ISG15 targets glycosylated PD-L1 and promotes its degradation to enhance antitumor immune effects in lung adenocarcinoma.

BACKGROUND: Immunocheckpoint inhibitors (ICIs) have been widely used in the clinical treatment of lung cancer. Although clinical studies and trials have shown that patients can benefit significantly after PD-1/PD-L1 blocking therapy, less than 20% of patients can benefit from ICIs therapy due to tumor heterogeneity and the complexity of immune microenvironment. Several recent studies have explored the immunosuppression of PD-L1 expression and activity by post-translational regulation. Our published articles demonstrate that ISG15 inhibits lung adenocarcinoma progression. Whether ISG15 can enhance the efficacy of ICIs by modulating PD-L1 remains unknown. METHODS: The relationship between ISG15 and lymphocyte infiltration was identified by IHC. The effects of ISG15 on tumor cells and T lymphocytes were assessed using RT-qPCR and Western Blot and in vivo experiments. The underlying mechanism of PD-L1 post-translational modification by ISG15 was revealed by Western blot, RT-qPCR, flow cytometry, and Co-IP. Finally, we performed validation in C57 mice as well as in lung adenocarcinoma tissues. RESULTS: ISG15 promotes the infiltration of CD4+ T lymphocytes. In vivo and in vitro experiments demonstrated that ISG15 induces CD4+ T cell proliferation and invalidity and immune responses against tumors. Mechanistically, we demonstrated that the ubiquitination-like modifying effect of ISG15 on PD-L1 increased the modification of K48-linked ubiquitin chains thus increasing the degradation rate of glycosylated PD-L1 targeting proteasomal pathway. The expression of ISG15 and PD-L1 was negatively correlated in NSCLC tissues. In addition, reduced accumulation of PD-L1 by ISG15 in mice also increased splenic lymphocyte infiltration as well as promoted cytotoxic T cell infiltration in the tumor microenvironment, thereby enhancing anti-tumor immunity. CONCLUSIONS: The ubiquitination modification of PD-L1 by ISG15 increases K48-linked ubiquitin chain modification, thereby increasing the degradation rate of glycosylated PD-L1-targeted proteasome pathway. More importantly, ISG15 enhanced the sensitivity to immunosuppressive therapy. Our study shows that ISG15, as a post-translational modifier of PD-L1, reduces the stability of PD-L1 and may be a potential therapeutic target for cancer immunotherapy.

Stretchable, self-healing and adhesive sodium alginate-based composite hydrogels as wearable strain sensors for expansion-contraction motion monitoring.

Developing multifunctional hydrogels with stretchability, self-healing ability, adhesiveness, and conductivity into flexible strain sensors for human motion and health monitoring has attracted great attention and is highly desired. However, the present motion detectors mainly focus on stretching, bending, and twisting of different body parts while the expansion-contraction motion has been rarely investigated. In this study, along with carbon nanotubes (CNTs) as conductive components, sodium alginate (Alg) modified with 3-aminophenylboronic acid (PBA) and dopamine (DA) were synthesized and employed as precursors to prepare a multifunctional Alg-CNT hydrogel. The formed dynamic covalent bonds between PBA and DA endowed the hydrogel with a rapid self-healing property (30 s) while the introduction of CNTs remarkably enhanced the mechanical strength and electrical conductivity of the hydrogel. Moreover, the as-prepared hydrogel displayed a satisfactory stretchability (500%) and self-adhesiveness to various substrates. When used as a strain sensor, the Alg-CNT hydrogel that exhibited a fast response (150 ms) and ultra-durability (over 30 000 cycles) was demonstrated to be capable of monitoring subtle expansion-contraction motions (e.g., human breathing and mouse heart beating) via periodic and repeatable electrical signals. Therefore, this multifunctional hydrogel is highly suitable for monitoring expansion-contraction motions, indicating its potential applications in personal health monitoring.

Serum Cytokine and Chemokine Profile in Relation to the Severity of Coronavirus Disease 2019 in China.

Coronavirus disease 2019 (COVID-19) is an emerging infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We investigated the serum cytokine and chemokine levels in asymptomatic, mild, moderate, severe, and convalescent SARS-CoV-2-infected cases. Proinflammatory cytokine and chemokine production induced by SARS-CoV-2 were observed not only in symptomatic patients but also in asymptomatic cases, and returned to normal after recovery. IL-6, IL-7, IL-10, IL-18, G-CSF, M-CSF, MCP-1, MCP-3, IP-10, MIG, and MIP-1α were found to be associated with the severity of COVID-19. Moreover, a set of cytokine and chemokine profiles were significantly higher in SARS-CoV-2-infected male than female patients. The serum levels of MCP-1, G-CSF, and VEGF were weakly and positively correlated with viral titers. We suggest that combinatorial analysis of serum cytokines and chemokines with clinical classification may contribute to evaluation of the severity of COVID-19 and optimize the therapeutic strategies.

Growth of NiMn layered double hydroxides on nanopyramidal BiVO4 photoanode for enhanced photoelectrochemical performance.

Photoelectrochemical water oxidation for hydrogen generation via utilizing sunlight is considered a very promising pathway for generating sustainable energy in an environmental manner. Here, a composite photoanode, consisting of nanopyramidal BiVO4 arrays and one layered double hydroxide (NiMn-LDH) was designed and fabricated via a facile route. The obtained BiVO4/NiMn-LDH composite photoelectrode presented a significant enhancement in the photoelectrochemical (PEC) current density, conversion efficiency and stability for solar water oxidation. With 2D NiMn-LDH decoration, an obvious cathodic shift of ∼480 mV in the onset potential can be observed, and more than two times enhancement in photocurrent performance is achieved. The improvement in photoelectrochemical activity for BiVO4/NiMn-LDH composite photoanode can be attributed to the enhanced water-oxidation kinetics leading to the efficient separation, transfer and collection of charge carriers at the photoanode/electrolyte interface. The result demonstrates NiMn-LDH represents one of the active oxygen evolution catalysts (OECs) to improve the PEC activity of metal oxide photoanode.

Transitional Goos-Hänchen effect due to the topological phase transitions.

We examine the Goos-Hänchen (GH) effect for a Gaussian beam impinging on the surface of silicene whose topological phase transitions can be modulated by external electric field and/or irradiating circular polarized light. It is shown that both the spatial and angular shifts in GH effect present a sharp jump due to the topological phase transitions. The transitional GH effect can be attributed to transitional optical conductivity, which relates to Berry curvature and Chern numbers. These results can be extensively extended to other two-dimensional atomic crystals in graphene family. We believe that the transitional GH effect may offer a possible way to determine the Berry curvature, Chern numbers, and topological phase transition by a direct optical measurement.

Precise identification of graphene layers at the air-prism interface via a pseudo-Brewster angle.

We propose a simple method for the precise identification of graphene layers at the air-prism interface via a pseudo-Brewster angle, where the horizontally polarized reflection is close to zero. We find that the pseudo-Brewster angle is sensitive to the variation of graphene layers where the pseudo-Brewster angle is approximately linearly increased about 0.5 deg as the layer numbers increased. Furthermore, the sensitivity of the pseudo-Brewster angle can be greatly enhanced and reaches 0.04 deg by eliminating the influence of the cross-polarization effect. Our scheme can provide a simple and effective method to identify the layer numbers of graphene.

Dual Vacancies: An Effective Strategy Realizing Synergistic Optimization of Thermoelectric Property in BiCuSeO.

Vacancy is a very important class of phonon scattering center to reduce thermal conductivity for the development of high efficient thermoelectric materials. However, conventional monovacancy may also act as an electron or hole acceptor, thereby modifying the electrical transport properties and even worsening the thermoelectric performance. This issue urges us to create new types of vacancies that scatter phonons effectively while not deteriorating the electrical transport. Herein, taking BiCuSeO as an example, we first reported the successful synergistic optimization of electrical and thermal parameters through Bi/Cu dual vacancies. As expected, as compared to its pristine and monovacancy samples, these dual vacancies further increase the phonon scattering, which results in an ultra low thermal conductivity of 0.37 W m(-1) K(-1) at 750 K. Most importantly, the clear-cut evidence in positron annihilation unambiguously confirms the interlayer charge transfer between these Bi/Cu dual vacancies, which results in the significant increase of electrical conductivity with relatively high Seebeck coefficient. As a result, BiCuSeO with Bi/Cu dual vacancies shows a high ZT value of 0.84 at 750 K, which is superior to that of its native sample and monovacancies-dominant counterparts. These findings undoubtedly elucidate a new strategy and direction for rational design of high performance thermoelectric materials.

Vacancy associates-rich ultrathin nanosheets for high performance and flexible nonvolatile memory device.

On the road of innovation in modern information technology, resistive switching random access memory (RRAM) has been considered to be the best potential candidate to replace the conventional Si-based technologies. In fact, the key prerequisite of high storage density and low power consumption as well as flexibility for the tangible next generation of nonvolatile memories has stimulated extensive research into RRAM. Herein, we highlight an inorganic graphene analogue, ultrathin WO3·H2O nanosheets with only 2-3 nm thickness, as a promising material to construct a high performance and flexible RRAM device. The abundant vacancy associates in the ultrathin nanosheets, revealed by the positron annihilation spectra, act not only carrier reservoir to provide carriers but also capture center to trap the actived Cu(2+) for the formation of conductive filaments, which synergistically realize the resistive switching memory with low operating voltage (+1.0 V/-1.14 V) and large resistance ON/OFF ratio (>10(5)). This ultrathin-nanosheets-based RRAM device also shows long retention time (>10(5) s), good endurance (>5000 cycles), and excellent flexibility. The finding of the existence of distinct defects in ultrathin nanosheets undoubtedly leads to an atomic level deep understanding of the underlying nature of the resistive switching behavior, which may serve as a guide to improve the performances and promote the rapid development of RRAM.

Low overpotential in vacancy-rich ultrathin CoSe2 nanosheets for water oxidation.

According to Yang Shao-Horn's principle, CoSe2 is a promising candidate as an efficient, affordable, and sustainable alternative electrocatalyst for the oxygen evolution reaction, owing to its well-suited electronic configuration of Co ions. However, the catalytic efficiency of pure CoSe2 is still far below what is expected, because of its poor active site exposure yield. Herein, we successfully overcome the disadvantage of insufficient active sites in bulk CoSe2 by reducing its thickness into the atomic scale rather than any additional modification (such as doping or hybridizing with graphene or noble metals). The positron annihilation spectrometry and XAFS spectra provide clear evidence that a large number of VCo″ vacancies formed in the ultrathin nanosheets. The first-principles calculations reveal that these VCo″ vacancies can serve as active sites to efficiently catalyze the oxygen evolution reaction, manifesting an OER overpotential as low as 0.32 V at 10 mA cm(-2) in pH 13 medium, which is superior to the values for its bulk counterparts as well as those for the most reported Co-based electrocatalysts. Considering the outstanding performance of the simple, unmodified ultrathin CoSe2 nanosheets as the only catalyst, further improvement of the catalytic activity is expected when various strategies of doping or hybridizing are used. These results not only demonstrate the potential of a notable, affordable, and earth-abundant water oxidation electrocatalyst based on ultrathin CoSe2 nanosheets but also open up a promising avenue into the exploration of excellent active and durable catalysts toward replacing noble metals for oxygen electrocatalysis.

Computational identification of epitopes in the glycoproteins of novel bunyavirus (SFTS virus) recognized by a human monoclonal antibody (MAb 4-5).

In this work, we have developed a new approach to predict the epitopes of antigens that are recognized by a specific antibody. Our method is based on the "multiple copy simultaneous search" (MCSS) approach which identifies optimal locations of small chemical functional groups on the surfaces of the antibody, and identifying sequence patterns of peptides that can bind to the surface of the antibody. The identified sequence patterns are then used to search the amino-acid sequence of the antigen protein. The approach was validated by reproducing the binding epitope of HIV gp120 envelop glycoprotein for the human neutralizing antibody as revealed in the available crystal structure. Our method was then applied to predict the epitopes of two glycoproteins of a newly discovered bunyavirus recognized by an antibody named MAb 4-5. These predicted epitopes can be verified by experimental methods. We also discuss the involvement of different amino acids in the antigen-antibody recognition based on the distributions of MCSS minima of different functional groups.

Corrigendum: Changes and net ecosystem productivity of terrestrial ecosystems and their influencing factors in China from 2000 to 2019.

[This corrects the article DOI: 10.3389/fpls.2023.1120064.].

Characteristics of the Northern Hemisphere cold regions changes from 1901 to 2019.

The accurate delineation of the spatial extent of cold regions provides the basis for the study of global environmental change. However, attention has been lacking on the temperature-sensitive spatial changes in the cold regions of the Earth in the context of climate warming. In this study, the mean temperature in the coldest month lower than - 3 °C, no more than 5 months over 10 °C, and an annual mean temperature no higher than 5 °C were selected to define cold regions. Based on the Climate Research Unit land surface air temperature (CRUTEM) of monthly mean surface climate elements, the spatiotemporal distribution and variation characteristics of the Northern Hemisphere (NH) continental cold regions from 1901 to 2019 are analyzed in this study, by adopting time trend and correlation analyses. The results show: (1) In the past 119 years, the cold regions of the NH covered on average about 4.074 × 107 km2, accounting for 37.82% of the total land area of the NH. The cold regions can be divided into the Mid-to-High latitude cold regions and the Qinghai-Tibetan Plateau cold regions, with spatial extents of 3.755 × 107 km2 and 3.127 × 106 km2, respectively. The Mid-to-High latitude cold regions in the NH are mainly distributed in northern North America, most of Iceland, the Alps, northern Eurasia, and the Great Caucasus with a mean southern boundary of 49.48° N. Except for the southwest, the entire region of the Qinghai-Tibetan Plateau, northern Pakistan, and most of Kyrgyzstan are cold regions. (2) In the past 119 years, the rates of change in the spatial extent of the cold regions in the NH, the Mid-to-High latitude, and the Qinghai-Tibetan Plateau were - 0.030 × 107 km2/10 a, - 0.028 × 107 km2/10 a, and - 0.013 × 106 km2/10 a, respectively, showing an extremely significant decreasing trend. In the past 119 years, the mean southern boundary of the Mid-to-High latitude cold regions has been retreating northward at all longitudes. For instance, the mean southern boundary of the Eurasian cold regions moved 1.82° to the north and that of North America moved 0.98° to the north. The main contribution of the study lies in the accurate definition of the cold regions and documentation of the spatial variation of the cold regions in the NH, revealing the response trends of the cold regions to climate warming, and deepening the study of global change from a new perspective.

Changes and net ecosystem productivity of terrestrial ecosystems and their influencing factors in China from 2000 to 2019.

Changes in net ecosystem productivity (NEP) in terrestrial ecosystems in response to climate warming and land cover changes have been of great concern. In this study, we applied the normalized difference vegetation index (NDVI), average temperature, and sunshine hours to drive the C-FIX model and to simulate the regional NEP in China from 2000 to 2019. We also analyzed the spatial patterns and the spatiotemporal variation characteristics of the NEP of terrestrial ecosystems and discussed their main influencing factors. The results showed that (1) the annual average NEP of terrestrial ecosystems in China from 2000 to 2019 was 1.08 PgC, exhibiting a highly significant increasing trend with a rate of change of 0.83 PgC/10 y. The terrestrial ecosystems in China remained as carbon sinks from 2000 to 2019, and the carbon sink capacity increased significantly. The NEP of the terrestrial ecosystem increased by 65% during 2015-2019 compared to 2000-2004 (2) There was spatial differences in the NEP distribution of the terrestrial ecosystems in China from 2000-2019. Taking the line along the Daxinganling-Yin Mountains-Helan Mountains-Transverse Range as the boundary, the NEP was significantly higher in the eastern part than in the western part. Among them, the NEP was positive (carbon sink) in northeastern, central, and southern China, and negative (carbon source) in parts of northwestern China and the Tibet Autonomous Region. The spatial variation of NEP in terrestrial ecosystems increased from 2000 to 2009. The areas with a significant increase accounted for 45.85% and were mainly located in the central and southwestern regions. (3) The simulation results revealed that vegetation changes and CO2 concentration changes both contributed to the increase in the NEP in China, contributing 85.96% and 36.84%, respectively. The vegetation changes were the main factor causing the increase in the NEP. The main contribution of this study is to further quantify the NEP of terrestrial ecosystems in China and identify the influencing factors that caused these changes.

Preparation and evaluation of recombinant severe fever with thrombocytopenia syndrome virus nucleocapsid protein for detection of total antibodies in human and animal sera by double-antigen sandwich enzyme-linked immunosorbent assay.

The recent emergence of the human infection confirmed to be caused by severe fever with thrombocytopenia syndrome virus (SFTSV) in China is of global concern. Safe diagnostic immunoreagents for determination of human and animal seroprevalence in epidemiological investigations are urgently needed. This paper describes the cloning and expression of the nucleocapsid (N) protein of SFTSV. An N-protein-based double-antigen sandwich enzyme-linked immunosorbent assay (ELISA) system was set up to detect the total antibodies in human and animal sera. We reasoned that as the double-antigen sandwich ELISA detected total antibodies with a higher sensitivity than traditional indirect ELISA, it could be used to detect SFTSV-specific antibodies from different animal species. The serum neutralization test was used to validate the performance of this ELISA system. All human and animal sera that tested positive in the neutralization test were also positive in the sandwich ELISA, and there was a high correlation between serum neutralizing titers and ELISA readings. Cross-reactivity was evaluated, and the system was found to be highly specific to SFTSV; all hantavirus- and dengue virus-confirmed patient samples were negative. SFTSV-confirmed human and animal sera from both Anhui and Hubei Provinces in China reacted with N protein in this ELISA, suggesting no major antigenic variation between geographically disparate virus isolates and the suitability of this assay in nationwide application. ELISA results showed that 3.6% of the human serum samples and 47.7% of the animal field serum samples were positive for SFTSV antibodies, indicating that SFTSV has circulated widely in China. This assay, which is simple to operate, poses no biohazard risk, does not require sophisticated equipment, and can be used in disease surveillance programs, particularly in the screening of large numbers of samples from various animal species.

Identification of key drivers of the microbial shikimic acid pathway during different materials composting.

Metabolites of shikimic acid (SA) pathway can be used as humic substance (HS) precursors. Due to the complexity of SA anabolism, there were few studies on SA pathway during composting. The aim of this study was to identify the key drivers of SA pathway during different materials composting. During composting, the SA, protocatechuic acid (PA) and gallic acid (GA) decreased by 57.09%, 72.27% and 54.04% on average, respectively. The structural equation model showed that SA had key driving factors (organic matter and pH) during lawn waste composting. In addition, the complexity of material structure was the main factor affecting PA driving factors. The factors and degree of influence on GA varied with different materials. Accordingly, this study provided theoretical support for the improvement of SA metabolic intensity by single material and mixed material composting, and further provided a new direction for future HS research.

Heterologous expression of GH5 chitosanase in Pichia pastoris and antioxidant biological activity of its chitooligosacchride hydrolysate.

Chitosanase was widely used in the production of bioactive chitooligosacchride (CHOS) due to their safety, controllability, environmental protection, and biodegradability. Studies showed that the bioactivity of CHOS is closely related to its degree of polymerization. Therefore, the production of ideal polymerized CHOS becomes our primary goal. In this study, the glycosyl hydrolase (GH) family 5 chitosanase was successfully expressed heterologously in Pichia pastoris. After 96 h of high-density fermentation, the chitosanase activity reached 90.62 U·mL-1, the protein content reached 9.76 mg·mL-1. When 2% chitosan was hydrolyzed by crude enzyme (20 U/mL), the hydrolysis rate reached 91.2% after 8 h, producing a mixture of CHOS with 2-4 desirable degrees of polymerization (DP). Then, the antioxidant activity of CHOS mixture was investigated, and the results showed that the antioxidant effect was concentration-dependent and had great application potential in the field of nutrition.

Evaluating differences in humic substances formation based on the shikimic acid pathway during different materials composting.

This study aimed to evaluate differences in humic substance (HS) formation based on the shikimic acid pathway (SAP) during five different materials composting. The results showed that compared with other three materials, gallic acid, protocatechuic acid and shikimic acid of the SAP products in lawn waste (LW) and garden waste (GW) compost decreased significantly. Furthermore, as important indicators for evaluating humification, humic acid and degree of polymerization increased by 39.4%, 79.5% and 21.8%, 87.9% in LW and GW, respectively. Correlation analysis showed that SAP products were strongly correlated with HS fractions in LW and GW. Meanwhile, network analysis indicated that more core bacteria associated with both SAP products and HS were identified in LW and GW. Finally, the structural equation model proved that SAP had more significant contribution to humification improvement in LW and GW. These findings provided theoretical foundation and feasible actions to improve compost quality by the SAP.

Engineering of a chitosanase fused to a carbohydrate-binding module for continuous production of desirable chitooligosaccharides.

Chitooligosaccharides (CHOS) with multiple biological activities are usually produced through enzymatic hydrolysis of chitosan or chitin. However, purification and recycling of the enzyme have largely limited the advancement of CHOS bioproduction. Here, we engineered a novel enzyme by fusing the native chitosanase Csn75 with a carbohydrate-binding module (CBM) that can specifically bind to curdlan. The recombinase Csn75-CBM was successfully expressed by Pichia pastoris and allowed one-step purification and immobilization in the chitosanase immobilized curdlan packed-bed reactor (CICPR), where a maximum adsorption capacity of 39.59 mg enzyme/g curdlan was achieved. CHOS with degrees of polymerization of 2-5 (a hydrolysis yield of 97.75%), 3-6 (75.45%), and 3-7 (73.2%) were continuously produced by adjusting the ratio of enzyme and chitosan or the flow rate of chitosan. Moreover, the CICPR exhibited good stability and reusability after several cycles. The recombinase Csn75-CBM has greatly improved the efficiency of the bioproduction of CHOS.

Full particle-in-cell simulation of the formation and structure of a collisional plasma shock wave.

The formation and structure of a collisional shock wave in a fully ionized plasma is studied via full particle-in-cell simulations, which allows the complex momentum and energy transfer processes between different charged particles to be treated self-consistently. The kinetic energy of the plasma flow drifting towards a reflecting piston is found to be rapidly converted into thermal motion under the cooperative effects of ion-ion collisions, ion-electron collisions, and electric field charged-particle interactions. The subsequent shock evolution is influenced by the "precursor" ion beam before a quasisteady state is reached. The shock wave structure is then analyzed from a two-fluid transport viewpoint, which is found to be affected by "flux-limiting" electron transport, the nonthermal ions, and the charge separation electric field.

Characterization of a distinct low-grade oncocytic renal tumor (CD117-negative and cytokeratin 7-positive) based on a tertiary oncology center experience: the new evidence from China.

To examine the clinicopathologic and immunohistochemical features of a group of newly defined low-grade oncocytic renal tumors (LOT) that have the "CD117 negative/cytokeratin (CK)7 positive" immunoprofile. We have queried our hospital database and found 4456 consecutive renal tumors between 2016 and 2019. Among these renal tumors, eight (8) cases meet the morphologic and immunohistochemical characterization for low-grade oncocytic renal tumor (LOT). The eight (8) patients' mean age is 56.6 years (range 39-70 years old), and the male to female ratio is 1:1. Macroscopically, these LOTs generally present with tan-brown and solid cut surfaces and demonstrate similar solid, compact nested growth pattern microscopically. Tumor cells exhibit oncocytic cytoplasm and uniformly rounded to oval nuclei. There are areas of edematous stroma containing dispersed single or small clustered tumor cells. All tumors are negative for CD117 and positive for CK7. Uniform reactivity is also found for BerEP4, cyclin D1, and SDHB. Besides, CD10, vimentin, and AMACR are either negative or only focally positive. All of the tumors are negative for CA9 and TFE. The Ki-67 index is less than 5% in the seven (7) internal cases. Seven (7) of the eight (8) patients who are available for follow-up are alive and without disease recurrence (mean follow-up period of 21.6 months, ranging from 6 to 43 months). We described a group of low-grade oncocytic renal tumors identified retrospectively in a large tertiary cancer center, which was probably the first report originated from China or even Asia in the English literature so far. These tumors demonstrated eosinophilic cytoplasm and low-grade appearing nuclei with a "CD117 negative/CK7 positive" immunoprofile. The incidence rate was about 3.7% of the oncocytic renal tumors and 0.18% of all the renal tumors that were received in our lab during the four-year period. It is necessary to separate this group of tumors by its characteristic morphologic and immunophenotypic features.