Modulate synthesis of CeMn solid solution using various alcohols for toluene catalytic oxidation: synergistic effect of Ce-Mn and reaction mechanism.

A redox co-precipitation method was employed to synthesize CeMn homogeneous solid solutions, utilizing various alcohols as activating agents. Ethanol effectively orchestrated the precipitation of CeO2 and MnOx, promoting their co-growth. As a result, the CeMn-EA achieved 90 % toluene conversion at 218 â„ƒ (T90 =218 â„ƒ) with a weight hourly space velocity (WHSV) of 48000 ml/(g·h). It also demonstrated high adaptability to increased WHSV, suggesting its potential for industrial-scale applications. The uniform dispersion of Ce and Mn accelerated the coupling between Ce3+/Ce4+ and Mn4+/Mn3+, engineering numerous oxygen vacancies, which enhanced the activation of gas-phase oxygen and the mobility of lattice oxygen. In situ DRIFTS confirmed that toluene oxidation accommodated both Langmuir-Hinshelwood (L-H) and Mars-van Krevelen (MvK) mechanisms, with benzoate identified as a pivotal intermediate. Enhanced oxygen mobility facilitated the cleavage of the benzene ring, which was the rate-determining step. Additionally, the introduction of H2O significantly enhanced the dissociation and adsorption of toluene and facilitated the activation of gas-phase oxygen. At higher temperatures, H2O could further activate lattice oxygen engaging in toluene oxidation. ENVIRONMENTAL IMPLICATION: Volatile organic compounds (VOCs) have emerged as major air pollutants due to the changes in air pollution patterns. They can act as precursors to near-surface ozone and haze. Toluene, a typical VOC, is primarily released from anthropogenic sources and poses significant risks to human health and the environment. Ce-based catalysts have been demonstrated efficiency in toluene oxidation due to their excellent oxygen storage and release properties. This study synthesized CeMn homogeneous solid solutions utilizing various alcohols as activating agents, which possessed abundant oxygen vacancies and optimum oxygen activation capacity to oxidize toluene in time.

Data Set and Benchmark (MedGPTEval) to Evaluate Responses From Large Language Models in Medicine: Evaluation Development and Validation.

Background: Large language models (LLMs) have achieved great progress in natural language processing tasks and demonstrated the potential for use in clinical applications. Despite their capabilities, LLMs in the medical domain are prone to generating hallucinations (not fully reliable responses). Hallucinations in LLMs' responses create substantial risks, potentially threatening patients' physical safety. Thus, to perceive and prevent this safety risk, it is essential to evaluate LLMs in the medical domain and build a systematic evaluation. Objective: We developed a comprehensive evaluation system, MedGPTEval, composed of criteria, medical data sets in Chinese, and publicly available benchmarks. Methods: First, a set of evaluation criteria was designed based on a comprehensive literature review. Second, existing candidate criteria were optimized by using a Delphi method with 5 experts in medicine and engineering. Third, 3 clinical experts designed medical data sets to interact with LLMs. Finally, benchmarking experiments were conducted on the data sets. The responses generated by chatbots based on LLMs were recorded for blind evaluations by 5 licensed medical experts. The evaluation criteria that were obtained covered medical professional capabilities, social comprehensive capabilities, contextual capabilities, and computational robustness, with 16 detailed indicators. The medical data sets include 27 medical dialogues and 7 case reports in Chinese. Three chatbots were evaluated: ChatGPT by OpenAI; ERNIE Bot by Baidu, Inc; and Doctor PuJiang (Dr PJ) by Shanghai Artificial Intelligence Laboratory. Results: Dr PJ outperformed ChatGPT and ERNIE Bot in the multiple-turn medical dialogues and case report scenarios. Dr PJ also outperformed ChatGPT in the semantic consistency rate and complete error rate category, indicating better robustness. However, Dr PJ had slightly lower scores in medical professional capabilities compared with ChatGPT in the multiple-turn dialogue scenario. Conclusions: MedGPTEval provides comprehensive criteria to evaluate chatbots by LLMs in the medical domain, open-source data sets, and benchmarks assessing 3 LLMs. Experimental results demonstrate that Dr PJ outperforms ChatGPT and ERNIE Bot in social and professional contexts. Therefore, such an assessment system can be easily adopted by researchers in this community to augment an open-source data set.

Branched-Chain Amino Acids Deficiency Promotes Diabetic Neuropathic Pain Through Upregulating LAT1 and Inhibiting Kv1.2 Channel.

Diabetic neuropathic pain (DNP), one of the most common complications of diabetes, is characterized by bilateral symmetrical distal limb pain and substantial morbidity. To compare the differences  is aimed at serum metabolite levels between 81 DNP and 73 T2DM patients without neuropathy and found that the levels of branched-chain amino acids (BCAA) are significantly lower in DNP patients than in T2DM patients. In high-fat diet/low-dose streptozotocin (HFD/STZ)-induced T2DM and leptin receptor-deficient diabetic (db/db) mouse models, it is verified that BCAA deficiency aggravated, whereas BCAA supplementation alleviated DNP symptoms. Mechanistically, using a combination of RNA sequencing of mouse dorsal root ganglion (DRG) tissues and label-free quantitative proteomic analysis of cultured cells, it is found that BCAA deficiency activated the expression of L-type amino acid transporter 1 (LAT1) through ATF4, which is reversed by BCAA supplementation. Abnormally upregulated LAT1 reduced Kv1.2 localization to the cell membrane, and inhibited Kv1.2 channels, thereby increasing neuronal excitability and causing neuropathy. Furthermore, intraperitoneal injection of the LAT1 inhibitor, BCH, alleviated DNP symptoms in mice, confirming that BCAA-deficiency-induced LAT1 activation contributes to the onset of DNP. These findings provide fresh insights into the metabolic differences between DNP and T2DM, and the development of approaches for the management of DNP.

PI3Kγ inhibition circumvents inflammation and vascular leak in SARS-CoV-2 and other infections.

Virulent infectious agents such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and methicillin-resistant Staphylococcus aureus (MRSA) induce tissue damage that recruits neutrophils, monocyte, and macrophages, leading to T cell exhaustion, fibrosis, vascular leak, epithelial cell depletion, and fatal organ damage. Neutrophils, monocytes, and macrophages recruited to pathogen-infected lungs, including SARS-CoV-2-infected lungs, express phosphatidylinositol 3-kinase gamma (PI3Kγ), a signaling protein that coordinates both granulocyte and monocyte trafficking to diseased tissues and immune-suppressive, profibrotic transcription in myeloid cells. PI3Kγ deletion and inhibition with the clinical PI3Kγ inhibitor eganelisib promoted survival in models of infectious diseases, including SARS-CoV-2 and MRSA, by suppressing inflammation, vascular leak, organ damage, and cytokine storm. These results demonstrate essential roles for PI3Kγ in inflammatory lung disease and support the potential use of PI3Kγ inhibitors to suppress inflammation in severe infectious diseases.

Characterization of active alkaloids and metabolites in rats after oral administration of Zuojin Pill using UHPLC-Q-TOF-MS combined with bioinformatics and molecular docking analyses.

Zuojin Pill (ZJP), a traditional Chinese medicine prescription composed of Rhizoma Coptidis and Euodiae Fructus in the ratio of 6:1 (w/w), has been widely used for the treatment of gastric disorders. However, an in-depth understanding of in vivo metabolism and distribution profiles of protoberberine alkaloids (PBAs) and indole alkaloids (IDAs) in ZJP is lacking. In this study, a method using ultra-high performance liquid chromatography coupled with quadruple time-of-flight mass spectrometry (UHPLC-Q-TOF-MS) was developed to systematically screen the alkaloids and their metabolites in rat plasma and various tissues after oral administration of ZJP. Furthermore, bioinformatics and molecular docking analyses were conducted to elucidate the contribution of the alkaloids and metabolites enriched in the stomach to the therapeutic effect of ZJP on gastritis. A total of 33 compounds, including 7 prototype alkaloids and 26 metabolites, were chemically defined or tentatively identified in this work. The metabolic pathways of PBAs (hydroxylation, oxidation, reduction, demethylation, demethylenation, glucuronide conjugation, sulfate conjugation) and IDAs (hydroxylation, glucuronide conjugation) were revealed. Notably, 7 prototype alkaloids and 18 metabolites were detected in the stomach, indicating their propensity for gastric distribution. These alkaloids and metabolites showed strong affinities with the 7 hub targets associated with gastritis, such as CCR7, CXCR4, IL6, IFNG, CCL2, TNF, and PTPRC, and could be considered the potential active substances of ZJP for treating gastritis. In conclusion, this study clarified the gastric distribution propensity of PBAs and IDAs and their metabolites, as well as their favorable binding interactions with gastritis-related targets, which could provide essential data for the further study of the pharmacodynamic material basis and gastroprotective mechanism of ZJP.

Biogenic silica in sediment core indicates the historical development of off-bottom oyster farming.

Sediment cores are commonly used for reconstructing historical events by determining the biogenic elements in sediment vertical profiles. The vertical flux of biogenic silica (BSi) can be enhanced by bivalve mollusks through biodeposition and can be subsequently recorded in the sediment core. However, whether BSi in sediment core can indicate the interactions between aquaculture farms and the ecosystem is unclear. In this study, sediment cores were collected from a typical off-bottom oyster farm in Sanggou Bay, China. Based on 210Pb chronology analysis of the sediment vertical profile, BSi content was determined to reflect the BSi burial flux during the farming history. The BSi biodeposition fluxes were estimated based on the biodeposition model, to identify the correspondence among BSi burial flux, BSi biodeposition flux, and annual oyster production during the historical development of the farm. The results show that the BSi density in the sediment increased obviously after 1980 when intensive oyster farming began, and reduced after 2000 when farming began to decline. Moreover, BSi burial flux had a corresponding relationship with oyster production and the simulated biodeposition rate, except for 1997-2001 when oyster production peaked. Our finding supported that the variation of BSi from biodeposition can be preserved and then recorded in the sediment, suggesting that BSi could be considered as an indicator to reconstruct the historical development of the oyster farm.

Colonization ability and uniformity of resources and environmental factors determine biological homogenization of soil protists in human land-use systems.

Humans have substantially transformed the global land surface, resulting in the decline in variation in biotic communities across scales, a phenomenon known as "biological homogenization." However, different biota are affected by biological homogenization to varying degrees, but this variation and the underlying mechanisms remain little studied, particularly in soil systems. To address this topic, we used metabarcoding to investigate the biogeography of soil protists and their prey/hosts (prokaryotes, fungi, and meso- and macrofauna) in three human land-use ecosystem types (farmlands, residential areas, and parks) and natural forest ecosystems across subtropical and temperate regions in China. Our results showed that the degree of community homogenization largely differed between taxa and functional groups of soil protists, and was strongly and positively linked to their colonization ability of human land-use systems. Removal analysis showed that the introduction of widespread, generalist taxa (OTUs, operational taxonomic units) rather than the loss of narrow-ranged, specialist OTUs was the major cause of biological homogenization. This increase in generalist OTUs seemingly alleviated the negative impact of land use on specialist taxa, but carried the risk of losing functional diversity. Finally, homogenization of prey/host biota and environmental conditions were also important drivers of biological homogenization in human land-use systems, with their importance being more pronounced in phagotrophic than parasitic and phototrophic protists. Overall, our study showed that the variation in biological homogenization strongly depends on the colonization ability of taxa in human land-use systems, but is also affected by the homogenization of resources and environmental conditions. Importantly, biological homogenization is not the major cause of the decline in the diversity of soil protists, and conservation and study efforts should target at taxa highly sensitive to local extinction, such as parasites.

ΔNp63α promotes cigarette smoke-induced renal cancer stem cell activity via the Sonic Hedgehog pathway.

Cigarette smoke (CS) has been generally recognized as a chief carcinogenic factor in renal cell carcinoma (RCC). The stimulative effect of CS on renal cancer stem cells (RCSCs) has been described previously. The Sonic Hedgehog (SHH) pathway plays an essential role in self-renewal, cell growth, drug resistance, metastasis, and recurrence of cancer stem cells (CSCs). Renal cancer-related gene ΔNp63α is highly expressed in renal epithelial tissues and contributes to the RCSCs characteristics of tumors. The aim of this study was to elucidate the role of ΔNp63α and the SHH pathway on the activity of RCSCs induced by CS through a series of in vivo and in vitro studies. It was shown that in renal cancer tissues, ΔNp63α and RCSCs markers in smokers are expressed higher than that in non-smokers. RCSCs were effectively enriched by tumor sphere formation assay. Besides, CS increased the expression of RCSCs markers and the capability of sphere-forming in vitro and in vivo. Moreover, the SHH pathway was activated, and the specialized inhibitor alleviated the promotion of CS on RCSCs. ΔNp63α activated the SHH pathway and promoted CS-induced enhancement of RCSCs activity. These findings indicate that ΔNp63α positively regulates the activity of CS-induced RCSCs via the SHH pathway.

Refining the optimal CAF cluster marker for predicting TME-dependent survival expectancy and treatment benefits in NSCLC patients.

The tumor microenvironment (TME) plays a pivotal role in the onset, progression, and treatment response of cancer. Among the various components of the TME, cancer-associated fibroblasts (CAFs) are key regulators of both immune and non-immune cellular functions. Leveraging single-cell RNA sequencing (scRNA) data, we have uncovered previously hidden and promising roles within this specific CAF subgroup, paving the way for its clinical application. However, several critical questions persist, primarily stemming from the heterogeneous nature of CAFs and the use of different fibroblast markers in various sample analyses, causing confusion and hindrance in their clinical implementation. In this groundbreaking study, we have systematically screened multiple databases to identify the most robust marker for distinguishing CAFs in lung cancer, with a particular focus on their potential use in early diagnosis, staging, and treatment response evaluation. Our investigation revealed that COL1A1, COL1A2, FAP, and PDGFRA are effective markers for characterizing CAF subgroups in most lung adenocarcinoma datasets. Through comprehensive analysis of treatment responses, we determined that COL1A1 stands out as the most effective indicator among all CAF markers. COL1A1 not only deciphers the TME signatures related to CAFs but also demonstrates a highly sensitive and specific correlation with treatment responses and multiple survival outcomes. For the first time, we have unveiled the distinct roles played by clusters of CAF markers in differentiating various TME groups. Our findings confirm the sensitive and unique contributions of CAFs to the responses of multiple lung cancer therapies. These insights significantly enhance our understanding of TME functions and drive the translational application of extensive scRNA sequence results. COL1A1 emerges as the most sensitive and specific marker for defining CAF subgroups in scRNA analysis. The CAF ratios represented by COL1A1 can potentially serve as a reliable predictor of treatment responses in clinical practice, thus providing valuable insights into the influential roles of TME components. This research marks a crucial step forward in revolutionizing our approach to cancer diagnosis and treatment.

3D-CT reconstruction for pedicle outer width assessment in patients with thoracolumbar spine fractures: a comparative analysis between age groups <60 years and ≥60 years.

Objective: This study aims to compare the utilization of 3D-CT reconstruction in measuring pedicle outer width (POW) between younger/middle-aged patients (<60 years) and older patients (≥60 years) with thoracolumbar spine fractures (TSF). Methods: We conducted a retrospective study from January 2021 to December 2022, involving a total of 108 patients with TSF. The study population consisted of 62 patients aged ≥60 years (observation group) and 46 patients aged <60 years (control group). We compared the POW on both the right and left sides of the thoracolumbar spine between the two groups. Additionally, we analyzed the POW by gender within each group and calculated the incidence of patients falling below the critical values for arch root puncture (5 mm) and arch root nailing (7 mm) in both groups. Results: There were no statistically significant differences observed in the POW between the two groups on both the left and right sides of each corresponding vertebra (P > 0.05). In the observation group, both male and female patients had significantly smaller POW compared to the control group (P < 0.05). However, no significant difference in POW was observed between the same-sex groups in the L4 to L5 vertebrae (P > 0.05). In the observation group, the POW was less than 5 mm in 9.33% (81/868) of cases and less than 7 mm in 49.88% (433/868) of cases, primarily observed from T11 to L3. In the control group, 4.81% (31/644) of cases had a POW of less than 5 mm, and 13.81% (88/644) had a POW of less than 7 mm. Conclusion: Utilizing preoperative 3D-CT reconstruction to measure POW in patients with TSF not only facilitates the assessment of surgical feasibility but also aids in surgical pathway planning, thus potentially reducing the incidence of postoperative complications.

A therapy for suppressing canonical and noncanonical SARS-CoV-2 viral entry and an intrinsic intrapulmonary inflammatory response.

The prevalence of "long COVID" is just one of the conundrums highlighting how little we know about the lung's response to viral infection, particularly to syndromecoronavirus-2 (SARS-CoV-2), for which the lung is the point of entry. We used an in vitro human lung system to enable a prospective, unbiased, sequential single-cell level analysis of pulmonary cell responses to infection by multiple SARS-CoV-2 strains. Starting with human induced pluripotent stem cells and emulating lung organogenesis, we generated and infected three-dimensional, multi-cell-type-containing lung organoids (LOs) and gained several unexpected insights. First, SARS-CoV-2 tropism is much broader than previously believed: Many lung cell types are infectable, if not through a canonical receptor-mediated route (e.g., via Angiotensin-converting encyme 2(ACE2)) then via a noncanonical "backdoor" route (via macropinocytosis, a form of endocytosis). Food and Drug Administration (FDA)-approved endocytosis blockers can abrogate such entry, suggesting adjunctive therapies. Regardless of the route of entry, the virus triggers a lung-autonomous, pulmonary epithelial cell-intrinsic, innate immune response involving interferons and cytokine/chemokine production in the absence of hematopoietic derivatives. The virus can spread rapidly throughout human LOs resulting in mitochondrial apoptosis mediated by the prosurvival protein Bcl-xL. This host cytopathic response to the virus may help explain persistent inflammatory signatures in a dysfunctional pulmonary environment of long COVID. The host response to the virus is, in significant part, dependent on pulmonary Surfactant Protein-B, which plays an unanticipated role in signal transduction, viral resistance, dampening of systemic inflammatory cytokine production, and minimizing apoptosis. Exogenous surfactant, in fact, can be broadly therapeutic.

Neoadjuvant therapy of sequential TACE, camrelizumab, and apatinib for single huge hepatocellular carcinoma (NEO-START): study protocol for a randomized controlled trial.

BACKGROUND: The high recurrence rate after liver resection emphasizes the urgent need for neoadjuvant therapy in hepatocellular carcinoma (HCC) to enhance the overall prognosis for patients. Immune checkpoint inhibitors, camrelizumab combined with an anti-angiogenic tyrosine kinase inhibitor (TKI) apatinib, have emerged as a first-line treatment option for patients with unresectable HCC, yet its neoadjuvant application in combination with transarterial chemoembolization (TACE) in HCC remains unexplored. Therefore, this study aims to investigate the efficacy and safety of sequential TACE, camrelizumab, and apatinib as a neoadjuvant therapy for single, huge HCC. METHODS: This multi-center, open-label randomized phase 3 trial will be conducted at 7 tertiary hospitals. Patients with single huge (≥ 10 cm in diameter), resectable HCC will be randomly assigned in a 1:1 ratio to arm of surgery alone or arm of neoadjuvant therapy followed by surgery. In the neoadjuvant therapy group, patients will receive TACE within 1 week after randomization, followed by camrelizumab (200 mg q2w, 4 cycles), along with apatinib (250 mg qd, 2 months). Patients will receive liver resection after neoadjuvant therapy unless the disease is assessed as progressive. The primary outcome is recurrence-free survival (RFS) at 1 year. The planned sample size of 60 patients will be calculated to permit the accumulation of sufficient RFS events in 1 year to achieve 80% power for the RFS primary endpoint. DISCUSSION: Synergistic effects provided by multimodality therapy of locoregional treatment, TKI, and anti-programmed cell death 1 inhibitor significantly improved overall survival for patients with unresectable HCC. Our trial will investigate the efficacy and safety of the triple combination of TACE, camrelizumab, and apatinib as a neoadjuvant strategy for huge, resectable HCC. TRIAL REGISTRATION: www.chitr.org.cn ChiCTR2300078086. Registered on November 28, 2023. Start recruitment: 1st January 2024. Expected completion of recruitment: 15th June 2025.

Brainstem Dbh+ neurons control allergen-induced airway hyperreactivity.

Exaggerated airway constriction triggered by repeated exposure to allergen, also called hyperreactivity, is a hallmark of asthma. Whereas vagal sensory neurons are known to function in allergen-induced hyperreactivity1-3, the identity of downstream nodes remains poorly understood. Here we mapped a full allergen circuit from the lung to the brainstem and back to the lung. Repeated exposure of mice to inhaled allergen activated the nuclei of solitary tract (nTS) neurons in a mast cell-, interleukin-4 (IL-4)- and vagal nerve-dependent manner. Single-nucleus RNA sequencing, followed by RNAscope assay at baseline and allergen challenges, showed that a Dbh+ nTS population is preferentially activated. Ablation or chemogenetic inactivation of Dbh+ nTS neurons blunted hyperreactivity whereas chemogenetic activation promoted it. Viral tracing indicated that Dbh+ nTS neurons project to the nucleus ambiguus (NA) and that NA neurons are necessary and sufficient to relay allergen signals to postganglionic neurons that directly drive airway constriction. Delivery of noradrenaline antagonists to the NA blunted hyperreactivity, suggesting noradrenaline as the transmitter between Dbh+ nTS and NA. Together, these findings provide molecular, anatomical and functional definitions of key nodes of a canonical allergen response circuit. This knowledge informs how neural modulation could be used to control allergen-induced airway hyperreactivity.

The role of CD8+ T-cells in colorectal cancer immunotherapy.

Immunotherapy has been an advanced and effective approach to treating various types of solid tumors in recent years, and the most successful strategy is immune checkpoint inhibitors (ICIs), which have shown beneficial effects in patients with colorectal cancer (CRC). Drug resistance to ICIs is usually associated with CD8+ T-cells targeting tumor antigens; thus, CD8+ T-cells play an important role in immunotherapy. Unfortunately, Under continuous antigen stimulation, tumor microenvironment(TME), hypoxia and other problems it leads to insufficient infiltration of CD8+ T-cells, low efficacy and mechanism exhaustion, which have become obstacles to immunotherapy. Thus, this article describes the relationship between CRC and the immune system, focuses on the process of CD8+ T-cells production, activation, transport, killing, and exhaustion, and expounds on related mechanisms leading to CD8+ T-cells exhaustion. Finally, this article summarizes the latest strategies and methods in recent years, focusing on improving the infiltration, efficacy, and exhaustion of CD8+ T-cells, which may help to overcome the barriers to immunotherapy.

Medical Resource Management in Emergency Hierarchical Diagnosis and Treatment Systems: A Research Framework.

The occurrence of major public health crises, like the COVID-19 epidemic, present significant challenges to healthcare systems and the management of emergency medical resources worldwide. This study, by examining the practices of emergency medical resource management in select countries during the COVID-19 epidemic, and reviewing the relevant literature, finds that emergency hierarchical diagnosis and treatment systems (EHDTSs) play a crucial role in managing emergency resources effectively. To address key issues of emergency resource management in EHDTSs, we examine the features of EHDTSs and develop a research framework for emergency resource management in EHDTSs, especially focusing on the management of emergency medical personnel and medical supplies during evolving epidemics. The research framework identifies key issues of emergency medical resource management in EHDTSs, including the sharing and scheduling of emergency medical supplies, the establishment and sharing of emergency medical supply warehouses, and the integrated dispatch of emergency medical personnel. The proposed framework not only offers insights for future research but also can facilitate better emergency medical resource management in EHDTSs during major public health emergencies.

Distribution patterns of soil bacteria, fungi, and protists emerge from distinct assembly processes across subcommunities.

Environmental change exerts a profound effect on soil microbial domains-including bacteria, fungi, and protists-that each perform vital ecological processes. While these microbial domains are ubiquitous and extremely diverse, little is known about how they respond to environmental changes in urban soil ecosystems and what ecological processes shape them. Here we investigated the community assembly processes governing bacteria, fungi, and protists through the lens of four distinct subcommunities: abundant, conditionally rare, conditionally abundant, and rare taxa. We show that transient taxa, including the conditionally rare and conditionally rare or abundant taxa, were the predominant subcommunities. Deterministic processes (e.g., environmental filtering) had major roles in structuring all subcommunities of fungi, as well as conditionally rare and abundant protists. Stochastic processes had strong effects in structuring all subcommunities of bacteria (except rare taxa) and conditionally rare protists. Overall, our study underscores the importance of complementing the traditional taxonomy of microbial domains with the subcommunity approach when investigating microbial communities in urban soil ecosystems.

Secondary metabolites of mulberry leaves exert anti-lung cancer activity through regulating the PD-L1/PD-1 signaling pathway.

Lung cancer ranks the top of malignancies that cause cancer-related deaths worldwide. The leaves of Morus alba L are traditional Chinese medicine widely applied in respiratory diseases. Our previous work has demonstrated the anti-lung cancer effect of secondary metabolites of mulberry leaf, but their mechanism of action has still not fully elucidated. We synthesized Moracin N (MAN)-Probe conjugated with alkyne to label lung cancer cells and identified protein targets by chemical proteomic analysis. MAN and its probe exerted similar growth-inhibitory effect on human lung cancer cells. Chemical proteomic results showed that MAN targeted the programmed death ligand 1 (PD-L1) checkpoint pathway and T cell receptor (TCR) signaling pathway, indicating its immune-regulatory function. Cell-free surface plasmon resonance (SPR) results showed the direct interaction of MAN with PD-L1 protein. Molecular docking analysis demonstrated that MAN bound to E158 residue of PD-L1 protein. MAN downregulated the expression levels of PD-L1 in a time- and dose-dependent manner and disrupted the PD-L1/programmed death 1 (PD-1) binding, including other secondary metabolites of mulberry leaves Guangsangon E (GSE) and Chalcomoracin (CMR). Human peripheral blood mononuclear cells (PBMCs) co-cultured with MAN-treated A549 cells, resulting in the increase of CD8+ GZMB+ T cells and the decrease of CD8+ PD-1+ T cells. It suggested that MAN exerts anti-cancer effect through blocking the PD-L1/PD-1 signaling. In vivo, MAN combined with anti-PD-1 antibody significantly inhibited lung cancer development and metastasis, indicating their synergistic effect. Taken together, secondary metabolites of mulberry leaves target the PD-L1/PD-1 signaling, enhance T cell-mediated immunity and inhibit the tumorigenesis of lung cancer. Their modulatory effect on tumor microenvironment makes them able to enhance the therapeutic efficacy of immune checkpoint inhibitors in lung cancer.

When birds of a feather flock together: Severe genomic erosion and the implications for genetic rescue in an endangered island passerine.

The Seychelles magpie-robin's (SMR) five island populations exhibit some of the lowest recorded levels of genetic diversity among endangered birds, and high levels of inbreeding. These populations collapsed during the 20th century, and the species was listed as Critically Endangered in the IUCN Red List in 1994. An assisted translocation-for-recovery program initiated in the 1990s increased the number of mature individuals, resulting in its downlisting to Endangered in 2005. Here, we explore the temporal genomic erosion of the SMR based on a dataset of 201 re-sequenced whole genomes that span the past ~150 years. Our sample set includes individuals that predate the bottleneck by up to 100 years, as well as individuals from contemporary populations established during the species recovery program. Despite the SMR's recent demographic recovery, our data reveal a marked increase in both the genetic load and realized load in the extant populations when compared to the historical samples. Conservation management may have reduced the intensity of selection by increasing juvenile survival and relaxing intraspecific competition between individuals, resulting in the accumulation of loss-of-function mutations (i.e. severely deleterious variants) in the rapidly recovering population. In addition, we found a 3-fold decrease in genetic diversity between temporal samples. While the low genetic diversity in modern populations may limit the species' adaptability to future environmental changes, future conservation efforts (including IUCN assessments) may also need to assess the threats posed by their high genetic load. Our computer simulations highlight the value of translocations for genetic rescue and show how this could halt genomic erosion in threatened species such as the SMR.

Analysis of the Economic Burden of Chronic Kidney Disease With Comorbidities Among Patients in Xuzhou, China.

Objectives: To analyze the costs and medication patterns of patients with chronic kidney disease (CKD) and comorbidities in Xuzhou, China, using a large electronic medical records database. Methods: Data were obtained from an electronic medical records database. The annual per-person and per-visit cost of hospitalization, as well as the proportions of those costs, are presented. Results: The majority of the participants were middle-aged men, and had medical insurance. Glomerulonephritis was the primary cause of CKD in patients with an identified etiology. The average per-visit cost of hospitalization for the CKD-renal anemia and CKD-mineral and bone disorder groups was 8,674.5 (5,154.3-13,949.6) and 8,182.6 (4,798.2-12,844.7) Yuan, respectively, which was greater than that of the other groups. The major expenses incurred were for diagnostics, drug usage, surgical procedures, laboratory tests and material costs. Conclusion: The substantial burden imposed by CKD with comorbidities indicates the importance of implementing public health strategies aimed at detecting and preventing these conditions in the general population. With the aging population, our nation may experience a greater CKD-related economic burden.