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Background: Melanoma is an aggressive cancer with poor response to traditional therapies. A combination of photothermal therapy and topical immunotherapy may enhance elimination of melanoma.. Materials and methods: C57BL/6 mice with early stage and metastatic melanoma were treated with laser immunotherapy (LIT), combining near-infrared laser-based photothermal therapy (PTT) and topical imiquimod (IMQ)-based immunotherapy. The volume of primary and abscopal melanoma, animal survival, tissue temperature, transcriptome, and immune cell response were investigated to evaluate the effect of LIT. Results: LIT could eliminate primary tumors, inhibite abscopal tumors, and prolong animal survival. The tumor tissues were selectively destroyed under a photothermal gradient between 38.2 ± 3.7 °C and 73.0 ± 2.3 °C. Gene expression analysis showed a significant increase in the expression of damage associated molecular patterns. Additionally, the population of mature dendritic cells, CD4+ T cells, and CD8+ T cells were increased, while myeloid-derived suppressor cells were downregulated after LIT. Conclusion: The study showed that LIT inhibited the growth of both primary and abscopal melanoma by activating systemic antitumor immune responses and reversing the immunosuppressive tumor microenvironment, making LIT a potential method for advanced melanoma treatment.

Abstract Anaplastic thyroid cancer (ATC) is the most aggressive thyroid cancer. Despite advances in tissue culture techniques, a robust model for ATC spheroid culture is yet to be developed. In this study, we created an efficient and cost-effective 3D tumor spheroids culture system from human ATC cells and existing cell lines that better mimic patient tumors and that can enhance our understanding of in vivo treatment response. We found that patient-derived ATC cells and cell lines can readily form spheroids in culture with a unique morphology, size, and cytoskeletal organization. We observed both cohesive (dense and solid structures) and discohesive (irregularly shaped structures) spheroids within the same culture condition across different cell lines. BRAF WT ATC spheroids grew in a cohesive pattern, while BRAF V600E -mutant ATC spheroids had a discohesive organization. In the patient-derived BRAF V600E -mutant ATC spheroids, we observed both growth patterns, but mostly the discohesive type. Histologically, ATC spheroids had a similar morphology to the patient’s tumor through H&E staining and proliferation marker staining. Moreover, RNA sequencing analysis revealed that the gene expression profile of tumor cells derived from the spheroids closely matched parental patient tumor-derived cells in comparison to monolayer cultures. In addition, treatment response to combined BRAF and MEK inhibition in BRAF V600E -mutant ATC spheroids exhibited a similar sensitivity to the patient clinical response. Our study provides a robust and novel ex vivo spheroid model system that can be used in both established ATC cell lines and patient-derived tumor samples to better understand the biology of ATC and to test therapeutics.

ABSTRACTContinuous emergence of new variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), enhanced transmissibility, significant immune escape, and waning immunity call for booster vaccination. We evaluated the safety, immunogenicity, and efficacy of heterologous booster with a SARS-CoV-2 mRNA vaccine SYS6006 versus an active control vaccine in a randomized, open-label, active-controlled phase 3 trial in healthy adults aged 18 years or more who had received two or three doses of SARS-CoV-2 inactivated vaccine in China. The trial started in December 2022 and lasted for 6 months. The participants were randomized (overall ratio: 3:1) to receive one dose of SYS6006 (N = 2999) or an ancestral receptor binding region-based, alum-adjuvanted recombinant protein SARS-CoV-2 vaccine (N = 1000), including 520 participants in an immunogenicity subgroup. SYS6006 boosting showed good safety profiles with most AEs being grade 1 or 2, and induced robust wild-type and Omicron BA.5 neutralizing antibody response on Days 14 and 28, demonstrating immunogenicity superiority versus the control vaccine and meeting the primary objective. The relative vaccine efficacy against COVID-19 of any severity was 51.6% (95% CI, 35.5–63.7) for any variant, 66.8% (48.6–78.5) for BA.5, and 37.7% (2.4–60.3) for XBB, from Day 7 through Month 6. In the vaccinated and infected hybrid immune participants, the relative vaccine efficacy was 68.4% (31.1–85.5) against COVID-19 of any severity caused by a second infection. All COVID-19 cases were mild. SYS6006 heterologous boosting demonstrated good safety, superior immunogenicity and high efficacy against BA.5-associated COVID-19, and protected against XBB-associated COVID-19, particularly in the hybrid immune population.Trial registration: Chinese Clinical Trial Registry: ChiCTR2200066941

Abstract Background Arterial transit artifact (ATA) observed on arterial spin labeling (ASL) was recently suggested to be associated with improved functional outcomes following acute ischemic stroke (AIS). AIS is a heterogeneous disease with diverse pathogenic mechanisms depending on the stroke subtype. This study aimed to investigate the association between ATA and 3-month functional outcomes in AIS patients according to etiology subtypes. Methods Consecutive patients with AIS were included. All patients underwent ASL MRI with postlabeling delay (PLD) of 1.5 and 2.5 s. ATA was assessed from the ASL images of both PLDs. Stroke etiologic subtypes were determined according to the modified TOAST (Trial of ORG 10172 in Acute Stroke Treatment) classification. Short-term functional outcomes were evaluated using the 3-month modified Rankin scale (mRS). Log-binomial regression was applied to analyze the association between ATA and functional outcomes at 3 months after stroke. Results Ninety-eight AIS patients (62.73 ± 13.05 years; 68 men) were finally included. ATA was detected in forty-six patients and most frequently seen in the large-artery atherosclerosis (LAA) subtype (35/46). The ATA group exhibited a lower percentage of patients with mRS > 2 compared to the group without ATA (36.5% vs. 19.6%; P

Abstract Engineering human tissue with diverse cell types and architectures remains challenging. The cerebral cortex, which has a layered cellular architecture composed of layer-specific neurons organised into vertical columns, delivers higher cognition through intricately wired neural circuits. However, current tissue engineering approaches cannot produce such structures. Here, we use a droplet printing technique to fabricate tissues comprising simplified cerebral cortical columns. Human induced pluripotent stem cells are differentiated into upper- and deep-layer neural progenitors, which are then printed to form cerebral cortical tissues with a two-layer organization. The tissues show layer-specific biomarker expression and develop a structurally integrated network of processes. Implantation of the printed cortical tissues into ex vivo mouse brain explants results in substantial structural implant-host integration across the tissue boundaries as demonstrated by the projection of processes and the migration of neurons, and leads to the appearance of correlated Ca2+ oscillations across the interface. The presented approach might be used for the evaluation of drugs and nutrients that promote tissue integration. Importantly, our methodology offers a technical reservoir for future personalized implantation treatments that use 3D tissues derived from a patient’s own induced pluripotent stem cells.

Tree allometry plays a crucial role in tree survival, stability, and timber quantity and quality of mixed-species plantations. However, the responses of tree allometry to resource utilisation within the framework of interspecific competition and complementarity remain poorly understood. Taking into consideration strong- and weak-space competition (SC and WC), as well as N2-fixing and non-N2-fixing tree species (FN and nFN), a mixed-species planting trial was conducted for Betula alnoides, a pioneer tree species, which was separately mixed with Acacia melanoxylon (SC ​+ ​FN), Erythrophleum fordii (WC ​+ ​FN), Eucalyptus cloeziana (SC ​+ ​nFN) and Pinus kesiya var. langbianensis (WC ​+ ​nFN) in southern China. Six years after planting, tree growth, total nitrogen (N) and carbon (C) contents, and the natural abundances of 15N and 13C in the leaves were measured for each species, and the mycorrhizal colonisation rates of B. alnoides were investigated under each treatment. Allometric variations and their relationships with space competition and nutrient-related factors were analyzed. The results showed a consistent effect of space competition on the height-diameter relationship of B. alnoides in mixtures with FN or nFN. The tree height growth of B. alnoides was significantly promoted under high space competition, and growth in diameter at breast height (DBH), tree height and crown size were all expedited in mixtures with FN. The symbiotic relationship between ectomycorrhizal fungi and B. alnoides was significantly influenced by both space competition and N2 fixation by the accompanying tree species, whereas such significant effects were absent for arbuscular mycorrhizal fungi. Furthermore, high space competition significantly decreased the water use efficiency (WUE) of B. alnoides, and its N use efficiency (NUE) was much lower in the FN mixtures. Structural equation modeling further demonstrated that the stem allometry of B. alnoides was affected by its NUE and WUE via changes in its height growth, and crown allometry was influenced by the mycorrhizal symbiotic relationship. Our findings provide new insights into the mechanisms driving tree allometric responses to above- and below-ground resource competition and complementarity in mixed-species plantations, which are instructive for the establishment of mixed-species plantations.

IntroductionNatural menopause is an inevitable biological process with significant implications for women's health. However, the molecular mechanisms underlying menopause are not well understood. This study aimed to investigate the molecular and cellular changes occurring in the ovary before and after perimenopause.MethodsSingle-cell sequencing data from the GTEx V8 cohort (30-39: 14 individuals; 40-49: 37 individuals; 50-59: 61 individuals) and transcriptome sequencing data from ovarian tissue were analyzed. Seurat was used for single-cell sequencing data analysis, while harmony was employed for data integration. Cell differentiation trajectories were inferred using CytoTrace. CIBERSORTX assessed cell infiltration scores in ovarian tissue. WGCNA evaluated co-expression network characteristics in pre- and post-perimenopausal ovarian tissue. Functional enrichment analysis of co-expression modules was conducted using ClusterprofileR and Metascape. DESeq2 performed differential expression analysis. Master regulator analysis and signaling pathway activity analysis were carried out using MsViper and Progeny, respectively. Machine learning models were constructed using Orange3.ResultsWe identified the differentiation trajectory of follicular cells in the ovary as ARID5B+ Granulosa -> JUN+ Granulosa -> KRT18+ Granulosa -> MT-CO2+ Granulosa -> GSTA1+ Granulosa -> HMGB1+ Granulosa. Genes driving Granulosa differentiation, including RBP1, TMSB10, SERPINE2, and TMSB4X, were enriched in ATP-dependent activity regulation pathways. Genes involved in maintaining the Granulosa state, such as DCN, ARID5B, EIF1, and HSP90AB1, were enriched in the response to unfolded protein and chaperone-mediated protein complex assembly pathways. Increased contents of terminally differentiated HMGB1+ Granulosa and GSTA1+ Granulosa were observed in the ovaries of individuals aged 50-69. Signaling pathway activity analysis indicated a gradual decrease in TGFb and MAPK pathway activity with menopause progression, while p53 pathway activity increased. Master regulator analysis revealed significant activation of transcription factors FOXR1, OTX2, MYBL2, HNF1A, and FOXN4 in the 30-39 age group, and GLI1, SMAD1, SMAD7, APP, and EGR1 in the 40-49 age group. Additionally, a diagnostic model based on 16 transcription factors (Logistic Regression L2) achieved reliable performance in determining ovarian status before and after perimenopause.ConclusionThis study provides insights into the molecular and cellular mechanisms underlying natural menopause in the ovary. The findings contribute to our understanding of perimenopausal changes and offer a foundation for health management strategies for women during this transition.

BackgroundAlthough cellular and animal studies have reported that resolvin D1 (RvD1) and resolvin D2 (RvD2) are mechanisms involved in the development of type 2 diabetes mellitus (T2DM), the impact of RvD1 and RvD2 on the risk of T2DM at a population level remains unclear.MethodsWe included 2755 non-diabetic adults from a community-based cohort in China and followed them for seven years. Cox proportional hazards model was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association of RvD1 and RvD2 with T2DM probability. Time-dependent receiver operator characteristics (ROC) curve was used to evaluate the predictive performance of RvD1 and RvD2 for the risk of T2DM based on the Chinese CDC T2DM prediction model (CDRS).ResultsA total of 172 incident T2DM cases were identified. Multivariate-adjusted HRs (95% CI) for T2DM across quartiles of RvD1 levels (Q1, Q2, Q3 and Q4) were 1.00, 1.64 (1.03-2.63), 1.80 (1.13-2.86) and 1.61 (1.01-2.57), respectively. Additionally, body mass index (BMI) showed a significant effect modification in the association of RvD1 with incident T2DM (Pinteraction = 0.026). After multivariate adjustment, the HR (95% CI) for T2DM in the fourth compared with the first quartile of RvD2 was 1.94 (95% CI: 1.24-3.03). Time-dependent ROC analysis showed that the area under time-dependent ROC curves of the “CDRS+RvD1+RvD2” model for the 3-, 5- and 7-year risk of T2DM were 0.842, 0.835 and 0.828, respectively.ConclusionsHigher RvD1 and RvD2 levels are associated with a higher risk of T2DM at the population level.

The tumor microenvironment (TME) promotes pro-tumor and anti-inflammatory metabolisms and suppresses the host immune system. It prevents immune cells from fighting against cancer effectively, resulting in limited efficacy of many current cancer treatment modalities. Different therapies aim to overcome the immunosuppressive TME by combining various approaches to synergize their effects for enhanced anti-tumor activity and augmented stimulation of the immune system. Immunotherapy has become a major therapeutic strategy because it unleashes the power of the immune system by activating, enhancing, and directing immune responses to prevent, control, and eliminate cancer. Phototherapy uses light irradiation to induce tumor cell death through photothermal, photochemical, and photo-immunological interactions. Phototherapy induces tumor immunogenic cell death, which is a precursor and enhancer for anti-tumor immunity. However, phototherapy alone has limited effects on long-term and systemic anti-tumor immune responses. Phototherapy can be combined with immunotherapy to improve the tumoricidal effect by killing target tumor cells, enhancing immune cell infiltration in tumors, and rewiring pathways in the TME from anti-inflammatory to pro-inflammatory. Phototherapy-enhanced immunotherapy triggers effective cooperation between innate and adaptive immunities, specifically targeting the tumor cells, whether they are localized or distant. Herein, the successes and limitations of phototherapy combined with other cancer treatment modalities will be discussed. Specifically, we will review the synergistic effects of phototherapy combined with different cancer therapies on tumor elimination and remodeling of the immunosuppressive TME. Overall, phototherapy, in combination with other therapeutic modalities, can establish anti-tumor pro-inflammatory phenotypes in activated tumor-infiltrating T cells and B cells and activate systemic anti-tumor immune responses.

Abstract In the past decades, machine learning (ML) has impacted the field of electrocatalysis. Modern researchers have begun to take advantage of ML‐based data‐driven techniques to overcome the computational and experimental limitations to accelerate rational catalyst design. Hence, significant efforts have been made to perform ML to accelerate calculation and aid electrocatalyst design for CO2 reduction. This review discusses recent applications of ML to discover, design, and optimize novel electrocatalysts. First, insights into ML aided in accelerating calculation are presented. Then, ML aided in the rational design of the electrocatalyst is introduced, including establishing a data set/data source selection and validation of descriptor selection of ML algorithms validation and predictions of the model. Finally, the opportunities and future challenges are summarized for the future design of electrocatalyst for CO2 reduction with the assistance of ML.

Nitrogen (N), phosphorus (P), and potassium (K) exert various effects on strawberry (Fragaria ananassa Duchesne) yields. In this study, we employed an orthogonal experimental design (T1-T9) with three fertilization treatments (N, P, and K) at three levels to identify an optimal fertilization scheme for strawberry cultivation. The effects of fertilizer combinations the rhizosphere soil microbial community were also explored by using bacterial full-length 16S rRNA and fungal ITS (internal transcribed spacer) sequencing (30 samples for each analysis). The results showed that the average plant height and leaf area of the fertilized groups were 24.6% and 41.6% higher than those of the non-fertilized group (T0). After 60 d of planting, the sucrase activity in the T6 group increased by 76.67% compared to the T0 group, with phosphate fertilizer exerting a more significant impact on sucrase activity. The T6 treatment group had the highest alpha diversity index among bacterial and fungal microorganisms, and had a different microbial community structure compared with the control group. The most abundant bacterial taxa in the strawberry rhizosphere soil were Proteobacteria, Bacteroidota, and Acidobacteriota, and the most abundant fungal phyla were Monoblepharomycota, Glomeromycota, and Mucoromycota. Application of the optimal combined fertilizer treatment (T6) significantly increased the abundance of Proteobacteria and altered the abundance of Gemmatimonas compared to other treatment groups. Notably, Gemmatimonas abundance positively correlated with strawberry plant height and soil N, P, and K levels. These findings indicated that the relative abundance of beneficial bacteria could be enhanced by the application of an optimal fertilizer ratio, ultimately improving strawberry agronomic traits.

BackgroundMetabolic syndrome (MS) is a group of complex medical conditions that can lead to serious cardiovascular and cerebrovascular diseases. According to the theory of traditional Chinese medicine (TCM), MS can be divided into two main subtypes termed ‘phlegm-dampness syndrome’ (TSZE) and ‘qi-yin deficiency syndrome’ (QYLX). At present, the research into intestinal microbiota of different TCM syndromes of MS and its association with clinical manifestation is lacking.Materials and methodsUsing 16S rRNA sequencing, we performed a cross-sectional analysis of human gut microbiota between two different TCM syndromes (QYLX and TSZE, n=60) of MS, and their differences with healthy participants (n=30).ResultsWe found that the QYLX and TSZE groups differ from the healthy control group in the overall gut microbiota composition, and some specific microbial taxa and functional pathways. Moreover, significantly differentially abundant taxa and distinct BMI-correlated taxa were observed between QYLX and TSZE groups, suggesting the potential contribution of gut microbiota to the distinction between the two TCM syndromes. The predicted functional profiles also showed considerable differences, especially pathways related to amino acid metabolism and lipopolysaccharide synthesis.ConclusionOur study highlights the gut microbiota’s contribution to the differentiation between two TCM syndromes of MS and may provide the rationale for adopting different microbiota-directed treatment strategies for different TCM syndromes of MS in the future.

Abstract Background Metastatic breast cancer poses great challenge in cancer treatment. N‐dihydrogalactochitosan (GC) is a novel immunoadjuvant that stimulates systemic immune responses when administered intratumourally following local tumour ablation. A combination of photothermal therapy (PTT) and GC, referred to as localized ablative immunotherapy (LAIT), extended animal survival and generates an activated B cell phenotype in MMTV‐PyMT mouse mammary tumour microenvironment (TME). However, how T cell populations respond to LAIT remains to be elucidated. Methods Using depletion antibodies, we studied the contributions of CD8+ and CD4+ T cells to the therapeutic effect of LAIT. Using single‐cell RNA‐sequencing (scRNAseq), we analysed tumour‐infiltrating T cell heterogeneity and dissected their transcriptomes upon treatments of PTT, GC, and LAIT (PTT+GC). Results Loss of CD8+ T cells after LAIT abrogated the therapeutic benefits of LAIT. Ten days after treatment, proportions of CD8+ and CD4+ T cells in untreated TME were 19.2% and 23.0%, respectively. Upon LAIT, both proportions were increased to 25.5% and 36.2%, respectively. In particular, LAIT increased the proportions of naïve and memory cells from a resting state to an activated state. LAIT consistently induced the expression of co‐stimulatory molecules, type I IFN responsive genes, and a series of antitumor cytokines, Ifng, Tnf, Il1, and Il17 in CD8+ and CD4+ T cells. LAIT also induced immune checkpoints Pdcd1, Ctla4, and Lag3 expression, consistent with T cell activation. Relevant to clinical translation, LAIT also upregulated genes in CD8+ and CD4+ T cells that positively correlated with extended survival of breast cancer patients. Conclusions Overall, our results reveal that LAIT prompts immunological remodelling of T cells by inducing broad proinflammatory responses and inhibiting suppressive signalling to drive antitumour immunity.

Summary: The thymus has a high capacity to support the differentiation of ILCs, especially when E protein transcription factors are ablated. Whether it contributes to the homeostasis of ILC pools in tissues is not clear. Single-cell RNA sequencing analysis shows a substantial amount of ILC precursors in wild type but not athymic nude blood. The precursors express CD3 intracellularly (ic) but not on the surface. The abundance of Lin−CD127+CD62L+icCD3ε+ precursors varies with age, peaking at 2–3 months. These cells can differentiate into various ILC subsets on OP9-DL1 stroma in vitro. In the lung, small intestine, and epidermis, icCD3ε+ cells differentiate into diverse ILC subsets in different tissue environments in steady state. Helminth infection promotes their differentiation toward functional ILC2s. Thus, the thymus appears to play a role in replenishing ILC pools in different peripheral tissues. Because thymic activity is age-dependent, this finding may help explain age-related differences in immune responses.

Abstract. Phototherapies offer promising alternatives to traditional cancer therapies. Phototherapies mainly rely on manipulation of target tissue through photothermal, photochemical, or photomechanical interactions. Combining phototherapy with immunotherapy has the benefit of eliciting a systemic immune response. Specifically, photothermal therapy (PTT) has been shown to induce apoptosis and necrosis in cancer cells, releasing tumor associated antigenic peptides while sparing healthy host cells, through temperature increase in targeted tissue. However, the tissue temperature must be monitored and controlled to minimize adverse thermal effects on normal tissue and to avoid the destruction of tumor-specific antigens, in order to achieve the desired therapeutic effects of PTT. Techniques for monitoring PTT have evolved from post-treatment quantification methods like enzyme linked immunosorbent assay, western blot analysis, and flow cytometry to modern methods capable of real-time monitoring, such as magnetic resonance thermometry, computed tomography, and photoacoustic imaging. Monitoring methods are largely chosen based on the type of light delivery to the target tissue. Interstitial methods of thermometry, such as thermocouples and fiber-optic sensors, are able to monitor temperature of the local tumor environment. However, these methods can be challenging if the phototherapy itself is interstitially administered. Increasingly, non-invasive therapies call for non-invasive monitoring, which can be achieved through magnetic resonance thermometry, computed tomography, and photoacoustic imaging techniques. The purpose of this review is to introduce the feasible methods used to monitor tissue temperature during PTT. The descriptions of different techniques and the measurement examples can help the researchers and practitioners when using therapeutic PTT.

Introduction: Non-Hodgkin lymphoma (NHL) has a much higher incidence rate than Hodgkin lymphoma. Approximately 40% NHL occurs in extranodal tissues or organs, and its clinical manifestations are often nonspecific. Primary bone NHL involving the mandible is an uncommon NHL that is characterized by fever, gum swelling and toothache. Therefore, it is often misdiagnosed as oral diseases.Case Presentation: A 52-year-old female had recurrent fever for more than 1 month, with numbness in her left jaw and toothache. PET/CT showed an uptake area in the left mandible, suggesting microbial infections. However, antibacterial, and antiviral treatment were ineffective. Furthermore, metagenomic sequencing of plasma reported no pathogens, but instead showed significant copy number variations of multiple chromosomes, which highly suggested the existence of tumor. Finally, diffuse large B-cell lymphoma (DLBCL) was diagnosed by mandibular biopsy, and the patient was transferred to Hematology department for chemotherapy.Conclusion: mNGS not only assists rapid etiological diagnosis, but also helps rule out infection and diagnose malignant neoplasm.

Broiler leg diseases are a common abnormal bone metabolism issue that leads to poor leg health in growing poultry. Bone metabolism is a complicated regulatory process controlled by genetic, nutritional, feeding management, environmental, or other influencing factors. The gut microbiota constitutes the largest micro-ecosystem in animals and is closely related to many metabolic disorders, including bone disease, by affecting the absorption of nutrients and the barrier function of the gastrointestinal tract and regulating the immune system and even the brain–gut–bone axis. Recently, probiotic-based dietary supplementation has emerged as an emerging strategy to improve bone health in chickens by regulating bone metabolism based on the gut–bone axis. This review aims to summarize the regulatory mechanisms of probiotics in the gut microbiota on bone metabolism and to provide new insights for the prevention and treatment of bone diseases in broiler chickens.

Technological advancements in recent decades have greatly transformed the field of material chemistry. Juxtaposing the accentuating energy demand with the pollution associated, urgent measures are required to ensure energy maximization, while reducing the extended experimental time cycle involved in energy production. In lieu of this, the prominence of catalysts in chemical reactions, particularly energy related reactions cannot be undermined, and thus it is critical to discover and design catalyst, towards the optimization of chemical processes and generation of sustainable energy. Most recently, artificial intelligence (AI) has been incorporated into several fields, particularly in advancing catalytic processes. The integration of intensive data set, machine learning models and robotics, provides a very powerful tool in modifying material synthesis and optimization by generating multifarious dataset amenable with machine learning techniques. The employment of robots automates the process of dataset and machine learning models integration in screening intermetallic surfaces of catalyst, with extreme accuracy and swiftness comparable to a number of human researchers. Although, the utilization of robots in catalyst discovery is still in its infancy, in this review we summarize current sway of artificial intelligence in catalyst discovery, briefly describe the application of databases, machine learning models and robots in this field, with emphasis on the consolidation of these monomeric units into a tripartite flow process. We point out current trends of machine learning and hybrid models of first principle calculations (DFT) for generating dataset, which is integrable into autonomous flow process of catalyst discovery. Also, we discuss catalyst discovery for renewable energy related reactions using this tripartite flow process with predetermined descriptors.

Abstract Background Dysfunction of p53 is a key cause of cancer development, while CCDC106 can reduce p53 stability and is associated with lung cancer. However, the roles of CCDC106 in other cancer types and its upstream regulators have not been investigated. Methods The phosphorylation status was investigated by in vitro kinase assay and Western blotting using phosphorylation-specific antibodies. Co-immunoprecipitation assay and GST-pulldown were used to detect protein interaction. Cell viability, apoptosis, colony formation, wound-healing and invasion assays were measured for in vitro functional analyses. The in vivo effect of CCDC106 on tumor growth was investigated using a subcutaneous xenograft tumor mouse model. Results We demonstrated that CCDC106 knockdown enhanced apoptosis by stabilizing p53 and suppressed cell viability, colony formation, migration and invasion in cervical cancer HeLa and breast cancer MCF7 cells with wild-type p53 (wtp53), whereas CCDC106 overexpression exerted the opposite effects in normal breast epithelial HBL100 and cervical cancer SiHa cells with wtp53. However, CCDC106 had no similar effects on p53-mutant cervical and breast cancer cells (C33A and MDA-MB-231). Further study showed that CK2 interacts with CCDC106 through its regulatory β subunit and then phosphorylates CCDC106 at Ser-130 and Ser-147. The phosphorylation of CCDC106 at Ser-130 and Ser-147 is required for its interaction with p53 and nuclear localization, respectively. Inhibiting CCDC106 phosphorylation by substituting both Ser-130 and Ser-147 with alanine or treating cells with the CK2 inhibitor CX-4945 abrogated CCDC106-induced p53 degradation and its oncogenic function in cells with wtp53. Wildtype CCDC106, but not Ser-130/− 147 mutant CCDC106, enhanced tumor growth and p53 degradation in a xenograft mouse model. Moreover, suppression of CCDC106 increased CX-4945 sensitivity of cancer cells with wtp53. Conclusion This study revealed a CK2/CCDC106/p53 signaling axis in the progression of breast and cervical cancers, which may provide a new therapeutic target for cancer treatment.

Abstract Background Xanthoangelol (XAG) was reported to exhibit antitumor properties in several cancer. However, the specific anti-tumor activity of XAG in human hepatocellular carcinoma (HCC) and the relevant mechanisms are not known. Methods The effects of XAG on HCC cell proliferation and apoptosis were respectively examined by CCK-8 assay and Annexin V-FITC/PI apoptosis kit. Western blotting was conducted to detect the expression of proteins. The effect of XAG on the development of acidic vesicle organelles was assessed using acridine orange staining. mRFP-GFP-LC3 adenovirus was used to transfect HCC cells and the formation of autolysosome was detected using a confocal microscope. Results Mechanistically, XAG promotes HCC cell death through triggering intrinsic apoptosis pathway, not extrinsic apoptotic pathway. Furthermore, XAG treatment induced autophagy in Bel 7402 and SMMC 7721 cells, as evidenced by an increase in autophagy-associated proteins, including LC3B-II, Beclin-1, and Atg5. Interestingly, inhibition of autophagy with 3-MA, Bafilomycin A1 (Baf A1), or siRNA targeting Atg5 effectively enhanced the apoptotic cell ratio in XAG-treated cells, indicating that protective effect of autophagy induced by XAG in HCC. Moreover, autophagy induced by XAG was mediated by activating endoplasmic reticulum stress (ERS), along with administration of XAG, the expression levels of ERS-associated proteins, including CHOP, GRP78, ATF6, p-eIF2α, IRE1α, and cleaved caspase-12 were significantly increased in HCC cells. Meanwhile, suppressing ERS with chemical chaperones (TUDCA) or CHOP shRNA could effectively abrogate the autophagy-inducing effect of XAG, and increase the apoptotic cell death. Further mechanistic studies showed that ERS-induced autophagy in XAG-treated cells was mediated by activation of JNK/c-jun pathway. XAG treatment resulted in the increase of p-JNK and p-c-jun, while suppressing ERS with TUDCA or CHOP shRNA could effectively reverse it. Meanwhile, SP600125, a JNK inhibitor, effectively reversed XAG-induced protective autophagy and enhanced cell apoptosis in XAG-treated HCC cells. In vivo results demonstrated that XAG exerts potent antitumor properties with low toxicity. Conclusions Collectively, these results suggested that XAG could be served as a promising candidate for the treatment and prevention of HCC.

Background: Epirubicin is a first-line chemotherapeutic drug for the clinical treatment of diffuse large B cell lymphoma (DLBCL), but the overexpression of multidrug resistance (MDR) transporter proteins, especially P-glycoprotein (P-gp), renders epirubicin ineffective. Some studies reveal the potential role of melatonin in chemotherapeutic synergy and MDR. Methods: The cell viability and apoptosis were determined by CCK-8 assay and acridine orange/ethidium bromide (AO/EB) fluorescence staining assay. Immunofluorescence and immunohistochemical staining were used to detect the expression of P-gp in DLBCL cells and tissues. Rhodamine-123 accumulation assay was used to evaluate the pump function of P-gp. The possible mechanisms of melatonin sensitize DLBCL cells to epirubicin were explored by western blotting, cytochrome C release, and pulldown assay. Results: Melatonin significantly enhanced the epirubicin-induced cell proliferation suppression, epirubicin-induced apoptosis, and reduced the IC50 value of epirubicin. Further, melatonin synergized with epirubicin to promote the activation of the mitochondria-mediated apoptosis pathway and increased the accumulation of epirubicin in DLBCL cells by inhibiting the expression and function of P-gp. Immunohistochemical staining studies revealed that P-gp expression was positively correlated with P65 expression. Epirubicin was subsequently discovered to upregulate the expression of P-gp by activating the NF-κB pathway in the DLBCL cells. Melatonin reduced the amount of P65 protein in the nucleus and abrogated the ability of P65 to bind to the ABCB1 promoter, decisively suppressing P-gp expression. Conclusions: Our results demonstrated that melatonin inactivates the NF-κB pathway and downregulates the expression of P-gp, ultimately sensitizing DLBCL cells to the epirubicin that suppresses their growth.

Neuroinflammation-related amyloid-beta peptide (Aβ) accumulation after cerebral ischemia/reperfusion (I/R) accounts for cerebral I/R injuries and poststroke dementia. Recently, pyroptosis, a proinflammatory cell death, has been identified as a crucial pathological link of cerebral I/R injuries. However, whether pyroptosis acts as a trigger of Aβ accumulation after cerebral I/R has not yet been demonstrated. Blood-brain barrier (BBB) and glymphatic system mediated by aquaporin-4 (AQP-4) on astrocytic endfeet are important pathways for the clearance of Aβ in the brain, and pyroptosis especially occurring in astrocytes after cerebral I/R potentially damages BBB integrity and glymphatic function and thus influences Aβ clearance and brain homeostasis. In present study, the method of middle cerebral artery occlusion/reperfusion (MCAO/R) was used for building models of focal cerebral I/R injuries in rats. Then, we used lipopolysaccharide and glycine as the agonist and inhibitor of pyroptosis, respectively, Western blotting for detections of pyroptosis, AQP-4, and Aβ1-42 oligomers, laser confocal microscopy for observations of pyroptosis and Aβ locations, and immunohistochemical stainings of SMI 71 (a specific marker for BBB integrity)/AQP-4 and Nissl staining for evaluating, respectively, BBB-glymphatic system and neuronal damage. The results showed that pyroptosis obviously promoted the loss of BBB integrity and AQP-4 polarization, brain edema, Aβ accumulation, and the formation of Aβ1-42 oligomers and thus increased neuronal damage after cerebral I/R. However, glycine could inhibit cerebral I/R-induced pyroptosis by alleviating cytomembrane damage and downregulating expression levels of cleaved caspase-11/1, N-terminal gasdermin D, NLRP3 (nucleotide-binding domain, leucine-rich repeat containing protein 3), interleukin-6 (IL-6) and IL-1β and markedly abate above pathological changes. Our study revealed that pyroptosis is a considerable factor causing toxic Aβ accumulation, dysfunctional BBB-glymphatic system, and neurological deficits after cerebral I/R, suggesting that targeting pyroptosis is a potential strategy for the prevention of ischemic stroke sequelae including dementia.

The sorption removal of radionuclides Sr2+ using a freestanding functional membrane is an interesting and significant research area in the remediation of radioactive wastes. Herein, a novel self-assembled membrane consisting of metal–organic framework (MOF) nanobelts and graphene oxides (GOs) are synthesized through a simple and facile filtration method. The membrane possesses a unique interwove morphology as evidenced from SEM images. Batch experiments suggest that the GO/Ni-MOF composite membrane could remove Sr2+ ions from aqueous solutions and the Sr2+ adsorption capacity and efficiency of the GO/Ni-MOF composite membrane is relevant to the MOF content in the composite. Thus, the dominant interaction mechanism was interface or surface complexation, electrostatic interaction as well as ion substitution. The maximum effective sorption of Sr2+ over GO/Ni-MOF membrane is 32.99% with 2 mg composite membrane containing a high content of Ni-MOF at 299 K in 100 mg/L Sr2+ aqueous solution. The FT-IR and XPS results suggest that the synergistic effect between GO and Ni-MOF is determinant in the sorption Sr2+ process. The GO/Ni-MOF composite membrane is demonstrated to have the advantages of efficient removal of Sr2+, low cost and simple synthesis route, which is promising in the elimination of radionuclide contamination.

Background: Many neuroprotective approaches targeting neurons in animal models fail to provide benefits for the treatment of ischemic stroke in clinic and glial cells have become the targets in some basic studies. Baicalin has neuroprotective effects but the mechanisms related to glial cells are not revealed. This study investigated whether and how baicalin can combat excitotoxicity via protecting the functions of astrocytes in early stage of ischemia/reperfusion (I/R) insult by focusing on glutamine synthetase (GS). Experimental approach: The role of baicalin was explored in primary astrocytes exposed to oxygen-glucose deprivation/reperfusion (OGD/R) and rats subjected to middle cerebral artery occlusion/reperfusion (MCAO/R). Key results: Mitochondrial succinate dehydrogenase (SDH) activation led to an excessive production of reactive oxygen species (ROS) via reverse electron transport (RET) under conditions of OGD/R or I/R, which increased the carbonylation and proteasomal degradation of GS in astrocytes. Treatment of baicalin decreased the oxidative stress mediated by SDH and reduced the subsequent loss of GS. This effect increased the glutamate disposal by astrocytes and protected neurons from excitotoxicity in response to I/R insults. Conclusions and implications: Baicalin inactivated SDH to suppress ROS production and protected GS protein stability against oxidative stress, contributing to the improvement of the glutamate disposal and decrease in excitotoxicity. These results suggest that protection of GS stability in astrocytes might be an effective strategy to prevent neuronal injury in acute ischemic stroke.

Summary: Neuroinflammation is a crucial mechanism in many neurological disorders. Injury to the peripheral sensory nerves leads to a neuroinflammatory response in the somatosensory pathway, from dorsal root ganglia (DRG) to the spinal cord, contributing to neuropathic pain. How the immune reaction is initiated peripherally and propagated to the spinal cord remains less clear. Here, we find that ciliary neurotrophic factor (CNTF), highly expressed in Schwann cells, mediates neuroinflammatory response through the activating signal transducer and activator of transcription 3 (STAT3) and inducing interleukin 6 (IL-6) in sensory neurons. Cntf deficiency attenuates neuroinflammation in DRG and the spinal cord with alleviated pain post-injury. Recombinant CNTF applied to the sensory nerves recapitulates neuroinflammation in the DRG and spinal cord, with consequent pain development. We delineate the CNTF-STAT3-IL-6 axis in mediating the onset and progression of the inflammatory cascade from the periphery to the spinal cord with therapeutic implications for neuropathic pain.

ABSTRACT Microglial activation occurs in divergent neuropathological conditions. Such microglial event has the key involvement in the progression of CNS diseases. However, the transcriptional mechanism governing microglial activation remains poorly understood. Here, we investigate the microglial response to traumatic injury-induced neurodegeneration by the 3D fluorescence imaging technique. We show that transcription factors IRF8 and PU.1 are both indispensible for microglial activation, as their specific post-developmental deletion in microglia abolishes the process. Mechanistically, we reveal that IRF8 and PU.1 directly target the gene transcription of each other in a positive feedback to sustain their highly enhanced expression during microglial activation. Moreover, IRF8 and PU.1 dictate the microglial response by cooperatively acting through the composite IRF-ETS motifs that are specifically enriched on microglial activation-related genes. This action of cooperative transcription can be further verified biochemically by the synergetic binding of IRF8 and PU.1 proteins to the composite-motif DNA. Our study has therefore elucidated the central transcriptional mechanism of microglial activation in response to neurodegenerative condition.

Summary: Traumatic injuries can trigger inflammatory reactions, leading to profound neuropathological consequences. However, the immune capacity of neurons, distinct from that of immune cells or glial cells, in response to traumatic insults remains to be fully characterized. In this study, we demonstrate that neurons can detect, cell autonomously, distant axonal damage, resulting in rapid production of a specific collection of cytokines and chemokines. This neuronal immune response appears spatially and temporally separated from injury-induced axon degeneration. We then identify through the genetic screen that this immune response is regulated by TIR-domain adaptor Sarm1/Myd88-5. We further show that Sarm1 functions through the downstream Jnk-c-Jun signal, and blockage of this Sarm1-Jnk-c-Jun pathway effectively abolishes the recruitment of immune cells to injury-afflicted neural tissues. We therefore uncover the key function of the Sarm1 signaling pathway, independent of its known role in axon degeneration, in the neuronal intrinsic immune response to traumatic axonal injuries. : Wang et al. report that neurons possess an intrinsic immune capacity in response to traumatic axonal injuries, which is spatially and temporally separated from injury-induced axon degeneration. This neuronal immune response is regulated by TIR-domain adaptor protein Sarm1/Myd88-5 and its downstream Jnk-c-Jun signal. Keywords: neuronal intrinsic immune response, traumatic injuries, neuroinflammation, Sarm1

An amendment to this paper has been published and can be accessed via the original article.

The study of model organisms has revolutionized our understanding of the mechanisms underlying normal development, adult homeostasis, and human disease. Much of what we know about gene function in model organisms (and its application to humans) has come from gene knockouts: the ability to show analogous phenotypes upon gene inactivation in animal models. The zebrafish (Danio rerio) has become a popular model organism for many reasons, including the fact that it is amenable to various forms of genetic manipulation. The RNA-guided CRISPR/Cas9-mediated targeted mutagenesis approaches have provided powerful tools to manipulate the genome toward developing new disease models and understanding the pathophysiology of human diseases. CRISPR-based approaches are being used for the generation of both knockout and knock-in alleles, and also for applications including transcriptional modulation, epigenome editing, live imaging of the genome, and lineage tracing. Currently, substantial effort is being made to improve the specificity of Cas9, and to expand the target coverage of the Cas9 enzymes. Novel types of naturally occurring CRISPR systems [Cas12a (Cpf1); engineered variants of Cas9, such as xCas9 and SpCas9-NG], are being studied and applied to genome editing. Since the majority of pathogenic mutations are single point mutations, development of base editors to convert C:G to T:A or A:T to G:C has further strengthened the CRISPR toolbox. In this review, we provide an overview of the increasing number of novel CRISPR-based tools and approaches, including lineage tracing and base editing.

Purpose: In forest insurance market, there are three main participants including the insurance company, the forest farmer and the government. As different participant has different benefit object, there will be a complex and dynamic game relationship among all participants. The purpose of this paper is to make the game relationship among all participants in forest insurance market clear, and then to put forward some policy suggestions on the implementation of forest insurance from the view of game theory. Design/methodology/approach: Firstly, the static game model between the insurance company and the forest farmer is set up. According to the result of static game model, it’s difficult to implement forest insurance without government. Secondly, the tripartite dynamic game model among the government, the insurance company and the forest farmer is proposed, and the equilibrium solution of tripartite dynamic game model is acquired. Finally, the behavioral characteristics of all participants are analyzed according to the equilibrium solution of tripartite dynamic game model. Findings: the government’s allowance will be an important positive factor to implement forest insurance. The loss of the insurance company, which the lower insurance premium brings, can be compensated by the allowance from the government. The more the government provides allowance, the more actively the insurance company will implement forest insurance at a low insurance premium. In this situation, the forest farmer will be more likely to purchase the forest insurance, then the scope of forest insurance implementation will expend. Originality/value: There is a complex and dynamic game relationship among all participants in forest insurance market. Based on the tripartite dynamic game model, to make the game relationship between each participant clear is conducive to the implementation of forest insurance market in China.

Radiation is a widely used therapeutic method for treating breast cancer. N-dihydrogalactochitosan (GC), a biocompatible immunostimulant, is known to enhance the effects of various treatment modalities in different tumor types. However, whether GC can enhance the radiosensitivity of cancer cells remains to be explored. In this study, triple-negative murine 4T1 breast cancer cells transduced with multi-reporter genes were implanted in immunocompetent Balb/C mice to track, dissect, and identify liver-metastatic 4T1 cells. These cells expressed cancer stem cell (CSC) -related characteristics, including the ability to form spheroids, the expression of the CD44 marker, and the increase of protein stability. We then ex vivo investigated the potential effect of GC on the radiosensitivity of the liver-metastatic 4T1 breast cancer cells and compared the results to those of parental 4T1 cells subjected to the same treatment. The cells were irradiated with increased doses of X-rays with or without GC treatment. Colony formation assays were then performed to determine the survival fractions and radiosensitivity of these cells. We found that GC preferably increased the radiosensitivity of liver-metastatic 4T1 breast cancer cells rather than that of the parental cells. Additionally, the single-cell DNA electrophoresis assay (SCDEA) and γ-H2AX foci assay were performed to assess the level of double-stranded DNA breaks (DSBs). Compared to the parental cells, DNA damage was significantly increased in liver-metastatic 4T1 cells after they were treated with GC plus radiation. Further studies on apoptosis showed that this combination treatment increased the sub-G1 population of cells, but not caspase-3 cleavage, in liver-metastatic breast cancer cells. Taken together, the current data suggest that the synergistic effects of GC and irradiation might be used to enhance the efficacy of radiotherapy in treating metastatic tumors.

The analysis of the spatiotemporal trends of precipitation and drought is relevant for the future development and sustainable management of water resources in a given region. In this study, precipitation and Standardized Precipitation Index (SPI) trends were analyzed through applying linear regression, Mann–Kendall, and Spearman’s Rho tests at the 5% significance level. For this goal, meteorological data from 9 meteorological stations in and around Aksu Basin during the period 1960–2010 was used, and two main annual drought periods were detected (1978-1979 and 1983–1986), while the extremely dry years were recorded in 1975 and 1985 at almost all of the stations. The monthly analysis of precipitation series indicates that all stations had increasing trend in July, October, and December, while both increasing and decreasing trends were found in other months. For the seasonal scale, precipitation series had increasing trends in summer and winter. 33% of the stations had the decreasing trend on precipitation in the spring series, and it was 11% in the autumn. At the same time, the SPI-12 values of all stations had the increasing trend. The significant trends were detected at Aheqi, Baicheng, Keping, and Kuche stations.