Micro-environment triple-responsive hyaluronic acid hydrogel dressings to promote antibacterial activity, collagen deposition, and angiogenesis for diabetic wound healing.

The clinical treatment of chronic diabetic wounds is a long-standing thorny issue. Strategies targeting the diabetic micro-environment have been developed to promote wound healing. However, it remains challenging to reverse the adverse conditions and re-activate tissue regeneration and angiogenesis. In this work, we develop injectable hydrogels that are responsive to acidic conditions, reactive oxygen species (ROS), and high glucose levels in a diabetic wound micro-environment to sustainably deliver tannic acid (TA) to augment antibacterial, anti-inflammatory, and anti-oxidative activities. This triple-responsive mechanism is designed by introducing dynamic acylhydrazone and phenylboronic ester bonds to crosslink modified hyaluronic acid (HA) chains. At a diabetic wound, the acylhydrazone bonds may be hydrolyzed at low pH. Meanwhile, glucose may compete with TA, and ROS may oxidize the C-B bond to release TA. Thus, sustained release of TA is triggered by the diabetic micro-environment. The released TA effectively scavenges ROS and kills bacteria. In vivo experiments on diabetic mice demonstrate that the hydrogel dressing highly promotes angiogenesis and extracellular matrix (ECM) deposition, leading to eventual full healing of diabetic skin wounds. This micro-environment-triggered triple-responsive drug release provides a promising method for chronic diabetic wound healing.

PqsA mutation-mediated enhancement of phage-mediated combat against Pseudomonas aeruginosa.

Phage therapy is a potential approach in the biocontrol of foodborne pathogens. However, the emergence of phage resistance and the narrow host range of most phage isolates continue to limit the antimicrobial efficacy of phages. Here, we investigated the potential of the pqsA gene, encoding the anthranilate-CoA ligase enzyme, as an adjuvant for phage therapy. The knockout of the pqsA gene significantly enhanced the bactericidal effect of phages vB_Pae_QDWS and vB_Pae_S1 against Pseudomonas aeruginosa. Under phage infection pressure, the growth of the PaΔpqsA was significantly inhibited within 8 h compared to the wild-type PAO1. Furthermore, we found that altering phage adsorption is not how PaΔpqsA responds to phage infection. Although pqsA represents a promising target for enhancing phage killing, it may not be applicable to all phages, such as types vB_Pae_W3 and vB_Pae_TR. Our findings provide new material reserves for the future design of novel phage-based therapeutic strategies.

Seawater intrusion-triggered high fluoride groundwater development on the eastern coast of China.

High-fluoride groundwater is commonly found in coastal areas worldwide, while its formation mechanism remains elusive. Herein, a comprehensive study was performed to identify the major controlling factor of high-fluoride groundwater occurrence along the eastern coast of China. Hydrogeochemical methods were employed to examine the distribution patterns of seawater intrusion and fluoride concentration and the impact of seawater intrusion on the fluoride concentration. The results indicate that seawater intrusion significantly influences the groundwater evolution process in the study areas. The groundwater in Laizhou Bay was affected by brine, and the groundwater in Tianjin and Jiangsu was affected by seawater with a mixing ratio lower than 40% and 20%, respectively. And the fluoride concentration in groundwater from Tianjin, Laizhou Bay, and Jiangsu generally exceeded 1 mg/L, with the average of 2.3 mg/L, 24.9 mg/L, and 34.6 mg/L, respectively. Both the degree of seawater intrusion and the fluoride concentration exhibit a consistent pattern: Laizhou Bay > Tianjin > Jiangsu. Cl- concentration in groundwater varies positively with the F- concentration (y = 0.66x - 1.31). Moreover, the spatial distribution of areas with high-fluoride groundwater mirrors that of seawater intrusion. The high-fluoride groundwater varies spatially and is related to the degree, stage, and type of seawater intrusion. In other words, when seawater intrusion intensifies more or groundwater in the freshwater renewal phase with higher Na+/Ca2+ or the presence of paleo-seawater intrusion with higher fluoride concentration of brine, the concentration of fluoride in groundwater is higher. As seawater intrusion intensifies, the high-fluoride groundwater in the study areas generally poses a higher health risk to human. These findings enhance our comprehension of the mechanisms underpinning high-fluoride groundwater in coastal regions and the environmental ramifications of seawater intrusion.

Identification of Putative Quantitative Trait Loci for Improved Seed Oil Quality in Peanuts.

Improving seed oil quality in peanut (Arachis hypogaea) has long been an aim of breeding programs worldwide. The genetic resources to achieve this goal are limited. We used an advanced recombinant inbred line (RIL) population derived from JH5 × KX01-6 to explore quantitative trait loci (QTL) affecting peanut oil quality and their additive effects, epistatic effects, and QTL × environment interactions. Gas chromatography (GC) analysis suggested seven fatty acids components were obviously detected in both parents and analyzed in a follow-up QTL analysis. The major components, palmitic acid (C16:0), oleic acid (C18:1), and linoleic acid (C18:2), exhibited considerable phenotypic variation and fit the two major gene and minor gene mixed-inheritance model. Seventeen QTL explained 2.57-38.72% of the phenotypic variation in these major components, with LOD values of 4.12-37.56 in six environments, and thirty-five QTL explained 0.94-32.21% of the phenotypic variation, with LOD values of 5.99-150.38 in multiple environments. Sixteen of these QTL were detected in both individual and multiple environments. Among these, qFA_08_1 was a novel QTL with stable, valuable and major effect. Two other major-effect QTL, qFA_09_2 and qFA_19_3, share the same physical position as FAD2A and FAD2B, respectively. Eleven stable epistatic QTL involving nine loci explained 1.30-34.97% of the phenotypic variation, with epistatic effects ranging from 0.09 to 6.13. These QTL could be valuable for breeding varieties with improved oil quality.

Single nuclei transcriptomics in human and non-human primate striatum in opioid use disorder.

In brain, the striatum is a heterogenous region involved in reward and goal-directed behaviors. Striatal dysfunction is linked to psychiatric disorders, including opioid use disorder (OUD). Striatal subregions are divided based on neuroanatomy, each with unique roles in OUD. In OUD, the dorsal striatum is involved in altered reward processing, formation of habits, and development of negative affect during withdrawal. Using single nuclei RNA-sequencing, we identified both canonical (e.g., dopamine receptor subtype) and less abundant cell populations (e.g., interneurons) in human dorsal striatum. Pathways related to neurodegeneration, interferon response, and DNA damage were significantly enriched in striatal neurons of individuals with OUD. DNA damage markers were also elevated in striatal neurons of opioid-exposed rhesus macaques. Sex-specific molecular differences in glial cell subtypes associated with chronic stress were found in OUD, particularly female individuals. Together, we describe different cell types in human dorsal striatum and identify cell type-specific alterations in OUD.

FOXM1 and CENPF are associated with a poor prognosis through promoting proliferation and migration in lung adenocarcinoma.

Lung adenocarcinoma (LUAD) is a clinically challenging disease due to its poor prognosis and limited therapeutic methods. The aim of the present study was to identify prognosis-related genes and therapeutic targets for LUAD. Raw data from the GSE32863, GSE41271 and GSE42127 datasets were downloaded from the Gene Expression Omnibus database. Following normalization, the data were merged into a matrix, which was first used to identify differentially expressed genes (DEGs). Weighted gene co-expression network analysis (WGCNA) and survival analysis were performed to screen potential prognosis-related genes. Gene overlaps among DEGs, survival-related genes and WGCNA genes were finally constructed to obtain candidate genes. An analysis with the STRING database was performed to construct a protein-protein interaction network and hub genes were selected using Cytoscape. The candidate genes were finally identified by univariate and multivariate Cox regression analysis. Furthermore, in vivo and in vitro experiments, including immunohistochemistry, immunofluorescence, Cell Counting Kit-8, colony-formation and migration assays, were performed to validate the potential mechanism of these genes in LUAD. Two genes, namely forkhead box M1 (FOXM1) and centromere protein F (CENPF), were identified as unfavorable indicators of prognosis in patients with LUAD. High expression of FOXM1 and CENPF were associated with poor survival. Furthermore, LUAD cells with FOXM1 and CENPF knockdown showed a significant reduction in proliferation and migration (P<0.05). FOXM1 and CENPF may have an essential role in the prognosis of patients with LUAD by influencing cell proliferation and migration, and they provide potential molecular targets for LUAD therapy.

Identification of Plasma Biomarkers in Drug-Naïve Schizophrenia Using Targeted Metabolomics.

OBJECTIVE: Schizophrenia (SCZ) is a severe psychiatric disorder with unknown etiology and lacking specific biomarkers. Herein, we aimed to explore plasma biomarkers relevant to SCZ using targeted metabolomics. METHODS: Sixty drug-naïve SCZ patients and 36 healthy controls were recruited. Psychotic symptoms were assessed using the Positive and Negative Syndrome Scale. We analyzed the levels of 271 metabolites in plasma samples from all subjects using targeted metabolomics, and identified metabolites that differed significantly between the two groups. Then we evaluated the diagnostic power of the metabolites based on receiver operating characteristic curves, and explored metabolites associated with the psychotic symptoms in SCZ patients. RESULTS: Twenty-six metabolites showed significant differences between SCZ patients and healthy controls. Among them, 12 metabolites were phosphatidylcholines and cortisol, ceramide (d18:1/22:0), acetylcarnitine, and γ-aminobutyric acid, which could significantly distinguish SCZ from healthy controls with the area under the curve (AUC) above 0.7. Further, a panel consisting of the above 4 metabolites had an excellent performance with an AUC of 0.867. In SCZ patients, phosphatidylcholines were positively related with positive symptoms, and cholic acid was positively associated with negative symptoms. CONCLUSION: Our study provides insights into the metabolite alterations associated with SCZ and potential biomarkers for its diagnosis and symptom severity assessment.

Research progress of 3D printed poly (ether ether ketone) in the reconstruction of craniomaxillofacial bone defects.

The clinical challenge of bone defects in the craniomaxillofacial region, which can lead to significant physiological dysfunction and psychological distress, persists due to the complex and unique anatomy of craniomaxillofacial bones. These critical-sized defects require the use of bone grafts or substitutes for effective reconstruction. However, current biomaterials and methods have specific limitations in meeting the clinical demands for structural reinforcement, mechanical support, exceptional biological performance, and aesthetically pleasing reconstruction of the facial structure. These drawbacks have led to a growing need for novel materials and technologies. The growing development of 3D printing can offer significant advantages to address these issues, as demonstrated by the fabrication of patient-specific bioactive constructs with controlled structural design for complex bone defects in medical applications using this technology. Poly (ether ether ketone) (PEEK), among a number of materials used, is gaining recognition as a feasible substitute for a customized structure that closely resembles natural bone. It has proven to be an excellent, conformable, and 3D-printable material with the potential to replace traditional autografts and titanium implants. However, its biological inertness poses certain limitations. Therefore, this review summarizes the distinctive features of craniomaxillofacial bones and current methods for bone reconstruction, and then focuses on the increasingly applied 3D printed PEEK constructs in this field and an update on the advanced modifications for improved mechanical properties, biological performance, and antibacterial capacity. Exploring the potential of 3D printed PEEK is expected to lead to more cost-effective, biocompatible, and personalized treatment of craniomaxillofacial bone defects in clinical applications.

Hydrochemical characterizations and groundwater quality assessment in the coastal region of the Jiaodong peninsula, North China.

Groundwater resources constitute a primary water source in the coastal region of Jiaodong Peninsula (CRJP), serving as an essential foundation for socio-economic development and municipal water supply. This study sought to evaluate the hydrogeochemical properties of the CRJP's groundwater using 73 samples collected in 2017, comprehensively analyzing the chemical composition and environmental factors using mathematical statistics and hydrochemical techniques. The results demonstrate that groundwater in the CRJP possesses TDS values ranging from 262 to 28,160 mg/L, with a pH ranging between 6.4 and 8.5, characterizing a weakly alkaline water system. The cation order in groundwater is Na+ > Ca2+ > Mg2+ > K+, while the anionic sequence comprises Cl- > HCO3- > SO42- > NO3-. According to the Piper diagram, groundwater samples predominantly clustered into SO4·Cl-Ca·Mg and SO4·Cl-Na types. Additionally, significant spatial variations exist in the primary chemical components of groundwater. Hydrogeochemical characteristics within the region are influenced both by natural and human activities; natural elements include weathering of silicate rocks, gypsum and carbonate minerals dissolution, while human practices comprise industrial and mining activities, agricultural practices, and domestic waste discharge. The results from a health risk assessment show that non-carcinogenic risks posed by nitrate intake via drinking water are considerably high for infants in comparison to adults, teenagers, and children. Furthermore, certain regions within the CRJP show notable seawater intrusion effects on groundwater studied.

Complete genome analysis and biological characterization of a novel phage vB_CP_qdyz_P5 with lytic activity against Clostridium perfringens.

Clostridium perfringens, a common foodborne pathogen, exhibit high-stress resistance. The prevailing reliance on antibiotics in the farming industry for its prevention and control has led to increasing concerns over antibiotic residue and bacterial resistance. Bacteriophages that possess specific lytic activity against C. perfringens are of significant interest. Here, a novel C. perfringens phage, named vB_CP_qdyz_P5, was isolated and characterized. The phage displayed high stability at temperatures below 70 °C and pH levels ranging from 4 to 12. Genome analysis revealed that vB_CP_qdyz_P5 has a double-stand DNA of 18,888 bp with a G + C composition of 28.8%. Among the 27 identified opening reading frames (ORFs), eight were found to be functional genes. BLASTn analysis showed that vB_CP_qdyz_P5 is closely related to phage DCp1, with a genome homology coverage of 83%. Phylogenetic analysis indicated that vB_CP_qdyz_P5 may be a novel phage of the family Guelinviridae, Susfortunavirus. This study provides important preliminary information for further research on the potential use of vB_CP_qdyz_P5 in protecting against C. perfringens and maintaining intestinal health.

The effectors of Phytophthora infestans impact host immunity upon regulation of antagonistic hormonal activities.

MAIN CONCLUSION: Phytophthora infestans effectors manipulate the antagonism of host hormones to interfere with the immune response of plants at different infection stages. Phytophthora infestans (P. infestans) poses a serious threat to global crop production, and its effectors play an indispensable role in its pathogenicity. However, the function of these effectors during the switch from biotrophy to necrotrophy of P. infestans remains unclear. Further research on the effectors that manipulate the antagonistic response of host hormones is also lacking. In this study, a coexpression analysis and infection assays were performed to identify distinct gene expression changes in both P. infestans and tomato. During the switch from biotrophy to necrotrophy, P. infestans secretes three types of effectors to interfere with host salicylic acid (SA), jasmonic acid (JA), ethylene (ET), and abscisic acid (ABA) levels. The three aforementioned effectors also regulate the host gene expression including NPR1, TGA2.1, PDF1.2, NDR1, ERF3, NCED6, GAI4, which are involved in hormone crosstalk. The changes in plant hormones are mediated by the three types of effectors, which may accelerate infection and drive completion of the P. infestans lifecycle. Our findings provide new insight into plant‒pathogen interactions that may contribute to the prevention growth of hemibiotrophic pathogens.

A20 promotes colorectal cancer immune evasion by upregulating STC1 expression to block "eat-me" signal.

Immune checkpoint inhibitors (ICIs) have induced durable clinical responses in a subset of patients with colorectal cancer (CRC). However, the dis-satisfactory response rate and the lack of appropriate biomarkers for selecting suitable patients to be treated with ICIs pose a major challenge to current immunotherapies. Inflammation-related molecule A20 is closely related to cancer immune response, but the effect of A20 on "eat-me" signal and immunotherapy efficacy remains elusive. We found that A20 downregulation prominently improved the antitumor immune response and the efficacy of PD-1 inhibitor in CRC in vitro and in vivo. Higher A20 expression was associated with less infiltration of immune cells including CD3 (+), CD8 (+) T cells and macrophages in CRC tissues and also poorer prognosis. Gain- and loss-A20 functional studies proved that A20 could decrease the "eat-me" signal calreticulin (CRT) protein on cell membrane translocation via upregulating stanniocalcin 1 (STC1), binding to CRT and detaining in mitochondria. Mechanistically, A20 inhibited GSK3ß phosphorylating STC1 at Thr86 to slow down the degradation of STC1 protein. Our findings reveal a new crosstalk between inflammatory molecule A20 and "eat-me" signal in CRC, which may represent a novel predictive biomarker for selecting CRC patients most likely to benefit from ICI therapy.

DAGLß is the principal synthesizing enzyme of 2-AG and promotes aggressive phenotype of intrahepatic cholangiocarcinoma via AP-1/DAGLß/miR4516 feedforward circuitry.

The endocannabinoid system (ECS) is dysregulated in various liver diseases. Previously, we had shown that the major endocannabinoid 2-arachidonoyl glycerol (2-AG) promoted tumorigenesis of intrahepatic cholangiocarcinoma (ICC). However, biosynthesis regulation and clinical significance of 2-AG remain elusive. In the present study, we quantified 2-AG by gas chromatography/mass spectrometry (GC/MS) and showed that 2-AG was enriched in patients with ICC samples as well as in thioacetamide-induced orthotopic rat ICC model. Moreover, we found that diacylglycerol lipase ß (DAGLß) was the principal synthesizing enzyme of 2-AG that significantly upregulated in ICC. DAGLß promoted tumorigenesis and metastasis of ICC in vitro and in vivo and positively correlated with clinical stage and poor survival in patients with ICC. Functional studies showed that activator protein-1 (AP-1; heterodimers of c-Jun and FRA1) directly bound to the promoter and regulated transcription of DAGLß, which can be enhanced by lipopolysaccharide (LPS). miR-4516 was identified as the tumor-suppressing miRNA of ICC that can be significantly suppressed by LPS, 2-AG, or ectopic DAGLß overexpression. FRA1 and STAT3 were targets of miR-4516 and overexpression of miRNA-4516 significantly suppressed expression of FRA1, SATA3, and DAGLß. Expression of miRNA-4516 was negatively correlated with FRA1, SATA3, and DAGLß in patients with ICC samples. Our findings identify DAGLß as the principal synthesizing enzyme of 2-AG in ICC. DAGLß promotes oncogenesis and metastasis of ICC and is transcriptionally regulated by a novel AP-1/DAGLß/miR4516 feedforward circuitry.NEW & NOTEWORTHY Dysregulated endocannabinoid system (ECS) had been confirmed in various liver diseases. However, regulation and function of 2-arachidonoyl glycerol (2-AG) and diacylglycerol lipase ß (DAGLß) in intrahepatic cholangiocarcinoma (ICC) remain to be elucidated. Here, we demonstrated that 2-AG was enriched in ICC, and DAGLß was the principal synthesizing enzyme of 2-AG in ICC. DAGLß promotes tumorigenesis and metastasis in ICC via a novel activator protein-1 (AP-1)/DAGLß/miR4516 feedforward circuitry.

Socioeconomic factors, perceived stress, and social support effect on neonatal nurse burnout in China: a cross-sectional study.

BACKGROUND: Neonatal nurses' working environments are highly stressful, and burnout is common. This study examines the effect of socioeconomic factors, perceived stress, and social support on neonatal nurse burnout. METHODS: A total of 311 neonatal nurses participated in this study. They were administered a validated Maslach Burnout Inventory. The study employed a 14-item perceived stress scale (PSS-14) and a social support rate scale (SSRS) to examine stress, socioeconomic factors, and lifestyles. RESULTS: Of the neonatal nurses, 40.19% had burnout, 89.60% had mild burnout, and 10.40% had moderate burnout; no neonatal nurse experienced severe burnout. Young nurses and those with low technical skills, poor interpersonal relationships, irregular diet, and insufficient rest were exposed to burnout (all p < 0.05).Most burnout nurses experienced moderate-severe perceived stress, and their PSS-14 scores were higher (all p < 0.05).The scores for objective social support, subjective social support, utilization of social support, total SSRS scores, and the level of social support were all lower in burnout nurses (all p < 0.05). Perceived stress was correlated positively and significantly with emotional exhaustion and personal accomplishment (all p < 0.05). Social support correlated significantly with and reduced personal accomplishments (p < 0.05). Age, poor interpersonal relationships, perceived stress, and social support were all independent factors associated with neonatal nurse burnout (all p < 0.05). CONCLUSION: The prevalence of burnout in neonatal nurses was higher than average. Socioeconomic factors, higher perceived stress, and lower social support contribute to neonatal nurse burnout. Nursing managers should pay attention to socioeconomic factors, perceived stress, and social support among neonatal nurses and employ strategies to reduce neonatal nurse burnout.

Effects of coal gangue on soil property and plant growth in mining area.

With indoor and outdoor treatments, coal gangue with different ratios (10%, 20%, 30%, 40% and 50%) and different particle sizes (0-2, 2-5, 5-8 and 8-10 mm) were mixed into soil, and formed reconstructed soil with different soil bulk densities (1.3, 1.35, 1.4, 1.45 and 1.5 g·cm-3). The effects of soil reconstruction modes on soil water condition, structure stability of aggregate and the growth of Lolium perenne, Medicago sativa, and Trifolium repens were investigated. Soil saturated water (SW), capillary water (CW), and field water capacity (FC) were decreased with increasing coal gangue ratio, particle size, and bulk density of reconstructed soil. >0.25 mm particle size aggregate (R0.25), mean weight diameter (MWD), and geometric mean diameter (GMD) increased first and then decreased with the increases of coal gangue particle size, reaching the peak at 2-5 mm coal gangue particle size. R0.25, MWD and GMD were significantly and negatively correlated with coal gangue ratio. Based on boosted regression tree (BRT) model, the coal gangue ratio contributed 59.3%, 67.0% and 40.3% to the variation of SW, CW and FC, respectively, which was a main influencing factor of soil water content. The coal gangue particle size contributed 44.7%, 32.3% and 62.1% to the variation of R0.25, MWD, and GMD, respecti-vely, which was the greatest influencing factor. Coal gangue ratio had a great effect on the growth of L. perenne, M. sativa, and T. repens, which contributed to 49.9%, 17.4% and 10.3% of their variations, respectively. Soil reconstruction mode of 30% coal gangue ratio and 5-8 mm coal gangue particle size was the best condition for plant growth, indicating that coal gangue could change soil water content and structure stability of aggregate. The soil reconstruction mode of 30% coal gangue ratio and 5-8 mm coal gangue particle size was recommended.

Genetic analysis and exploration of major effect QTLs underlying oil content in peanut.

KEY MESSAGE: AhyHOF1, likely encoding a WRI1 transcription factor, plays critical roles in peanut oil synthesis. Although increasing the oil content of peanut to meet growing demand has long been a primary aim of breeding programs worldwide, the mining of genetic resources to achieve this objective has obviously lagged behind that of other oil crops. In the present study, we developed an advanced recombinant inbred line population containing 192 F9:11 families derived from parents JH5 and KX01-6. We then constructed a high-resolution genetic map covering 3,706.382 cM, with an average length of 185.32 cM per linkage group, using 2840 polymorphic SNPs. Two stable QTLs, qCOA08_1 and qCOA08_2 having the highest contributions to genetic variation (16.1% and 20.7%, respectively), were simultaneously detected in multiple environments and closely mapped within physical intervals of approximately 2.9 Mb and 1.7 Mb, respectively, on chromosome A08. In addition, combined analysis of whole-genome and transcriptome resequencing data uncovered a strong candidate gene encoding a WRI1 transcription factor and differentially expressed between the two parents. This gene, designated as High Oil Favorable gene 1 in Arachis hypogaea (AhyHOF1), was hypothesized to play roles in oil accumulation. Examination of near-inbred lines of #AhyHOF1/#Ahyhof1 provided further evidence that AhyHOF1 increases oil content, mainly by affecting the contents of several fatty acids. Taken together, our results provide valuable information for cloning the favorable allele for oil content in peanut. In addition, the closely linked polymorphic SNP markers within qCOA08_1 and qCOA08_2 loci may be useful for accelerating marker-assisted selection breeding of peanut.

Malonylation of Acetyl-CoA carboxylase 1 promotes hepatic steatosis and is attenuated by ketogenic diet in NAFLD.

Protein post-translational modifications (PTMs) participate in important bioactive regulatory processes and therefore can help elucidate the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Here, we investigate the involvement of PTMs in ketogenic diet (KD)-improved fatty liver by multi-omics and reveal a core target of lysine malonylation, acetyl-coenzyme A (CoA) carboxylase 1 (ACC1). ACC1 protein levels and Lys1523 malonylation are significantly decreased by KD. A malonylation-mimic mutant of ACC1 increases its enzyme activity and stability to promote hepatic steatosis, whereas the malonylation-null mutant upregulates the ubiquitination degradation of ACC1. A customized Lys1523ACC1 malonylation antibody confirms the increased malonylation of ACC1 in the NAFLD samples. Overall, the lysine malonylation of ACC1 is attenuated by KD in NAFLD and plays an important role in promoting hepatic steatosis. Malonylation is critical for ACC1 activity and stability, highlighting the anti-malonylation effect of ACC1 as a potential strategy for treating NAFLD.

Transcriptomic analysis of albendazole resistance in human diarrheal parasite Giardia duodenalis.

Benzimidazole-2-carbamates (BZ, e.g., albendazole; ALB), which bind ß-tubulin to disrupt microtubule polymerization, are one of two primary compound classes used to treat giardiasis. In most parasitic nematodes and fungi, BZ-resistance is caused by ß-tubulin mutations and its molecular mode of action (MOA) is well studied. In contrast, in Giardia duodenalis BZ MOA or resistance is less well understood, may involve target-specific and broader impacts including cellular damage and oxidative stress, and its underlying cause is not clearly determined. Previously, we identified acquisition of a single nucleotide polymorphism, E198K, in ß-tubulin in ALB-resistant (ALB-R) G. duodenalis WB-1B relative to ALB-sensitive (ALB-S) parental controls. E198K is linked to BZ-resistance in fungi and its allelic frequency correlated with the magnitude of BZ-resistance in G. duodenalis WB-1B. Here, we undertook detailed transcriptomic comparisons of these ALB-S and ALB-R G. duodenalis WB-1B cultures. The primary transcriptional changes with ALB-R in G. duodenalis WB-1B indicated increased protein degradation and turnover, and up-regulation of tubulin, and related genes, associated with the adhesive disc and basal bodies. These findings are consistent with previous observations noting focused disintegration of the disc and associated structures in Giardia duodenalis upon ALB exposure. We also saw transcriptional changes with ALB-R in G. duodenalis WB-1B consistent with prior observations of a shift from glycolysis to arginine metabolism for ATP production and possible changes to aspects of the vesicular trafficking system that require further investigation. Finally, we saw mixed transcriptional changes associated with DNA repair and oxidative stress responses in the G. duodenalis WB-1B line. These changes may be indicative of a role for H2O2 degradation in ALB-R, as has been observed in other G. duodenalis cell cultures. However, they were below the transcriptional fold-change threshold (log2FC > 1) typically employed in transcriptomic analyses and appear to be contradicted in ALB-R G. duodenalis WB-1B by down-regulation of the NAD scavenging and conversion pathways required to support these stress pathways and up-regulation of many highly oxidation sensitive iron-sulphur (FeS) cluster based metabolic enzymes.

Evaluation of the star family doctors training program: an observational cohort study of a novel continuing medical education program for general practitioners within a compact medical consortium: a quantitative analysis.

INTRODUCTION: To determine the effectiveness of the Star Family Doctors Training Program, a comprehensive Continuing professional development (CPD) program for general practitioners (GPs) in a compact medical consortium. PATIENTS AND METHODS: Observational cohort study with a quantitative analyses in primary health care institutions in Sichuan Province. The interventions were as following: (1) The Star Family Doctors Training Program is a full-time, local government allocation program certified by the Health Department of Sichuan Province, emphasizing small group learning and practice, and using standard patients and medical patient simulators; 30 participants were selected by their institutions. (2) The control group underwent a self-financed after-work CPD program using conventional lectures; 50 participants were self-selected. Short-term effectiveness assessed using immediate post-training tests and self-evaluations; long-term (1 year) effectiveness evaluated using self-reported surveys. RESULTS: The study involved 80 GPs (28.75% men; mean age: 38.2 ± 9.2 years). The average post-training total score was higher in the STAR group than in the control group (72.83 ± 5.73 vs. 68.18 ± 7.64; p = 0.005). Compared to the controls, STAR participants reported seeing more patients (all p < 0.05), and had more patients who signed family-doctor contracts (p = 0.001) as well as increased patient satisfaction (p = 0.03), respectively. STAR-group trainees appraised the program higher and were more willing to recommend it to colleagues (90% vs. 64%, p = 0.011). CONCLUSION: The Star Family Doctors Training Program achieved good responses and provides a reference for future CPD programs.