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The key to managing urban heat island (UHI) is identifying and cooling the core areas of UHI. Studies have shown that spatial differences in urban green space (UGS) indicators have a significant impact on spatial differences in land surface temperature (LST). However, previous studies have mainly explored UGS and LST in the entire region, with few focusing on the urban core area. In this study, we extracted the urban core area based on the Point of Interest (POI) and kernel density methods. Correlation and regression analyses were then used to investigate the correlation between UGS indicators and seasonal LST in the urban core area. Our results confirm the significant cooling effect of UGS at the urban core scale. The effects of UGS landscape composition and configuration on LST varied across seasons and across urban green space ratio (UGSR) gradients. In the warm season, increasing the UGSR proved to be the most effective way to mitigate the urban thermal environment. In urban core areas where expanding UGS is not possible or in cores with high UGSR, designing UGS with complex shapes and clusters can better achieve the cooling effect. These results suggest that the influence of UGS landscape features on the urban surface thermal environment at the urban core area scale is very complex. Therefore, implementing urban greening to mitigate the UHI problem requires considering the premise of multifactorial analysis.

The establishment of nature reserves (NRs) is widely acknowledged as one of the most effective measures to mitigate the threats on habitat quality (HB) posed by human activities (HAs). Precise and scientific assessment of the effectiveness of NRs holds crucial significance in improving management and promoting conservation. In this study, key indicators were creatively selected and applied to the propensity score matching (PSM) model to comprehensively assess the variations in HAs and HB within national NRs on the Qinghai-Tibet Plateau. The results indicated that between 2000 and 2020, 67.4 % of the NR area experienced a decline in HA-related impacts, while 53.8 % of the area saw improvements in HB. Additionally, with the exclusion of external environmental factors, in 2020, the difference in HAs and HB between NRs and non-protected areas was −0.131 and 0.179, respectively. Finally, based on an assessment of the overall conservation effectiveness, seven NRs were classified as “Class I'', 18 as “Class II'', and another seven as “Class III''. These results not only confirmed the effectiveness of national NRs in alleviating anthropogenic pressure and enhancing HB but also served as an important basis for accurately assessing the conservation effectiveness of other NRs and formulating more scientifically sound and appropriate management policies.

Autophagy leads to cellular tolerance of the therapeutic pressure of chemotherapeutic drugs, resulting in treatment resistance. Therefore, the effective monitoring of the autophagy status of tumors in vivo and the regulating of the autophagy level are crucial for improving the efficacy of chemotherapy. In this work, we grafted nitroxide radicals onto the surface of iron oxide nanoparticles (Fe3O4 NPs) using dendrimer polymers, yielding Fe3O4-NO· NPs that are responsive to reactive oxygen species (ROS) and possess enhanced T1 and T2 signal capabilities in a magnetic resonance imaging (MRI) measurement. The ROS in tumor cells generated by autophagy quenches the nitroxide radicals, thereby weakening the T1 signal. In contrast, Fe3O4 NPs are unaffected by intracellular ROS, leading to a stable T2 signal. By comparing the intensity ratio of T1 to T2 in Fe3O4-NO· NPs, we can evaluate the in vivo autophagy status within tumors in real time. It also revealed that Fe3O4-NO· NPs loaded with doxorubicin (Dox) and combining the autophagy inhibitor exhibited high antitumor activity in cells and tumor-bearing mice. This system, which combines real-time monitoring of tumor cell autophagy with the delivery of chemotherapeutic drugs, provides an innovative and effective strategy for tumor treatment with potential clinical application prospects.

Urban vibrancy is an important indicator of urban prosperity. Evaluating the correlation between urban vibrancy and housing prices is increasingly necessary. However, most studies have ignored the temporal characteristics of urban vibrancy and only considered its spatial nature. This study optimizes the identification model of urban vibrancy centers and proposes a novel model for evaluating the time-dynamic accessibility of urban vibrancy centers. The model takes into account real-time changes in travel costs and analyses its spatial correlation with housing prices. The case study of Chengdu shows significant variations in the spatiotemporal distribution of urban vibrancy centers. High-vibrancy areas are concentrated near commercial complexes. The time distribution of urban vibrancy accessibility is more concentrated at night (18:00–24:00), and the high-accessibility areas are located around the old city and the newly planned Central Business District in the south. Housing prices and urban vibrancy centers accessibility are mainly negatively correlated spatially. The study emphasizes the temporal nature of urban vibrancy and accessibility and enriches the evaluation model of urban vibrancy centers. It also contributes to the improvement of the framework of urban vibrancy research and deepens the understanding of the important variable of “time” in urban planning.

The COP9 signalosome (CSN) is a conserved protein complex, with CSN1 being one of the largest and most important subunits in the COP9 complex. To investigate the N-terminus function of OsCSN1, we edited the N-terminus of OsCSN1 and found that the mutant of OsCSN1 with 102 amino acids missing at the N-terminus showed insensitivity to red light in terms of the embryonic sheath, stem elongation, and main-root elongation. Moreover, the mutant was able to produce, develop, and bear fruit normally. The research results indicate that OsCSN1 is a negative regulator of stem elongation in rice seedlings regulated by red light. Under red-light treatment, OsCSN1 assembles into CSN, which degrades SLR1 through de NEDDylation, affecting PIL11 activity and ultimately inhibiting stem elongation. OsCSN1 also plays an important regulatory role in the inhibition of rice embryonic sheath elongation under red light. By regulating the degradation of SLR1 and PIL14 through the ubiquitin/26S protease pathway, the elongation of the embryonic sheath is ultimately inhibited. OsCSN1 forms a COP9 complex and is modified with RUB/NEDD8 of the E3 ligase of CUL1 to promote the degradation of SLR1 and PIL14, ultimately affecting the elongation of the embryonic sheath. The regulatory domain is located at the N-terminus of CSN1.

5-methylcytosine modifications play a significant role in carcinogenesis; however, studies exploring 5-methylcytosine-related genes in diffuse large B-cell lymphoma patients are lacking. In this study, we aimed to understand the potential role and clinical prognostic impact of 5-methylcytosine regulators in diffuse large B-cell lymphoma and identify a prognostic biomarker based on 5-methylcytosine-associated genes. Gene expression profiles and corresponding clinical information of diffuse large B-cell lymphoma patients and normal controls were obtained from The Cancer Genome Atlas, Gene Expression Omnibus, and Genotype-Tissue Expression databases. Diffuse large B-cell lymphoma was divided into three clusters according to the 5-methylcytosine regulators, and differentially expressed genes were screened among the three clusters. Univariate Cox and Lasso-Cox regression analyses were used to screen prognostic genes and construct a prognostic risk model. Kaplan-Meier curve analysis, univariate and multivariate Cox regression analyses, and time-dependent receiver operator characteristic curve analysis were used to evaluate prognostic factors. GSVA was used to enrich potential pathways associated with 5-methylcytosine modification patterns. SsGSEA and CIBERSORT were used to assess immune cell infiltration. Six 5-methylcytosine-related genes (TUBB4A, CD3E, ZNF681, HAP1, IL22RA2, and POSTN) were used to construct a prognostic risk model, which was proved to have a good predictive effect. In addition, univariate and multivariate Cox regression risk scores were independent prognostic factors for diffuse large B-cell lymphoma. Further analysis showed that the 5-methylcytosine risk score was significantly correlated with immune cell infiltration and immune checkpoint of diffuse large B-cell lymphoma. Our study reveals for the first time a potential role for 5-methylcytosine modifications in diffuse large B-cell lymphoma, provides novel insights for future studies on diffuse large B-cell lymphoma, and offers potential prognostic biomarkers and therapeutic targets for patients with diffuse large B-cell lymphoma.

Angioimmunoblastic T-cell lymphoma (AITL) is a subtype of peripheral T-cell lymphoma (PTCL) strongly correlated with worse clinical outcomes. However, the role of characteristic pathway-related genes in patients with AITL (e.g., subtype typing and pathogenesis) remains unknown. In this study, we intended to understand the potential role and prognostic value of characteristic pathways in AITL and identified a model for subtype identification based on pathway-related functional status. Transcriptomic (RNA-seq) data were obtained from the Gene Expression Omnibus database for three sets of tumor tissues from AITL patients. AITL was divided into three clusters based on the pathway profile of patients and the best clustering k = 3, and differentially expressed genes (DEGs) in the three clusters were analyzed. The top 45 important variables associated with characteristic pathways, such as Huntington's disease, VEGF signaling pathway, nucleotide excision repair, ubiquitin-mediated proteolysis, purine metabolism, olfactory transduction, etc., were used to construct a subtype identification model. The model was experimentally validated and proved to possess good predictive efficacy. In addition, pathway-related subtype typing was significantly associated with different immune cell infiltration in AITL. Further analysis revealed that the drug IC50 values predicted also differed markedly among the different subtypes, thus further identifying some subtype-specific drugs. Our study indicates a potential role of characteristic pathways in AITL staging for the first time, provides novel insights for future research targeting AITL, and points to potential therapeutic options for patients with different subtypes of AITL.

Abstract Background The mortality of castration‐resistant prostate cancer (CRPC) is high due to lack of an effective treatment. Chimeric antigen receptor (CAR)‐based therapy is a promising immunotherapeutic strategy. Here, we aimed to design a novel CAR‐natural killer (NK) cells with a clinically significant tumoricidal effect on CRPC. Methods We constructed novel CAR‐NK92MI cells with a CD244‐based recombinant lentiviral vector. Different intracellular segments (CD244, NKG2D, or CD3ζ) were screened to identify the best candidate according to cell lysis assay and CD107a expression levels. To enhance the affinity of the CAR to the tumor antigen, we compared an antibody specific for prostate‐specific membrane antigen (anti‐PSMA) with PSMA‐targeted polypeptide (p‐PSMA), which was screened by phage display combinatorial library. Then, CAR‐NK92MI cells with both a high affinity for PSMA and a strong tumoricidal capacity were generated. In addition, we verified their tumor‐killing effect in vitro and in vivo. The release of cytokine by NK92MI cells was compared with that by CAR‐NK92MI cells through flow cytometry and enzyme‐linked immunosorbent assay. Moreover, ferroptosis‐related cell death was explored as a possible underlying mechanism. Results Three different CAR intracellular regions CAR1 (CD244), CAR2 (CD244, NKG2D) and CAR3 (CD244, NKG2D, and CD3ζ) were constructed. CAR2 was chosen to confer a stronger tumoricidal ability on CAR‐NK92MI cells. Compared with anti‐PSMA, p‐PSMA exhibited enhanced affinity for the tumor antigen. Thus, p‐PSMA‐CAR‐NK92MI cells, which expressed CAR with a polypeptide‐based antigen‐binding region, an intracellular CD244 and a NKG2D costimulatory domain, were generated. They could selectively and successfully kill PSMA+ target cells and exhibited specific lysis rate of 73.19% for PSMA‐positive C4‐2 cells and 33.04% for PSMA‐negative PC3 cells. Additionally, p‐PSMA‐CAR‐NK92MI cells had significantly higher concentrations of IFN‐γ, TNF‐α and granzyme B than NK92MI cells. In a CRPC cancer xenograft model, p‐PSMA‐CAR‐NK92MI cells significantly inhibited tumor growth and exerted a more consistent killing effect than NK92MI cells. Moreover, ferroptosis is a potential mechanism through which CAR‐NK92MI cells attack cancer cells, and is triggered by IFN‐γ. Conclusions p‐PSMA‐CAR‐NK92MI cells can effectively kill CRPCPSMA+ cells in vitro and in vivo. This strategy may provide additional treatment options for patients with CRPC.

Abstract Targeting immune checkpoints has achieved great therapeutic effects in the treatment of early-stage tumors. However, most patients develop adaptive resistance to this therapy. The latest evidence demonstrates that tumor-derived exosomes may play a key role in systemic immune suppression and tumor progression. In this article, we highlight the role of exosomal immune checkpoint proteins in tumor immunity, with an emphasis on programmed death ligand 1 (PD-L1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), as well as emerging evidence on roles of T cell immunoglobulin-3 (TIM-3), arginase 1 (ARG1), and estrogen receptor binding fragment-associated antigen 9 (EBAG9) expressed by exosomes.

Abstract Background Panax ginseng is a well-known medicinal plant worldwide. As an herbal medicine, ginseng is also known for its long lifecycle, which can reach several decades. WRKY proteins play regulatory roles in many aspects of biological processes in plants, such as responses to biotic or abiotic stress, plant development, and adaptation to environmental challenges. Genome-wide analyses of WRKY genes in P. ginseng have not been reported. Results In this study, 137 PgWRKY genes were identified from the ginseng genome. Phylogenetic analysis showed that the PgWRKYs could be clustered into three primary groups and five subgroups. Most of the PgWRKY gene promoters contained several kinds of hormone- and stress-related cis-regulatory elements. The expression patterns of PgWRKY genes in 14 different tissues were analyzed based on the available public RNA-seq data. The responses of the PgWRKY genes to heat, cold, salt and drought treatment were also investigated. Most of the PgWRKY genes were expressed differently after heat treatment, and expression trends changed significantly under drought and cold treatment but only slightly under salt treatment. The coexpression analysis of PgWRKY genes with the ginsenoside biosynthesis pathway genes identified 11 PgWRKYs that may have a potential regulatory role in the biosynthesis process of ginsenoside. Conclusions This work provides insights into the evolution, modulation and distribution of the WRKY gene family in ginseng and extends our knowledge of the molecular basis along with modulatory mechanisms of WRKY transcription factors in ginsenoside biosynthesis.

The identification of conservation priority areas (CPAs) based on multiple ecosystem services (ESs) is a prerequisite and important basis for decision-makers in implementing regional ecological restoration. However, the trade-offs between different services pose great challenges to determining the locations of priority areas. Based on the identification and assessment of key ESs in the Hengduan Mountain region from 2000 to 2020, a multicriteria ordered weighted average (OWA) method was used to balance the conflicts among different services and determine the location of CPAs. The results indicated that the optimal CPAs in the Hengduan Mountain region totaled 89,699 km2, accounting for 20.30% of the study area, and were located mainly in the southwestern and eastern regions. Moreover, the OWA method balanced the trade-offs among multiple services. In the four CPA scenarios that protected each service exclusively, the protection efficiency (PE) of each respective service was greater, but the PE of the remaining three services was always smaller than the corresponding PEs in the optimal scenario. The comprehensive PE of the optimal CPA scenario was 1.27, and the PE values of net primary productivity, water yield, soil conservation, and cultural service were 1.45, 1.20, 1.08, and 1.39, respectively. The CPA determination method in this study can provide a scientific blueprint for regional ecological restoration and the determination of the CPAs in other regions.

Wetland is one of the most critical ecosystems with various functions, it produces the highest ecosystem services value (ESV) per unit area among all land types, thus, its decline has become a global concern in recent years. Since the 21st century, many developing countries have been continuously encroaching on wetlands due to rapid economic and population growth, resulting in the replacement of a large number of wetlands by cities, and how to reconcile urban expansion and wetland conservation has become a significant problem that needs to be considered. In this context, we mapped the spatial distribution of wetlands occupied by the expansion of global artificial impervious surface area (ISA) for 2001–2018 and discussed its temporal and spatial change characteristics at the global, continental, and national scales using the annual maps of global annual impervious area data set and global dynamic land cover data set based on Google Earth Engine platform, the loss of ESV due to wetland occupation was also measured at each spatial scale level. The results show that: (1) A total of 1301.24 km2 of wetlands were occupied by ISA expansion globally for 2001–2018, and their interannual variation showed an upward trend for 2001–2015, then began to decline rapidly since 2016. The occupation results in a global loss of US$3.46 billion in ecosystem service value; (2) Asia has the highest loss of ESV due to occupation of wetlands by ISA expansion, 624.18 km2 of occupation of wetlands resulted in a loss of US$1.66 billion in ESV, making it the continent with the largest area of occupied wetlands. Taking into account the different sizes of the continents, Oceania is the continent where ISA expansion occupies the wetlands most, while South America is the continent where it is relatively least severe; (3) China, the USA and Russia account for 50.9 % of global ESV loss due to wetland occupation by ISA expansion, a total of 663.95 km2 of wetlands were occupied. Although countries have made great efforts to protect wetland resources and deal with urban land expansion, our results show that the problem of wetlands occupied by global urban land expansion is still severe.

The core areas of the urban heat island (CAUHI) are the most concentrated and closely associated with humans, and they are key to managing the urban heat island (UHI). It is widely acknowledged that one of the best ways to reduce the risk of UHI is the creation of urban green spaces (UGSs). However, most of the current studies are based on the grid or block scale to explore the impact of UGS on UHI. The key to mitigating the urban heat environment is to plan urban UGS rationally in the CAUHI and explore the thermal environmental benefits of UGS. This paper provides an assessment model for the thermal environmental advantages of UGS and uses ten UGS metrics as explanatory factors for seasonal land surface temperature (LST). It quantitatively evaluates the potential differences in landscape characteristics between LST and UGS under different seasons, as well as the seasonal impact on CAUHI. This study found the following: (1) The overall distribution pattern of CAUHI shows a characteristic of spreading from the central part to the surrounding area. Most of the extremely significant CAUHI is dispersed in the center and southeastern regions of the city, where there is a much greater density of impermeable surfaces and essentially no distribution of CAUHI on the natural surface represented by forest land and water bodies. (2) Except for the aggregation index (AI), correlation analysis revealed that other metrics were highly connected with LST. Among the metrics used in this study, the largest patch index (LPI) and landscape division index (DIVISION) had the highest significant correlation with LST. Patch density (PD) was strongly negatively correlated with LST, indicating that fragmented and complex UGS patches could promote vegetation cooling. (3) The green environmental benefit index (GEBI) results showed a significant degree of spatial and temporal variability in the extracted CAUHI. This study found higher GEBI values in the larger thermal patches and lower GEBI in the surrounding smaller patches. The highest mean GEBI was found in winter, at 0.6083, and the largest distribution of large high-value patches. This study revealed the geographical and temporal variability of UGS and CAUHI, and with the help of the constructed scientific evaluation model, it offered suggestions for the optimization of urban greenery.

AIM: To analyze the situations of poor vision and the incidence of myopia in adolescents of Chifeng and to explore the factors that affect the occurrence of myopia.METHODS: A multi-stage random sampling method was adopted from September to December in 2019. A total of 2 070 students from primary 4th grade to junior in high school in Chifeng were selected for questionnaire surveys and visual inspections to analyze influencing factors and the occurrence of myopia in the region.RESULTS: Among 2 070 students in this research, the incidence of poor vision was 56.96% and the incidence of myopia was 52.22%. Multivariate Logistic regression analysis showed that the risk factors of myopia were senior grade, female, genetic history, loving to eat sweets, fried food, no breakfast, longer time homework and cram school, using mobile devices, having bad eye habits and using eyes for long time once. The protective factors of myopia were no other poor vision, eating fresh fruits, adjusting the height of tables and chairs, doing eye exercises, doing outdoor activities between classes, a one-foot sitting posture, supervising the sitting posture by parents and teachers, less watching TV, increasing outdoor exercise and sleeping time.CONCLUSION: The myopia incidence of adolescents in Chifeng is generally higher. We should actively pay attention to the personal situation of students, improve visual environment inside and outside school, correct bad visual habits, and increase outdoor exercise and sleep time.

Sinomenine (SIN), an alkaloid extracted from the root of S. acutum. sinomenine, has been shown to have antiarrhythmic, antioxidant, and anti-inflammatory effects in myocardial ischemia-reperfusion injury (MIRI) ex vivo. In this study, we investigated the cardioprotective effects of SIN in an in vivo mouse model of MIRI. Adult male C57BL/6J mice received SIN (80 mg/kg) for 5 days and underwent 30 min of percutaneous occlusion of the left anterior descending artery (LAD) followed by 24 h of reperfusion. Results showed that pretreatment with SIN significantly reduced myocardial infarct size and concentrations of markers of cardiac injury and improved left ventricular ejection fraction (EF) and shortening fraction (FS) in MIRI mice. The SIN pretreatment prevented the MIRI-induced decrease in the expression levels of Bcl-2, increase in the expression levels of caspase-3, caspase-9, and Bax, and increase in the number of TUNEL-positive cells in ischemic heart tissue. It was also found that pretreatment with SIN prevented the MIRI-induced oxidative stress imbalance in ischemic heart tissue, as shown by the increase in total antioxidant capacity (T-AOC) and glutathione (GSH) and the decrease in malondialdehyde (MDA), reactive oxygen species (ROS), and dihydroethidium (DHE) density. Further studies showed that the stimulus of cardiac ischemia/reperfusion caused a remarkable increase in the expression levels of interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α) mRNA in ischemic heart tissue, which was effectively prevented by pretreatment with SIN. These results demonstrate that SIN can attenuate MIRI-induced cardiac injury in vivo by preventing oxidative stress, inflammation, and apoptosis.

Abstract Background The chimeric antigen receptor NK‐92 (CAR NK‐92) cell targeting the prostate‐specific membrane antigen (PSMA) has shown antitumour effects in castration‐resistant prostate cancer (CRPC). However, the expression changes of programmed death ligand 1 (PD‐L1) and its mechanisms on CAR NK‐92 and CRPC cells and the effect of the anti‐PD‐L1 monoclonal antibody (mAb) on PD‐L1 expressed on CAR NK‐92 cells remain unknown. Methods Human dendritic cells and CD8+ T cells were acquired from blood samples of healthy donors and cocultured with C4‐2 cells. Changes in PD‐L1 expression were detected by flow cytometry. Differential gene expressions were investigated by RNA sequence analysis, while the regulation of PD‐L1 molecular signaling was explored using western blotting. In vitro cytotoxicity was evaluated using the Cell Counting Kit‐8 assay and the bioluminescent intensity (BLI) of green fluorescent protein‐labelled C4‐2 cells. CRPC growth in vivo was monitored using callipers and BLI in male NOD/SCID mice subcutaneously injected with C4‐2 cells and treated intravenously with anti‐PD‐L1/PD‐1 mAb, CAR NK‐92 or cocultured CD8+ T cells. Results Significantly upregulated expression of PD‐L1k was observed in cocultured C4‐2 and CAR NK‐92 cells. In addition, upregulation of PD‐L1 expression was dependent on interferon‐γ in C4‐2 cells, while it was dependent on direct cell‐to‐cell interaction via the NK group 2 member D/ phosphatidylinositol 3‐kinase/AKT pathway in CAR NK‐92 cells. The anti‐PD‐L1 mAb directly acted on PD‐L1 expressed on CAR NK‐92 cells and augmented the cytotoxicity of CAR NK‐92 cells against C4‐2 and CRPC cells from one patient in vitro. Anti‐PD‐L1 mAb significantly enhanced the antitumour effect of CAR NK‐92 cells against CRPC cells in vivo when compared to treatment with CAR NK‐92 cells or combined with anti‐PD‐1 mAb in the absence or presence of cocultured CD8+ T cells. Conclusion Combined treatment with CAR NK‐92 and anti‐PD‐L1 mAb improved the antitumour efficacy against CRPC, which is of extraordinary translational value in the clinical treatment of CRPC.

The intensity of human pressure (HP) has an important impact on the biodiversity and ecosystem services of nature reserves (NRs), and the conflict and the coordination between NRs and human activities are now key issues to solve in the construction of NR systems. This study improved and applied a human footprint (HF) model that considers population density, land use, night light, grazing intensity, and road construction as indicators of human activity to evaluate the effectiveness of NRs in the Qinghai–Tibet Plateau in mitigating HP from 2000 to 2020. The results indicated that during this period, the average HP in the national NRs of the plateau increased from 1.47646 to 1.76687, where values were generally high in the east and low in the west. The average value in wetland NRs was the largest and had the smallest growth rate, while that in desert NRs was the smallest and had the largest growth rate. From 2000 to 2020, the average HP in the core areas, buffer areas, and experimental areas of the NRs increased by 0.12969, 0.29909, and 0.44244, respectively. It is a challenge for the Chinese government to strengthen the ability of NRs to mitigate HP on the wetland reserves and experimental zones in the Qinghai–Tibet Plateau region.

Owing to the recent emergence of drug resistance to Bruton’s tyrosine kinase inhibitors (BTK) in chronic lymphocytic leukemia (CLL) treatment, it is crucial to identify alternative therapeutic targets. Therefore, we aimed to identify therapeutic options for CLL besides BTK. We identified that HIF1A expression was higher in CLL patients than in controls, which may suggest good prognosis. We used a lentiviral knockdown of EGLN1 (encoding hypoxia-inducible factor prolyl hydroxylase [HIF-PH]) and found that the growth of MEC-1 cells slowed in the knockdown group. Treatment of CLL cell lines MEC-1 and HG3 with the HIF-PH inhibitor molidustat showed that molidustat could induce apoptosis in a concentration-dependent manner in CLL cells and had low cytotoxicity at this concentration. CXCR4, HIF1A, SLC2AI, and VEGF, the downstream molecules of the HIF pathway, were upregulated after molidustat treatment. Western blotting results indicated that molidustat increased HIF1A expression in CLL cell lines and cells from CLL patients, and sequencing/quantitative PCR analysis demonstrated that the ribosome biogenesis pathway was inhibited in MEC-1 cells after molidustat treatment. We further identified synergistic cytotoxicity of molidustat in combination with ibrutinib on the MEC-1 and HG3 cell lines at certain concentrations. Therefore, molidustat is a potential therapeutic option for CLL.

Ecosystem services (ESs), as important indicators for ecosystem conditions, are always interacted complexly, however, the underlying mechanisms remain not fully understood. The Beijing-Tianjin-Hebei (BTH) region is a typical example of this complexity and is one of the most populous regions globally. In this study, we take the BTH region as the study area and try to identify the spatiotemporally complex relationships and dominant drivers of ESs, by utilizing multiple methods: Pearson correlation analysis, partial correlation analysis and the GeoDetector method. Three critically important ESs: soil erosion, water yield, and net primary production (NPP) are simulated for the period of 2000 to 2018. The results show that the Pearson correlation coefficient indicated a synergistic relationship between soil erosion and water yield and between water yield and NPP and a trade-off relationship between soil erosion and NPP, while the partial correlation analysis using the normalized difference vegetation index (NDVI) and precipitation as controlling factors showed that the relationships between soil erosion and water yield and between water yield and NPP were transformed to trade-offs. We confirmed that the drivers (especially the shared drivers and dominant drivers of each ecosystem service) played important roles in the direction of complex relationships; when different factors were involved in the relationships, the direction of positive or negative relationships may be diverse. Furthermore, the slope (q = 0.32), precipitation (q = 0.42) and NDVI (q = 0.72) were the dominant factors for soil erosion, water yield and NPP, respectively. The power of determinants for ESs showed high spatial heterogeneity in different geomorphological types due to differences in each type of inner characteristic; for example, the q value of slope for soil erosion decreased with increasing mountain relief, but the q value of NDVI increased. In addition, the trade-off degree among the three ESs was spatially heterogeneous; in mountainous areas the trade-off scores were much higher than those in relatively flat areas. Our general approaches and results provide useful references for researchers and policy makers to understand the mechanisms governing complex relationships among ESs and to manage ESs by manipulating these drivers to enhance synergies or weaken trade-offs.

In the last few decades, land use/land cover (LULC) has changed significantly under the influence of local planning and policy implementation, and this has had a profound impact on the regional ecological environment. By taking the Hengduan Mountain region as the study area, this study considered the demands of various commodities and services and applied the CLUMondo model to predict the trajectory of change in the land system for the years 2010–2030. The results indicate that the forest system expands significantly in this time, while the grassland and cropland systems are projected to develop intensively under the three scenarios. The high demand for livestock products is the main cause of the intensification of the grassland system under the TREND scenario, the demand for forests leads to the expansion of the forest land system under the FOREST scenario, and the significant intensification of the cropland system under the CONSERVATION scenario is closely related to an increase in the area of ecological land. The results of this study can provide a scientific reference for the optimal management of land systems in other mountainous areas.

Although paternal age has been linked to certain psychiatric disorders, the nature of any causal relationship remains elusive. Here, we aimed to comprehensively assess the magnitude of a wide range of offsprings psychiatric risk conferred by paternal age, leveraging a pedigree inferred from covered-insurance relationship (accuracy >98%) in Taiwans single-payer compulsory insurance program. We also examined whether there is an independent role of paternal age and explored the potential effect of parental age difference. A total cohort of 7,264,788 individuals born between 1980 and 2018 were included; 5,572,232 with sibling(s) were selected for sibling-comparison analyses and 1,368,942 and 1,044,420 children with information of paternal-grandparents and maternal-grandparents, respectively, were selected for multi-generation analyses. Using inpatient/outpatient claims data (1997-2018), we identified schizophrenia, autism, bipolar disorder (BPD), attention deficit-hyperactivity disorder (ADHD), major depressive disorder (MDD), eating disorder (ED), substance use disorder (SUD), mental retardation (MR), tic disorder, obsessive-compulsive disorder (OCD), anxiety, and somatoform disorder. We identified suicides using death certificates. Logistic regression analysis was used to estimate the paternal/maternal/grand-paternal age association with psychiatric risk in the offspring. The total cohort and sibling-comparison cohort resulted in similar estimates. Paternal age had a U-shaped relationship with offsprings MDD, ED, SUD, and anxiety. A very young maternal age (25 years) was linearly associated with offsprings schizophrenia, autism, BPD, ADHD, MDD, ED, SUD, MR, OCD, anxiety, and suicide. Older grand-paternal age was linearly associated with offsprings schizophrenia, autism, ADHD, and MR. Dissimilar parental age was positively associated with offsprings ADHD, MDD, SUD, MR, anxiety, and suicide, and negatively associated with offsprings OCD. This comprehensive assessment provides solid evidence for the independent role of paternal age in psychiatric risk in the offspring and clarifies the significance of both early parenthood and delayed paternity.

The use of wireless sensor networks for indoor localization application has emerged as a significant area of interest over the last decade, primarily motivated by its low cost and convenient deployment. The weighted centroid localization algorithm is a suitable positioning technique in a wireless sensor network due to its easy implementation. However, the performance of this method is easily affected by outliers and interference in the measurement of radio signal strength. In order to overcome this limitation, a more robust ARMA filter using generalized t-distribution noise model based on influence function approach is proposed. A hardware prototype was implemented to demonstrate that the ARMA filter could improve system performance, especially when dealing with the case of measurement outliers.