Association of lifestyles and multimorbidity with mortality among individuals aged 60 years or older: Two prospective cohort studies.

Lifestyles are associated with all-cause mortality, yet limited research has explored the association in the elderly population with multimorbidity. We aim to investigate the impact of adopting a healthy lifestyle on reducing the risk of all-cause mortality in older individuals with or without multimorbidity in both China and UK. This prospective study included 29,451 and 173,503 older adults aged 60 and over from Chinese Longitudinal Healthy Longevity Survey (CLHLS) and UK Biobank. Lifestyles and multimorbidity were categorized into three groups, respectively. Cox proportional hazards regression was used to estimate the Hazard Ratios (HRs), 95% confidence intervals (95% CIs), and dose-response for all-cause mortality in relation to lifestyles and multimorbidity, as well as the combination of both factors. During a mean follow-up period of 4.7 years in CLHLS and 12.14 years in UK Biobank, we observed 21,540 and 20,720 deaths, respectively. For participants with two or more conditions, compared to those with an unhealthy lifestyle, adopting a healthy lifestyle was associated with a 27%-41% and 22%-42% reduction in mortality risk in the CLHLS and UK Biobank, respectively; Similarly, for individuals without multimorbidity, this reduction ranged from 18% to 41%. Among participants with multimorbidity, individuals with an unhealthy lifestyle had a higher mortality risk compared to those maintaining a healthy lifestyle, with HRs of 1.15 (95% CI: 1.00, 1.32) and 1.27 (95% CI: 1.16, 1.39) for two conditions, and 1.24 (95% CI: 1.06, 1.45) and 1.73 (95% CI: 1.56, 1.91) for three or more conditions in CLHLS and UK Biobank, respectively. Adherence to a healthy lifestyle can yield comparable mortality benefits for older individuals, regardless of their multimorbidity status. Furthermore, maintaining a healthy lifestyle can alleviate the mortality risks linked to a higher number of diseases.

Association of Combined Healthy Lifestyle Factors With Incident Dementia in Participants With and Without Multimorbidity: A Large Population-Based Prospective Cohort Study.

BACKGROUND: The effect of a healthy lifestyle on dementia associated with multimorbidity is not well understood. Our objective is to examine whether the adoption of a healthy lifestyle could potentially reduce the elevated risk of dementia in individuals with and without multimorbidity. METHODS: We utilized data from the UK Biobank cohort. A comprehensive healthy lifestyle score, ranging from 0 to 6, was generated. Cox proportional hazards models were used to examine the associations between multimorbidity, the healthy lifestyle score, and the incidence risk of dementia. RESULTS: Over a median follow-up period of 12.5 years, 5 852 all-cause dementia were recorded. Multimorbidity including cardiovascular, metabolic, neuropsychiatric, and inflammation-related diseases was associated with a higher risk of subsequent dementia. Each additional chronic disease was associated with a hazard ratio (HR) of 1.38 (95% CI: 1.33, 1.44). Compared to individuals without multimorbidity and a healthy lifestyle score of 5-6, patients with multimorbidity and a lifestyle score of 0-1 had a significantly higher risk of dementia (HR: 3.13; 95% CI: 2.64, 3.72), but the risk was markedly attenuated among those with multimorbidity and a lifestyle score of 5-6. Among patients with 3 or more diseases, the HR for dementia was 0.53 (95%CI: 0.42, 0.68) when comparing a lifestyle score of 5-6 to 0-1. And we observed more pronounced association between them among people younger than 60 years old. CONCLUSIONS: Adherence to a combination of healthy lifestyle factors, especially at a young age, was associated with a significantly lower risk of dementia among participants with multimorbidity.

Individual transmembrane domains of SfABCC2 from Spodoptera frugiperda do not serve as functional Cry1F receptors.

The fall armyworm (Spodoptera frugiperda) is a major global pest causing severe damage to various crops, especially corn. Transgenic corn producing the Cry1F pesticidal protein from the bacterium Bacillus thuringiensis (Cry1F corn) showed effectiveness in controlling this pest until S. frugiperda populations at locations in North and South America evolved practical resistance. The mechanism for practical resistance involved disruptive mutations in an ATP binding cassette transporter subfamily C2 gene (SfABCC2), which serves as a functional Cry1F receptor in the midgut cells of susceptible S. frugiperda. The SfABCC2 protein contains two transmembrane domains (TMD1 and TMD2), each with a cytosolic nucleotide (ATP) binding domain (NBD1 and NBD2, respectively). Previous reports have demonstrated that disruptive mutations in TMD2 were linked with resistance to Cry1F, yet whether the complete SfABCC2 structure is needed for receptor functionality or if a single TMD-NBD protein can serve as functional Cry1F receptor remains unknown. In the present study, we separately expressed TMD1 and TMD2 with their corresponding NBDs in cultured insect cells and tested their Cry1F receptor functionality. Our results show that the complete SfABCC2 structure is required for Cry1F receptor functionality. Moreover, binding competition assays revealed that Cry1F specifically bound to SfABCC2, whereas neither SfTMD1-NBD1 nor SfTMD2-NBD2 exhibited any significant binding. These results provide insights into the molecular mechanism of Cry1F recognition by SfABCC2 in S. frugiperda, which could facilitate the development of more effective insecticidal proteins.

Suppurative Meningitis Complicated with Arthritis Caused by Streptococcus Suis Infection: A Case Report.

Background: Streptococcus suis (S. suis) is a common gram-positive bacterium in pigs. Its natural infection sites are the upper respiratory tract (especially tonsils and nasal cavity), reproductive tract and digestive tract of pigs. It is a new emerging human and animal disease. A co-morbid pathogen that can cause serious infections in humans, including meningitis, sepsis, septic arthritis, and sometimes deafness. No cases have been reported in Huzhou City, Zhejiang Province, China. Case Presentation: A 50-year-old male patient who had Worked as a butcher in a slaughterhouse for 20 years. Admitted to the hospital due to abdominal pain, joint pain, fever, and headache.His condition rapidly worsened causing altered consciousness, drowsiness and developed hearing loss. S. suis induced pyogenic meningitis complicated by arthritis was suspected based on the results of biochemical and culture analysis of the cerebrospinal fluid, and metagenomic next-generation sequencing, The patient's symptoms significantly improved after treatment with antibiotics such as ceftriaxone, meropenem, and linezolid, as well as supportive therapies including steroids and hyperbaric oxygen therapy, and his hearing improved significantly.After about 2 years of follow-up, the hearing was significantly better than before, but hearing impairment still remained. Conclusion: Streptococcus suis is endemic in pork-consuming and pig-raising countries, but can occur throughout the world, especially among individuals with occupational exposure to pigs and/or pork, such as slaughterhouse workers, butchers, farmers, etc. Strengthen science education among key groups. This case was diagnosed as Streptococcus suis meningitis combined with arthritis. However, abdominal pain in the early stage of the disease is very rare and is easy to be misdiagnosed. It is necessary to identify whether it is complicated by peritonitis. For hearing loss caused by Streptococcus suis infection, the use of hyperbaric oxygen chamber treatment has obvious therapeutic effects.

Effect of Additional Mass on Natural Frequencies of Weight-Sensing Structures.

The phenomena of variability and interference in the natural frequencies of weight-sensing structures applied in complex working conditions must solve the problem of reducing or eliminating resonance under low-frequency vibrations to maximize stability, accuracy and reliability. The influence laws of the additional mass with relevant characteristics on the natural frequencies, which include the components of mass, stiffness and center-of-mass distribution, etc. Firstly, the theoretical formulas of the mathematical model are given based on different characteristics of the weight-sensing structure, and various combinations of additional masses on the weight-sensing structures are adjusted in the X-, Y-, and Z-directions. The key factors to be specifically considered in the theoretical formulas are discussed through simulation analysis and experimental validation. Secondly, the locking strength of the fastening screws of some components was changed, and another component was placed on the experimental platform in the experiment. The results show that the mass, center-of-mass, stiffness distribution and other factors of the additional mass have different effects on the natural frequencies, which are important for the demand for high-precision, high-stability weighing measurement. The results of this research can provide an effective scientific evaluation basis for the reliable prediction of natural frequencies.

Targeted heart repair by Tß4-loaded cardiac-resident macrophage-derived extracellular vesicles modified with monocyte membranes.

Recent studies have demonstrated the critical role of cardiac-resident macrophages (cMacs) in the maintenance of physiological homeostasis. However, recruitment of circulating monocyte-derived macrophages decreases cMac levels post-myocardial infarction (MI). Transplanting cMacs is not an ideal option due to their low survival rates and the risk of immunological rejection. However, extracellular vesicle therapy has the potential to provide a feasible and safe alternative for cardiac repair. In this study, cell membrane-modified extracellular vesicles (MmEVs) were developed for heart repair by modifying cMac-derived extracellular vesicles (mEVs) with monocyte membranes, resulting in immune evasion and sequential targeted localization to damaged regions through expression of CD47 on MmEVs and strong affinity between monocyte membrane proteins and CCL2. Additionally, to fully exploit the potential clinical application of MmEVs and achieve a better curative effect, thymosin ß4 (Tß4) was loaded into the nanoparticles, resulting in Tß4-MmEVs. In vitro experiments indicated that both the MmEVs and Tß4-MmEVs promoted cardiomyocyte proliferation and endothelial cell migration. Animal experiments suggested that MI mice treated with MmEVs and Tß4-MmEVs exhibited reduced myocardial fibrosis and increased vascular density compared to the control group. Thus, we posit that these targeted nanoparticles hold significant potential for MI adjuvant therapy and may open new avenues for cardiac repair and regeneration. STATEMENT OF SIGNIFICANCE: Extracellular vesicles (EVs) derived from bioactive parent cell sources involved in pathological and repair processes for cardiovascular disease have emerged as a compelling strategy for regenerative therapy. In this study, we constructed monocyte membrane-modified extracellular vesicles loaded with a drug (Tß4-MmEVs) for heart repair that exhibit extraordinary abilities of immune evasion and sequential localization to damaged regions owing to the presence of CD47 and the strong affinity between monocytes and damaged cardiomyocytes and endothelial cells. The bioactivities of Tß4-MmEVs on enhancing cardiomyocyte and endothelial cell proliferation were validated both in vitro and in vivo. Effective development and implementation of therapeutically membrane-modified nanoparticles from homologous origins can provide a reference for adjuvant therapy in clinical MI management.

Microbial degradation as a powerful weapon in the removal of sulfonylurea herbicides.

Sulfonylurea herbicides have been widely used worldwide and play a significant role in modern agricultural production. However, these herbicides have adverse biological effects that can damage the ecosystems and harm human health. As such, rapid and effective techniques that remove sulfonylurea residues from the environment are urgently required. Attempts have been made to remove sulfonylurea residues from environment using various techniques such as incineration, adsorption, photolysis, ozonation, and microbial degradation. Among them, biodegradation is regarded as a practical and environmentally responsible way to eliminate pesticide residues. Microbial strains such as Talaromyces flavus LZM1, Methylopila sp. SD-1, Ochrobactrum sp. ZWS16, Staphylococcus cohnii ZWS13, Enterobacter ludwigii sp. CE-1, Phlebia sp. 606, and Bacillus subtilis LXL-7 can almost completely degrade sulfonylureas. The degradation mechanism of the strains is such that sulfonylureas can be catalyzed by bridge hydrolysis to produce sulfonamides and heterocyclic compounds, which deactivate sulfonylureas. The molecular mechanisms associated with microbial degradation of sulfonylureas are relatively poorly studied, with hydrolase, oxidase, dehydrogenase and esterase currently known to play a pivotal role in the catabolic pathways of sulfonylureas. Till date, there are no reports specifically on the microbial degrading species and biochemical mechanisms of sulfonylureas. Hence, in this article, the degradation strains, metabolic pathways, and biochemical mechanisms of sulfonylurea biodegradation, along with its toxic effects on aquatic and terrestrial animals, are discussed in depth in order to provide new ideas for remediation of soil and sediments polluted by sulfonylurea herbicides.

New roles for Bacillus thuringiensis in the removal of environmental pollutants.

For a long time, the well-known Gram-positive bacterium Bacillus thuringiensis (Bt) has been extensively studied and developed as a biological insecticide for Lepidoptera and Coleoptera pests due to its ability to secrete a large number of specific insecticidal proteins. In recent years, studies have found that Bt strains can also potentially biodegrade residual pollutants in the environment. Many researchers have isolated Bt strains from multiple sites polluted by exogenous compounds and characterized and identified their xenobiotic-degrading potential. Furthermore, its pathway for degradation was also investigated at molecular level, and a number of major genes/enzymes responsible for degradation have been explored. At present, a variety of xenobiotics involved in degradation in Bt have been reported, including inorganic pollutants (used in the field of heavy metal biosorption and recovery and precious metal recovery and regeneration), pesticides (chlorpyrifos, cypermethrin, 2,2-dichloropropionic acid, etc.), organic tin, petroleum and polycyclic aromatic hydrocarbons, reactive dyes (congo red, methyl orange, methyl blue, etc.), and ibuprofen, among others. In this paper, the biodegrading ability of Bt is reviewed according to the categories of related pollutants, so as to emphasize that Bt is a powerful agent for removing environmental pollutants.

Clinical features of Omicron variant infection in 445 patients with coronavirus 19 disease.

BACKGROUND: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) can mutate frequently and many new strains have emerged thus far. The clinical and epidemiological characteristics differ with each dominant strain. OBJECTIVES: Obtain an understanding of the clinical characteristics of patients infected with the Omicron variants of the SARS CoV-2. DESIGN: Retrospective cohort SETTINGS: Teaching hospital in China. PATIENTS AND METHODS: Data on sociodemography, signs/symptoms, hospital stay, viral shedding period, comorbidities, treatment options and final outcome were retrieved from hospital electronic medical record. We collected nasopharyngeal samples, laboratory data, and clinical data from patients admitted to the hospital with SARS CoV-2. MAIN OUTCOME MEASURES: Clinical characteristics of the patients infected with Omicron variant of SARS CoV-2. SAMPLE SIZE: 445 patients RESULTS: The median age was 43.0 years with a range from 2 to 75 years. Two-thirds of the participants were male and one-third were female. Almost half of the participants (51.9%) had no symptoms, whereas 48.1% had at least one symptom. Of symptomatic patients, 26.7% had mild symptoms and 21.3% had moderate symptoms. No patients were admitted with severe or critical symptoms. All patients discharged from the hospital after complete recovery without any serious complications or death. The most common symptom was cough followed by sore throat and fever. Less common symptoms were having sputum, stuffy nose, and muscle pain. Rare symptoms were weakness, headache, diarrhea, hemoptysis and nausea/vomiting. CONCLUSIONS: All patients had mild to moderate symptoms. Shortness of breath was not a common symptom among the study group. No patients needed invasive oxygen therapy in this cohort. LIMITATIONS: Single center and retrospective design. CONFLICT OF INTEREST: None.

Current insights into the microbial degradation of nicosulfuron: Strains, metabolic pathways, and molecular mechanisms.

Nicosulfuron is among the sulfonylurea herbicides that are widely used to control annual and perennial grass weeds in cornfields. However, nicosulfuron residues in the environment are likely to cause long-lasting harmful environmental and biological effects. Nicosulfuron degrades via photo-degradation, chemical hydrolysis, and microbial degradation. The latter is crucial for pesticide degradation and has become an essential strategy to remove nicosulfuron residues from the environment. Most previous studies have focused on the screening, degradation characteristics, and degradation pathways of biodegrader microorganisms. The isolated nicosulfuron-degrading strains include Bacillus, Pseudomonas, Klebsiella, Alcaligenes, Rhodopseudomonas, Ochrobactrum, Micrococcus, Serratia, Penicillium, Aspergillus, among others, all of which have good degradation efficiency. Two main intermediates, 2-amino-4,6-dimethoxypyrimidine (ADMP) and 2-aminosulfonyl-N,N-dimethylnicotinamide (ASDM), are produced during microbial degradation and are derived from the C-N, C-S, and S-N bond breaks on the sulfonylurea bridge, covering almost every bacterial degradation pathway. In addition, enzymes related to the degradation of nicosulfuron have been identified successively, including the manganese ABC transporter (hydrolase), Flavin-containing monooxygenase (oxidase), and E3 (esterase). Further in-depth studies based on molecular biology and genetics are needed to elaborate on their role in the evolution of novel catabolic pathways and the microbial degradation of nicosulfuron. To date, few reviews have focused on the microbial degradation and degradation mechanisms of nicosulfuron. This review summarizes recent advances in nicosulfuron degradation and comprehensively discusses the potential of nicosulfuron-degrading microorganisms for bioremediating contaminated environments, providing a reference for further research development on nicosulfuron biodegradation in the future.

Hsa_circ_0063329 inhibits prostate cancer growth and metastasis by modulating the miR-605-5p/tgif2 axis.

Circular RNAs play crucial regulatory roles in the progression of various cancers. Nevertheless, the underlying mechanisms of circRNAs in prostate cancer (PCa) proliferation and metastasis remain largely uncertain. Here, we performed circRNA microarray analyses to identify differentially expressed circRNAs in a normal prostate epithelial cell line and PCa cell lines. We found that hsa_circ_0063329 was significantly downregulated in PCa. A series of in vitro and in vivo functional assays showed that overexpression of hsa_circ_0063329 inhibits PCa cell progression, while silencing of hsa_circ_0063329 achieved the opposite effects. Mechanistically, bioinformatics analysis, RNA pulldown, RNA-seq and dual-luciferase reporter assays demonstrated that hsa_circ_0063329 exerts its effect by sponging miR-605-5p to derepress TG-interacting factor 2 (TGIF2) and inactivate the TGF-ß pathway. In conclusion, hsa_circ_0063329 inhibits the proliferation and metastasis of PCa via modulation of the miR-605-5p/TGIF2 axis, and targeting hsa_circ_0063329 may provide a promising treatment strategy for aggressive PCa.

Associations of systolic blood pressure and in-hospital mortality in critically ill patients with acute kidney injury.

PURPOSE: Although systolic blood pressure (SBP) is associated with acute renal injury (AKI), the relationship between baseline SBP and prognosis in critically ill patients with AKI is unclear. We aimed to assess the linearity and profile of the relationship between SBP at intensive care unit (ICU) admission and in-hospital mortality in these patients. METHODS: Data of AKI patients in the ICU settings were extracted from the Medical Information Mart for Intensive Care III database. The association between seven SBP categories (< 100, 100-109, 110-119, 120-129, 130-139, 140-149, and ≥ 150 mmHg) and all-cause in-hospital mortality was assessed by Cox proportional hazard models. Restricted cubic spline analysis for the multivariate Cox model was performed to explore the shape of the relationship between SBP and mortality. RESULTS: A total of 24,202 patients with AKI were included in this study. A typically U-shaped relationship was found between SBP at admission and in-hospital mortality. Among all SBP categories, the lowest risk of death was observed in patients with SBP around 110-119 mmHg, whereas the highest was noted in patients with extremely low SBP (< 100 mmHg), followed by those with extremely high SBP (≥ 150 mmHg). SBP showed a significant interaction with vasopressor use and AKI stage in relation to the risk of in-hospital mortality. CONCLUSIONS: SBP upon admission showed a non-linear association with all-cause in-hospital mortality in critically ill patients with AKI. Patients with low or high SBP show an increased risk of mortality compared to patients with normal SBP.

Bioremediation potential of laccase for catalysis of glyphosate, isoproturon, lignin, and parathion: Molecular docking, dynamics, and simulation.

The present study aimed to investigate the catalytic degradation produced by laccase in the detoxification of glyphosate, isoproturon, lignin polymer, and parathion. We explored laccase-glyphosate, laccase-lignin polymer, laccase-isoproturon, and laccase-parathion using molecular docking (MD) and molecular dynamics simulation (MDS) approaches. The results suggest that laccase interacts well with glyphosate, lignin polymer, isoproturon, and parathion during biodegradation. We calculated the root mean square deviations (RMSD) of laccase-glyphosate, laccase-lignin polymer, laccase-isoproturon, and laccase-parathion as 0.24 ± 0.02, 0.59 ± 0.32, 0.43 ± 0.07, and 0.43 ± 0.06 nm, respectively. In an aqueous solution, the stability of laccase with glyphosate, lignin polymer, isoproturon, and parathion is mediated through the formation of hydrophobic interactions, hydrogen bonds, and van der Waals interactions. The presence of xenobiotic toxic compounds in the active site changed the conformation of laccase. MDS of the laccase-substrate complexes confirmed their stability during catalytic degradation. Laccase assay results confirmed that the degradation of syringol, dihydroconiferyl alcohol, guaiacol, parathion, isoproturon, and glyphosate were 100%, 99.31%, 95.69%, 60.96%, 54.51%, and 48.34% within 2 h, respectively. Taken together, we describe a novel method to understand the molecular-level biodegradation of xenobiotic compounds through laccase and its potential application in contaminant removal.

Insights into the microbial degradation and resistance mechanisms of glyphosate.

Glyphosate, as one of the broad-spectrum herbicides for controlling annual and perennial weeds, is widely distributed in various environments and seriously threatens the safety of human beings and ecology. Glyphosate is currently degraded by abiotic and biotic methods, such as adsorption, photolysis, ozone oxidation, and microbial degradation. Of these, microbial degradation has become the most promising method to treat glyphosate because of its high efficiency and environmental protection. Microorganisms are capable of using glyphosate as a phosphorus, nitrogen, or carbon source and subsequently degrade glyphosate into harmless products by cleaving C-N and C-P bonds, in which enzymes and functional genes related to glyphosate degradation play an indispensable role. There have been many studies on the abiotic and biotic treatment technologies, microbial degradation pathways and intermediate products of glyphosate, but the related enzymes and functional genes involved in the glyphosate degradation pathways have not been further discussed. There is little information on the resistance mechanisms of bacteria and fungi to glyphosate, and previous investigations of resistance mechanisms have mainly focused on how bacteria resist glyphosate damage. Therefore, this review explores the microorganisms, enzymes and functional genes related to the microbial degradation of glyphosate and discusses the pathways of microbial degradation and the resistance mechanisms of microorganisms to glyphosate. This review is expected to provide reference for the application and improvement of the microbial degradation of glyphosate in microbial remediation.

Screening and identification of vancomycin anti-idiotypic antibodies for against Staphylococcus aureus from a human phage display domain antibody library.

Staphylococcus aureus is a common food-borne pathogenic microorganism that poses a serious threat to food quality and safety, and can do harm to human health. In the past, researchers relied on antibiotics to control Staphylococcus aureus, though very effective, yet it was also worrying in the aspect of bio-safety. In fact, anti-idiotypic antibody (Anti-Id) shows its potential to mimic some of the structural and biological functions of antigens. Therefore, in this study, based on Anti-Id theory and technology, we expect to obtain the vancomycin Anti-Id which can mimic vancomycin against Staphylococcus aureus from a human phage display domain antibody library. After four rounds of bio-panning, a total of 18 positive Anti-Ids were obtained. Among them, two Anti-Ids named Anti-Id-2C12 and Anti-Id-1F5 were identified as "ß" type Anti-Ids, and afterwards they were selected for gene cloning and protein expression in prokaryotic expression system. As a result, a concentration of purified proteins with 568.6 µg/mL (Anti-Id-2C12) and 602.3 µg/mL (Anti-Id-1F5) were successfully obtained, and their minimum inhibitory concentration (MIC) values for Staphylococcus aureus were 125 and 200 µg/mL, respectively. As they are human heavy-chain domain antibodies, which were theoretically harmless to humans, they have the potential application value as preservatives in food and edible agricultural products.

In-vitro antiviral activity of doxepin hydrochloride against group B coxsackievirus.

Group B coxsackievirus is an enterovirus that can cause a variety of diseases, including myocarditis, aseptic meningitis, and hand, foot, and mouth disease. Currently, there is no effective antiviral drug against this virus. In this study, we used a cytopathic effect-based viral inhibition assay to screen an FDA-approved drug library and found that doxepin hydrochloride had potential antiviral activity. Doxepin hydrochloride exhibited strong antiviral activity against coxsackievirus B types 1-3 with a 50% inhibitory concentration of 10.12 ± 0.85 µM. Moreover, doxepin hydrochloride did not exert antiviral activity against other enteroviruses, including enterovirus A71 (subtypes BrCr/C4) and coxsackievirus A (subtypes 6/10/16). Furthermore, doxepin hydrochloride inhibited virus replication in the early stage of the infection cycle rather than affecting the entry or assembly process. In addition, a few mechanism-related pharmacophores were discovered through gene association network analysis. These findings identify a possible lead compound for treating coxsackievirus B infection and simultaneously offer valuable clues for drug repositioning.

Advances in Renal Cell Carcinoma Drug Resistance Models.

Renal cell carcinoma (RCC) is the most common form of kidney cancer. Systemic therapy is the preferred method to eliminate residual cancer cells after surgery and prolong the survival of patients with inoperable RCC. A variety of molecular targeted and immunological therapies have been developed to improve the survival rate and prognosis of RCC patients based on their chemotherapy-resistant properties. However, owing to tumor heterogeneity and drug resistance, targeted and immunological therapies lack complete and durable anti-tumor responses; therefore, understanding the mechanisms of systemic therapy resistance and improving clinical curative effects in the treatment of RCC remain challenging. In vitro models with traditional RCC cell lines or primary cell culture, as well as in vivo models with cell or patient-derived xenografts, are used to explore the drug resistance mechanisms of RCC and screen new targeted therapeutic drugs. Here, we review the established methods and applications of in vivo and in vitro RCC drug resistance models, with the aim of improving our understanding of its resistance mechanisms, increasing the efficacy of combination medications, and providing a theoretical foundation for the development and application of new drugs, drug screening, and treatment guidelines for RCC patients.

Heat Shock Protein A6 Is Especially Involved in Enterovirus 71 Infection.

Hand foot and mouth disease (HFMD) caused by Enterovirus 71 (EV71) infection is still a major infectious disease threatening children's life and health in the absence of effective antiviral drugs due to its high prevalence and neurovirulence. A study of EV71-specific host response might shed some light on the reason behind its unique epidemiologic features and help to find means to conquer EV71 infection. We reported that host heat shock protein A6 (HSPA6) was induced by EV71 infection and involved infection in both Rhabdomyosarcoma (RD) cells and neurogliocytes. Most importantly, we found that EV71 did not induce the expression of other heat shock proteins HSPA1, HSPA8, and HSPB1 under the same conditions, and other HFMD-associated viruses including CVA16, CVA6, CVA10, and CVB1-3 did not induce the upregulation of HSPA6. In addition, EV71 infection enhanced the cytoplasmic aggregation of HSPA6 and its colocalization with viral capsid protein VP1. These findings suggest that HSPA6 is a potential EV71-specific host factor worthy of further study.

Identification of single domain antibodies with insect cytotoxicity using phage-display antibody library screening and Plutella xylostella ATP-binding cassette transporter subfamily C member 2 (ABCC2) -based insect cell expression system.

It is extremely imminent to study a new strategy to manage agricultural pest like Plutella xylostella (P. xylostella) which is currently resistant to most of pesticides, including three domain-Cry toxins from Bacillus thuringiensis (Bt). In this study, we reported a phage displayed single domain antibody screening from human domain antibody (DAb) library targeted on Spodoptera frugiperda 9 (Sf9) cells expressed Cry1Ac toxin receptor, ATP-dependent binding cassette transporter C2 in P. xylostella (PxABCC2). After three rounds of panning, three cytotoxic antibodies (1D2, 2B7, 3C4) were obtained from thirty-eight antibodies and displayed high binding ability towards PxABCC2-expressed Sf9 cells. Through homology modeling and molecular docking, the interaction mode indicated that the most cytotoxic 1D2 of the three antibodies presented the lowest binding free energy required and had the most hydrogen bond formed with PxABCC2 in molecular docking analysis. Functional assay of key regions in 1D2 via Alanine replacement indicated that complementarity-determining region (CDR) 3 played a crucial role in antibody exerts binding activity and cytotoxicity. This study provides the first trial for discovering of potential cytotoxic antibodies from the human antibody library via specific receptor-expressed insect cell system biopanning.

TCDD-induced IL-24 secretion in human chorionic stromal cells inhibits placental trophoblast cell migration and invasion.

Environmental pollutant dioxins are potentially harmful to pregnant women and can lead to severe adverse outcomes in pregnancy, such as spontaneous abortion and stillbirth. However, little is currently known about the underlying toxicological mechanism. Our previous study reported that the IL-24 gene is a dioxin response gene during 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) treatment. Here, we further tested the effect of TCDD on IL-24 expression in human chorionic stromal cells. We also investigated the effect of IL-24 on the behaviors of human placental trophoblast cells and predicted the potential mechanism underlying these behaviors using functional network analysis. We found that TCDD stimulates IL-24 expression in human chorionic stromal cells in an AhR (aromatic hydrocarbon receptor)-related manner. We also found that IL-24 inhibits the migration and invasion of human placental trophoblast cells, the possible mechanism of which involves thirteen key proteins and mitochondrial function. Our findings suggest that IL-24 is a potential factor induced by TCDD to regulate trophoblast cell invasion, which potentially involves in TCDD-induced abortion.