The OsSRO1c-OsDREB2B complex undergoes protein phase transition to enhance cold tolerance in rice.

Cold stress is one of the major abiotic stress factors affecting rice growth and development, leading to significant yield loss in the context of global climate change. Exploring natural variants that confer cold resistance and the underlying molecular mechanism responsible for this is the major strategy to breed cold tolerant rice varieties. Here, we show that the natural variations of a SIMILAR to RCD ONE (SRO) gene, OsSRO1c, confer cold tolerance in rice at both seedling and booting stages. OsSRO1c possesses intrinsic liquid-liquid phase separation ability in vivo and in vitro and recruits an AP2/ERF transcription factor and positive cold stress regulator, OsDREB2B, into its biomolecular condensates in the nucleus, resulting in elevated transcriptional activity of OsDREB2B. The OsSRO1c-OsDREB2B complex directly responds to low temperature through dynamic phase transitions and regulates key cold response genes, including COLD1. Furthermore, introgression of an elite haplotype of OsSRO1c into a cold susceptible indica rice significantly increases its cold resistance. Collectively, our work reveals a novel cold tolerance regulatory module in rice and provides promising genetic targets for molecular breeding of cold-tolerant rice varieties.

Effect of case management based on Omaha system on clinical symptoms and quality of life of coronary heart disease patients after percutaneous coronary intervention.

To investigate the effect of case management (CM) based on the Omaha system on clinical symptoms and quality of life (QOL) of coronary heart disease patients after percutaneous coronary intervention (PCI). Patients with coronary heart disease after their first PCI in the People's Hospital of Longhua in Shenzhen were randomly divided into a control group (received CM based on the Omaha system) and an observation group (received routine nursing) using a random number table. Nursing problems and the knowledge-behavior-status (KBS) score of patients were evaluated on the day after surgery, on the day before discharge, at 5 weeks after discharge, and at 12 weeks after discharge. The QOL of patients was evaluated using the coronary intervention coronary revascularization outcome questionnaire (CROQ-PTCA-Post, Chinese version) score on the day after surgery and at 12 weeks after discharge. A total of 104 patients completed the study (51 in the control group, 53 in the observation group). There were no significant differences in baseline data between the 2 groups (P gr.05). The main nursing problems were circulation, mental health, and pain in both groups on the day after surgery, whereas they were circulation, sleep and rest, and mental health after nursing. There were no significant differences in the KBS scores of the co-existing nursing problems on the day after surgery (P Th.05). The KBS scores of the co-existing nursing problems were significantly increased between the 2 groups (P < .01) on the day before discharge and at 5 weeks and 12 weeks after discharge. The KBS scores of the most co-existing nursing problems in the observation group were significantly higher at 12 weeks after discharge than at the day before discharge and at 5 weeks after discharge. Moreover, there were no significant differences in the CROQ-PTCA-Post scores on the first day after surgery between the 2 groups (P gr.05). These scores were significantly increased between the 2 groups at 12 weeks after discharge (P < .01). CM based on the Omaha system for patients after PCI can effectively improve the KBS scores and QOL of PCI patients with postoperative nursing problems, making this approach worthy of clinical promotion.

Drug Exposure and Treatment Outcomes in Patients With Multidrug-Resistant Tuberculosis and Diabetes Mellitus: A Multicenter Prospective Cohort Study From China.

BACKGROUND: The management of multidrug-resistant tuberculosis (MDR-TB) remains challenging. Treatment outcome is influenced by multiple factors; the specific roles of diabetes and glycemic control remain uncertain. This study aims to assess the impact of glycemic control on drug exposure, to investigate the association between drug exposure and treatment outcomes, and to identify clinically significant thresholds predictive of treatment outcome, among patients with diabetes. METHODS: This multicenter prospective cohort study involved patients with confirmed MDR-TB and diabetes. Drug exposure level was estimated by noncompartmental analysis. The minimum inhibitory concentrations (MICs) were determined for the individual Mycobacterium tuberculosis isolates. The influence of poor glycemic control (glycated hemoglobin ≥7%) on drug exposure and the associations between drug exposure and treatment outcome were evaluated by univariate and multivariate analysis. Classification and regression tree analysis was used to identify the drug exposure/susceptibility thresholds. RESULTS: Among the 131 diabetic participants, 43 (32.8%) exhibited poor glycemic control. Poor glycemic control was independently associated with decreased exposure to moxifloxacin, linezolid, bedaquiline, and cycloserine, but not clofazimine. Additionally, a higher ratio of drug exposure to susceptibility was found to be associated with a favorable MDR-TB treatment outcome. Thresholds predictive of 6-month culture conversion and favorable outcome were bedaquiline area under the concentration-time curve (AUC)/MIC ≥245 and moxifloxacin AUC/MIC ≥67, demonstrating predictive accuracy in patients, regardless of their glycemic control status. CONCLUSIONS: Glycemic control and optimal TB drug exposure are associated with improved treatment outcomes. This dual management strategy should be further validated in randomized controlled trials of patients with MDR-TB and diabetes.

Genomic and spatial analysis reveal the transmission dynamics of tuberculosis in areas with high incidence of Zhejiang, China: A prospective cohort study.

In the mountainous, rural regions of eastern China, tuberculosis (TB) remains a formidable challenge; however, the long-term molecular epidemiological surveillance in these regions is limited. This study aimed to investigate molecular and spatial epidemiology of TB in two mountainous, rural counties of Zhejiang Province, China, from 2015 to 2021, to elucidate the recent transmission and drug-resistance profiles. The predominant Lineage 2 (L2) Beijing family accounted for 80.1% of total 532 sequenced Mycobacterium tuberculosis (Mtb) strains, showing consistent prevalence over seven years. Gene mutations associated with drug resistance were identified in 19.4% (103/532) of strains, including 47 rifampicin or isoniazid-resistant strains, eight multi-drug-resistant (MDR) strains, and five pre-extensively drug-resistant (pre-XDR) strains. Genomic clustering revealed 53 distinct clusters with an overall transmission clustering rate of 23.9% (127/532). Patients with a history of retreatment and those infected with L2 strains had a higher risk of recent transmission. Spatial and epidemiological analysis unveiled significant transmission hotspots, especially in densely populated urban areas, involving various public places such as medical institutions, farmlands, markets, and cardrooms. The study emphasizes the pivotal role of Beijing strains and urban-based TB transmission in the western mountainous regions in Zhejiang, highlighting the urgent requirement for specific interventions to mitigate the impact of TB in these unique communities.

The diagnostic performance of GeneXpert MTB/RIF in tuberculosis meningitis: A multicentre accuracy study.

OBJECTIVES: To evaluate the performance of GeneXpert MTB/RIF (Xpert) for tuberculous meningitis (TBM) and to identify additional indicators to improve diagnostic accuracy. METHODS: An accuracy study was conducted. During 2011-2019, 243 TBM with 140 non-TBM in three TB-designated facilities in China were enrolled. Microbiological evidence of M tuberculosis (Mtb) in CSF was used as the reference. Additional indicators were identified by Boosted-Classification and Regression Tree (CART), the improvement of diagnostic performance was evaluated by ROC. RESULTS: The diagnostic sensitivity of Xpert was 71.1 % for definite TBM, and 5.5 % for probable/possible TBM. The positive rate of Xpert was improved with cerebrospinal fluid (CSF) increasing volume and was associated with CSF color (yellow). The additional indicators obtained by CART were CSF lactate and glucose and increased the sensitivity to 96.1 % (definite TBM) and 84.6 % (probable/possible TBM). CONCLUSIONS: The diagnostic performance of Xpert was satisfactory in definite TBM and would significantly be improved by the additional use of CSF lactate and glucose.

A double-stranded RNA binding protein enhances drought resistance via protein phase separation in rice.

Drought stress significantly impacts global rice production, highlighting the critical need to understand the genetic basis of drought resistance in rice. Here, through a genome-wide association study, we reveal that natural variations in DROUGHT RESISTANCE GENE 9 (DRG9), encoding a double-stranded RNA (dsRNA) binding protein, contribute to drought resistance. Under drought stress, DRG9 condenses into stress granules (SGs) through liquid-liquid phase separation via a crucial α-helix. DRG9 recruits the mRNAs of OsNCED4, a key gene for the biosynthesis of abscisic acid, into SGs and protects them from degradation. In drought-resistant DRG9 allele, natural variations in the coding region, causing an amino acid substitution (G267F) within the zinc finger domain, increase DRG9's binding ability to OsNCED4 mRNA and enhance drought resistance. Introgression of the drought-resistant DRG9 allele into the elite rice Huanghuazhan significantly improves its drought resistance. Thus, our study underscores the role of a dsRNA-binding protein in drought resistance and its promising value in breeding drought-resistant rice.

FGF19 Promotes the Proliferation and Insulin Secretion from Human Pancreatic ß Cells Via the IRS1/GLUT4 Pathway.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a commonly observed complication associated with obesity. The effect of fibroblast growth factor 19 (FGF19), a promising therapeutic agent for metabolic disorders, on pancreatic ß cells in obesity-associated T2DM remains poorly understood. METHODS: Human pancreatic ß cells were cultured with high glucose (HG) and palmitic acid (PA), followed by treatment with FGF19. The cell proliferation, apoptosis, and insulin secretion were evaluated by CCK-8, qRT-PCR, ELISA, flow cytometry, and western blotting. The expression of the insulin receptor substrate (IRS)/glucose transporter (GLUT) pathway was evaluated. The interaction between FGF19 and IRS1 was predicted using the STRING database and verified by co-immunoprecipitation and immunofluorescence. The regulatory effects of the IRS1/GLUT4 pathway on human pancreatic ß cells were assessed by overexpressing IRS1 and silencing IRS1 and GLUT4. RESULTS: HG+PA treatment reduced the human pancreatic ß cell proliferation and insulin secretion and promoted cell apoptosis. However, FGF19 treatment restored these alterations and significantly increased the expressions of IRS1, GLUT1, and GLUT4 in the IRS/GLUT pathway. Furthermore, FGF19 and IRS1 were found to interact. IRS1 overexpression partially promoted the proliferation of pancreatic ß cells and insulin secretion through GLUT4. Additionally, the silencing of IRS1 or GLUT4 attenuated the therapeutic effects of FGF19. CONCLUSION: In conclusion, FGF19 partly promoted the proliferation and insulin secretion of human pancreatic ß cells and inhibited apoptosis by upregulating the IRS1/GLUT4 pathway. These findings establish a theoretical framework for the clinical utilization of FGF19 in the treatment of obesity-associated T2DM.

Turbid Waters and Clearer Standards: Refining Water Quality Criteria for Coastal Environments by Encompassing Metal Bioavailability from Suspended Particles.

Suspended particulate matter (SPM) carries a major fraction of metals in turbid coastal waters, markedly influencing metal bioaccumulation and posing risks to marine life. However, its effects are often overlooked in current water quality criteria for metals, primarily due to challenges in quantifying SPM's contribution. This contribution depends on the SPM concentration, metal distribution coefficients (Kd), and the bioavailability of SPM-bound metals (assimilation efficiency, AE), which can collectively be integrated as a modifying factor (MF). Accordingly, we developed a new stable isotope method to measure metal AE by individual organisms from SPM, employing the widely distributed filter-feeding clam Ruditapes philippinarum as a representative species. Assessing SPM from 23 coastal sites in China, we found average AEs of 42% for Zn, 26% for Cd, 20% for Cu, 8% for Ni, and 6% for Pb. Moreover, using stable isotope methods, we determined metal Kd of SPM from these sites, which can be well predicted by the total organic carbon and iron content (R2 = 0.977). We calculated MFs using a Monte Carlo method. The calculated MFs are in the range 9.9-43 for Pb, 8.5-37 for Zn, 2.9-9.7 for Cu, 1.4-2.7 for Ni, and 1.1-1.6 for Cd, suggesting that dissolved-metal-based criteria values should be divided by MFs to provide adequate protection to aquatic life. This study provides foundational guidelines to refine water quality criteria in turbid waters and protect coastal ecosystems.

Epon Post Embedding Correlative Light and Electron Microscopy.

Correlative light and electron microscopy (CLEM) is a comprehensive microscopy that combines the localization information provided by fluorescence microscopy (FM) and the context of cellular ultrastructure acquired by electron microscopy (EM). CLEM is a trade-off between fluorescence and ultrastructure, and usually, ultrastructure compromises fluorescence. Compared with other hydrophilic embedding resins, such as glycidyl methacrylate, HM20, or K4M, Epon is superior in ultrastructure preservation and sectioning properties. Previously, we had demonstrated that mEosEM can survive osmium tetroxide fixation and Epon embedding. Using mEosEM, we achieved, for the first time, Epon post embedding CLEM, which maintains the fluorescence and the ultrastructure simultaneously. Here, we provide step-by-step details about the EM sample preparation, the FM imaging, the EM imaging, and the image alignment. We also improve the procedures for identifying the same cell imaged by FM imaging during the EM imaging and detail the registration between the FM and EM images. We believe one can easily achieve Epon post embedding correlative light and electron microscopy following this new protocol in traditional EM facilities.

Second-line antituberculosis drug exposure thresholds predictive of adverse events in multidrug-resistant tuberculosis treatment.

OBJECTIVES: This study aimed to investigate the association between drug exposure and adverse events (AEs) during the standardized multidrug-resistant tuberculosis (MDR-TB) treatment, as well as to identify predictive drug exposure thresholds. METHODS: We conducted a prospective, observational multicenter study among participants receiving standardized MDR-TB treatment between 2016 and 2019 in China. AEs were monitored throughout the treatment and their relationships to drug exposure (e.g., the area under the drug concentration-time curve from 0 to 24 h, AUC0-24 h) were analyzed. The thresholds of pharmacokinetic predictors of observed AEs were identified by boosted classification and regression tree (CART) and further evaluated by external validation. RESULTS: Of 197 study participants, 124 (62.9%) had at least one AE, and 15 (7.6%) experienced serious AEs. The association between drug exposure and AEs was observed including bedaquiline, its metabolite M2, moxifloxacin and QTcF prolongation (QTcF >450 ms), linezolid and mitochondrial toxicity, cycloserine and psychiatric AEs. The CART-derived thresholds of AUC0-24 h predictive of the respective AEs were 3.2 mg·h/l (bedaquiline M2); 49.3 mg·h/l (moxifloxacin); 119.3 mg·h/l (linezolid); 718.7 mg·h/l (cycloserine). CONCLUSIONS: This study demonstrated the drug exposure thresholds predictive of AEs for key drugs against MDR-TB treatment. Using the derived thresholds will provide the knowledge base for further randomized clinical trials of dose adjustment to minimize the risk of AEs.

Mechanisms underlying the combination effect of arsenite and high-fat diet on aggravating liver injury in mice.

Arsenic (As) is a highly toxic metalloid that can be found in insufficiently purified drinking water and exerts adverse effects on the physiology of living organisms that can negatively affect human health after subchronic exposure, causing several diseases, such as liver damage. A high-fat diet, which is increasing in frequency worldwide, can aggravate hepatic pathology. However, the mechanisms behind liver injury caused by the combinatory effects of As exposure and a high-fat diet remain unclear. In this study, we investigated such underlying mechanisms by focusing on three different aspects: As biotransformation, pathological liver damage, and differential expression of signaling pathway components. We employed mice that were fed a regular diet or a high-fat diet and exposed them to a range of arsenite concentrations (As(III), 0.05-50 mg/L) for 12 weeks. Our results showed that a high-fat diet increased the absorption of As into the liver and enhanced liver toxicity, which became progressively more severe as the As concentration increased. Co-exposure to a high-fat diet and As(III) activated PI3K/AKT and PPAR signaling as well as fatty acid metabolism pathways. In addition, the expression of proteins related to lipid cell function, lipid metabolism, and the regulation of body weight was also affected. Our study provides insights into the mechanisms that contribute to liver injury from subchronic combinatory exposure to As and a high-fat diet and showcases the importance of a healthy lifestyle, which may be of particular benefit to people living in areas with high As(III) concentrations, as a means to reduce or prevent aggravated liver damage.

Control of rice ratooning ability by a nucleoredoxin that inhibits histidine kinase dimerization to attenuate cytokinin signaling in axillary buds.

Rice ratooning, the fast outgrowth of dormant buds on stubble, is an important cropping practice in rice production. However, the low ratooning ability (RA) of most rice varieties restricts the application of this cost-efficient system, and the genetic basis of RA remains unknown. In this study, we dissected the genetic architecture of RA by a genome-wide association study in a natural rice population. Rice ratooning ability 3 (RRA3), encoding a hitherto not characterized nucleoredoxin involved in reduction of disulfide bonds, was identified as the causal gene of a major locus controlling RA. Overexpression of RRA3 in rice significantly accelerated leaf senescence and reduced RA, whereas knockout of RRA3 significantly delayed leaf senescence and increased RA and ratoon yield. We demonstrated that RRA3 interacts with Oryza sativa histidine kinase 4 (OHK4), a cytokinin receptor, and inhibits the dimerization of OHK4 through disulfide bond reduction. This inhibition ultimately led to decreased cytokinin signaling and reduced RA. In addition, variations in the RRA3 promoter were identified to be associated with RA. Introgression of a superior haplotype with weak expression of RRA3 into the elite rice variety Guichao 2 significantly increased RA and ratoon yield by 23.8%. Collectively, this study not only uncovers an undocumented regulatory mechanism of cytokinin signaling through de-dimerization of a histidine kinase receptor-but also provides an eximious gene with promising value for ratoon rice breeding.

Effect of weekend admission on mortality risk in patients with sepsis and septic shock: A systematic review and meta-analysis.

BACKGROUND: There is an ongoing debate if weekend admissions of critically ill patients are associated with higher mortality rates. The current review aimed to specifically assess this effect in sepsis and septic shock patients by comparing mortality rates with weekend versus weekday admissions. METHODS: PubMed, CENTRAL, Scopus, Web of Science, and Embase were searched up to 20th February 2023 with an additional search of Google Scholar for gray literature. RESULTS: Nine studies were eligible. Meta-analysis of all nine studies with data from 1,134,417 patients demonstrated that sepsis or septic shock patients admitted on weekends don't have higher mortality as compared to those admitted on weekdays (OR: 1.04; 95% CI: 1.00, 1.09; p = 0.05; I2 = 93%). On subgroup analysis based on sample size (>2000 or <2000 patients) and timing of mortality, we noted no difference in the significance of the results. However, there was a small significant increased risk of mortality with weekend admission noted in studies on the Asian population and including septic shock patients. CONCLUSION: Weekend admission does not have an adverse impact on mortality rates of sepsis and septic shock patients. Results must be interpreted with caution owing to high interstudy heterogeneity and variation in confounders adjusted by individual studies.

Serine protease NAL1 exerts pleiotropic functions through degradation of TOPLESS-related corepressor in rice.

NARROW LEAF 1 (NAL1) is a breeding-valuable pleiotropic gene that affects multiple agronomic traits in rice, although the molecular mechanism is largely unclear. Here, we report that NAL1 is a serine protease and displays a novel hexameric structure consisting of two ATP-mediated doughnut-shaped trimeric complexes. Moreover, we identified TOPLESS-related corepressor OsTPR2 involved in multiple growth and development processes as the substrate of NAL1. We found that NAL1 degraded OsTPR2, thus modulating the expression of downstream genes related to hormone signalling pathways, eventually achieving its pleiotropic physiological function. An elite allele, NAL1A, which may have originated from wild rice, could increase grain yield. Furthermore, the NAL1 homologues in different crops have a similar pleiotropic function to NAL1. Our study uncovers a NAL1-OsTPR2 regulatory module and provides gene resources for the design of high-yield crops.

Dietary Cholesterol Supplementation Inhibits the Steroid Biosynthesis but Does Not Affect the Cholesterol Transport in Two Marine Teleosts: A Hepatic Transcriptome Study.

Cholesterol has been used as additive in fish feeds due to the reduced use of fish meal and fish oil. In order to evaluate the effects of dietary cholesterol supplementation (D-CHO-S) on fish physiology, a liver transcriptome analysis was performed following a feeding experiment on turbot and tiger puffer with different levels of dietary cholesterol. The control diet contained 30% fish meal (0% fish oil) without cholesterol supplementation, while the treatment diet was supplemented with 1.0% cholesterol (CHO-1.0). A total of 722 and 581 differentially expressed genes (DEG) between the dietary groups were observed in turbot and tiger puffer, respectively. These DEG were primarily enriched in signaling pathways related to steroid synthesis and lipid metabolism. In general, D-CHO-S downregulated the steroid synthesis in both turbot and tiger puffer. Msmo1, lss, dhcr24, and nsdhl might play key roles in the steroid synthesis in these two fish species. Gene expressions related to cholesterol transport (npc1l1, abca1, abcg1, abcg2, abcg5, abcg8, abcb11a, and abcb11b) in the liver and intestine were also extensively investigated by qRT-PCR. However, the results suggest that D-CHO-S rarely affected the cholesterol transport in both species. The protein-protein interaction (PPI) network constructed on steroid biosynthesis-related DEG showed that in turbot, Msmo1, Lss, Nsdhl, Ebp, Hsd17b7, Fdft1, and Dhcr7 had high intermediary centrality in the dietary regulation of steroid synthesis. In conclusion, in both turbot and tiger puffer, the supplementation of dietary cholesterol inhibits the steroid metabolism but does not affect the cholesterol transport.

Evolution and epidemic success of Mycobacterium tuberculosis in eastern China: evidence from a prospective study.

BACKGROUND: Lineage distribution of Mycobacterium tuberculosis (Mtb) isolates is strongly associated with geographically distinct human populations, and its transmission can be further impacted by the bacterial genome. However, the epidemic success of Mtb isolates at an individual level was unknown in eastern China. Knowledge regarding the emergence and transmission of Mtb isolates as well as relevant factors may offer a new solution to curb the spread of the disease. Thus, this study aims to reveal the evolution and epidemic success of Mtb isolates in eastern China. RESULTS: Of initial 1040 isolates, 997 were retained after removing duplicates and those with insufficient sequencing depth. Of the final samples, 733 (73.52%) were from Zhejiang Province, and 264 (26.48%) were from Shanghai City. Lineage 2 and lineage 4 accounted for 80.44% and 19.56%, with common ancestors dating around 7017 years ago and 6882 years ago, respectively. Sub-lineage L2.2 (80.34%) contributed the majority of total isolates, followed by L4.4 (8.93%) and L4.5 (8.43%). Additionally, 51 (5.12%) isolates were identified to be multidrug-resistant (MDR), of which 21 (29.17%) were pre-extensively drug-resistant (pre-XDR). One clade harboring katG S315T mutation may date back to 65 years ago and subsequently acquired mutations conferring resistance to another five antibiotic drugs. The prevalence of compensatory mutation was the highest in pre-XDR isolates (76.19%), followed by MDR isolates (47.06%) and other drug-resistant isolates (20.60%). Time-scaled haplotypic density analyses suggested comparable success indices between lineage 2 and lineage 4 (P = 0.306), and drug resistance did not significantly promote the transmission of Mtb isolates (P = 0.340). But for pre-XDR isolates, we found a higher success index in those with compensatory mutations (P = 0.025). Mutations under positive selection were found in genes associated with resistance to second-line injectables (whiB6) and drug tolerance (prpR) in both lineage 2 and lineage 4. CONCLUSIONS: Our study demonstrates the population expansion of lineage 2 and lineage 4 in eastern China, with comparable transmission capacity, while accumulation of resistance mutations does not necessarily facilitate the success of Mtb isolates. Compensatory mutations usually accompany drug resistance and significantly contribute to the epidemiological transmission of pre-XDR strains. Prospective molecular surveillance is required to further monitor the emergence and spread of pre-XDR/XDR strains in eastern China.

Population Pharmacokinetics and Dose Evaluation of Cycloserine among Patients with Multidrug-Resistant Tuberculosis under Standardized Treatment Regimens.

Although cycloserine is a recommended drug for the treatment of multidrug-resistant tuberculosis (MDR-TB) according to World Health Organization (WHO), few studies have reported on pharmacokinetics (PK) and/or pharmacodynamics (PD) data of cycloserine in patients with standardized MDR-TB treatment. This study aimed to estimate the population PK parameters for cycloserine and to identify clinically relevant PK/PD thresholds, as well as to evaluate the current recommended dosage. Data from a large cohort with full PK curves was used to develop a population PK model. This model was used to estimate drug exposure in patients with MDR-TB from a multicentre prospective study in China. The classification and regression tree was used to identify the clinically relevant PK/PD thresholds. Probability of target attainment was analyzed to evaluate the currently recommended dosing strategy. Cycloserine was best described by a two-compartment disposition model. A percentage of time concentration above MICs (T>MIC) of 30% and a ratio of area under drug concentration-time curve (AUC0-24h) over MIC of 36 were the valid predictors for 6-month sputum culture conversion and final treatment outcome. Simulations showed that with WHO-recommended doses (500 mg and 750 mg for patients weighing <45 kg and ≥45 kg), the probability of target attainment exceeded 90% at MIC ≤16 mg/L in MGIT for both T>MIC of 30% and AUC0-24h/MIC of 36. New clinically relevant PK/PD thresholds for cycloserine were identified in patients with standardized MDR-TB treatment. WHO-recommended doses were considered adequate for the MGIT MIC distribution in our cohort of Chinese patients with MDR-TB.

Phytochrome B regulates reactive oxygen signaling during abiotic and biotic stress in plants.

Reactive oxygen species (ROS) and the photoreceptor protein phytochrome B (phyB) play a key role in plant acclimation to stress. However, how phyB that primarily functions in the nuclei impacts ROS signaling mediated by respiratory burst oxidase homolog (RBOH) proteins that reside on the plasma membrane, during stress, is unknown. Arabidopsis thaliana and Oryza sativa mutants, RNA-Seq, bioinformatics, biochemistry, molecular biology, and whole-plant ROS imaging were used to address this question. Here, we reveal that phyB and RBOHs function as part of a key regulatory module that controls apoplastic ROS production, stress-response transcript expression, and plant acclimation in response to excess light stress. We further show that phyB can regulate ROS production during stress even if it is restricted to the cytosol and that phyB, respiratory burst oxidase protein D (RBOHD), and respiratory burst oxidase protein F (RBOHF) coregulate thousands of transcripts in response to light stress. Surprisingly, we found that phyB is also required for ROS accumulation in response to heat, wounding, cold, and bacterial infection. Our findings reveal that phyB plays a canonical role in plant responses to biotic and abiotic stresses, regulating apoplastic ROS production, possibly while at the cytosol, and that phyB and RBOHD/RBOHF function in the same regulatory pathway.