Molecular weight control of poly-γ-glutamic acid reveals novel insights into extracellular polymeric substance synthesis in Bacillus licheniformis.

BACKGROUND: The structural diversity of extracellular polymeric substances produced by microorganisms is attracting particular attention. Poly-gamma-glutamic acid (γ-PGA) is a widely studied extracellular polymeric substance from Bacillus species. The function of γ-PGA varies with its molecular weight (Mw). RESULTS: Herein, different endogenous promoters in Bacillus licheniformis were selected to regulate the expression levels of pgdS, resulting in the formation of γ-PGA with Mw values ranging from 1.61 × 103 to 2.03 × 104 kDa. The yields of γ-PGA and exopolysaccharides (EPS) both increased in the pgdS engineered strain with the lowest Mw and viscosity, in which the EPS content was almost tenfold higher than that of the wild-type strain. Subsequently, the compositions of EPS from the pgdS engineered strain also changed. Metabolomics and RT-qPCR further revealed that improving the transportation efficiency of EPS and the regulation of carbon flow of monosaccharide synthesis could affect the EPS yield. CONCLUSIONS: Here, we present a novel insight that increased pgdS expression led to the degradation of γ-PGA Mw and changes in EPS composition, thereby stimulating EPS and γ-PGA production. The results indicated a close relationship between γ-PGA and EPS in B. licheniformis and provided an effective strategy for the controlled synthesis of extracellular polymeric substances.

Experimental Study on the Migration and Distribution of Microplastics in Desert Farmland Soil Under Drip Irrigation.

The microplastics (MPs) formed by broken plastic film may migrate in the soil under drip irrigation. To investigate the migration distribution of MPs in desert farmland soil under drip irrigation conditions, our study was conducted on farmland in Xinjiang (China). A MP drip irrigation penetration migration testing device was set up in combination with Xinjiang farmland irrigation methods to conduct a migration simulation experiment. The results showed that the migration amount of MPs in soil was significantly positively correlated with the amount of drip irrigation, and significantly negatively correlated with the soil depth; in addition, the relationship between the migration amount of MPs in different types of soil was: clay < sandy loam < sandy soil. Under drip irrigation conditions, the migration rates of MPs were 30.51%, 19.41%, and 10.29% in sandy soil, sandy loam soil, and clay, respectively. The migration ability of these three particle sizes of polyethylene MPs in soil was ranked as follows: 25 to 147 µm > 0 to 25 µm > 147 to 250 µm. When the drip irrigation volume was 2.6 to 3.2 L, horizontal migration distances of MPs exceeded 5 cm, and vertical migration distances reached more than 30 cm. Our findings provide reference data for the study of soil MP migration. Environ Toxicol Chem 2024;00:1-10. © 2024 SETAC.

Multi-Omics Analysis Reveals the Distinct Features of Metabolism Pathways Supporting the Fruit Size and Color Variation of Giant Pumpkin.

Pumpkin (Cucurbita maxima) is an important vegetable crop of the Cucurbitaceae plant family. The fruits of pumpkin are often used as directly edible food or raw material for a number of processed foods. In nature, mature pumpkin fruits differ in size, shape, and color. The Atlantic Giant (AG) cultivar has the world's largest fruits and is described as the giant pumpkin. AG is well-known for its large and bright-colored fruits with high ornamental and economic value. At present, there are insufficient studies that have focused on the formation factors of the AG cultivar. To address these knowledge gaps, we performed comparative transcriptome, proteome, and metabolome analysis of fruits from the AG cultivar and a pumpkin with relatively small fruit (Hubbard). The results indicate that up-regulation of gene-encoded expansins contributed to fruit cell expansion, and the increased presence of photoassimilates (stachyose and D-glucose) and jasmonic acid (JA) accumulation worked together in terms of the formation of large fruit in the AG cultivar. Notably, perhaps due to the rapid transport of photoassimilates, abundant stachyose that was not converted into glucose in time was detected in giant pumpkin fruits, implying that a unique mode of assimilate unloading is in existence in the AG cultivar. The potential molecular regulatory network of photoassimilate metabolism closely related to pumpkin fruit expansion was also investigated, finding that three MYB transcription factors, namely CmaCh02G015900, CmaCh01G018100, and CmaCh06G011110, may be involved in metabolic regulation. In addition, neoxanthin (a type of carotenoid) exhibited decreased accumulation that was attributed to the down-regulation of carotenoid biosynthesis genes in AG fruits, which may lead to pigmentation differences between the two pumpkin cultivars. Our current work will provide new insights into the potential formation factors of giant pumpkins for further systematic elucidation.

Diagenetic Genesis and Evolution of Coal-Bearing Tight Sandstone Reservoir in the Yangxia Formation, Northern Kuqa Depression, Tarim Basin.

Coal seams of the Yangxia Formation are widespread in the northern part of the Kuqa Depression in the Tarim Basin. During the thermal evolution of the coal seams, the generated fluids of different periods and natures have a significant impact on tight sandstone reservoirs. To further investigate the diagenetic characteristics and reservoir genesis of the tight sandstones due to the influence of coal seams, an in-depth exploration of the causes of dissolution and cementation in the reservoirs was conducted through thin-section casting, cathode luminescence, scanning electron microscopy, carbon-oxygen isotopic analyses, and X-ray diffraction of whole rock and authigenic clay minerals, along with burial evolution history and fluid evolution history. It is suggested that two phases of acidic fluids are mainly produced during the thermal evolution process of coal seams, including an early humic acid and a late organic carboxylic acid. The early phase humic acid plays a purifying role in reservoirs with coarse particles, rigidity-rich particles, and good permeability conditions. It selectively dissolves sedimentary calcareous mud and calcite, and the dissolution products are completely migrated. At the same time, it inhibits early carbonate cementation. The late organic carboxylic acid will dissolve potassium feldspar and some volcanic rock debris, and the dissolution products are difficult to migrate under the sealing conditions caused by lithological differences, which often take the cementation form of siliceous overgrowth and kaolinite or illite. In addition to the cementation resulting from the dissolution products of acidic fluids produced by the coal seams, the CO2-rich fluids generated by the coal seam thermal evolution will combine with ions such as Ca2+ from different sources, resulting in two phases of carbonate cementation. Based on the above research, this study summarizes a set of diagenetic evolution models for coal-bearing reservoirs.

Optimizing Trilobatin Production via Screening and Modification of Glycosyltransferases.

Trilobatin (TBL) is a key sweet compound from the traditional Chinese sweet tea plant (Rubus suavissimus S. Lee). Because of its intense sweetness, superior taste profile, and minimal caloric value, it serves as an exemplary natural dihydrochalcone sweetener. It also has various health benefits, including anti-inflammatory and glucose-lowering effects. It is primarily produced through botanical extraction, which impedes its scalability and cost-effectiveness. In a novel biotechnological approach, phloretin is used as a precursor that is transformed into TBL by the glycosyltransferase enzyme ph-4'-OGT. However, this enzyme's low catalytic efficiency and by-product formation limit the large-scale synthesis of TBL. In our study, the enzyme Mdph-4'-OGT was used to screen 17 sequences across species for TBL synthesis, of which seven exhibited catalytic activity. Notably, PT577 exhibited an unparalleled 97.3% conversion yield within 3 h. We then optimized the reaction conditions of PT577, attaining a peak TBL bioproduction of 163.3 mg/L. By employing virtual screening, we identified 25 mutation sites for PT577, thereby creating mutant strains that reduced by-products by up to 50%. This research enhances the enzymatic precision for TBL biosynthesis and offers a robust foundation for its industrial-scale production, with broader implications for the engineering and in silico analysis of glycosyltransferases.

Aerosol delivery and spatiotemporal tissue distribution of hydroxychloroquine in rat lung.

Inhalation enables the delivery of drugs directly to the lung, increasing the retention for prolonged exposure and maximizing the therapeutic index. However, the differential regional lung exposure kinetics and systemic pharmacokinetics are not fully known, and their estimation is critical for pulmonary drug delivery. The study evaluates the pharmacokinetics of hydroxychloroquine in different regions of the respiratory tract for multiple routes of administration. We also evaluated the influence of different inhaled formulations on systemic and lung pharmacokinetics by identifying suitable nebulizers followed by early characterization of emitted aerosol physicochemical properties. The salt- and freebase-based formulations required different nebulizers and generated aerosol with different physicochemical properties. An administration of hydroxychloroquine by different routes resulted in varied systemic and lung pharmacokinetics, with oral administration resulting in low tissue concentrations in all regions of the respiratory tract. A nose-only inhalation exposure resulted in higher and sustained lung concentrations of hydroxychloroquine with a lung parenchyma-to-blood ratio of 386 after 1440 min post-exposure. The concentrations of hydroxychloroquine in different regions of the respiratory tract (i.e., nasal epithelium, larynx, trachea, bronchi, and lung parenchyma) varied over time, indicating different retention kinetics. The spatiotemporal distribution of hydroxychloroquine in the lung is different due to the heterogeneity of cell types, varying blood perfusion rate, clearance mechanisms, and deposition of inhaled aerosol along the respiratory tract. In addition to highlighting the varied lung physiology, these results demonstrate the ability of the lung to retain increased levels of inhaled lysosomotropic drugs. Such findings are critical for the development of future inhalation-based therapeutics, aiming to optimize target site exposure, enable precision medicine, and ultimately enhance clinical outcomes.

Spatial-temporal pattern and spatial convergence of carbon emission intensity of rural energy consumption in China.

Based on the panel data of 30 provinces (municipalities and autonomous regions) in China from 2005 to 2019, this paper uses Gini coefficient decomposition and kernel density estimation to investigate the regional differences and dynamic evolution trend of rural energy carbon emission intensity in China. Then, the convergence model is used to analyze the convergence characteristics and influencing factors of carbon emission intensity. The study found the following: (1) During the observation period, the carbon emissions of coal energy and oil energy were much higher than those of gas energy. The carbon emissions of rural energy consumption experienced three stages of development, and the carbon emission intensity showed a downward trend as a whole. The spatial distribution pattern of total carbon emissions present an "adder" distribution, and the spatial agglomeration phenomenon gradually strengthens with the passage of time. (2) The Gini coefficient of China's rural energy consumption carbon emission intensity shows a trend of "Inverted N-shaped." The Gini coefficient of carbon emission intensity in the eastern and northeastern regions shows an increasing trend, while the Gini coefficient of carbon emission intensity in the western and central regions shows a downward trend. The super variable density is the main source of carbon emission intensity difference. The peak value of the main peak of the nuclear density curve of the carbon emission intensity increased significantly, the bimodal form evolved into a single peak form, and the density center moved to the left. (3) The carbon emission intensity of rural energy consumption in the whole, central, and western regions of China has the characteristic of σ convergence, while the carbon emission intensity in the eastern and northeastern regions does not have the characteristic of σ convergence. There is a significant spatial positive correlation in the carbon emission intensity, there is also a significant ß convergence characteristic, the speed of conditional ß convergence is significantly higher than that of absolute ß convergence, and the spatial interaction will further improve the convergence speed. Industrial structure, industrial agglomeration, and energy efficiency will increase the convergence speed. In terms of sub-regions, the conditional convergence rate of carbon emission intensity in the four regions shows a decreasing trend in the northeast, central, eastern, and western regions.

Identification and Optimization of more Efficient Olivetolic Acid Synthases.

Introduction: Olivetolic acid (OLA) is a key intermediate in cannabidiol (CBD) synthesis, and cannabinoids are important neuroactive drugs. However, the catalytic activity of olivetolic acid synthase (OLS), the key enzyme involved in OLA biosynthesis, remains low and its catalytic mechanism is unclear. Materials and Methods: In this study, we conducted a scrupulous screening of the pivotal rate-limiting enzyme and analyzed its amino acid sites that are critical to enzyme activity as validated by experiments. Results: Through stringent enzyme screening, we pinpointed a highly active OLS sequence, OLS4. Then, we narrowed down three critical amino acid sites (I258, D198, E196) that significantly influence the OLS activity. Conclusions: Our findings laid the groundwork for the efficient biosynthesis of OLA, and thereby facilitate the biosynthesis of CBD.

Estimated pulse wave velocity added additional prognostic information in general population: Evidence from National Health and Nutrition Examination Survey (NHANES) 1999-2018.

Background: As an indicator of arterial stiffness, there is controversy over whether estimated pulse wave velocity (ePWV) add additional prognostic information other than cardiovascular risk factors or traditional risk estimation model in general population. Methods: Data from National Health and Nutrition Examination Survey in 1999-2018 was analyzed. Cardiovascular risk factors were collected and Framingham Risk Score (FRS) was calculated. Using all-cause and cardiovascular mortality as outcomes, Cox and restricted cubic spline (RCS) analysis was performed. Receiver operator characteristic (ROC) curves, Harrell's C-statistic and net reclassification index (NRI) analysis were used to assess whether ePWV adds additional predictive value. Results: The association between ePWV and outcomes was independent of cardiovascular risk factors (HR = 1.23 [95%CI 1.23-1.50] per m/s for all-cause mortality, and 1.52 [1.30-1.78] for cardiovascular mortality) and FRS (1.22 [1.12-1.32] for all-cause mortality, and 1.32 [1.10-1.59] for cardiovascular mortality). Except for ePWV and all-cause mortality adjusted by FRS, a liner association was found between ePWV and outcomes. For predictive value, the area under ROC and C-index of the model added with ePWV was higher than the one with FRS or risk factors alone (P < 0.01). The elevated ePWV upgraded 1338456 subjects from high-intermediate to high FRS category, and NRI was 3.61 % and 2.62 % for all-cause and cardiovascular deaths, respectively (all P < 0.001). Conclusions: In general population, the present study demonstrated the association between ePWV and all-cause, cardiovascular mortality is independent of cardiovascular risk factors and traditional risk estimated model. ePWV also added additional information to them in predicting clinical outcomes.

Ozone, Heat Wave, and Cardiovascular Disease Mortality: A Population-Based Case-Crossover Study.

A case-crossover study among 511,767 cardiovascular disease (CVD) deaths in Jiangsu province, China, during 2015-2021 was conducted to assess the association of exposure to ambient ozone (O3) and heat wave with CVD mortality and explore their possible interactions. Heat wave was defined as extreme high temperature for at least two consecutive days. Grid-level heat waves were defined by multiple combinations of apparent temperature thresholds and durations. Residential O3 and heat wave exposures were assessed using grid data sets (spatial resolution: 1 km × 1 km for O3; 0.0625° × 0.0625° for heat wave). Conditional logistic regression models were applied for exposure-response analyses and evaluation of additive interactions. Under different heat wave definitions, the odds ratios (ORs) of CVD mortality associated with medium-level and high-level O3 exposures ranged from 1.029 to 1.107 compared with low-level O3, while the ORs for heat wave exposure ranged from 1.14 to 1.65. Significant synergistic effects on CVD mortality were observed for the O3 and heat wave exposures, which were generally greater with higher levels of the O3 exposure, higher temperature thresholds, and longer durations of heat wave exposure. Up to 5.8% of the CVD deaths were attributable to O3 and heat wave. Women and older adults were more vulnerable to the exposure to O3 and heat wave exposure. Exposure to both O3 and heat wave was significantly associated with an increased odds of CVD mortality, and O3 and heat wave can interact synergistically to trigger CVD deaths.

Chromosome-level genome assembly of Przevalski's partridge (Alectoris magna).

Przevalski's partridge (Alectoris magna) is one of the birds in the genus Alectoris endemic to China. The distribution of A. magna was narrow, and it was only found in parts of the Qinghai, Gansu, and Ningxia provinces. A. magna was considered a monotypic species until it was distinguished into two subspecies. However, external morphological characteristics, rather than genetic differences or evolutionary relationships, are now commonly used as evidence of subspecies differentiation. In this study, a chromosome-level reference genome of A. magna has been constructed by combining Illumina, PacBio and Hi-C sequencing data. The 1135.01 Mb A. magna genome was ultimately assembled. The genome showed 96.9% completeness (BUSCO), with a contig N50 length of 23.34 Mb. The contigs were clustered and oriented on 20 chromosomes, covering approximately 99.96% of the genome assembly. Additionally, altogether 19,103 protein-coding genes were predicted, of which 95.10% were functionally annotated. This high-quality genome assembly could serve as a valuable genomic resource for future research on the functional genomics, genetic protection, and interspecific hybridization of A. magna.

Genome-Wide Identification and Expression Patterns of Cucumber Invertases and Their Inhibitor Genes.

Invertases and their inhibitors play important roles in sucrose metabolism, growth and development, signal transduction, and biotic and abiotic stress tolerance in many plant species. However, in cucumber, both the gene members and functions of invertase and its inhibitor families remain largely unclear. In this study, in comparison with the orthologues of Citrullus lanatus (watermelon), Cucumis melo (melon), and Arabidopsis thaliana (Arabidopsis), 12 invertase genes and 12 invertase inhibitor genes were identified from the genome of Cucumis sativus (cucumber). Among them, the 12 invertase genes were classified as 4 cell wall invertases, 6 cytoplasmic invertases, and 2 vacuolar invertases. Most invertase genes were conserved in cucumber, melon, and watermelon, with several duplicate genes in melon and watermelon. Transcriptome analysis distinguished these genes into various expression patterns, which included genes CsaV3_2G025540 and CsaV3_2G007220, which were significantly expressed in different tissues, organs, and development stages, and genes CsaV3_7G034730 and CsaV3_5G005910, which might be involved in biotic and abiotic stress. Six genes were further validated in cucumber based on quantitative real-time PCR (qRT-PCR), and three of them showed consistent expression patterns as revealed in the transcriptome. These results provide important information for further studies on the physiological functions of cucumber invertases (CSINVs) and their inhibitors (CSINHs).

NAD+ exhaustion by CD38 upregulation contributes to blood pressure elevation and vascular damage in hypertension.

Hypertension is characterized by endothelial dysfunction and arterial stiffness, which contribute to the pathogenesis of atherosclerotic cardiovascular diseases. Nicotinamide adenine dinucleotide (NAD+) is an indispensable cofactor in all living cells that is involved in fundamental biological processes. However, in hypertensive patients, alterations in NAD+ levels and their relation with blood pressure (BP) elevation and vascular damage have not yet been studied. Here we reported that hypertensive patients exhibited lower NAD+ levels, as detected by high-performance liquid chromatography-mass spectrometry (HPLC-MS), in both peripheral blood mononuclear cells (PBMCs) and aortas, which was parallel to vascular dysfunction. NAD+ boosting therapy with nicotinamide mononucleotide (NMN) supplement reduced BP and ameliorated vascular dysfunction in hypertensive patients (NCT04903210) and AngII-induced hypertensive mice. Upregulation of CD38 in endothelial cells led to endothelial NAD+ exhaustion by reducing NMN bioavailability. Pro-inflammatory macrophages infiltration and increase in IL-1ß generation derived from pro-inflammatory macrophages resulted in higher CD38 expression by activating JAK1-STAT1 signaling pathway. CD38 KO, CD38 inhibitors treatment, or adeno-associated virus (AAV)-mediated endothelial CD38 knockdown lowered BP and improved vascular dysfunction in AngII-induced hypertensive mice. The present study demonstrated for the first time that endothelial CD38 activation and subsequently accelerated NAD+ degradation due to enhanced macrophage-derived IL-1ß production was responsible for BP elevation and vascular damage in hypertension. NAD+ boosting therapy can be used as a novel therapeutic strategy for the management of hypertensive patients.

Metabolomics and Transcription Profiling of Pumpkin Fruit Reveals Enhanced Bioactive Flavonoids and Coumarins in Giant Pumpkin (Cucurbita maxima).

Atlantic giant (AG, Cucurbita maxima) is a type of giant pumpkin in the Cucurbitaceae family and has the world's largest fruit. AG possesses excellent ornamental and economic value due to its well-known large fruit. However, giant pumpkins are usually thrown away after viewing, thus generating a waste of resources. To explore the additional value of giant pumpkins, a metabolome assay was performed between AG and Hubbard (a small fruit pumpkin) fruits. We found that bioactive compounds, especially flavonoids (including 8-prenylnaringenin, tetrahydrocurcumin, galangin, and acacetin) and coumarins (including coumarin, umbelliferone, 4-coumaryl alcohol, and coumaryl acetate), with extensive antioxidant and pharmacological functions, showed higher accumulation in AG fruit than in Hubbard fruits. Comparative transcriptomics of the two pumpkin fruits indicated that the differentially expressed genes (DEGs) encoding PAL, C4H, 4CL, CSE, HCT, CAD, and CCoAOMT were relatively highly expressed, which promoted an increased accumulation of the identified flavonoids and coumarins in giant pumpkins. In addition, the construction of a co-expression network and cis-element analysis of the promoter demonstrated that differentially expressed MYB, bHLH, AP2, and WRKY transcription factors might play vital roles in regulating the expression of DEGs involved in the biosynthesis of several flavonoids and coumarins. Our current results provide new insights into the accumulation of active compounds in giant pumpkins.

Dapagliflozin restores diabetes-associated decline in vasculogenic capacity of endothelial progenitor cells via activating AMPK-mediated inhibition of inflammation and oxidative stress.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) provide added vascular protection beyond glucose lowering to patients with type 2 diabetes mellitus (T2DM). Endothelial progenitor cells (EPCs) are an important endogenous repair mechanism for diabetic vascular complications. Yet, whether SGLT2i protect vessels in diabetic patients by improving the function of EPCs remains to be elucidated. Here we enrolled Sixty-three T2DM patients and 60 healthy participants and 15 of T2DM group took dapagliflozin for 3 months. Retinal capillary density (RCD) was examined before and after meditation. Moreover, vasculogenic capacity of EPCs cocultured with or without dapagliflozin in vitro and in vivo (hind limb ischemia model) were assessed. Mechanically, genes related to inflammation/oxidative stress, and the AMPK signaling of EPCs were determined. Our results found T2DM demonstrated a declined RCD and a decreased number of circulating EPCs compared with healthy controls. Compared with the EPCs from healthy individuals, vasculogenic capacity of T2DM EPCs was significantly impaired, which could be restored by dapagliflozin meditation or dapagliflozin coculture. Increased expression of inflammation correlative genes and decreased anti-oxidative stress related genes expression were found in EPCs form T2DM, which were accompanied with reduced phosphorylation level of AMPK. Dapagliflozin treatment activated AMPK signaling, decreased the level of inflammation and oxidative stress, and rescued vasculogenic capacity of EPCs from T2DM. Furthermore, AMPK inhibitor pretreatment diminished the enhancement vasculogenic capacity of diabetic EPCs from dapagliflozin treatment. This study demonstrates for the first time that dapagliflozin restores vasculogenic capacity of EPCs via activating AMPK-mediated inhibition of inflammation and oxidative stress in T2DM.

Effectiveness and safety of vedolizumab for ulcerative colitis: a single-center retrospective real-world study in China.

Introduction: The effectiveness and safety of vedolizumab (VDZ) against ulcerative colitis (UC) have been validated in several randomized controlled trials and real-world studies in Western countries. However, there are few studies on VDZ in Asia, and the follow-up period for these studies is generally short. Therefore, this study evaluates the long-term effectiveness and safety of VDZ in Chinese patients with UC. Methods: This retrospective study included patients with moderate to severe UC treated with VDZ between September 2019 and April 2022 at Sir Run Run Shaw Hospital, College of Medicine Zhejiang University. Clinical response and remission were assessed using the patient reported outcomes and the partial Mayo Score, and mucosal remission and healing were assessed using the Mayo Endoscopy Score. The primary endpoint was defined as clinical remission at week 14, and secondary endpoints included clinical response and steroid-free clinical remission at week 14, clinical response, clinical remission, and steroid-free clinical remission at week 52, and mucosal remission and healing at weeks 14 ± 8 and 52 ± 8. Results: Overall, 64 patients with moderate to severe UC were enrolled. The clinical response, clinical remission, and steroid-free clinical remission rates at week 14 were 73.4% (47/64), 65.6% (42/64), and 54.7% (35/64), respectively. Mucosal remission and healing rates at week 14 ± 8 were 64.7% (22/34) and 38.2% (13/34), respectively. A total of 48 patients were treated with VDZ for 52 weeks. Based on intention-to-treat analysis, the clinical response, clinical remission, and steroid-free clinical remission rates at week 52 were 68.8% (44/64), 64.1% (41/64), and 64.1% (41/64), respectively. Mucosal remission and healing rates at week 52 ± 8 were 70.6% (12/17) and 35.3% (6/17), respectively. During the follow-up period, the most common adverse event was skin rash (6/64). No cases of acute infusion reactions, delayed allergic reactions, new hepatitis B infections, active tuberculosis, or malignant tumors were reported. Conclusion: In this single-center retrospective real-world study, the effectiveness of long-term use of VDZ for Chinese patients with UC was similar to the outcomes previously reported in other geographical regions and populations; no new safety signals were found compared with other registered studies.

Body weight time in target range and cardiovascular outcomes in adults with overweight/obesity and type 2 diabetes.

AIMS: Prescription of weight loss to individuals is often characterized by weight fluctuations. However, current body weight management metrics may have difficulty characterizing the changes in body weight over time. We aim to characterize the long-term changes using body weight time in target range (TTR) and test its independent association with cardiovascular outcomes. METHODS AND RESULTS: We included 4468 adults from the Look AHEAD (Action for Health in Diabetes) trial. Body weight TTR was defined as the percentage of time during which body weight was within the Look AHEAD weight loss goal range. The associations of body weight TTR with cardiovascular outcomes were analysed using multivariable Cox modelling and restricted cubic spline function. Among the participants (mean age 58.9 years, 58.5% women, 66.5% White), there were 721 incident primary outcomes [cumulative incidence: 17.5%, 95% confidence interval (CI): 16.3-18.8%] during a median of 9.5 years of follow-up. Each 1 SD increase in body weight TTR was significantly associated with a decreased risk of the primary outcome (hazard ratio: 0.84, 95% CI: 0.75-0.94) after adjusting for mean and variability of body weight and traditional cardiovascular risk factors. Further analyses using restricted cubic spline indicated the inverse association between body weight TTR and the primary outcome in a dose-dependent manner. Similar associations remained significant among the participants with lower baseline or mean body weight. CONCLUSION: In adults with overweight/obesity and type 2 diabetes, higher body weight TTR was independently associated with lower risks of cardiovascular adverse events in a dose-response manner.

We used time in target range (TTR) to characterize the long-term changes in body weight among 4468 adults with overweight/obesity and type 2 diabetes and assessed the associations of body weight TTR with cardiovascular outcomes.Participants with TTR of >50­100% achieved and maintained the target of body weight loss during the 10 years of follow-up.Higher body weight TTR was independently associated with lower risks of cardiovascular adverse events in a dose­response manner.

The role of cholesterol metabolism in tumor therapy, from bench to bed.

Cholesterol and its metabolites have important biological functions. Cholesterol is able to maintain the physical properties of cell membrane, play an important role in cellular signaling, and cellular cholesterol levels reflect the dynamic balance between biosynthesis, uptake, efflux and esterification. Cholesterol metabolism participates in bile acid production and steroid hormone biosynthesis. Increasing evidence suggests a strict link between cholesterol homeostasis and tumors. Cholesterol metabolism in tumor cells is reprogrammed to differ significantly from normal cells, and disturbances of cholesterol balance also induce tumorigenesis and progression. Preclinical and clinical studies have shown that controlling cholesterol metabolism suppresses tumor growth, suggesting that targeting cholesterol metabolism may provide new possibilities for tumor therapy. In this review, we summarized the metabolic pathways of cholesterol in normal and tumor cells and reviewed the pre-clinical and clinical progression of novel tumor therapeutic strategy with the drugs targeting different stages of cholesterol metabolism from bench to bedside.

Effect of extreme pH conditions on methanogenesis: Methanogen metabolism and community structure.

The control of pH is effective for inhibiting methanogenesis in the chain elongation fermentation (CEF) system. However, obscure conclusions exist especially with regard to the underlying mechanism. This study comprehensively explored the responses of methanogenesis in granular sludge at various pH levels, ranging from 4.0 to 10.0, from multiple aspects including methane production, methanogenesis pathway, microbial community structure, energy metabolism and electron transport. Results demonstrated that compared with that at pH 7.0, pH at 4.0, 5.5, 8.5 and 10.0 triggered a 100%, 71.7%, 23.8% and 92.1% suppression on methanogenesis by the end of 3 cycles lasting 21 days. This might be explained by the remarkably inhibited metabolic pathways and intracellular regulations. To be more specific, extreme pH conditions decreased the abundance of the acetoclastic methanogens. However, obligate hydrogenotrophic and facultative acetolactic/hydrogenotrophic methanogens were significantly enriched by 16.9%-19.5 fold. pH stress reduced the gene abundance and/or activity of most enzymes involved in methanogenesis such as acetate kinase (by 81.1%-93.1%), formylmethanofuran dehydrogenase (by 10.9%-54.0%) and tetrahydromethanopterin S-methyltransferase (by 9.3%-41.5%). Additionally, pH stress suppressed electron transport via improper electron carriers and decreased electron amount as evidenced by 46.3%-70.4% reduced coenzyme F420 content and diminished abundance of CO dehydrogenase (by 15.5%-70.5%) and NADH:ubiquinone reductase (by 20.2%-94.5%). pH stress also regulated energy metabolism with inhibited ATP synthesis (e.g., ATP citrate synthase level reduced by 20.1%-95.3%). Interestingly, the protein and carbohydrate content secreted in EPS failed to show consistent responses to acidic and alkaline conditions. Specifically, when compared with pH 7.0, the acidic condition remarkably reduced the levels of total EPS and EPS protein while both levels were enhanced in the alkaline condition. However, the EPS carbohydrate content at pH 4.0 and 10.0 both decreased. This study is expected to promote the understanding of the pH control-induced methanogenesis inhibition in the CEF system.

Genome-Wide Identification of WD40 Proteins in Cucurbita maxima Reveals Its Potential Functions in Fruit Development.

WD40 proteins, a super gene family in eukaryotes, are involved in multiple biological processes. Members of this family have been identified in several plants and shown to play key roles in various development processes, including acting as scaffolding molecules with other proteins. However, WD40 proteins have not yet been systematically analyzed and identified in Cucurbita maxima. In this study, 231 WD40 proteins (CmWD40s) were identified in C. maxima and classified into five clusters. Eleven subfamilies were identified based on different conserved motifs and gene structures. The CmWD40 genes were distributed in 20 chromosomes; 5 and 33 pairs of CmWD40s were distinguished as tandem and segmental duplications, respectively. Overall, 58 pairs of orthologous WD40 genes in C. maxima and Arabidopsis thaliana, and 56 pairs of orthologous WD40 genes in C. maxima and Cucumis sativus were matched. Numerous CmWD40s had diverse expression patterns in fruits, leaf, stem, and root. Several genes were involved in responses to NaCl. The expression pattern of CmWD40s suggested their key role in fruit development and abiotic stress response. Finally, we identified 14 genes which might be involved in fruit development. Our results provide valuable basis for further functional verification of CmWD40s in C. maxima.