The degradation of α--synuclein is limited by dynein to drive the AALP pathway through HDAC6 upon paraquat exposure.

Lewy body disease (LBD), one of the most common neurodegenerative diseases (NDDs), is characterized by excessive accumulation of α-synuclein (α-syn) in neurons. In recent years, environmental factors such as exposure to herbicides and pesticides have been attributed to the development of this condition. While majority of the studies on neurotoxic effects of paraquat (PQ) have focused on α-syn-mediated neuronal damage in the early stages of α-syn accumulation in neurons, efforts to explore the key target for α-syn degradation are limited. Recent research has suggested that histone deacetylase 6 (HDAC6) might possibly regulate amyloid clearance, and that the metabolism of compounds in neurons is also directly affected by axonal transport in neurons. Dynein predominantly mediates reverse transportation of metabolites and uptake of signal molecules and other compounds at the end of axons, which is conducive to the reuse of cell components. However, the role of interaction of dynein with HDAC6 in metabolites transport is still unclear. Therefore, this study aimed to investigate the role of HDAC6 in α-syn accumulation/clearance in neurons and the associated possible influencing factors. The results revealed that HDAC6 could transport ubiquitinated α-syn, bind to dynein, form an aggresome, and relocate to the center of the microtubule tissue, ultimately reducing abnormal accumulation of α-syn. However, PQ treatment resulted in HDAC6 upregulation, causing abnormal aggregation of α-syn. Taken together, these findings indicated that PQ exposure caused abnormal accumulation of α-syn and decreased effective degradation of α-syn by HDAC6-mediated aggresome-autophagy-lysosome pathway.

Efficacy of immune checkpoint inhibitors in advanced non-small cell lung cancer patients with rare KRAS mutations: a real-world retrospective study.

Background: Kirsten rat sarcoma homolog (KRAS) mutations are one of the key drivers in non-small cell lung cancer (NSCLC) and FDA-approved specific inhibitors of KRAS-G12C mutation are available clinically. However, inhibitors of certain KRAS mutation subtypes remain unavailable, especially rare KRAS mutations including G13C, G13D, and Q61H. In this study, we retrospectively investigated the outcomes of NSCLC patients with rare KRAS-mutation to determine if they may benefit from immune checkpoint inhibitors (ICIs). Methods: Our retrospective study involved 240 advanced NSCLC patients with KRAS mutations, who visited Shanghai Chest Hospital from July 2018 to July 2021. Complete clinical and pathological data were recorded and progression-free survival (PFS) and overall survival (OS) were adopted as primary endpoints. Results: The median follow-up time was 36.5 months (range, 30.8-42.1 months) and the median OS was 9.7 months (range, 7.6-11.8 months). Of the 240 patients evaluated, 130 (54.2%) received chemotherapy and 110 (45.8%) received ICI-based treatment. Among the patients who received chemotherapy, patients with rare KRAS-mutations presented worse survival outcomes (median PFS, 3.4 vs. 4.1 months, P=0.047; median OS, 5.2 vs. 7.1 months, P=0.02) than conventional KRAS-mutant patients. PFS and OS of rare KRAS-mutation patients were prolonged after immunotherapy (median PFS 7.3 vs. 3.4 months, P<0.001; median OS, 13.3 vs. 5.2 months, P<0.001) and had no significant difference compared with conventional KRAS-mutant patients, in part of them whose programmed death-ligand 1 (PD-L1) expression data before immunotherapy were available (n=72), patients with a higher rate of PD-L1 positive tumor cells (≥50%) presented elevated PFS and OS. Conclusions: Despite having potential survival disadvantage compared with other NSCLC patients, rare KRAS-mutant patients (other than G12A, C, D, V) could benefit specifically from ICI-based therapy and survival outcomes are correlated with PD-L1 expression.

Proteomics analysis of immune response-related proteins in Guillain-Barré Syndrome (GBS) and Chronic Inflammatory Demyelinating Polyneuropathy (CIDP).

The objective is to characterize differentially expressed proteins (DEPs) in Guillain-Barré Syndrome (GBS) and Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) through high-throughput analysis. Sera from 11 healthy controls (HCs), 21 GBS and 19 CIDP patients were subjected to Olink Proteomics Analysis. In the comparison between CIDP and GBS groups, up-regulation of ITM2A and down-regulation of NTF4 were observed. Comparing GBS with HCs revealed 18 up-regulated and 4 down-regulated proteins. Comparing CIDP with the HCs identified 15 up-regulated and 4 down-regulated proteins. Additionally, the correlation between clinical characteristics and DEPs were uncovered. In conclusion, the DEPs have significant potential to advance our understanding of the pathogenesis in these debilitating neurological disorders.

Residential greenspace and COVID-19 Severity: A cohort study of 313,657 individuals in Greater Manchester, United Kingdom.

BACKGROUND: Greenspaces contribute positively to mental and physical well-being, promote social cohesion, and alleviate environmental stressors, such as air pollution. Ecological studies suggest that greenspace may affect incidence and severity of Coronavirus Disease 2019 (COVID-19). OBJECTIVE: This study examines the association between residential greenspace and COVID-19 related hospitalization and death. METHOD: In this retrospective cohort based on patient records from the Greater Manchester Care Records, all first COVID-19 cases diagnosed between March 1, 2020, and May 31, 2022 were followed until COVID-19 related hospitalization or death within 28 days. Residential greenspace availability was assessed using the Normalized Difference Vegetation Index per lower super output area in Greater Manchester. The association of greenspace with COVID-19 hospitalization and mortality were estimated using multivariate logistic regression models after adjusting for potential individual, temporal, and spatial confounders. We explored potential effect modifications of the associations with greenspace and COVID-19 severity by age, sex, body mass index, smoking, deprivation, and certain comorbidities. Combined effects of greenspace and air pollution (NO2 and PM2.5) were investigated by mutually adjusting pairs with correlation coefficients ≤ 0·7. RESULTS: Significant negative associations were observed between greenspace availability and COVID-19 hospitalization and mortality with odds ratios [OR] (95 % Confidence Intervals [CI]) of 0·96 (0·94-0·97) and 0·84 (0·80-0·88) (per interquartile range [IQR]), respectively. These were significantly modified by deprivation (P-value for interaction < 0.05), showing that those most deprived obtained largest benefits from greenspace. Inclusion of NO2 and PM2.5 diminished associations to null for COVID-19 hospitalization, but only reduced them slightly for mortality, where inverse associations remained. CONCLUSION: In the Greater Manchester area, residential greenspace is associated with reduced risk of hospitalization or death in individuals with COVID-19, with deprived groups obtaining the greatest benefits. Associations were strongest for COVID-19 mortality, which were robust to inclusion of air pollutants in the models.

Theabrownin from Pu-erh Tea Improves DSS-Induced Colitis via Restoring Gut Homeostasis and Inhibiting TLR2&4 Signaling Pathway.

BACKGROUND: Theabrownin (TB) is a dark brown pigment from Pu-erh tea or other dark teas. It is formed by further oxidization of theaflavins and thearubigins, in combination with proteins, polysaccharides, and caffeine etc. TB is a characteristic ingredient and bioactive substance of Pu-erh tea. However, the effects of TB on ulcerative colitis (UC) remains unclear. PURPOSE: This study aims to elucidate the mechanism of TB on UC in terms of recovery of intestinal homeostasis and regulation of toll-like receptor (TLR) 2&4 signaling pathway. METHODS: The colitis models were established by administering 5% dextran sulfate sodium (DSS) to C57BL/6 mice for 5 days to evaluate the therapeutic and preventive effects of TB on UC. Mesalazine was used as a positive control. H&E staining, complete blood count, enzyme-linked immunosorbent assay, immunohistochemistry, flow cytometry, and 16S rRNA sequencing were employed to assess histological changes, blood cells analysis, content of cytokines, expression and distribution of mucin (MUC)2 and TLR2&4, differentiation of CD4+T cells in lamina propria, and changes in intestinal microbiota, respectively. Western blot was utilized to study the relative expression of tight junction proteins and the key proteins in TLR2&4-mediated MyD88-dependent MAPK, NF-κB, and AKT signaling pathways. RESULTS: TB outstanding alleviated colitis, inhibited the release of pro-inflammatory cytokines, reduced white blood cells while increasing red blood cells, hemoglobin, and platelets. TB increased the expression of occludin, claudin-1 and MUC2, effectively restored intestinal barrier function. TB also suppressed differentiation of Th1 and Th17 cells in the colon's lamina propria, increased the fraction of Treg cells, and promoted the balance of Treg/Th17 to tilt towards Tregs. Moreover, TB increased the Firmicutes to Bacteroides (F/B) ratio, as well as the abundance of Akkermansia, Muribaculaceae, and Eubacterium_coprostanoligenes_group at the genus level. In addition, TB inhibited the activation of TLR2&4-mediated MAPK, NF-κB, and AKT signaling pathways in intestinal epithelial cells of DSS-induced mice. CONCLUSION: TB acts in restoring intestinal homeostasis and anti-inflammatory in DSS-induced UC, and exhibiting a preventive effect after long-term use. In a word, TB is a promising beverage, health product and food additive for UC.

Resistance mechanisms of cereal plants and rhizosphere soil microbial communities to chromium stress.

Agricultural soils contaminated with heavy metals poison crops and disturb the normal functioning of rhizosphere microbial communities. Different crops and rhizosphere microbial communities exhibit different heavy metal resistance mechanisms. Here, indoor pot studies were used to assess the mechanisms of grain and soil rhizosphere microbial communities on chromium (Cr) stress. Millet grain variety 'Jingu 21' (Setaria italica) and soil samples were collected prior to control (CK), 6 hours after (Cr_6h), and 6 days following (Cr_6d) Cr stress. Transcriptomic analysis, high-throughput sequencing and quantitative polymerase chain reaction (qPCR) were used for sample determination and data analysis. Cr stress inhibited the expression of genes related to cell division, and photosynthesis in grain plants while stimulating the expression of genes related to DNA replication and repair, in addition to plant defense systems resist Cr stress. In response to chromium stress, rhizosphere soil bacterial and fungal community compositions and diversity changed significantly (p < 0.05). Both bacterial and fungal co-occurrence networks primarily comprised positively correlated edges that would serve to increase community stability. However, bacterial community networks were larger than fungal community networks and were more tightly connected and less modular than fungal networks. The abundances of C/N functional genes exhibited increasing trends with increased Cr exposure. Overall, these results suggest that Cr stress primarily prevented cereal seedlings from completing photosynthesis, cell division, and proliferation while simultaneously triggering plant defense mechanisms to resist the toxic effects of Cr. Soil bacterial and fungal populations exhibited diverse response traits, community-assembly mechanisms, and increased expression of functional genes related to carbon and nitrogen cycling, all of which are likely related to microbial survival during Cr stress. This study provides new insights into resistance mechanisms, microbial community structures, and mechanisms of C/N functional genes responses in cereal plants to heavy metal contaminated agricultural soils. Portions of this text were previously published as part of a preprint (https://www.researchsquare.com/article/rs-2891904/v1).

Efficacy of fractional radiofrequency in the treatment of erythematous capillary rosacea: A split-face study.

OBJECTIVE: To assess the effectiveness and safety of treating erythematotelangiectatic rosacea using fractional radiofrequency (FRF). METHODS: Twenty patients with a confirmed diagnosis of erythema capillaris rosacea were selected, and one side of each patient's face was randomly assigned to receive FRF treatments for three to six times, with an interval of 2 weeks between each treatment. VISIA, dermoscopy, and the Clinician's Erythema Evaluation Scale (CEA) were applied to evaluate the efficacy of the treatment before and after the treatment, to record the VAS scores and adverse reactions, and to conduct a patient satisfaction survey. RESULTS: The characteristic counts and scores of red zone and porphyrin as assessed by VISIA test were significantly decreased, and the difference between the treated side and the pretreatment side was statistically significant (p < 0.05), and the efficacy of the treatment was statistically insignificant compared with the control side, except for the red zone and porphyrin which were statistically significant before and after the treatment (p > 0.05). By CEA score, the difference between the treated side after treatment and the control side was statistically significant (p < 0.05), and the difference between the treated side before and after treatment was statistically significant (p < 0.05); the difference between the control side before and after treatment was not statistically significant (p > 0.05). Dermatoscopic observation showed reduction in pore size, reduction of yellowish-white and black horn plugs within the pores, lightening of the red background and thinning and blurring of the capillary structure on the treated side of the skin compared to the control side, and the skin on the treated side showed the above mentioned changes before and after the treatment as well. The mean pain score of the subjects was obtained by VAS score 3.67 ± 0.90. Adverse effects included mild edema, erythema, and microscopic crusting; no long-term adverse effects were seen in all patients. The efficacy of FRF treatment was evaluated 1 month after the final treatment, and 85% of the subjects rated it as satisfactory, very satisfactory, and very satisfactory. CONCLUSION: FRF for the treatment of erythematous capillary dilatation rosacea is effective, safe, and suitable for clinical promotion.

Impact of Geko Neuromuscular Stimulator on Preoperative Preparation in Ankle Fractures.

OBJECTIVE: To explore the impact of the Geko neuromuscular stimulator on preoperative preparation in patients with ankle fractures. STUDY DESIGN: Quasi-experiment study. Place and Duration of the Study: Department of Foot and Ankle Surgery and Department of Orthopaedics, Beijing Tongren Hospital, Capital Medical University, Beijing, China, between December 2020 and 2021. METHODOLOGY: This quasi-experiment study included patients with ankle fractures treated with Geko neuromuscular stimulator before surgical fixation. The primary outcome was limb swelling at 24, 48, and 72 hours (h) after admission, and the secondary outcomes were pain according to visual analogue scale (VAS) at 12, 24, and 48 hours after admission, preoperative waiting time, and comfort 4 and 72 h after admission. RESULTS: A total of 60 patients were included in the study; 30 in the conventional treatment group (mean age 41.16 ± 2.01 years) and 30 in the Geko group (mean age 40.22 ± 2.68 years). The limb swelling in patients was significantly different between the Geko and conventional treatment groups (p = 0.004). Besides, the swelling values at 48 (p < 0.001) and 72 (p < 0.001) hours were significantly lower than those at 24 hours. The pain in patients was significantly different between the Geko and conventional treatment groups (p = 0.007). Besides, the swelling values at 24 (p < 0.001) and 48 (p < 0.001) hours are significantly lower than those at 24 hours. Comfort was significantly higher at 4 h (69.54 ± 2.18 vs. 67.22 ± 3.14, p = 0.002) and 72 h [(88.50 (84.00 - 94.00) vs. 82.14 ± 3.08, p < 0.001)] after admission. The preoperative waiting time (3.52 ± 1.8 vs. 5.15 ± 2.1 hours, p = 0.002) was significantly shorter in the Geko group. CONCLUSION: The Geko neuromuscular stimulator is a useful option for preoperative preparation in patients with ankle fractures to reduce local swelling and pain and improve patients' comfort. KEY WORDS: Ankle fractures, Lower extremity, Neuromuscular stimulator, Peroneal nerve, Pain.

Deletion of Tgm2 suppresses BMP-mediated hepatocyte-to-cholangiocyte metaplasia in ductular reaction.

Transglutaminase 2 (Tgm2) plays an essential role in hepatic repair following prolonged toxic injury. During cholestatic liver injury, the intrahepatic cholangiocytes undergo dynamic tissue expansion and remodelling, referred to as ductular reaction (DR), which is crucial for liver regeneration. However, the molecular mechanisms governing the dynamics of active cells in DR are still largely unclear. Here, we generated Tgm2-knockout mice (Tgm2-/-) and Tgm2-CreERT2-Rosa26-mTmG flox/flox (Tgm2CreERT2-R26T/Gf/f) mice and performed a three-dimensional (3D) collagen gel culture of mouse hepatocytes to demonstrate how Tgm2 signalling is involved in DR to remodel intrahepatic cholangiocytes. Our results showed that the deletion of Tgm2 adversely affected the functionality and maturity of the proliferative cholangiocytes in DR, thus leading to more severe cholestasis during DDC-induced liver injury. Additionally, Tgm2 hepatocytes played a crucial role in the regulation of DR through metaplasia. We unveiled that Tgm2 regulated H3K4me3Q5ser via serotonin to promote BMP signalling activation to participate in DR. Besides, we revealed that the activation or inhibition of BMP signalling could promote or suppress the development and maturation of cholangiocytes in DDC-induced DR. Furthermore, our 3D collagen gel culture assay indicated that Tgm2 was vital for the development of cholangiocytes in vitro. Our results uncovered a considerable role of BMP signalling in controlling metaplasia of Tgm2 hepatocytes in DR and revealed the phenotypic plasticity of mature hepatocytes.

g-C3N4 as ballistic electron transport "Tunnel" in CsPbBr3-based ternary photocatalyst for gas phase CO2 reduction.

Perovskite CsPbBr3 quantum dot shows great potential in artificial photosynthesis, attributed to its outstanding optoelectronic properties. Nevertheless, its photocatalytic activity is hindered by insufficient catalytic active sites and severe charge recombination. In this work, a CsPbBr3@Ag-C3N4 ternary heterojunction photocatalyst is designed and synthesized for high-efficiency CO2 reduction. The CsPbBr3 quantum dots and Ag nanoparticles are chemically anchored on the surface of g-C3N4 sheets, forming an electron transfer tunnel from CsPbBr3 quantum dots to Ag nanoparticles via g-C3N4 sheets. The resulting CsPbBr3@Ag-C3N4 ternary photocatalyst, with spatial separation of photogenerated carriers, achieves a remarkable conversion rate of 19.49 µmol·g-1·h-1 with almost 100 % CO selectivity, a 3.13-fold enhancement in photocatalytic activity as compared to CsPbBr3 quantum dots. Density functional theory calculations reveal the rapid CO2 adsorption/activation and the decreased free energy (0.66 eV) of *COOH formation at the interface of Ag nanoparticles and g-C3N4 in contrast to the g-C3N4, leading to the excellent photocatalytic activity, while the thermodynamically favored CO desorption contributes to the high CO selectivity. This work presents an innovative strategy of constructing perovskite-based photocatalyst by modulating catalyst structure and offers profound insights for efficient CO2 conversion.

A chromosome-level genome of Chenghua pig provides new insights into the domestication and local adaptation of pigs.

As a country with abundant genetic resources of pigs, the domestication history of pigs in China and the adaptive evolution of Chinese pig breeds at different latitudes have rarely been elucidated at the genome-wide level. To fill this gap, we first assembled a high-quality chromosome-level genome of the Chenghua pig and used it as a benchmark to analyse the genomes of 272 samples from three genera of three continents. The divergence of the three species belonging to three genera, Phacochoerus africanus, Potamochoerus porcus, and Sus scrofa, was assessed. The introgression of pig breeds redefined that the migration routes were basically from southern China to central and southwestern China, then spread to eastern China, arrived in northern China, and finally reached Europe. The domestication of pigs in China occurred ∼12,000 years ago, earlier than the available Chinese archaeological domestication evidence. In addition, FBN1 and NR6A1 were identified in our study as candidate genes related to extreme skin thickness differences in Eurasian pig breeds and adaptive evolution at different latitudes in Chinese pig breeds, respectively. Our study provides a new resource for the pig genomic pool and refines our understanding of pig genetic diversity, domestication, migration, and adaptive evolution at different latitudes.

Optimal Treatment Based on Interferon No Longer Makes Clinical Cure of Chronic Hepatitis B Far Away: An Evidence-Based Review on Emerging Clinical Data.

Chronic hepatitis B (CHB) remains a major global public health problem. The functional cure is the ideal therapeutic target recommended by the latest guidelines, and pursuing a functional cure has become the key treatment end point of current therapy and for upcoming clinical trials. In this review, based on the latest published clinical research evidence, we analyzed the concept and connotation of clinical cures and elaborated on the benefits of clinical cures in detail. Secondly, we have summarized various potential treatment methods for achieving clinical cures, especially elaborating on the latest research progress of interferon-based optimized treatment strategies in achieving clinical cures. We also analyzed which populations can achieve clinical cures and conducted a detailed analysis of relevant virological and serological markers in screening clinical cure advantage populations and predicting clinical cure achievement. In addition, we also introduced the difficulties that may be encountered in the current pursuit of achieving a clinical cure.

Establishment and analysis of artificial neural network diagnosis model for coagulation-related molecular subgroups in coronary artery disease.

Background: Coronary artery disease (CAD) is the most common type of cardiovascular disease and cause significant morbidity and mortality. Abnormal coagulation cascade is one of the high-risk factors in CAD patients, but the molecular mechanism of coagulation in CAD is still limited. Methods: We clustered and categorized 352 CAD paitents based on the expression patterns of coagulation-related genes (CRGs), and then we explored the molecular and immunological variations across the subgroups to reveal the underlying biological characteristics of CAD patients. The feature genes between CRG-subgroups were further identified using a random forest model (RF) and least absolute shrinkage and selection operator (LASSO) regression, and an artificial neural network prediction model was constructed. Results: CAD patients could be divided into the C1 and C2 CRG-subgroups, with the C1 subgroup highly enriched in immune-related signaling pathways. The differential expressed genes between the two CRG-subgroups (DE-CRGs) were primarily enriched in signaling pathways connected to signal transduction and energy metabolism. Subsequently, 10 feature DE-CRGs were identified by RF and LASSO. We constructed a novel artificial neural network model using these 10 genes and evaluated and validated its diagnostic performance on a public dataset. Conclusion: Diverse molecular subgroups of CAD patients may each have a unique gene expression pattern. We may identify subgroups using a few feature genes, providing a theoretical basis for the precise treatment of CAD patients with different molecular subgroups.

Tomato SlMAPK3 Modulates Cold Resistance by Regulating the Synthesis of Raffinose and the Expression of SlWRKY46.

Mitogen-activated protein kinase (MAPK) cascades and raffinose have been observed to increase in plants exposed to cold. However, it remains elusive whether and how MAPK regulates raffinose synthesis under cold stress. Here, overexpression of SlMAPK3 promoted the accumulation of galactinol and raffinose under cold stress, while CRISPR/Cas9-mediated mutants showed the opposite results. Moreover, SlMAPK3 promoted the expression of SlWRKY46 at low temperatures and interacted with SlWRKY46 protein. Overexpression of SlWRKY46 enhanced cold resistance. Furthermore, SlWRKY46 directly bound to the promoter of SlGols1 to enhance its expression and promoted the accumulation of raffinose. Virus-induced gene-silencing (VIGS)-mediated knockdown of SlGols1 remarkably elevated cold sensitivity and reduced raffinose content. Meanwhile, exogenous supplementation of raffinose could improve the cold tolerance of tomato plants. Thus, our data indicates that SlMAPK3 modulates cold resistance by regulating raffinose content and SlWRKY46 expression. SlWRKY46 also promotes the accumulation of raffinose by inducing the expression of SlGols1.

Role of differentiated embryo-chondrocyte expressed gene 2 in immunity.

Differentiated embryo-chondrocyte expressed gene 2 (DEC2) is a member of the basic helix-loop-helix (bHLH) subfamily of transcription factors. DEC2 is implicated in tumor immunotherapy, immune system function regulation, and autoimmune diseases. DEC2 enhances Th2 cell differentiation by regulating the IL-2 and IL-4 signaling pathways and mediates the growth of B-1a cells, thereby promoting the occurrence and development of inflammatory responses. In this study, we review the reported roles of DEC2, including the regulation of immune cell differentiation and cytokine production in various cells in humans, and discuss its potential in treating autoimmune diseases and tumors.

A novel approach to evaluation of tumor response for advanced pulmonary adenocarcinoma using the intertumoral heterogeneity response score.

Treatment response and prognosis estimation in advanced pulmonary adenocarcinoma are challenged by the significant heterogeneity of the disease. The current Response Evaluation Criteria in Solid Tumors (RECIST) criteria, despite providing a basis for solid tumor response evaluation, do not fully encompass this heterogeneity. To better represent these nuances, we introduce the intertumoral heterogeneity response score (THRscore), a measure built upon and expanding the RECIST criteria. This retrospective study included patients with 3-10 measurable advanced lung adenocarcinoma lesions who underwent first-line chemotherapy or targeted therapy. The THRscore, derived from the coefficient of variation in size for each measurable tumor before and 4-6 weeks posttreatment, unveiled a correlation with patient outcomes. Specifically, a high THRscore was associated with shorter progression-free survival, lower tumor response rate, and a higher tumor mutation burden. These associations were further validated in an external cohort, confirming THRscore's effectiveness in stratifying patients based on progression risk and treatment response, and enhancing the utility of RECIST in capturing complex tumor behaviors in lung adenocarcinoma. These findings affirm the promise of THRscore as an enhanced tool for tumor response assessment in advanced lung adenocarcinoma, extending the RECIST criteria's utility.

Development of Injectable Thermosensitive Nanocomposite Hydrogel for Ratiometric Drug Delivery to Treat Drug Resistant Chondrosarcoma In Vivo.

Chondrosarcoma(CS), a prevalent primary malignant bone tumor, frequently exhibits chemotherapy resistance attributed to upregulated anti-apoptosis pathways such as the Bcl-2 family. In this manuscript, a new strategy is presented to augment chemosensitivity and mitigate systemic toxicity by harnessing a nano-enabled drug delivery hydrogel platform. The platform utilizes "PLGA-PEG-PLGA", an amphiphilic triblock copolymer combining hydrophilic polyethylene glycol (PEG) and hydrophobic polylactide glycolide (PLGA) blocks, renowned for its properties conducive to crafting a biodegradable, temperature-sensitive hydrogel. This platform is tailored to encapsulate a ratiometrically designed dual-loaded liposomes containing a first-line chemo option for CS, Doxorubicin (Dox), plus a calculated amount of small molecule inhibitor for anti-apoptotic Bcl-2 pathway, ABT-737. In vitro and in vivo evaluations demonstrate successful Bcl-2 suppression, resulting in the restoration of Dox sensitivity, evident through impeded tumor growth and amplified necrosis rates at the tumor site. This delivery system showcases remarkable thermal responsiveness, injectability, and biodegradability, all finely aligned with the clinical demands of CS treatment. Collectively, this study introduces a transformative avenue for tackling drug resistance in CS chemotherapy, offering significant clinical potential.

The early development of offspring born to women with polycystic ovary syndrome: Insights from a prospective birth cohort study in Southwestern China.

PURPOSE: This prospective cohort study aimed to investigate the effect of maternal polycystic ovary syndrome (PCOS) on the offspring early development. METHODS: A total of 91 mother-child pairs, consisting of 33 PCOS and 58 non-PCOS, were recruited. Peripheral blood tests were performed during 12-16, 24-28, and 32-36 weeks of gestation. Ages & Stages Questionnaires (ASQ) were utilized to assess the motor development of offspring at 27 months of age. Logistic regression models were employed to compare groups and control confounding variables. RESULTS: Women with PCOS had a higher level of testosterone and free androgen index than the non-PCOS group in all three detection windows. There were no intergroup differences in any of the five domains of specific ASQ domain scores or the body measurements of the offspring at 27 months old. Stratification by sex of offspring suggested that no significant differences were detected in the male offspring. However, in the female offspring, the PCOS group exhibited lower gross motor scores in female offspring than the non-PCOS group (48.1 ± 11.8 vs. 55.2 ± 8.1, P = 0.027), as well as lower fine motor scores (48.5 ± 8.5 vs. 53.6 ± 11.0, P = 0.028). The gross motor score of female offspring in the PCOS group remained lower even after adjustments. Each 1 ng/mL increase in testosterone at 12-16 weeks of gestation was associated with a decrease in gross motor score of female offspring by 12.2 (95% CI = -23.3 to -1.0, P = 0.038). The highest tertile of testosterone at 12-16 weeks of gestation was associated with a 7.75-point decrease in gross motor score of female offspring compared to the lowest tertile of testosterone (95% CI = -14.9 to -0.6, P = 0.040), with a significant linear trend observed (P for trend = 0.031). CONCLUSIONS: The findings of this study suggest that maternal PCOS could exert a negative influence on the gross motor development of female offspring, potentially associated with intrauterine androgen exposure during the early stages of pregnancy.

Recent Advances in Dissecting the Function of Ethylene in Interaction between Host and Pathogen.

Pathogens influence the growth and development of plants, resulting in detrimental damage to their yields and quality. Ethylene, a gaseous phytohormone, serves a pivotal function in modulating diverse physiological processes in plants, including defense mechanisms against pathogen invasion. Ethylene biosynthesis is involved in both plants and pathogens. Recent empirical research elucidates the intricate interactions and regulatory mechanisms between ethylene and pathogens across various plant species. In this review, we provide a comprehensive overview of the latest findings concerning ethylene's role and its regulatory networks in host-pathogen interactions. Additionally, we explore the crosstalk between ethylene and other phytohormones. Points regarding ethylene emission and its modulation by pathogens are also emphasized. Moreover, we also discuss potential unresolved issues in the field that warrant further investigation.