models. Delay differential equations were applied to quantify the delays in biomarker response profiles. For LPS kinetics, our estimates of clearance and volume of distribution were 35.7 L h-1 and 6.35 L, respectively. Our model adequately captured the dynamics of multiple inflammatory biomarkers. The time delay for the secretion of TNF-α, IL-6 and IL-8 were estimated to be 0.924, 1.46 and 1.48 h, respectively. A second IDR model was used to describe the induced changes of CRP in relation to IL-6, with a delayed time of 4.2 h. The quantitative models developed in this study can be used to inform design of clinical LPS challenge studies and may help to translate preclinical LPS challenge studies to humans.

A system pharmacology Boolean network model for the TLR4-mediated inflammatory response in early sepsis.

Sepsis is a life-threatening condition driven by the dysregulation of the host immune response to an infection. The complex and interacting mechanisms underlying sepsis remain not fully understood. By integrating prior knowledge from literature using mathematical modelling techniques, we aimed to obtain a deeper mechanistic insight into sepsis pathogenesis and to evaluate promising novel therapeutic targets, with a focus on Toll-like receptor 4 (TLR4)-mediated pathways. A Boolean network of regulatory relationships was developed for key immune components associated with sepsis pathogenesis after TLR4 activation. Perturbation analyses were conducted to identify therapeutic targets associated with organ dysfunction or antibacterial activity. The developed model consisted of 42 nodes and 183 interactions. Perturbation analyses suggest that over-expression of tumour necrosis factor alpha (TNF-α) or inhibition of soluble receptor sTNF-R, tissue factor, and inflammatory cytokines (IFN-γ, IL-12) may lead to a reduced activation of organ dysfunction related endpoints. Over-expression of complement factor C3b and C5b led to an increase in the bacterial clearance related endpoint. We identified that combinatory blockade of IFN-γ and IL-10 may reduce the risk of organ dysfunction. Finally, we found that combining antibiotic treatment with IL-1ß targeted therapy may have the potential to decrease thrombosis. In summary, we demonstrate how existing biological knowledge can be effectively integrated using Boolean network analysis for hypothesis generation of potential treatment strategies and characterization of biomarker responses associated with the early inflammatory response in sepsis.

Carbon dots combined with masking agent for high selectivity detection of Cr(VI) to overcome interference associated challenges.

Hexavalent chromium (Cr(VI)) determination is of great importance to the public health because of its extensive sources and high toxicity. However, interference from non-target ions and complex matrix remains challenges for Cr(VI) detection. In this work, we constructed a novel sensing system for high selectivity detection of Cr(VI), which is composed of strong emitting carbon dots (CE-CDs) and a specific masking agent. The detection conditions, anti-interference capability and the sensing and masking mechanisms of CE-CDs-based sensing method were systematically investigated. The results revealed that the optimal detection conditions included pH 4-10, reaction time 180 s and CE-CDs concentration 18 mg/L. Under optimal conditions, the linear range of the method was up to 500 µm, and the detection limit was as low as 23 nM. In addition, the interference of Hg(II) can be accurately eliminated by using DMPS, an effective masking agent. During the sensing process, inner filter effect and ion-molecular interaction between Cr(VI) and CE-CDs accounted for the fluorescence quenching mechanism, while the efficient masking was attributed to the strong coordination interaction between Hg(II) and DMPS. Most notably, this method had broad applicability, even for the trace detection of Cr(VI) in colored leather with complex matrix. These findings indicate that this approach is expected to open up new avenues for Cr(VI) detection.

Histone methyltransferase activity programs nuclear peripheral genome positioning.

Spatial organization of the genome in the nucleus plays a critical role in development and regulation of transcription. A genomic region that resides at the nuclear periphery is part of the chromatin layer marked with histone H3 lysine 9 dimethyl (H3K9me2), but chromatin reorganization during cell differentiation can cause movement in and out of this nuclear compartment with patterns specific for individual cell fates. Here we describe a CRISPR-based system that allows visualization coupled with forced spatial relocalization of a target genomic locus in live cells. We demonstrate that a specified locus can be tethered to the nuclear periphery through direct binding to a dCas9-Lap2ß fusion protein at the nuclear membrane, or via targeting of a histone methyltransferase (HMT), G9a fused to dCas9, that promotes H3K9me2 labeling and localization to the nuclear periphery. The enzymatic activity of the HMT is sufficient to promote this repositioning, while disruption of the catalytic activity abolishes the localization effect. We further demonstrate that dCas9-G9a-mediated localization to the nuclear periphery is independent of nuclear actin polymerization. Our data suggest a function for epigenetic histone modifying enzymes in spatial chromatin organization and provide a system for tracking and labeling targeted genomic regions in live cells.

Verticillin A increases the BIMEL/MCL-1 ratio to overcome ABT-737-resistance in human colon cancer cells by targeting the MEK/ERK pathway.

ABT-737, a small molecule BH-3 mimetic, is less effective against human colon cancers due to its resistance. Verticillin A is a natural compound, which was previously purified from verticillium-infected mushrooms. Hence, we aimed at overcoming the ABT737 resistance observed in CRC tumors by combining Verticillin A with ABT-737 and figuring out the potential mechanism. In this study, we observed that Verticillin A could sensitize colon cancer to ABT-737-induced cell death through induction of mitochondrial-dependent apoptosis. Verticillin A could significantly increase the BIMEL/MCL-1 ratio to overcome ABT737 resistance through the suppression of the MEK/ERK pathway. In addition, up-regulation of BIM protein levels to activate BAX translocation results in apoptosis induction. Altogether, our work suggested the potential application of Verticillin A as a MEK inhibitor in BH3-mimetic-based therapy.

BMI and risk of all-cause mortality in normotensive and hypertensive adults: the rural Chinese cohort study.

OBJECTIVE: The impact of baseline hypertension status on the BMI-mortality association is still unclear. We aimed to examine the moderation effect of hypertension on the BMI-mortality association using a rural Chinese cohort. DESIGN: In this cohort study, we investigated the incident of mortality according to different BMI categories by hypertension status. SETTING: Longitudinal population-based cohort. PARTICIPANTS: 17 262 adults ≥18 years were recruited from July to August of 2013 and July to August of 2014 from a rural area in China. RESULTS: During a median 6-year follow-up, we recorded 1109 deaths (610 with and 499 without hypertension). In adjusted models, as compared with BMI 22-24 kg/m2, with BMI ≤ 18, 18-20, 20-22, 24-26, 26-28, 28-30 and >30 kg/m2, the hazard ratios for mortality in normotensive participants were 1·92 (95% CI 1·23, 3·00), 1·44 (95% CI 1·01, 2·05), 1·14 (95% CI 0·82, 1·58), 0·96 (95% CI 0·70, 1·31), 0·96 (95% CI 0·65, 1·43), 1·32 (95% CI 0·81, 2·14) and 1·32 (95% CI 0·74, 2·35), respectively, and in hypertensive participants were 1·85 (95% CI 1·08, 3·17), 1·67 (95% CI 1·17, 2·39), 1·29 (95% CI 0·95, 1·75), 1·20 (95% CI 0·91, 1·58), 1·10 (95% CI 0·83, 1·46), 1·10 (95% CI 0·80, 1·52) and 0·61 (95% CI 0·40, 0·94), respectively. The risk of mortality was lower in individuals with hypertension with overweight or obesity v. normal weight, especially in older hypertensives (≥60 years old). Sensitivity analyses gave consistent results for both normotensive and hypertensive participants. CONCLUSIONS: Low BMI was significantly associated with increased risk of all-cause mortality regardless of hypertension status in rural Chinese adults, but high BMI decreased the mortality risk among individuals with hypertension, especially in older hypertensives.

Dose-response association between adult height and all-cause mortality: a systematic review and meta-analysis of cohort studies.

BACKGROUND: We conducted a systematic review and meta-analysis from published cohort studies to examine the association of adult height and all-cause mortality and to further explore the dose-response association. METHODS: PubMed, The Cochrane Library, The Ovid, CNKI, CQVIP and Wanfang databases were searched for articles published from database inception to 6 February 2018. We used the DerSimonian-Laird random-effects model to estimate the quantitative association between adult height and all-cause mortality and the restricted cubic splines to model the dose-response association. RESULTS: We included 15 articles, with 1 533 438 death events and 2 854 543 study participants. For each 5-cm height increase below the average, the risk of all-cause mortality was reduced by 7% [relative risk (RR) = 0.93, 95% confidence interval (CI), 0.89-0.97] for men and 5% (RR = 0.95, 95% CI, 0.90-0.99) for women. All-cause mortality had a U-shaped association with adult height, the lowest risk occurring at 174 cm for men and 158 cm for women (both Pnonlinearity < 0.001). Relative to the shortest adult height (147 cm for men and 137 cm for women), men at 174 cm had a 47% lower likelihood of all-cause mortality and women at 158 cm a 33% lower risk of all-cause mortality. CONCLUSIONS: Our study suggests that the relation between adult height and all-cause mortality is approximately U-shaped in both men and women.

Baseline serum albumin and its dynamic change is associated with type 2 diabetes risk: A large cohort study in China.

BACKGROUND: The study aimed to investigate the associations of baseline serum albumin level and its dynamic change with type 2 diabetes mellitus (T2DM) risk in a large Chinese cohort study. METHODS: This cohort study included 30 442 adults without T2DM at first entry, who completed at least one follow-up of annual examinations between 2009 and 2016. Serum albumin level was measured at baseline and at every annual check-up. The dynamic change in serum albumin level (∆ALB) was calculated by subtracting serum albumin level at baseline from that at the last follow-up. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated with Cox regression models. RESULTS: During 7 years of follow-up, we identified 1634 T2DM events. From the lowest to the highest quartile of serum albumin level, adjusted HRs (95% CI) were 1.00 (reference), 0.96 (0.94, 1.01), 0.98 (0.95, 1.02) and 0.88 (0.85, 0.98), respectively. As compared with stable change in serum albumin (-0.2 ≤ ∆ALB <1.0 g/L), the risk of T2DM increased for ∆ALB < -2.0 g/L (HR 1.44, 95% CI 1.24-1.68) and decreased for ∆ALB ≥3.0 g/L (0.81, 0.68-0.97) after adjusting for potential confounding factors. Restricted cubic splines showed a linear dose-response association between baseline serum albumin level and T2DM risk (Pnonlinearity 0.715) and a nonlinear dose-response association between ∆ALB and T2DM risk (Pnonlinearity 0.011). CONCLUSIONS: Baseline serum albumin level appears to be inversely associated with T2DM risk. Adults with reduced serum albumin level could be early identified for diabetes risk in clinical practice.

Association of total sedentary behaviour and television viewing with risk of overweight/obesity, type 2 diabetes and hypertension: A dose-response meta-analysis.

AIMS: To explore the quantitative dose-response association of total sedentary behaviour and television viewing with overweight/obesity, type 2 diabetes and hypertension in a meta-analysis. MATERIALS AND METHODS: We searched three databases to identify English-language reports that assessed the association of total sedentary behaviour or television viewing with the aforementioned health outcomes. Restricted cubic splines were used to evaluate possible linear or non-linear associations of total sedentary behaviour and television viewing with these health outcomes. RESULTS: We included 48 articles (58 studies) with a total of 1 071 967 participants in the meta-analysis; 21 (six cohort and 15 cross-sectional) studies examined the association of total sedentary behaviour with overweight/obesity, 23 (13 cohort and 10 cross-sectional) studies examined the association with type 2 diabetes and 14 (one cohort and 13 cross-sectional) studies examined the association with hypertension. We found linear associations between total sedentary behaviour and type 2 diabetes (Pnon-linearity = 0.190) and hypertension (Pnon-linearity = 0.225) and a non-linear association between total sedentary behaviour and overweight/obesity (Pnon-linearity = 0.003). For each 1-h/d increase in total sedentary behaviour, the risk increased by 5% for type 2 diabetes and 4% for hypertension. We also found linear associations between television viewing and type 2 diabetes (Pnon-linearity = 0.948) and hypertension (Pnon-linearity = 0.679) and a non-linear association for overweight/obesity (Pnon-linearity = 0.007). For each 1-h/d increase in television viewing, the risk increased by 8% for type 2 diabetes and 6% for hypertension. CONCLUSIONS: High levels of total sedentary behaviour and television viewing were associated with overweight/obesity, type 2 diabetes and hypertension.

Race- and sex-specific association between alcohol consumption and hypertension in 22 cohort studies: A systematic review and meta-analysis.

BACKGROUND AND AIMS: The alcohol-hypertension relation has been well documented, but whether women have protective effect or race and type of beverage consumed affect the association remain unclear. To quantify the relation between total or beverage-specific alcohol consumption and incident hypertension by considering the effect of sex and race. METHODS AND RESULTS: Articles were identified in PubMed and Embase databases with no restriction on publication date. Pooled relative risks (RRs) and 95% confidence intervals (CIs) were calculated by random effects models. Restricted cubic splines were used to model the dose-response association. This study involved 22 articles (31 studies) and included 414,477 participants. The hypertension risk was different among liquor, wine, and beer at 5.1-10 g/d of ethanol consumption (P-across subgroups = 0.002). The hypertension risk differed between men (RR: 1.14, 95% CI: 1.07, 1.20) and women (RR: 0.98, 95% CI: 0.89, 1.06) at 10 g/d (P-across subgroups = 0.005). We found a linear alcohol-hypertension association among white (P-linearity = 0.017), black people (P-linearity = 0.035), and Asians (P-linearity<0.001). With 10 g/d increment of consumption, the RRs for hypertension were 1.06 (95% CI: 1.04, 1.08), 1.14 (95% CI: 1.01, 1.28), and 1.06 (95% CI: 1.01, 1.10) for Asians, black, and white people, respectively. CONCLUSION: Sex modifies the alcohol-hypertension association at low level of alcohol consumption and we did not find evidence of a protective effect of alcohol consumption among women. Black people may have higher hypertension risk than Asians and white people at the same ethanol consumption.

Association of weight-adjusted-waist index with incident hypertension: The Rural Chinese Cohort Study.

AIMS: To explore the association between WWI and the incidence of HTN in the Rural Chinese Cohort Study. METHODS AND RESULTS: We examined data for 10,338 non-hypertensive participants (39.49% men) aged ≥ 18 years from the Rural Chinese Cohort Study who completed a baseline examination during 2007-2008 and follow-up during 2013-2014. WWI was calculated as waist circumference (cm) divided by the square root of weight (kg). Multiple logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the probability of HTN across four WWI categories. Restricted cubic splines analysis was used to model the dose-response association of WWI and HTN. A total of 2078 participants had HTN during a median follow-up of 6 years. After adjusting for potential confounders, as compared with the lowest WWI category (<9.94 cm/√kg), with WWI 9.94 to 10.42, 10.42 to 10.91 and ≥ 10.91 cm/√kg, the ORs (95% CIs) for HTN were 1.12 (0.93-1.35), 1.40 (1.17-1.69) and 1.50 (1.24-1.82), respectively. Results of the sensitivity analyses were robust. The ORs were generally consistent on subgroup analysis by sex, smoking status, systolic blood pressure and diastolic blood pressure. Multiple logistic regression models with restricted cubic splines showed a non-linear positive association between WWI and HTN (Pnonlinearity < 0.001). CONCLUSION: The highest WWI category was significantly associated with increased risk of HTN. Our findings may facilitate the development and promotion of obesity prevention strategies aimed at reducing the risk of HTN and provide evidence for healthcare policy in rural China.

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.