Therapeutic Effect of Targeting Branched-Chain Amino Acid Catabolic Flux in Pressure-Overload Induced Heart Failure.

Background Branched-chain amino acid (BCAA) catabolic defect is an emerging metabolic hallmark in failing hearts in human and animal models. The therapeutic impact of targeting BCAA catabolic flux under pathological conditions remains understudied. Methods and Results BT2 (3,6-dichlorobenzo[b]thiophene-2-carboxylic acid), a small-molecule inhibitor of branched-chain ketoacid dehydrogenase kinase, was used to enhance BCAA catabolism. After 2 weeks of transaortic constriction, mice with significant cardiac dysfunctions were treated with vehicle or BT2. Serial echocardiograms showed continuing pathological deterioration in left ventricle of the vehicle-treated mice, whereas the BT2-treated mice showed significantly preserved cardiac function and structure. Moreover, BT2 treatment improved systolic contractility and diastolic mechanics. These therapeutic benefits appeared to be independent of impacts on left ventricle hypertrophy but associated with increased gene expression involved in fatty acid utilization. The BT2 administration showed no signs of apparent toxicity. Conclusions Our data provide the first proof-of-concept evidence for the therapeutic efficacy of restoring BCAA catabolic flux in hearts with preexisting dysfunctions. The BCAA catabolic pathway represents a novel and potentially efficacious target for treatment of heart failure

Efficient detoxication of hydroxylamine and nitrite through heterotrophic nitrification and aerobic denitrification by Acinetobacter johnsonii EN-J1

The co-existence of hydroxylamine (NH2OH) and nitrite (NO2–-N) can aggravate the difficulty of wastewater treatment. The roles of hydroxylamine (NH2OH) and nitrite (NO2–-N) in accelerating the elimination of multiple nitrogen sources by a novel isolated strain of Acinetobacter johnsonii EN-J1 were investigated in this study. The results demonstrated that strain EN-J1 could eliminate 100.00% of NH2OH (22.73 mg/L) and 90.09% of NO2–-N (55.32 mg/L), with maximum consumption rates of 1.22 and 6.75 mg/L/h, respectively. Prominently, the toxic substances NH2OH and NO2–-N could both facilitate nitrogen removal rates. Compared with the control treatment, the elimination rates of nitrate (NO3–-N) and NO2–-N were enhanced by 3.44 and 2.36 mg/L/h after supplementation with 10.00 mg/L NH2OH, and those of ammonium (NH4+-N) and NO3–-N were improved by 0.65 and 1.00 mg/L/h after the addition of 50.00 mg/L NO2–-N. Furthermore, the nitrogen balance results indicated that over 55.00% of the initial total nitrogen was transformed into gaseous nitrogen by heterotrophic nitrification and aerobic denitrification (HN-AD). Ammonia monooxygenase (AMO), hydroxylamine oxidoreductase (HAO), nitrate reductase (NR), and nitrite reductase (NIR), which are essential for HN-AD, were detected at levels of 0.54, 0.15, 0.14, and 0.01 U/mg protein, respectively. All findings confirmed that strain EN-J1 could efficiently execute HN-AD, detoxify NH2OH and NO2–-N, and ultimately promote nitrogen removal rates

Integrative transcriptome and proteome revealed high-yielding mechanisms of epsilon-poly-L-lysine by Streptomyces albulus

Introductionε-poly-L-lysine (ε-PL) is a high value, widely used natural antimicrobial peptide additive for foods and cosmetic products that is mainly produced by Streptomyces albulus. In previous work, we developed the high-yield industrial strain S. albulus WG-608 through successive rounds of engineering.MethodsHere, we use integrated physiological, transcriptomic, and proteomics association analysis to resolve the complex mechanisms underlying high ε-PL production by comparing WG-608 with the progenitor strain M-Z18.ResultsOur results show that key genes in the glycolysis, pentose phosphate pathway, glyoxylate pathway, oxidative phosphorylation, and L-lysine biosynthesis pathways are differentially upregulated in WG-608, while genes in the biosynthetic pathways for fatty acids, various branched amino acids, and secondary metabolite by-products are downregulated. This regulatory pattern results in the introduction of more carbon atoms into L-lysine biosynthesis and ε-PL production. In addition, significant changes in the regulation of DNA replication, transcription, and translation, two component systems, and quorum sensing may facilitate the adaptability to environmental pressure and the biosynthesis of ε-PL. Overexpression of ppk gene and addition of polyP6 further enhanced the ε-PL production.DiscussionThis study enables comprehensive understanding of the biosynthetic mechanisms of ε-PL in S. albulus WG-608, while providing some genetic modification and fermentation strategies to further improve the ε-PL production

Uncovering the dispersion history, adaptive evolution and selection of wheat in China

Wheat was introduced to China approximately 4500 years ago, where it adapted over a span of time to various environments in agro-ecological growing zones. We investigated 717 Chinese and 14 Iranian/Turkish geographically diverse, locally adapted wheat landraces with 27,933 DArTseq (for 717 landraces) and 312,831 Wheat660K (for a subset of 285 landraces) markers. This study highlights the adaptive evolutionary history of wheat cultivation in China. Environmental stresses and independent selection efforts have resulted in considerable genome-wide divergence at the population level in Chinese wheat landraces. In total, 148 regions of the wheat genome show signs of selection in at least one geographic area. Our data show adaptive events across geographic areas, from the xeric northwest to the mesic south, along and among homoeologous chromosomes, with fewer variations in the D genome than in the A and B genomes. Multiple variations in interdependent functional genes, such as regulatory and metabolic genes controlling germination and flowering time were characterized, showing clear allelic frequency changes corresponding to the dispersion of wheat in China. Population structure and selection data reveal that Chinese wheat spread from the northwestern Caspian Sea region to south China, adapting during its agricultural trajectory to increasingly mesic and warm climatic areas

Comparative proteomic and clinicopathological analysis of breast adenoid cystic carcinoma and basal-like triple-negative breast cancer

BackgroundAdenoid cystic carcinoma (ACC) is a rare type of triple-negative breast cancer that has an indolent clinical behavior. Given the substantial overlapping morphological, immunohistochemical, and molecular features with other basal-like triple-negative breast cancer (BL-TNBC), accurate diagnosis of ACC is crucial for effective clinical treatment. The integrative analysis of the proteome and clinicopathological characteristics may help to distinguish these two neoplasms and provide a deep understanding on biological behaviors and potential target therapy of ACC.MethodsWe applied mass spectrometry-based quantitative proteomics to analyze the protein expression in paired tumor and adjacent normal breast tissue of five ACC and five BL-TNBC. Bioinformatic analyses and the clinicopathological characteristics, including histological features, immunohistochemistry, and FISH results, were also collected to get comprehensive information.ResultsA total of 307 differentially expressed proteins (DEPs) were identified between ACC and BL-TNBC. Clustering analysis of DEPs clearly separated ACC from BL-TNBC. GSEA found downregulation of the immune response of ACC compared with BL-TNBC, which is consistent with the negative PD-L1 expression of ACC. Vesicle-mediated transport was also inhibited, while ECM organization was enriched in ACC. The top upregulated proteins in DEPs were ITGB4, VCAN, and DPT. Moreover, in comparison with normal breast tissue, ACC showed elevated ribosome biogenesis and RNA splicing activity.ConclusionThis study provides evidence that ACC presents a substantially different proteomic profile compared with BL-TNBC and promotes our understanding on the molecular mechanisms and biological processes of ACC, which might be useful for differential diagnosis and anticancer strategy

Identification of candidate gene for the defective kernel phenotype using bulked segregant RNA and exome capture sequencing methods in wheat

Wheat is a significant source of protein and starch worldwide. The defective kernel (Dek) mutant AK-3537, displaying a large hollow area in the endosperm and shrunken grain, was obtained through ethyl methane sulfonate (EMS) treatment of the wheat cultivar Aikang 58 (AK58). The mode of inheritance of the AK-3537 grain Dek phenotype was determined to be recessive with a specific statistical significance level. We used bulked segregant RNA-seq (BSR-seq), BSA-based exome capture sequencing (BSE-seq), and the ΔSNP-index algorithm to identify candidate regions for the grain Dek phenotype. Two major candidate regions, DCR1 (Dek candidate region 1) and DCR2, were identified on chromosome 7A between 279.98 and 287.93 Mb and 565.34 and 568.59 Mb, respectively. Based on transcriptome analysis and previous reports, we designed KASP genotyping assays based on SNP variations in the candidate regions and speculated that the candidate gene is TraesCS7A03G0625900 (HMGS-7A), which encodes a 3-hydroxy-3-methylglutaryl-CoA synthase. One SNP variation located at position 1,049 in the coding sequence (G>A) causes an amino acid change from Gly to Asp. The research suggests that functional changes in HMGS-7A may affect the expression of key enzyme genes involved in wheat starch syntheses, such as GBSSII and SSIIIa

Impact of lockdown on the growth of children in China aged 3-6 years during the COVID-19 pandemic

BackgroundLockdowns in COVID-19 pandemic led to less physical activity and more intake of unhealthy food in children. The aim of this study was to investigate the negative impact of major lockdowns on the growth of children aged 3-6 years during COVID-19 pandemic period.MethodsPhysical examination results in 2019 to 2022 from 5834 eligible children (2972 males and 2862 females) from Southwestern China who were 3 years old in 2019 were retrospectively collected. Height and weight data points were extracted from the results, and percentiles of height (height%), weight (weight%), and BMI (BMI%), and rates of overweight and obesity were calculated and compared between different years during the pandemic.ResultsAfter analyzing the 15404 growth data points from 5834 children, a slowly increasing trend of height% from 2019 to 2022 was observed. Weight%, BMI%, overweight rate, obesity rate, and combined overweight and obesity rate had two peaks in 2020 and 2022 when major lockdowns were adopted and a drop in between (year 2021), except for obesity rate which did not drop in 2021. Similar results were shown after stratification by gender.ConclusionThe lockdowns in COVID-19 pandemic promoted obesity of kindergarten children, but did not show any negative impact on their height growth possibly due to over-nutrition of children during lockdowns. More efforts need to be made to limit the increase of obesity rate in kindergarten children during possible future lockdowns

Functioning styles of personality disorders and five-factor normal personality traits: a correlation study in Chinese students

BACKGROUND: Previous studies show that both the categorical and dimensional descriptors of personality disorders are correlated with normal personality traits. Recently, a 92-item inventory, the Parker Personality Measure (PERM) was designed as a more efficient and precise first-level assessment of personality disorders. Whether the PERM constructs are correlated with those of the five-factor models of personality needs to be clarified. METHODS: We therefore invited 913 students from poly-technical schools and colleges in China to answer the PERM, the Five-Factor Nonverbal Personality Questionnaire (FFNPQ), and the Zuckerman-Kuhlman Personality Questionnaire (ZKPQ). RESULTS: Most personality constructs had satisfactory internal alphas. PERM constructs were loaded with FFNPQ and ZKPQ traits clearly on four factors, which can be labelled as Dissocial, Emotional Dysregulation, Inhibition and Compulsivity, as reported previously. FFNPQ Openness to Experience, Conscientiousness and Extraversion formed another Factor, named Experience Hunting, which was not clearly covered by PERM or ZKPQ. CONCLUSION: The PERM constructs were loaded in a predictable way on the disordered super-traits, suggesting the PERM might offer assistance measuring personality function in clinical practice