A comprehensive review of bioinformatics tools for chromatin loop calling.

Precisely calling chromatin loops has profound implications for further analysis of gene regulation and disease mechanisms. Technological advances in chromatin conformation capture (3C) assays make it possible to identify chromatin loops in the genome. However, a variety of experimental protocols have resulted in different levels of biases, which require distinct methods to call true loops from the background. Although many bioinformatics tools have been developed to address this problem, there is still a lack of special introduction to loop-calling algorithms. This review provides an overview of the loop-calling tools for various 3C-based techniques. We first discuss the background biases produced by different experimental techniques and the denoising algorithms. Then, the completeness and priority of each tool are categorized and summarized according to the data source of application. The summary of these works can help researchers select the most appropriate method to call loops and further perform downstream analysis. In addition, this survey is also useful for bioinformatics scientists aiming to develop new loop-calling algorithms.

Multimodal neuroimaging fusion unravel structural-functional-neurotransmitter change in Parkinson's disease with impulse control disorders.

BACKGROUND: Impulse control disorders (ICD) in Parkinson's disease (PD) is highly multifactorial in etiology and has intricate neural mechanisms. Our multimodal neuroimaging study aimed to investigate the specific patterns of structure-function-neurotransmitter interactions underlying ICD. METHODS: Thirty PD patients with ICD (PD-ICD), 30 without ICD (PD-NICD) and 32 healthy controls (HCs) were recruited. Gyrification and perivascular spaces (PVS) were computed to capture the alternations of cortical surface morphology and glymphatic function. Seed-based functional connectivity (FC) were performed to identify the corresponding functional changes. Further, JuSpace toolbox were employed for cross-modal correlations to evaluate whether the spatial patterns of functional alterations in ICD patients were associated with specific neurotransmitter system. RESULTS: Compared to PD-NICD, PD-ICD patients showed hypogyrification and enlarged PVS volume fraction in the left orbitofrontal gyrus (OFG), as well as decreased FC between interhemispheric OFG. The interhemispheric OFG connectivity reduction was associated with spatial distribution of µ-opioid pathway (r = -0.186, p = 0.029, false discovery rate corrected). ICD severity was positively associated with the PVS volume fraction of left OFG (r = 0.422, p = 0.032). Furthermore, gyrification index (LGI) and percent PVS (pPVS) in OFG and their combined indicator showed good performance in differentiating PD-ICD from PD-NICD. CONCLUSIONS: Our findings indicated that the co-altered structure-function-neurotransmitter interactions of OFG might be involved in the pathogenesis of ICD.

Oncoprotein LAMTOR5-mediated CHOP silence via DNA hypermethylation and miR-182/miR-769 in promotion of liver cancer growth.

C/EBP homologous protein (CHOP) triggers the death of multiple cancers via endoplasmic reticulum (ER) stress. However, the function and regulatory mechanism of CHOP in liver cancer remain elusive. We have reported that late endosomal/lysosomal adapter, mitogen-activated protein kinase and mTOR activator 5 (LAMTOR5) suppresses apoptosis in various cancers. Here, we show that the transcriptional and posttranscriptional inactivation of CHOP mediated by LAMTOR5 accelerates liver cancer growth. Clinical bioinformatic analysis revealed that the expression of CHOP was low in liver cancer tissues and that its increased expression predicted a good prognosis. Elevated CHOP contributed to destruction of LAMTOR5-induced apoptotic suppression and proliferation. Mechanistically, LAMTOR5-recruited DNA methyltransferase 1 (DNMT1) to the CpG3 region (-559/-429) of the CHOP promoter and potentiated its hypermethylation to block its interaction with general transcription factor IIi (TFII-I), resulting in its inactivation. Moreover, LAMTOR5-enhanced miR-182/miR-769 reduced CHOP expression by targeting its 3'UTR. Notably, lenvatinib, a first-line targeted therapy for liver cancer, could target the LAMTOR5/CHOP axis to prevent liver cancer progression. Accordingly, LAMTOR5-mediated silencing of CHOP via the regulation of ER stress-related apoptosis promotes liver cancer growth, providing a theoretical basis for the use of lenvatinib for the treatment of liver cancer.

Transport of polyethylene and polypropylene microplastics under the action of agricultural chemicals: Role of pesticide adjuvants and neonicotinoid active ingredients.

Understanding the impact of various agricultural chemical components on the fate and transport of microplastics (MPs) in the subsurface is essential. In this study, column experiments on saturated porous media were conducted to explore the influence of the coexistence environment of pesticide adjuvants (surfactants) and active ingredients (neonicotinoids) on the transport of polyethylene (PE) and polypropylene (PP) MPs. An anionic surfactant (sodium dodecyl sulfate (SDS)), a nonionic surfactant (nonylphenol ethoxylate (NP-40)), and three neonicotinoid insecticides (acetamiprid, dinotefuran, and nitenpyram) could independently increase MP migration by 9.31%-61.01% by improving the hydrophilicity. Acetamiprid or dinotefuran reduced the adhesion work of the binary system by competing with SDS for adsorption sites, thereby inhibiting PE mobility. However, nitenpyram in the mixture was not easily adsorbed on the surface of PE MPs together with SDS because of nitenpyram's high hydrophilicity. Neonicotinoid molecules could not reduce the hydrophilic modification of SDS on PP MPs by competing for adsorption sites. Owing to their weak charge and adhesion work of nonionic surfactants (-4.80 mV and 28.45 kT for PE and -8.21 mV and 17.64 kT for PP), neonicotinoids tended to occupy the adsorption sites originally belonging to NP-40. The long molecular chain of NP-40 made it difficult for high-concentration neonicotinoids to affect the adhesion on MPs. In addition, NP-40 was harder to peel off from the MP surface than SDS, leading to a larger MP transport ability in the sand column.

Effects of dietary selenized glucose on intestinal microbiota and tryptophan metabolism in rats: Assessing skatole reduction potential.

3-Methylindole (Skatole), a degradation product of tryptophan produced by intestinal microbial activity, significantly contributes to odor nuisance. Its adverse effects on animal welfare, human health, and environmental pollution have been noted. However, it is still unclear whether the intestinal microbiota mediates the impact of selenium (Se) on skatole production and what the underlying mechanisms remain elusive. A selenized glucose (SeGlu) derivative is a novel organic selenium compound. In this study, a diverse range of dietary SeGlu-treated levels, including SeGlu-deficient (CK), SeGlu-adequate (0.15 mg Se per L), and SeGlu-supranutritional (0.4 mg Se per L) conditions, were used to investigate the complex interaction of SeGlu on intestinal microbiome and serum metabolome changes in male Sprague-Dawley (SD) rats. The study showed that SeGlu supplementation enhanced the antioxidant ability in rats, significantly manifested in the increases of the activity of catalase (CAT) and glutathione peroxidase (GSH-Px), while no change in the level of malonaldehyde (MDA). Metagenomic sequencing analysis verified that the SeGlu treatment group significantly increased the abundance of beneficial microorganisms such as Clostridium, Ruminococcus, Faecalibacterium, Lactobacillus, and Alloprevotella while reducing the abundance of opportunistic pathogens such as Bacteroides and Alistipes significantly. Further metabolomic analysis revealed phenylalanine, tyrosine, and tryptophan biosynthesis changes in the SeGlu treatment group. Notably, the biosynthesis of indole, a critical pathway, was affected by SeGlu treatment, with several crucial enzymes implicated. Correlation analysis demonstrated strong associations between specific bacterial species - Treponema, Bacteroides, and Ruminococcus, and changes in indole and derivative concentrations. Moreover, the efficacy of SeGlu-treated fecal microbiota was confirmed through fecal microbiota transplantation, leading to a decrease in the concentration of skatole in rats. Collectively, the analysis of microbiota and metabolome response to diverse SeGlu levels suggests that SeGlu is a promising dietary additive in modulating intestinal microbiota and reducing odor nuisance in the livestock and poultry industry.

Lipid droplet accumulation in Wdr45-deficient cells caused by impairment of chaperone-mediated autophagic degradation of Fasn.

BACKGROUND: ß-Propeller protein-associated neurodegeneration (BPAN) is a genetic neurodegenerative disease caused by mutations in WDR45. The impairment of autophagy caused by WDR45 deficiency contributes to the pathogenesis of BPAN; however, the pathomechanism of this disease is largely unknown. Lipid dyshomeostasis is involved in neurogenerative diseases, but whether lipid metabolism is affected by Wdr45 deficiency and whether lipid dyshomeostasis contributes to the progression of BPAN are unclear. METHODS: We generated Wdr45 knockout SN4741 cell lines using CRISPR‒Cas9-mediated genome editing, then lipid droplets (LDs) were stained using BODIPY 493/503. Chaperone-mediated autophagy was determined by RT-qPCR and western blotting. The expression of fatty acid synthase (Fasn) was detected by western blot in the presence or absence of the lysosomal inhibitor NH4Cl and the CMA activator AR7. The interaction between Fasn and HSC70 was analyzed using coimmunoprecipitation (Co-IP) assay. Cell viability was measured by a CCK-8 kit after treatment with the Fasn inhibitor C75 or the CMA activator AR7. RESULTS: Deletion of Wdr45 impaired chaperone-mediated autophagy (CMA), thus leading to lipid droplet (LD) accumulation. Moreover, Fasn can be degraded via CMA, and that defective CMA leads to elevated Fasn, which promotes LD formation. LD accumulation is toxic to cells; however, cell viability was not rescued by Fasn inhibition or CMA activation. Inhibition of Fasn with a low concentration of C75 did not affect cell viability but decreases LD density. CONCLUSIONS: These results suggested that Fasn is essential for cell survival but that excessive Fasn leads to LD accumulation in Wdr45 knockout cells.

The Enigma of Tau Protein Aggregation: Mechanistic Insights and Future Challenges.

Tau protein misfolding and aggregation are pathological hallmarks of Alzheimer's disease and over twenty neurodegenerative disorders. However, the molecular mechanisms of tau aggregation in vivo remain incompletely understood. There are two types of tau aggregates in the brain: soluble aggregates (oligomers and protofibrils) and insoluble filaments (fibrils). Compared to filamentous aggregates, soluble aggregates are more toxic and exhibit prion-like transmission, providing seeds for templated misfolding. Curiously, in its native state, tau is a highly soluble, heat-stable protein that does not form fibrils by itself, not even when hyperphosphorylated. In vitro studies have found that negatively charged molecules such as heparin, RNA, or arachidonic acid are generally required to induce tau aggregation. Two recent breakthroughs have provided new insights into tau aggregation mechanisms. First, as an intrinsically disordered protein, tau is found to undergo liquid-liquid phase separation (LLPS) both in vitro and inside cells. Second, cryo-electron microscopy has revealed diverse fibrillar tau conformations associated with different neurodegenerative disorders. Nonetheless, only the fibrillar core is structurally resolved, and the remainder of the protein appears as a "fuzzy coat". From this review, it appears that further studies are required (1) to clarify the role of LLPS in tau aggregation; (2) to unveil the structural features of soluble tau aggregates; (3) to understand the involvement of fuzzy coat regions in oligomer and fibril formation.

Decoding Cosmetic Complexities: A Comprehensive Guide to Matrix Composition and Pretreatment Technology.

Despite advancements in analytical technologies, the complex nature of cosmetic matrices, coupled with the presence of diverse and trace unauthorized additives, hinders the application of these technologies in cosmetics analysis. This not only impedes effective regulation of cosmetics but also leads to the continual infiltration of illegal products into the market, posing serious health risks to consumers. The establishment of cosmetic regulations is often based on extensive scientific experiments, resulting in a certain degree of latency. Therefore, timely advancement in laboratory research is crucial to ensure the timely update and adaptability of regulations. A comprehensive understanding of the composition of cosmetic matrices and their pretreatment technologies is vital for enhancing the efficiency and accuracy of cosmetic detection. Drawing upon the China National Medical Products Administration's 2021 Cosmetic Classification Rules and Classification Catalogue, we streamline the wide array of cosmetics into four principal categories based on the following compositions: emulsified, liquid, powdered, and wax-based cosmetics. In this review, the characteristics, compositional elements, and physicochemical properties inherent to each category, as well as an extensive overview of the evolution of pretreatment methods for different categories, will be explored. Our objective is to provide a clear and comprehensive guide, equipping researchers with profound insights into the core compositions and pretreatment methods of cosmetics, which will in turn advance cosmetic analysis and improve detection and regulatory approaches in the industry.

Efficacy of Danzhixiaoyao tablets combined with methylcobalamin tablets in the treatment of burning mouth syndrome: an open-label, randomized controlled trial.

OBJECTIVES: This randomized controlled trial compared the efficacy and tolerability of danzhixiaoyao pills in the accurate treatment of patients with burning mouth syndrome (BMS). METHOD: Collect a total of 78 patients (75 female patients and 3 male patients) from the oral mucosa department who were considered eligible fromOctober 2020 to October 2022.The patients were randomized and divided into trial group and control group.The trail group received danzhixiaoyao pills and mecobalamine tablets while the control group was given mecobalamine tablets.The Visual Analogue Scale (VAS), Beck Anxiety Inventory(BAI), Beck Depression Inventory (BDI), Oral Health Impact Profile (OHIP-14), Traditional Chinese medicine(TCM) syndrome integral and adverse reactions were performed at baseline and after 2, 4, and 6 weeks of treatment. Descriptive statistics, including the Wilcoxon rank-sum test and the Chi-square test for median comparisons between different times, were used. RESULT: 1.After treatment, the VAS, BDI,OHIP-14, and TCM syndrome integral in the trial group had a significant decrease than the control group(P< 0.05).However, there was no statistical difference in the BAI scores between the two groups (P> 0.05). 2.According to the efficacy determination criteria , the total effective rate of the test group was 73.68% , the control group was 52.94% and the recurrence rate was 0. There was a significant difference between the two groups (Z=-2.688, P < 0.05). The results showed that the curative effect of test group was better than that of control group.3. No adverse effects occurred in patients in either group. CONCLUSION: Danzhixiaoyao pills has demonstrated to have a positive effect in relieving BMS symptoms and in improving a patient's overall quality of life with no AEs compared with the control group. The efficacy evaluation systems that can be verified and complementary in this study provide a perfect, effective and referential evaluation system for the use of Chinese patent medicine in the treatment of oral mucosal diseases. TRIAL REGISTRATION: Registry name: Chinese Clinical trail Registry Registration number: ChiCTR2000038189 Date of Registration: 2020-09-13 Please visit ( https://www.chictr.org.cn/showproj.html?proj=61462 ) to the protocol.

Dynamic functional connectivity reveals hyper-connected pattern and abnormal variability in freezing of gait of Parkinson's disease.

BACKGROUND: Freezing of gait (FOG) is an intractable and paroxysmal gait disorder that seriously affects the quality of life of Parkinson's disease (PD) patients. Emerging studies have reported abnormal brain activity of distributed networks in FOG patients, whereas ignoring the intrinsic dynamic fluctuations of functional connectivity. The purpose of this study was to examine the dynamic functional network connectivity (dFNC) of PD-FOG. METHODS: In total, 52 PD patients with FOG (PD-FOG), 73 without FOG (PD-NFOG) and 38 healthy controls (HCs) received resting state functional magnetic resonance imaging (rs-fMRI). Sliding window method, k-means clustering and graph theory analysis were employed to retrieve dynamic characteristics of PD-FOG. Partial correlation analysis was conducted to verify whether the dFNC was related to freezing gait severity. RESULTS: Seven brain networks were identified and configured into seven states. Compared to PD-NFOG, significant spatial pattern was identified for state 2 in freezers, showing increased functional coupling between default mode network (DMN) and basal ganglia network (BG), as a concrete manifestation of increased precuneus-caudate coupling. The mean dwell time and fractional window of state 2 had a positive correlation with FOG severity. Furthermore, PD-FOG group exhibited lower variance in nodal efficiency of independent components (IC) 7 (left precuneus). CONCLUSIONS: Our study suggested that aberrant coupling of precuneus-caudate and disrupted variability of precuneus efficiency might be associated to the neural mechanisms of FOG.

Branched-chain keto-acid dehydrogenase kinase regulates vascular permeability and angiogenesis to facilitate tumor metastasis in renal cell carcinoma.

Branched-chain keto-acid dehydrogenase kinase (BCKDK) is the rate-limiting enzyme of branched-chain amino acid (BCAA) metabolism. In the last six years, BCKDK has been used as a kinase to promote tumor proliferation and metastasis. Renal cell carcinoma (RCC) is a highly vascularized tumor. A high degree of vascularization promotes tumor metastasis. Our objective is to explore the relationship between BCKDK and RCC metastasis and its specific mechanism. In our study, BCKDK is highly expressed in renal clear cell carcinoma and promotes the migration of clear cell renal cell carcinoma (ccRCC). Exosomes from ccRCC cells can promote vascular permeability and angiogenesis, especially when BCKDK is overexpressed in ccRCC cells. BCKDK can also augment the miR-125a-5p expression in ccRCC cells and derived exosomes, thereby decreasing the downstream target protein VE-cadherin level, weakening adhesion junction expression, increasing vascular permeability, and promoting angiogenesis in HUVECs. The novel BCKDK/Exosome-miR-125a-5p/VE-cadherin axis regulates intercellular communication between ccRCC cells and HUVECs. BCKDK plays a critical role in renal cancer metastasis, may be used as a molecular marker of metastatic ccRCC, and even may become a potential target of clinical anti-vascular therapy for ccRCC.

Protein arginine methyltransferase 5 mediates arginine symmetric dimethylation of influenza A virus PB2 and supports viral replication.

Influenza A virus (IAV) relies on intricate and highly coordinated associations with host factors for efficient replication and transmission. Characterization of such factors holds great significance for development of anti-IAV drugs. Our study identified protein arginine methyltransferase 5 (PRMT5) as a novel host factor indispensable for IAV replication. Silencing PRMT5 resulted in drastic repression of IAV replication. Our findings revealed that PRMT5 interacts with each protein component of viral ribonucleoproteins (vRNPs) and promotes arginine symmetric dimethylation of polymerase basic 2 (PB2). Overexpression of PRMT5 enhanced viral polymerase activity in a dose-dependent manner, emphasizing its role in genome transcription and replication of IAV. Moreover, analysis of PB2 protein sequences across various subtypes of IAVs demonstrated the high conservation of potential RG motifs recognized by PRMT5. Overall, our study suggests that PRMT5 supports IAV replication by facilitating viral polymerase activity by interacting with PB2 and promoting its arginine symmetric dimethylation. This study deepens our understanding of how IAV manipulates host factors to facilitate its replication and highlights the great potential of PRMT5 to serve as an anti-IAV therapeutic target.

Cortical Disinhibition Drives Freezing of Gait in Parkinson's Disease and an Exploratory Repetitive Transcranial Magnetic Stimulation Study.

BACKGROUND: Dysfunction of the primary motor cortex, participating in regulation of posture and gait, is implicated in freezing of gait (FOG) in Parkinson's disease (PD). OBJECTIVE: The aim was to reveal the mechanisms of "OFF-period" FOG (OFF-FOG) and "levodopa-unresponsive" FOG (ONOFF-FOG) in PD. METHODS: We measured the transcranial magnetic stimulation (TMS) indicators and gait parameters in 21 healthy controls (HCs), 15 PD patients with ONOFF-FOG, 15 PD patients with OFF-FOG, and 15 PD patients without FOG (Non-FOG) in "ON" and "OFF" medication conditions. Difference of TMS indicators in the four groups and two conditions and its correlations with gait parameters were explored. Additionally, we explored the effect of 10 Hz repetitive TMS on gait and TMS indicators in ONOFF-FOG patients. RESULTS: In "OFF" condition, short interval intracortical inhibition (SICI) exhibited remarkable attenuation in FOG patients (both ONOFF-FOG and OFF-FOG) compared to Non-FOG patients and HCs. The weakening of SICI correlated with impaired gait characteristics in FOG. However, in "ON" condition, SICI in ONOFF-FOG patients reduced compared to OFF-FOG patients. Pharmacological treatment significantly improved SICI and gait in OFF-FOG patients, and high-frequency repetitive TMS distinctly improved gait in ONOFF-FOG patients, accompanied by enhanced SICI. CONCLUSIONS: Motor cortex disinhibition, represented by decreased SICI, is related to FOG in PD. Refractory freezing in ONOFF-FOG patients correlated with the their reduced SICI insensitive to dopaminergic medication. SICI can serve as an indicator of the severity of impaired gait characteristics in FOG and reflect treatments efficacy for FOG in PD patients. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Effects of Lianhuaqingwen Capsules in adults with mild-to-moderate coronavirus disease 2019: an international, multicenter, double-blind, randomized controlled trial.

BACKGROUND: In a randomized trial, Lianhuaqingwen (LHQW) capsule was effective for accelerating symptom recovery among patients with coronavirus disease 2019 (COVID-19). However, the lack of blinding and limited sample sizes decreased the level of clinical evidence. OBJECTIVES: To evaluate the efficacy and safety of LHQW capsule in adults with mild-to-moderate COVID-19. METHODS: We conducted a double-blind randomized controlled trial in adults with mild-to-moderate COVID-19 (17 sites from China, Thailand, Philippine and Vietnam). Patients received standard-of-care alone or plus LHQW capsules (4 capsules, thrice daily) for 14 days. The primary endpoint was the median time to sustained clinical improvement or resolution of nine major symptoms. RESULTS: The full-analysis set consisted of 410 patients in LHQW capsules and 405 in placebo group. LHQW significantly shortened the primary endpoint in the full-analysis set (4.0 vs. 6.7 days, hazards ratio: 1.63, 95% confidence interval: 1.39-1.90). LHQW capsules shortened the median time to sustained clinical improvement or resolution of stuffy or runny nose (2.8 vs. 3.7 days), sore throat (2.0 vs. 2.6 days), cough (3.2 vs. 4.9 days), feeling hot or feverish (1.0 vs. 1.3 days), low energy or tiredness (1.3 vs. 1.9 days), and myalgia (1.5 vs. 2.0 days). The duration to sustained clinical improvement or resolution of shortness of breath, headache, and chills or shivering did not differ significantly between the two groups. Safety was comparable between the two groups. No serious adverse events were reported. INTERPRETATION: LHQW capsules promote recovery of mild-to-moderate COVID-19 via accelerating symptom resolution and were well tolerated. Trial registration ChiCTR2200056727 .

Targeting the hedgehog pathway in MET mutation cancers and its effects on cells associated with cancer development.

The mutation of MET plays a crucial role in the initiation of cancer, while the Hedgehog (Hh) pathway also plays a significant role in cell differentiation and the maintenance of tumor stem cells. Conventional chemotherapy drugs are primarily designed to target the majority of cell populations within tumors rather than tumor stem cells. Consequently, after a brief period of remission, tumors often relapse. Moreover, the exclusive targeting of tumor stemness cell disregards the potential for other tumor cells to regain stemness and acquire drug resistance. As a result, current drugs that solely target the HGF/c-MET axis and the Hh pathway demonstrate only moderate efficacy in specific types of cancer. Mounting evidence indicates that these two pathways not only play important roles in cancer but also exert significant influence on the development of resistance to single-target therapies through the secretion of their own ligands. In this comprehensive review, we analyze and compare the potential impact of the Hh pathway on the tumor microenvironment (TME) in HGF/c-MET-driven tumor models, as well as the interplay between different cell types. Additionally, we further substantiate the potential and necessity of dual-pathway combination therapy as a critical target in MET addicted cancer treatment. Video Abstract.

Sorafenib triggers ferroptosis via inhibition of HBXIP/SCD axis in hepatocellular carcinoma.

Sorafenib, which inhibits multiple kinases, is an effective frontline therapy for hepatocellular carcinoma (HCC). Ferroptosis is a form of iron-dependent programmed cell death regulated by lipid peroxidation, which can be induced by sorafenib treatment. Oncoprotein hepatitis B X-interacting protein (HBXIP) participates in multiple biological pro-tumor processes, including growth, metastasis, drug resistance, and metabolic reprogramming. However, the role of HBXIP in sorafenib-induced ferroptotic cell death remains unclear. In this study, we demonstrated that HBXIP prevents sorafenib-induced ferroptosis in HCC cells. Sorafenib decreased HBXIP expression, and overexpression of HBXIP blocked sorafenib-induced HCC cell death. Interestingly, suppression of HBXIP increased malondialdehyde (MDA) production and glutathione (GSH) depletion to promote sorafenib-mediated ferroptosis and cell death. Ferrostatin-1, a ferroptosis inhibitor, reversed the enhanced anticancer effect of sorafenib caused by HBXIP silencing in HCC cells. Regarding the molecular mechanism, HBXIP transcriptionally induced the expression of stearoyl-CoA desaturase (SCD) via coactivating the transcriptional factor ZNF263, resulting in the accumulation of free fatty acids and suppression of ferroptosis. Functionally, activation of the HBXIP/SCD axis reduced the anticancer activity of sorafenib and suppressed ferroptotic cell death in vivo and in vitro. HBXIP/SCD axis-mediated ferroptosis can serve as a novel downstream effector of sorafenib. Our results provide new evidence for clinical decisions in HCC therapy.

Alternations of gene expression in PI3K and AR pathways and DNA methylation features contribute to metastasis of prostate cancer.

OBJECTIVE: The molecular heterogeneity of prostate cancer (PCa) gives rise to distinct tumor subclasses based on epigenetic modification and gene expression signatures. Identification of clinically actionable molecular subtypes of PCa is key to improving patient outcome, and the balance between specific pathways may influence PCa outcome. It is also urgent to identify progression-related markers through cytosine-guanine (CpG) methylation in predicting metastasis for patients with PCa. METHODS: We performed bioinformatics analysis of transcriptomic, and clinical data in an integrated cohort of 551 prostate samples. The datasets included retrospective The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) cohorts. Two algorithms, Least Absolute Shrinkage and Selector Operation and Support Vector Machine-Recursive Feature Elimination, were used to select significant CpGs. RESULTS: We found that PCa progression is more likely to occur after the third year through conditional survival (CS) analysis, and prostate-specific antigen (PSA) was a better predictor of Progression-free survival (PFS) than Gleason score (GS). Our study first demonstrated that PCa tumors have distinct expression profiles based on the expression of genes involved in androgen receptor (AR) and PI3K-AKT, which influence disease outcome. Our results also indicated that there are multiple phenotypes relevant to the AR-PI3K axis in PCa, where tumors with mixed phenotype may be more aggressive or have worse outcome than quiescent phenotype. In terms of epigenetics, we obtained CpG sites and their corresponding genes which have a good predictive value of PFS. However, various evidences showed that the predictive value of CpGs corresponding genes was much lower than GpG sites in Overall survival (OS) and PFS. CONCLUSIONS: PCa classification specific to AR and PI3K pathways provides novel biological insight into previously established PCa subtypes and may help develop personalized therapies. Our results support the potential clinical utility of DNA methylation signatures to distinguish tumor metastasis and to predict prognosis and outcomes.

Oral Administration of Artemisia argyi Polysaccharide Increases Estrogen Level and Maintains Blood Lipid Homeostasis in Ovariectomized Rats.

INTRODUCTION: Artemisia argyi polysaccharide (AAP) has a beneficial effect on menstruation-related symptoms and the potential regulation of lipid metabolism. It is expected to be a safe and effective ingredient for estrogen deficiency and lipid metabolic disorders. Here, we investigate the effect of AAP on body weight gain, estrogen level, and blood lipid changes in ovariectomized (OVX) rats. METHODS: Thirty-six female Wistar rats were randomly divided into six treatment groups, including a sham-operated (Sham) group, OVX group, estrogen replacement (OVX + E2) group, and AAP treatment (OVX + 125, 250, 500 mg/kg AAP) group. The body weight and feed intake were recorded every week. The level of estrogen and blood lipid was determined. The gene expressions and protein expressions of estrogen receptors (ERs), fatty acid synthetase (FAS), acetyl CoA carboxylase 2 (ACC2), and 3-hydroxy-3-methyl glutaryl coenzyme A reductase (HMGR) were determined. RESULTS: AAP treatment significantly decreased the body weight gain and average daily food intake of rats in the OVX group. Treatment with AAP significantly increased the relative weight of the uterus, plasma estrogen level, and the gene expression and protein expression of ER-α in the uterus. For blood lipids, plasma levels of triglyceride, total cholesterol, and low-density lipoprotein cholesterol were significantly reduced by AAP treatment in OVX rats. AAP treatment decreased the expression of FAS and HMGR in the liver of OVX rats. Furthermore, AAP treatment significantly increased the gene expression of ACC2, the protein expression of P-ACC2, and the ratio of P-ACC2/ACC2. CONCLUSION: In summary, AAP treatment exerts beneficial effects on body weight gain and lipid metabolism disorder induced by ovariectomy through increasing estrogen levels, inhibiting FAS, and promoting fatty acid oxidation.

Acute, repeated inhalation toxicity, respiratory system irritation, and mutagenicity studies of 1,1,2,2-tetrafluoroethane (HFC-134) as the impurity in the pharmaceutical propellant 1,1,1,2-tetrafluoroethane (HFA-134a).

HFC-134 is the main impurity of HFA-134a. In order to verify the rationality of HFC-134 limits in HFA-134a and ensure the safety of HFA-134a as propellant in pharmaceutical metered-dose inhalers, acute inhalation toxicity, seven-day repeat dose inhalation irritation study, 21-day repeat dose inhalation toxicity study and reverse mutation assay of HFC-134 were tested to evaluate its inhalation safety. In acute inhalation studies, Sprague-Dawley rats were exposed nose-only to HFC-134 at levels of 100 000, 200 000, 400 000, 600 000, and 800 000 ppm for 4 h. Based on the mortality incidence, the calculated four-hour LC50 value for HFC-134 is 532 069 ppm for males and 502 058 ppm for females and acute inhalation toxicity is manifested as the lung lobes turn dark red. Exposures to 836 ± 67 ppm for 4 hours/day 7 days/week continuously did not induce local irritation of the respiratory system in Sprague-Dawley rats. Sprague-Dawley rats were exposed nose-only to HFC-134 at levels of 0 (control), 203 929 ppm and 394 871 ppm 2 h/day for 21 consecutive days, no significant treatment-related adverse effects was noted. Results from Ames studies demonstrated that HFC-134 was not mutagenic. Although HFC-134 has a very low acute inhalation toxicity, considering that its acute inhalation toxicity is higher than that of HFA-134a, and due to the high frequency of use of MDI by asthma patients, acceptance criteria of HFC-134 as the impurity in aerosol propellant HFA-134a should be lower than 8-h TWA WEEL value of 1000 ppm to ensure the safety of the MDI.

Predictors of psychological resilience trajectories in patients with knee arthroplasty: A longitudinal study.

AIMS: To identify the different classes of total knee arthroplasty patients according to the heterogenous trajectories of psychological resilience and investigate the predictors for different patterns of resilience. DESIGN: A prospective cohort study. METHODS: A total of 210 patients with total knee arthroplasty from March to December 2021 were included. Baseline assessment (T0) data were collected before surgery and included demographic, biological (clinical characteristics), psychological (psychological resilience, self-efficacy, psychological distress, hope, medical coping mode) and social (social support) factors. Resilience measurements were repeated at 3 days after surgery (T1), the date of discharge (T2), and 1 month (T3) and 3 months (T4) after discharge. Latent growth mixture modelling was employed to define different resilience trajectories. Predictors of class membership were identified using multinomial logistic regression. RESULTS: Data from 198 patients were analysed. Three latent classes were identified with similar patterns in different intercepts, showing a significant decrease in resilience from admission (T0) to 3 days after surgery (T1) followed by an increase from T1 to T4. The three trajectories of psychological resilience were named the stable-resilience class (65.66%), high-resilience class (17.68%), and low-resilience class (16.66%). Multinomial logistic regression showed that compared with the stable-resilience class, the high-resilience class was predicted by having a higher level of hope, having higher education, living in urban areas and having more children, while the low-resilience class was predicted by having lower levels of self-efficacy and hope, living in semirural areas, and having more children. CONCLUSIONS: The three trajectories indicated that surgery was the major stressor influencing patients' psychological resilience and that patients in the low-resilience class needed to be intervened. IMPACT: Predictors of patients in different classes provide evidence for the identification of vulnerable populations and lay a foundation for future research contributing to the development of targeted interventions for improving patients' psychological resilience. No patient or public contribution but the time points of investigation were decided based on our interviews with 12 total knee arthroplasty patients.