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Introduction: To investigate the effect of high myopia on the expression of retinal osteopontin (OPN) and integrin αVβ 3 receptor in guinea pigs and determined the relationship between high myopia and diabetic retinopathy. Methods: Ninety 3-week-old male guinea pigs were randomly divided into four groups that included normal control group (NOR，n=18), high myopia group (HM，n=24), diabetes group (DR，n=24), and diabetes with high myopia group (DR+HM，n=24). HM was induced by form deprivation (FDHM) in the right eye. The DR group was injected with 5% streptozotocin(STZ) 280 mg/kg intraperitoneally in the lower left abdomen of guinea pigs. The DRHM group was subjected to the same treatment as the HM and DR groups. Eighteen guinea pigs in each group were randomly selected to complete the experimental measurement. After enucleation of eyeballs, HE and immunohistochemical staining were performed to observe the retina morphology and count the positive rate of OPN and integrin αvβ 3 receptor. Results: Diabetic retinal changes were found in group DR and HM+DR. The degree of retinal change in group HM+DR was less than that in group DR. In the DR group, the morphology of retinal tissue was loose, the number of cells decreased, increased retinal microaneurysms, and a small amount of small artery embolism and venous thrombosis were observed. Although the retinal structure in the HM+DR group also became thinner, looser, and disordered, only a small number of microaneurysms were observed compared with the diabetic group. Immunohistochemical staining showed that the expression of OPN and integrin αvβ 3 receptors in the diabetic groups (DR, HM+DR) was significantly higher than in the HM and NOR groups. The positive expression rates of OPN and integrin αvβ 3 receptors in group HM+DR were significantly lower than those in group DR (P < 0.05).Conclusion: The expression of OPN and integrin αvβ 3 receptor in the retina of diabetic guinea pigs with high myopia was lower than that of diabetic models, which may be due to the influence of high myopia on neovascularization in DR.

Introduction Diabetes management permeates patients’ daily routines and interacts with their living context. Less is known about how older Chinese couples view their supportive roles and the allocation of the management responsibility between them. Objectives To explore dyadic appraisal, coping and the barriers to diabetes management shared by older Chinese couples. Methods A qualitative study of older couples where at least one partner had type 2 diabetes mellitus was implemented in four communities of Guangzhou, China. Four focus groups containing 11 couples, and ten in-depth interviews with individual couples were conducted sequentially. All of the data were coded with Nvivo 11 using thematic analysis. Results The majority of the older couples interviewed appraised diabetes as a shared problem, taking part in monitoring and altering each other’s health status and behaviour. Limited knowledge and a lack of accurate information about diabetes negatively impacted the patients’ self-management and their spouse’s ability to support them. A female dominated-care pattern was evident that female spouses, regardless of their health status, were actively involved in or fully responsible for managing their husband’s health. Older couples’ management practices were also shaped by family responsibilities and their living environment. Conclusions Our study provides first-hand evidence of older Chinese couples’ daily interactions and the main barriers to diabetes management. It is vital to provide health education directly to older couples to empower them to access adequate mutual support when managing chronic diseases.

IKBKE, a non-canonical inflammatory kinase, is frequently amplified or activated, and plays predominantly oncogenic roles in human cancers, especially in breast cancer. However, the potential function and underlying mechanism of IKBKE contributing to breast cancer metastasis remain largely elusive. Here, we report that depletion of Ikbke markedly decreases polyoma virus middle T antigen (PyVMT)-induced mouse mammary tumorigenesis and subsequent lung metastasis. Biologically, ectopic expression of IKBKE accelerates, whereas depletion of IKBKE attenuates breast cancer invasiveness and migration in vitro and tumor metastasis in vivo. Mechanistically, IKBKE tightly controls the stability of transcriptional factor Snail in different layers, in particular by directly phosphorylating Snail, which markedly blocks the E3 ligase β-TRCP1-mediated Snail degradation, resulting in breast cancer epithelial-mesenchymal transition (EMT) and metastasis. These findings together reveal a novel oncogenic function of IKBKE in promoting breast cancer metastasis by governing Snail abundance, and highlight the potential of targeting IKBKE for metastatic breast cancer therapies.

Background Low-income Chinese women aged 60 years and older are more likely to have multiple non-communicable diseases (NCDs). Neither the independent healthcare system nor the social work system based on the communities is equipped to address their complex needs of health and daily care. The objective was to design and evaluate a social worker-led self-management program for older community-dwelling women with NCDs. MethodsA total of 144 and 138 subjects were recruited in the intervention and control groups from 10 communities in Guangzhou, China. The intervention group was designed as follows: each community recruited two social workers to carry out an NCD self-management program. A health care professional assisted social workers to complete six weekly two-hour sessions. The control group had no extra intervention. The evaluation was conducted at baseline and 12-months follow-up. Outcomes included changes in weight, blood pressure, fasting plasma glucose (FPG), lipid profile, self-management behaviors, and NCD-related knowledge. Results After 12 months, participants had gained 3.6 and 6.6 kg (P=0.025 for between-group difference) in the intervention and control groups, respectively. NCD-related knowledge increased by 15.4% and 11.3% (PP difference=0.031). General linear regression analysis showed that the intervention effects were significant for FPG (P=0.013) and total cholesterol (TC) (P=0.046).ConclusionsA social worker-led NCD self-management program successfully promoted NCD-related knowledge and decreased metabolic risk factors in low-income Cantonese women.Trial registrationChinese Clinical Trial Registry:Evaluation on effectiveness of Non-communicable Disease Self-management models led by social organization. ChiCTR1800015659. Registered 13 April 2018 - Retrospectively registered, http://www.chictr.org.cn/showproj.aspx?proj=15005

Transcriptional factors (TFs) play a central role in governing gene expression under physiological conditions including the processes of embryonic development, metabolic homeostasis and response to extracellular stimuli. Conceivably, the aberrant dysregulations of TFs would dominantly result in various human disorders including tumorigenesis, diabetes and neurodegenerative diseases. Serving as the most evolutionarily reserved TFs, Fox family TFs have been explored to exert distinct biological functions in neoplastic development, by manipulating diverse gene expression. Recently, among the Fox family members, the pilot roles of FoxAs attract more attention due to their functions as both pioneer factor and transcriptional factor in human tumorigenesis, particularly in the sex-dimorphism tumors. Therefore, the pathological roles of FoxAs in tumorigenesis have been well-explored in modulating inflammation, immune response and metabolic homeostasis. In this review, we comprehensively summarize the impressive progression of FoxA functional annotation, clinical relevance, upstream regulators and downstream effectors, as well as valuable animal models, and highlight the potential strategies to target FoxAs for cancer therapies.

Constipation is characterized by reduced number of bowel movements, dry stools, and difficult defecation. Yangyin Tongmi capsule (YTC), a traditional Chinese formula, is used in the treatment of constipation, while the underlying mechanisms remain unknown. Herein, this work attempted to prove the effects of YTC on constipation treatment and its possible mechanisms. KM mice were randomly divided into four groups (n = 10/group) and treated with double distilled water (Control), diphenoxylate (Model: 10 mg/kg), or diphenoxylate plus low-dose YTC (L-YTC: 0.6 g/kg) or high-dose YTC (H-YTC: 1.2 g/kg). The data indicated that YTC can significantly shorten the discharge time of the first black stool, improve intestinal propulsion rate, and increase the water content and quantity of feces in mice. ELISA suggested that YTC regulate the content of intestinal hormones and neurotransmitters, such as motilin (MTL), gastrin (GT), somatostatin (SST), substance P (SP), acetylcholine (Ach), and nitric oxide (NO). The expression levels of aquaporin 3 (AQP3) and aquaporin 8 (AQP8) in the colon were examined by immunohistochemistry. In the meantime, the expression levels of P2X2, C-kit, and stem cell factor (SCF) in the colon were examined by western blot analysis. The results of this study suggest that YTC has mitigative effects on diphenoxylate-induced constipation by regulating the content of intestinal hormones and neurotransmitters and regulating the expression of related proteins in the colon.

Additional file 2. Activity planning demonstration. A demonstration of the intervention implemented on participants specific to each single day of the week.

Additional file 3. Evaluation of couple intervention. Evalutaion of patients and their spouses during intervention implementation.

Additional file 1. The SPIRIT reporting guidelines. The SPIRIT 2013 checklist our manuscript follows according to the recommendations on it.

20(S)-Protopanaxadiol (PPD) is one of the major active metabolites in ginseng saponin. Our previous studies revealed a broad spectrum of antitumor effects of PPD. Angiotensin II (Ang II), the biologically active peptide of the renin-angiotensin system (RAS), plays a critical role in the metastasis of various cancers. However, its role in the anti-metastatic effects of PPD is not clearly understood. In this study, we investigated the inhibitory effect of PPD on Ang II-induced epithelial-mesenchymal transition (EMT) in non-small cell lung cancer (NSCLC) cells, and the potential molecular mechanisms of suppression of NSCLC migration and metastasis by PPD. Treatment of A549 cells with Ang II increased metastases in an experimental model of cancer metastasis in vivo. PPD effectively prevented Ang II-induced EMT, as indicated by upregulation of E-cadherin and downregulation of vimentin. Additionally, Ang II upregulated the class III deacetylase sirtuin 1 (SIRT1) expression in EMT progression, while downregulation of SIRT1 was involved in suppression of Ang II-induced EMT by PPD. Moreover, the inhibitory effect of PPD was reversed by SIRT1 upregulation, and PPD demonstrated synergy with an SIRT1 inhibitor on Ang II-induced EMT. Taken together, our data reveal the mechanism of the anti-metastatic effects of PPD on Ang II-induced EMT and indicate that PPD can be used as an effective anti-tumor treatment.

Background Health literacy and health-information seeking behaviour (HISB) play vital roles in health outcome improvements. This study examines the extent of income-related inequality in health literacy and health-information seeking as well as the contributions of the main socioeconomic determinants in China. Methods We analysed representative data of participants aged over 18 years as well as older adults from the Guangzhou Community Health Survey. A concentration index (CI) was used to quantify the degree of income-related inequity in health literacy and health-information seeking. Probit regression models were employed to decompose the CI into the contributions to each factor. Results Results showed a significant pro-rich distribution of adequate health literacy (CI: 0.0602, P < 0.001; horizontal index [HI]: 0.0562, P < 0.001) and HISB from healthcare professionals (CI: 0.105, P < 0.001; HI: 0.0965, P < 0.001). The pro-rich distribution of health literacy was mainly attributable to education background (contribution: 54.76%), whereas income inequalities contributed most to the pro-rich distribution of health-information seeking among an urban population (contribution: 62.53%). Conclusion Public interventions in China to reduce inequality in health literacy and HISBs among the urban population, coupled with easily accessible information sources on health, warrant further attention from policymakers.

Ribosomal protein S1 of Mycobacterium tuberculosis (MtRpsA) binds to ribosome and mRNA, and plays significant role in the regulation of translation initiation, conventional protein synthesis and transfer-messenger RNA (tmRNA) mediated trans-translation. It has been identified as the target of pyrazinoic acid (POA), a bactericidal moiety from hydrolysis of pyrazinamide, which is a mainstay of combination therapy for tuberculosis. POA prevented the interactions between the C-terminal S1 domain of MtRpsA (residues 280-368, MtRpsA(CTD)_S1) and tmRNA; so that POA can inhibit the trans-translation, which is a key component of multiple quality control pathways in bacteria. However, the details of molecular mechanism and dynamic characteristics for MtRpsA(CTD)_S1 interactions with POA, tmRNA or mRNA are still unclear. Here we present the (1)H, (15)N, (13)C resonance assignments of MtRpsA(CTD)_S1 as well as the secondary structure information based on backbone chemical shifts, which lay foundation for further solution structure determination, dynamic properties characterization and interactions investigation between MtRpsA(CTD)_S1 and tmRNA, RNA or POA.

BACKGROUND Hypertension is a growing problem worldwide and can often result in a variety of negative health outcomes. The aim of this study was to assess the effects of age at diagnosis, calendar period, and birth cohort on the change in the prevalence rate of hypertension in Guangzhou from 2004 to 2013. METHODS We used data from the Guangzhou Community Health Survey, a population-based study designed by the National Health and Family Planning Commission of the PRC every 5 years. A total of 27,299, 23,467, and 18,362 participants aged 15–79 years completed the survey in 2004, 2009, and 2013, respectively. RESULTS Age effects increased slowly before the age of 42 years but increased rapidly after the age of 42 years, peaking at 79 years. Cohort effects grew slowly before the end of the 1960s but grew quickly after the end of the 1960s. The risk of suffering from hypertension among people born in 1962, 1972, 1982, and 1992 was 1.39, 2.68, 5.55, and 11.53 times, respectively, than that of people born in 1952. The period effects increased 25% from 2004 to 2009 and later declined 27% from 2009 to 2013 in the entire population. There was no gender difference in age effects and period effects, but strong cohort effects on hypertension were observed among males compared with females. CONCLUSIONS For Chinese individuals, the later one is born, the higher the risk is of suffering from hypertension. Strong cohort effects for hypertension were observed among males compared with females, indicating that males are more easily affected by hypertension based on the change in birth cohort.

Background: We aimed to describe the trends and associated factors of hypertension among residents aged ≥15 yr in Guangzhou, China. Methods: Three standardized cross-sectional health surveys were conducted in 2004, 2009 and 2013 using a multi-stage cluster sampling method, and a total of 69128 qualified participants were included in the study. The data were obtained through physical health examination and questionnaire survey. Results: The age-standardised prevalence of hypertension increased from 12.5% to 16.0% between 2004 and 2009 and declined from 16.0% to 14.0% between 2009 and 2013, and crude prevalence respectively was 14.6%, 19.1% and 18.8% in 2004, 2009 and 2013. The proportion of optimal blood pressure dropped from 51.1% to 33.2%, high-normal blood pressure increased from 20.1% to 28.9%, grade 1 hypertension and grade 2 or 3 hypertension increased from 11.5% to 13.6% and 3.9% to 5.8% between 2004 and 2013. The average age was significantly increased (P

Genetic variation of NEDD4L has been associated with hypertension and related phenotypes with conflicting results, probably attributable to gender-, age- and ethnicity-related variations in its phenotypic expression. We evaluated the association of three representative polymorphisms in NEDD4L (rs2288774, rs3865418 and rs4149601) with essential hypertension (EH) in a community-based sample of men (n = 1029) and women (n = 869) belonging to Han Chinese, Southern China, to probe whether gender interacts with NEDD4L in contributing to the risk of EH. In this population sample, rs4149601 was excluded from further analysis due to deviation from Hardy-Weinberg equilibrium. For two other variants tested, the allele frequencies and genotype distributions did not differ between cases and controls (p 0.05) when both genders were combined. However, sex-stratified analysis revealed that the distribution of the dominant model of rs2288774 (TC + CC versus TT) and the additive and dominant (CT + TT versus CC) models of rs3865418 differed significantly between cases and controls in men (p = 0.044, 0.041 and 0.016, respectively) but not in women. After adjusting for confounding factors, logistic regression analysis showed that rs2288774 and rs3865418 (in the dominant model) were still significantly associated with EH (rs2288774: OR = 0.73, 95% CI = 0.57-0.95, p = 0.017 and rs3865418: OR = 0.71, 95% CI = 0.55-0.92, p = 0.009) in men. There was a significant interaction between the NEDD4L genotype and gender (p for interaction: 0.046 for rs2288774 and 0.033 for rs3865418). Genetic variation in NEDD4L may have sex-dependent effects in the development of EH in Han Chinese. Previous studies that ignore gender-specific effects in their design and interpretation could have failed to identify a uniform conclusion.

Objective data on hypertension prevalence and management in local areas are scarce. We assessed the prevalence of hypertension and its management in Guangzhou adult population.A stratified multistage cluster sampling with probability proportional to size method was used in this survey. Information on a total of 23 939 respondents, aged 15 years old or above, having a gender ratio of 0.997 (male versus female) with completed questionnaire and blood pressure measurement, was obtained. Hypertension was defined as having a mean SBP of at least 140 mm Hg, a DBP of at least 90 mm Hg, and/or the prescription of antihypertensive drugs. Information related to the history of hypertension and treatment of hypertension was collected through a questionnaire.The prevalence of hypertension was 11.8%. Among patients with hypertension, 54.4% were aware of their elevated BP, 49.3% had treatment, and 23.3% achieved targeted BP control. Among those who were aware of their hypertension, 90.4% underwent treatment, and among those who were treated, 43.6% were well controlled. Although the prevalence, awareness and treatment of hypertension varied significantly among adults with several social economics status, the control of hypertension did not show significant differences. Among treated patients, the control of hypertension showed significant differences among adults with education, occupation, insurance and income.It is the first time for Guangzhou to describe epidemic and management of hypertension. A baseline was established, which could provide useful information not only to policymakers but also to developing countries with a close urbanization and aging rate similar to Guangzhou.

Prion diseases are a group of fatal neurodegenerative illnesses, resulting from the conformational conversion of the cellular prion protein (PrPC) into a misfolded form (PrPSc). The formation of neurotoxic soluble prion protein oligomer (PrPO) is regarded as a key step in the development of prion diseases. About 10%-15% of human prion diseases are caused by mutations in the prion protein gene; however, the underlying molecular mechanisms remain unclear. In the present work, we compared the biophysical properties of wild-type (WT) human prion protein 91-231 (WT HuPrP91-231) and its disease-associated variants (P105L, D178N, V203I, and Q212P) using several biophysical techniques. In comparison with WT HuPrPC, the Q212P and D178N variants possessed greatly increased conversion propensities of PrPC into PrPO, while the V203I variant had dramatically decreased conversion propensity. The P105L variant displayed a similar conversion propensity to WT HuPrPC Guanidine hydrochloride-induced unfolding experiments ranked the thermodynamic stabilities of these proteins as Q212P

Human α-defensins are cationic peptides that self-associate into dimers and higher-order oligomers. They bind protein toxins, such as anthrax lethal factor (LF), and kill bacteria, including Escherichia coli and Staphylococcus aureus, among other functions. There are six members of the human α-defensin family: four human neutrophil peptides, including HNP1, and two enteric human defensins, including HD5. We subjected HD5 to comprehensive alanine scanning mutagenesis. We then assayed LF binding by surface plasmon resonance, LF activity by enzyme kinetic inhibition, and antibacterial activity by the virtual colony count assay. Most mutations could be tolerated, resulting in activity comparable with that of wild type HD5. However, the L29A mutation decimated LF binding and bactericidal activity against Escherichia coli and Staphylococcus aureus. A series of unnatural aliphatic and aromatic substitutions at position 29, including aminobutyric acid (Abu) and norleucine (Nle) correlated hydrophobicity with HD5 function. The crystal structure of L29Abu-HD5 depicted decreased hydrophobic contacts at the dimer interface, whereas the Nle-29-HD5 crystal structure depicted a novel mode of dimerization with parallel β strands. The effect of mutating Leu29 is similar to that of a C-terminal hydrophobic residue of HNP1, Trp26. In addition, in order to further clarify the role of dimerization in HD5 function, an obligate monomer was generated by N-methylation of the Glu21 residue, decreasing LF binding and antibacterial activity against S. aureus. These results further characterize the dimer interface of the α-defensins, revealing a crucial role of hydrophobicity-mediated dimerization.

The human α-defensins (HNP) are synthesized in vivo as inactive prodefensins, and contain a conserved glycine, Gly(17), which is part of a β-bulge structure. It had previously been shown that the glycine main chain torsion angles are in a D-configuration, and that d-amino acids but not L-alanine could be substituted at that position to yield correctly folded peptides without the help of a prodomain. In this study, the glycine to L-alanine mutant defensin was synthesized in the form of a prodefensin using native chemical ligation. The ligation product folded correctly and yielded an active peptide upon CNBr cleavage. The L-Ala(17)-HNP1 crystal structure depicted a β-bulge identical to wild-type HNP1. However, dimerization was perturbed, causing one monomer to tilt with respect to the other in a dimerization model. Inhibitory activity against the anthrax lethal factor showed a 2-fold reduction relative to wild-type HNP1 as measured by the inhibitory concentration IC(50). Self-association was slightly reduced, as detected by surface plasmon resonance measurements. According to the results of the virtual colony count assay, the antibacterial activity against Escherichia coli, Staphylococcus aureus, and Bacillus cereus exhibited a less than 2-fold reduction in virtual lethal dose values. Prodefensins with two other L-amino acid substitutions, Arg and Phe, at the same position did not fold, indicating that only small side chains are tolerable. These results further elucidate the factors governing the region of the β-bulge structure that includes Gly(17), illuminating why glycine is conserved in all mammalian α-defensins.

The chaperone activity of Hsp70 in protein folding and its conformational switching are regulated through the hydrolysis of ATP and the ATP-ADP exchange cycle. It was reported that, in the presence of physiological concentrations of ATP (approximately 5 mM) and ADP (approximately 0.5 mM), Hsp70 catalyzes ATP-ADP exchange through transfer of gamma-phosphate between ATP and ADP, via an autophosphorylated intermediate, whereas it only catalyzes the hydrolysis of ATP in the absence of ADP. To clarify the functional domain of the ATP-ADP exchange activity of Hsp70, we isolated the 44-kD ATPase domain of Hsp70 after limited proteolysis with alpha-chymotrypsin (EC 3.4.21.1). The possibility of ATP-ADP exchange activity of a contaminating nucleoside diphosphate kinase (EC 2.7.4.6) was monitored throughout the experiments. The purified 44-kD ATPase domain exhibited intrinsic ATP-ADP exchange by catalyzing the transfer of gamma-phosphate between ATP and ADP with acid-stable autophosphorylation at Thr204.

The 14-3-3 proteins are highly conserved molecules that function as intracellular adaptors in a variety of biological processes, such as signal transduction, cell cycle control, and apoptosis. Here, we show that a 14-3-3 protein is a heat-shock protein (Hsp) that protects cells against physiological stress as its new cellular function. We have observed that, in Drosophila cells, the 14-3-3ζ is up-regulated under heat stress conditions, a process mediated by a heat shock transcription factor. As the biological action linked to heat stress, 14-3-3ζ interacted with apocytochrome c, a mitochondrial precursor protein of cytochrome c, in heat-treated cells, and the suppression of 14-3-3ζ expression by RNA interference resulted in the formation of significant amounts of aggregated apocytochrome c in the cytosol. The aggregated apocytochrome c was converted to a soluble form by the addition of 14-3-3ζ protein and ATP in vitro. 14-3-3ζ also resolubilized heat-aggregated citrate synthase and facilitated its reactivation in cooperation with Hsp70/Hsp40 in vitro. Our observations provide the first direct evidence that a 14-3-3 protein functions as a stress-induced molecular chaperone that dissolves and renaturalizes thermal-aggregated proteins.

A novel methodology for the creating C—P bond via the oxidative coupling of a wide range of arylboronic acids with various H-phosphine oxides in the presence of palladium catalyst under dry air as the green oxidant is described.

The RV144 vaccine trial implicated epitopes in the C1 region of gp120 (A32-like epitopes) as targets of potentially protective antibody-dependent cellular cytotoxicity (ADCC) responses. A32-like epitopes are highly immunogenic, as infected or vaccinated individuals frequently produce antibodies specific for these determinants. Antibody titers, as measured by enzyme-linked immunosorbent assay (ELISA) against these epitopes, however, do not consistently correlate with protection. Here, we report crystal structures of CD4-stabilized gp120 cores complexed with the Fab fragments of two nonneutralizing, A32-like monoclonal antibodies (MAbs), N5-i5 and 2.2c, that compete for antigen binding and have similar antigen-binding affinities yet exhibit a 75-fold difference in ADCC potency. We find that these MAbs recognize overlapping epitopes formed by mobile layers 1 and 2 of the gp120 inner domain, including the C1 and C2 regions, but bind gp120 at different angles via juxtaposed V H and V L contact surfaces. A comparison of structural and immunological data further showed that antibody orientation on bound antigen and the capacity to form multivalent antigen-antibody complexes on target cells were key determinants of ADCC potency, with the latter process having the greater impact. These studies provide atomic-level definition of A32-like epitopes implicated as targets of protective antibodies in RV144. Moreover, these studies establish that epitope structure and mode of antibody binding can dramatically affect the potency of Fc-mediated effector function against HIV-1. These results provide key insights for understanding, refining, and improving the outcome of HIV vaccine trials, in which relevant immune responses are facilitated by A32-like elicited responses. IMPORTANCE HIV-1 Env is a primary target for antibodies elicited during infection. Although a small number of infected individuals elicit broadly neutralizing antibodies, the bulk of the humoral response consists of antibodies that do not neutralize or do so with limited breadth but may effect protection through Fc receptor-dependent processes, such as antibody-dependent cellular cytotoxicity (ADCC). Understanding these nonneutralizing responses is an important aspect of elucidating the complete spectrum of immune response against HIV-1 infection. With this report, we provide the first atomic-level definition of nonneutralizing CD4-induced epitopes in the N-terminal region of the HIV-1 gp120 (A32-like epitopes). Further, our studies point to the dominant role of precise epitope targeting and mode of antibody attachment in ADCC responses even when largely overlapping epitopes are involved. Such information provides key insights into the mechanisms of Fc-mediated function of antibodies to HIV-1 and will help us understand the outcome of vaccine trials based on humoral immunity.

Introduction This article reports on the prevalence of noncommunicable diseases (NCDs) and their risk factors in the city of Guangzhou, China, and shows a trend toward epidemic proportions when municipal data are compared with provincial data. Methods We conducted the Guangzhou Community Health Survey in the 12 administrative districts of Guangzhou to learn about NCDs and their risk factors. A community-based, face-to-face survey with a stratified multistage cluster sampling was used. Information was gathered on 27,743 respondents, aged 0 to 108 years, with a male to female ratio of 1 to 1. All participants completed a questionnaire, and those aged 15 years or older had a physical examination. Survey results were compared with the provincial results of the 2002 Guangdong Nutrition and Health Survey (GNHS). Results The data were weighted to the respondent’s probability of selection and to the age- and sex-specific population. Prevalence estimate of self-reported NCDs was 16.0%. Hypertension and diabetes were reported as the most important NCDs. Of those who responded, 6.8% reported having more than 2 chronic conditions. The adjusted prevalence of hypertension decreased by 13.3% since 2002. Awareness, treatment, and control of hypertension and diabetes were improved. The estimated prevalence of current smoking decreased, and the prevalence of former smoking increased from 2002. However, the prevalence of overweight and obesity, especially central obesity, increased. Conclusion Results were encouraging with regard to hypertension and diabetes. However, the unfavorable trends, especially for overweight, central obesity, and passive smoking, call for additional action.

We present a novel and highly efficient methodology that allows for the construction of C–P bonds via the palladium-catalyzed air-based oxidative coupling of various commercially available arylboronic acids with easily oxidized H-phosphine oxides leading to valuable aryl phosphine oxides, particularly triarylphosphine oxides, with the use of air as the green oxidant, broad substrate applicability and good to excellent yields. The described catalytic system should be an efficient complement to the Chan–Lam type reaction and be useful in synthetic programs.

HNP1 is a human alpha defensin that forms dimers and multimers governed by hydrophobic residues, including Tyr¹⁶, Ile²⁰, Leu²⁵, and Phe²⁸. Previously, alanine scanning mutagenesis identified each of these residues and other hydrophobic residues as important for function. Here we report further structural and functional studies of residues shown to interact with one another across oligomeric interfaces: I20A-HNP1 and L25A-HNP1, plus the double alanine mutants I20A/L25A-HNP1 and Y16A/F28A-HNP1, and the quadruple alanine mutant Y16A/I20A/L25A/F28A-HNP1. We tested binding to HIV-1 gp120 and HNP1 by surface plasmon resonance, binding to HIV-1 gp41 and HNP1 by fluorescence polarization, inhibition of anthrax lethal factor, and antibacterial activity using the virtual colony count assay. Similar to the previously described single mutant W26A-HNP1, the quadruple mutant displayed the least activity in all functional assays, followed by the double mutant Y16A/F28A-HNP1. The effects of the L25A and I20A single mutations were milder than the double mutant I20A/L25A-HNP1. Crystallographic studies confirmed the correct folding and disulfide pairing, and depicted an array of dimeric and tetrameric structures. These results indicate that side chain hydrophobicity is the critical factor that determines activity at these positions.

OBJECTIVES: This research aimed to (i) determine the prevalence of metabolic syndrome (MetS) and its components; (ii) assess factors associated with MetS, and (iii) define optimal ethnic-specific cutoffs of obesity- and atherogenic-based markers to predict MetS among postmenopausal women in rural Canton. METHODOLOGY/PRINCIPAL FINDINGS: The Rural Canton Diabetes and Metabolic Disorders Study, a population based cross-sectional study, was conducted during 2011-2012 in Canton. In person interviews, blood glucose and lipid measurements were completed for 4,706 postmenopausal women who did not receive hormone replacement therapy. MetS was diagnosed using criteria of the Joint-Interim-Statement (JIS), the International-Diabetes-Federation (IDF) and the Modified-Third-Adult-Treatment-Panel (M-ATPIII). Age-standardized prevalence of MetS was 38.4%, 28.8%, and 37.1% according to JIS, IDF, and M-ATPIII criteria, respectively. Excellent agreement was observed between three definitions (κ ≥ 0.79), in particular between JIS and ATPIII (κ = 0.98, 95%CI: 0.97-0.98). Factors positively associated with MetS were living in Southern Canton, personal income, current smoking, higher BMI, and family history of cardiovascular disease. However, regular leisure-time physical activity can have protective effects. The optimal cutoff values for waist-circumference (WC), waist-to-hip ratio (WHR), waist-to-height ratio(WHtR), BMI, HDL-cholesterol to total cholesterol ratio (HDL/TC), HDL-cholesterol to LDL-cholesterol ratio (HDL/LDL), and triglyceride to HDL-cholesterol ratio (TG/HDL) that predicted the presence of MetS were 79.5 cm, 0.86, 0.53, 22.47 kg/m(2), 0.33, 0.68, and 0.88, respectively. CONCLUSIONS: This study highlights the importance of MetS among postmenopausal women in rural Canton. Our findings contribute to help selecting Cantonese-specific markers to predict MetS and support the need to establish educational program for promoting healthy-lifestyles among this population.

Trehalose-6-phosphate phosphatase (TPP) is an essential enzyme for growth of mycobacteria, which has been identified to be a potential anti-tuberculosis drug target. However, the biochemical and ligand-binding properties and the 3D structure of TPP remain unclear so far. In the present study, we expressed the recombinant TPP protein from Mycobacterium tuberculosis (otsB2/Rv3372). Results from the far-ultraviolet circular dichroism experiments indicated that the secondary structure of TPP was rich in α-helix with a lower structural stability (Cm = 2.099 ± 0.134 M). Ligand-binding assay by isothermal titration calorimetry demonstrated that the recombinant TPP protein could bind with trehalose-6-P in the presence of Mg(2+) (Kd = 39.52 ± 1.78 μM) with a molar ratio of 1 : 1. In addition, the 3D structure of TPP was modeled by I-TASSER, indicating that the TPP protein was composed of a hydrolase domain, a cap domain, and an N-terminal domain. Flexible docking was further conducted by using the Simulations/Dock module of the Molecular Operating Environment software. The binding pocket of TPP for both trehalose-6-P and Mg(2+) was determined, which was located on the interface between the hydrolase domain and the cap domain. Asp149, Gly186, Arg187, Arg291, and Glu295 were identified to be the key residues for TPP binding with trehalose-6-P. This work may lay the basis for further structural and functional studies of TPP and TPP-related novel drug development.

NEDD4L is a candidate gene for hypertension, both functionally and genetically. Recently, studies showed evidence for the association of NEDD4L with obesity, a key intermediate phenotype in hypertension. To further investigate the relationship between NEDD4L and body mass-related phenotypes, we genotyped three common variants (rs2288774, rs3865418 and rs4149601) in a population-based study of 892 unrelated Han Cantonese using the Sequenom MALDI-TOF-MS platform. Allele frequencies and genotype distribution were calculated in lean controls and overweight/obese cases and analyzed for association by the Chi-squared test and Logistic regression. Linear regression analysis was used to analyze the effect of individual genotypes on quantitative traits. Multivariate analyses demonstrated that the minor allele of rs4149601(A = 20.9%) was associated with a 2.60 kg, 2.78 cm and 0.97 kg/m2 decrease per allele copy in weight, waist and BMI, respectively. Carriers of this allele also had a significant lower risk of overweight/obesity (p < 0.0001, OR = 0.52, 95% CI: 0.37–0.74) as compared to non-carriers. However, no significant association between genotypes at rs2288774 and rs3865418 and covariate-adjusted overweight/obesity or any related phenotypes was observed. These results suggested that the functional variant of NEDD4L, rs4149601, may be associated with obesity and related phenotypes, and further genetic and functional studies are required to understand its role in the manifestation of obesity.

The HIV-1 envelope glycoprotein (Env) undergoes conformational transitions consequent to CD4 binding and coreceptor engagement during viral entry. The physical steps in this process are becoming defined, but less is known about their significance as targets of antibodies potentially protective against HIV-1 infection. Here we probe the functional significance of transitional epitope exposure by characterizing 41 human mAbs specific for epitopes exposed on trimeric Env after CD4 engagement. These mAbs recognize three epitope clusters: cluster A, the gp120 face occluded by gp41 in trimeric Env; cluster B, a region proximal to the coreceptor-binding site (CoRBS) and involving the V1/V2 domain; and cluster C, the coreceptor-binding site. The mAbs were evaluated functionally by antibody-dependent, cell-mediated cytotoxicity (ADCC) and for neutralization of Tiers 1 and 2 pseudoviruses. All three clusters included mAbs mediating ADCC. However, there was a strong potency bias for cluster A, which harbors at least three potent ADCC epitopes whose cognate mAbs have electropositive paratopes. Cluster A epitopes are functional ADCC targets during viral entry in an assay format using virion-sensitized target cells. In contrast, only cluster C contained epitopes that were recognized by neutralizing mAbs. There was significant diversity in breadth and potency that correlated with epitope fine specificity. In contrast, ADCC potency had no relationship with neutralization potency or breadth for any epitope cluster. Thus, Fc-mediated effector function and neutralization coselect with specificity in anti-Env antibody responses, but the nature of selection is distinct for these two antiviral activities.

The oncoprotein MDM2 negatively regulates the activity and stability of the p53 tumor suppressor and is an important molecular target for anticancer therapy. Aided by mirror image phage display and native chemical ligation, we have previously discovered several proteolysis-resistant duodecimal d-peptide antagonists of MDM2, termed (D)PMI-α, β, γ. The prototypic d-peptide inhibitor (D)PMI-α binds ((25-109))MDM2 at an affinity of 220 nM and kills tumor cells in vitro and inhibits tumor growth in vivo by reactivating the p53 pathway. Herein, we report the design of a superactive d-peptide antagonist of MDM2, termed (D)PMI-δ, of which the binding affinity for ((25-109))MDM2 has been improved over (D)PMI-α by 3 orders of magnitude (K(d) = 220 pM). X-ray crystallographic studies validate (D)PMI-δ as an exceedingly potent inhibitor of the p53-MDM2 interaction, promising to be a highly attractive lead drug candidate for anticancer therapeutic development.

CcmG is a periplasmic, membrane-anchored protein widely distributed in a variety of species. In Escherichia coli, the CcmG protein always acts as a weak reductant in the electron transport chain during cytochrome c maturation (Ccm). Here we report (1)H, (15)N and (13)C backbone and side-chain resonance assignments of the reduced CcmG protein (residues 19-185, renumbered as 1-167) from E. coli. This work lays the essential basis for the further structural and functional analysis of reduced CcmG.

Peptidyl-prolyl isomerase Pin1 specifically catalyzes the cis/trans-isomerization of proline in the target sequence of phosphorylated Ser/Thr-Pro in over 50 critical regulatory proteins. Pin1 is abnormally overexpressed in a range of human cancers, including lung, breast, colon and prostate cancers. However, few reports of Pin1 overexpression are currently available in clinical samples. Therefore, we examined the expression of Pin1 and p53 in non-pathological human tissues and esophageal cancer tissues. In esophageal cancer tissues, Pin1 and p53 immunoreactivity was detected in cancer cells in 67 and 58% of cases, respectively. Moreover, Pin1 and p53 immunoreactivity was significantly correlated with lymph node-positive disease and more advanced cancer stage. The results demonstrated that high expression levels of Pin1 correlated with high levels of p53. Therefore, Pin1 is suggested to play key roles in the regulation of esophageal cancer.

Inactivation of tumor-related genes by promoter hypermethylation is a common epigenetic event in the development of variety of tumors. Dermo1 (also called twist2) is a novel cancer-related gene which belongs to the basic helix-loop-helix (bHLH) transcription factor family. Herein, we report that dermo1 expression was sporadically abrogated in human cancer cells by transcriptional silencing associated with CpG island promoter hypermethylation. Direct sequencing of bisulfite-modified DNA from a panel of seven human cancer cell lines (HL60, Molm14, MV4-11, RS4:11, MDM-BA231, H358, and H1299) revealed that CpG dinucleotides in the dermo1 promoter were methylated. RT-PCR results demonstrated that dermo1 CpG island hypermethylation was accompanied by a low basal dermo1 expression level. Our data implicate dermo1 as a tumor suppressor gene and a valuable molecular marker for human cancer.