Radiotherapy and immunology.

The majority of cancer patients receive radiotherapy during the course of treatment, delivered with curative intent for local tumor control or as part of a multimodality regimen aimed at eliminating distant metastasis. A major focus of research has been DNA damage; however, in the past two decades, emphasis has shifted to the important role the immune system plays in radiotherapy-induced anti-tumor effects. Radiotherapy reprograms the tumor microenvironment, triggering DNA and RNA sensing cascades that activate innate immunity and ultimately enhance adaptive immunity. In opposition, radiotherapy also induces suppression of anti-tumor immunity, including recruitment of regulatory T cells, myeloid-derived suppressor cells, and suppressive macrophages. The balance of pro- and anti-tumor immunity is regulated in part by radiotherapy-induced chemokines and cytokines. Microbiota can also influence radiotherapy outcomes and is under clinical investigation. Blockade of the PD-1/PD-L1 axis and CTLA-4 has been extensively investigated in combination with radiotherapy; we include a review of clinical trials involving inhibition of these immune checkpoints and radiotherapy.

Copper-Catalyzed [4+1+1] Annulation of Ammonium Salts and Anthranils: Synthesis of 2,3-Diaroylquinolines.

A copper(I)-catalyzed protocol is developed for the synthesis of various 2,3-diaroylquinolines starting from achiral ammonium salts and anthranils through [4+1+1] annulation. Using copper(I) chloride as the sole catalyst, this reaction is featured with easily available starting materials, broad substrate scope, good yields and simple reaction conditions.

HBV and HCV Co-Infection in Chinese Newly Diagnosed HIV+ Subjects in 2015 and 2023: A Cross-Sectional Study.

With shared routes of transmission, HBV and HCV co-infection are estimated to occur more in subjects with HIV. This study aimed to characterize and describe the prevalence of HBV and HCV co-infections in a cohort of newly diagnosed HIV+ subjects living in China. We conducted a cross-sectional study among newly diagnosed HIV+ subjects aged 18-100 who participated in surveys on the national HIV molecular epidemiology in 2015 and 2023. (The epidemiological table survey is located in the national database alongside serologic testing). The chi-square test was used to identify changes in infections between the studying populations in 2015 and 2023, and conditional logistic regression models were fit to identify risk factors for each co-infection. Among the 11,024 newly diagnosed HIV+ subjects who were surveyed (n = 4501 in 2015; n = 6523 in 2023), the prevalence of HBV, HCV, and HBV/HCV in 2023 was lower than that in 2015, respectively. No decrease was observed in HCV co-infection in men who had sex with men (MSM) in North China, Northeast China, and East China. Increasing recognition among those at high risk of heterosexual transmission and those with low educational backgrounds is paramount to the prevention and control of HIV/HBV/HCV infections.

Targeting the dendritic cell-secreted immunoregulatory cytokine CCL22 alleviates radioresistance.

PURPOSE: Radiation-mediated immune suppression limits efficacy and is a barrier in cancer therapy. Radiation induces negative regulators of tumor immunity including regulatory T cells (Treg). Mechanisms underlying Treg infiltration after radiotherapy (RT) are poorly defined. Given that dendritic cells (cDC) maintain Treg we sought to identify and target cDC signaling to block Treg infiltration after radiation. EXPERIMENTAL DESIGN: Transcriptomics and high dimensional flow cytometry revealed changes in murine tumor cDC that not only mediate Treg infiltration after RT, but associate with worse survival in human cancer datasets. Antibodies perturbing a cDC-CCL22-Treg axis were tested in syngeneic murine tumors. A prototype interferon-anti-epidermal growth factor receptor fusion protein (αEGFR-IFNα) was examined to block Treg infiltration and promote a CD8+ T cell response after RT. RESULTS: Radiation expands a population of mature cDC1 enriched in immunoregulatory markers that mediates Treg infiltration via the Treg-recruiting chemokine CCL22. Blocking CCL22 or Treg depletion both enhanced RT efficacy. αEGFR-IFNα blocked cDC1 CCL22 production while simultaneously inducing an antitumor CD8+ T cell response to enhance RT efficacy in multiple EGFR-expressing murine tumor models, including following systemic administration. CONCLUSIONS: We identify a previously unappreciated cDC mechanism mediating Treg tumor infiltration after RT. Our findings suggest blocking the cDC1-CCL22-Treg axis augments RT efficacy. αEGFR-IFNα added to RT provided robust antitumor responses better than systemic free interferon administration, and may overcome clinical limitations to interferon therapy. Our findings highlight the complex behavior of cDC after RT and provide novel therapeutic strategies for overcoming RT-driven immunosuppression to improve RT efficacy.

Impact of healthy lifestyle on the incidence and progression trajectory of mental disorders: A prospective study in the UK Biobank.

BACKGROUND: Healthier lifestyle decreased the risk of mental disorders (MDs) such as depression and anxiety. However, research on the effects of a comprehensive healthy lifestyle on their progression is lacking. METHODS: 385,704 individuals without baseline MDs from the UK Biobank cohort were included. A composite healthy lifestyle score was computed by assessing alcohol intake, smoking status, television viewing time, physical activity, sleep duration, fruit and vegetable intake, oily fish intake, red meat intake, and processed meat intake. Follow-up utilized hospital and death register records. Multistate model was used to examine the role of healthy lifestyle on the progression of specific MDs, while a piecewise Cox regression model was utilized to assess the influence of healthy lifestyle across various phases of disease progression. RESULTS: Higher lifestyle score reduced risks of transitions from baseline to anxiety and depression, as well as from anxiety and depression to comorbidity, with corresponding hazard ratios (HR) and 95 % confidence intervals (CI) of 0.94 (0.93, 0.95), 0.90 (0.89, 0.91), 0.94 (0.91, 0.98), and 0.95 (0.92, 0.98), respectively. Healthier lifestyle decreased the risk of transitioning from anxiety to comorbidity within 2 years post-diagnosis, with HR 0.93 (0.88, 0.98). Higher lifestyle scores at 2-4 years and 4-6 years post-depression onset were associated with reduced risk of comorbidity, with HR 0.93 (0.87, 0.99) and 0.92 (0.86, 0.99), respectively. LIMITATION: The generalizability to other ethnic groups is limited. CONCLUSION: This study observed a protective role of holistic healthy lifestyle in the trajectory of MDs and contributed to identifying critical progression windows.

A new species of Populus and the extensive hybrid speciation arising from it on the Qinghai-Tibet Plateau.

While the diversity of species formation is broadly acknowledged, significant debate exists regarding the universal nature of hybrid species formation. Through an 18-year comprehensive study of all Populus species on the Qinghai-Tibet Plateau, 23 previously recorded species and 8 new species were identified. Based on morphological characteristics, these can be classified into three groups: species in section Leucoides, species with large leaves, and species with small leaves in section Tacamahaca. By conducting whole-genome re-sequencing of 150 genotypes from these 31 species, 2.28 million single nucleotide polymorphisms (SNPs) were identified. Phylogenetic analysis utilizing these SNPs not only revealed a highly intricate evolutionary network within the large-leaf species of section Tacamahaca but also confirmed that a new species, P. curviserrata, naturally hybridized with P. cathayana, P. szechuanica, and P. ciliata, resulting in 11 hybrid species. These findings indicate the widespread occurrence of hybrid species formation within this genus, with hybridization serving as a key evolutionary mechanism for Populus on the plateau. A novel hypothesis, "Hybrid Species Exterminating Their Ancestral Species (HSEAS)," is introduced to explain the mechanisms of hybrid species formation at three different scales: the entire plateau, the southeastern mountain region, and individual river valleys.

Construction of carbon sequestration ecological network in Linyi City based on supply and demand of ecosystem service.

The increasing carbon emissions is one of the important reasons for global warming. As a key area of carbon emissions, carbon sequestration capacity of cities is urgently needed to be improved. Carbon sequestration ser-vices can be transferred between supply and demand areas due to the circulation of atmosphere. With Linyi City as an example, we used the minimum cumulative resistance model to extract the matching path of supply and demand, and constructed a carbon sequestration ecological network. The results showed that the regions with high supply of carbon sequestration services were located in the north and south of the study area, and that current total supply could solve about 60% of the total demand. Although the spatial distribution of supply and demand was uneven, 54% of the areas that could meet the surrounding carbon sequestration demand were still idle. The optimized supply-demand matching paths could maintain good transmission efficiency of material and energy, with lower costs. Paths with strong potential carbon sequestration capacity were located in the central and northwest part of the research area. In the construction of carbon sequestration ecological network, it is necessary to strengthen the protection and restoration of the supply side of carbon sequestration services, realize carbon reduction and strengthen carbon sequestration on the demand side, and optimize the matching path of supply and demand. This method provided services to the demand areas through the oversupply of ecosystem services, optimized the overall resource allocation, which could advance regional carbon sequestration capacity.

Dipeptidyl peptidase 4 inhibitors vs. metformin for new-onset dementia: a propensity score-matched cohort study.

BACKGROUND: Hypoglycemic pharmacotherapy interventions for alleviating the risk of dementia remains controversial, particularly about dipeptidyl peptidase 4 (DPP4) inhibitors versus metformin. Our objective was to investigate whether the initiation of DPP4 inhibitors, as opposed to metformin, was linked to a reduced risk of dementia. METHODS: We included individuals with type 2 diabetes over 40 years old who were new users of DPP4 inhibitors or metformin in the Chinese Renal Disease Data System (CRDS) database between 2009 and 2020. The study employed Kaplan-Meier and Cox regression for survival analysis and the Fine and Gray model for the competing risk of death. RESULTS: Following a 1:1 propensity score matching, the analysis included 3626 DPP4 inhibitor new users and an equal number of metformin new users. After adjusting for potential confounders, the utilization of DPP4 inhibitors was associated with a decreased risk of all-cause dementia compared to metformin (hazard ratio (HR) 0.63, 95% confidence interval (CI) 0.45-0.89). Subgroup analysis revealed that the utilization of DPP4 inhibitors was associated with a reduced incidence of dementia in individuals who initiated drug therapy at the age of 60 years or older (HR 0.69, 95% CI 0.48-0.98), those without baseline macrovascular complications (HR 0.62, 95% CI 0.41-0.96), and those without baseline microvascular complications (HR 0.67, 95% CI 0.47-0.98). CONCLUSION: In this real-world study, we found that DPP4 inhibitors presented an association with a lower risk of dementia in individuals with type 2 diabetes than metformin, particularly in older people and those without diabetes-related comorbidities.

Enhancing the Weld Quality of Polylactic Acid Biomedical Materials Using Rotary Friction Welding.

Polylactic acid (PLA) stands out as a biomaterial with immense potential, primarily owing to its innate biodegradability. Conventional methods for manufacturing PLA encompass injection molding or additive manufacturing (AM). Yet, the fabrication of sizable medical devices often necessitates fragmenting them into multiple components for printing, subsequently requiring reassembly to accommodate the constraints posed by the dimensions of the AM platform. Typically, laboratories resort to employing nuts and bolts for the assembly of printed components into expansive medical devices. Nonetheless, this conventional approach of jointing is susceptible to the inherent risk of bolts and nuts loosening or dislodging amid the reciprocating movements inherent to sizable medical apparatus. Hence, investigation into the joining techniques for integrating printed components into expansive medical devices has emerged as a critical focal point within the realm of research. The main objective is to enhance the joint strength of PLA polymer rods using rotary friction welding (RFW). The mean bending strength of welded components, fabricated under seven distinct rotational speeds, surpasses that of the underlying PLA substrate material. The average bending strength improvement rate of welding parts fabricated by RFW with three-stage transformation to 4000 rpm is about 41.94% compared with the average bending strength of PLA base material. The average surface hardness of the weld interface is about 1.25 to 3.80% higher than the average surface hardness of the PLA base material. The average surface hardness of the weld interface performed by RFW with variable rotational speed is higher than the average surface hardness of the weld interface performed at a fixed rotating friction speed. The temperature rise rate and maximum temperature recorded during RFW in the X-axis of the CNC turning machine at the outer edge of the welding part surpassed those observed in the internal temperature of the welding part. Remarkably, the proposed method in this study complies with the Sustainable Development Goals due to its high energy efficiency and low environmental pollution.

A 15-Inflammation-Related Gene Signature Predicts the Prognosis of Patients With Pancreatic Ductal Adenocarcinoma.

Chronic inflammation promotes the development of pancreatic ductal adenocarcinoma (PDAC) and PDAC-related inflammatory tumor microenvironment facilitates tumor growth and metastasis. Thus, we aimed to study the association between inflammatory response and prognosis in patients with PDAC. We conducted the whole transcriptomic sequencing using tissue samples collected from patients diagnosed with PDAC (n = 106) recruited from Shandong Cancer Hospital. We first constructed a prognostic signature using 15 inflammation-related genes in The Cancer Genome Atlas (TCGA) cohort (n = 177) and further validated it in an independent International Cancer Genome Consortium (ICGC) cohort (n = 90) and our in-house cohort. PDAC patients with a higher risk score had poorer overall survival (OS) (P < 0.001; HR, 3.02; 95% CI, 1.94-4.70). The association between the prognostic signature and OS remained significant in the multivariable Cox regression adjusting for age, sex, alcohol exposure, diabetes, and stage (P < 0.001; HR, 2.91; 95% CI, 1.73-4.89). This gene signature also robustly predicted prognosis in the ICGC cohort (P = 0.01; HR, 1.94; 95% CI, 1.14-3.30) and our cohort (P < 0.001; HR, 2.40; 95% CI, 1.45-3.97). Immune subtype C3 (inflammatory) was enriched and CD8+ T cells were higher in patients with a lower risk score (P < 0.05). Furthermore, PDAC patients with higher risk scores were more sensitive to chemotherapy, immunotherapy, and PARP inhibitors (P < 0.05). In sum, we identified a novel gene signature that was associated with inflammatory response for risk stratification, prognosis prediction, and therapy guidance in PDAC patients. Future studies are warranted to validate the clinical utility of the signature.

Myofibroblast-derived exosomes enhance macrophages to myofibroblasts transition and kidney fibrosis.

A critical event in the pathogenesis of kidney fibrosis is the transition of macrophages into myofibroblasts (MMT). Exosomes play an important role in crosstalk among cells in the kidney and the development of renal fibrosis. However, the role of myofibroblast-derived exosomes in the process of MMT and renal fibrosis progression remains unknown. Here, we examined the role of myofibroblast-derived exosomes in MMT and kidney fibrogenesis. In vitro, transforming growth factor-ß1 stimulated the differentiation of kidney fibroblasts into myofibroblasts and promoted exosome release from myofibroblasts. RAW264.7 cells were treated with exosomes derived from myofibroblasts. We found purified exosomes from myofibroblasts trigger the MMT. By contrast, inhibition of exosome production with GW4869 or exosome depletion from the conditioned media abolished the ability of myofibroblasts to induce MMT. Mice treatment with myofibroblast-derived exosomes (Myo-Exo) exhibited severe fibrotic lesion and more abundant MMT cells in kidneys with folic acid (FA) injury, which was negated by TANK-banding kinase-1 inhibitor. Furthermore, suppression of exosome production reduced collagen deposition, extracellular matrix protein accumulation, and MMT in FA nephropathy. Collectively, Myo-Exo enhances the MMT and kidney fibrosis. Blockade of exosomes mediated myofibroblasts-macrophages communication may provide a novel therapeutic target for kidney fibrosis.

[Characterization of Reductive Dechlorination of Chlorinated Ethylenes by Anaerobic Consortium].

Tetrachloroethylene （PCE） and trichloroethylene （TCE） are typical volatile halogenated organic compounds in groundwater that pose serious threats to the ecological environment and human health. To obtain an anaerobic microbial consortium capable of efficiently dechlorinating PCE and TCE to a non-toxic end product and to explore its potential in treating contaminated groundwater， an anaerobic microbial consortium W-1 that completely dechlorinated PCE and TCE to ethylene was obtained by repeatedly feeding PCE or TCE into the contaminated groundwater collected from an industrial site. The dechlorination rates of PCE and TCE were （120.1 ±4.9） µmol·ï¼ˆL·d）-1 and （172.4 ±21.8） µmol·ï¼ˆL·d）-1 in W-1， respectively. 16S rRNA gene amplicon sequencing and quantitative PCR （qPCR） showed that the relative abundance of Dehalobacter increased from 1.9% to 57.1%， with the gene copy number increasing by 1.7×107 copies per 1 µmol Cl- released when 98.3 µmol of PCE was dechlorinated to cis-1，2-dichloroethylene （cis-1，2-DCE）. The relative abundance of Dehalococcoides increased from 1.1% to 53.8% when cis-1，2-DCE was reductively dechlorinated to ethylene. The growth yield of Dehalococcoides gene copy number increased by 1.7×108 copies per 1 µmol Cl- released for the complete reductive dechlorination of PCE to ethylene. The results indicated that Dehalobacter and Dehalococcoides cooperated to completely detoxify PCE. When TCE was used as the only electron acceptor， the relative abundance of Dehalococcoides increased from （29.1 ±2.4）% to （7.7 ±0.2）%， and gene copy number increased by （1.9 ±0.4）×108 copies per 1 µmol Cl- released， after dechlorinating 222.8 µmol of TCE to ethylene. The 16S rRNA gene sequence of Dehalococcoides LWT1， the main functional dehalogenating bacterium in enrichment culture W-1， was obtained using PCR and Sanger sequencing， and it showed 100% similarity with the 16S rRNA gene sequence of D. mccartyi strain 195. The anaerobic microbial consortium W-1 was also bioaugmented into the groundwater contaminated by TCE at a concentration of 418.7 µmol·L-1. The results showed that （69.2 ±9.8）% of TCE could be completely detoxified to ethylene within 28 days with a dechlorination rate of （10.3 ±1.5） µmol·ï¼ˆL·d）-1. This study can provide the microbial resource and theoretical guidance for the anaerobic microbial remediation in PCE or TCE-contaminated groundwater.

Radiotherapy Enhances Metastasis Through Immune Suppression by Inducing PD-L1 and MDSC in Distal Sites.

PURPOSE: Radiotherapy (RT) is a widely employed anticancer treatment. Emerging evidence suggests that RT can elicit both tumor-inhibiting and tumor-promoting immune effects. The purpose of this study is to investigate immune suppressive factors of radiotherapy. EXPERIMENTAL DESIGN: We used a heterologous two-tumor model in which adaptive concomitant immunity was eliminated. RESULTS: Through analysis of PD-L1 expression and myeloid-derived suppressor cells (MDSC) frequencies using patient peripheral blood mononuclear cells and murine two-tumor and metastasis models, we report that local irradiation can induce a systemic increase in MDSC, as well as PD-L1 expression on dendritic cells and myeloid cells, and thereby increase the potential for metastatic dissemination in distal, nonirradiated tissue. In a mouse model using two distinct tumors, we found that PD-L1 induction by ionizing radiation was dependent on elevated chemokine CXCL10 signaling. Inhibiting PD-L1 or MDSC can potentially abrogate RT-induced metastasis and improve clinical outcomes for patients receiving RT. CONCLUSIONS: Blockade of PD-L1/CXCL10 axis or MDSC infiltration during irradiation can enhance abscopal tumor control and reduce metastasis.

Unlocking the Potential of Oxidative Asymmetric Catalysis with Continuous Flow Electrochemistry.

In the field of catalytic asymmetric synthesis, the less-treated path lies in oxidative catalytic asymmetric transformations. The hurdles of pinpointing the appropriate chemical oxidants and addressing their compatibility issues with catalysts and functionalities present significant challenges. Organic electrochemistry, employing traceless electrons for redox reactions, is underscored as a promising solution. However, the commonly used electrolysis in batch cells introduces its own set of challenges, hindering the advancement of electrochemical asymmetric catalysis. Here we introduce a microfluidic electrochemistry platform with single-pass continuous flow reactors that exhibits a wide-ranging applicability to various oxidative asymmetric catalytic transformations. This is exemplified through the sulfenylation of 1,3-dicarbonyls, dehydrogenative C-C coupling, and dehydrogenative alkene annulation processes. The unique properties of microfluidic electrochemical reactors not only eliminate the need for chemical oxidants but also enhance reaction efficiency and reduce the use of additives and electrolytes. These salient features of microfluidic electrochemistry expedite the discovery and development of oxidative asymmetric transformations. In addition, the continuous production facilitated by parallel single-pass reactors ensures straightforward reaction upscaling, removing the necessity for reoptimization across various scales, as evidenced by direct translation from milligram screening to hectogram asymmetric synthesis.

Evidence for the smallest fossil Pongo in southern China.

The rarity of Pongo fossils with precise absolute dating from the Middle Pleistocene hampers our understanding of the taxonomy and spatiotemporal distribution of Quaternary orangutans in southern China. Here, we report a newly discovered sample of 113 isolated teeth of fossil Pongo from Zhongshan Cave in the Bubing Basin, Guangxi, southern China. We describe the Pongo specimens from Zhongshan Cave and compare them metrically to other samples of fossil Pongo species (i.e., Pongo weidenreichi, Pongo devosi, Pongo duboisi, Pongo palaeosumatrensis, Pongo javensis, and Pongo sp.) and to extant orangutans (i.e., Pongo pygmaeus and Pongo abelii). The Zhongshan Pongo assemblage is dated using U-series and coupled electron spin resonance/U-series methods. Our results reasonably constrain the Zhongshan Pongo assemblage to 184 ± 16 ka, which is consistent with the biostratigraphic evidence. The Zhongshan Pongo teeth are only 6.5% larger on average than those of extant Pongo. The Zhongshan teeth are smaller overall than those of Pongo from all other cave sites in southern China, and they currently represent the smallest fossil orangutans in southern China. Based on their dental size, and the presence of a well-developed lingual pillar and lingual cingulum on the upper and lower incisors, an intermediate frequency of lingual cingulum remnants on the upper molars, and a higher frequency of moderate to heavy wrinkling on the upper and lower molars, we provisionally assign the Zhongshan fossils to P. devosi. Our results confirm earlier claims that P. weidenreichi is replaced by a smaller species in southern China, P. devosi, by the late Middle Pleistocene. The occurrence of P. devosi in Zhongshan Cave further extends its spatial and temporal distribution. The Pongo specimens from Zhongshan provide important new evidence to demonstrate that the dental morphological features of Pongo in southern China changed substantially during the late Middle Pleistocene.

Comparison of changes in adipokine and inflammatory cytokine levels in patients with newly diagnosed type 2 diabetes treated with exenatide, insulin, or pioglitazone: A post-hoc study of the CONFIDENCE trial.

Background: Adipokines and inflammatory cytokines (ADICs) play important roles in type 2 diabetes mellitus (T2DM). This study aimed to compare the changes of ADIC levels (ΔADICs) in patients with newly diagnosed T2DM treated with different antihyperglycemic agents, and further investigate the impact of these changes on metabolic indices, ß-cell function and insulin resistance (IR). Methods: Four hundred and sixteen patients with newly diagnosed T2DM from 25 centers in China randomly received 48-week intervention with exenatide, insulin or pioglitazone. Anthropometric and laboratory data, indices of ß-cell function and IR, and levels of AIDCs, including interleukin-1 beta (IL-1ß), interferon-gamma (IFN-γ), leptin, and fibroblast growth factor 21 (FGF21) were detected at baseline and the end of the study. Results: In total, 281 participants (68 % male, age: 50.3 ± 9.4 years) completed the study. After 48- week treatment, IL-1ß and IFN-γ were significantly decreased with exenatide treatment (P < 0.001 and P = 0.001, respectively), but increased with insulin (P = 0.009 and P = 0.026, respectively). However, pioglitazone treatment had no impact on ADICs. No significant change in leptin or FGF21 was detected with any of the treatments. After adjustment for baseline values and changes of body weight, waist and HbA1c, the between-group differences were found in ΔIL-1ß (exenatide vs. insulin: P = 0.048; and exenatide vs. pioglitazone: P = 0.003, respectively) and ΔIFN-γ (exenatide vs. insulin: P = 0.049; and exenatide vs. pioglitazone: P < 0.001, respectively). Multiple linear regression analysis indicated that Δweight was associated with ΔIL-1ß (ß = 0.753; 95 % CI, 0.137-1.369; P = 0.017). After adjusting for treatment effects, Δweight was also be correlated with ΔFGF21 (ß = 1.097; 95%CI, 0.250-1.944; P = 0.012); furthermore, ΔHOMA-IR was correlated with Δleptin (ß = 0.078; 95%CI, 0.008-0.147; P = 0.029) as well. However, ΔHOMA-IR was not significantly associated with ΔIL-1ß after adjusting for treatment effects (P = 0.513). Conclusion: Exenatide treatment led to significant changes of inflammatory cytokines levels (IL-1ß and IFN-γ), but not adipokines (leptin and FGF21), in newly diagnosed T2DM patients. The exenatide-mediated improvement in weight and IR may be associated with a decrease in inflammatory cytokine levels.

Remimazolam attenuates inflammation and kidney fibrosis following folic acid injury.

The transition of acute kidney injury (AKI) to chronic kidney disease (CKD) is characterized by intense inflammation and progressive fibrosis. Remimazolam is widely used for procedural sedation in intensive care units, such as AKI patients. Remimazolam has been shown to possess anti-inflammatory and organ-protective properties. However, the role of remimazolam in inflammation and renal fibrosis following AKI remains unclear. Here, we explored the effects of remimazolam on the inflammatory response and kidney fibrogenesis of mice subjected to folic acid (FA) injury. Our results showed that remimazolam treatment alleviated kidney damage and dysfunction. Mice treated with remimazolam presented less collagen deposition in FA-injured kidneys compared with FA controls, which was accompanied by a reduction of extracellular matrix proteins accumulation and fibroblasts activation. Furthermore, remimazolam treatment reduced inflammatory cells infiltration into the kidneys of mice with FA injury and inhibited proinflammatory or profibrotic molecules expression. Finally, remimazolam treatment impaired the activation of bone marrow-derived fibroblasts and blunted the transformation of macrophages to myofibroblasts in FA nephropathy. Additionally, the benzodiazepine receptor antagonist PK-11195 partially reversed the protective effect of remimazolam on the FA-injured kidneys. Overall, remimazolam attenuates the inflammatory response and renal fibrosis development following FA-induced AKI, which may be related to the peripheral benzodiazepine receptor pathway.

Assessment of nonlinear dose-response relationships via nonparametric regression.

We propose a simple approach to assess whether a nonlinear parametric model is appropriate to depict the dose-response relationships and whether two parametric models can be applied to fit a dataset via nonparametric regression. The proposed approach can compensate for the ANOVA, which is sometimes conservative, and is very easy to implement. We illustrate the performance by analyzing experimental examples and a small simulation study.

A model of hybrid speciation process drawn from three new poplar species originating from distant hybridization between sections.

Although numerous studies have been conducted on hybrid speciation, our understanding of this process remains limited. Through an 18-year systematic investigation of all taxa of Populus on the Qinghai-Tibet Plateau, we discovered three new taxa with clear characteristics of sect. Leucoides. Further evidence was gathered from morphology, whole-genome bioinformatics, biogeography, and breeding to demonstrate synthetically that they all originated from distant hybridization between sect. Leucoides and sect. Tacamahaca. P. gonggaensis originated from the hybridization of P. lasiocarpa with P. cathayana, P. butuoensis from the hybridization of P. wilsonii with P. szechuanica, and P. dafengensis from the hybridization of P. lasiocarpa with P. szechuanica. Due to heterosis, the three hybrid taxa possess greater ecological adaptability than their ancestral species. We propose a hybrid speciation process model that incorporates orthogonal, reverse, and backcrossing events. This model can adequately explain some crucial evolutionary concerns, such as the nuclear-cytoplasmic conflict on phylogeny and the extinction of ancestral species within the distribution range of hybrid species.