Paeoniflorin loaded liposomes modified with glycyrrhetinic acid for liver-targeting: preparation, characterization, and pharmacokinetic study.

OBJECTIVE: To enhance the retention times and therapeutic efficacy of paeoniflorin (PF), a liver-targeted drug delivery system has been developed using glycyrrhetinic acid (GA) as a ligand. SIGNIFICANCE: The development and optimization of GA-modified PF liposomes (GPLs) have shown promising potential for targeted delivery to the liver, opening up new possibilities for liver disease treatment. METHODS: This study aimed to identify the best prescriptions using single-factor experiments and response surface methodology. The formulation morphology was determined using transmission electron microscopy. Tissue distribution was observed through in vivo imaging, and pharmacokinetic studies were conducted. RESULTS: The results indicated that GPLs, prepared using the thin film dispersion method and response surface optimization, exhibited well-dispersed and uniformly sized particles. The in vitro release rate of GPLs was slower compared to PF monomers, suggesting a sustained release effect. The liver-targeting ability of GA resulted in stronger fluorescence signals in the liver for targeted liposomes compared to non-targeted liposomes. Furthermore, pharmacokinetic studies demonstrated that GPLs significantly prolonged the residence time of PF in the bloodstream, thereby contributing to prolonged efficacy. CONCLUSION: These findings suggest that GPLs are more effective than PF monomers in terms of controlling drug release and delivering drugs to specific targets, highlighting the potential of PF as a liver-protective drug.

Meta-analytic and MaxEnt model prediction, the distribution of the Bactrocera minax (Diptera: Tephritidae), in China under changing climate.

The Tephritidae family causes damage to fruits in tropical and subtropical regions around the world, with Bactrocera minax Enderlein (Diptera: Tephritidae) widely distributed in China, causing severe economic damage to Chinese citrus. Currently, preventing the rapid spread of B. minax remains an effective strategy to control it as the climate continues to warm in the future. In this context, it is crucial to understand the potential geographic range of B. minax under climate change. We used meta-analysis to assess the survival of Tephritidae insects under temperature stress. We also used the maximum entropy (MaxEnt) model to predict the suitable regions and migration trajectories of B. minax in China under current and future climatic conditions. Through comprehensive analysis of the experimental data, we found that the survival rate of Tephritidae insects in the suitable temperature range showed an increasing trend with the increase in warming extent. Using the MaxEnt model, we observed that the highly suitable area, as well as the moderately suitable area of B. minax, were expanding in all 3 future climate scenarios, with the distribution moving toward the high latitude region and the coastal region of China. Our results also indicate that temperature and precipitation contribute more to the model in the current year. Combining multiexperiment data, our study demonstrates that the potential distribution of B. minax in China will expand under future climate warming scenarios, and these predictions will provide important information for monitoring B. minax and informing managers in developing control strategies.

Geographical distribution of two major quarantine fruit flies (Bactrocera minax Enderlein and Bactrocera dorsalis Hendel) in Sichuan Basin based on four SDMs.

Both Bactrocera minax and Bactrocera dorsalis are phytophagous insects, and their larvae are latent feeders, which cause great damage and economic losses to agriculture production and trade. This study aimed to provide a scientific reference for researching and developing the feasible countermeasures against these two pests. Based on the distribution data of B. minax and B. dorsalis in China, obtained from the Chinese herbaria, investigation and literature. Four niche models (Garp, Bioclim, Domain, and Maxent) were used to analyze the key environmental factors affecting the distribution of both pests and to build prediction models of the potential distribution in Sichuan Basin. Combined with two statistical standards, area under the receiver operating characteristic curve (AUC) and Kappa, the validity of prediction models were analyzed and compared. The results show that: the average AUC values of the four models are all above 0.90, and the average Kappa values are all above 0.75, indicating that the four models are suitable for predicting the potential distribution area of B. minax and B. dorsalis. The annual range of temperature, the mean temperature in the driest quarter, the mean temperature in the warmest quarter, the annual precipitation, and the precipitation in driest month are the key environmental factors affecting the distribution of B. minax, while the mean diurnal temperature range, the mean temperature in the driest quarter, the seasonal temperature variations and the precipitation in driest month affect the potential distribution of B. dorsalis. The suitable areas for B. minax are mainly concentrated in the eastern of Sichuan Basin, while the suitable areas for B. dorsalis are concentrated in the southeastern. Except for the Bioclim model, the highly-suitable area for both pests predicted by the other three models are all greater than 15.94 × 104 km2 and the moderately-suitable areas are greater than 13.57 × 104 km2. In conclusion, the suitable areas for both pests in Sichuan Basin are quite wide. Therefore, the relevant authorities should be given strengthened monitoring of both pests, especially in areas with high incursion rates.

Preparation of paeoniflorin-glycyrrhizic acid complex transethosome gel and its preventive and therapeutic effects on melasma.

Paeoniflorin (PF) and glycyrrhizic acid (GL) have skin beautifying effects of anti-inflammation, anti-oxidation, inhibition of melanin formation, and reduction of skin pigmentation. To improve the transdermal permeability of PF and GL in transdermal drug delivery system (TDDS) and enhance their anti-melasma efficacy, PF-GL transethosome (PF-GL-TE) was prepared by ethanol injection method, and finally gelled with carbomer-940 to form PF-GL-TE gel. Consequently, the obtained PF-GL-TE is small and uniform, with an average particle size and a PDI value of about 167.9 nm and 0.102. PF-GL-TE gel showed sustained release behavior and high transdermal permeability in vitro release and transdermal tests. Meanwhile, PF-GL-TE gel played significant preventive effects on melasma induced by progesterone injection and ultraviolet radiation B (UVB) irradiation. According to the results of H&E staining and Masson staining of rat skin, PF-GL-TE gel can alleviate the skin inflammation of and reduce the loss of collagen fibers of back skin in the melasma model rats. Compared with the PF-GL mixture gel, PF-GL-TE gel significantly attenuated the oxidative damage of liver and skin by increasing the activity of SOD and reducing the content of MDA. The results of Western blot showed that PF-GL-TE gel might down-regulate melanin-related proteins expressions of MITF/TYR/TRP1 and TRP2 to prevent and treat melasma. These findings indicate that PF-GL-TE gel is an effective TDDS for delivering PF and GL into the skin, providing a promising preparation for effective prevention and treatment of melasma.

CD4 T cell-activating neoantigens enhance personalized cancer vaccine efficacy.

Personalized cancer vaccines aim to activate and expand cytotoxic antitumor CD8+ T cells to recognize and kill tumor cells. However, the role of CD4+ T cell activation in the clinical benefit of these vaccines is not well defined. We previously established a personalized neoantigen vaccine (PancVAX) for the pancreatic cancer cell line Panc02, which activates tumor-specific CD8+ T cells but required combinatorial checkpoint modulators to achieve therapeutic efficacy. To determine the effects of neoantigen-specific CD4+ T cell activation, we generated a vaccine (PancVAX2) targeting both major histocompatibility complex class I- (MHCI-) and MHCII-specific neoantigens. Tumor-bearing mice vaccinated with PancVAX2 had significantly improved control of tumor growth and long-term survival benefit without concurrent administration of checkpoint inhibitors. PancVAX2 significantly enhanced priming and recruitment of neoantigen-specific CD8+ T cells into the tumor with lower PD-1 expression after reactivation compared with the CD8+ vaccine alone. Vaccine-induced neoantigen-specific Th1 CD4+ T cells in the tumor were associated with decreased Tregs. Consistent with this, PancVAX2 was associated with more proimmune myeloid-derived suppressor cells and M1-like macrophages in the tumor, demonstrating a less immunosuppressive tumor microenvironment. This study demonstrates the biological importance of prioritizing and including CD4+ T cell-specific neoantigens for personalized cancer vaccine modalities.

Future habitat changes of Bactrocera minax Enderlein along the Yangtze River Basin using the optimal MaxEnt model.

Background: Bactrocera minax (Enderlein, 1920) (Diptera: Tephritidae) is a destructive citrus pest. It is mainly distributed throughout Shaanxi, Sichuan, Chongqing, Guizhou, Yunnan, Hubei, Hunan, and Guangxi in China and is considered to be a second-class pest that is prohibited from entering that country. Climate change, new farming techniques, and increased international trade has caused the habitable area of this pest to gradually expand. Understanding the suitable habitats of B. minax under future climate scenarios may be crucial to reveal the expansion pattern of the insect and develop corresponding prevention strategies in China. Methods: Using on the current 199 distribution points and 11 environmental variables for B. minax, we chose the optimal MaxEnt model to screen the dominant factors that affect the distribution of B. minax and to predict the potential future distribution of B. minax in China under two shared socio-economic pathways (SSP1-2.6, SSP5-8.5). Results: The current habitat of B. minax is located at 24.1-34.6°N and 101.1-122.9°E, which encompasses the provinces of Guizhou, Sichuan, Hubei, Hunan, Chongqing, and Yunnan (21.64 × 104 km2). Under future climate scenarios, the potential suitable habitat for B. minax may expand significantly toward the lower-middle reaches of the Yangtze River. The land coverage of highly suitable habitats may increase from 21.64 × 104 km2 to 26.35 × 104 × 104 km2 (2050s, SSP5-8.5) ~ 33.51 × 104 km2 (2090s, SSP5-8.5). This expansion area accounts for 29% (2050s, SSP1-2.6) to 34.83% (2090s, SSP1-2.6) of the current habitat. The center of the suitable habitat was predicted to expand towards the northeast, and the scenario with a stronger radiative force corresponded to a more marked movement of the center toward higher latitudes. A jackknife test showed that the dominant variables affecting the distribution of B. minax were the mean temperature of the driest quarter (bio9), the annual precipitation (bio12), the mean diurnal range (bio2), the temperature annual range (bio7), and the altitude (alt). Discussion: Currently, it is possible for B. minax to expand its damaging presence. Regions with appropriate climate conditions and distribution of host plants may become potential habitats for the insects, and local authorities should strengthen their detection and prevention strategies. Climate changes in the future may promote the survival and expansion of B. minax species in China, which is represented by the significant increase of suitable habitats toward regions of high altitudes and latitudes across all directions but with some shrinkage in the east and west sides.

MYC-driven increases in mitochondrial DNA copy number occur early and persist throughout prostatic cancer progression.

Increased mitochondrial function may render some cancers vulnerable to mitochondrial inhibitors. Since mitochondrial function is regulated partly by mitochondrial DNA copy number (mtDNAcn), accurate measurements of mtDNAcn could help reveal which cancers are driven by increased mitochondrial function and may be candidates for mitochondrial inhibition. However, prior studies have employed bulk macrodissections that fail to account for cell type-specific or tumor cell heterogeneity in mtDNAcn. These studies have often produced unclear results, particularly in prostate cancer. Herein, we developed a multiplex in situ method to spatially quantify cell type-specific mtDNAcn. We show that mtDNAcn is increased in luminal cells of high-grade prostatic intraepithelial neoplasia (HGPIN), is increased in prostatic adenocarcinomas (PCa), and is further elevated in metastatic castration-resistant prostate cancer. Increased PCa mtDNAcn was validated by 2 orthogonal methods and is accompanied by increases in mtRNAs and enzymatic activity. Mechanistically, MYC inhibition in prostate cancer cells decreases mtDNA replication and expression of several mtDNA replication genes, and MYC activation in the mouse prostate leads to increased mtDNA levels in the neoplastic prostate cells. Our in situ approach also revealed elevated mtDNAcn in precancerous lesions of the pancreas and colon/rectum, demonstrating generalization across cancer types using clinical tissue samples.

Convergent alterations in the tumor microenvironment of MYC-driven human and murine prostate cancer.

The tissue microenvironment in prostate cancer is profoundly altered. While such alterations have been implicated in driving prostate cancer initiation and progression to aggressive disease, how prostate cancer cells and their precursors mediate those changes is unclear, in part due to the inability to longitudinally study the disease evolution in human tissues. To overcome this limitation, we performed extensive single-cell RNA-sequencing (scRNA-seq) and rigorous molecular pathology of the comparative biology between human prostate cancer and key time points in the disease evolution of a genetically engineered mouse model (GEMM) of prostate cancer. Our studies of human tissues, with validation in a large external data set, revealed that cancer cell-intrinsic activation of MYC signaling was the top up-regulated pathway in human cancers, representing a common denominator across the well-known molecular and pathological heterogeneity of human prostate cancer. Likewise, numerous non-malignant cell states in the tumor microenvironment (TME), including non-cancerous epithelial, immune, and fibroblast cell compartments, were conserved across individuals, raising the possibility that these cell types may be a sequelae of the convergent MYC activation in the cancer cells. To test this hypothesis, we employed a GEMM of prostate epithelial cell-specific MYC activation in two mouse strains. Cell communication network and pathway analyses suggested that MYC oncogene-expressing neoplastic cells, directly and indirectly, reprogrammed the TME during carcinogenesis, leading to the emergence of cascading cell state alterations in neighboring epithelial, immune, and fibroblast cell types that paralleled key findings in human prostate cancer. Importantly, among these changes, the progression from a precursor-enriched to invasive-cancer-enriched state was accompanied by a cell-intrinsic switch from pro-immunogenic to immunosuppressive transcriptional programs with coinciding enrichment of immunosuppressive myeloid and Treg cells in the immune microenvironment. These findings implicate activation of MYC signaling in reshaping convergent aspects of the TME of prostate cancer as a common denominator across the otherwise well-documented molecular heterogeneity of human prostate cancer.

Intravenous BCG vaccination reduces SARS-CoV-2 severity and promotes extensive reprogramming of lung immune cells.

Bacillus Calmette-Guérin (BCG) confers heterologous immune protection against viral infections and has been proposed as vaccine against SARS-CoV-2 (SCV2). Here, we tested intravenous BCG vaccination against COVID-19 using the golden Syrian hamster model. BCG vaccination conferred a modest reduction on lung SCV2 viral load, bronchopneumonia scores, and weight loss, accompanied by a reversal of SCV2-mediated T cell lymphopenia, and reduced lung granulocytes. BCG uniquely recruited immunoglobulin-producing plasma cells to the lung suggesting accelerated local antibody production. BCG vaccination also recruited elevated levels of Th1, Th17, Treg, CTLs, and Tmem cells, with a transcriptional shift away from exhaustion markers and toward antigen presentation and repair. Similarly, BCG enhanced recruitment of alveolar macrophages and reduced key interstitial macrophage subsets, that show reduced IFN-associated gene expression. Our observations indicate that BCG vaccination protects against SCV2 immunopathology by promoting early lung immunoglobulin production and immunotolerizing transcriptional patterns among key myeloid and lymphoid populations.

MYC-driven increases in mitochondrial DNA copy number occur early and persist throughout prostatic cancer progression.

Increased mitochondrial function may render some cancers vulnerable to mitochondrial inhibitors. Since mitochondrial function is regulated partly by mitochondrial DNA copy number (mtDNAcn), accurate measurements of mtDNAcn could help reveal which cancers are driven by increased mitochondrial function and may be candidates for mitochondrial inhibition. However, prior studies have employed bulk macrodissections that fail to account for cell type-specific or tumor cell heterogeneity in mtDNAcn. These studies have often produced unclear results, particularly in prostate cancer. Herein, we developed a multiplex in situ method to spatially quantify cell type specific mtDNAcn. We show that mtDNAcn is increased in luminal cells of high-grade prostatic intraepithelial neoplasia (HGPIN), is increased in prostatic adenocarcinomas (PCa), and is further elevated in metastatic castration-resistant prostate cancer. Increased PCa mtDNAcn was validated by two orthogonal methods and is accompanied by increases in mtRNAs and enzymatic activity. Mechanistically, MYC inhibition in prostate cancer cells decreases mtDNA replication and expression of several mtDNA replication genes, and MYC activation in the mouse prostate leads to increased mtDNA levels in the neoplastic prostate cells. Our in situ approach also revealed elevated mtDNAcn in precancerous lesions of the pancreas and colon/rectum, demonstrating generalization across cancer types using clinical tissue samples.

Suitability changes of Citrus medica L. var. sarcodactylis Swingle, a medicine-food plants affected by climate warming using the optimized MaxEnt model.

Climatic variables are important conditions for plant growth, development and reproduction. Citrus medica L. var. sarcodactylis Swingle (Rutaceae: Citrus) is one of the traditional bulk Chinese medicinal materials in China with the effects of bacteriostasis, anti-inflammatory, anti-oxidation, anti-cancer cells, regulating the immun. Analyzing the impact of climate change on geographical distribution of C. medica L. var. sarcodactylis can provide strong support for its production layout and agricultural zoning. In our paper, MaxEnt and ArcGIS were applied to simulate the suitable areas of C. medica L. var. sarcodactylis in China from the perspectives of bioclimate, soil, topographic factors and human activities, and the future climate scenarios generated by global climate models (GCMs) were selected to predict its suitable areas in 2050s and 2090s. Results showed that, 1) Under current climate condition, areas of the total, most, moderately and poorly suitable habitats of C. medica L. var. sarcodactylis in China were 177.36×104 km2, 22.27×104 km2, 51.96×104 km2 and 103.13×104 km2 respectively. The range of the most suitable habitat was the narrowest, which was located in the middle east of Sichuan, western Chongqing in the upstream of the Yangtze River Basin, southern Guizhou and western Guangxi in the upstream of the Pearl River Basin, central and southern Yunnan and Southeast Tibet in the Middle-Lower reaches of the Southwest River Basin and western Taiwan. 2) Under the future climate change scenarios, the total suitable area showed a significant increase trend in 2090s, and the change of most, moderately and poorly suitable habitats showed no obvious law. 3) Under SSP1-2.6, SSP2-4.5 and SSP5-8.5 scenarios, the centroid of the most suitable habitat of C. medica L. var. sarcodactylis would move to the northwest, southeast and southwest respectively.

Single-cell atlas of epithelial and stromal cell heterogeneity by lobe and strain in the mouse prostate.

BACKGROUND: Evaluating the complex interplay of cell types in the tissue microenvironment is critical to understanding the origin and progression of diseases in the prostate and potential opportunities for intervention. Mouse models are an essential tool to investigate the molecular and cell-type-specific contributions of prostate disease at an organismal level. While there are well-documented differences in the extent, timing, and nature of disease development in various genetically engineered and exposure-based mouse models in different mouse strains and prostate lobes within each mouse strain, the underlying molecular phenotypic differences in cell types across mouse strains and prostate lobes are incompletely understood. METHODS: In this study, we used single-cell RNA-sequencing (scRNA-seq) methods to assess the single-cell transcriptomes of 6-month-old mouse prostates from two commonly used mouse strains, friend virus B/NIH jackson (FVB/NJ) (N = 2) and C57BL/6J (N = 3). For each mouse, the lobes of the prostate were dissected (anterior, dorsal, lateral, and ventral), and individual scRNA-seq libraries were generated. In situ and pathological analyses were used to explore the spatial and anatomical distributions of novel cell types and molecular markers defining these cell types. RESULTS: Data dimensionality reduction and clustering analysis of scRNA-seq data revealed that basal and luminal cells possessed strain-specific transcriptomic differences, with luminal cells also displaying marked lobe-specific differences. Gene set enrichment analysis comparing luminal cells by strain showed enrichment of proto-Oncogene targets in FVB/NJ mice. Additionally, three rare populations of epithelial cells clustered independently of strain and lobe: one population of luminal cells expressing Foxi1 and components of the vacuolar ATPase proton pump (Atp6v0d2 and Atp6v1g3), another population expressing Psca and other stem cell-associated genes (Ly6a/Sca-1, Tacstd2/Trop-2), and a neuroendocrine population expressing Chga, Chgb, and Syp. In contrast, stromal cell clusters, including fibroblasts, smooth muscle cells, endothelial cells, pericytes, and immune cell types, were conserved across strain and lobe, clustering largely by cell type and not by strain or lobe. One notable exception to this was the identification of two distinct fibroblast populations that we term subglandular fibroblasts and interstitial fibroblasts based on their strikingly distinct spatial distribution in the mouse prostate. CONCLUSIONS: Altogether, these data provide a practical reference of the transcriptional profiles of mouse prostate from two commonly used mouse strains and across all four prostate lobes.

Prediction of the potential suitable habitat of Echinococcus granulosus, the pathogen of echinococcosis, in the Tibetan Plateau under future climate scenarios.

Echinococcosis is a zoonotic parasitic infectious disease caused by human or domestic animals infected with Echinococcus granulosus. China is the country with the heaviest disease burden caused by Echinococcosis in the world. Therefore, it is feasible to evaluate the prevalence and distribution of echinococcosis using relevant ecological methods, combined with environmental factors and human activities. In this study, MaxEnt was used to predict the distribution range of E. granulosus in China under current and future climate scenarios and explain the impact of environmental variables on its distribution. The results showed that elevation (El), annual mean temperature (bio1), human footprint (Hf), annual precipitation (bio12), mean temperature of warmest quarter (bio10), and mean temperature of wettest quarter (bio8) were identified as the dominant environmental variables. In Tibet, the most suitable habitats (25.9 × 104 km2) of E. granulosus were distributed in Nyingchi and Qamdo in the east, Shigatse and Shannan in the south, and Ali in the west. In Sichuan, the most suitable habitat (18.83 × 104 km2) was located in Aba, Ganzi, and Liangshan. In Qinghai, the most suitable habitat (13.05 × 104 km2) mainly included Yushu in the southwest; Guoluo in the southeast; Haidong, Huangnan, Xining, and Hainan in the east; and Haixi in the west. In Gansu, the most suitable habitat (7.36 × 104 km2) was located in Gannan and Linxia in the southwest and Wuwei and Dingxi in the middle. In Yunnan, the most suitable habitat (1.53 × 104 km2) was distributed in Diqing in the northwest. Under future climate scenarios, the area of the most suitable habitat of E. granulosus showed an obvious expansion trend, with an increase of 44.64-70.76%. Trajectory trend of centroids showed that the most suitable habitat would move to the west in the future, and the increased areas were mainly located in the west of the current most suitable habitat. AUC values of the training data and test data were 0.936 ± 0.001 ~ 0.97 ± 0.006 and 0.912 ± 0.006 ~ 0.956 ± 0.015, respectively. The result can provide a theoretical basis for the prevention, monitoring, and early warning of echinococcosis in China.

Paeoniflorin alleviates 17α-ethinylestradiol-induced cholestasis via the farnesoid X receptor-mediated bile acid homeostasis signaling pathway in rats.

Cholestasis, characterized by disturbance of bile formation, is a common pathological condition that can induce several serious liver diseases. As a kind of trigger, estrogen-induced cholestasis belongs to drug-induced cholestasis. Paeoniflorin is the most abundant bioactive constituent in Paeonia lactiflora Pall., Paeonia suffruticosa Andr., or Paeonia veitchii Lynch, a widely used herbal medicine for treating hepatic disease over centuries in China. However, the pharmacologic effect and mechanism of paeoniflorin on estrogen-induced cholestasis remain unclear. In this experiment, the pharmacological effect of paeoniflorin on EE-induced cholestasis in rats was evaluated comprehensively for the first time. Ultra-high-performance liquid chromatography coupled with Q-Exactive orbitrap mass spectrometer was used to monitor the variation of bile acid levels and composition. It was demonstrated that paeoniflorin alleviated 17α-ethinylestradiol (EE)-induced cholestasis dose-dependently, characterized by a decrease of serum biochemical indexes, recovery of bile flow, amelioration of hepatic and ileal histopathology, and reduction of oxidative stress. In addition, paeoniflorin intervention restored EE-disrupted bile acid homeostasis in enterohepatic circulation. Further mechanism studies using western blot, quantitative Real-Time PCR, and immunohistochemical showed that paeoniflorin could upregulate hepatic efflux transporters expression but downregulate hepatic uptake transporter expression. Meanwhile, paeoniflorin reduced bile acids synthesis by repressing cholesterol 7α-hydroxylase in hepatocytes. Paeoniflorin affected the above transporters and enzyme via activation of a nuclear receptor, farnesoid X receptor (FXR), which was recognized as a vital regulator for maintaining bile acid homeostasis. In conclusion, paeoniflorin alleviated EE-induced cholestasis and maintained bile acid homeostasis via FXR-mediated regulation of bile acids transporters and synthesis enzyme. The findings indicated that paeoniflorin might exert a potential therapeutic medicine for estrogen-induced cholestasis.

Preconditioning of the immune system modulates the response of papillary thyroid cancer to immune checkpoint inhibitors.

BACKGROUND: The response of solid tumors such as papillary thyroid cancer (PTC) to immune checkpoint inhibitors (ICIs) is highly variable. The biological basis of this variability remains unknown. METHODS: To test the hypothesis that preconditioning of the immune system modulates the therapeutic effect of ICIs, we used a murine model where PTC and iodine exacerbated thyroiditis (IET) can be induced in a temporally predictable fashion. A total of 122 mice were divided into 3 experimental groups. In the first one, named concomitant IET and PTC (No.=40), IET, and PTC were induced at the same time; in the second one, named pre-existing IET (No.=44), IET was induced prior to the induction of PTC; in the third one, named no IET (No.=38), only PTC was induced. Following disease induction, mice of each group were treated with anti-PD-1 antibody, anti-lymphocyte activation gene 3 antibody (anti-Lag3), anti-T-cell immunoglobulin and mucin domain 3 antibody (anti-Tim3), or IgG control. Ten weeks after the initial ICI injection, mice were sacrificed to collect the thyroid gland for histological analysis, to quantify the incidence and burden of PTC, and to perform high-throughput single-cell RNA sequencing of infiltrating CD45+ cells. RESULTS: In the concomitant IET and PTC group, ICI treatment reduced PTC incidence (p=0.002 comparing treatment with any ICI vs control), while it had no effect in the pre-existing IET and no IET groups. Single-cell sequencing of thyroidal CD45+ cells showed that the different ICIs tested had both specific and shared effects on all the components of the thyroidal immune cell infiltrate. The shared effect of the tested ICIs was dependent on the presence of pre-existing versus concomitant IET. In the context of concomitant IET, ICI treatment resulted in the modulation of a greater number of pathways related to both innate and adaptive immunity. CONCLUSIONS: Response to ICIs depends on the status of the immune system of the treated individual. Modulation of the immune system should be explored as a tool to improve response to ICIs in patients with PTC or other forms of cancer.

Predicting the distributions of Scleroderma guani (Hymenoptera: Bethylidae) under climate change in China.

The wasp Scleroderma guani is an important parasitic natural enemy of a variety of stem borers such as longicorn beetles. Studying and clarifying the suitable area of this wasp plays an important role in controlling stem borers. Based on information about the actual distribution of S. guani and on a set of environmental variables, MaxEnt niche model and ArcGIS were exploited to predict the potential distribution of this insect in China. This work simulated the geographical distribution of potential climatic suitability of S. guani in China at present and in different periods in the future. Combining the relative percent contribution score of environmental factors and the Jackknife test, the dominant environmental variables and their appropriate values restricting the potential geographical distribution of S. guani were screened. The results showed that the prediction of the MaxEnt model was highly in line with the actual distribution under current climate conditions, and the simulation accuracy was very high. The distribution of S. guani is mainly affected by bio18 (Precipitation of Warmest Quarter), bio11 (Mean Temperature of Coldest Quarter), bio13 (Precipitation of Wettest Month), and bio3 (Isothermality). The suitable habitat of S. guani in China is mainly distributed in the Northeast China Plain, North China Plain, middle-lower Yangtze Plain, and Sichuan Basin, with total suitable area of 547.05 × 104 km2, accounting for 56.85% of China's territory. Furthermore, under the RCP2.6, RCP4.5, and RCP8.5 climate change scenarios in the 2050s and 2090s, the areas of high, medium, and low suitability showed different degrees of change compared to nowadays, exhibiting expansion trend in the future. This work provides theoretical support for related research on pest control and ecological protection.

First-Principles Nonequilibrium Green's Function Approach to Energy Conversion in Nanoscale Optoelectronics.

Understanding photon-electron conversion on the nanoscale is essential for future innovations in nano-optoelectronics. In this article, based on nonequilibrium Green's function (NEGF) formalism, we develop a quantum-mechanical method for modeling energy conversion in nanoscale optoelectronic devices. The method allows us to study photoinduced charge transport and electroluminescence processes in realistic devices. First, we investigate the electroluminescence properties of a two-level model with two different treatments of inelastic scatterings. We show the regime where self-consistency between electron and photon is important for correct description of the inelastic scatterings. The method is then applied to model single-molecule junctions based on the density-functional tight-binding approach. The predicted emission spectra are found to be in very good agreement with experimental measurements. For nanostructured materials, the method is further applied to study the photoresponse of a two-dimensional graphene/graphite-C3N4 heterojunction photovoltaic device. The simulations demonstrate clearly the impact of atomistic details on the optoelectronic properties of nanodevices. This work provides a practical theoretical framework that can be applied to model and design realistic nanodevices.

Assessing and mapping human well-being for sustainable development amid drought and flood hazards: Dadu River Basin of China.

Drought and flood are two of the most destructive natural disasters with the most significant impact and greatest losses in the Dadu River basin (DRB). However, their impacts on people's life have not attracted enough attention from scholars. In this study, the Standardized Precipitation Index (SPI) describing the drought/flood situation and the Composite Index of Human Well-being (CIHW) are calculated, and a framework is further constructed to assess the impacts of drought and flood disasters on human well-being in the DRB. The results show that the annual and seasonal SPI in the DRB generally exhibit an increasing trend in fluctuations during 2000-2009, indicating a wetting climate in this basin. Overall, the upper reaches of the DRB have experienced an evolution of flood-drought-flood state transition, where the variation amplitude of the SPI in the western sub-basin is greater than that in the eastern sub-basin. In addition, the lower reaches of the DRB have suffered more dramatic and periodic changes from the drought/flood disasters in terms of the SPI. For human well-being during 2000-2019, Maerkang City in the upper reaches, Kangding City in the middle reaches, and Shimian County in the lower reaches of the DRB are at a relatively higher level, with the CIHW decreasing from administrative centers to the around. Moreover, the CIHW over the whole basin increases gradually from 2000 to 2019. The SPI has significantly negative effects on different capitals, following a descending order of financial, social, physical, human and natural capitals. The counties of the basin are divided into four groups, namely the group with high disaster risks and high human well-being, the group with high disaster risks and low human well-being, the group with low disaster risks and high human well-being, and the group with low disaster risks and low human well-being. The panel regression results suggest that the construction of water conservancy facilities, the financial inputs in agriculture and meteorology, and the educational level have positive impacts on human well-being, but the impacts differ from different groups. The construction of water conservancy facilities has highly significant impacts on human well-being in all groups; the education level has no significant impact on the group with high disaster risk and high human well-being, which has not passed the significance test; while the financial inputs in agriculture and meteorology have relatively higher impacts on the whole basin and on the group with low disaster risk and low human well-being compared with other groups. Therefore, it is suggested that the negative impacts of drought and flood disasters can be mitigated through strengthening infrastructure construction, responding appropriately to climate change, avoiding disasters at the source of major projects and improving the disaster prevention and mitigation systems.

Prediction of the potential distribution of the predatory mite Neoseiulus californicus (McGregor) in China under current and future climate scenarios.

Neoseiulus californicus is a predatory mite with a wide global distribution that can effectively control a variety of pest mites. In this study, MaxEnt was used to analyse the potential distribution of N. californicus in China and the BCC-CSM2-MR model was used to predict changes in the suitable areas for the mite from 2021 to 2100 under the scenarios of SSP126, SSP245 and SSP585. The results showed that (1) the average of area under curve value of the model was over 0.95, which demonstrated an excellent model accuracy. (2) Annual mean temperature (Bio1), precipitation of coldest quarter (Bio19), and precipitation of driest quarter (Bio17) were the main climatic variables that affected and controlled the potential distribution of N. californicus, with suitable ranges of 6.97-23.27 °C, 71.36-3924.8 mm, and 41.94-585.08 mm, respectively. (3) The suitable areas for N. californicus were mainly distributed in the southern half of China, with a total suitable area of 226.22 × 104 km2 in current. Under the future climate scenario, compared with the current scenario, lowly and moderately suitable areas of N. californicus increased, while highly suitable areas decreased. Therefore, it may be necessary to cultivate high-temperature resistant strains of N. californicus to adapt to future environmental changes.

Potential geographic distribution of relict plant Pteroceltis tatarinowii in China under climate change scenarios.

Pteroceltis tatarinowii (Pteroceltis: Ulmaceae) is a deciduous tree that has a cultivation history of more than 2000 years in China. As an excellent afforestation tree species and rare and endangered tertiary relic plant, P. tatarinowii has high ecological protection value. Due to the forest destruction caused by predatory logging and natural environmental factors, the population of P. tatarinowii in China has decreased significantly. In this study, the potential geographical distribution of P. tatarinowii in China under climate change was predicted using MaxEnt model and ArcGIS based on 223 effective distribution points of P. tatarinowii and 11 environmental variables. The results showed that: (1) the prediction accuracy of MaxEnt model was extremely high, and the areas under curve (AUC) value of the training data was 0.936; The area of the potential suitable habitat area of P. tatarinowii under current climate condition was 180.84×104 km2, and mainly located in the central and southeast regions of China. (2) The domain environmental variables affecting the potential geographical distribution of P. tatarinowii were min temperature of coldest month (12.1~22.7°C), isothermality (26.6~35.8), mean diurnal range 6.9~9.3°C and precipitation of wettest month (189.5 ~955.5 mm). (3) In 2050s and 2070s, compared with current (4.19×104 km2), the area of highly suitable habitat will increase by 0.2%-0.3% (RCP2.6) and 1.22%-3.84% (RCP8.5) respectively. while the poorly, moderately and total suitable habitats will decrease. The gravity center of P. tatarinowii showed a trend of migration to higher latitudes and northern regions in the future. These results will provide theoretical basis for cultivation management and resource protection of P. tatarinowii.