Over-activation of cold tolerance in arabidopsis causes carbohydrate shortage compared with Chorispora bungeana.

Many plants cope with cold stress by developing acquired freezing tolerance (AFT) through cold acclimation (CA), and some species have strong basal freezing tolerance (BFT) independent of CA. Although CA has been extensively studied, its potential in agricultural applications is still unclear. Here, carbohydrate metabolism and transcriptome in AFT plant Arabidopsis and BFT plant Chorispora bungeana were compared with each other. The results showed that, although both species were able to accumulate soluble sugars during CA, leaf starch accumulation in the daytime was almost blocked in Arabidopsis while it was greatly enhanced in C. bungeana, revealing that Arabidopsis experienced carbohydrate shortage during CA. Transcriptome and pathway enrichment analysis found that genes for photosynthesis antenna proteins were generally repressed by cold stress in both species. However, cold-up-regulated genes were enriched in protein translation in Arabidopsis, whilst they were enriched in carotenoid biosynthesis, flavonoid biosynthesis, and beta-amylases in C. bungeana. Furthermore, weighted gene co-expression network analysis (WGCNA) showed that the inhibition of starch accumulation was associated with down-regulation of genes for photosynthesis antenna proteins and up-regulation of genes for protein translation, DNA repair, and proteasome in Arabidopsis but not in C. bungeana. Taken together, our results revealed that over-activation of common tolerant mechanisms resulted in insufficient carbohydrate supplies in Arabidopsis during CA, and photoprotective mechanisms played important roles in cold adaptation of C. bungeana. These findings uncovered the drawback of CA in improving freezing tolerance and highlighted photoprotection as a possible solution for agricultural applications.

The Efficacy and Frequency of Self-monitoring of Blood Glucose in Non-insulin-Treated T2D Patients: a Systematic Review and Meta-analysis.

BACKGROUND: Self-monitoring of blood glucose (SMBG) is a useful tool in diabetes management, but its efficacy and optimal application in type 2 diabetes (T2D) patients treated without insulin have been controversial. We aimed to evaluate the efficacy of SMBG in controlling blood glucose levels in non-insulin-treated T2D patients and to determine the optimal frequency and the most appropriate population to benefit from SMBG. METHODS: Eligible publications from January 2000 to April 2022 were retrieved from PubMed, Embase, Cochrane Library, and ClinicalTrials.gov databases. Randomized controlled trials comparing SMBG with no SMBG or structured SMBG (S-SMBG, SMBG with defined timing and frequency of glucose measurements) were included. Meta-analyses and sub-analyses were performed to assess the efficacy, optimal frequency, and most appropriate population for SMBG. Risk of bias was assessed regarding randomization, allocation sequence concealment, blinding, incomplete outcome data, selective outcome reporting, and other biases. RESULTS: Twenty-two studies involving 6204 participants were identified, including 17 comparing SMBG with no SMBG and 4 comparing SMBG with S-SMBG. SMBG reduced HbA1c (MD -0.30%, 95% CI -0.42 to -0.17) compared with no SMBG, and S-SMBG performed better than SMBG (MD -0.23%, 95% CI -0.38 to -0.07). Subgroup analyses showed that HbA1c control was better with SMBG at 8-11 times weekly (MD -0.35%, 95% CI -0.51 to -0.20) compared with other frequencies and with lifestyle adjustments (MD -0.37%, 95% CI -0.50 to -0.23) than with no adjustments. No significant differences in HbA1c were observed between baseline HbA1c subgroups (≤ 8% and > 8%, P = 0.63) and between diabetes duration subgroups (≤ 6 years and > 6 years, P = 0.72), respectively. DISCUSSION: SMBG was effective for controlling HbA1c in non-insulin-treated T2D patients, although lacking detailed monitoring design. Better outcomes were seen with SMBG at 8-11 times weekly and lifestyle adjustment based on SMBG results. TRIAL REGISTRATION: PROSPERO (CRD42021285604).

Dose Optimization of Vancomycin for Critically Ill Patients Undergoing CVVH: A Prospective Population PK/PD Analysis.

The optimal dose of vancomycin in critically ill patients receiving continuous venovenous hemofiltration (CVVH) remains unclear. The objective of this study was to identify factors that significantly affect pharmacokinetic profiles and to further investigate the optimal dosage regimens for critically ill patients undergoing CVVH based on population pharmacokinetics and pharmacodynamic analysis. A prospective population pharmacokinetic analysis was performed at the surgical intensive care unit in a level A tertiary hospital. We included 11 critically ill patients undergoing CVVH and receiving intravenous vancomycin. Serial blood samples were collected from each patient, with a total of 131 vancomycin concentrations analyzed. Nonlinear mixed effects models were developed using NONMEM software. Monte Carlo Simulation was used to optimize vancomycin dosage regimens. A two-compartment model with first-order elimination was sufficient to characterize vancomycin pharmacokinetics for CVVH patients. The population typical vancomycin clearance (CL) was 1.15 L/h and the central volume of distribution was 16.9 L. CL was significantly correlated with ultrafiltration rate (UFR) and albumin level. For patients with normal albumin and UFR between 20 and 35 mL/kg/h, the recommended dosage regimen was 10 mg/kg qd. When UFR was between 35 and 40 mL/kg/h, the recommended dosage regimen was 5 mg/kg q8h. For patients with hypoalbuminemia and UFR between 20 and 25 mL/kg/h, the recommended dosage regimen was 5 mg/kg q8h. When UFR was between 25 and 40 mL/kg/h, the recommended dosage regimen was 10 mg/kg q12h. We recommend clinicians choosing the optimal initial vancomycin dosage regimens for critically ill patients undergoing CVVH based on these two covariates.

Population Pharmacokinetic Modeling and Dose Optimization of Vancomycin in Chinese Patients with Augmented Renal Clearance.

Patients with augmented renal clearance (ARC) have been described as having low vancomycin concentration. However, the pharmacokinetic model that best describes vancomycin in patients with ARC has not been clarified. The purpose of this study is to determine the pharmacokinetic of vancomycin in Chinese adults and the recommend dosage for patients with different renal function, including patients with ARC. We retrospectively collected 424 vancomycin serum concentrations from 209 Chinese patients and performed a population pharmacokinetic model using NONMEM 7.4.4. The final model indicated that the clearance rate of vancomycin increased together with the creatinine clearance, and exhibited a nearly saturated curve at higher creatinine clearance. The estimated clearance of vancomycin was between 3.46 and 5.58 L/h in patients with ARC, with 5.58 being the maximum theoretical value. The central volume of distribution increased by more than three times in patients admitted to Intensive Care Unit. Monte Carlo simulations were conducted to explore the probability of reaching the target therapeutic range (24-h area under the curve: 400-650 mg·h/L, trough concentration: 10-20 mg/L) when various dose regimens were administered. The simulations indicated that dose should increase together with the creatinine clearance until 180 mL/min. These findings may contribute to improving the efficacy and safety of vancomycin in patients with ARC.

Application of a Physiologically Based Pharmacokinetic Model to Characterize Time-dependent Metabolism of Voriconazole in Children and Support Dose Optimization.

Background: Voriconazole is a potent antifungal drug with complex pharmacokinetics caused by time-dependent inhibition and polymorphisms of metabolizing enzymes. It also exhibits different pharmacokinetic characteristics between adults and children. An understanding of these alterations in pharmacokinetics is essential for pediatric dose optimization. Objective: To determine voriconazole plasma exposure in the pediatric population and further investigate optimal dosage regimens. Methods: An adult and pediatric physiologically based pharmacokinetic (PBPK) model of voriconazole, integrating auto-inhibition of cytochrome P450 3A4 (CYP3A4) and CYP2C19 gene polymorphisms, was developed. The model was evaluated with visual predictive checks and quantitative measures of the predicted/observed ratio of the area under the plasma concentration-time curve (AUC) and maximum concentration (Cmax). The validated pediatric PBPK model was used in simulations to optimize pediatric dosage regimens. The probability of reaching a ratio of free drug (unbound drug concentration) AUC during a 24-h period to minimum inhibitory concentration greater than or equal to 25 (fAUC24h/MIC ≥ 25) was assessed as the pharmacokinetic/pharmacodynamic index. Results: The developed PBPK model well represented voriconazole's pharmacokinetic characteristics in adults; 78% of predicted/observed AUC ratios and 85% of Cmax ratios were within the 1.25-fold range. The model maintained satisfactory prediction performance for intravenous administration in pediatric populations after incorporating developmental changes in anatomy/physiology and metabolic enzymes, with all predicted AUC values within 2-fold and 73% of the predicted Cmax within 1.25-fold of the observed values. The simulation results of the PBPK model suggested that different dosage regimens should be administered to children according to their age, CYP2C19 genotype, and infectious fungal genera. Conclusion: The PBPK model integrating CYP3A4 auto-inhibition and CYP2C19 gene polymorphisms successfully predicted voriconazole pharmacokinetics during intravenous administration in children and could further be used to optimize dose strategies. The infectious fungal genera should be considered in clinical settings, and further research with large sample sizes is required to confirm the current findings.

Comparison with Arabidopsis reveals optimal nitrogen allocation strategy and mechanism in Chorispora bungeana, a cryophyte with strong freezing tolerance.

The stress responses of plant compete for resources with growth and development. Resource allocations among these processes may have been optimized in plants adapted to natural habitats. Here, nitrogen (N) allocations were compared in leaves of Arabidopsis and Chorispora bungeana, a cryophyte with strong freezing tolerance. The results showed that the two species differed not only in N partitions among N forms and allocations among leaves, but also in their responses to cold stress. Interestingly, leaf protein contents were enhanced in C. bungeana while reduced in Arabidopsis, though the N allocations to leaves were reduced in both plants upon cold stress. Profoundly, when grown at warm temperature, contents of total free amino acids (FAAs) in leaves of C. bungeana were 6-11 times higher than those in Arabidopsis. In contrast, cold treatment induced FAAs accumulation in leaves of Arabidopsis without having significant effect in any leaf of C. bungeana. Considerable discrepancy was also found between the two species in the expressions of nitrate transporter genes and the activities of nitrate assimilation enzymes. Correlation and network analysis showed that most NPFs were clustered in a single network module and had loose relations with protein synthesis in Arabidopsis, while they were distributed in different modules in a decentralized network in C. bungeana. Therefore, our results reveal that C. bungeana may have optimized its N allocation strategy by producing and storing amino acids as efficient N reserve and adopting a decentralized network for N utilization, which may equip the plant with powerful capabilities for environmental adaptions.

[Association between the JAG2 gene polymorphism and the occurrence of nonsyndromic cleft lip with or without cleft palate in northwest Chinese population].

OBJECTIVE: To assess the association of JAG2 gene single nucleotide polymorphisms with the occurrence of nonsyndromic cleft lip with or without cleft palate (NSCLP) among northwest Chinese population. METHODS: A case-control study was carried out on 301 NSCLP patients and 304 healthy controls. An iMLDR(TM) genotyping technique was used to detect three single nucleotide polymorphisms (SNPs) [rs741859 (T/C), rs11621316 (A/G) and rs1057744(C/T)] of the JAG2 gene. Allelic and genotypic frequencies and haplotypic distribution among the two groups were compared. RESULTS: A significant difference was found in the frequency of C and T alleles for rs741859 between the two groups. The CT genotype of rs741859 could significantly reduce the risk for NSCLP to 65% (P< 0.05) and the risk for cleft lip with or without cleft palate (CL/P) to 62% (P< 0.05). rs11621316 and rs1057744 are in the same linkage disequilibrium (LD) region with a high degree of linkage (γ 2> 0.8), whose distribution difference between the two groups was not statistically significant (P> 0.05). CONCLUSION: The CT genotype of the JAG2 gene rs741859 may confer a protective effect for NSCLP among northwest Chinese population.