Growth of millimeter-sized 2D metal iodide crystals induced by ion-specific preference at water-air interfaces.

Conventional liquid-phase methods lack precise control in synthesizing and processing materials with macroscopic sizes and atomic thicknesses. Water interfaces are ubiquitous and unique in catalyzing many chemical reactions. However, investigations on two-dimensional (2D) materials related to water interfaces remain limited. Here we report the growth of millimeter-sized 2D PbI2 single crystals at the water-air interface. The growth mechanism is based on an inherent ion-specific preference, i.e. iodine and lead ions tend to remain at the water-air interface and in bulk water, respectively. The spontaneous accumulation and in-plane arrangement within the 2D crystal of iodide ions at the water-air interface leads to the unique crystallization of PbI2 as well as other metal iodides. In particular, PbI2 crystals can be customized to specific thicknesses and further transformed into millimeter-sized mono- to few-layer perovskites. Additionally, we have developed water-based techniques, including water-soaking, spin-coating, water-etching, and water-flow-assisted transfer to recycle, thin, pattern, and position PbI2, and subsequently, perovskites. Our water-interface mediated synthesis and processing methods represents a significant advancement in achieving simple, cost-effective, and energy-efficient production of functional materials and their integrated devices.

The performance of OPC and OPC3 water models in predictions of 2D structures under nanoconfinement.

Nanoconfined water plays an important role in broad fields of science and engineering. Classical molecular dynamics (MD) simulations have been widely used to investigate water phases under nanoconfinement. The key ingredient of MD is the force field. In this study, we systematically investigated the performance of a recently introduced family of globally optimal water models, OPC and OPC3, and TIP4P/2005 in describing nanoconfined two-dimensional (2D) water ice. Our studies show that the melting points of the monolayer square ice (MSI) of all three water models are higher than the melting points of the corresponding bulk ice Ih. Under the same conditions, the melting points of MSI of OPC and TIP4P/2005 are the same and are ∼90 K lower than that of the OPC3 water model. In addition, we show that OPC and TIP4P/2005 water models are able to form a bilayer AA-stacked structure and a trilayer AAA-stacked structure, which are not the cases for the OPC3 model. Considering the available experimental data and first-principles simulations, we consider the OPC water model as a potential water model for 2D water ice MD studies.

Historical context, process, and development trends of pediatric thyroid cancer research: a bibliometric analysis.

Objective: At present, the structure of knowledge in the field of childhood thyroid cancer is not clear enough, and scholars lack a sufficient understanding of the developing trends in this field, which has led to a shortage of forward-looking outputs. The purpose of this research is to help scholars construct a complete knowledge framework and identify current challenges, opportunities, and development trends. Methods: We searched the literature in the Web of Science Core Collection database on August 7, 2023 and extracted key information from the top 100 most cited articles, such as the countries, institutions, authors, themes, and keywords. We used bibliometric tools such as bibliometrix, VOSviewer, and CiteSpace for a visualization analysis and Excel for statistical descriptions. Results: The top 100 most cited articles fluctuated over time, and the research was concentrated in European countries, the United States, and Japan, among which scientific research institutions and scholars from the United States made outstanding contributions. Keyword analysis revealed that research has shifted from simple treatment methods for pediatric thyroid cancer (total thyroidectomy) and inducing factors (the Chernobyl power station accident) to the clinical applications of genetic mutations (such as the BRAF and RET genes) and larger-scale genetic changes (mutation studies of the DICER1 gene). The thematic strategy analysis showed an increasing trend towards the popularity of fusion oncogenes, while the popularity of research on traditional treatments and diagnostics has gradually declined. Conclusion: Extensive research has been conducted on the basic problems of pediatric thyroid cancer, and there has been significant outputs in the follow-up and cohort analysis of conventional diagnostic and treatment methods. However, these methods still have certain limitations. Therefore, scholars should focus on exploring fusion genes, the clinical applications of molecular targets, and novel treatment methods. This study provides a strong reference for scholars in this field.

Development and validation of a model for predicting the expression of Ki-67 in pancreatic ductal adenocarcinoma with radiological features and dual-energy computed tomography quantitative parameters.

OBJECTIVE: To construct and validate a model based on the dual-energy computed tomography (DECT) quantitative parameters and radiological features to predict Ki-67 expression levels in pancreatic ductal adenocarcinoma (PDAC). MATERIALS AND METHODS: Data from 143 PDAC patients were analysed. The variables of clinic, radiology and DECT were evaluated. In the arterial phase and portal venous phase (PVP), the normalized iodine concentration (NIC), normalized effective atomic number and slope of the spectral attenuation curves were measured. The extracellular volume fraction (ECVf) was measured in the equilibrium phase. Univariate analysis was used to screen independent risk factors to predict Ki-67 expression. The Radiology, DECT and DECT-Radiology models were constructed, and their diagnostic effectiveness and clinical applicability were obtained through area under the curve (AUC) and decision curve analysis, respectively. The nomogram was established based on the optimal model, and its goodness-of-fit was assessed by a calibration curve. RESULTS: Computed tomography reported regional lymph node status, NIC of PVP, and ECVf were independent predictors for Ki-67 expression prediction. The AUCs of the Radiology, DECT, and DECT-Radiology models were 0.705, 0.884, and 0.905, respectively, in the training cohort, and 0.669, 0.835, and 0.865, respectively, in the validation cohort. The DECT-Radiology nomogram was established based on the DECT-Radiology model, which showed the highest net benefit and satisfactory consistency. CONCLUSIONS: The DECT-Radiology model shows favourable predictive efficacy for Ki-67 expression, which may be of value for clinical decision-making in PDAC patients. CRITICAL RELEVANCE STATEMENT: The DECT-Radiology model could contribute to the preoperative and non-invasive assessment of Ki-67 expression of PDAC, which may help clinicians to screen out PDAC patients with high Ki-67 expression. KEY POINTS: • Dual-energy computed tomography (DECT) can predict Ki-67 in pancreatic ductal adenocarcinoma (PDAC). • The DECT-Radiology model facilitates preoperative and non-invasive assessment of PDAC Ki-67 expression. • The nomogram may help screen out PDAC patients with high Ki-67 expression.

Impact of κ-Carrageenan on the Cold-Set Pea Protein Isolate Emulsion-Filled Gels: Mechanical Property, Microstructure, and In Vitro Digestive Behavior.

More understanding of the relationship among the microstructure, mechanical property, and digestive behavior is essential for the application of emulsion gels in the food industry. In this study, heat-denatured pea protein isolate particles and κ-carrageenan were used to fabricate cold-set emulsion gels induced by CaCl2, and the effect of κ-carrageenan concentration on the gel formation mechanism, microstructure, texture, and digestive properties was investigated. Microstructure analysis obtained by confocal microscopy and scanning electron microscopy revealed that pea protein/κ-carrageenan coupled gel networks formed at the polysaccharide concentration ranged from 0.25% to 0.75%, while the higher κ-carrageenan concentration resulted in the formation of continuous and homogenous κ-carrageenan gel networks comprised of protein enriched microdomains. The hydrophobic interactions and hydrogen bonds played an important role in maintaining the gel structure. The water holding capacity and gel hardness of pea protein emulsion gels increased by 37% and 75 fold, respectively, through increasing κ-carrageenan concentration up to 1.5%. Moreover, in vitro digestion experiments based on the INFOGEST guidelines suggested that the presence of 0.25% κ-carrageenan could promote the digestion of lipids, but the increased κ-carrageenan concentration could delay the lipid and protein hydrolysis under gastrointestinal conditions. These results may provide theoretical guidance for the development of innovative pea protein isolate-based emulsion gel formulations with diverse textures and digestive properties.

Safety, pharmacokinetics, and efficacy of rifasutenizol, a novel dual-targeted antibacterial agent in healthy participants and patients in China with Helicobacter pylori infection: four randomised clinical trials.

BACKGROUND: Due to the rapid development of antimicrobial resistance, the efficacy of most Helicobacter pylori eradication therapies have progressively decreased to an unacceptable level. Rifasutenizol (TNP-2198) is a new molecular entity with a synergistic dual mechanism of action currently under clinical development for the treatment of microaerophilic and anaerobic bacterial infections. We aimed to evaluate the safety, pharmacokinetics, and efficacy of rifasutenizol in healthy Chinese participants and patients with H pylori. METHODS: We conducted four clinical trials of rifasutenizol capsules in healthy participants (aged 18-55 years) and patients with asymptomatic H pylori infection (aged 18-65 years) in a clinical trial centre in Jilin province, China. Trial 1 was a phase 1, double-blind, randomised, placebo-controlled, single ascending dose study, in which participants were enrolled into one of seven rifasutenizol dose groups (50 mg, 100 mg, 200 mg, 400 mg, 600 mg, 800 mg, or 1000 mg) and were randomly assigned in a 4:1 ratio to study drug or placebo. Trial 2 was a phase 1, double-blind, randomised, placebo-controlled, multiple ascending dose study, in which patients were enrolled into one of three rifasutenizol dose groups (200 mg, 400 mg, or 600 mg) and were randomly assigned in a 3:1 ratio to study drug or placebo. Trial 3 was a phase 2a, open-label, randomised, multiple-dose, dose-finding study in which patients enrolled into one of four cohorts were randomly assigned in a 1:1:1:1 ratio to a rifasutenizol dual or triple regimen. Trial 4 was a phase 2b, open-label, randomised, multiple-dose, regimen exploration study, in which patients enrolled into one of five cohorts were randomly assigned in a 2:2:1:1:2 ratio to a rifasutenizol dual therapy, triple therapy, or a control cohort. Block randomisation (block size 4 or 8) was used in all four trials. The key primary endpoints for trials 1, 2, and 3 were the tolerability, safety, and pharmacokinetics of rifasutenizol. For trial 4, the primary endpoint was the eradication rate of H pylori. These four trials were registered at ClinicalTrials.gov (NCT06081699, NCT06081712, NCT06076681, and NCT06076694) and chinadrugtrials.org.cn (CTR20190734, CTR20192553, CTR20212050, and CTR20220625) and are completed. FINDINGS: Between May 9, 2019, and Sept 14, 2022, 78 healthy participants (trial 1: n=10 per cohort in a 4:1 rifasutenizol:placebo ratio; and an additional eight for the food-effect cohort) and 168 patients with asymptomatic H pylori infection (trial 2: n=16 per cohort in a 3:1 rifasutenizol:placebo ratio; trial 3: n=10 per cohort; trial 4: n=10 or n=20 per cohort) were enrolled in the four clinical trials. Single doses of rifasutenizol (50-1000 mg) and multiple doses of rifasutenizol (200 mg to 600 mg, twice a day), either as monotherapy or co-administered with rabeprazole and amoxicillin, showed favourable safety and tolerability profiles. Most adverse events were mild, and no serious adverse events were reported. Rifasutenizol demonstrated a linear pharmacokinetic profile over the dose range of 50-800 mg, and there were no apparent pharmacokinetic interactions between rifasutenizol and the co-administrated drugs. Food intake slightly elevated the area under the plasma concentration-time curve (AUC) of rifasutenizol, and the geometric mean of AUC from time 0 to the last timepoint with a quantifiable concentration (AUC0-t) and AUC from time 0 to infinity (AUC0-∞) in the fed state were 1·334 and 1·396 times of those in the fasted state, respectively. There was mild accumulation after continuous administration of rifasutenizol, and the Rac(AUC) of rifasutenizol 400 mg in the dual and triple regiments in trial 3 were 1·37 and 1·49, respectively. In trial 3, the eradication rates of H pylori with 200 mg, 400 mg, or 600 mg of rifasutenizol in combination with rabeprazole, twice a day for 14 days, were 0% (95% CI 0-31), 30% (7-65), and 40% (12-74), respectively, identifying rifasutenizol 400 mg as the effective dose. In trial 4, H pylori eradication rates with the triple regimen in cohort A (400 mg rifasutenizol, 20 mg rabeprazole sodium, and 1 g amoxicillin) twice a day for 14 days was 95% (95% CI 74-100), and triple therapy (600 mg rifasutenizol, 20 mg rabeprazole sodium, and 1 g amoxicillin) three times a day for 7 days was 100% (69-100). INTERPRETATION: Rifasutenizol monotherapy and combination therapy was generally safe and well tolerated in healthy participants and patients with H pylori infection. A triple regimen of 400 mg rifasutenizol capsules, 20 mg rabeprazole sodium enteric-coated tablets, and 1 g amoxicillin capsules twice a day for 14 days showed promising efficacy as a new treatment regimen for H pylori infection. FUNDING: TenNor Therapeutics and National Natural Science Foundation of China. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Safety, Tolerability, Pharmacokinetics, and Immunogenicity of the Anti-IFNAR1 Monoclonal Antibody QX006N: A First-in-Human Single Ascending Dose Study in Healthy Chinese Volunteers.

BACKGROUND AND OBJECTIVE: QX006N is a novel, humanized, IgG4κ monoclonal antibody targeting IFNAR1, developed for the treatment of systemic lupus erythematosus. This study aims to investigate the pharmacokinetics, safety, tolerability, and immunogenicity of QX006N when administered intravenously to healthy Chinese individuals. METHODS: A double-blind, randomized, placebo-controlled, single-ascending-dose, phase I clinical trial was conducted comprising five cohorts (n = 10 per cohort, except n = 5 for the first cohort). Subjects in each cohort were randomly assigned in a 4:1 ratio to receive a single intravenous infusion of QX006N (0.3 mg/kg, 1.0 mg/kg, 3.0 mg/kg, 6.0 mg/kg, or 10.0 mg/kg) or placebo for 30 minutes. Tolerability assessments included adverse events, vital signs, 12-lead electrocardiogram, physical examination, and clinical laboratory tests. The serum concentration of QX006N was measured using the enzyme-linked immunosorbent assay method, and the anti-drug antibodies were detected using the electrochemiluminescence assay method. RESULTS: QX006N demonstrated a favorable safety and tolerability profile throughout the study. All treatment-emergent adverse events were of Grade 1-2 (CTCAE Version 5.0), and no serious adverse events, deaths, or drug discontinuations because of treatment-emergent adverse events were observed. All drug-related treatment-emergent adverse events showed no clear dose-related trends. Following an intravenous infusion of QX006N at doses that ranged from 0.3 mg/kg to 10 mg/kg, the half-life increased from 24.7 to 208 hours in a dose-dependent manner, while clearance decreased from 0.0828 to 0.0065 L/h. The maximum concentration exhibited nearly dose-proportional increases, and the area under the curve displayed a more than dose-proportional increment with non-linear pharmacokinetic characteristics. The incidence of anti-drug antibodies was observed to increase over time for doses that ranged from 1.0 mg/kg to 10.0 mg/kg of QX006N, reaching its peak at day 57 (range 62.50-87.50%). Conversely, the incidence of anti-drug antibodies in the QX006N 0.3-mg/kg and placebo cohorts remained low. CONCLUSIONS: QX006N demonstrated acceptable safety, tolerability, and pharmacokinetic characteristics in healthy subjects when administered as a single intravenous infusion at doses that ranged from 0.3 mg/kg to 10.0 mg/kg. Based on the pharmacokinetic and safety outcomes, a recommended effective dose of 300 mg is proposed for future phase Ib studies. CLINICAL TRIAL REGISTRATION: This study has been registered at http://www.chinadrugtrials.org.cn/ under identifier CTR20212834.

Microvascular Changes in Pituitary Adenoma Correlate with Structural Measurements and Visual Field Loss.

Purpose: This study aimed to determine the relationship among microvascular changes, retinal nerve fiber layer (RNFL) thickness, and visual field loss in pituitary adenoma (PA) patients. Patients and Methods: Optic disc and macular vessel densities were measured, using optical coherence tomography angiography (OCTA) in the eyes from PA patients with radiographic chiasmal compression. Comparisons of retinal microvascular and structural parameters were conducted between PA patients and age/sex-matched healthy controls. The PA group was subdivided into PA with temporal visual field defects (perimetric PA) and PA without visual field defect (preperimetric PA) groups. The study determined correlation between microvascular parameters and optic nerve damage, including visual field and structural measurements. Subgroup analyses were performed to distinguish the different microcirculation characteristics of the perimetric PA eyes and preperimetric PA eyes. Results: Forty-five eyes from 40 PA patients and 24 eyes from 24 healthy controls were recruited prospectively. Eyes in the perimetric PA group had significantly decreased optic disc vessel density but slightly increased macular vessel density at superficial retinal capillary plexus (SCP) level. Eyes in the preperimetric PA group had significantly increased macular vessel density at SCP level. Optic disc vessel density was inversely correlated with visual field mean deviation and positively correlated with RNFL thickness. Conclusion: Significantly decreased optic disc vessel density in the perimetric stage but increased SCP macular vessel density in the preperimetric stage were found in PA patients. Our data suggest that increased SCP macular vessel density may serve as an early biomarker of preperimetric PA eyes, while decreased optic disc vessel density could be a late biomarker of perimetric PA eyes. Optic disc vessel density was correlated with RNFL thickness and visual field loss in PA eyes. OCTA is a useful tool to detect retinal microvascular changes and access the severity of neural impairments in chiasmal compression caused by PA.

Comparison of pharmacokinetics and safety between CE-fosphenytoin sodium, fosphenytoin sodium, and phenytoin sodium after intravenous and intramuscular administration in healthy volunteers.

Background: Captisol®-enabled-fosphenytoin sodium (CE-fosphenytoin sodium) injection is a modified formulation of fosphenytoin sodium. Objective: We aim to compare the intravenous and intramuscular bioavailability and safety between CE-fosphenytoin sodium, fosphenytoin sodium (Cerebyx®), and phenytoin sodium (intravenous injection only). Methods: In pivotal study 1, 54 subjects were divided into three sequence groups that receive intravenous injection of 250 mg of phenytoin sodium equivalent (PE), CE-fosphenytoin sodium (T), or fosphenytoin sodium (R1) and 250 mg of phenytoin sodium (R2) in period 1. After a 14-day washout period, 36 subjects were randomized to two treatment sequence groups (T-R1 or R1-T, n = 18 per group) in period 2, in which the subjects who received R2 in period 1 were removed, those who received T in period 1 used R1 (T-R1), while those who previously received R1 used T (R1-T). In pivotal study 2, a single intramuscular dose of T (400 mg PE) or R1 (400 mg PE) was administered according to the individual sequential treatment assignment in each period. There was a washout (14 days) period before receiving the next period study drug. Results: T and R1 have similar pharmacokinetic characteristics regarding total and free phenytoin, showing bioequivalence of both drugs in the intravenous and intramuscular administration. The geometric mean ratio was close to 1 (0.98-1.06). The AUC of total and free phenytoin in subjects who intravenously received T and R1 was very similar to those who received R2, although their Cmax was lower than that of the subjects who received R2. Overall, treatment with T and R1 was safe and well-tolerated, without serious adverse events (SAEs) or grade III adverse events (AEs). With intravenous (i.v.) or intramuscular (i.m.) treatment, the incidence of drug-related AEs using T was similar to that using R1. Treatment with T and R1 had clearly superior tolerability than that with R2. Conclusion: CE-fosphenytoin sodium is a promising substitute for fosphenytoin sodium. Clinical Trial Registration: http://www.chinadrugtrials.org.cn/, CTR20202154 (11 November 2020).

Global incidence and death estimates of chronic kidney disease due to hypertension from 1990 to 2019, an ecological analysis of the global burden of diseases 2019 study.

BACKGROUND: The intricate relationship between hypertension and chronic kidney disease (CKD) presents a global challenge for prevention of hypertension-related CKD. This study's objective is to analyze age, gender, regional disparities, and evolving trends in the disease burden of hypertension-related CKD. We aim to estimate changing spatial and temporal trends in incidence and mortality rates, considering the socio-demographic index (SDI), to inform health strategies effectively. METHOD: Age-standardized incidence rates (ASIR) and death rates (ASDR) were collected from the GBD 2019. Trend analysis was conducted by Joinpoint regression of ASRs from 1990 to 2019. Spatial autocorrelation analysis was performed to obtain spatial patterns. The association between SDI and burden of CKD due to hypertension was estimated using a Pearson correlation analysis. RESULTS: The global ASIR and ASDR due to hypertension-related CKD were 19.45 (95% CI, 17.85 to 21.09) and 5.88 (95% CI, 4.95 to 6.82) per 100 K population in 2019, representing increases of 17.89% and 13.29% compared to 1990, respectively. The elderly population and males were found the highest ASIR and ASDR. The high SDI region had the highest ASIRs, while low SDI regions experienced the highest ASDRs. Joinpoint regression found both global ASIR and ASDR showed increasing trends, with the highest increases observed in middle- and high-SDI regions, respectively. The SDI exhibited a positive association with ASIRs but displayed an inverse V-shaped correlation with the average annual percentage change (AAPC) of ASIRs. Spatial autocorrelation analysis revel significant positive spatial autocorrelation for the AAPC of ASDRs and ASIRs, from 1990 to 2019. CONCLUSIONS: Results met the objectives, and demonstrated a rising global burden of hypertension-related CKD. Factors such as aging, gender, and regional variations should be considered when designing control measures and developing healthcare systems to effectively address the burden of this complex condition.

Distribution characteristics, risk assessment, and relevance with surrounding soil of heavy metals in coking solid wastes from coking plants in Shanxi, China.

Heavy metal concentrations represent important pollution evaluation indices, and it is necessary to assess the potential environmental and health risks from heavy metals associated with coking wastes from coking plants. In this study, coking sludge (CS), tar residue (TR), coke powder (CP), and sulfur paste (SP) from three coking plants (Plant A, Plant B, and Plant C) in central, western, and southern Shanxi Province and from soils surrounding Plant A were selected as the research objects, and the distributions of Cu, Ni, Pb, Zn, Mn, Cd, and Cr were determined. The results showed that Cd in the four solid wastes far exceeded the soil background value by a factor of 16~195, and the contents of Pb in TR (three plants) and CS (Plant C) exceeded the soil background values 19.70-, 23.57-, 14.46-, and 12.56-fold, respectively. Similarly, the concentrations of Cu, Ni, Pb, Zn, and Cd in soils were higher than the background values by factors of 31.18, 8.35, 34.79, 29.48, and 3.43, respectively. In addition, the Cu, Ni, Pb, and Cr in the four solid wastes and soils mainly existed in the residual state. As depth increased, the overall Ni, Pb, Mn, and Cd concentrations in soils increased. The high ecological risks associated with the four solid wastes were mainly due to the enrichment of Cd. Workers in coking plants face certain Cr health risks. This study provides theoretical support for the coking industry with respect to the treatment, disposal, and management of solid wastes.

Development of a CT radiomics nomogram for preoperative prediction of Ki-67 index in pancreatic ductal adenocarcinoma: a two-center retrospective study.

OBJECTIVES: To develop and validate a contrast-enhanced computed tomography (CECT)-based radiomics nomogram for the preoperative evaluation of Ki-67 proliferation status in pancreatic ductal adenocarcinoma (PDAC). METHODS: In this two-center retrospective study, a total of 181 patients (95 in the training cohort; 42 in the testing cohort, and 44 in the external validation cohort) with PDAC who underwent CECT examination were included. Radiomic features were extracted from portal venous phase images. The radiomics signatures were built by using two feature-selecting methods (relief and recursive feature elimination) and four classifiers (support vector machine, naive Bayes, linear discriminant analysis (LDA), and logistic regression (LR)). Multivariate LR was used to build a clinical model and radiomics-clinical nomogram. The predictive performances of the models were evaluated using area under receiver operating characteristic curve (AUC) and decision curve analysis (DCA). RESULTS: The relief selector and LDA classifier using twelve features built the optimal radiomics signature, with AUCs of 0.948, 0.927, and 0.824 in the training, testing, and external validation cohorts, respectively. The radiomics-clinical nomogram incorporating the optimal radiomics signature, CT-reported lymph node status, and CA19-9 showed better predictive performance with AUCs of 0.976, 0.955, and 0.882 in the training, testing, and external validation cohorts, respectively. The calibration curve and DCA demonstrated goodness-of-fit and improved benefits in clinical practice of the nomogram. CONCLUSIONS: The radiomics-clinical nomogram is an effective and non-invasive computer-aided tool to predict the Ki-67 expression status in patients with PDAC. CLINICAL RELEVANCE STATEMENT: The radiomics-clinical nomogram is an effective and non-invasive computer-aided tool to predict the Ki-67 expression status in patients with pancreatic ductal adenocarcinoma. KEY POINTS: The radiomics analysis could be helpful to predict Ki-67 expression status in patients with pancreatic ductal adenocarcinoma (PDAC). The radiomics-clinical nomogram integrated with the radiomics signature, clinical data, and CT radiological features could significantly improve the differential diagnosis of Ki-67 expression status. The radiomics-clinical nomogram showed satisfactory calibration and net benefit for discriminating high and low Ki-67 expression status in PDAC.

Probiotics attenuate valproate-induced liver steatosis and oxidative stress in mice.

Valproate (valproic acid, VPA), a drug for the treatment of epilepsy and bipolar disorder, causes liver steatosis with enhanced oxidative stress. Accumulating evidences exhibite that gut microbiota plays an important role in progression of nonalcoholic fatty liver disease (NAFLD). However, whether gut microbiota contributes to VPA-caused hepatic steatosis needs to be elucidated. A mixture of five probiotics was selected to investigate their effects on liver steatosis and oxidative stress in mice orally administered VPA for 30 days. Probiotics treatment significantly attenuated the hepatic lipid accumulation in VPA-treated mice via inhibiting the expression of cluster of differentiation 36 (CD36) and distinct diacylglycerol acyltransferase 2 (DGAT2). Meanwhile, probiotics exerted a protective effect against VPA-induced oxidative stress by decreasing the pro-oxidant cytochrome P450 2E1 (CYP2E1) level and activating the Nrf2/antioxidant enzyme pathway. Moreover, VPA treatment altered the relative abundance of gut microbiota at the phylum, family and genera levels, while probiotics partially restored these changes. Spearman's correlation analysis showed that several specific genera and family were significantly correlated with liver steatosis and oxidative stress-related indicators. These results suggest that probiotics exert their health benefits in the abrogation of liver steatosis and oxidative stress in VPA-treated mice by manipulating the microbial homeostasis.

PH13 improves soybean shade traits and enhances yield for high-density planting at high latitudes.

Shading in combination with extended photoperiods can cause exaggerated stem elongation (ESE) in soybean, leading to lodging and reduced yields when planted at high-density in high-latitude regions. However, the genetic basis of plant height in adaptation to these regions remains unclear. Here, through a genome-wide association study, we identify a plant height regulating gene on chromosome 13 (PH13) encoding a WD40 protein with three main haplotypes in natural populations. We find that an insertion of a Ty1/Copia-like retrotransposon in the haplotype 3 leads to a truncated PH13H3 with reduced interaction with GmCOP1s, resulting in accumulation of STF1/2, and reduced plant height. In addition, PH13H3 allele has been strongly selected for genetic improvement at high latitudes. Deletion of both PH13 and its paralogue PHP can prevent shade-induced ESE and allow high-density planting. This study provides insights into the mechanism of shade-resistance and offers potential solutions for breeding high-yielding soybean cultivar for high-latitude regions.

ZSP1601, a novel pan-phosphodiesterase inhibitor for the treatment of NAFLD, A randomized, placebo-controlled phase Ib/IIa trial.

Non-alcoholic fatty liver disease is a growing health burden with limited treatment options worldwide. Herein we report a randomized, double-blind, placebo-controlled, multiple-dose trial of a first-in-class pan-phosphodiesterase inhibitor ZSP1601 in 36 NAFLD patients (NCT04140123). There were three cohorts. Each cohort included twelve patients, nine of whom received ZSP1601 50 mg once daily, 50 mg twice daily, or 100 mg twice daily, and three of whom received matching placebos for 28 days. The primary outcomes were the safety and tolerability of ZSP1601. A total of 27 (27/36, 75%) patients experienced at least one treatment-emergent adverse event (TEAE). Most TEAEs were mild to moderate. There was no Serious Adverse Event. Diarrhea, transiently elevated creatinine and adaptive headache were frequently reported adverse drug reaction. We conclude that ZSP1601 is well-tolerated and safe, showing effective improvement in liver chemistries, liver fat content and fibrosis in patients with NAFLD.

Pathogenic fungi shape the fungal community, network complexity, and pathogenesis in kiwifruit.

Kiwifruit decay caused by endophytic fungi is affected by exogenous pathogens that trigger changes in fungal community composition and interact with the endophytic fungal community. Four fungal pathogens of kiwifruit were identified. These were Aspergillus japonicus, Aspergillus flavus, Botryosphaeria dothidea, and Penicillium oxalicum. Except for P. oxalicum, the remaining three species represent newly described pathogens of kiwifruit. All four fungal species caused disease and decay in mature kiwifruit. Results of the fungal community analysis indicated that three pathogens that A. japonicus, A. flavus and P. oxalicum were the most dominant, however, other fungal species that did not cause disease symptoms were also present. Positive interactions between fungal species were found in asymptomatic, symptomatic, and infected kiwifruit. The ability of all four pathogens to infect kiwifruit was confirmed in an inoculation experiment. The presence of any one of the four identified pathogens accelerated decay development and limited the postharvest longevity of harvested kiwifruit. Results of the study identified and confirmed the ability of four fungal species to infect and cause decay in harvested kiwifruit. Changes in the structure and composition of the kiwifruit microbiome during the decay process were also characterized. This provides a foundation for the further study of the microbiome of kiwifruit and their involvement in postharvest diseases.

Puckered Zigzag Monolayer Ice: Does a Confined Flat Four-Coordinated Monolayer Ice Always Have a Corresponding Puckered Phase?

We note that a flat, four-coordinated monolayer ice under confinement always has a corresponding puckered phase. Recently, a monolayer ice consisting of an array of zigzag water chains (ZZMI) predicted by first-principles calculations of water under confinement is a flat four-coordinated monolayer ice. Herein, to investigate whether puckered ZZMI exists stably, we perform molecular dynamics simulations of two-dimensional (2D) ice formation for water constrained in graphene nanocapillaries. We find a novel monolayer ice structure that can be viewed as the ZZMI puckered along the direction perpendicular to the zigzag chain (pZZMI). Unlike ZZMI that does not satisfy the ice rule, each water molecule in pZZMI can form four hydrogen bonds (HBs) via forming two stable intersublayer HBs and two intrasublayer HBs. This work provides a fresh perspective on 2D confined ice, highlighting the intrinsic connections between 2D confined ices.

Diagnostic accuracy of dual-energy computed tomography-based nomogram for differentiating papillary thyroid microcarcinomas from micronodular goiters.

Background: The misdiagnosis of papillary thyroid microcarcinoma (PTMC) and micronodular goiter (MNG) may lead to overtreatment and unnecessary medical expenditure by patients. This study developed and validated a dual-energy computed tomography (DECT)-based nomogram for the preoperative differential diagnosis of PTMC and MNG. Methods: This retrospective study analyzed the data of 366 pathologically confirmed thyroid micronodules, of which 183 were PTMCs and 183 were MNGs, from 326 patients who underwent DECT examinations. The cohort was divided into the training (n=256) and validation cohorts (n=110). The conventional radiological features and DECT quantitative parameters were analyzed. The iodine concentration (IC), normalized iodine concentration (NIC), effective atomic number, normalized effective atomic number, and slope of the spectral attenuation curves in the arterial phase (AP) and venous phase (VP) were measured. A univariate analysis and stepwise logistic regression analysis were performed to screen the independent indicators for PTMC. A radiological model, DECT model, and DECT-radiological nomogram were constructed, and the performances of the 3 models were assessed using the receiver operating characteristic curve, DeLong test, and a decision curve analysis (DCA). Results: The IC in the AP [odds ratio (OR) =0.172], NIC in the AP (OR =0.003), punctate calcification (OR =2.163), and enhanced blurring (OR =3.188) were identified as independent predictors in the stepwise-logistic regression. The areas under the curve with 95% confidence intervals (CIs) of the radiological model, DECT model, and DECT-radiological nomogram were 0.661 (95% CI: 0.595-0.728), 0.856 (95% CI: 0.810-0.902), and 0.880 (95% CI: 0.839-0.921), respectively, in the training cohort; and 0.701 (95% CI: 0.601-0.800), 0.791 (95% CI: 0.704-0.877), and 0.836 (95% CI: 0.760-0.911), respectively, in the validation cohort. The diagnostic performance of the DECT-radiological nomogram was better than that of the radiological model (P<0.05). The DECT-radiological nomogram was found to be well calibrated and had a good net benefit. Conclusions: DECT provides valuable information for differentiating between PTMC and MNG. The DECT-radiological nomogram could serve as an easy-to-use, noninvasive, and effective method for differentiating between PTMC and MNG and help clinicians in decision-making.

Ozone micro-nano bubble water preserves the quality of postharvest parsley.

The production and use of ozone micro-nano bubble water (O3-MNBW) is an innovative technology that prolongs the reactivity of aqueous-phase ozone and maintains the freshness and quality of fruits and vegetables by removing pesticides, mycotoxins, and other contaminants. The quality of parsley treated with different concentrations of O3-MNBW was investigated during storage at 20 ℃ for 5 d, and found that a ten-minute exposure of parsley to 2.5 mg·L-1 O3-MNBW effectively preserved the sensory quality of parsley, and resulted in lower weight loss, respiration rate, ethylene production, MDA levels, and a higher level of firmness, vitamin C, and chlorophyll content, relative to untreated parsley. The O3-MNBW treatment also increased the level of total phenolics and flavonoids, enhanced peroxidase and ascorbate peroxidase activity, and inhibited polyphenol oxidase activity in stored parsley. Five volatile signatures identified using an electronic nose (W1W, sulfur-compounds; W2S, ethanol; W2W, aromatic- and organic- sulfur compounds; W5S, oxynitride; W1S, methane) exhibited a significant decrease in response to the O3-MNBW treatment. A total of 24 major volatiles were identified. A metabolomic analysis identified 365 differentially abundant metabolites (DMs). Among them, 30 and 19 DMs were associated with characteristic volatile flavor substance metabolism in O3-MNBW and control groups, respectively. The O3-MNBW treatment increased the abundance of most DMs related to flavor metabolism and reduced the level of naringin and apigenin. Our results provide insight into the mechanisms that are regulated in response to the exposure of parsley to O3-MNBW, and confirmed the potential use of O3-MNBW as a preservation technology.