Epidemiological characteristics of neuroendocrine neoplasms in Beijing: a population-based retrospective study.

BACKGROUND: The incidence of neuroendocrine neoplasms (NENs) is rising rapidly worldwide. However, there are few reports on these heterogeneous diseases in China. Our study aimed to explore the epidemiological characteristics of NENs in Beijing. METHODS: We conducted a retrospective cohort study using population-based cancer surveillance data in Beijing, China. All data were extracted from the Beijing Cancer Registry with incidence dates from 1 January 1998 to 31 December 2018; the follow-up period was through 31 December 2021. Segi's world standard population was used to estimate the age-standardized rate. Survival was estimated using the Kaplan-Meier method. RESULTS: From 1998 to 2018, the incidence of NENs in Beijing initially showed a significant increasing trend, from 1.07/100,000 to 3.53/100,000; this began to plateau after 2013. The age-specific incidence rate increased with age and peaked in the age group 70-74 years. The incidence in men was significantly higher than that in women (4.41/100,000 vs. 1.69/100,000). The most common sites of NENs were the lung (2.38/100,000) and rectum (0.14/100,000). Most NENs were diagnosed at a late stage. We found that NENs originating from the lung had worse overall survival than extrapulmonary NENs, and male patients had worse survival than female patients. CONCLUSIONS: This study retrospectively analyzed the epidemiological characteristics of NENs in Beijing from 1998 to 2018. Our findings provide a reference regarding the epidemiological statistics of NENs in Beijing to contribute to the prevention, diagnosis, and treatment of these specific tumors.

Proteomic Ligandability Maps of Spirocycle Acrylamide Stereoprobes Identify Covalent ERCC3 Degraders.

Covalent chemistry coupled with activity-based protein profiling (ABPP) offers a versatile way to discover ligands for proteins in native biological systems. Here, we describe a set of stereo- and regiochemically defined spirocycle acrylamides and the analysis of these electrophilic "stereoprobes" in human cancer cells by cysteine-directed ABPP. Despite showing attenuated reactivity compared to structurally related azetidine acrylamide stereoprobes, the spirocycle acrylamides preferentially liganded specific cysteines on diverse protein classes. One compound termed ZL-12A promoted the degradation of the TFIIH helicase ERCC3. Interestingly, ZL-12A reacts with the same cysteine (C342) in ERCC3 as the natural product triptolide, which did not lead to ERCC3 degradation but instead causes collateral loss of RNA polymerases. ZL-12A and triptolide cross-antagonized one another's protein degradation profiles. Finally, we provide evidence that the antihypertension drug spironolactone─previously found to promote ERCC3 degradation through an enigmatic mechanism─also reacts with ERCC3_C342. Our findings thus describe monofunctional degraders of ERCC3 and highlight how covalent ligands targeting the same cysteine can produce strikingly different functional outcomes.

Efficacy and safety of first-line chemotherapies for patients with advanced pancreatic ductal adenocarcinoma: A systematic review and network meta-analysis.

Background: Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease, often diagnosed at an advanced stage. Systemic chemotherapy is the primary treatment, but direct comparisons of different regimens are limited. This study conducted a systematic review and network meta-analysis (NMA) to compare the efficacy and safety of various chemotherapy regimens, with the unique advantage of only including Phase III randomized controlled trials (RCTs). Methods: NMA was conducted regarding the searched phase III RCTs by comparing overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and adverse events (AEs) of different chemotherapy protocols. Results: The analysis included 24 studies with 11470 patients across 25 treatment modalities. Among the chemotherapy regimens evaluated, FOLFIRINOX (fluorouracil, leucovorin, irinotecan, and oxaliplatin) demonstrated the highest OS and PFS, with a risk ratio (logHR) of 4.5 (95 % confidence interval 4.32-4.68) compared to gemcitabine monotherapy. The PEFG regimen (cisplatin, epirubicin, 5-fluorouracil, and gemcitabine) exhibited the highest ORR, with an odds ratio (OR) of 6.67 (2.08-20) compared to gemcitabine monotherapy. Notably, gemcitabine plus sorafenib was associated with the lowest hematological toxicity, with an odds ratio (OR) of 0.1 (0.02-0.48). Conclusion: Combination therapies may offer greater benefits but also cause more toxic effects. However, combinations with targeted agents seem to have fewer adverse reactions.

Climate, litter quality and radiation duration jointly regulate the net effect of UV radiation on litter decomposition.

Photodegradation via ultraviolet (UV) radiation is an important factor driving plant litter decomposition. Despite increasing attention to the role of UV photodegradation in litter decomposition, the specific impact of UV radiation on the plant litter decomposition stage within biogeochemical cycles remains unclear at regional and global scales. To clarify the variation rules of magnitude of UV effect on plant litter decomposition and their regulatory factors, we conducted a meta-analysis based on 54 published papers. Our results indicated that UV significantly promoted the mass loss of litter by facilitating decay of carbonaceous fractions and release of nitrogen and phosphorus. The promotion effect varied linearly or non-linearly with the time that litter exposed to UV, and with climatic factors. The UV effect on litter decomposition decreased first than increased on precipitation and temperature gradients, reaching its minimum in the area with a precipitation of 400-600 mm, and a temperature of 15-20 °C. This trend might be attributed to a potential equilibrium between the photofacilitation and photo-inhibition effects of UV under this condition. This variation in UV effect on precipitation gradient was in agreement with the fact that UV photodegradation effect was weakest in grassland ecosystems compared to that in forest and desert ecosystems. In addition, initial litter quality significantly influenced the magnitude of UV effect, but had no influence on the correlation between UV effect and climate gradient. Litter with lower initial nitrogen and lignin content shown a greater photodegradation effect, whereas those with higher hemicellulose and cellulose content had a greater photodegradation effect. Our study provides a comprehensive understanding of photodegradation effect on plant litter decomposition, indicates potentially substantial impacts of global enhancements of litter decomposition by UV, and highlights the necessity to quantify the contribution of photochemical minerallization pathway and microbial degradation pathway in litter decomposition.

Assigning functionality to cysteines by base editing of cancer dependency genes.

Covalent chemistry represents an attractive strategy for expanding the ligandability of the proteome, and chemical proteomics has revealed numerous electrophile-reactive cysteines on diverse human proteins. Determining which of these covalent binding events affect protein function, however, remains challenging. Here we describe a base-editing strategy to infer the functionality of cysteines by quantifying the impact of their missense mutation on cancer cell proliferation. The resulting atlas, which covers more than 13,800 cysteines on more than 1,750 cancer dependency proteins, confirms the essentiality of cysteines targeted by covalent drugs and, when integrated with chemical proteomic data, identifies essential, ligandable cysteines in more than 160 cancer dependency proteins. We further show that a stereoselective and site-specific ligand targeting an essential cysteine in TOE1 inhibits the nuclease activity of this protein through an apparent allosteric mechanism. Our findings thus describe a versatile method and valuable resource to prioritize the pursuit of small-molecule probes with high function-perturbing potential.

Green Extraction of Polyphenols via Deep Eutectic Solvents and Assisted Technologies from Agri-Food By-Products.

Polyphenols are the largest group of phytochemicals with important biological properties. Their presence in conveniently available low-cost sources, such as agri-food by-products, has gained considerable attention in their recovery and further exploitation. Retrieving polyphenols in a green and sustainable way is crucial. Recently, deep eutectic solvents (DESs) have been identified as a safe and environmentally benign medium capable of extracting polyphenols efficiently. This review encompasses the current knowledge and applications of DESs and assisted technologies to extract polyphenols from agri-food by-products. Particular attention has been paid to fundamental mechanisms and potential applications in the food, cosmetic, and pharmaceutical industries. In this way, DESs and DESs-assisted with advanced techniques offer promising opportunities to recover polyphenols from agri-food by-products efficiently, contributing to a circular and sustainable economy.

Performance of different colorectal cancer screening strategies: a long-term passive follow-up population-based screening program in Beijing, China.

BACKGROUND: We aimed to assess the performance of the risk assessment questionnaire and fecal immunochemical test (FIT) in a population-based colorectal cancer (CRC) screening program to provide timely evidence for tailored screening strategies in China. METHODS: This analysis was conducted using data from Beijing Cancer Screening Prospective Cohort Study (BCSPCS). A risk assessment questionnaire and FIT were selected as the primary screening methods, and participants with any positive results were referred to undergo a diagnostic colonoscopy. RESULTS: From 2015 to 2020, 148,636 Beijing residents aged 40-69 years were invited from designated communities, with 147,807 finishing the risk assessment questionnaire and 115,606 (78.2%) completing the FIT. Among the 42,969 (29.1%) high-risk CRC participants, 23,824 (55.4%) underwent colonoscopy. One year after enrollment, all subjects were linked to the Beijing Cancer Registry (BCR) database and 241 cases of CRC were confirmed. The CRC incidence rate was 58.2/100,000 for the low-risk arm and 418.9/100,000 for the high-risk arm. For participants who underwent colonoscopy, 91 CRC cases were detected, with a detection rate of 91.9% and 63.7% of them were early-stage cases. Furthermore, the sensitivities of utilizing the risk assessment questionnaire alone, FIT alone, combined risk assessment questionnaire and FIT were 75.7%, 50.1%, and 95.1%, and the specificities were 75.3%, 87.3%, and 70.7%, respectively. CONCLUSION: The Beijing CRC screening program can effectively detect early-onset CRC; however, the compliance with colonoscopy still needs to be improved.

Cultivar difference characterization of kiwifruit wines on phenolic profiles, volatiles and antioxidant activity.

Antioxidant activity and volatiles of kiwifruit wine with different flesh colors were investigated in this study. Green (Guichang and Xuxiang), red (Donghong and Hongyang), and yellow (Jinyan) kiwifruits were analyzed to determine their alcohol content, phenolic profiles, antioxidant activity, and aroma composition. The results showed that Hongyang and Donghong wines had higher antioxidant activity and content of antioxidant substances. Hongyang wine possessed the most abundance of polyphenolic compounds, chlorogenic acid and catechins were the main polyphenols of kiwi wines. The 101 aromatic components were detected, Xuxiang wine possessed 64 aromatic compounds, Donghong and Hongyang wines had the higher esters compositions, 79.87%, and 78.0% respectively. From PCA (Principal Component Analysis), the volatile substances of kiwi wine with the same flesh color were similar. Five kinds of kiwi wines shared 32 kinds of volatile compounds, these compounds may be the core volatiles in kiwi wine. Therefore, the color of kiwi flesh can impact wine flavor, with Hongyang and Donghong kiwis owning red flesh being the most suitable for producing kiwi wine which would be a new milestone to the wine manufactures.

Proteomic discovery of chemical probes that perturb protein complexes in human cells.

Most human proteins lack chemical probes, and several large-scale and generalizable small-molecule binding assays have been introduced to address this problem. How compounds discovered in such "binding-first" assays affect protein function, nonetheless, often remains unclear. Here, we describe a "function-first" proteomic strategy that uses size exclusion chromatography (SEC) to assess the global impact of electrophilic compounds on protein complexes in human cells. Integrating the SEC data with cysteine-directed activity-based protein profiling identifies changes in protein-protein interactions that are caused by site-specific liganding events, including the stereoselective engagement of cysteines in PSME1 and SF3B1 that disrupt the PA28 proteasome regulatory complex and stabilize a dynamic state of the spliceosome, respectively. Our findings thus show how multidimensional proteomic analysis of focused libraries of electrophilic compounds can expedite the discovery of chemical probes with site-specific functional effects on protein complexes in human cells.

Remodeling oncogenic transcriptomes by small molecules targeting NONO.

Much of the human proteome is involved in mRNA homeostasis, but most RNA-binding proteins lack chemical probes. Here we identify electrophilic small molecules that rapidly and stereoselectively decrease the expression of transcripts encoding the androgen receptor and its splice variants in prostate cancer cells. We show by chemical proteomics that the compounds engage C145 of the RNA-binding protein NONO. Broader profiling revealed that covalent NONO ligands suppress an array of cancer-relevant genes and impair cancer cell proliferation. Surprisingly, these effects were not observed in cells genetically disrupted for NONO, which were instead resistant to NONO ligands. Reintroduction of wild-type NONO, but not a C145S mutant, restored ligand sensitivity in NONO-disrupted cells. The ligands promoted NONO accumulation in nuclear foci and stabilized NONO-RNA interactions, supporting a trapping mechanism that may prevent compensatory action of paralog proteins PSPC1 and SFPQ. These findings show that NONO can be co-opted by covalent small molecules to suppress protumorigenic transcriptional networks.

Green and sustainable extraction of lignin by deep eutectic solvent, its antioxidant activity, and applications in the food industry.

Lignin, an amorphous biomacromolecule abundantly distributed in the plant kingdom, has gained considerable attention due to its intrinsic bioactivities and renewable nature. Owing to its polyphenolic structure, lignin has a variety of human health activities, including antioxidant, antimicrobial, antidiabetic, antitumor, and other activities. The extraction of lignin from various sources in a green and sustainable manner is critical in the food industry. Deep eutectic solvent (DES) has recently been recognized as a class of safe and environmentally friendly media capable of efficiently extracting lignin. This article comprehensively reviews the recent advances in lignin extraction using DES, discusses the influential factors on the antioxidant activity of lignin, interprets the relationship between antioxidant activity and lignin structure, and overviews the applications of lignin in the food industry. We aim to highlight the advantages of DES in lignin extraction and valorization from the nutrition and food views.

TMEM164 is an acyltransferase that forms ferroptotic C20:4 ether phospholipids.

Ferroptosis is an iron-dependent form of cell death driven by oxidation of polyunsaturated fatty acid (PUFA) phospholipids. Large-scale genetic screens have uncovered a specialized role for PUFA ether phospholipids (ePLs) in promoting ferroptosis. Understanding of the enzymes involved in PUFA-ePL production, however, remains incomplete. Here we show, using a combination of pathway mining of genetic dependency maps, AlphaFold-guided structure predictions and targeted lipidomics, that the uncharacterized transmembrane protein TMEM164-the genetic ablation of which has been shown to protect cells from ferroptosis-is a cysteine active center enzyme that selectively transfers C20:4 acyl chains from phosphatidylcholine to lyso-ePLs to produce PUFA ePLs. Genetic deletion of TMEM164 across a set of ferroptosis-sensitive cancer cell lines caused selective reductions in C20:4 ePLs with minimal effects on C20:4 diacyl PLs, and this lipid profile produced a variable range of protection from ferroptosis, supportive of an important but contextualized role for C20:4 ePLs in this form of cell death.

Exploring the mechanism of C473D mutation on CDC25B causing weak binding affinity with CDK2/CyclinA by molecular dynamics study.

CDC25B belongs to the CDC25 family, and it plays an important part in regulating the activity of CDK/CyclinA. Studies have shown that CDC25B is closely related to cancer development. When CYS473 on CDC25B is mutated into ASP, the affinity between CDC25B and CDK2/CyclinA weakens, and their dissociation speed is greatly improved. However, the mechanism by which the CDC25BC473D mutant weakens its binding to CDK2/CyclinA is unclear. In order to study the effect of CDC25BC473D mutants on CDK2/CyclinA substrates, we constructed and verified the rationality of the CDC25BWT:CDK2/CyclinA system and CDC25BC473D:CDK2/CyclinA system and conducted molecular dynamics (MD) simulation analysis. In the post-analysis, the fluctuations of residues ARG488-SER499, LYS541-TRP550 on CDC25B and residues ASP206-ASP210 on CDK2 were massive in the mutant CDC25BC473D:CDK2/CyclinA system. And the interactions between residue ARG492 and residue GLU208, residue ARG544 and residue GLU42, residue ARG544 and TRP550 were weakened in the mutant CDC25BC473D:CDK2/CyclinA system. The results showed that when CYS473 on CDC25B was mutated into ASP473, the mutant CDC25BC473D:CDK2/CyclinA system was less stable than the wild-type CDC25BWT:CDK2/CyclinA system. Finally, active site CYS473 of CDC25B was speculated to be the key residue, which had great effects on the binding between CDC25BCYS473 and CDK2 in the CDC25BC473D:CDK2/CyclinA system. Consequently, overall analyses appeared in this study ultimately provided a useful understanding of the weak interactions between CDC25BCYS473D and CDK2/CyclinA.Communicated by Ramaswamy H. Sarma.

Epidemiological Characteristics of Peripheral T-Cell Lymphoma: A Population-Based Study.

Objects: The aim of this study is to explore the epidemiological characteristics of peripheral T-cell lymphoma in Beijing. Methods:  All data were extracted from the Beijing Cancer Registry database from January 1, 2007, to December 31, 2018. Segi's World Standard Population was used to estimate the age-standardized rate (ASR). Changes in trends were examined using joinpoint regression analysis. The observed survival was estimated by the Kaplan-Meier method. Relative survival was calculated using Ederer II and standardized using the Brenner method and International Cancer Survival Standard (ICSS) group 1 age structure. Stratified by gender, area, and histological type, incidence, mortality, and age of onset trends were observed in Beijing. Results:  In Beijing, there were 801 new cases and 463 deaths of T-cell lymphoma from 2007 to 2018. Peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) was the most prevalent subtype (37.45%), followed by angioimmunoblastic T-cell lymphoma (AITL; 20.35%), NK/T-cell lymphoma (NK/TCL; 17.60%), and anaplastic large cell lymphoma (ALCL; 10.24%). The crude incidence and mortality rates were 0.52 and 0.30 per 100,000 person-years, respectively, whereas the age-standardized incidence and mortality rates (ASIR and ASMR) were 0.35 and 0.18 per 100,000 person-years, respectively. Both ASIR and ASMR were more prevalent in men (0.48 and 0.24 per 100,000) and urban area (0.38 and 0.19 per 100,000) than in women (0.22 and 0.11 per 100,000) and rural area (0.30 and 0.15 per 100,000). The average annual percentage change (AAPC) of ASIR and ASMR was 5.72% (95% confidence interval (CI): 1.79%-9.81%) and 4.35% (95% CI: -0.09%-8.99%), respectively. The age-specific incidence rate increased with age and peaked at the age groups of 10-14 and 80-84. The mean and median age of onset increased between 2007 and 2018. In addition, it decreased after the age of onset was age standardization (ß = -0.41, P = 0.26). The 5-year age-standardized relative survival was 39.02% for all patients, 58.14% for NK/TCL, 57.60% for ALCL, 31.38% for AITL, and 29.18% for PTCL-NOS. Conclusions:  T-cell lymphoma incidence was rising, but survival was dismal in Beijing, indicating the need for improved early diagnosis and standardized treatment.

Phospholipase Cγ2 regulates endocannabinoid and eicosanoid networks in innate immune cells.

Human genetic studies have pointed to a prominent role for innate immunity and lipid pathways in immunological and neurodegenerative disorders. Our understanding of the composition and function of immunomodulatory lipid networks in innate immune cells, however, remains incomplete. Here, we show that phospholipase Cγ2 (PLCγ2 or PLCG2)-mutations in which are associated with autoinflammatory disorders and Alzheimer's disease-serves as a principal source of diacylglycerol (DAG) pools that are converted into a cascade of bioactive endocannabinoid and eicosanoid lipids by DAG lipase (DAGL) and monoacylglycerol lipase (MGLL) enzymes in innate immune cells. We show that this lipid network is tonically stimulated by disease-relevant human mutations in PLCγ2, as well as Fc receptor activation in primary human and mouse macrophages. Genetic disruption of PLCγ2 in mouse microglia suppressed DAGL/MGLL-mediated endocannabinoid-eicosanoid cross-talk and also caused widespread transcriptional and proteomic changes, including the reorganization of immune-relevant lipid pathways reflected in reductions in DAGLB and elevations in PLA2G4A. Despite these changes, Plcg2-/- mice showed generally normal proinflammatory cytokine and chemokine responses to lipopolysaccharide treatment, instead displaying a more restricted deficit in microglial activation that included impairments in prostaglandin production and CD68 expression. Our findings enhance the understanding of PLCγ2 function in innate immune cells, delineating a role in cross-talk with endocannabinoid/eicosanoid pathways and modulation of subsets of cellular responses to inflammatory stimuli.

Scaffold-based selective SHP2 inhibitors design using core hopping, molecular docking, biological evaluation and molecular simulation.

PTPN11 (coding the gene of SHP2), a classic non-receptor protein tyrosine phosphatase, is implicated in multiple cell signaling pathway. Abnormal activation of SHP2 has been shown to contribute to a variety of human diseases, including Juvenile myelomonocytic leukemia (JMML), Noonan syndrome and tumors. Thus, the SHP2 inhibitors have important therapeutic value. Here, based on the compound PubChem CID 8,478,960 (IC50 = 45.01 µM), a series of thiophene [2,3-d] pyrimidine derivatives (IC50 = 0.4-37.87 µM) were discovered as novel and efficient inhibitors of SHP2 through powerful "core hopping" and CDOCKER technology. Furthermore, the SHP2-PTP phosphatase activity assay indicated that Comp#5 (IC50 = 0.4 µM) was the most active SHP2 inhibitor. Subsequently, the effects of Comp#5 on the structure and function of SHP2 were investigated through molecular dynamics (MD) simulation and post-kinetic analysis. The result indicated that Comp#5 enhanced the interaction of residues THR357, ARG362, LYS366, PRO424, CYS459, SER460, ALA461, ILE463, ARG465, THR507 and GLN510 with the surrounding residues, improving the stability of the catalytic active region and the entrance of catalytic active region. In particular, the Comp#5 conjugated with residue ARG362, elevating the efficient and selectivity of SHP2 protein. The study here may pave the way for discovering the novel SHP2 inhibitors for suffering cancer patients.

Leakage behavior of toxic substances of naphthalene sulfonate-formaldehyde condensation from cement based materials.

Naphthalene sulfonate-formaldehyde condensatation (NSF) is the main component of the naphthalene based water reducers for cement based materials, as well as an organic substance with potential toxicity. However it is still uncertain whether it can leak from the cement based materials. In this work, the leakage ratio and adsorption behavior of NSF from various cement based materials such as the different water/cement (w/c) ratio, NSF content, types of cementitious materials as well as at different hydration time were evaluated. The product components of the cement based materials cured for different times were also quantified to explore the mechanisms which are responsible for the leakage and adsorption behaviors. The results indicate that more NSF, lower w/c ratio and less mineral admixture decrease the NSF leakage ratio. The leakage ratio of NSF from cement paste mixed 0.3% NSF is up to 50.8% at 0.5 h, and it decreases to 31.0% at 28 d. The leakage ratio of NSF from cement paste decreases as the hydration time prolongs. The lower leakage ratio corresponds to the higher adsorption capacity. Less adsorption capacity and thinner adsorption film imply that lower temperature and mineral admixture decrease the NSF adsorption behavior. When 0.3% NSF is added into the cement paste, the adsorption amount and NSF layer thickness are 5.53 mg/g and 0.98 nm, 5.87 mg/g and 4.7  nm at 0.5 h and 28 d respectively. The result demonstrates that the adsorption behavior of NSF in cement significantly increases at the initial several hours and gradually stabilizes after the first day. The X-ray powder diffractometer (XRD) results show that the contents of tricalcium silicate (C3S) and dicalcium silicate (C2S) continuously decline and the amorphous phases and ettringite (AFt) increase rapidly in the early stage. NSF adsorption and leakage behaviors are closely related to the hydration process of cement. These results indicate that NSF can definitely leak from the cement based materials and thus the NSF potential environmental pollution cannot be ignored. At least, it should be restricted or cautious to produce the water tower and pipe concrete structure with it. These results will sever as a theoretically reference for the pollution control as well as better application of NSF in cement-based materials.

Cytochrome P450 oxidoreductase contributes to phospholipid peroxidation in ferroptosis.

Ferroptosis is widely involved in degenerative diseases in various tissues including kidney, liver and brain, and is a targetable vulnerability in multiple primary and therapy-resistant cancers. Accumulation of phospholipid hydroperoxides in cellular membranes is the hallmark and rate-limiting step of ferroptosis; however, the enzymes contributing to lipid peroxidation remain poorly characterized. Using genome-wide, CRISPR-Cas9-mediated suppressor screens, we identify cytochrome P450 oxidoreductase (POR) as necessary for ferroptotic cell death in cancer cells exhibiting inherent and induced susceptibility to ferroptosis. By genetic depletion of POR in cancer cells, we reveal that POR contributes to ferroptosis across a wide range of lineages and cell states, and in response to distinct mechanisms of ferroptosis induction. Using systematic lipidomic profiling, we further map POR's activity to the lipid peroxidation step in ferroptosis. Hence, our work suggests that POR is a key mediator of ferroptosis and potential druggable target for developing antiferroptosis therapeutics.

Genetic risk, adherence to a healthy lifestyle, and type 2 diabetes risk among 550,000 Chinese adults: results from 2 independent Asian cohorts.

BACKGROUND: Whether genetic susceptibility to type 2 diabetes is modified by a healthy lifestyle among Chinese remains unknown. OBJECTIVES: The aim of the study was to determine whether genetic risk and adherence to a healthy lifestyle contribute independently to the risk of developing type 2 diabetes. METHODS: We defined a lifestyle score using BMI, alcohol intake, smoking, physical activities, and diets in 461,030 participants from the China Kadoorie Biobank and 38,434 participants from the Singapore Chinese Health Study. A genetic risk score was constructed based on type 2 diabetes loci among 100,175 and 16,172 participants in each cohort, respectively. A Cox proportional-hazards model was used to estimate the interaction between genetic and lifestyle factors on the risk of type 2 diabetes. RESULTS: In 2 independent Asian cohorts, we consistently found a healthy lifestyle (the bottom quintile of lifestyle score) was associated with a substantially lower risk of type 2 diabetes than an unhealthy lifestyle (the top quintile of lifestyle score) regardless of genetic risk. In those at a high genetic risk, the risk of type 2 diabetes was 57% lower among participants with a healthy lifestyle than among those with an unhealthy lifestyle in the pooled cohorts. Among participants at high genetic risk, the standardized 10-y incidence of type 2 diabetes was 7.11% in those with an unhealthy lifestyle vs. 2.45% in those with a healthy lifestyle. CONCLUSIONS: In 2 independent cohorts involving 558,302 Chinese participants, we did not observe an interaction between genetics and lifestyle with type 2 diabetes risk, but our findings provide replicable evidence to show lifestyle factors and genetic factors were independently associated with the risk of type 2 diabetes. Within any genetic risk category, a healthy lifestyle was associated with a significantly lower risk of type 2 diabetes among the Chinese population.

DeepRiPP integrates multiomics data to automate discovery of novel ribosomally synthesized natural products.

Microbial natural products represent a rich resource of evolved chemistry that forms the basis for the majority of pharmacotherapeutics. Ribosomally synthesized and posttranslationally modified peptides (RiPPs) are a particularly interesting class of natural products noted for their unique mode of biosynthesis and biological activities. Analyses of sequenced microbial genomes have revealed an enormous number of biosynthetic loci encoding RiPPs but whose products remain cryptic. In parallel, analyses of bacterial metabolomes typically assign chemical structures to only a minority of detected metabolites. Aligning these 2 disparate sources of data could provide a comprehensive strategy for natural product discovery. Here we present DeepRiPP, an integrated genomic and metabolomic platform that employs machine learning to automate the selective discovery and isolation of novel RiPPs. DeepRiPP includes 3 modules. The first, NLPPrecursor, identifies RiPPs independent of genomic context and neighboring biosynthetic genes. The second module, BARLEY, prioritizes loci that encode novel compounds, while the third, CLAMS, automates the isolation of their corresponding products from complex bacterial extracts. DeepRiPP pinpoints target metabolites using large-scale comparative metabolomics analysis across a database of 10,498 extracts generated from 463 strains. We apply the DeepRiPP platform to expand the landscape of novel RiPPs encoded within sequenced genomes and to discover 3 novel RiPPs, whose structures are exactly as predicted by our platform. By building on advances in machine learning technologies, DeepRiPP integrates genomic and metabolomic data to guide the isolation of novel RiPPs in an automated manner.