A Selection of Macrocyclic Peptides That Bind STING From an mRNA-Display Library With Split Degenerate Codons.

Recent improvements in mRNA display have enabled the selection of peptides that incorporate non-natural amino acids, thus expanding the chemical diversity of macrocycles beyond what is accessible in nature. Such libraries have incorporated non-natural amino acids at the expense of natural amino acids by reassigning their codons. Here we report an alternative approach to expanded amino-acid diversity that preserves all 19 natural amino acids (no methionine) and adds 6 non-natural amino acids, resulting in the highest sequence complexity reported to date. We have applied mRNA display to this 25-letter library to select functional macrocycles that bind human STING, a protein involved in immunoregulation. The resulting STING-binding peptides include a 9-mer macrocycle with a dissociation constant (KD ) of 3.4 nM, which blocks binding of cGAMP to STING and induces STING dimerization. This approach is generalizable to expanding the amino-acid alphabet in a library beyond 25 building blocks.

Energy recovery and emissions of PBDD/Fs and PBDEs from cocombustion of woodchip and wastewater sludge in an industrial boiler.

The emissions of polybrominated dibenzo-pdioxins,dibenzofurans (PBDD/Fs), and polybrominated diphenyl ethers (PBDEs) from trial combustion of 10 wt % dried industrial wastewater-treatment sludge (IWTS) and 90 wt % woodchip in an industrial boiler were investigated and compared to that from woodchip combustion. The PBDD/F toxic equivalent (TEQ) andPBDE emissions increased from 0.121 pg TEQ Nm−3 and 2260 pgNm−3, respectively, of the woodchip combustion to 0.211 pg TEQNm−3 and 4200 pg Nm−3, respectively, of the trial combustion.PBDD/F and PBDE congener profiles of inputs and outputs of the same type of combustion were similar; they also show similarity between woodchip and trial combustions, revealing that the destruction pathway was little affected by the introduction of the IWTS. The fates of PBDD/Fs and PBDEs show that the indigenous pollutants in the feed were effectively depleted (>93.5%). The dominant releasing route of PBDD/F and PBDE shifted from the stack flue gas of woodchip combustion to the ashes of trial combustion. This study demonstrates that co-combustion not only handles the fast growing sludge stream but also yields a saving of 26.3% in the fuel cost and treatment fees of sludge and ashes.

Incidence of gastric cancer and risk factors in Suzhou cohort / 中华流行病学杂志

Objective: To describe gastric cancer incidence in Suzhou cohort, explore the environmental risk factors of gastric cancer in Suzhou, and provide appropriate suggestions for gastric cancer prevention and control. Methods: The participants were from the Suzhou cohort of China Kadoorie Biobank. Baseline survey was conducted from 2004 to 2008, followed by long-term follow-up until December 31, 2013. After the exclusion of those who had been previously diagnosed with peptic ulcer and malignant tumor reported at baseline survey and gastric cancer within six months after enrollment, a total of 50,136 participants were included. Cox proportional risk models were used to identify risk factors of gastric cancer and their hazard ratios in Suzhou. The effect modifications of gender on the association between risk factors and gastric cancer were analyzed. Results: In the follow-up of 7.19 years (median), 374 gastric cancers cases occurred. The standardized incidence was 94.57 per 100 000 person-years. Multivariate Cox proportional risk model analysis found that age (10 years old as a age group, HR=2.20, 95%CI: 1.92-2.53, P<0.001), current smoking (HR=1.84, 95%CI: 1.10-3.07 P=0.020), consumption of preserved vegetables weekly (HR=2.28, 95%CI: 1.28-4.07, P=0.005) and daily (HR=2.05, 95%CI: 1.16-3.61, P=0.013) were risk factors for gastric cancer. Female (HR=0.44, 95%CI: 0.25-0.76, P=0.003) and refrigerator use (10 years as a limit, HR=0.85, 95%CI: 0.74-0.97, P=0.016) were protective factors for gastric cancer. Further analysis showed that there was heterogeneity between males and females in the association between refrigerator use years and the incidence of gastric cancer (P=0.009), and there was an interaction effect between gender and refrigerator use on the incidence of gastric cancer (P=0.010). Conclusions: The incidence of gastric cancer in Suzhou cohort was high. The risk factors of gastric cancer varied. There was a synergistic interaction effect between gender and refrigerator use years on the incidence of gastric cancer.

Application of Lee-Carter model in the prediction of mortality risk in digestive tract cancer in Suzhou / 中华疾病控制杂志

Objective A Lee-Carter model was used to predict the risk and trend of mortality in the digestive tract cancer in Suzhou from 2002 to 2016. Methods The crude and standardized mortality rates were calculated based on deaths of digestive tract cancer which was identified from Suzhou chronic disease surveillance system.We used Lee-Carter model to predict the trend of mortality in digestive tract cancer. Results The effectiveness of the results forecasted by Lee-Carter model was validated in the data of digestive tract cancer mortality from 2012 to 2016 in Suzhou. The mean absolute percentage error (MAPE) values for the model were 2.48% and 4.13% for the age and year respectively, which indicated a well accepted prediction value. The mortality index was on the down trend in overall digestive tract cancer from 2002 to 2016, among which the mortality index in upper digestive tract cancer decreased, while the mortality index in lower digestive tract cancer increased. The mortality rate of upper digestive tract cancer was 4.23 fold higher than that of lower digestive tract cancer, and mortality rate in male was 2.17 times higher than that in female. Conclusions Our study observed a downward mortality trend in digestive tract cancer overall. Notably, the male mortality rate of lower digestive tract cancer was on an upward trend. In recent years, Suzhou has been undergoing a rapid population aging with medical and health level was increasing as well.

Association between PM2.5 pollution in ambient air and cardio-cerebrovascular mortality in Suzhou in 2016：a time series analysis / 中华疾病控制杂志

Objective To explore the effect of PM2.5 on the mortality of cardio-cerebrovascular disease in Suzhou, China. Methods The death data, air pollutant data and meteorological data from January 1, 2016 to December 31, 2017 in Suzhou were collected. The general additive Poisson regression model was used to analyse the association of exposure to PM2.5 with the daily deaths due to cardio-cerebrovascular disease, and to calculate the relative risk (RR) and 95% confidence intervals (95%CI) for an interquartile range (IQR) increase in PM2.5. Results The number of deaths from cardio-cerebrovascular disease was 30 200. On average, there were approximately 41 deaths per day. The daily median concentration of PM2.5 was 37.13 μg/m3 and IQR was 30.75 μg/m3. The RR values of single-day death and average death from cardio-cerebrovascular disease were 1.017(1.001-1.034) and 1.055(1.019-1.093)with an IQR increase of PM2.5 concentration, respectively. Stratified by gender and age, female and the elderly aged over 65 had higher risks of death from the cardio-cerebrovascular disease. Conclusion The elevated level of ambient PM2.5was positively associated with the increase of mortality of cardio-cerebrovascular disease.

Change trend and prediction of lung cancer mortality in Suzhou in 2001-2020 / 公共卫生与预防医学

Objective To explore the epidemiological characteristics and trend of lung cancer mortality in Suzhou, to predict the future lung cancer mortality by ARIMA model, and to provide a scientific basis for the research of lung cancer prevention and control strategy. Methods The annual change percentage (APC) was used to analyze the annual change trend of lung cancer mortality from 2001 to 2020, and the ARIMA optimal model was employed to predict the lung cancer mortality from 2021 to 2025. Results The average annual crude mortality of lung cancer in Suzhou from 2001 to 2020 was 46.45/100 000, while the standardized mortality was 23.51/100 000. In recent 20 years, the crude mortality showed an upward trend and the standardized mortality showed a downward trend (APC crude rate = 2.51%, APC standardized rate = -0.78% , P < 0.001). The standardized mortality of lung cancer in men was 3.22 times that in women. The mortality of lung cancer in people over 45 years old increased with the increase of age, but the mortality in the 30-59 years old group showed a downward trend year by year. ARIMA model predicted that the annual trend of lung cancer crude mortality will tend to be flat in the next five years. Conclusion The crude mortality rate of lung cancer in Suzhou shows an upward trend, while the standardized mortality rate decreases year by year, suggesting that we should pay attention to the prevention and control of lung cancer in the elderly, accurately identify high-risk population of lung cancer, promote health publicity and education, carry out lifestyle intervention, and popularize the early screening of lung cancer.

Short-term effect evaluation of self-management group projects for chronic disease patients in Suzhou / 公共卫生与预防医学

Objective To evaluate the short-term effect of self-management group project for chronic disease patients in Suzhou. Methods Eight to ten streets / towns were randomly selected from 10 cities and districts under the jurisdiction of Suzhou. Each street / town set up a chronic disease self-management group and carried out group activities. The awareness rate of chronic disease related knowledge, health management behavior and health status of the group members after and before the activities were compared to evaluate the short-term effect of the self-management group project. Results A total of 89 chronic disease self-management groups were set up in Suzhou in 2020. Among them, there were 47 hypertension groups and 42 diabetes groups. A total of 1176 people were surveyed at baseline, and 1161 people participated in the evaluation survey after the group activities. By setting up self-management groups, the awareness rates of chronic disease-related knowledge (BMI range, variety of food intake per day per week, moderate-intensity activity time per week, daily salt intake, harm of excessive salt intake, diagnostic criteria for hypertension, sodium content in low sodium salt, fasting blood glucose criteria, low-density lipoprotein control targets) in hypertension and diabetes patients after the intervention were improved compared with those before the intervention, and the differences were statistically significant (P“self-monitoring blood pressure” increased from 52.80% before the intervention to 66.32%, while the proportion of "having a blood glucose monitoring system at home" increased from 52.80% before the intervention to 66.32%, and the proportion of “self-monitoring blood glucose” increased from 25.67% before the intervention to 38.67%. The percentage of "drinking alcohol in the past 30 days" dropped from 12.14% before the intervention to 8.35%. All these differences were statistically significant. There was no difference in the number of "smoking in the past 30 days" compared with before the activity (P≥0.05). The number of days with poor health resulting from injuries in the past 30 days also decreased but the difference was not statistically significant (P≥0.05). In terms of the severity of depression, the number of people with moderate and severe depression decreased after the intervention, and the number of people who turned into mild depression increased, and the difference was statistically significant (P<0.05). Conclusion The self-management group project for chronic disease patients in Suzhou has achieved good results and is suitable for continued promotion and application in this region.

Gastrointestinal cancer influenced by genetic effect of cancer history of first-degree relatives / 上海预防医学

[Objective] To compare the influence of first-degree relatives' cancer history on the genetic tendency of gastric and colorectal cancer. [Methods] Patients with gastric and colorectal cancer from six towns of Suzhou City were investigated by means of face-to-face survey based on the "Family History and History of Population Diseases Questionnaire"which included general conditions, family composition and cancer occurrence of all their three degree relatives. [Results] If there were first-degree relatives with history of cancer, individual risk of gastric cancer would be higher than that of colorectal cancer by 55％, with the adjusted OR (95％ CI) being 1.551 (1.021, 2.356). If there were first-degree relatives with history of digestive tract cancer, the risk of the subject would increase to 104％, with the adjusted OR (95％CI) being 2.037 (1.279, 3.246). Men with first-degree relatives who had cancer history was at91％ higher risk of developing gastric cancer than colorectal cancer, with the adjusted OR (95％CI) being1.911 (1.080, 3.381). And for history of digestive tract cancer, the risk would reach 156％, with the adjusted OR (95％ CI) being 2.559 (1.337, 4.897). The number of cancers suffered by first-degree relatives of those patients with gastric cancer was higher than that of patients with colorectal cancer, with Z =-6.873, P<0.001, while the number of digestive tract cancer was also higher, with Z =-6.137, P<0.001. [Conclusion] The history of cancer and digestive tract cancer with first-degree relatives, is more common in patients with gastric cancer than with colorectal cancer. It is necessary to focus health education on men with first-degree relatives suffering from cancer or digestive tract cancer and suggest some changes in their living habits and regular medical examinations to reduce the occurrence of gastric cancer.

An expanded set of amino acid analogs for the ribosomal translation of unnatural peptides.

BACKGROUND: The application of in vitro translation to the synthesis of unnatural peptides may allow the production of extremely large libraries of highly modified peptides, which are a potential source of lead compounds in the search for new pharmaceutical agents. The specificity of the translation apparatus, however, limits the diversity of unnatural amino acids that can be incorporated into peptides by ribosomal translation. We have previously shown that over 90 unnatural amino acids can be enzymatically loaded onto tRNA. METHODOLOGY/PRINCIPAL FINDINGS: We have now used a competition assay to assess the efficiency of tRNA-aminoacylation of these analogs. We have also used a series of peptide translation assays to measure the efficiency with which these analogs are incorporated into peptides. The translation apparatus tolerates most side chain derivatives, a few alpha,alpha disubstituted, N-methyl and alpha-hydroxy derivatives, but no beta-amino acids. We show that over 50 unnatural amino acids can be incorporated into peptides by ribosomal translation. Using a set of analogs that are efficiently charged and translated we were able to prepare individual peptides containing up to 13 different unnatural amino acids. CONCLUSIONS/SIGNIFICANCE: Our results demonstrate that a diverse array of unnatural building blocks can be translationally incorporated into peptides. These building blocks provide new opportunities for in vitro selections with highly modified drug-like peptides.

Transglutaminase-catalyzed site-specific conjugation of small-molecule probes to proteins in vitro and on the surface of living cells.

Site-specific protein labeling methods allow cell biologists to access the vast array of existing chemical probes for the study of specific proteins of interest in the live cell context. Here we describe the use of the transglutaminase enzyme from guinea pig liver (gpTGase), whose natural function is to cross-link glutamine and lysine side chains, to covalently conjugate various small-molecule probes to recombinant proteins fused to a 6- or 7-amino acid transglutaminase recognition sequence, called a Q-tag. We demonstrate labeling of Q-tag fusion proteins both in vitro and on the surface of living mammalian cells with biotin, fluorophores, and a benzophenone photoaffinity probe. To illustrate the utility of this labeling, we tagged the NF-kappaB p50 transcription factor with benzophenone, cross-linked with UV light, and observed increased levels of p50 homodimerization in the presence of DNA and the binding protein myotrophin.

A nested case-control study on the relationship between occupational physical activity,heredity factors and metabolic syndrome / 中华流行病学杂志

Objective To examine the associations between occupational physical activity,heredity factors and metabolic syndrome (MS) in a Chinese population.Methods Based on the MS cohort study in Jiangsu province,subjects were followed-up,and blood samples were collected at the same time for biochemical indicators measurement.Newly confirmed MS patients according to US.National Cholesterol Education Program Adult Treatment Guidelines Ⅲ (NCEP-ATP Ⅲ ) were recruited as eases.Controls were 1 :1 matched with eases by region,gender and age (±2 years).In total,389 MS patients and 389 eontrols were recruited as study subjects.Nested ease-control study was applied for the present analysis.TaqMan fluorescence probe method was used to detect the genetic polymorphism of PPARα intron 1A/C (rs135539).Results (1)Compared to low physical activity group,the subjects with heavy physical activity were positively associated with MS (OR=2.18,95%CI:1.08-4.38).(2)The subjects,with a family history of hypertension (OR= 1.44,95% CI:1.02-2.03 )or type 2 diabetes (OR=3.25,95CI:1.28-8.20),were significantly indreased the occurrence of MS.(3)The genotype(AA,AC,CC) of PPARα intron 1A/C was not found to be related to MS.The OR of AC and CC genotype (compared to the genotype AA) were 0.98(95%CI:0.70-1.36) and 0.75 (95% CI:0.44-1.29) ,respectively.(4) Effect modifications were observed between family history of hypertension and moderate physical activity (OR=2.47,95% CI:1.00-6.06 ) or heavy physical activity (OR=3.82,95%CI:1.31-11.15) on the development of MS.Conclusion Heavy physical activity,with family history of hypertension or type 2 diabetes,seemed to be positively correlated with the risk of MS.Effect modifications were observed between occupational physical activity and family history of hypertension which might be associated with an increased risk of MS.

Relationship between peroxisome proliferator-activated receptor alpha intron 1A/C genetic polymorphism and metabolic syndrome / 中华预防医学杂志

<p><b>OBJECTIVE</b>To identify the relationship between genetic polymorphisms of peroxisome proliferator-activated receptor alpha (PPARalpha) intron 1A/C and metabolic syndrome (MS) in a Chinese population.</p><p><b>METHODS</b>A population-based case-control study was conducted in Suzhou city, Changshu County and Ganyu County in Jiangsu Province China, on the basis of an ongoing cohort study and 2348 cases were investigated. After the exclusion of the known MS cases, 1847 eligible subjects were successfully followed-up and their waist circumference (WC), body mass index, blood pressure, total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), triglycerides (TG) and fasting plasma glucose were measured. Newly diagnosed MS patients were recruited as cases, controls were individual matched with each case. TaqMan fluorescence probe method was used to detect the genetic polymorphism of PPARalpha intron 1A/C.</p><p><b>RESULTS</b>The current analysis consisted of 389 MS patients and 389 matched controls. The C allele gene frequency of PPARalpha intron 1A/C in the case group was 22.24% (173/778), lower than that in the control group, which was 24.68% (192/778); whereas the difference was not statistically significant (chi(2) = 1.29, P > 0.05). In the genotypes AA + AC and CC, MS patients were accounted for 50.70% (363/716) and 41.94% (26/62) and hyperglycemia accounted for 21.37% (153/716) and 11.29% (7/62). Compared to the genotypes AA + AC, genotype CC was observed to be inversely associated with hyperglycemia (the adjusted OR = 0.39; 95%CI: 0.17 - 0.90) but not related to the occurrence of MS (OR = 0.75; 95%CI: 0.44 - 1.28) and other components of MS e.g., abdominal obesity (the adjusted OR = 0.67; 95%CI: 0.38 - 1.17), hypertriglyceridemia (the adjusted OR = 0.97; 95%CI: 0.53 - 1.76), low HDL-C (the adjusted OR = 0.72; 95%CI: 0.41 - 1.25) and hypertension (the adjusted OR = 0.72; 95%CI: 0.42 - 1.25) all P values > 0.05.</p><p><b>CONCLUSION</b>C allele of PPARalpha intron 1A/C is not found to be associated with MS in the Chinese population. But comparing with the genotypes AA + AC, there is an inverse association between CC genotype and hyperglycemia.</p>

Genetically encoded fluorescent reporters of histone methylation in living cells.

We report the design and characterization of two genetically encoded fluorescent reporters of histone protein methylation. The reporters are four-part chimeric proteins consisting of a substrate peptide from the N-terminus of histone H3 fused to a chromodomain (a natural methyllysine-specific recognition domain), sandwiched between a fluorescence resonance energy transfer (FRET)-capable pair of fluorophores, cyan fluorescent protein (CFP) and yellow fluorescent protein (YFP). Enzymatic methylation by a methyltransferase induces complexation of the methylated substrate peptide to the chromodomain, changing the FRET level between the flanking CFP and YFP domains. Reporters developed using the chromodomains from HP1 and Polycomb respond to enzymatic methylation at the lysine 9 and lysine 27 positions of histone H3, respectively, giving 60% and 28% YFP/CFP emission ratio increases in vitro or in single living cells. These reporters should be useful for studying gene silencing and X-chromosome inactivation with high spatial and temporal resolution in intact cells and may also aid in the search for conjectured histone demethylase activity.