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Abstract Systems theory and complex science, especially knowledge of social–ecological interdependencies, are urgently needed in planning and decision-making on sustainable urban development due to the intensification of the contradiction between human development and nature conservation. Here, we present an analytical framework, the “social–ecological coupling trajectory”, that integrates the social–ecological coupling, multi-stability, causal feedbacks and sustainable management through understanding the evolution of the urban social–ecological system (SES). This framework is applied to a typical urban SES, i.e., China’s rapidly prosperous Pearl River Delta (PRD). Our results indicate that the SES evolution in the PRD is a phased process, which is accompanied by a continuous decline in major ecosystem services (ESs) and the disproportionate decline of ecological management performance. Further analysis shows that social and economic policies have a decisive role in driving the evolution of SES and the cumulative effect of sustained human interference is directly linked to the disproportionate increase in sustainability challenges. The findings of critical slowing down and evolution patterns of SES in the PRD may provide evidence for the threshold recognition and regime shift prediction in SES. In sum, this study expands the theoretical framework and empirical knowledge of SES evolution and provides a pathway for sustainable development of regions seeking prosperity from the social–ecological coupling perspective.

Wind plays a crucial role in the formation of coastal dunes, and in China, these dunes are shaped by the combined effects of typhoons and winter monsoons. However, the unique characteristics of Chinese coastal dunes impacted by these forces remain poorly understood, as prior research has predominantly focused on their separate impacts. This study employed RTK-GPS technology to conduct 14 high-precision morphological assessments of coastal dunes in Tannan Bay, Pingtan Island, Fujian, China, between 2014 and 2017, aiming to investigate the response patterns of coastal dunes to typhoons and winter monsoons. Our findings indicate that coastal dunes respond variably to typhoons of differing intensities, with considerable height changes across different sections; however, winter monsoons contribute to an overall increase in dune height. Both dune volume and height increased due to continuous sediment accumulation at the base of the windward slopes. Additionally, the average high-water level advanced seaward by 3.0–4.0 m. We concluded that in Tannan Bay, typhoons exert only a temporary “braking” effect on dune morphology, whereas the winter monsoon is the primary driver of its long-term evolution. These findings contribute to a comprehensive understanding of coastal dune dynamics and provide insights for effective coastal sand management and disaster prevention strategies.

Landscape patterns have a global impact on ecosystem services (ESs). Managing land to enhance the provision of multiple ESs is vital for ecological resilience and sustainable development. Identifying critical landscape patterns that simultaneously influence multiple ESs provision based on understanding ES trade-offs is needed. Our study aims to develop an approach to find the relationship between multiple ESs provision and landscape patterns, identify the critical landscape patterns that simultaneously promote multiple ESs provision, and give suggestions on land management based on an understanding of the relationships of ESs. Taking the central district of Wuhu City as an example, production possibility frontier (PPF) and Pareto ranks are used to identify relationships between ESs and extract the landscape pattern characteristics of samples that effectively enhance multiple ESs. Our analysis of trade-offs between ESs highlights the complexity of ES relationships and emphasizes the necessity for multi-dimensional investigative approaches. Landscape metrics of Mean Perimeter Area Ratio (PARA_MN), Coefficient of Variation of Perimeter (PERI_CV), Area-weighted Mean Fractal Dimension (FRAC_AM), and Relative Mutual Information (RELMUTINF) emerged as critical determinants of multiple ESs supply. Our findings suggest enhancing patch shape complexity when conducting land use planning to avoid homogenization and keeping differences between the diversity of land use categories and the diversity of adjacencies small. Also, we recommend caution in using high contagion as the only criterion for land use planning, as its effects may vary on different ES targets.

Objective: The immune microenvironment influenced clinical outcomes and treatment response of gastric cancer (GC) patients. Though thousands of immune-related genes (IRGs) have been identified, their effects on GC are not fully understood. The objective of the study is to analyze the correlations between the expression and effect of IRGs and clinical outcomes. Moreover, we evaluate the efficacy and value of utilizing the immune-related genes signature as a prognosis prediction model for GC patients. Methods: We identified the differentially expressed IRGs and systematically analyzed their functions. We constructed a novel GC prognostic signature and a new nomogram, Moreover, we explored the infiltrated immune cell types in the immune microenvironment and discussed the genetic variation in GC IRGs. Results: Eight IRGs, including CCL15, MSR1, GNAI1, NR3C1, ITGAV, NMB, AEN, and TGFBR1 were identified. Based on the prognostic signature, GC patients were distinguished into two subtype groups. As verified in multiple datasets, the prognostic signature exhibited good performance in predicting the prognosis (AUC = 0.803, P-value

BackgroundImmunogenic cell death (ICD) is considered a particular cell death modality of regulated cell death (RCD) and plays a significant role in various cancers. The connection between kidney renal clear cell carcinoma (KIRC) and ICD remains to be thoroughly explored.MethodsWe conducted a variety of bioinformatics analyses using R software, including cluster analysis, prognostic analysis, enrichment analysis and immune infiltration analysis. In addition, we performed Quantitative Real-time PCR to evaluate RNA levels of specific ICD genes. The proliferation was measured through Cell Counting Kit-8 (CCK-8) assay and colony-formation assay in RCC cell lines. ResultsWe determined two ICD subtypes through consensus clustering analysis. The two subtypes showed significantly different clinical outcomes, genomic alterations and tumor immune microenvironment. Moreover, we constructed the ICD prognostic signature based on TF, FOXP3, LY96, SLC7A11, HSP90AA1, UCN, IFNB1 and TLR3 and calculated the risk score for each patient. Kaplan-Meier survival analysis and ROC curve demonstrated that patients in the high-risk group had significantly poorer prognosis compared with the low-risk group. We then validated the signature through external cohort and further evaluated the relation between the signature and clinical features, tumor immune microenvironment and immunotherapy response. Given its critical role in ICD, we conducted further analysis on LY96. Our results indicated that downregulation of LY96 inhibited the proliferation ability of RCC cells.ConclusionsOur research revealed the underlying function of ICD in KIRC and screened out a potential biomarker, which provided a novel insight into individualized immunotherapy in KIRC.

Abstract Background Mitochondria play an essential role in cellular redox homeostasis maintenance and meanwhile serve as an important target for organelle targeted therapy. Photodynamic therapy (PDT) is a promising strategy for organelle targeted therapy with noninvasive nature and highly spatiotemporal selectivity. However, the efficacy of PDT is not fully achieved due to tumor hypoxia. Moreover, aerobic respiration constantly consumes oxygen and leads to a lower oxygen concentration in mitochondria, which continuously limited the therapeutic effects of PDT. The lack of organelle specific oxygen delivery method remains a main challenge. Methods Herein, an Oxygen Tank is developed to achieve the organelle targeted synergistic hypoxia reversal strategy, which not only act as an oxygen storage tank to open sources and reduce expenditure, but also coated with red blood cell membrane like the tank with stealth coating. Within the oxygen tank, a mitochondrion targeted photosensitizer (IR780) and a mitochondria respiration inhibitor (atovaquone, ATO) are co-loaded in the RBC membrane (RBCm) coated perfluorocarbon (PFC) liposome core. Results Inside these bio-mimic nanoparticles, ATO effectively inhibits mitochondrial respiration and economized endogenous oxygen consumption, while PFC supplied high-capacity exogenous oxygen. These Oxygen modulators reverse the hypoxia status in vitro and in vivo, and exhibited a superior anti-tumor activity by mitochondria targeted PDT via IR780. Ultimately, the anti-tumor effects towards gastric cancer and colon cancer are elicited in vivo. Conclusions This oxygen tank both increases exogeneous oxygen supply and decreases endogenous oxygen consumption, may offer a novel solution for organelle targeted therapies.

The railway industry has shown a strong interest in utilizing sustainable materials, including recycled materials and composites, in construction. Bamboo, as a highly renewable natural resource, has been proposed as a construction material for the railway industry. This material offers several advantages, such as high strength and durability, sustainability, low embodied energy, and ease of handling. It has been used in various construction materials like plywood, scrimber, laminates, and fibers. This paper aims to review the application of bamboo as a material in the railway industry and provide suggestions for its future use as railway sleepers. The mechanical properties of bamboo and its desirable features for sleeper construction, such as versatility, durability, low embodied energy and carbon footprint, lightweight, and ease of handling, are discussed. Bamboo-based products like plywood and scrimber can offer higher mechanical properties compared to traditional timber sleepers. Moreover, due to its rapid growth rate, bamboo is considered an environmentally friendly material. However, there are certain factors that limit the widespread deployment of bamboo in the railway industry. For instance, the lightweight nature of bamboo can reduce the lateral resistance of sleepers. Additionally, long-term performance studies and its performance in regions with varying weather conditions need to be further investigated. This review paper aims to promote the increased utilization of bamboo in the railway industry, contributing to the development of sustainable railway tracks. By considering the mechanical properties and advantageous characteristics of bamboo, it is possible to explore its potential as a viable and eco-friendly material for railway sleepers.

Prostate adenocarcinoma (PRAD) is a common malignancy with increasing morbidity and mortality. Kinetochore scaffold 1 (KNL1) has been reported to be involved in tumor progression and prognosis in other tumors, but its role in PRAD has not been reported in detail. KNL1 expression analysis, clinicopathological parameters analysis, prognostic correlation analysis, molecular interaction network and functional abdominal muscle analysis and immune infiltration analysis by using multiple online databases and downloaded expression profile. The results suggest that KNL1 is highly expressed in PRAD, which is associated with worse prognosis in PRAD patients. KnL1-related genes are highly enriched in mitotic function, which is considered to be highly related to the development of cancer. Finally, KNL1 expression is associated with a variety of tumor infiltrating immune cells, especially Treg and Th2 cells. In conclusion, our findings provide preliminary evidence that KNL1 may be an independent prognostic predictor of PRAD and is associated with immune infiltration.

Abstract Background Breast cancer is one of the main malignant tumors that threaten the lives of women, which has received more and more clinical attention worldwide. There are increasing evidences showing that the immune micro-environment of breast cancer (BC) seriously affects the clinical outcome. This study aims to explore the role of tumor immune genes in the prognosis of BC patients and construct an immune-related genes prognostic index. Methods The list of 2498 immune genes was obtained from ImmPort database. In addition, gene expression data and clinical characteristics data of BC patients were also obtained from the TCGA database. The prognostic correlation of the differential genes was analyzed through Survival package. Cox regression analysis was performed to analyze the prognostic effect of immune genes. According to the regression coefficients of prognostic immune genes in regression analysis, an immune risk scores model was established. Gene set enrichment analysis (GSEA) was performed to probe the biological correlation of immune gene scores. P

Abstract Background The cardiotoxicity of isoniazid on zebrafish embryos and its underlying mechanism is unclear. Methods Here, we exposed zebrafish embryos at 4 h post-fertilization to different levels of isoniazid and recorded the morphology and number of malformed and dead embryos under the microscope. Results The high concentration of isoniazid group showed more malformed and dead embryos than the low concentration of isoniazid group and control group. The morphology of the heart and its alteration were visualized using transgenic zebrafish (cmlc2: GFP) and confirmed by in situ hybridization. The negative effects of isoniazid on the developing heart were characterized by lower heart rate and more heart looping disorders. Mechanistically, PCR showed decreased expression of heart-specific transcription factors when exposed to isoniazid. Oxidative stress was induced by isoniazid in cardiomyocytes, mediated by decreased activities of catalase and superoxide dismutase, which were rescued by scavengers of reactive oxygen species. Conclusion In conclusion, this study demonstrated that isoniazid led to heart looping disturbance by the downregulation of cardiac-specific transcription factors and induction of cardiomyocyte apoptosis.

Abstract Background It is very important for clinicians and dieticians to explore reasonable weight management strategies for obese people that address both short-term weight loss and subsequent weight maintenance. We hypothesized that resistance training combined with a high-protein diet would result in similar short-term weight loss but better long-term weight maintenance than either a conventional low-fat diet control or a high-protein diet alone. Methods/design This is an 8-week randomized parallel controlled trial followed by a 24-week observational follow-up study. A 48-week supplementary follow-up study will be carried out if necessary. The study will be conducted between June 2019 and October 2020. The 90 overweight or obese participants will be randomly assigned to the conventional low-fat diet group, the high-protein diet group and the high-protein diet and resistance training combination group. Primary outcomes are body weight change at week 8 and week 24 compared with the baseline level. Discussion High-quality research on the effect of a high-protein diet combined resistance training on weight loss and weight maintenance is limited in the Chinese population. Our study will provide a basis for obesity management in China and will promote the development of exercise- and diet-related studies. Trial registration Chinese Clinical Trial Registry, ChiCTR1900023841. Registered on 14 June 2019.

Gastric cancer (GC) is one of the most prevalent malignancies with an unfavorable survival rate. Immunotherapy may contribute to a better prognosis. However, several phase III trials failed. Circular RNA (circRNA) is a novel type of non-coding RNA, plays a vital role in the progression of tumors. The expression and function of circRNA in the GC immune microenvironment remain obscure. In this study, we utilized a bioinformatic analysis to construct a circRNA/microRNA (miRNA)/messenger RNA (mRNA) network involved in the progression and prognosis of GC. CircRNA DYRK1A_017, circRNA FLNA_118, miR-6512-3p, miR-6270-5p, and VCAN were identified as the key molecules in the hub regulatory axis. Dysregulation of this axis contributed to the cancer-associated signaling pathways (epithelial-mesenchymal transition [EMT], Nuclear factor kappa β-Tumor necrosis factor-α (NFκβ-TNFα) signaling, and angiogenesis) and aberrant immune microenvironment (infiltration by tumor associated macrophage, regulatory T cell, and mast cell). More importantly, the immunosuppressive tumor microenvironment may reveal the mechanism of novel circRNAs in tumors and serve as the target of immunotherapy.

Abstract Collective memory plays a controlling role in adaptation to potential flood risks, by learning from past disasters. However, with little quantitative empirical data, previous socio‐hydrological models have conceptualized the decaying process of flood memory in an oversimple approach. Here, based on survey data of 683 respondents on Ningxia Floodplain, we confirmed that flood memory decays overtime via two channels: oral communication (communicative memory) and physical recording of information (cultural memory). Using the Universal Decay Model (UDM) proposed by previous researchers provides better fitting of results to the decay of flooding memory (adjusted R2 coefficient are 0.97, 0.90, 0.95 when data of all, rural or urban respondents used, respectively) compared with the original exponential model (adjusted R2 coefficient are 0.91, 0.74, 0.59, corresponding). Then, significantly reduced losses for the same flood sequence predicted by integrating the UDM into a socio‐hydrological model by 16% and the differences between different clusters (urban and rural respondents) can even reach 22.81%. These differences suggest that previous socio‐hydrological models have been too simplistic in their conceptualizations of decaying processes associated with collective memory, which may have limited deeper insights into flood risk management.

BackgroundCircular RNAs (circRNAs) are now under hot discussion as novel promising biomarkers for patients with hepatocellular carcinoma (HCC). The purpose of our study is to identify several competing endogenous RNA (ceRNA) networks related to the prognosis and progression of HCC and to further investigate the mechanism of their influence on tumor progression.MethodsFirst, we obtained gene expression data related to liver cancer from The Cancer Genome Atlas (TCGA) database (http://www.portal.gdc.cancer.gov/), including microRNA (miRNA) sequence, RNA sequence, and clinical information. A co-expression network was constructed through the Weighted Correlation Network Analysis (WGCNA) software package in R software. The differentially expressed messenger RNAs (DEmRNAs) in the key module were analyzed with the Database for Annotation Visualization and Integrated Discovery (DAVID) (https://david.ncifcrf.gov/summary.jsp) to perform functional enrichment analysis including Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO). The data of miRNA expression and clinical information downloaded from TCGA were utilized for survival analysis to detach the prognostic value of the DEmiRNAs of the key module.ResultsThe 201 differentially expressed miRNAs (DEmiRNAs) and 3,783 DEmRNAs were preliminarily identified through differential expression analysis. The co-expression networks of DEmiRNAs and DEmRNAs were constructed with WGCNA. Further analysis confirmed four miRNAs in the most significant module (blue module) were associated with the overall survival (OS) of patients with liver cancer, including hsa-miR-92b-3p, hsa-miR-122-3p, hsa-miR-139-5p, and hsa-miR-7850-5p. DAVID was used for functional enrichment analysis of 286 co-expressed mRNAs. The GO analysis results showed that the top enriched GO terms were oxidation–reduction process, extracellular exosome, and iron ion binding. In KEGG pathway analysis, the top three enriched terms included metabolic pathways, fatty acid degradation, and valine, leucine, and isoleucine degradation. In addition, we intersected the miRNA–mRNA interaction prediction results with the differentially expressed and prognostic mRNAs. We found that hsa-miR-92b-3p can be related to CPEB3 and ACADL. By overlapping the data of predicted circRNAs by circBank and differentially expressed circRNAs of GSE94508, we screened has_circ_0077210 as the upstream regulatory molecule of hsa-miR-92b-3p. Hsa_circ_0077210/hsa-miR-92b-3p/cytoplasmic polyadenylation element binding protein-3 (CPEB3) and acyl-Coenzyme A dehydrogenase, long chain (ACADL) were validated in HCC tissue.ConclusionOur research provides a mechanistic elucidation of the unknown ceRNA regulatory network in HCC. Hsa_circ_0077210 might serve a momentous therapeutic role to restrain the occurrence and development of HCC.

Ecosystem services (ES)-related decision-making is important to promote sustainable conservation and urban development. However, there is limited information regarding the use of ES research in a planning context. We explored this gap between ES research and planning practice by evaluating whether and to what extent the ES concept is explicitly used in planning and decision-making processes. This paper selected 101 pieces of target literature, reviewed their research status and characteristics, discussed the motivation and interests, and summarized the research content. In particular, we discussed the contributions that demonstrated the significance of incorporating ES into planning and achieved beneficial results. A series of abstract strategic methods and quantitative methodological approaches were used for subsequent reference research. The ES concept existed earlier than the perception in early-stage planning documents, while its practical application was superficial, with insufficient depth, which was a challenge worthy of attention. To identify the research paradigm in previous planning related to ES, we found that ES analyses for planning were largely theory-inspired, rather than practice-inspired, and used the Schön–Stokes model of the wicked and tame to theorize problems in socio-ecological systems. Our study highlighted that Pasteur’s paradigm may be an essential and useful research style for maintaining and improving ES in socio-ecological practice.

Abstract Hedgehog (Hh) pathway is involved in epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC) maintenance resulting in tumor progression. GDC-0449, an inhibitor of Hh pathway component smoothened (Smo) has shown promise in the treatment of various cancers including pancreatic cancer. However, the emergence of resistance during GDC-0449 treatment with numerous side effects limits its use. Therefore, here we report the design, synthesis and evaluation of novel GDC-0449 analogs using N-[3-(2-pyridinyl) phenyl] benzamide scaffold. Cell-based screening followed by molecular simulation revealed 2-chloro-N 1-[4-chloro-3-(2-pyridinyl)phenyl]-N 4,N 4-bis(2-pyridinylmethyl)-1,4-benzenedicarboxamide (MDB5) as most potent analog, binding with an extra interactions in seven-transmembrane (7-TM) domain of Smo due to an additional 2-pyridylmethyl group than GDC-0449. Moreover, MDB5 was more efficient in inhibiting Hh pathway components as measured by Gli-1 and Shh at transcriptional and translational levels. Additionally, a significant reduction of ALDH1, CD44 and Oct-3/4, key markers of pancreatic CSC was observed when MIA PaCa-2 cells were treated with MDB5 compared to GDC-0449. In a pancreatic tumor mouse model, MDB5 containing nanoparticles treated group showed significant inhibition of tumor growth without loss in body weight. These evidence highlight the enhanced Hh pathway inhibition and anticancer properties of MDB5 leaving a platform for mono and/or combination therapy.

Abstract This study analyzed carbon fixation across different land use types in the Pearl River Delta to identify the influence of different geographical factors on carbon fixation ability. The methodology was based on interpreting land use data from TM imagery, MODIS13Q1 data, and climate data, using the improved CASA and GeogDetector models. The results show that: (1) From 2000 to 2013, the total carbon sink increased slightly, from 15.58 × 106 t to 17.52 × 106 t, being spatially low at the center and increasing outwards; (2) Proxy variables (topography and landform characteristics), influencing urbanization, significantly affect the carbon sink function of the Pearl River Delta region. The proportion of urban and other construction land showed increasing effect on the regional carbon sink each year. However, the spatial structure of land in the study area changed from complex to simple, with enhanced stability; consequently, the influence of landscape characteristics (landscape dominance and landscape perimeter area fractal dimension) on the regional carbon sink gradually decreased; (3) The influence of the same factors differed with different land use types. Slope and altitude were found to have the greatest influence on the carbon sink of cultivated land, while landscape perimeter area fractal dimension more significantly affected the forest carbon sink.

In recent decades, the approach known as Finite-Dimension Thermodynamics has provided a fruitful theoretical framework for the optimization of heat engines operating between a heat source (at temperature Ths) and a heat sink (at temperature Tcs). We will show in this paper that the approach detailed in a previous paper [1] can be used to analytically model irreversible heat engines (with an additional assumption on the linearity of the heat transfer laws). By defining two dimensionless parameters, the intensity of internal dissipation and heat leakage within a heat engine were quantified. We then established the analogy between an endoreversible heat engine and an irreversible heat engine by using the apparent temperatures (Tcs ��� Tλ,φ cs, Ths → Tλ,φ hs) and apparent conductances (Kh → Kλ h, Kc → Kλ c). We thus found the analytical expression of the maximum power of an irreversible heat engine. However, these apparent temperatures should not be used to calculate the conversion efficiency at the optimal operating point by analogy with the case of an endoreversible heat engine.

In recent decades, the approach known as Finite-Time Thermodynamics has provided a fruitful theoretical framework for the optimization of heat engines operating between a heat source (at temperature ) and a heat sink (at temperature ). The aim of this paper is to propose a more complete approach based on the association of Finite-Time Thermodynamics and the Bond-Graph approach for modeling endoreversible heat engines. This approach makes it possible for example to find in a simple way the characteristics of the optimal operating point at which the maximum mechanical power of the endoreversible heat engine is obtained with entropy flow rate as control variable. Furthermore it provides the analytical expressions of the optimal operating point of an irreversible heat engine where the energy conversion is accompanied by irreversibilities related to internal heat transfer and heat dissipation phenomena. This original approach, applied to an analysis of the performance of a thermoelectric generator, will be the object of a future publication.

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The reactions of achiral dispiro-1,2,4-trioxolane and dispiro-1,2,4-trioxanes with ferrous bromide and 4-oxo-TEMPO are presented. The results suggest a small preference for attack of Fe(II) on the nonketal peroxide oxygen atom of artemisinin.

Objective: This study determined whether the effect of combination therapy for hepatic carcinoma (HCC) is comparable to surgical resection (SR). According to the guidelines of the American Association for the Study of Liver Disease, radiofrequency ablation (RFA) and SR are recommended for early HCC. However, patients treated with RFA had worse long‑term survival than those who received SR. Many studies utilizing the combination therapy with RFA and transarterial chemoembolization (TACE) have reported better prognosis as compared to RFA alone. Materials and Methods: A comprehensive search in databases was conducted. Six retrospective studies and one cohort were enrolled in this meta‑analysis. The overall survival (OS), disease‑free survival (DFS), and major complications were compared between RFA plus TACE and SR. The pooled hazard ratio and 95% confidence interval (CI) were calculated and analyzed. Results: After comparison, no significant difference in the OS and DFS at 1 and 3 years between the combination therapy and SR was observed (OS1: pooled relative risk [RR]: 0.82, 95% CI [0.56, 1.21]; OS3: pooled RR: 1.07, 95% CI [0.82, 1.39]; DFS1: pooled RR: 0.92, 95% CI [0.58, 1.45]; DFS3: pooled RR: 1.18, 95% CI [1.00, 1.40]). SR had better clinical outcomes than combination therapy with respect to long‑term survival and disease progression (OS5: pooled RR: 1.12, 95% CI [1.03, 1.23]; DFS5: pooled RR: 1.15, 95% CI [1.03, 1.28]). Major complications were reduced with combination therapy (pooled RR: 0.46, 95% CI [0.25, 0.85]). Conclusion: SR should remain as the first‑line therapy for early HCC. [ABSTRACT FROM AUTHOR]

Spatial explicit information related to ecosystem services is key in decisionmaking for attainment of sustainable development. Ecosystems in the Karst mountainous region of the southwest China subtropical zone contribute a substantial number of products and services. Based on the Integrated Valuation of Ecosystem Services and Tradeoffs (InVEST) model, multiple ecosystem services including water supply, sediment retention, carbon storage and habitat quality in the Guizhou Province of southwest China were assessed and mapped at the watershed scale in this study. The correlation among multiple ecosystem services was investigated and effects of the ecological condition and human pressure on ecosystem services explored. Results indicated obvious spatial heterogeneity in multiple ecosystem services and ecosystem services bundling; 51.09% of the area was designated at a moderate-level for "hotspot" (high ecosystem services provision) area. Tradeoffs existed between water supply and sediment retention and also between carbon storage and sediment retention. The spatial pattern of water supply in Guizhou was heavily affected by precipitation, evaporation and root depth associated with each land use type, while the rainfall erosivity, topography, covermanagement factor and support practice associated with land use types played important roles in spatial distribution of sediment retention. The area and proportion of forestland were considered to be dominant factors affecting carbon storage. Habitat suitability of natural land use and the weight and effect distance of human land use were key driving factors affecting the habitat quality score and its spatial pattern. A weak negative correlation was demonstrated between human pressure indicators including the urbanization rate, GDP per person and population density and ecosystem services. [ABSTRACT FROM AUTHOR]

Building on insights gained from the discovery of the antimalarial ozonide arterolane (OZ277), we now describe the structure-activity relationship (SAR) of the antimalarial ozonide artefenomel (OZ439). Primary and secondary amino ozonides had higher metabolic stabilities than tertiary amino ozonides, consistent with their higher pKa and lower log D7.4 values. For primary amino ozonides, addition of polar functional groups decreased in vivo antimalarial efficacy. For secondary amino ozonides, additional functional groups had variable effects on metabolic stability and efficacy, but the most effective members of this series also had the highest log D7.4 values. For tertiary amino ozonides, addition of polar functional groups with H-bond donors increased metabolic stability but decreased in vivo antimalarial efficacy. Primary and tertiary amino ozonides with cycloalkyl and heterocycle substructures were superior to their acyclic counterparts. The high curative efficacy of these ozonides was most often associated with high and prolonged plasma exposure, but exposure on its own did not explain the presence or absence of either curative efficacy or in vivo toxicity. [ABSTRACT FROM AUTHOR]