Association Between the XRCC1, GSTM1, and GSTT1 Polymorphisms in Model of Thyroid Cancer: A Meta-Analysis.

Thyroid cancer is the most common malignant tumor of the endocrine system, and its incidence is increasing worldwide each year. This study aimed to explore the association between XRCC1, GSTM1, and GSTT1 polymorphisms in the model of thyroid cancer. The experiment was conducted by searching PubMed, Embase, and Web of Science, with the last search performed in March 2022. A total of 12 studies were included in this meta-analysis, with sample sizes ranging from 211 to 1124. The proportion of XRCC1 polymorphisms (rs25489, GG) in thyroid cancer was slightly lower than that of the normal control group, but the difference was not statistically significant (Mean difference=1.13, 95% CI: 0.99-1.28, p=0.08). The proportion of XRCC1 polymorphisms (rs25489, GA) in thyroid cancer was significantly lower than that of the normal control group (Mean difference=1.32, 95% CI: 1.16-1.52, p<0.00001). The proportion of XRCC1 polymorphisms (rs25489, AA) in thyroid cancer was slightly lower than that of the normal control group, but again, the difference was not statistically significant (Mean difference=0.78, 95% CI: 0.61-1.01, p=0.06). Similarly, the proportion of XRCC1 polymorphisms (rs25487, GG) and (rs25487, GA) in thyroid cancer was lower than that of the normal control group, but the differences were not statistically significant (p=0.22 and p=0.49, respectively). In conclusion, this study found that the proportion of XRCC1 polymorphisms (rs25489, AA) in thyroid cancer was lower than that of the normal control group.

Evaluation of cuspid cortical anchorage with different sagittal patterns using cone-beam computed tomography: a retrospective study.

BACKGROUND: No studies have focused on cortical anchorage resistance in cuspids, this study aimed to characterize the cortical anchorage according to sagittal skeletal classes using cone-beam computed tomography (CBCT). METHODS: CBCT images of 104 men and 104 women were divided into skeletal class I, II, and III malocclusion groups. Skeletal and dental evaluations were performed on the sagittal and axial cross-sections. One-way analysis of variance followed by least significant difference post-hoc tests was used for group differences. Multiple linear regression was performed to evaluate the relationship between influential factors and cuspid cortical anchorage. RESULTS: All cuspids were close to the labial bone cortex in different sagittal skeletal patterns and had different inclinations. There was a significant difference in the apical root position of cuspids in the alveolar bone; however, no significant difference in the middle or cervical portions of the root was found between different sagittal facial patterns. The middle of the cuspid root was embedded to the greatest extent in the labial bone cortex, with no significant difference between the sagittal patterns. For all sagittal patterns, 6.03 ± 4.41° (men) and 6.08 ± 4.45° (women) may be appropriate root control angles to keep maxillary cuspids' roots detached from the labial bone cortex. CONCLUSIONS: Comparison of skeletal class I, II, and III malocclusion patients showed that dental compensation alleviated sagittal skeletal discrepancies in the cuspid positions of all patients, regardless of the malocclusion class. Detailed treatment procedures and clear treatment boundaries of cuspids with different skeletal patterns can improve the treatment time, periodontal bone remodeling, and post-treatment long-term stability. Future studies on cuspids with different dentofacial patterns and considering cuspid morphology and periodontal condition may provide more evidence for clinical treatment.

The Exocyst Regulates Hydrolytic Enzyme Secretion at Hyphal Tips and Septa in the Banana Fusarium Wilt Fungus Fusarium odoratissimum.

Hyphal polarized growth in filamentous fungi requires tip-directed secretion, while additional evidence suggests that fungal exocytosis for the hydrolytic enzyme secretion can occur at other sites in hyphae, including the septum. In this study, we analyzed the role of the exocyst complex involved in the secretion in the banana wilt fungal pathogen Fusarium odoratissimum. All eight exocyst components in F. odoratissimum not only localized to the tips ahead of the Spitzenkörper in growing hyphae but also localized to the outer edges of septa in mature hyphae. To further analyze the exocyst in F. odoratissimum, we attempted single gene deletion for all the genes encoding the eight exocyst components and only succeeded in constructing the gene deletion mutants for exo70 and sec5; we suspect that the other 6 exocyst components are encoded by essential genes. Deletion of exo70 or sec5 led to defects in vegetative growth, conidiation, and pathogenicity in F. odoratissimum. Notably, the deletion of exo70 resulted in decreased activities for endoglucosidase, filter paper enzymes, and amylase, while the loss of sec5 only led to a slight reduction in amylase activity. Septum-localized α-amylase (AmyB) was identified as the marker for septum-directed secretion, and we found that Exo70 is essential for the localization of AmyB to septa. Meanwhile the loss of Sec5 did not affect AmyB localization to septa but led to a higher accumulation of AmyB in cytoplasm. This suggested that while Exo70 and Sec5 both take part in the septum-directed secretion, the two play different roles in this process. IMPORTANCE The exocyst complex is a multisubunit tethering complex (MTC) for secretory vesicles at the plasma membrane and contains eight subunits, Sec3, Sec5, Sec6, Sec8, Sec10, Sec15, Exo70, and Exo84. While the exocyst complex is well defined in eukaryotes from yeast (Saccharomyces cerevisiae) to humans, the exocyst components in filamentous fungi show different localization patterns in the apical tips of hyphae, which suggests that filamentous fungi have evolved divergent strategies to regulate endomembrane trafficking. In this study, we demonstrated that the exocyst components in Fusarium odoratissimum are localized not only to the tips of growing hyphae but also to the outer edge of the septa in mature hyphae, suggesting that the exocyst complex plays a role in the regulation of septum-directed protein secretion in F. odoratissimum. We further found that Exo70 and Sec5 are required for the septum-directed secretion of α-amylase in F. odoratissimum but with different influences.

External evaluation of published population pharmacokinetic models of polymyxin B.

OBJECTIVES: Several population pharmacokinetics (popPK) models for polymyxin B have been constructed to optimize therapeutic regimens. However, their predictive performance remains unclear when extrapolated to different clinical centers. Therefore, this study aimed to evaluate the predictive ability of polymyxin B popPK models. METHODS: A literature search was conducted, and the predictive performance was determined for each selected model using an independent dataset of 20 patients (92 concentrations) from the Third Xiangya Hospital. Prediction- and simulation-based diagnostics were used to evaluate model predictability. The influence of prior information was assessed using Bayesian forecasting. RESULTS: Eight published studies were evaluated. In prediction-based diagnostics, the prediction error within ± 30% was over 50% in two models. In simulation-based diagnostics, the prediction- and variability-corrected visual predictive check (pvcVPC) showed satisfactory predictivity in three models, while the normalized prediction distribution error (NPDE) tests indicated model misspecification in all models. Bayesian forecasting demonstrated a substantially improvement in the model predictability even with one prior observation. CONCLUSION: Not all published models were satisfactory in prediction- and simulation-based diagnostics; however, Bayesian forecasting improved the predictability considerably with priors, which can be applied to guide polymyxin B dosing recommendations and adjustments for clinicians.

Trends and socio-economic disparities in catastrophic health expenditure and health impoverishment in China: 2010 to 2016.

OBJECTIVES: To investigate trends and socio-economic disparities in the catastrophic health expenditure (CHE) and health impoverishment in China after major reform of the health system and to examine the impacts of the chronic disease on CHE and impoverishment. METHODS: We obtained data from four rounds of the China Family Panel Studies 2010-2016, with a sample size of 14 960 households. We defined CHE as the point at which annual household health payments exceeded 40% of annual capacity to pay. Impoverishment is measured by the $1.90 per day poverty line. Multivariate logistic regression models were performed to identify impacts of the family member with chronic disease on CHE and impoverishment. RESULTS: Between 2010 and 2016, the incidence of CHE in China decreased from 19.37% to 15.11% and from 7.39% to 5.14% for health impoverishment; however, the decrease in level of impoverishment was less in rural areas (from 6.16% down to 3.03%) than in urban areas (from 8.46% down to 7.81%). The gap between impoverishment rates across the income quartiles is growing. Multivariable analysis showed that households with two or more members suffering chronic diseases were significantly more likely to incur CHE (aOR: 2.46, 95% CI: 1.93-3.13) and impoverishment (aOR: 2.66, 95% CI: 1.87-3.78) than households with no members suffering chronic diseases, after adjusting for sociodemographic covariates. CONCLUSIONS: Important advances have been made in achieving greater financial protection for Chinese citizens. Nevertheless, greater attention to the poor households with chronic disease members is needed. Policymakers in China should focus on optimising integrated rural-urban health insurance by expanding the current benefit packages and strengthening poverty alleviation efforts.

OBJECTIFS: Investiguer les tendances et les disparités socioéconomiques dans les dépenses de santé catastrophiques (DSC) et l'appauvrissement de la santé en Chine après une réforme majeure du système de santé et examiner les impacts de la maladie chronique sur les DSC et l'appauvrissement. MÉTHODES: Nous avons obtenu des données provenant de quatre séries des Etudes du Panel de la Famille de Chine 2010-2016 sur un échantillon de 14.960 ménages. Nous avons défini la DSC comme le point à partir duquel les paiements annuels pour la santé des ménages dépassaient 40% de la capacité de paiement annuelle. L'appauvrissement a été mesuré par le seuil de pauvreté de 1,90 $ par jour. Des modèles de régression logistique multivariée ont été effectués pour identifier les impacts du membre de la famille atteint d'une maladie chronique sur la DSC et l'appauvrissement. RÉSULTATS: Entre 2010 et 2016, l'incidence des DSC en Chine est passée de 19,37% à 15,11% et de 7,39% à 5,14% pour l'appauvrissement de la santé. Cependant, la baisse du niveau d'appauvrissement a été moindre dans les zones rurales (de 8,46% à 7,81%) que dans les zones urbaines (de 6,16% à 3,03%). L'écart entre les taux d'appauvrissement dans les quartiles de revenu se creuse. L'analyse multivariée a montré que les ménages comptant deux membres ou plus souffrant de maladies chroniques étaient significativement plus susceptibles de subir une DSC (aOR: 2,46; IC95%: 1,93-3,13) et un appauvrissement (aOR: 2,66 ; IC95%: 1,87-3,78) que les ménages sans membres souffrant de maladies chroniques, après ajustement pour les covariables sociodémographiques. CONCLUSIONS: D'importants progrès ont été réalisés pour assurer une meilleure protection financière des citoyens chinois. Néanmoins, une plus grande attention aux ménages pauvres comptant des membres atteints de maladies chroniques reste nécessaire. Les décideurs de politiques en Chine devraient se concentrer sur l'optimisation de l'assurance maladie intégrée rurale-urbaine en élargissant les avantages sociaux actuels et en renforçant les efforts de lutte contre la pauvreté.

Correlation between symptoms and cognitive function changes in patients with primary insomnia and pathways in gut microbiota.

Background: Primary insomnia (PI) refers to syndromes of difficulty falling asleep, poor sleep quality, early awakening, and difficulty falling asleep after waking up. Although there have been numerous studies, the specific etiology and pathogenesis of PI are still misunderstanding. In recent years, the gut microbiota has been proved to be involved in the metabolism of many mental disorders. But the specific mechanisms of its involvement in PI have not been fully elucidated. This study aims to explore the relationship between the gut microbiota and the symptoms, cognitive function changes in PI. Methods: In this study, the gut microbiota of PI patients and healthy controls was profiled by performing stool 16s rRNA gene sequencing. The co-occurrence network was constructed by using Weight Gene Co-expression Network Analysis (WGCNA) algorithm. The correlation between gut microbiota associated pathways and traits in PI were predicted. Results: WGCNA results demonstrated several Operational Taxonomic Units (OTU) modules are correlated to symptoms. By using PICRUSt2 software, we predicted the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways of microbiota in modules. For instance, sleep efficiency may be correlated with the presence of Insulin signaling pathway, Flavonoid biosynthesis, Ascorbate and aldarate metabolism, Nitrotoluene degradation, Biotin metabolism, RNA polymerase and Chlorocyclohexane and chlorobenzene degradation. Total sleep time may be correlated with the presence of Tyrosine metabolism, Propanoate metabolism, Carbon fixation pathways in prokaryotes, Carotenoid biosynthesis, Systemic lupus erythematosus, Nitrotoluene degradation and Biosynthesis of unsaturated fatty acids. The severity of insomnia may be correlated with Insulin signaling pathway, Flavonoid biosynthesis, Ascorbate and aldarate metabolism, Nitrotoluene degradation, Biotin metabolism and RNA polymerase. Change of name score in Montreal Cognitive Assessment (MoCA) may be correlated with Tyrosine metabolism, Propanoate metabolism, Carbon fixation pathways in prokaryotes, Carotenoid biosynthesis, Systemic lupus erythematosus, Nitrotoluene degradation, Biosynthesis of unsaturated fatty acids, Apoptosis, Steroid hormone biosynthesis, Geraniol degradation, Protein digestion and absorption and Bisphenol degradation in Gut Microbiota (GM). Conclusion: This study revealed the potential relationships between gut microbiota and PI. By using pathway prediction and enrichment analysis, we concluded many metabolic pathways may associated with some important traits of insomnia patients, including sleep efficiency, severe insomnia, total sleep time and change of name score in MoCA. The metabolic pathways include Insulin signaling pathway, Flavonoid biosynthesis, Ascorbate and aldarate metabolism, Nitrotoluene degradation, Biotin metabolism, RNA polymerase and Chlorocyclohexane, chlorobenzene degradation, Tyrosine metabolism, Propanoate metabolism, Carbon fixation pathways in prokaryotes, Carotenoid biosynthesis, Systemic lupus erythematosus, Biosynthesis of unsaturated fatty acids, Apoptosis, Steroid hormone biosynthesis, Geraniol degradation, Protein digestion and absorption and Bisphenol degradation.Our study demonstrated that PI patients demonstrate significant changes in gut microbiota, which will help delineate the relationship between gut microbiota and syndromes of PI.

Sustained free chlorine-releasing polydimethylsiloxane/Ca(ClO)2 materials with long-lasting disinfection efficacy.

A novel sustained chlorine-releasing polydimethylsiloxane/Ca(ClO)2 (PDMS/Ca(ClO)2) material was fabricated by encapsulating Ca(ClO)2 in a PDMS matrix due to its high hydrophobicity and high chemical stability, which showed immediate-responsive and long-lasting antibacterial capabilities in aqueous conditions. Free chlorine could be released from the PDMS/Ca(ClO)2 after immersion in water for 2 min and could also be sustainedly released for 2 weeks, while the released concentration is negatively related to the duration time and positively with the initial Ca(ClO)2 contents. Additionally, Ca(ClO)2 powder as a filler significantly affects the crosslinking and pore size of PDMS. The PDMS/Ca(ClO)2 materials exhibited enduring antibacterial performance against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) in both planktonic and multispecies-biofilm status. It is expected that this PDMS/Ca(ClO)2 material and its similar composite would be promising candidates for wide sustainable disinfection applications in biomedical and industrial fields.

Yttrium-preintercalated layered manganese oxide as a durable cathode for aqueous zinc-ion batteries.

Rechargeable aqueous zinc-ion batteries (RAZIBs) are regarded as competitive alternatives for large-scale energy storage on account of cost-effectiveness and inherent safety. In particular, rechargeable Zn-MnO2 batteries have drawn increasing attention due to high manufacturing readiness level. However, obtaining MnO2 with high electrochemical activity and high cyclic stability toward Zn2+/H+ storage still remains challenging. Herein, we reveal that incorporating yttrium ions (Y3+) into layered MnO2 can regulate the electronic structure of the MnO2 cathode by narrowing its band gap (from 3.25 to 2.50 eV), thus boosting the electrochemical performance in RAZIBs. Taking advantage of this feature, the optimized Y-MnO2 (YMO) sample exhibits greater capacity (212 vs. 152 mA h g-1 at 0.5 A g-1), better rate capability (94 vs. 61 mA h g-1 at 8 A g-1), reduced charge-transfer resistance (79 vs. 148 Ω), and promoted mass transfer kinetics (3.13 × 10-11vs. 2.37 × 10-11 cm2 s-1) in comparison with Y-free MnO2 (MO). More importantly, compared to MO, YMO-0.1 exhibits enhanced energy storage capability by nearly 40% (309 vs. 222 W h kg-1) and stable cycle performance (94 vs. 52 mA h g-1 after 3000 cycles). In situ Raman microscopy further reveals that the presence of Y3+ endows MnO2 with remarkable electrochemical reversibility during charge/discharge processes. This work highlights the importance of the Y3+ preintercalation strategy, which can be further developed to obtain better cathode materials for aqueous batteries.

The Signal Peptidase FoSpc2 Is Required for Normal Growth, Conidiation, Virulence, Stress Response, and Regulation of Light Sensitivity in Fusarium odoratissimum.

Signal peptidase (SPase) is responsible for cleavage of N-terminal signal peptides in most secretory precursor proteins and many membrane proteins during maturation. In this study, we identified four components of the SPase complex (FoSec11, FoSpc1, FoSpc2, and FoSpc3) in the banana wilt fungal pathogen Fusarium odoratissimum. We proved that interactions exist among the four SPase subunits by bimolecular fluorescence complementation (BiFC) and affinity purification and mass spectrometry (AP-MS) assays. Among the four SPase genes, FoSPC2 was successfully deleted. FoSPC2 deletion caused defects in vegetative growth, conidiation, and virulence. Loss of FoSPC2 also affected the secretion of some pathogenicity-related extracellular enzymes, suggesting that SPase without FoSpc2 may have a lower efficiency in managing the maturation of the extracellular enzymes in F. odoratissimum. In addition, we found that the ΔFoSPC2 mutant had increased sensitivity to light, and the colonies of the mutant grew faster under all-dark conditions than under all-light conditions. We further observed that deletion of FoSPC2 affected expression of the blue light photoreceptor gene FoWC2, leading to cytoplasmic accumulation of FoWc2 under all-light conditions. Since FoWc2 has signal peptides, FoSpc2 may regulate the expression and subcellular localization of FoWc2 indirectly. Contrary to its response to light, the ΔFoSPC2 mutant displayed a significant decreased sensitivity to osmotic stress, and culturing the mutant under osmotic stress conditions restored both the localization of FoWc2 and light sensitivity of the ΔFoSPC2, suggesting that a cross talk between osmotic stress and light response pathways in F. odoratissimum and FoSpc2 takes part in these processes. IMPORTANCE In this study, we identified four components of SPase in the banana wilt pathogen Fusarium odoratissimum and characterized the SPase FoSpc2. Loss of FoSPC2 affected the secretion of extracellular enzymes, suggesting that SPase without FoSpc2 may have a lower efficiency in managing the maturation of the extracellular enzymes in F. odoratissimum. In addition, this is the first time that we have found a relationship between the SPase and fungal light response. Deletion of FoSPC2 resulted in decreased sensitivity to the osmotic stresses but with increased sensitivity to light. Continuous light inhibited the growth rate of the ΔFoSPC2 mutant and affected the cellular localization of the blue light photoreceptor FoWc2 in this mutant, but culturing the mutant under osmotic stress both restored the localization of FoWc2 and eliminated the light sensitivity of the ΔFoSPC2 mutant, suggesting that loss of FoSPC2 may affect a cross talk between the osmotic stress and light response pathways in F. odoratissimum.

A Network of Sporogenesis-Responsive Genes Regulates the Growth, Asexual Sporogenesis, Pathogenesis and Fusaric Acid Production of Fusarium oxysporum f. sp. cubense.

The conidia produced by Fusarium oxysporum f. sp. cubense (Foc), the causative agent of Fusarium Wilt of Banana (FWB), play central roles in the disease cycle, as the pathogen lacks a sexual reproduction process. Until now, the molecular regulation network of asexual sporogenesis has not been clearly understood in Foc. Herein, we identified and functionally characterized thirteen (13) putative sporulation-responsive genes in Foc, namely FocmedA(a), FocmedA(b), abaA-L, FocflbA, FocflbB, FocflbC, FocflbD, FocstuA, FocveA, FocvelB, wetA-L, FocfluG and Foclae1. We demonstrated that FocmedA(a), abaA-L, wetA-L, FocflbA, FocflbD, FocstuA, FocveA and Foclae1 mediate conidiophore formation, whereas FocmedA(a) and abaA-L are important for phialide formation and conidiophore formation. The expression level of abaA-L was significantly decreased in the ΔFocmedA(a) mutant, and yeast one-hybrid and ChIP-qPCR analyses further confirmed that FocMedA(a) could bind to the promoter of abaA-L during micro- and macroconidiation. Moreover, the transcript abundance of the wetA-L gene was significantly reduced in the ΔabaA-L mutant, and it not only was found to function as an activator of micro- and macroconidium formation but also served as a repressor of chlamydospore production. In addition, the deletions of FocflbB, FocflbC, FocstuA and Foclae1 resulted in increased chlamydosporulation, whereas FocflbD and FocvelB gene deletions reduced chlamydosporulation. Furthermore, FocflbC, FocflbD, Foclae1 and FocmedA(a) were found to be important regulators for pathogenicity and fusaric acid synthesis in Foc. The present study therefore advances our understanding of the regulation pathways of the asexual development and functional interdependence of sporulation-responsive genes in Foc.

Population pharmacokinetics of omeprazole in obese and normal-weight adults.

BACKGROUND: Obesity is related to many pathophysiological changes that may result in altered drug disposition. Omeprazole is the most common option utilized for acid-related disorders ; however, the pharmacokinetic (PK) and dosing recommendations for the obese patient population are lacking. METHODS: Data from 40 healthy subjects with normal weights and data from 61 obese subjects were included. The subjects all received a single dose of 20 mg of omeprazole. Nonlinear mixed effects modeling were performed to characterize the effect of obesity on omeprazole PK. RESULTS: A one-compartment model with twelve transit absorption compartments and linear elimination described the data best. A lower clearance was observed in the obese patient population than in the normal-weight subjects. Moreover, the CYP2C19 genotype was identified as a significant covariate for clearance. CONCLUSION: Given the potential adverse events related to high exposure to proton pump inhibitors over time, obese patients may require a lower dose of omeprazole for long-term treatment. Further studies in obese individuals into other drugs metabolized by CYP2C19 are warranted, especially those with a narrow therapeutic window. CLINICAL TRIAL REGISTRATION: www.chictr.org.cn identifier is ChiCTR2100046578; www.chinadrugtrials.org.cn identifier is CTR20190175.

Effect of Laparoscopic Sleeve Gastrectomy on the Pharmacokinetics of Oral Omeprazole Using a Population Approach.

Omeprazole is commonly prescribed to obese patients and patients after laparoscopic sleeve gastrectomy (LSG). The pharmacokinetics of oral omeprazole after LSG are still unknown. Therefore, the aim of this study was to investigate the pharmacokinetics of oral omeprazole in obese patients before and after LSG. A total of 331 blood samples were collected from 62 obese patients preoperatively (visit 1) followed by 41 patients 7 days post-LSG (visit 2) and 20 patients 1 month post-LSG (visit 3). Population pharmacokinetic analysis was performed using NONMEM to characterize the effect of LSG on omeprazole absorption and disposition. A one-compartment model with 12 transit absorption compartments and linear elimination successfully described the data. Compared with pre-surgery, the oral omeprazole time to maximum plasma concentration (Tmax) was reduced and maximum plasma concentration (Cmax) was higher, but the apparent clearance (CL/F) and area under the plasma concentration-time curve (AUC) were unchanged 7 days and 1 month after surgery. In addition, the CYP2C19 genotype and liver function exhibited a significant influence on omeprazole CL/F. LSG increased the rate of omeprazole absorption but did not affect omeprazole exposure. A dose of 20 mg omeprazole once daily may be adequate for relieving gastrointestinal tract discomfort at short-term follow-up post-LSG.

Small GTPase FoSec4-Mediated Protein Secretion Is Important for Polarized Growth, Reproduction and Pathogenicity in the Banana Fusarium Wilt Fungus Fusarium odoratissimum.

Apical secretion at hyphal tips is important for the growth and development of filamentous fungi. In this study, we analyzed the role of the Rab GTPases FoSec4 involved in the secretion of the banana wilt fungal pathogen Fusarium odoratissimum. We found that the deletion of FoSEC4 affects the activity of extracellular hydrolases and protein secretion, indicating that FoSec4 plays an important role in the regulation of protein secretion in F. odoratissimum. As a typical Rab GTPase, Sec4 participates in the Rab cycle through the conversion between the active GTP-bound state and the inactive GDP-bound state, which is regulated by guanine nucleate exchange factors (GEFs) and GTPase-activating proteins (GAPs). We further found that FoSec2 can interact with dominant-negative FoSec4 (GDP-bound and nucleotide-free form, FoSec4DN), and that FoGyp5 can interact with dominant active FoSec4 (GTP-bound and constitutively active form, FoSec4CA). We evaluated the biofunctions of FoSec4, FoSec2 and FoGyp5, and found that FoSec4 is involved in the regulation of vegetative growth, reproduction, pathogenicity and the environmental stress response of F. odoratissimum, and that FocSec2 and FoGyp5 perform biofunctions consistent with FoSec4, indicating that FoSec2 and FoGyp5 may work as the GEF and the GAP, respectively, of FoSec4 in F. odoratissimum. We further found that the amino-terminal region and Sec2 domain are essential for the biological functions of FoSec2, while the carboxyl-terminal region and Tre-2/Bub2/Cdc16 (TBC) domain are essential for the biological functions of FoGyp5. In addition, FoSec4 mainly accumulated at the hyphal tips and partially colocalized with Spitzenkörper; however, FoGyp5 accumulated at the periphery of Spitzenkörper, suggesting that FoGyp5 may recognize and inactivate FoSec4 at a specific location in hyphal tips.

Biosimilarity of HS-20090 to Denosumab in healthy Chinese subjects: a randomized, double-blinded, pharmacokinetics/pharmacodynamics study.

OBJECTIVE: HS-20090 is a proposed biosimilar candidate of Denosumab (Xgeva®). The study aimed to evaluate the similarity of pharmacokinetics (PK), pharmacodynamics (PD), safety, and immunogenicity between HS-20090 and Xgeva® in healthy Chinese subjects. METHODS: A single-center, randomized, double-blinded, active-controlled study was conducted in healthy Chinese adult male subjects. A total of 154 subjects were planned to be randomly assigned (1:1) to receive 120 mg of either HS-20090 or Xgeva® in a single subcutaneous injection, with a follow-up period of 155 days. The primary objective was to evaluate the bioequivalence of PK. The primary endpoints were Cmax and AUC0-∞. The secondary objectives were to evaluate the similarity of PD, safety, and immunogenicity. RESULTS: All 154 subjects were included in the PK, PD, and safety analyses. The 90% CIs of GMRs of HS-20090/Xgeva® for Cmax, AUC0-t, and AUC0-∞ were 90.49 ~ 100.23%, 94.45 ~ 104.61%, and 94.08 ~ 105.23%, respectively, achieving the bioequivalence criteria of 80 ~ 125%. The PD parameters and incidence of adverse events between HS-20090 and denosumab were also similar, with no detection of ADA in both the groups. CONCLUSION: HS-20090 was highly similar to Xgeva®, with regard to PK, PD, safety profiles, and immunogenicity in healthy Chinese subjects. These data support subsequently comparative clinical study for bone metastases in solid tumors. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov identifier is NCT04494373.

Type 2C Protein Phosphatases MoPtc5 and MoPtc7 Are Crucial for Multiple Stress Tolerance, Conidiogenesis and Pathogenesis of Magnaporthe oryzae.

Protein kinases and phosphatases catalyze the phosphorylation and dephosphorylation of their protein substrates, respectively, and these are important mechanisms in cellular signal transduction. The rice blast fungus Magnaporthe oryzae possesses 6 protein phosphatases of type 2C class, including MoPtc1, 2, 5, 6, 7 and 8. However, only very little is known about the roles of these phosphatases in filamentous fungi. Here in, we deployed genetics and molecular biology techniques to identify, characterize and establish the roles of MoPtc5 and MoPtc7 in M. oryzae development and pathogenicity. We found that during pathogen-host interaction, MoPTC7 is differentially expressed. Double deletion of MoPTC7 and MoPTC5 suppressed the fungal vegetative growth, altered its cell wall integrity and reduced its virulence. The two genes were found indispensable for stress tolerance in the phytopathogen. We also demonstrated that disruption of any of the two genes highly affected appressorium turgor generation and Mps1 and Osm1 phosphorylation levels. Lastly, we demonstrated that both MoPtc5 and MoPtc7 are localized to mitochondria of different cellular compartments in the blast fungus. Taken together, our study revealed synergistic coordination of M. oryzae development and pathogenesis by the type 2C protein phosphatases.

Predictors of early postoperative hypocalcemia in patients with secondary hyperparathyroidism undergoing total parathyroidectomy.

OBJECTIVE: To summarize the clinical features of secondary hyperparathyroidism (SHPT) in patients with chronic renal failure and to explore the predictive factors of postoperative hypocalcemia after total parathyroidectomy in these patients. METHODS: The clinical data of 87 patients admitted to Guangdong Electric Power Hospital from May 2013 to February 2020 were reviewed. All patients underwent total parathyroid resection and sternocleidomastoid microtransplantation. Age, sex, and the serum calcium, phosphorus, alkaline phosphatase (ALP), and intact parathyroid hormone (iPTH) concentrations were analyzed as predictive factors of postoperative hypocalcemia. RESULTS: Bone pain was the most common clinical manifestation in this study population, and all 87 patients experienced relief from their clinical symptoms after the surgical procedure. Age and the preoperative serum calcium, ALP, and iPTH concentrations were determined to be early predictive factors of postoperative hypocalcemia. CONCLUSIONS: Age and the preoperative calcium, ALP, and iPTH concentrations are independent risk factors for postoperative hypocalcemia in patients with SHPT and renal disease who undergo total parathyroidectomy with sternocleidomastoid microtransplantation. These factors can help identify high-risk patients who can be managed by a multidisciplinary team to improve graft survival and quality of life.

Effect of laparoscopic sleeve gastrectomy on drug pharmacokinetics.

INTRODUCTION: Given its feasibility and efficacy, laparoscopic sleeve gastrectomy (LSG) has become a widely accepted bariatric surgery for patients with clinically diagnosed severe obesity. LSG induces anatomical changes and subsequent weight loss which may affect drug pharmacokinetics (PK) and consequently impact dosing regimens. This review aims to examine the effect of LSG on drug PK and identify relevant gastrointestinal physiological alterations. AREAS COVERED: PubMed, Embase, Scopus, and the Cochrane Library were searched for articles related to drug PK and LSG from inception to July 2021. Moreover, literature concerning postoperative physiological conditions in the gastrointestinal tract, such as gastric pH, gastric emptying, and small bowel transit time, etc., which may affect the PK profile of drug products was also reviewed. EXPERT OPINION: Although LSG is classified as having restrictive property without malabsorptive bypass, postoperative changes in gastrointestinal physiology and subsequent weight loss may also lead to increased, decreased or unaltered drug exposure levels. General monitoring on drug efficacy or safety using biomarkers is proposed. In addition, therapeutic drug monitoring for those drugs when it is applicable and available is recommended to ensure efficient drug dosing and avoid adverse effects. Further research into many individual drugs are warranted.

Ct Dosimetry for The Australian Cohort Data Linkage Study.

Children undergoing computed tomography (CT) scans have an increased risk of cancer in subsequent years, but it is unclear how much of the excess risk is due to reverse causation bias or confounding, rather than to causal effects of ionising radiation. An examination of the relationship between excess cancer risk and organ dose can help to resolve these uncertainties. Accordingly, we have estimated doses to 33 different organs arising from over 900 000 CT scans between 1985 and 2005 in our previously described cohort of almost 12 million Australians aged 0-19 years. We used a multi-tiered approach, starting with Medicare billing details for government-funded scans. We reconstructed technical parameters from national surveys, clinical protocols, regulator databases and peer-reviewed literature to estimate almost 28 000 000 individual organ doses. Doses were age-dependent and tended to decrease over time due to technological improvements and optimisation.

Synthesis of Sulfur-Selenium Doped Carbon Quantum Dots for Biological Imaging and Scavenging Reactive Oxygen Species.

The sulfur-selenium doped carbon quantum dots (S,Se-CQDs) were synthesized by one-step through hydrothermal method in this study, which have high fluorescence quantum yield (43%) and advanced ability to scavenge reactive oxygen species (ROS). They were characterized by transmission electron microscope (TEM), nuclear magnetic resonance (NMR), X-ray photoelectron spectroscopy (XPS), fourier transform infrared spectroscopy (FTIR). The results showed that the clearance rate of free radical reached to 40% with 200 µg/mL of S,Se-CQDs. The antioxidant activity of S,Se-CQDs is related to -SH and Se-SH on carbon quantum dots. S,Se-CQDs were able to access to cells which is beneficial to enhance the removal efficiency to ROS. In the biocompatibility experiment, the cell survival rate exceeded 95%, there was little effect on hatching rate, survival rate and heart rate of zebrafish which demonstrated that S,Se-CQDs have an excellent biocompatibility. It prompts that S,Se-CQDs will has proud application prospects in the field of biomedicine.