Biomass burning records of the Shulehe Glacier No. 4 from Qilian Mountains, Northeastern Tibetan Plateau.

Biomass burning play a key role in the global carbon cycle by altering the atmospheric composition, and affect regional and global climate. Despite its importance, a very few high-resolution records are available worldwide, especially for recent climate change. This study analyzes levoglucosan, a specific tracer of biomass burning emissions, in a 38-year ice core retrieved from the Shulehe Glacier No. 4, northeastern Tibetan Plateau. The levoglucosan concentration in the Shulehe Glacier No. 4 ice core ranged from 0.1 to 55 ng mL-1, with an average concentration of 8 ± 8 ng mL-1. The concentrations showed a decreasing trend from 2002 to 2018. Meanwhile, regional wildfire activities in Central Asian also exhibited a declining trend during the same period, suggesting the potential correspondence between levoglucosan concentration of the Shulehe Glacier No. 4 ice core and the fire activity of Central Asia. Furthermore, a positive correlation also exists between the levoglucosan concentration of the Shulehe Glacier No. 4 ice core and the wildfire counts in Central Asia from 2002 to 2018. While backward air mass trajectory analysis and fire spots data showed a higher distribution of fire counts in South Asia compared to Central Asia, but the dominance of westerly circulation in the northern TP throughout the year. Therefore, the levoglucosan in the Shulehe Glacier No. 4 provides clear evidence of Central Asian wildfire influence on Tibetan Plateau glaciers through westerlies. This highlights a great importance of ice core data for wildfire history reconstruction in the Tibetan Plateau Glacier regions.

Flow2GNN: Flexible Two-Way Flow Message Passing for Enhancing GNNs Beyond Homophily.

Message passing (MP) is crucial for effective graph neural networks (GNNs). Most local message-passing schemes have been shown to underperform on heterophily graphs due to the perturbation of updated representations caused by local redundant heterophily information. However, our experiment findings indicate that the distribution of heterophily information during MP can be disrupted by disentangling local neighborhoods. This finding can be applied to other GNNs, improving their performance on heterophily graphs in a more flexible manner compared to most heterophily GNNs with complex designs. This article proposes a new type of simple message-passing neural network called Flow2GNN. It uses a two-way flow message-passing scheme to enhance the ability of GNNs by disentangling and redistributing heterophily information in the topology space and the attribute space. Our proposed message-passing scheme consists of two steps in topology space and attribute space. First, we introduce a new disentangled operator with binary elements that disentangle topology information in-flow and out-flow between connected nodes. Second, we use an adaptive aggregation model that adjusts the flow amount between homophily and heterophily attribute information. Furthermore, we rigorously prove that disentangling in message-passing can reduce the generalization gap, offering a deeper understanding of how our model enhances other GNNs. The extensive experiment results show that the proposed model, Flow2GNN, not only outperforms state-of-the-art GNNs, but also helps improve the performance of other commonly used GNNs on heterophily graphs, including GCN, GAT, GCNII, and H 2 GCN, specifically for GCN, with up to a 25.88% improvement on the Wisconsin dataset.

The diversity and risk of potential pathogenic bacteria on the surface of glaciers in the southeastern Tibetan Plateau.

Glaciers, which constitute the world's largest global freshwater reservoir, are also natural microbial repositories. The frequent pandemic in recent years underscored the potential biosafety risks associated with the release of microorganisms from the accelerated melting of glaciers due to global warming. However, the characteristics of pathogenic microorganisms in glaciers are not well understood. The glacier surface is the primary area where glacier melting occurs that is often the main subject of research on the dynamics of pathogenic microbial communities in efforts to assess glacier biosafety risks and devise preventive measures. In this study, high-throughput sequencing and quantitative polymerase chain reaction methods were employed in analyses of the composition and quantities of potential pathogenic bacteria on the surfaces of glaciers in the southeastern Tibetan Plateau. The study identified 441 potential pathogenic species ranging from 215 to 4.39 × 1011 copies/g, with notable seasonal and environmental variations being found in the composition and quantity of potential pathogens. The highest level of diversity was observed in April and snow, while the highest quantities were observed in October and cryoconite. Host analysis revealed that >70 % of the species were pathogens affecting animals, with the highest proportion of zoonotic pathogens being observed in April. Analysis of aerosols and glacial meltwater dispersion suggested that these microbes originated from West Asia, primarily affecting the central and southern regions of China. Null model analysis indicated that the assembly of potential pathogenic microbial communities on glacier surfaces was largely governed by deterministic processes. In conclusion, potential pathogenic bacteria on glacier surfaces mainly originated from the snow and exhibited significant temporal and spatial variation patterns. These findings can be used to enhance researchers' ability to predict potential biosafety risks associated with pathogenic bacteria in glaciers and to prevent their negative impact on populations and ecological systems.

The SAMHD1-MX2 axis restricts HIV-1 infection at postviral DNA synthesis.

HIV-1 replication is tightly regulated in host cells, and various restriction factors have important roles in inhibiting viral replication. SAMHD1, a well-known restriction factor, suppresses HIV-1 replication by hydrolyzing intracellular dNTPs, thereby limiting the synthesis of viral cDNA in quiescent cells. In this study, we revealed an additional and distinct mechanism of SAMHD1 inhibition during the postviral cDNA synthesis stage. Using immunoprecipitation and mass spectrometry analysis, we demonstrated the interaction between SAMHD1 and MX2/MxB, an interferon-induced antiviral factor that inhibits HIV-1 cDNA nuclear import. The disruption of endogenous MX2 expression significantly weakened the ability of SAMHD1 to inhibit HIV-1. The crucial region within SAMHD1 that binds to MX2 has been identified. Notably, we found that SAMHD1 can act as a sensor that recognizes and binds to the incoming HIV-1 core, subsequently delivering it to the molecular trap formed by MX2, thereby blocking the nuclear entry of the HIV-1 core structure. SAMHD1 mutants unable to recognize the HIV-1 core showed a substantial decrease in antiviral activity. Certain mutations in HIV-1 capsids confer resistance to MX2 inhibition while maintaining susceptibility to suppression by the SAMHD1-MX2 axis. Overall, our study identifies an intriguing antiviral pattern wherein two distinct restriction factors, SAMHD1 and MX2, collaborate to establish an alternative mechanism deviating from their actions. These findings provide valuable insight into the complex immune defense networks against exogenous viral infections and have implications for the development of targeted anti-HIV therapeutics. IMPORTANCE: In contrast to most restriction factors that directly bind to viral components to exert their antiviral effects, SAMHD1, the only known deoxynucleotide triphosphate (dNTP) hydrolase in eukaryotes, indirectly inhibits viral replication in quiescent cells by reducing the pool of dNTP substrates available for viral cDNA synthesis. Our study provides a novel perspective on the antiviral functions of SAMHD1. In addition to its role in dNTP hydrolysis, SAMHD1 cooperates with MX2 to inhibit HIV-1 nuclear import. In this process, SAMHD1 acts as a sensor for incoming HIV-1 cores, detecting and binding to them, before subsequently delivering the complex to the molecular trap formed by MX2, thereby immobilizing the virus. This study not only reveals a new antiviral pathway for SAMHD1 but also identifies a unique collaboration and interaction between two distinct restriction factors, establishing a novel line of defense against HIV-1 infection, which challenges the traditional view of restriction factors acting independently. Overall, our findings further indicate the intricate complexity of the host immune defense network and provide potential targets for promoting host antiviral immune defense.

Evaluating the Role of Neddylation Modifications in Kidney Renal Clear Cell Carcinoma: An Integrated Approach Using Bioinformatics, MLN4924 Dosing Experiments, and RNA Sequencing.

BACKGROUND: Neddylation, a post-translational modification process, plays a crucial role in various human neoplasms. However, its connection with kidney renal clear cell carcinoma (KIRC) remains under-researched. METHODS: We validated the Gene Set Cancer Analysis Lite (GSCALite) platform against The Cancer Genome Atlas (TCGA) database, analyzing 33 cancer types and their link with 17 neddylation-related genes. This included examining copy number variations (CNVs), single nucleotide variations (SNVs), mRNA expression, cellular pathway involvement, and methylation. Using Gene Set Variation Analysis (GSVA), we categorized these genes into three clusters and examined their impact on KIRC patient prognosis, drug responses, immune infiltration, and oncogenic pathways. Afterward, our objective is to identify genes that exhibit overexpression in KIRC and are associated with an adverse prognosis. After pinpointing the specific target gene, we used the specific inhibitor MLN4924 to inhibit the neddylation pathway to conduct RNA sequencing and related in vitro experiments to verify and study the specificity and potential mechanisms related to the target. This approach is geared towards enhancing our understanding of the prognostic importance of neddylation modification in KIRC. RESULTS: We identified significant CNV, SNV, and methylation events in neddylation-related genes across various cancers, with notably higher expression levels observed in KIRC. Cluster analysis revealed a potential trade-off in the interactions among neddylation-related genes, where both high and low levels of gene expression are linked to adverse prognoses. This association is particularly pronounced concerning lymph node involvement, T stage classification, and Fustat score. Simultaneously, our research discovered that PSMB10 exhibits overexpression in KIRC when compared to normal tissues, negatively impacting patient prognosis. Through RNA sequencing and in vitro assays, we confirmed that the inhibition of neddylation modification could play a role in the regulation of various signaling pathways, thereby influencing the prognosis of KIRC. Moreover, our results underscore PSMB10 as a viable target for therapeutic intervention in KIRC, opening up novel pathways for the development of targeted treatment strategies. CONCLUSION: This study underscores the regulatory function and potential mechanism of neddylation modification on the phenotype of KIRC, identifying PSMB10 as a key regulatory target with a significant role in influencing the prognosis of KIRC.

Efficacy and safety of oral ibrexafungerp in Chinese patients with vulvovaginal candidiasis: a phase III, randomized, double-blind study.

PURPOSE: To evaluate the efficacy and safety of oral ibrexafungerp (HS-10366) versus placebo in Chinese patients with vulvovaginal candidiasis (VVC). METHODS: A double-blind, placebo-controlled, randomized, multicenter phase III study was conducted in symptomatic VVC patients. Patients received (2:1) twice-daily oral ibrexafungerp 300 mg or matching placebo for 1 day. The primary endpoint was clinical cure (vulvovaginal signs and symptoms [VSS] score = 0) at test-of-cure (TOC) on day 11 ± 3. The secondary endpoints included mycological eradication, overall response, and clinical improvement (VSS score ≤ 1) at TOC, and vulvovaginal symptom resolution at follow-up on day 25 ± 4. RESULTS: In total, 360 patients were included in the modified intention-to-treat set (defined as positive Candida cultured and receiving at least one study drug; 239 for ibrexafungerp, 121 for placebo). Compared with placebo, patients receiving ibrexafungerp had a significantly higher proportion of clinical cure (51.0% vs. 25.6%), mycological eradication (55.6% vs. 18.2%), overall response (33.9%, vs. 8.3%) at TOC and complete symptom resolution (74.5% vs. 39.7%, all P < 0.001) at follow-up. Subgroup analysis of clinical cure indicated that patients with C. albicans could benefit from ibrexafungerp over placebo. A similar benefit trend was also observed in those with non-albicans Candida by post-hoc analysis. Further analyses revealed similar efficacy of ibrexafungerp between patients with fluconazole non-susceptible C. albicans and fluconazole susceptible C. albicans regarding clinical cure and mycological eradication. Ibrexafungerp was generally well tolerated. Adverse events were primarily gastrointestinal and were mainly mild in severity. CONCLUSIONS: As a first-in-class antifungal agent, ibrexafungerp demonstrated promising efficacy and favorable safety for VVC treatment in Chinese patients. CHINADRUGTRIALS.ORG. CN REGISTRY NUMBER: CTR20220918.

South and Southeast Asia controls black carbon characteristics of Meili Snow Mountains in southeast Tibetan Plateau.

South and Southeast Asia (SSA) emitted black carbon (BC) exerts potential effects on glacier and snow melting and regional climate change in the Tibetan Plateau. In this study, online BC measurements were conducted for 1 year at a remote village located at the terminus of the Mingyong Glacier below the Meili Snow Mountains. The Weather Research and Forecasting model coupled with Chemistry (WRF-Chem) was used to investigate the contribution and potential effect of SSA-emitted BC. In addition, variations in the light absorption characteristics of BC and brown carbon (BrC) were examined. The results indicated that the annual mean concentration of BC was 415 ± 372 ngm-3, with the highest concentration observed in April (monthly mean: 930 ± 484 ngm-3). BC exhibited a similar diurnal variation throughout the year, with two peaks observed in the morning (from 8:00 to 9:00 AM) and in the afternoon (from 4:00 to 5:00 PM), with even lower values at nighttime. At a short wavelength of 370 nm, the absorption coefficient (babs) reached its maximum value, and the majority of babs values were < 20 Mm-1, indicating that the atmosphere was not overloaded with BC. At the same wavelength, BrC substantially contributed to babs, with an annual mean of 25.2 % ± 12.8 %. SSA was the largest contributor of BC (annual mean: 51.1 %) in the study area, particularly in spring (65.6 %). However, its contributions reached 20.2 % in summer, indicating non-negligible emissions from activities in other regions. In the atmosphere, the SSA BC-induced radiative forcing (RF) over the study region was positive. While at the near surface, the RF exhibited a significant seasonal variation, with the larger RF values occurring in winter and spring. Overall, our findings highlight the importance of controlling BC emissions from SSA to protect the Tibetan Plateau against pollution-related glacier and snow cover melting.

Frontiers in sarcopenia: Advancements in diagnostics, molecular mechanisms, and therapeutic strategies.

The onset of sarcopenia is intimately linked with aging, posing significant implications not only for individual patient quality of life but also for the broader societal healthcare framework. Early and accurate identification of sarcopenia and a comprehensive understanding of its mechanistic underpinnings and therapeutic targets paramount to addressing this condition effectively. This review endeavors to present a cohesive overview of recent advancements in sarcopenia research and diagnosis. We initially delve into the contemporary diagnostic criteria, specifically referencing the European Working Group on Sarcopenia in Older People (EWGSOP) 2 and Asian Working Group on Sarcopenia (AWGS) 2019 benchmarks. Additionally, we elucidate comprehensive assessment techniques for muscle strength, quantity, and physical performance, highlighting tools such as grip strength, chair stand test, dual-energy X-ray Absorptiometry (DEXA), bioelectrical impedance analysis (BIA), gait speed, and short physical performance battery (SPPB), while also discussing their inherent advantages and limitations. Such diagnostic advancements pave the way for early identification and unequivocal diagnosis of sarcopenia. Proceeding further, we provide a deep-dive into sarcopenia's pathogenesis, offering a thorough examination of associated signaling pathways like the Myostatin, AMP-activated protein kinase (AMPK), insulin/IGF-1 Signaling (IIS), and the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathways. Each pathway's role in sarcopenia mediation is detailed, underscoring potential therapeutic target avenues. From a mechanistic perspective, the review also underscores the pivotal role of mitochondrial dysfunction in sarcopenia, emphasizing elements such as mitochondrial oxidative overload, mitochondrial biogenesis, and mitophagy, and highlighting their therapeutic significance. At last, we capture recent strides made in sarcopenia treatment, ranging from nutritional and exercise interventions to potential pharmacological and supplementation strategies. In sum, this review meticulously synthesizes the latest scientific developments in sarcopenia, aiming to enhance diagnostic precision in clinical practice and provide comprehensive insights into refined mechanistic targets and innovative therapeutic interventions, ultimately contributing to optimized patient care and advancements in the field.

The potential value of the Purinergic pathway in the prognostic assessment and clinical application of kidney renal clear cell carcinoma.

The Purinergic pathway is involved in a variety of important physiological processes in living organisms, and previous studies have shown that aberrant expression of the Purinergic pathway may contribute to the development of a variety of cancers, including kidney renal clear cell carcinoma (KIRC). The aim of this study was to delve into the Purinergic pathway in KIRC and to investigate its potential significance in prognostic assessment and clinical treatment. 33 genes associated with the Purinergic pathway were selected for pan-cancer analysis. Cluster analysis, targeted drug sensitivity analysis and immune cell infiltration analysis were applied to explore the mechanism of Purinergic pathway in KIRC. Using the machine learning process, we found that combining the Lasso+survivalSVM algorithm worked well for predicting survival accuracy in KIRC. We used LASSO regression to pinpoint nine Purinergic genes closely linked to KIRC, using them to create a survival model for KIRC. ROC survival curve was analyzed, and this survival model could effectively predict the survival rate of KIRC patients in the next 5, 7 and 10 years. Further univariate and multivariate Cox regression analyses revealed that age, grading, staging, and risk scores of KIRC patients were significantly associated with their prognostic survival and were identified as independent risk factors for prognosis. The nomogram tool developed through this study can help physicians accurately assess patient prognosis and provide guidance for developing treatment plans. The results of this study may bring new ideas for optimizing the prognostic assessment and therapeutic approaches for KIRC patients.

Oteseconazole versus fluconazole for the treatment of severe vulvovaginal candidiasis: a multicenter, randomized, double-blinded, phase 3 trial.

Vulvovaginal candidiasis (VVC) is a common condition among women. Fluconazole remains the dominant treatment option for VVC. Oteseconazole is a highly selective inhibitor of fungal CYP51. This randomized, double-blinded, phase 3 trial was conducted to evaluate the efficacy and safety of oteseconazole compared with fluconazole in treating severe VVC. Female subjects presenting with vulvovaginal signs and symptoms score of ≥7 and positive Candida infection determined by potassium hydroxide test or Gram staining were randomly assigned to receive oteseconazole (600 mg on D1 and 450 mg on D2) or fluconazole (150 mg on D1 and D4) in a 1:1 ratio. The primary endpoint was the proportion of subjects achieving therapeutic cure [defined as achieving both clinical cure (absence of signs and symptoms of VVC) and mycological cure (negative culture of Candida species)] at D28. A total of 322 subjects were randomized and 321 subjects were treated. At D28, a statistically significantly higher proportion of subjects achieved therapeutic cure in the oteseconazole group than in the fluconazole group (66.88% vs 45.91%; P = 0.0002). Oteseconazole treatment resulted in an increased proportion of subjects achieving mycological cure (82.50% vs 59.12%; P < 0.0001) and clinical cure (71.25% vs 55.97%; P = 0.0046) compared with fluconazole. The incidence of treatment-emergent adverse events was similar between the two groups. No subjects discontinued study treatment or withdrew study due to adverse events. Oteseconazole showed statistically significant and clinically meaningful superiority over fluconazole for the treatment of severe VVC and was generally tolerated.

Tailoring Broadband Nonlinear Optical Characteristics and Ultrafast Photocarrier Dynamics of Bi2O2S Nanosheets by Defect Engineering.

Low-dimensional bismuth oxychalcogenides have shown promising potential in optoelectronics due to their high stability, photoresponse, and carrier mobility. However, the relevant studies on deep understanding for Bi2O2S is quite limited. Here, comprehensive experimental and computational investigations are conducted in the regulated band structure, nonlinear optical (NLO) characteristics, and carrier dynamics of Bi2O2S nanosheets via defect engineering, taking O vacancy (OV) and substitutional Se doping as examples. As the OV continuously increased to ≈35%, the optical bandgaps progressively narrow from ≈1.21 to ≈0.81 eV and NLO wavelengths are extended to near-infrared regions with enhanced saturable absorption. Simultaneously, the relaxation processes are effectively accelerated from tens of picoseconds to several picoseconds, as the generated defect energy levels can serve as both additional absorption cross-sections and fast relaxation channels supported by theoretical calculations. Furthermore, substitutional Se doping in Bi2O2S nanosheets also modulate their optical properties with the similar trends. As a proof-of-concept, passively mode-locked pulsed lasers in the ≈1.0 µm based on the defect-rich samples (≈35% OV and ≈50% Se-doping) exhibit excellent performance. This work deepens the insight of defect functions on optical properties of Bi2O2S nanosheets and provides new avenues for designing advanced photonic devices based on low-dimensional bismuth oxychalcogenides.

Evaluation of the diagnostic utility on 1.5T and 3.0T 1H magnetic resonance spectroscopy for temporal lobe epilepsy.

BACKGROUND: 1H magnetic resonance spectroscopy (1H-MRS) can be used to study neurological disorders because it can be utilized to examine the concentrations of related metabolites. However, the diagnostic utility of different field strengths for temporal lobe epilepsy (TLE) remains unclear. The purpose of this study is to make quantitative comparisons of metabolites of TLE at 1.5T and 3.0T and evaluate their efficacy. METHODS: Our retrospective collections included the single-voxel 1H-MRS of 23 TLE patients and 17 healthy control volunteers (HCs) with a 1.5T scanner, as well as 29 TLE patients and 17 HCs with a 3.0T scanner. Particularly, HCs were involved both the scans with 1.5T and 3.0T scanners, respectively. The metabolites, including the N-acetylaspartate (NAA), creatine (Cr), and choline (Cho), were measured in the left or right temporal pole of brain. To analyze the ratio of brain metabolites, including NAA/Cr, NAA/Cho, NAA/(Cho + Cr) and Cho/Cr, four controlled experiments were designed to evaluate the diagnostic utility of TLE on 1.5T and 3.0T MRS, included: (1) 1.5T TLE group vs. 1.5T HCs by the Mann-Whitney U Test, (2) 3.0T TLE group vs. 3.0T HCs by the Mann-Whitney U Test, (3) the power analysis for the 1.5T and 3.0T scanner, and (4) 3.0T HCs vs. 1.5T HCs by Paired T-Test. RESULTS: Three metabolite ratios (NAA/Cr, NAA/Cho, and NAA/(Cho + Cr) showed the same statistical difference (p < 0.05) in distinguishing the TLE from HCs in the bilateral temporal poles when using 1.5T or 3.0T scanners. Similarly, the power analysis demonstrated that four metabolite ratios (NAA/Cr, NAA/Cho, NAA/(Cho + Cr), Cho/Cr) had similar distinction abilities between 1.5T and 3.0T scanner, denoting both 1.5T and 3.0T scanners were provided with similar sensitivities and reproducibilities for metabolites detection. Moreover, the metabolite ratios of the same healthy volunteers were not statistically different between 1.5T and 3.0T scanners, except for NAA/Cho (p < 0.05). CONCLUSIONS: 1.5T and 3.0T scanners may have comparable diagnostic potential when 1H-MRS was used to diagnose patients with TLE.

Confounders of Serum Phosphatidylethanol: Role of Red Blood Cell Turnover and Cirrhosis.

Purpose: Ethyl glucuronide (EtG), ethyl sulfate (EtS) and phosphatidylethanol (PEth) are considered specific direct biomarkers for detecting alcohol consumption. However, PEth, which is produced in red blood cells (RBC), varies considerably between patients for unknown reasons. We here studied various confounders of PEth elimination including fibrosis after alcohol withdrawal. Patients and Methods: EtG, EtS and PEth together with routine laboratory and clinical parameters were studied in 100 Caucasian heavy drinkers prior and after alcohol detoxification. In addition, fibrosis stage and degree of steatosis were assessed by transient elastography (Fibroscan, Echosens, Paris). Results: All three biomarkers were highly correlated (0.61-0.72) with initial serum alcohol levels, but only PEth correlated with daily alcohol consumption. After alcohol withdrawal, PEth significantly decreased within 6.1 days from 1708 to 810 ng/mL (half-life varied from 1.6 to 15.2 days). Both levels of serum alcohol but also EtG and EtS were higher in patients with liver cirrhosis as compared to patients without fibrosis despite comparable alcohol consumption suggesting a decreased alcohol elimination in patients with cirrhosis. PEth was also elevated in cirrhosis but not significantly. In contrast, PEth elimination rate was significantly higher in patients with enhanced RBC turnover and signs of alcohol-mediated hemolytic anemia with elevated ferritin, LDH and increased mean corpuscular volume (MCV). Conclusion: We here demonstrate that alcohol elimination is decreased in patients with liver cirrhosis. In patients with cirrhosis, PEth levels are both affected in opposite directions by enhanced red blood cell turnover and elevated alcohol levels. Our data have important implications for the use and interpretation of PEth in the clinical setting.

The mechanism and clinical application of DNA damage repair inhibitors combined with immune checkpoint inhibitors in the treatment of urologic cancer.

Urologic cancers such as kidney, bladder, prostate, and uroepithelial cancers have recently become a considerable global health burden, and the response to immunotherapy is limited due to immune escape and immune resistance. Therefore, it is crucial to find appropriate and effective combination therapies to improve the sensitivity of patients to immunotherapy. DNA damage repair inhibitors can enhance the immunogenicity of tumor cells by increasing tumor mutational burden and neoantigen expression, activating immune-related signaling pathways, regulating PD-L1 expression, and reversing the immunosuppressive tumor microenvironment to activate the immune system and enhance the efficacy of immunotherapy. Based on promising experimental results from preclinical studies, many clinical trials combining DNA damage repair inhibitors (e.g., PARP inhibitors and ATR inhibitors) with immune checkpoint inhibitors (e.g., PD-1/PD-L1 inhibitors) are underway in patients with urologic cancers. Results from several clinical trials have shown that the combination of DNA damage repair inhibitors with immune checkpoint inhibitors can improve objective rates, progression-free survival, and overall survival (OS) in patients with urologic tumors, especially in patients with defective DNA damage repair genes or a high mutational load. In this review, we present the results of preclinical and clinical trials of different DNA damage repair inhibitors in combination with immune checkpoint inhibitors in urologic cancers and summarize the potential mechanism of action of the combination therapy. Finally, we also discuss the challenges of dose toxicity, biomarker selection, drug tolerance, drug interactions in the treatment of urologic tumors with this combination therapy and look into the future direction of this combination therapy.

The opening of high-speed rail and environmental pollution of the Yangtze River Delta Region in China-based on SDID model test.

In recent years, environmental problems have attracted attention at home and abroad, so exploring the causes of environmental pollution has become a research content for scholars. The opening of high-speed railway has improved the economic development of China's Yangtze River Delta, and with the economic growth, the construction of high-speed railway has also led to environmental pollution in China's Yangtze River Delta. Therefore, using the data from 41 prefecture-level cities in China's Yangtze River Delta from 2003 to 2020, the SDID model was constructed, and the comprehensive index of environmental pollution was calculated by factor analysis to calculate the impact of high-speed railway construction on environmental pollution in China's Yangtze River Delta. The conclusions are as follows: The opening of high-speed railway significantly reduces the overall pollution level in China's Yangtze River Delta. The opening of high-speed rail has played a role in restraining the environmental pollution of the first and second tier cities and the third and fourth tier cities, but the pollution level of the third and fourth tier cities has decreased significantly.

Advances in early detection methods for solid tumors.

During the last decade, non-invasive methods such as liquid biopsy have slowly replaced traditional imaging and invasive pathological methods used to diagnose and monitor cancer. Improvements in the available detection methods have enabled the early screening and diagnosis of solid tumors. In addition, advances in early detection methods have made the continuous monitoring of tumor progression using repeat sampling possible. Previously, the focus of liquid biopsy techniques included the following: 1) the isolation of circulating tumor cells, circulating tumor DNA, and extracellular tumor vesicles from solid tumor cells in the patient's blood; in addition to 2) analyzing genomic and proteomic data contained within the isolates. Recently, there has been a rapid devolvement in the techniques used to isolate and analyze molecular markers. This rapid evolvement in detection techniques improves their accuracy, especially when few samples are available. In addition, there is a tremendous expansion in the acquisition of samples and targets for testing; solid tumors can be detected from blood and other body fluids. Test objects have also expanded from samples taken directly from cancer to include indirect objects affected in cancer development. Liquid biopsy technology has limitations. Even so, this detection technique is the key to a new phase of oncogenetics. This review aims to provide an overview of the current advances in liquid biopsy marker selection, isolation, and detection methods for solid tumors. The advantages and disadvantages of liquid biopsy technology will also be explored.

Impact of spatial structure of urban agglomerations on PM2.5 pollution：Based on resource misallocation.

The spatial structure of urban agglomerations affects the economic development and environmental conditions of urban agglomerations. Severe air pollution makes green development an empty talk, and how the spatial structure of urban agglomerations affects air pollution is an urgent problem to be solved in pursuit of high-quality economic development. The panel data of 20 urban agglomerations in China from 2002 to 2017 are used to test how the spatial structure of urban agglomerations affects regional PM2.5 concentration in resource misallocation mediation effect. The empirical results show that (1) most urban agglomerations are polycentric, and only Guanzhong, Poyang Lake Ring, Wuhan and Nanqin Beifang urban agglomerations are monocentric. (2) The spatial structure and PM2.5 concentration have U-shaped characteristics, with the inflection point of centrality equal to 1. To reduce PM2.5 concentration in polycentric urban agglomerations can be achieved by increasing the centrality, while the opposite is true for monocentric urban agglomerations. (3) Improving the resource allocation of urban agglomerations can reduce PM2.5 concentration. The spatial structure of urban agglomerations with a limited degree of centrality can improve the resource allocation of urban agglomerations and further reduce PM2.5 pollution. This also indicates to a certain extent that a reasonable spatial structure of urban agglomerations is conducive to optimizing resource allocation and improving air pollution.

Regulatory roles of ferroptosis-related non-coding RNAs and their research progress in urological malignancies.

Ferroptosis is a new type of cell death characterized by damage to the intracellular microenvironment, which causes the accumulation of lipid hydroperoxide and reactive oxygen species to cause cytotoxicity and regulated cell death. Non-coding RNAs (ncRNAs) play an important role in gene expression at the epigenetic, transcriptional, and post-transcriptional levels through interactions with different DNAs, RNAs, or proteins. Increasing evidence has shown that ferroptosis-related ncRNAs are closely related to the occurrence and progression of several diseases, including urological malignancies. Recently, the role of ferroptosis-associated ncRNAs (long non-coding RNAs, micro RNAs, and circular RNAs) in the occurrence, drug resistance, and prognosis of urological malignancies has attracted widespread attention. However, this has not yet been addressed systematically. In this review, we discuss this issue as much as possible to expand the knowledge and understanding of urological malignancies to provide new ideas for exploring the diagnosis and treatment of urological malignancies in the future. Furthermore, we propose some challenges in the clinical application of ferroptosis-associated ncRNAs.