The E3 ligase adapter cereblon targets the C-terminal cyclic imide degron.

The ubiquitin E3 ligase substrate adapter cereblon (CRBN) is a target of thalidomide and lenalidomide1, therapeutic agents used in the treatment of haematopoietic malignancies2-4 and as ligands for targeted protein degradation5-7. These agents are proposed to mimic a naturally occurring degron; however, the structural motif recognized by the thalidomide-binding domain of CRBN remains unknown. Here we report that C-terminal cyclic imides, post-translational modifications that arise from intramolecular cyclization of glutamine or asparagine residues, are physiological degrons on substrates for CRBN. Dipeptides bearing the C-terminal cyclic imide degron substitute for thalidomide when embedded within bifunctional chemical degraders. Addition of the degron to the C terminus of proteins induces CRBN-dependent ubiquitination and degradation in vitro and in cells. C-terminal cyclic imides form adventitiously on physiologically relevant timescales throughout the human proteome to afford a degron that is endogenously recognized and removed by CRBN. The discovery of the C-terminal cyclic imide degron defines a regulatory process that may affect the physiological function and therapeutic engagement of CRBN.

Risk factors associated with weak and asymmetric handgrip strength in older Chinese adults.

OBJECTIVES: This study sought to investigate the potential risk factors associated with weak and asymmetric handgrip strength (HGS) in older Chinese adults. METHODS: A total of 2702 participants aged ≥65 years from the two waves of data (2011 and 2013) from the China Health and Retirement Longitudinal Study were analyzed. The highest recorded HGS values (Method A) or the average HGS values (Method B) for the dominant hand were used to compute the HGS asymmetry (nondominant HGS/dominant HGS out of 0.9-1.1) and HGS weakness (male <28 kg, female <18 kg). Risk factors associated with the weak and asymmetric HGS were identified by logistic regression analysis. RESULTS: Risk factors associated with weak and asymmetric HGS of varying severity differed between the two methods. Both methods identified age and illiteracy as risk factors for weak HGS with 10%-20% asymmetry. Method A also identified speech impediment, stroke, and sleep duration as additional risk factors. Similarly, both methods identified age, illiteracy, primary school education and below, diabetes, and stroke as risk factors for weak HGS and asymmetry over 30.1%. Method B additionally identified a history of falls as a risk factor. However, apart from age, the risk factors for weak HGS with 20.1%-30% asymmetry differed between the two methods-Method A identified kidney disease, while Method B identified illiteracy and asthma. CONCLUSIONS: The results revealed that risk factors associated with the abnormal HGS in older adults varied based on the methods used to define these conditions.

Prediction of the effects of small molecules on the gut microbiome using machine learning method integrating with optimal molecular features.

BACKGROUND: The human gut microbiome (HGM), consisting of trillions of microorganisms, is crucial to human health. Adverse drug use is one of the most important causes of HGM disorder. Thus, it is necessary to identify drugs or compounds with anti-commensal effects on HGM in the early drug discovery stage. This study proposes a novel anti-commensal effects classification using a machine learning method and optimal molecular features. To improve the prediction performance, we explored combinations of six fingerprints and three descriptors to filter the best characterization as molecular features. RESULTS: The final consensus model based on optimal features yielded the F1-score of 0.725 ± 0.014, ACC of 82.9 ± 0.7%, and AUC of 0.791 ± 0.009 for five-fold cross-validation. In addition, this novel model outperformed the prior studies by using the same algorithm. Furthermore, the important chemical descriptors and misclassified anti-commensal compounds are analyzed to better understand and interpret the model. Finally, seven structural alerts responsible for the chemical anti-commensal effect are identified, implying valuable information for drug design. CONCLUSION: Our study would be a promising tool for screening anti-commensal compounds in the early stage of drug discovery and assessing the potential risks of these drugs in vivo.

JAK2 inhibitors for the treatment of Philadelphia-negative myeloproliferative neoplasms: current status and future directions.

The overactivation of Janus kinases 2 (JAK2) by gain-of-function mutations in the JAK2, Myeloproliferative leukemia virus oncogene, or Calreticulin genes are the most important factor in the development of Philadelphia-negative myeloproliferative neoplasms (MPNs). The discovery of the JAK2V617F mutation is a significant breakthrough in understanding the pathogenesis of MPNs, and inhibition of JAK2 abnormal activation has become one of the most effective strategies against MPNs. Currently, three JAK2 inhibitors for treating MPNs have been approved, and several are being evaluated in clinical trials. However, persistent challenges in terms of drug resistance and off-target effects remain unresolved. In this review, we introduce and classify the available JAK2 inhibitors in terms of their mechanisms and clinical considerations. Additionally, through an analysis of target points, binding modes, and structure-activity inhibitor relationships, we propose strategies such as combination therapy and allosteric inhibitors to overcome specific challenges. This review offers valuable insights into current trends and future directions for optimal management of MPNs using JAK2 inhibitors.

Association of Educational Level and Marital Status With Obesity: A Study of Chinese Twins.

The prevalence of overweight and obesity is growing rapidly in many countries. Socioeconomic inequalities might be important for this increase. The aim of this study was to determine associations of body mass index (BMI), overweight and obesity with educational level and marital status in Chinese twins. Participants were adult twins recruited through the Chinese National Twin Registry (CNTR), aged 18 to 79 years, and the sample comprised 10,448 same-sex twin pairs. Current height, weight, educational attainment, and marital status were self-reported. Regression analyses and structural equation models were conducted to evaluate BMI, overweight, and obesity associated with educational level and marital status in both sexes. At an individual level, both educational level and marital status were associated with higher BMI and higher risk of being overweight and obesity in men, while in women the effects of educational level on BMI were in the opposite direction. In within-Monozygotic (MZ) twin-pair analyses, the effects of educational level on BMI disappeared in females. Bivariate structural equation models showed that genetic factors and shared environmental confounded the relationship between education and BMI in females, whereas marital status was associated with BMI on account of significant positive unique environmental correlation apart in both sexes. The present data suggested that marital status and BMI were associated, independent of familiar factors, for both sexes of this study population, while common genetic and shared environmental factors contributed to education-associated disparities in BMI in females.

Molecular epidemiology is becoming complex under the dynamic HIV prevalence: The perspective from Harbin, China.

Unlike most areas of China, HIV transmission via men who have sex with men (MSM) is increasing rapidly, and has become the main route of HIV transmission in Harbin city. The purpose of the current study was to elaborate the molecular epidemiologic characteristics of the new HIV epidemic. Eighty-one HIV-1 gag gene sequences (HXB2:806-1861) from local HIV infections were isolated; CRF01_AE predominated among HIV infections (71.6%), followed by subtype B (16.5%), CRF07_BC (6.2%), and unique recombinant strains (URFs; 6.2%). URFs were most often identified in the MSM population, which consisted of a recombination of CRF01_AE with subtype B or CRF07_BC. Six clusters were formed in this analysis; clusters I and II mainly circulated in southwest China. Clusters III and IV mainly circulated in southwest, southeast, and central China. Clusters V and VI mainly circulated in north and northeast China. Clusters III and IV may facilitate the transmission of the CRF01_AE strain from the southwest to the north and northeast regions of China. HIV subtypes are becoming diverse with the persistent epidemic in this geographic region. In brief, our results indicate that the molecular epidemiology of HIV is trending to be more complex. Thus, timely molecular epidemiologic supervision of HIV is necessary, especially for the MSM population.

The association of cigarette smoking and alcohol drinking with body mass index: a cross-sectional, population-based study among Chinese adult male twins.

BACKGROUND: Obesity is a multifactorial abnormality which has an underlying genetic control but requires environmental influences to trigger. Numerous epidemiological studies have examined the roles of physical inactivity and dietary factors in obesity development. Interactions between obesity-related genes and these lifestyles have also been confirmed. However, less attention has been paid to these complex relationship between cigarette smoking, alcohol drinking and obesity. The purpose of this study was to assess whether cigarette smoking and alcohol drinking were associated with body mass index (BMI), and whether these lifestyle factors modified the genetic variance of BMI. METHODS: Subjects were twins recruited through the Chinese National Twin Registry, aged 18 to 79 years, and the sample comprised 6121 complete male twin pairs. Information on height, weight, cigarette smoking and alcohol drinking status were assessed with self-report questionnaires. The associations of cigarette smoking and alcohol drinking with BMI were evaluated by linear regression models. Further, structure equation models were conducted to estimate whether cigarette smoking and alcohol drinking status modified the degree of genetic variance of BMI. RESULTS: After adjustment for a variety of socio-demographic and lifestyle factors, former smokers had higher BMI (ß = 0.475; 95 % CI, 0.196 to 0.754) whereas moderate to heavy smokers had lower BMI (ß = -0.115; 95 % CI, -0.223 to -0.007) when compared with nonsmokers. BMI decreased with increased cigarette pack-years (ß = -0.008; 95 % CI, -0.013 to -0.003). These effects still existed substantially in within-MZ twin pair analyses. By contrast, current alcohol drinking had no significant influence on BMI when additionally controlled for shared factors in within-pair analyses. Genetic modification by alcohol drinking was statistically significant for BMI (ß = -0.137; 95 % CI, -0.215 to -0.058), with the intake of alcohol decreasing the additive genetic component of BMI. CONCLUSIONS: Cigarette smoking was negatively associated with BMI independent of genetic influences. The influence of genes on BMI was moderated by alcohol drinking, such that for individuals who were regular drinkers, genetic factors became less influential. Our findings highlight gene-alcohol interaction in finding candidate genes of BMI and elucidating the etiological factors of obesity.

Genetic and Environmental Influences on Obesity-Related Phenotypes in Chinese Twins Reared Apart and Together.

The relative importance of genetic and environmental influences on obesity-related phenotypes remains unclear, and few studies have targeted the Chinese population. Here, we used Chinese twins reared apart and together to explore genetic and environmental influences on body mass index (BMI), waist circumference (WC) and waist-height ratio (WHtR), further to differentiate phenotype heritability between different age groups and genders separately and to differentiate influences of rearing environment and correlated environment. Phenotype heritability was calculated using the structural equation model in 11,401 twin pairs aged 25-85 years. BMI (0.70, 95 % confidence interval (CI) 0.66-0.74) of the total population was highly heritable, while WC (0.53, 95 %CI 0.50-0.57) and WHtR (0.48, 95 %CI 0.45-0.51) were moderately heritable. Age and gender stratified analyses found higher heritability in the younger group and males than the older group and females. The correlated environment had a greater influence on the phenotypes than the rearing environment, especially on WC and WHtR, indicating that more correlated environment actions should be taken to prevent the rising trend of abdominal obesity.

The relationship between anthropometric indices and type 2 diabetes mellitus among adults in north-east China.

OBJECTIVE: The present study was performed to test the predictive value of different cut-off points of anthropometric parameters for the presence of type 2 diabetes (T2DM) or glucose tolerance abnormalities in north-east Chinese adults. DESIGN: Multistage random cluster sampling method in a cross-sectional study. SETTING: Height, body weight, maximal body weight in the past, waist and hip circumferences, blood pressure, 2 h post-load glucose and other lifestyle factors were measured. SUBJECTS: We used data from 1058 adults aged 20 years or over, selected in the city of Mudanjiang, in 2005. RESULTS: BMI, maximal BMI in the past (MAXBMI), waist:hip ratio (WHR), waist:height ratio (WHtR) and waist circumference (WC) were significantly correlated with each other. Partial correlation coefficients between WHtR and WC, and between MAXBMI and BMI, were higher than those between the other indices. The association of anthropometric indices with T2DM or glucose tolerance abnormalities was significantly highest for the collaboration cut-off points of MAXBMI (≥ 23.0 kg/m(2) for T2DM, ≥ 22.0 kg/m(2) for glucose tolerance abnormalities) with WHtR (≥ 0.52). Areas under the receiver-operating characteristic curves also showed that WHtR was a better anthropometric index that discriminated between the presence and absence of T2DM and an excellent indicator with high Youden's index. CONCLUSIONS: MAXBMI combined with WHtR was a better anthropometric index associated with T2DM or glucose tolerance abnormalities. The combined use of these two measures is a good choice for T2DM prevention and screening.

Genetic and Environmental Effects on Weight, Height, and BMI Under 18 Years in a Chinese Population-Based Twin Sample.

This study examined the genetic and environmental effects on variances in weight, height, and body mass index (BMI) under 18 years in a population-based sample from China. We selected 6,644 monozygotic and 5,969 dizygotic twin pairs from the Chinese National Twin Registry (CNTR) aged under 18 years (n = 12,613). Classic twin analyses with sex limitation were used to estimate the genetic and environmental components of weight, height, and BMI in six age groups. Sex-limitation of genetic and shared environmental effects was observed, especially when puberty begins. Heritability for weight, height, and BMI was low at 0-2 years old (less than 20% for both sexes) but increased over time, accounting for half or more of the variance in the 15-17 year age group for boys. For girls, heritabilities for weight, height and BMI was maintained at approximately 30% after puberty. Common environmental effects on all body measures were high for girls (59-87%) and presented a small peak during puberty. Genetics appear to play an increasingly important role in explaining the variation in weight, height, and BMI from early childhood to late adolescence, particularly in boys. Common environmental factors exert their strongest and most independent influence specifically in the pre-adolescent period and more significantly in girls. These findings emphasize the need to target family and social environmental interventions in early childhood years, especially for females. Further studies about puberty-related genes and social environment are needed to clarify the mechanism of sex differences.

Utilizing the resource of twins reared apart: their distribution across nine provinces or cities of China.

Twins reared apart provide a fascinating experiment to distinguish genetic from environmental influences. However, there is as yet no broad report on distribution of twins reared apart, especially in the Chinese population. In this study, information on 18,295 volunteer twin pairs of all age groups was compiled in nine provinces or cities of China, and questionnaires were used for zygosity determination. It was discovered that twins reared apart from 0 to 10 years of age accounted for 2.2% of all twin interviewees, with the proportion of this 0-10 group separated before 1, 2, and 5 years old, accounting for 65.3%, 76.1%, and 91.3%, respectively. The proportion of twins reared apart is not significantly related to zygosity or gender, but it is related to region and twin age. As the age of twins lowers, the proportion of those reared apart gradually decreases. Twins reared apart will become rarer in the future and therefore should be cherished as a resource.

Potential for targeting small heat shock protein modifications.

Small heat shock proteins (sHSPs) play key roles in cellular stress and several human diseases. The direct effects of some post-translational modifications (PTMs) on certain sHSPs have been characterized, raising the possibility that small molecules could be used to modulate these modifications and indirectly up- or downregulate sHSP activity.

PGC-1α participates in regulating mitochondrial function in aged sarcopenia through effects on the Sestrin2-mediated mTORC1 pathway.

BACKGROUND: Mitochondrial dysregulation in skeletal myocytes is considered a major factor in aged sarcopenia. In this study, we aimed to study the effects of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) on Sestrin2-mediated mechanistic target of rapamycin complex 1 (mTORC1) in aged skeletal muscles. METHODS: C2C12 myoblasts were stimulated by 50 µM 7ß-hydroxycholesterol (7ß-OHC) to observe the changes of DNA damage, mitochondrial membrane potential (Δψm), mitochondrial ROS and PGC-1α protein. The PGC-1α silence in the C2C12 cells was established by siRNA transfection. The levels of DNA damage, Δψm, mitochondrial ROS, Sestrin2 and p-S6K1/S6K1 proteins were observed after the PGC-1α silence in the C2C12 cells. Recombinant Sestrin2 treatment was used to observe the changes of DNA damage, Δψm, mitochondrial ROS and p-S6K1/S6K1 protein in the 7ß-OHC-treated or PGC-1α siRNA-transfected C2C12 cells. Wild-type (WT) mice and muscle-specific PGC-1α conditional knockout (MKO) mice, including young and old, were used to analyse the effects of PGC-1α on muscle function and the levels of Sestrin2 and p-S6K1 in the white gastrocnemius muscles. Recombinant Sestrin2 was administrated to analyse its effects on muscle function in the old WT mice and old MKO mice. RESULTS: 7ß-OHC treatment induced DNA damage, mitochondrial dysfunction and decrease of PGC-1α protein in the C2C12 cells. PGC-1α silence also induced DNA damage and mitochondrial dysfunction in the C2C12 cells. Additionally, PGC-1α silence or 7ß-OHC treatment decreased the levels of Sestrin2 and p-S6K1/S6K1 protein in the C2C12 cells. Recombinant Sestrin2 treatment significantly improved the DNA damage and mitochondrial dysfunction in the 7ß-OHC-treated or PGC-1α siRNA-transfected C2C12 cells. At the same age, muscle-specific PGC-1α deficiency aggravated aged sarcopenia and decreased the levels of Sestrin2 and p-S6K1 in the white gastrocnemius muscles when compared to the WT mice. Recombinant Sestrin2 treatment improved muscle function and increased p-S6K1 levels in the old two genotypes. CONCLUSION: This research demonstrates that PGC-1α participates in regulating mitochondrial function in aged sarcopenia through effects on the Sestrin2-mediated mTORC1 pathway.

The accuracy of different calculation methods when identifying handgrip strength asymmetry among middle-aged and older Chinese adults.

At present, there is no uniform standard mean of identifying handgrip strength (HGS) asymmetry based on maximum or average HGS values. Therefore, this study aimed to explore the accuracy of different calculation methods in the evaluation of HGS asymmetry. Using the maximum reading of two trials from both hands (Method A) as the reference standard, the accuracy of the HGS asymmetry identified by the average value of two trials of both hands (Method B) was determined by using various indicators, including specificity, sensitivity, the area under the receiver operating characteristic curve (AUC), positive, and negative predictive values. Overall, 12,163 individuals were included in this study, of whom 47.61% (5791/12,163) were male. The percentages of individuals with HGS asymmetry differed as a function of age and sex when using these two different methods. When employing Method A, 38.52%, 41.57%, and 44.57% of males 45 ≤ age<60, 60 ≤ age<80, and ≥ 80 years of age exhibited HGS asymmetry as compared to 40.78%, 39%, and 39.63% of females. Using Method B, the corresponding proportions were 41.69%, 42.5%, and 40% in males and 42.01%, 41.18%, and 40.55% in females, respectively. When compared to Method A, Method B was found to be effective in identifying HGS asymmetry, with AUC values ranging from 0.844 to 0.877. However, there was only moderate agreement between the two methods in assessing HGS asymmetry. Specifically, the Kappa values for the two Methods were 0.692, 0.694, and 0.766 in males aged 45 to 60, 60 to 80, and 80 years and above, respectively. For females, the Kappa values were 0.674, 0.661, and 0.751, respectively. These results demonstrated that the maximal or average HGS values from two trials using both hands has a significant impact on the consequent identification of HGS asymmetry.

Post-translational Modification of α-Synuclein Modifies Monomer Dynamics and Aggregation Kinetics.

The intrinsically disordered protein α-Synuclein is identified as a major toxic aggregate in Parkinson's as well as several other neurodegenerative diseases. Recent work on this protein has focused on the effects of posttranslational modifications on aggregation kinetics. Among these, O-GlcNAcylation of α-Synuclein has been observed to inhibit the aggregation propensity of the protein. Here we investigate the monomer dynamics of two O-GlcNAcylated α-Synucleins, α-Syn(gT72) and α-Syn(gS87) and correlate them with the aggregation kinetics. We find that, compared to the unmodified protein, glycosylation at T72 makes the protein less compact and more diffusive while glycosylation at S87 makes the protein more compact and less diffusive. Based on a model of the earliest steps in aggregation, we predict that T72 should aggregate slower than unmodified protein, which is confirmed by ThT fluorescence measurements. In contrast, S87 should aggregate faster, which is not mirrored in ThT kinetics of later fibril formation but does not rule out a higher rate of formation of small oligomers. Together, these results show that posttranslational modifications do not uniformly affect aggregation propensity.

HSP27 Inhibitory Activity against Caspase-3 Cleavage and Activation by Caspase-9 Is Enhanced by Chaperone O-GlcNAc Modification in Vitro.

One of the O-GlcNAc modifications is the protection of cells against a variety of stressors that result in cell death. Previous experiments have focused on the overall ability of O-GlcNAc to prevent protein aggregation under stress as well as its ability to affect stress-response signaling pathways. Less attention has been paid to the potential role for O-GlcNAc in the direct inhibition of a major cell-death pathway, apoptosis. Apoptosis involves the sequential activation of caspase proteases, including the transfer of cell-stress information from initiator caspase-9 to effector caspase-3. Cells have multiple mechanisms to slow the apoptotic cascade, including heat shock protein HSP27, which can directly inhibit the activation of caspase-3 by caspase-9. We have previously shown that O-GlcNAc modification increases the chaperone activity of HSP27 against amyloid aggregation, raising the question as to whether this modification may play important roles in other facets of HSP27 biology. Here, we use protein chemistry to generate different versions of O-GlcNAc modified HSP27 and demonstrate that the modification enhances this antiapoptotic function of the chaperone, at least in an in vitro context. These results provide additional molecular insight into how O-GlcNAc functions as a mediator of cellular stress with important implications for human diseases like cancer and neurodegeneration.

Prevalence and risk factors for dementia in the Tibetan region: A population-based cross-sectional study.

BACKGROUND: As China's population ages, the nationwide prevalence of dementia is increasing. However, the epidemiology of dementia among the Tibetan population remains unclear. OBJECTIVE: A cross-sectional study was conducted involving 9116 participants aged >50 years in the Tibetan population to investigate the risk factors and prevalence of dementia among this population. Permanent residents of the region were invited to participate, and the response rate was 90.7 %. METHODS: The participants underwent neuropsychological testing and clinical assessments, from which physical measurements (e.g., body mass index, blood pressure), demographic information (e.g., gender, age), and lifestyle details (e.g., family living arrangement, smoking, alcohol arrangement) were recorded. Dementia diagnoses were made using the standard consensus diagnostic criteria. The risk factors of dementia were identified using stepwise multiple logistic regression. RESULTS: The average age of the participants was 63.71 (standard deviation = 9.36), and there were 44.86 % males. The prevalence of dementia was 4.66 %. The multivariate logistic regression analysis revealed that older age, unmarried status, lower education level, obesity, hypertension, diabetes, coronary heart disease, cerebral vascular disease, and HAPC were independently and positively associated with dementia (P < 0.05). However, no association was found between the frequency of religious activities and the prevalence of dementia in this population (P > 0.05). CONCLUSIONS: There exist a number of contributory risk factors for dementia in the Tibetan population, with variations associated with high altitude, religious activities (i.e., scripture turning, chanting, spinning Buddhist beads, and bowing), and dietary habits. These findings suggest that social activities, such as religious activities, are protective factors for dementia.

O-GlcNAc Modification Alters the Chaperone Activity of HSP27 Charcot-Marie-Tooth Type 2 (CMT2) Variants in a Mutation-Selective Fashion.

Increased O-GlcNAc is a common feature of cellular stress, and the upregulation of this dynamic modification is associated with improved survival under these conditions. Likewise, the heat shock proteins are also increased under stress and prevent protein misfolding and aggregation. We previously linked these two phenomena by demonstrating that O-GlcNAc directly increases the chaperone of certain small heat shock proteins, including HSP27. Here, we examine this linkage further by exploring the potential function of O-GlcNAc on mutants of HSP27 that cause a heritable neuropathy called Charcot-Marie-Tooth type 2 (CMT2) disease. Using synthetic protein chemistry, we prepared five of these mutants bearing an O-GlcNAc at the major site of modification. Upon subsequent biochemical analysis of these proteins, we found that O-GlcNAc has different effects, depending on the location of the individual mutants. We believe that this has important implications for O-GlcNAc and other PTMs in the context of polymorphisms or diseases with high levels of protein mutation.

Enhanced Vaccine Immunogenicity Enabled by Targeted Cytosolic Delivery of Tumor Antigens into Dendritic Cells.

Molecular vaccines comprising antigen peptides and inflammatory cues make up a class of therapeutics that promote immunity against cancer and pathogenic diseases but often exhibit limited efficacy. Here, we engineered an antigen peptide delivery system to enhance vaccine efficacy by targeting dendritic cells and mediating cytosolic delivery. The delivery system consists of the nontoxic anthrax protein, protective antigen (PA), and a single-chain variable fragment (scFv) that recognizes the XCR1 receptor on dendritic cells (DCs). Combining these proteins enabled selective delivery of the N-terminus of lethal factor (LFN) into XCR1-positive cross-presenting DCs. Incorporating immunogenic epitope sequences into LFN showed selective protein translocation in vitro and enhanced the priming of antigen-specific T cells in vivo. Administering DC-targeted constructs with tumor antigens (Trp1/gp100) into mice bearing aggressive B16-F10 melanomas improved mouse outcomes when compared to free antigen, including suppressed tumor growth up to 58% at 16 days post tumor induction (P < 0.0001) and increased survival (P = 0.03). These studies demonstrate that harnessing DC-targeting anthrax proteins for cytosolic antigen delivery significantly enhances the immunogenicity and antitumor efficacy of cancer vaccines.

Meta-analysis of the association of the C677T polymorphism of the methylenetetrahydrofolate reductase gene with hyperuricemia.

BACKGROUND: The association between the MTHFR C677T polymorphism and hyperuricemia has been investigated in several studies. Although these epidemiological studies have shown that genetic factors are determinants of serum uric acid levels, the power of the association is weak due to the small sample size. METHODS: To study whether the MTHFR C677T polymorphism has an effect on hyperuricemia, we carried out a meta-analysis of case-control studies from PubMed, EMBASE and CNKI (China National Knowledge Infrastructure) databases mainly in English and Chinese. We used the odds ratio (OR) as main effect size; explored potential sources of heterogeneity; performed subgroup analyses by race and performed sensitivity analyses of studies meeting the Hardy-Weinberg equilibrium (HWE). RESULTS: Six studies with 1,470 subjects were included in the meta-analysis. Tests for heterogeneity showed the difference in OR among studies was not statistically significant (p = 0.63, I(2) = 0). When excluding the study of Caucasians not in HWE, the association remained robust (OR = 1.82, 95% CI 1.52-2.17) in the East Asian subgroup and sensitivity analyses. CONCLUSIONS: Although the mechanism of the relationship between the C677T polymorphism and uric acid still remains unclear, these original articles showed that the MTHFR C677T polymorphism may be an independent risk factor for hyperuricemia.