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Global transcriptomic analysis on primary CD49a+ and CD49a- NK cells.

Clinicopathological characteristics of patients in each cohort

Figure S1 shows (A) Cumulative percentage of CD160 or BTLA on CD8+ T cells from representative normal liver, PT and IT of HCC patient; (B) Cumulative percentage of CD160+ or BTLA+ CD8+ T cells in healthy liver, IT and PT of HCC patients; (C) Absolute count of CD160+ or BTLA+ CD8+ T cells in healthy liver, IT and PT of HCC patients; and (D) The strategy for gating liver-infiltrating leukocytes and NK cells via flow cytometry.

We previously reported that deficiencies in natural killer (NK)–cell number and function play an important role in the progression of hepatocellular carcinoma (HCC). However, the mechanisms underlying this phenomenon remain obscure. In this study, we analyzed the expression of CD160 on intrahepatic NK cells by evaluating peritumoral and intratumoral tissues of 279 patients with HCC and 20 healthy livers. We observed reduced expression of CD160 on intratumoral NK cells, and patients with lower CD160 cell densities within tumors exhibited worse disease and a higher recurrence rate. High-resolution microarray and gene set enrichment analysis of flow cytometry–sorted primary intrahepatic CD160+ and CD160− NK cells of healthy livers indicated that human CD160+ NK cells exhibited functional activation, high IFNγ production, and NK-mediated immunity. In addition, global transcriptomic analysis of sorted peritumoral and intratumoral CD160+ NK cells revealed that intratumoral CD160+ NK cells are more exhausted than peritumoral CD160+ NK cells and produce less IFNγ. High levels of TGFβ1 interfered with production of IFNγ by CD160+ NK cells, blocking of which specifically restored IFNγ production in CD160+ NK cells to normal levels. These findings indicate that reduced numbers of CD160+ NK cells, together with the functional impairment of CD160+ NK cells by TGFβ1, contribute to tumor immune escape. In addition, restoring the expression of CD160 and blocking TGFβ1 appear a promising therapeutic strategy against liver cancer.Significance:These findings show that reduced number and function of CD160+ NK cells in the tumor microenvironment contributes to immune escape of HCC; blocking TGFβ1 restores IFNγ production of CD160+ NK cells.

Summary and details of HCC patients in cohort 1 and 2.

Clinicopathological characteristics of each cohort in the study.

Glacier retreat is altering the water regime of the Tibetan Plateau (TP) as the region's climate changes, but there remain substantial gaps in our knowledge of recent glacier loss in this region due to the difficulty of making direct high-mountain observations, and this limits our ability to predict the future of this important water resource. Here, we assessed 44 years of glacier area and volume changes in the major west Nyainqentanglha Range (WNR) that supplies meltwater to the densely populated Lhasa River basin and Nam Co, the second largest endorheic lake on the TP. Between the two periods 1976–2000 and 2000–2020, we found that the glacier areal retreat rate more than doubled (from -0.54±0.21 % a−1 to -1.17±0.30 % a−1), and surface lowering also accelerated (from -0.26±0.09 to -0.37±0.15 m w.e a−1) with particularly intense melting after 2014. This acceleration is similar in both timing and magnitude to that observed for Himalayan glaciers farther south. Besides, the areal retreat rate and mass loss rate of most glaciers in the WNR were not synchronized. To understand the sensitivity of WNR glaciers to climate forcing, we examined the effects of topography, debris cover and the presence of proglacial lakes on our observed changes. We found consistently faster areal retreat but slower thinning rates on steeper slopes and an inconsistent relationship with aspect. We concluded that our observed spatial and temporal patterns of glacier change were dominated by observed local variations in temperature and precipitation, the melt-reducing role of supraglacial debris, and the increasing influence of ice-marginal lakes on glacier ablation.

Immunotherapy based on natural killer (NK) cells is a promising approach for treating a variety of cancers. Unlike T cells, NK cells recognize target cells via a major histocompatibility complex (MHC)-independent mechanism and, without being sensitized, kill the cells directly. Several strategies for obtaining large quantities of NK cells with high purity and high cytotoxicity have been developed. These strategies include the use of cytokine-antibody fusions, feeder cells or membrane particles to stimulate the proliferation of NK cells and enhance their cytotoxicity. Various materials, including peripheral blood mononuclear cells (PBMCs), umbilical cord blood (UCB), induced pluripotent stem cells (iPSCs) and NK cell lines, have been used as sources to generate NK cells for immunotherapy. Moreover, genetic modification technologies to improve the proliferation of NK cells have also been developed to enhance the functions of NK cells. Here, we summarize the recent advances in expansion strategies with or without genetic manipulation of NK cells derived from various cellular sources. We also discuss the closed, automated and GMP-controlled large-scale expansion systems used for NK cells and possible future NK cell-based immunotherapy products.

The catalytic hydrolysis/alcoholysis of biomass carbohydrates into levulinic acid/levulinate esters (alkyl levulinates) as green biofuels and value-added chemicals holds great promise for achieving the goals of sustainable chemistry. Bifunctional catalysts...

Conversion of levulinic acid and its esters into versatile γ-valerolactone (GVL) is a pivotal and challenging step in biorefineries, limited by high catalyst cost, the use of hydrogen atmosphere, or tedious catalyst preparation and recycling process. Here we have successfully synthesized a ternary magnetic nanoparticle catalyst (Al2O3-ZrO2/Fe3O4(5)), over which biomass-derived methyl levulinate (ML) can be quantitively converted to GVL with an extremely high selectivity of > 99% and yield of ~98% in the absence of molecular hydrogen. Al2O3-ZrO2/Fe3O4(5) incorporates simultaneously inexpensive alumina and zirconia onto magnetite support by a facile coprecipitation method, giving rise to a core-shell structure, well-distributed acid-base sites, and strong magnetism, as evidenced by the X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), scanning electron microscopy (SEM), transmission electron microscopy (TEM), high-angle annular dark-field scanning-TEM (HAADF-STEM), SEM-energy dispersive X-ray spectroscopy (SEM-EDX), temperature-programmed desorption of ammonia (NH3-TPD), temperature-programmed desorption of carbon dioxide (CO2-TPD), pyridine-adsorption infrared spectra (Py-IR), and vibrating sample magnetometry (VSM). Such characteristics enable it to be highly active and easily recycled by a magnet for at least five cycles with a slight loss of its catalytic activity, avoiding a time-consuming and energy-intensive reactivation process. It is found that there was a synergistic effect among the metal oxides, and the high efficiency and selectivity originating from such synergism are evidenced by kinetic studies. Furthermore, a reaction mechanism regarding the hydrogenation of ML to GVL is proposed by these findings, coupled with gas chromatography-mass spectrometry (GC-MS) analysis. Accordingly, this readily synthesized and recovered magnetic nanocatalyst for conversion of biomass-derived ML into GVL can provide an eco-friendly and safe way for biomass valorization.

In order to evaluate the applicability of Fengyun 2G and GPM IMERG satellite precipitation products in the Lancang River Basin, four evaluation indicators are selected in this paper. The results show that: (1) In terms of correlation coefficient (CC), the GPM IMERG products are better than Fengyun 2G. Among them, GPM IMERG Late Run is better than Early Run, and Final Run is better than Late Run; (2) In terms of root mean square error (RMSE) and mean absolute error (MAE), the values of GPM products are higher; (3) The GPM IMERG products show that the CC of the lower reaches is better than that of the upper reaches; (4) The RMSE and MAE are better in the upper reaches than in the lower reaches, and the high value of the error is mainly concentrated in the lower reaches. This study provides a more reliable precipitation data guarantee for the cascade management of Lancang River Basin, and has certain scientific significance and practical value.

Inter-basin water transfer projects are powerful measures for resolving the uneven distribution of water resources, but their scale directly affects the associated investment and income. Therefore, determining the scale of an inter-basin water transfer project is essential. Based on the inter-basin agricultural water transfer project in the Sanjiang Plain, Northeast China, combined with the suitable development scale of the irrigation area with the joint allocation of existing water sources, this research proposes a technique to demonstrate the scale of an inter-basin water transfer project based on dynamic trial feedback under the condition of the optimization method of despiking of the groundwater allocation; the water transfer project scale is demonstrated for each section in reverse order. According to the water demand prediction results in the study area, the scale of water transfer project BC is demonstrated, and the scale of water transfer project AB is demonstrated on the basis of the BC scale. The final AB and BC water transfer scales decrease by 15% and 13%, respectively, compared with the conventional method under the premise that the water supply guarantee rate is 75%. When the water is transferred, the process is stable, and the utilization rate of the canal is high, thereby saving investment funds and facilitating project scheduling and management.

Immune cells are involved in skeletal muscle regeneration. The mechanism by which Treg cells are involved in the regeneration of injured skeletal muscle is still unclear. The purpose of this study was to explore the role of programmed death-1 in contused skeletal muscle regeneration, and to clarify the regulation of programmed death-1 on Treg cell generation and macrophage polarization, in order to deepen our understanding of the relationship between the immune system and injured skeletal muscle regeneration. The results show that programmed death-1 knockdown reduced the number of Treg cells and impaired contused skeletal muscle regeneration compared with those of wild-type mice. The number of pro-inflammatory macrophages in the contused skeletal muscle of programmed death-1 knockout mice increased, and the expression of pro-inflammatory factors and oxidative stress factors increased, while the number of anti-inflammatory macrophages and the expression of anti-inflammatory factors, antioxidant stress factors, and muscle regeneration-related factors decreased. These results suggest that programmed death-1 can promote contused skeletal muscle regeneration by regulating Treg cell generation and macrophage polarization., Immune cells are involved in skeletal muscle regeneration, but the mechanisms are unclear. In this paper, the authors show that programmed death-1 (PD-1), a key immunosuppressive receptor that is involved in adaptive immune responses, can promote contused skeletal muscle regeneration by regulating Treg cell generation and macrophage polarization.

Maize (Zea mays L.) is one of the most important crops in China. Since 2020, a new leaf spot disease has occurred in southwest China in areas such as Yunnan, Sichuan and Hubei provinces. Typical symptoms appeared after tasseling. The spots are scattered on the leaf surface, round to oval in shape with diameter range 3-20 mm. Spots are initially water-soaked, gradually turning yellow or white. In 2021, diseased leaf samples with typical white spot were collected for pathogen isolation and identification in Qujing, Yunnan province. Four small pieces of leaf tissue (about 0.25 cm2 in area) were excised from the edge of the necrotic lesion of each plant, surface sterilized with 75% ethanol for 1 min, rinsed three times with sterile distilled water, and soaked in sterile distilled water for 5 min. The solution was plated on Luria Broth medium (LB) plate (Shin et al. 2022) . After incubation at 28°C for 24 h, round, smooth-edged yellow colonies appeared in the LB plate. The bacterium isolated was gram-negative, negative for oxidase, positive for peroxidase, indole, citrate (Wells et al. 1987). Three strains (PA21QJ01, PA21QJ02 and PA21QJ03) showed identical colony morphology. PA21QJ01 was used for further molecular analyses. DNA was extracted from fresh colonies cultured in LB(Shin et al. 2022), and the fragments at the 16S rDNA, gyrB and rpoB loci were amplified using primers 27F/1492R (Galkiewicz and Kellogg 2008), UP-1/UP-2r (Yamamoto and Harayama 1995) and rpoBCM81-F/rpoBCM32b-R (Brady et al. 2008), respectively. The sequences of fragments of 16S rDNA, gyrB and rpoB from isolate PA21QJ01 were was deposited in GenBank (accession number: OM184301.1, OM302500, OM302499). A search for homologous sequences using BLAST resulted in 99.9, 99.6 and 99.8% identity of 16S rDNA, gyrB and rpoB, respectively, with sequences from the NN08200 of Pantoea ananatis (GenBank accession numbers: MK415050.1 for 16S rDNA, CP035034.1 for gyrB and CP035034.1.1 for rpoB). Above molecular results indicated that PA21QJ01 isolated from maize white spot is P. ananatis. Pathogenicity tests were performed on tasseled plants of the suscptible maize variety Wugu1790. After culture in LB medium plate at 30°C for 12 h, the bacterial solution was used for inoculation at a concentration of 1 × 108 CFU ml-1. After 7 days of inoculation, the leaves of the plants appeared water-soaked. After 10 days, white spot developed with brown margin. In contrast, the control plants remained healthy and symptomless. The same P. ananatis was reisolated in the inoculated maize plants, fulfilled Koch's law. In the last decade, P. ananatis has been reported to cause maize white spot in South Africa, Mexico, Poland, Argentina, Brazil (Sauer et al. 2015), and Ecuador (Toaza et al.2021). It has caused crop diseases with other crops, such as onion, rice, pineapple, melon, and sorghum, and others (Sauer et al. 2015). It caused leaf blight and leaf steak in rice in China (Yu et al. 2021). This is the first report of maize white spot caused by P. ananatis in China. However, to our knowledge, this is the first report of maize white spot disease in China. Attentions should be paid to screening for disease-resistant resources and breeding disease-resistant hybrids. Reference: Wells, J. M. et al. 1987. Int. J. Syst. Bacteriol. 37:136-143. Shin, G. Y. et al. 2022. Plant Dis. Doi: 10.1094/PDIS-08-21-1810-SC. Brady, C., et al. 2008. Syst. Appl. Microbiol. 31:447. Galkiewicz, J. P., and Kellogg, C. A. 2008. APPL ENVIRON MICROB, 74.24: 7828-7831. Toaza, A. et al. 2021. Plant Dis. Doi:10.1094/PDIS-02-21-0298-PDN Yamamoto, S., and Harayama, S. 1995. APPL ENVIRON MICROB, 61:1104.L. Sauer, A. V. et al. 2015. Agronomy Science and Biotechnology. Doi:10.33158/ASB.2015v1i1p21 Yu et al. 2021. Plant Dis. Doi:10.1094/PDIS-05-21-0988-PDN.

Understanding changes in the intensity and frequency of extreme precipitation is vital for flood control, disaster mitigation, and water resource management. In this study, 12 extreme precipitation indices and the best-fitting extreme value distribution were used to analyze the spatiotemporal characteristics of extreme precipitation in the upper reaches of the Hongshui River Basin (UHRB). The possible links between extreme precipitation and large-scale circulation were also investigated. Most extreme precipitation indices increased from west to east in the UHRB, indicating that the eastern region is a humid area with abundant precipitation. The indices for consecutive wet days (CWD) and precipitation events (R0.1) decreased significantly, indicating that the UHRB tends to be dry, with few precipitation events. The probability distribution functions of most extreme precipitation indices, especially that of R0.1, shifted significantly to the left in 1988–2016 compared with 1959–1987, further indicating that the UHRB has experienced a significant drying trend in recent decades. The East Asian summer monsoon and the El Niño–Southern Oscillation/Pacific Decadal Oscillation were confirmed to influence extreme precipitation in the UHRB. These findings are helpful for understanding extreme precipitation variation trends in the UHRB and provide references for further research. HIGHLIGHTS We do not focus on the Pearl River Basin (453,690 km2) but pay attention to a sub-basin (98,500 km2) within it.; Most extreme precipitation indices decreased slightly and nonsignificantly in the UHRB.; The number of consecutive wet days and precipitation events decreased significantly.; The UHRB has tended to be dry, with few precipitation events.; The El Niño–Southern Oscillation /Pacific Decadal Oscillation and East Asian summer monsoon have strong effects on extreme precipitation.

Because of the distinct and complex anatomy of the ampullary region, the exact origin of the periampullary tumors was often difficult to ascertain. In this study, we evaluated 78 patient samples, including 26 small intestinal adenocarcinomas, 35 pancreatic ductal adenocarcinomas, and 17 cholangiocarcinomas by immunohistochemical detection of cadherin-17 (CDH17), CDX2, CK20, and CK19 protein expression. The result showed that CDH17 and CDX2 expression was higher in small intestinal adenocarcinoma (73.1% and 65.4%) than in pancreatic (14.3% and 2.9%) and bile duct (41.2% and 23.5%) cancers, respectively. CK20 expression was low in 78 tumor tissues, but relatively high in small intestinal adenocarcinoma (42.3%). CK19 showed a strong positive expression in all 78 adenocarcinoma tissues. The CDH17-high/CDX2-high pattern was predominantly expressed in small intestinal cancer tissues (75%), whereas the CDH17-low/CDX2-low pattern was observed in pancreatic cancers (63.8%) and bile duct cancers (20.9%). The study concluded that CDH17-high/CDX2-high adenocarcinomas more likely originated from small intestine versus pancreas or bile duct, whereas CDH17-low/CDX2-low ones are more likely of pancreatic origin. The combined use of CDH17 and CDX2 could be helpful in providing support for the histologic origin of periampullary adenocarcinoma.

Agkisacucetin, a snake C-type lectin-like protein isolated from the venom of Deinagkistrodon acutus (formerly Agkistrodon acutus), is a novel antithrombotic drug candidate in phase 2 clinical trials. Agkisacucetin specifically recognizes the platelet surface receptor glycoprotein Ib α chain (GPIbα) to block GPIb and von Willebrand factor (VWF). In this study, we solved the crystal structure of the GPIbα N-terminal domain (residues 1-305) in complex with agkisacucetin to understand their molecular recognition mechanism. The crystal structure showed that agkisacucetin primarily contacts GPIbα at the C-terminal part of the conserved leucine-rich repeat (LRR) domain (LRR-6 to LRR-8) and the previously described “β-switch” region through the β chain. In addition, we found that agkisacucetin α chain contacts part of the GPIbα C-terminal peptide after the LRR domain through complementary charge interactions. This C-terminal peptide plays a key role in GPIbα and thrombin recognition. Therefore, our structure revealed that agkisacucetin can sterically block the interaction between the GPIb receptor and VWF and thrombin proteins to inhibit platelet function. Our structural work provides key molecular insights into how an antithrombotic drug candidate recognizes the GPIb receptor to modulate platelet function to inhibit thrombosis.

It is important to understand how actual evapotranspiration (ETa) changes occur and what the dominant contributing factors are. This study investigated the impacts of climatic factor and vegetation coverage on the variations of ETa using a Budyko-based framework. Climatic seasonal index and vegetation coverage index were selected as indicating factors. Two reservoir watersheds, i.e. the Wangkuai Reservoir Watershed and the Xidayang Reservoir Watershed, of the Daqing River Basin were selected as case studies. Also, relationships between the ETa and climatic and vegetation factors were analyzed. Results showed that the improved vegetation conditions positively contributed to the ETa changes, leading to an increase of 42.15 and 58.56 mm of ETa in the two watersheds, while the increasing climate seasonality had a negative effect, resulting in a drop of 11.48 and 13.47 mm of ETa. Vegetation coverage was recognized as the dominant factor to the changes of ETa, compared to the climatic factor. Our research could offer supporting information for water resources management, agricultural production improvement and eco-environment construction in arid regions. HIGHLIGHTS This study investigated the impacts of climatic factor and vegetation coverage on the variations of actual evapotranspiration using a Budyko-based framework.; The water-heat coupling controlling parameter of the Budyko-based framework was quantified by fitting the simulated actual evapotranspiration to observed actual evapotranspiration in a semi-empirical formula.

Glacier retreat is altering the water regime of the Tibetan Plateau (TP) as the region’s climate changes, but there remain substantial gaps in our knowledge of recent glacier loss in this region due to the difficulty of making- direct high-mountain observations and this limits our ability to predict the future of this important water resource. Here, we assessed 44 years of glacier area and volume changes in the major West Nyainqentanglha Range (WNT) that supplies meltwater to the densely populated Lhasa River basin and Nam Co, the second largest endorheic lake on the TP. Between the two periods 1976–2000 and 2000–2020, we found that the glacier areal retreat rate was more than doubled (from -0.54 ± 0.21 % a-1 to -1.17 ± 0.30 % a-1) and surface lowering also accelerated ( from -0.26 ± 0.09 m w.e.a-1 to -0.37 ± 0.15 m w.e.a-1) with particularly intense melting after 2014. This acceleration is similar in both timing and magnitude to that observed for Himalayas glaciers farther south. Besides, the areal retreat rate and mass loss rate of most glaciers in WNT were not synchronized. To understand the sensitivity of WNT glaciers to climate forcing, we examined the effects of topography, debris-cover, and the presence of proglacial lakes on our observed changes. We found consistently faster areal retreat but slower thinning rates on steeper slopes and an inconsistent relationship with aspect. We concluded that our observed spatial and temporal patterns of glacier change were dominated by observed local variations temperature and precipitation, the melt-reducing role of supraglacial debris, and the increasing influence of ice-marginal lakes on glacier retreat.