Advances in biotin biosynthesis and biotechnological production in microorganisms.

Biotin, also known as vitamin H or B7, acts as a crucial cofactor in the central metabolism processes of fatty acids, amino acids, and carbohydrates. Biotin has important applications in food additives, biomedicine, and other fields. While the ability to synthesize biotin de novo is confined to microorganisms and plants, humans and animals require substantial daily intake, primarily through dietary sources and intestinal microflora. Currently, chemical synthesis stands as the primary method for commercial biotin production, although microbial biotin production offers an environmentally sustainable alternative with promising prospects. This review presents a comprehensive overview of the pathways involved in de novo biotin synthesis in various species of microbes and insights into its regulatory and transport systems. Furthermore, diverse strategies are discussed to improve the biotin production here, including mutation breeding, rational metabolic engineering design, artificial genetic modification, and process optimization. The review also presents the potential strategies for addressing current challenges for industrial-scale bioproduction of biotin in the future. This review is very helpful for exploring efficient and sustainable strategies for large-scale biotin production.

Expression dynamics of periodic transcripts during cancer cell cycle progression and their correlation with anticancer drug sensitivity.

BACKGROUND: The cell cycle is at the center of cellular activities and is orchestrated by complex regulatory mechanisms, among which transcriptional regulation is one of the most important components. Alternative splicing dramatically expands the regulatory network by producing transcript isoforms of genes to exquisitely control the cell cycle. However, the patterns of transcript isoform expression in the cell cycle are unclear. Therapies targeting cell cycle checkpoints are commonly used as anticancer therapies, but none of them have been designed or evaluated at the alternative splicing transcript level. The utility of these transcripts as markers of cell cycle-related drug sensitivity is still unknown, and studies on the expression patterns of cell cycle-targeting drug-related transcripts are also rare. METHODS: To explore alternative splicing patterns during cell cycle progression, we performed sequential transcriptomic assays following cell cycle synchronization in colon cancer HCT116 and breast cancer MDA-MB-231 cell lines, using flow cytometry and reference cell cycle transcripts to confirm the cell cycle phases of samples, and we developed a new algorithm to describe the periodic patterns of transcripts fluctuating during the cell cycle. Genomics of Drug Sensitivity in Cancer (GDSC) drug sensitivity datasets and Cancer Cell Line Encyclopedia (CCLE) transcript datasets were used to assess the correlation of genes and their transcript isoforms with drug sensitivity. We identified transcripts associated with typical drugs targeting cell cycle by determining correlation coefficients. Cytotoxicity assays were used to confirm the effect of ENST00000257904 against cyclin dependent kinase 4/6 (CDK4/6) inhibitors. Finally, alternative splicing transcripts associated with mitotic (M) phase arrest were analyzed using an RNA synthesis inhibition assay and transcriptome analysis. RESULTS: We established high-resolution transcriptome datasets of synchronized cell cycle samples from colon cancer HCT116 and breast cancer MDA-MB-231 cells. The results of the cell cycle assessment showed that 43,326, 41,578 and 29,244 transcripts were found to be periodically expressed in HeLa, HCT116 and MDA-MB-231 cells, respectively, among which 1280 transcripts showed this expression pattern in all three cancer cell lines. Drug sensitivity assessments showed that a large number of these transcripts displayed a higher correlation with drug sensitivity than their corresponding genes. Cell cycle-related drug screening showed that the level of the CDK4 transcript ENST00000547281 was more significantly associated with the resistance of cells to CDK4/6 inhibitors than the level of the CDK4 reference transcript ENST00000257904. The transcriptional inhibition assay following M phase arrest further confirmed the M-phase-specific expression of the splicing transcripts. Combined with the cell cycle-related drug screening, the results also showed that a set of periodic transcripts, for example, ENST00000314392 (a dolichyl-phosphate mannosyltransferase polypeptide 2 isoform transcript), was more associated with drug sensitivity than the levels of their corresponding gene transcripts. CONCLUSIONS: In summary, we identified a panel of cell cycle-related periodic transcripts and found that the levels of transcripts of drug target genes showed different values for predicting drug sensitivity, providing novel insights into alternative splicing-related drug development and evaluation.

Role of Diabetes Mellitus on Treatment Effects in Drug-susceptible Initial Pulmonary Tuberculosis Patients in China / 生物医学与环境科学（英文）

We assessed the role of diabetes mellitus (DM) on treatment effects in drug-susceptible initial pulmonary tuberculosis (PTB) patients. A prospective study was conducted in eight provinces of China from October 2008 to December 2010. We enrolled 1,313 confirmed drug-susceptible initial PTB patients, and all subjects received the treatment regimen (2H3R3E3Z3/4H3R3) as recommended by the national guidelines. Of the 1,313 PTB patients, 157 (11.9%) had DM; these patients had more sputum smear-positive rates at the end of the second month [adjusted odds ratios (aOR) 2.829, 95% confidence intervals (CI) 1.783-4.490], and higher treatment failure (aOR 2.120, 95% CI 1.565-3.477) and death rates (aOR 1.536, 95% CI 1.011-2.628). DM was a contributing factor for culture-positive rates at the end of the second month and treatment failure and death of PTB patients, thus playing an unfavorable role in treatment effects of PTB.

Risk of Treatment Failure in Patients with Drug-susceptible Pulmonary Tuberculosis in China / 生物医学与环境科学（英文）

The objective of this prospective study of the risks of treatment failure in patients with drug-susceptible pulmonary tuberculosis (PTB) was to provide reference data to help develop a disease control strategy. Participants were recruited in eight provinces of China from October 2008 to December 2010. A total of 1447 patients with drug-susceptible PTB and older than 15 years of age were enrolled. Demographic characteristics, bacteriological test results, and patient outcome, i.e., cure or treatment failure were recorded and compared using the chi-square or Fisher's exact tests. Multivariate logistic regression was used to identify factors associated with risk of treatment failure. Of the 1447 patients who were enrolled, 1349 patients (93.2%) were successfully treated and 98 (6.8%) failed treatment. Failure was significantly associated with age 365 years [odds ratio (OR)=2.522, 95% confidence interval (CI): (1.097-5.801)], retreatment [OR=2.365, 95% CI: (1.276-4.381)], missed medicine [OR=1.836, 95% CI: (1.020-3.306)], treatment not observed [OR=1.879 95% CI: (1.105-3.195)], and positive culture result after the first [OR=1.971, 95% CI: (1.080-3.597)] and second month [OR=4.659, 95% CI: (2.590-8.382)]. The risk factors associated with treatment failure were age 365 years, retreatment, missed medication, treatment not observed, and positive culture at the end of month 1 or month 2. These risk factors should be monitored during treatment and interventions carried out to reduce or prevent treatment failure and optimize treatment success.