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Cytokines are critical for intercellular communication in human health and disease, but the investigation of cytokine signaling activity has remained challenging due to the short half-lives of cytokines and the complexity/redundancy of cytokine functions. To address these challenges, we developed the Cytokine Signaling Analyzer (CytoSig; https://cytosig.ccr.cancer.gov/), providing both a database of target genes modulated by cytokines and a predictive model of cytokine signaling cascades from transcriptomic profiles. We collected 20,591 transcriptome profiles for human cytokine, chemokine and growth factor responses. This atlas of transcriptional patterns induced by cytokines enabled the reliable prediction of signaling activities in distinct cell populations in infectious diseases, chronic inflammation and cancer using bulk and single-cell transcriptomic data. CytoSig revealed previously unidentified roles of many cytokines, such as BMP6 as an anti-inflammatory factor, and identified candidate therapeutic targets in human inflammatory diseases, such as CXCL8 for severe coronavirus disease 2019.CytoSig, an interactive database and model to predict cytokine signaling activity at bulk and single-cell levels.

The platinum‐based DNA damaging agent cisplatin is used as a standard therapy for locally advanced head and neck squamous cell carcinoma (HNSCC). However, the mechanisms underpinning the cytotoxic effects of this compound are not entirely elucidated. Cisplatin produces anticancer effects primarily via activation of the DNA damage response, followed by inducing BCL‐2 family dependent mitochondrial apoptosis. We have previously demonstrated that cisplatin induces the expression of proapoptotic BCL‐2 family protein, Noxa, that can bind to the prosurvival BCL‐2 family protein, MCL‐1, to inactivate its function and induce cell death. Here, we show that the upregulation of Noxa is critical for cisplatin‐induced apoptosis in p53‐null HNSCC cells. This induction is regulated at the transcriptional level. With a series of Noxa promoter‐luciferase reporter assays, we find that the CRE (cAMP response element) in the promoter is critical for the Noxa induction by cisplatin treatment. Among the CREB/ATF transcription factors, ATF3 and ATF4 are induced by cisplatin, and downregulation of ATF3 or ATF4 reduced cisplatin‐induced Noxa. ATF3 and ATF4 bind to and cooperatively activate the Noxa promoter. Furthermore, ERK1 is involved in cisplatin‐induced ATF4 and Noxa induction. In conclusion, ATF3 and ATF4 are important regulators that induce Noxa by cisplatin treatment in a p53‐independent manner. Platinum‐based DNA damaging agent, cisplatin, is used as standard therapy for locally advanced head and neck squamous cell carcinoma (HNSCC). However, the mechanisms underpinning the cytotoxic effects of this compound are not entirely elucidated. Here, we demonstrate that ATF3 and ATF4 are important transcription factors that induce Noxa by cisplatin treatment in a p53‐independent manner.

Several international non-governmental organizations (INGOs) function as boundary organizations and try to promote ecosystem-based adaptation (EbA) as a pivotal climate change adaptation strategy for coastal areas. This is being done in Vietnam. Few studies, however, have investigated how these INGOs operate, what challenges they face, and what conditions support them to successfully promote the implementation of EbA. To address this knowledge gap, the literature on international boundary work and boundary organizations was first reviewed, deriving four categories of conditions for a successful promotion of EbA: knowledge, networks, resources, and context. Next, we applied this framework in a case study of the International Union for Conservation (IUCN) and the Foundation of Netherlands Volunteers (SNV) led EbA project on the restoration and sustainable use of mangroves in two provinces, Ca Mau and Ben Tre, which are located in the Vietnamese Mekong Delta. We interviewed 25 key informants representing INGOs, Vietnamese governmental agencies, farmers, scientists, and market parties. Our case study not only revealed how most literature-based success conditions were met but also found some additional conditions. We found that INGOs will have a greater chance of successfully promoting the implementation of the EbA in cases in which they can act as a knowledge broker, have a strong international network, can supply enough resources, and use context-specific strategies. A supportive context appeared to be essential.

Staphylococcus aureus is a common pathogen causing infections in humans with various degrees of severity, with pneumonia being one of the most severe infections. In as much as staphylococcal pneumonia is a disease driven in large part by α-hemolysin (Hla) and Panton-Valentine leukocidin (PVL), we evaluated whether active immunization with attenuated forms of Hla (HlaH35L/H48L) alone, PVL components (LukS-PVT28F/K97A/S209A and LukF-PVK102A) alone, or combination of all 3 toxoids could prevent lethal challenge in a rabbit model of necrotizing pneumonia caused by the USA300 community-associated methicillin-resistant S. aureus (MRSA). Rabbits vaccinated with Hla toxoid alone or PVL components alone were only partially protected against lethal pneumonia, whereas those vaccinated with all 3 toxoids had 100% protection against lethality. Vaccine-mediated protection correlated with induction of polyclonal antibody response that neutralized not only α-hemolysin and PVL, but also other related toxins, produced by USA300 and other epidemic MRSA clones.

Despite advanced therapeutics, esophageal squamous cell carcinoma (ESCC) remains one of the deadliest cancers. Here, we propose a novel therapeutic strategy based on synthetic lethality combining trifluridine/tipiracil and MK1775 (WEE1 inhibitor) as a treatment for ESCC. This study demonstrates that trifluridine induces single‐strand DNA damage in ESCC cells, as evidenced by phosphorylated replication protein 32. The DNA damage response includes cyclin‐dependent kinase 1 (CDK1) (Tyr15) phosphorylation as CDK1 inhibition and a decrease of the proportion of phospho‐histone H3 (p‐hH3)‐positive cells, indicating cell cycle arrest at the G2 phase before mitosis entry. The WEE1 inhibitor remarkedly suppressed CDK1 phosphorylation (Try15) and reactivated CDK1, and also increased the proportion of p‐hH3‐positive cells, which indicates an increase of the number of cells into mitosis. Trifluridine combined with a WEE1 inhibitor increased trifluridine‐mediated DNA damage, namely DNA double‐strand breaks, as shown by increased γ‐H2AX expression. Moreover, the combination treatment with trifluridine/tipiracil and a WEE1 inhibitor significantly suppressed tumor growth of ESCC‐derived xenograft models. Hence, our novel combination treatment with trifluridine/tipiracil and a WEE1 inhibitor is considered a candidate treatment strategy for ESCC. We suggest combining trifluridine/tipiracil and a WEE1 inhibitor as a novel therapeutic strategy against esophageal squamous cell carcinoma. This approach has demonstrated efficacy by combining the induction of DNA damage with the suppression of the DNA damage response.

Solar hydrogen production is one of the ultimate technologies needed to realize a carbon-neutral, sustainable society. However, an energy-intensive water oxidation half-reaction together with the poor performance of conventional inorganic photocatalysts have been big hurdles for practical solar hydrogen production. Here we present a photoelectrochemical cell with a record high photocurrent density of 19.8 mA cm −2 for hydrogen production by utilizing a high-performance organic–inorganic halide perovskite as a panchromatic absorber and lignocellulosic biomass as an alternative source of electrons working at lower potentials. In addition, value-added chemicals such as vanillin and acetovanillone are produced via the selective depolymerization of lignin in lignocellulosic biomass while cellulose remains close to intact for further utilization. This study paves the way to improve solar hydrogen productivity and simultaneously realize the effective use of lignocellulosic biomass. While light-driven water splitting offers a means to produce renewable H 2 fuel, water oxidation limits performances and yields low-value products. Here, authors demonstrate a photoelectrochemical cell that converts lignocellulosic biomass into valuable products alongside H 2 .

Despite breakthroughs in cancer immunotherapy, most tumor-reactive T cells cannot persist in solid tumors due to an immunosuppressive environment. We developed Tres (tumor-resilient T cell, https://resilience.ccr.cancer.gov/ ), a computational model utilizing single-cell transcriptomic data to identify signatures of T cells that are resilient to immunosuppressive signals, such as transforming growth factor-β1, tumor necrosis factor-related apoptosis-inducing ligand and prostaglandin E2. Tres reliably predicts clinical responses to immunotherapy in melanoma, lung cancer, triple-negative breast cancer and B cell malignancies using bulk T cell transcriptomic data from pre-treatment tumors from patients who received immune-checkpoint inhibitors ( n  = 38), infusion products for chimeric antigen receptor T cell therapies ( n  = 34) and pre-manufacture samples for chimeric antigen receptor T cell or tumor-infiltrating lymphocyte therapies ( n  = 84). Further, Tres identified FIBP , whose functions are largely unknown, as the top negative marker of tumor-resilient T cells across many solid tumor types. FIBP knockouts in murine and human donor CD8 +  T cells significantly enhanced T cell-mediated cancer killing in in vitro co-cultures. Further, Fibp knockout in murine T cells potentiated the in vivo efficacy of adoptive cell transfer in the B16 tumor model. Fibp knockout T cells exhibit reduced cholesterol metabolism, which inhibits effector T cell function. These results demonstrate the utility of Tres in identifying biomarkers of T cell effectiveness and potential therapeutic targets for immunotherapies in solid tumors. Gene signatures associated with T cell resilience to tumor-derived immunosuppressive signals predict responses to immune-checkpoint inhibitors and adoptive cell therapy and identify FIBP as a negative regulator of T cell activity

Lignin is a major component of lignocellulosic biomass. Although it is highly recalcitrant to break down, it is a very abundant natural source of valuable aromatic carbons. Thus, the effective valorisation of lignin is crucial for realising a sustainable biorefinery chain. Here, we report a compartmented photo-electro-biochemical system for unassisted, selective, and stable lignin valorisation, in which a TiO 2 photocatalyst, an atomically dispersed Co-based electrocatalyst, and a biocatalyst (lignin peroxidase isozyme H8, horseradish peroxidase) are integrated, such that each system is separated using Nafion and cellulose membranes. This cell design enables lignin valorisation upon irradiation with sunlight without the need for any additional bias or sacrificial agent and allows the protection of the biocatalyst from enzyme-damaging elements, such as reactive radicals, gas bubbles, and light. The photo-electro-biochemical system is able to catalyse lignin depolymerisation with a 98.7% selectivity and polymerisation with a 73.3% yield using coniferyl alcohol, a lignin monomer. The effective valorisation of lignin is crucial for realizing a sustainable biorefinery. Here, the authors report that a compartmented photo-electro-biochemical design enables unassisted, selective, and stable solar lignin valorisation without the need for any additional bias or chemicals.

Dracaena cochinchinensis Lour. is an ethnomedicinally important plant used in traditional Chinese medicine known as dragon’s blood. Excessive utilization of the plant for extraction of dragon’s blood had resulted in the destruction of the important niche. During a study to provide a sustainable way of utilizing the resources, the endophytic Actinobacteria associated with the plant were explored for potential utilization of their medicinal properties. Three hundred and four endophytic Actinobacteria belonging to the genera Streptomyces, Nocardiopsis, Brevibacterium, Microbacterium, Tsukamurella, Arthrobacter, Brachybacterium, Nocardia, Rhodococcus, Kocuria, Nocardioides, and Pseudonocardia were isolated from different tissues of D. cochinchinensis Lour. Of these, 17 strains having antimicrobial and anthracyclines-producing activities were further selected for screening of antifungal and cytotoxic activities against two human cancer cell lines, MCF-7 and Hep G2. Ten of these selected endophytic Actinobacteria showed antifungal activities against at least one of the fungal pathogens, of which three strains exhibited cytotoxic activities with IC50-values ranging between 3 and 33 μg·mL−1. Frequencies for the presence of biosynthetic genes, polyketide synthase- (PKS-) I, PKS-II, and nonribosomal peptide synthetase (NRPS) among these 17 selected bioactive Actinobacteria were 29.4%, 70.6%, and 23.5%, respectively. The results indicated that the medicinal plant D. cochinchinensis Lour. is a good niche of biologically important metabolites-producing Actinobacteria.

Warming, acidification and deoxygenation of the ocean are already affecting the productivity and stability of marine ecosystems. It is projected also that climate change will force the fish stocks that cross through two or more exclusive economic zones to shift significantly from their historical habitats and migration that may lead to international conflict on the transboundary fish stocks. Meanwhile, overfishing and habitat destruction has had long-term effect on marine environment. Recently, the 2023 UNGA Resolution on sustainable fisheries reported the decline in global fish stocks. The resolution called upon the States to identify the impacts on fisheries due to climate change, thus it is crucial for States to consider effective adaptation and strategies to tackle the challenges. The present study is designed to analyse the impacts of climate change on fish and their interdependent ecosystems, but also impacts upon the laws and policies relevant to their exploitation and conservation. By using a comparative approach between three vulnerable countries to climate change, the paper highlights how Indonesia, India, and Vietnam are working to cope with the issues arising from climate change on the fisheries sector. The finding shows how the three countries must modernize their legal frameworks for fisheries management to reflect the current challenges such as climate change and ecosystem-based management.