Multiomics characterization of pyroptosis in the tumor microenvironment and therapeutic relevance in metastatic melanoma.

BACKGROUND: Pyroptosis, mediated by gasdermins with the release of multiple inflammatory cytokines, has emerged as playing an important role in targeted therapy and immunotherapy due to its effectiveness at inhibiting tumor growth. Melanoma is one of the most commonly used models for immunotherapy development, though an inadequate immune response can occur. Moreover, the development of pyroptosis-related therapy and combinations with other therapeutic strategies is limited due to insufficient understanding of the role of pyroptosis in the context of different tumor immune microenvironments (TMEs). METHODS: Here, we present a computational model (pyroptosis-related gene score, PScore) to assess the pyroptosis status. We applied PScore to 1388 melanoma samples in our in-house cohort and eight other publicly available independent cohorts and then calculated its prognostic power of and potential as a predictive marker of immunotherapy efficacy. Furthermore, we performed association analysis for PScore and the characteristics of the TME by using bulk, single-cell, and spatial transcriptomics and assessed the association of PScore with mutation status, which contributes to targeted therapy. RESULTS: Pyroptosis-related genes (PRGs) showed distinct expression patterns and prognostic predictive ability in melanoma. Most PRGs were associated with better survival in metastatic melanoma. Our PScore model based on genes associated with prognosis exhibits robust performance in survival prediction in multiple metastatic melanoma cohorts. We also found PScore to be associated with BRAF mutation and correlate positively with multiple molecular signatures, such as KRAS signaling and the IFN gamma response pathway. Based on our data, melanoma with an immune-enriched TME had a higher PScore than melanoma with an immune-depleted or fibrotic TME. Additionally, monocytes had the highest PScore and malignant cells and fibroblasts the lowest PScore based on single-cell and spatial transcriptome analyses. Finally, a higher PScore was associated with better therapeutic efficacy of immune checkpoint blockade, suggesting the potential of pyroptosis to serve as a marker of immunotherapy response. CONCLUSIONS: Collectively, our findings indicate that pyroptosis is a prognostic factor and is associated with the immune response in metastatic melanoma, as based on multiomics data. Our results provide a theoretical basis for drug combination and reveal potential immunotherapy response markers.

Floods and cause-specific mortality in the UK: a nested case-control study.

BACKGROUND: Floods are the most frequent weather-related disaster, causing significant health impacts worldwide. Limited studies have examined the long-term consequences of flooding exposure. METHODS: Flood data were retrieved from the Dartmouth Flood Observatory and linked with health data from 499,487 UK Biobank participants. To calculate the annual cumulative flooding exposure, we multiplied the duration and severity of each flood event and then summed these values for each year. We conducted a nested case-control analysis to evaluate the long-term effect of flooding exposure on all-cause and cause-specific mortality. Each case was matched with eight controls. Flooding exposure was modelled using a distributed lag non-linear model to capture its nonlinear and lagged effects. RESULTS: The risk of all-cause mortality increased by 6.7% (odds ratio (OR): 1.067, 95% confidence interval (CI): 1.063-1.071) for every unit increase in flood index after confounders had been controlled for. The mortality risk from neurological and mental diseases was negligible in the current year, but strongest in the lag years 3 and 4. By contrast, the risk of mortality from suicide was the strongest in the current year (OR: 1.018, 95% CI: 1.008-1.028), and attenuated to lag year 5. Participants with higher levels of education and household income had a higher estimated risk of death from most causes whereas the risk of suicide-related mortality was higher among participants who were obese, had lower household income, engaged in less physical activity, were non-moderate alcohol consumers, and those living in more deprived areas. CONCLUSIONS: Long-term exposure to floods is associated with an increased risk of mortality. The health consequences of flooding exposure would vary across different periods after the event, with different profiles of vulnerable populations identified for different causes of death. These findings contribute to a better understanding of the long-term impacts of flooding exposure.

Multifunctional Catalytic Hierarchical Interfaces of Ni12 P5 -Ni2 P Porous Nanosheets Enabled Both Sulfides Reaction Promotion and Li-Dendrite Suppression for High-Performance Li-S Full Batteries.

The development of lithium-sulfur (Li-S) batteries is very promising and yet faces the issues of hindered polysulfides conversion and Li dendrite growth. Different from using different materials strategies to overcome these two types of problems, here multifunctional catalytic hierarchical interfaces of Ni12 P5 -Ni2 P porous nanosheets formed by Ni2 P partially in situ converted from Ni12 P5 are proposed. The unique electronic structure in the interface endows Ni12 P5 -Ni2 P effective electrocatalysis effect toward both sulfides' reduction and oxidation through reducing Gibbs free energies, indicating a bidirectional conversion acceleration. Importantly, Ni12 P5 -Ni2 P porous nanosheets with hierarchical interfaces also reduced the Li nucleation energy barrier, and a dendrite-free Li deposition is realized during the overall Li deposition and stripping steps. To this end, Ni12 P5 -Ni2 P decorated carbon nanotube/S cathode showing a high capacity of over 1500 mAh g-1 , and a high rate capability of 8 C. Moreover, the coin full cell delivered a high capacity of 1345 mAh g-1 at 0.2 C and the pouch full cell delivered a high capacity of 1114 mAh g-1 at 0.2 C with high electrochemical stability during 180° bending. This work inspires the exploration of hierarchical structures of 2D materials with catalytically active interfaces to improve the electrochemistry of Li-S full battery.

Adding salt to foods and risk of psoriasis: A prospective cohort study.

BACKGROUND: High salt intake may play a critical role in the etiology of psoriasis. Yet, evidence on the association of high salt intake with risk of psoriasis is limited. OBJECTIVE: To estimate the association between frequency of adding salt to foods and risk of psoriasis. METHODS: We conducted a prospective cohort study of 433,788 participants from the UK Biobank. Hazard ratios (HRs) and their 95 % confidence intervals (CIs) for risk of psoriasis in relation to frequency of adding salt to foods were estimated using multivariable Cox proportional hazards models. We further evaluated the joint association of adding salt to foods and genetic susceptibility with risk of psoriasis. We conducted a mediation analysis to assess how much of the effect of adding salt to foods on risk of psoriasis was mediated through several selected mediators. RESULTS: During a median of 14.0 years of follow-up, 4279 incident cases of psoriasis were identified. In the multivariable-adjusted model, a higher frequency of adding salt to foods was significantly associated with an increased risk of psoriasis ("always" versus "never/rarely" adding salt to foods, HR = 1.25, 95 % CI: 1.10, 1.41). The observed positive association was generally similar across subgroups. In the joint association analysis, we observed that participants with a high genetic risk (above the second tertile) and the highest frequency of adding salt to foods experienced 149 % higher risk of psoriasis, when compared with participants with a low genetic risk (below the first tertile) and the lowest frequency of adding salt to foods (HR = 2.49, 95 % CI: 2.05, 3.02). Mediation analysis revealed that 1.8 %-3.2 % of the positive association between frequency of adding salt and risk of psoriasis was statistically significantly mediated by obesity and inflammatory biomarkers such as C-reactive protein and systemic immune-inflammation index (all P values < 0.004). CONCLUSIONS: Our study demonstrated a positive association between frequency of adding salt to foods and risk of psoriasis. The positive association was independent of multiple other risk factors, and may be partially mediated through obesity and inflammation.

The impacts of biologic treatment on metabolic profiling in psoriasis.

Psoriasis is an immune-mediated inflammatory disease commonly accompanied by various metabolic disorders. It is widely known that biologics could affect the metabolic status and comorbidities in psoriasis patients, however, the effects of biologics on metabolism in psoriasis patients remain poorly understood. The aim of this study was to elucidate the characteristic changes of metabolic profiling in psoriasis vulgaris (PsV) patients before and after applying biologics. Plasma samples were collected from a retrospective cohort of 43 PsV patients. Non-targeted metabolomics analyses were performed using liquid chromatography-mass spectrometry (LC-MS) to compare the metabolic profiles before and after applying adalimumab (ADA) or ixekizumab (IXE) for 4 weeks. Additionally, correlation analyses were conducted to investigate the associations between metabolite expression levels and clinical characteristics. The biologics significantly affected the metabolic profiles of PsV patients especially in glycerophospholipids (GPs). First, phosphatidylcholine (PC), unsaturated lysophosphatidylcholine (LPC), unsaturated lysophosphatidic acid (LPA) and unsaturated lysophosphatidylethanolamine (LPE) were significantly up-regulated, whereas phosphatidylethanolamine (PE), saturated LPC, saturated LPA and saturated LPE were predominantly down-regulated after biologic treatment. What is more, the changes in PE and LPA were mainly observed after applying IXE instead of ADA. Second, we also found GPs including PC, unsaturated LPC, unsaturated LPA and unsaturated LPE were primarily negatively correlated with disease severity, whereas, PE, saturated LPC, saturated LPA and saturated LPE displayed inverse correlations. Biologics could affect GP metabolism and facilitate the transition of metabolic status from a pro-inflammatory to an anti-inflammatory phenotype in PsV patients.

Highly efficient and fast modulation of magnetic coupling interaction in the SrCoO2.5/La0.7Ca0.3MnO3 heterostructure.

Effective manipulation of magnetic properties in transition-metal oxides is one of the crucial issues for the application of materials. Up to now, most investigations have focused on electrolyte-based ionic control, which is limited by the slow speed. In this work, the interfacial coupling of the SrCoO2.5/La0.7Ca0.3MnO3 (LCMO) bilayer is effectively modulated with fast response time. After being treated with diluted acetic acid, the bilayer changes from antiferromagnetic/ferromagnetic (AFM/FM) coupling to FM/FM coupling and the Curie temperature is also effectively increased. Meanwhile, the corresponding electric transport properties are modulated within a very short time. Combined with the structure characterization and X-ray absorption measurements, we find that the top SrCoO2.5 layer is changed from the antiferromagnetic insulator to the ferromagnetic metal phase, which is attributed to the formation of the active oxygen species due to the reaction between the protons in the acid and the SrCoO2.5 layer. The bottom LCMO layer remains unchanged during this process. The response time of the bilayer with the acid treatment method is more than an order of magnitude faster than other methods. It is expected that this acid treatment method may open more possibilities for manipulating the magnetic and electric properties in oxide-based devices.

Effects of cadmium on the intestinal health of the snail Bradybaena ravida Benson.

The heavy metal cadmium (Cd) is a toxic and bioaccumulative metal that can be enriched in the tissues and organs of living organisms through the digestive tract. However, more research is needed to determine whether food-sourced Cd affects the homeostasis of host gut microflora. In this study, the snail Bradybaena ravida (Benson) was used as a model organism fed with mulberry leaves spiked with different concentrations of Cd (0, 0.052, 0.71, and 1.94 mg kg-1). By combining 16S rRNA high-throughput sequencing with biochemical characterization, it was found that there were increases in the overall microbial diversity and abundances of pathogenic bacteria such as Corynebacterium, Enterococcus, Aeromonas, and Rickettsia in the gut of B. ravida after exposure to Cd. However, the abundances of potential Cd-resistant microbes in the host's gut, including Sphingobacterium, Lactococcus, and Chryseobacterium, decreased with increasing Cd concentrations in the mulberry leaves. In addition, there was a significant reduction in activities of energy, nutrient metabolism, and antioxidant enzymes for gut microbiota of snails treated with high concentrations of Cd compared to those with low ones. These findings highlight the interaction of snail gut microbiota with Cd exposure, indicating the potential role of terrestrial animal gut microbiota in environmental monitoring through rapid recognition and response to environmental pollution.

One-Step Synthesis of Polyethyleneimine-Grafted Styrene-Maleic Anhydride Copolymer Adsorbents for Effective Adsorption of Anionic Dyes.

Wastewater containing organic dyes has become one of the important challenges in water treatment due to its high salt content and resistance to natural degradation. In this work, a novelty adsorbent, PEI-SMA, was prepared by grafting polyethyleneimine (PEI) onto styrene-maleic anhydride copolymer (SMA) through an amidation reaction. The various factors, such as pH, adsorbent dosage, contact time, dye concentration, and temperature, which may affect the adsorption of PEI-SMA for Reactive Black 5 (RB5), were systematically investigated by static adsorption experiments. The adsorption process of PEI-SMA for RB5 was more consistent with the Langmuir isotherm model and the pseudo-second-order model, suggesting a single-layer chemisorption. PEI-SMA exhibits excellent adsorption performance for RB5 dye, with a maximum adsorption capacity of 1749.19 mg g-1 at pH = 2. Additionally, PEI-SMA exhibited highly efficient RB5 competitive adsorption against coexisting Cl- and SO42- ions and cationic dyes. The adsorption mechanism was explored, and it can be explained as the synergistic effect of electrostatic interaction, hydrogen bonding and π-π interaction. This study demonstrates that PEI-SMA could act as a high performance and promising candidate for the effective adsorption of anionic dyes from aqueous solutions.

Rare Earth Single-Atom Catalysis for High-Performance Li-S Full Battery with Ultrahigh Capacity.

Lithium-sulfur (Li-S) batteries have many advantages but still face problems such as retarded polysulfides redox kinetics and Li dendrite growth. Most reported single atom catalysts (SACs) for Li-S batteries are based on d-band transition metals whose d orbital constitutes active valence band, which is inclined to occur catalyst passivation. SACs based on 4f inner valence orbital of rare earth metals are challenging for their great difficulty to be activated. In this work, we design and synthesize the first rare earth metal Sm SACs which has electron-rich 4f inner orbital to promote catalytic conversion of polysulfides and uniform deposition of Li. Sm SACs enhance the catalysis by the activated 4f orbital through an f-d-p orbital hybridization. Using Sm-N3C3 modified separators, the half cells deliver a high capacity over 600 mAh g-1 and a retention rate of 84.3 % after 2000 cycles. The fabricated Sm-N3C3-Li|Sm-N3C3@PP|S/CNTs full batteries can provide an ultra-stable cycling performance of a retention rate of 80.6 % at 0.2 C after 100 cycles, one of the best full Li-S batteries. This work provides a new perspective for the development of rare earth metal single atom catalysis in electrochemical reactions of Li-S batteries and other electrochemical systems for next-generation energy storage.

Adenosine 5'monophosphate-activated protein kinase activation reduces the risks of psoriasis and its comorbidities: a mendelian randomisation study in the UK Biobank.

OBJECTIVE: Whether metformin and its adenosine 5'monophosphate-activated protein kinase (AMPK) activation protect from psoriasis risk is unconcluded. We investigated the effect of AMPK, a pharmacological target of metformin, on the risk of psoriasis and its comorbidities and mortality among participants in the UK Biobank(UKB). METHODS: To avoid immortal-time-biases in pharmacoepidemiologic studies, Mendelian randomisation was used to infer the AMPK pathway-dependent effects. The cut-off age for distinguishing early-onset/late-onset psoriasis (EOP/LOP) was set at 60 years, based on the incident psoriasis peak in UKB. A genetic instrument comprising 44 single-nucleotide polymorphisms associated with HbA1c, serving as a proxy for AMPK genetic risk score (negatively associated with AMPK activation), was employed as previously reported in the literature. Log-binomial models were used to estimate the effect size of AMPK regarding relative risk (RR) and 95% confidence interval (CI). RESULTS: A total of 407 159 participants were analyzed, including 9,126 EOP and 3,324 LOP. The AMPK-genetic-risk-score was associated with a 12.4% increase in the risk of LOP in men (RR = 1.124, 95% CI: 1.022-1.236). This association was not significant for EOP or women. AMPK genetic risk score exhibited an elevated risk of ischemic heart disease (RR = 1.217, 95% CI 1.062-1.395) in male psoriasis patients. CONCLUSIONS: AMPK activation may protect against LOPs and associated ischemic heart disease in men. A sex-specific, comorbidity-targeted intervention for psoriasis is needed.

Rapid shifts in thermal reaction norms and tolerance of brooded coral larvae following parental heat acclimation.

Thermal priming of reef corals can enhance their heat tolerance; however, the legacy effects of heat stress during parental brooding on larval resilience remain understudied. This study investigated whether preconditioning adult coral Pocillopora damicornis to high temperatures (29°C and 32°C) could better prepare their larvae for heat stress. Results showed that heat-acclimated adults brooded larvae with reduced symbiont density and shifted thermal performance curves. Reciprocal transplant experiments demonstrated higher bleaching resistance and better photosynthetic and autotrophic performance in heat-exposed larvae from acclimated adults compared to unacclimated adults. RNA-seq revealed strong cellular stress responses in larvae from heat-acclimated adults that could have been effective in rescuing host cells from stress, as evidenced by the widespread upregulation of genes involved in cell cycle and mitosis. For symbionts, a molecular coordination between light harvesting, photoprotection and carbon fixation was detected in larvae from heat-acclimated adults, which may help optimize photosynthetic activity and yield under high temperature. Furthermore, heat acclimation led to opposing regulations of symbiont catabolic and anabolic pathways and favoured nutrient translocation to the host and thus a functional symbiosis. Notwithstanding, the improved heat tolerance was paralleled by reduced light-enhanced dark respiration, indicating metabolic depression for energy saving. Our findings suggest that adult heat acclimation can rapidly shift thermal tolerance of brooded coral larvae and provide integrated physiological and molecular evidence for this adaptive plasticity, which could increase climate resilience. However, the metabolic depression may be maladaptive for long-term organismal performance, highlighting the importance of curbing carbon emissions to better protect corals.

Predictive value of intravascular ultrasound for the function of intermediate coronary lesions.

BACKGROUND: Intravascular ultrasound (IVUS) can provide detailed coronary anatomic parameters. The purpose of our study was to evaluate the parameters measured by IVUS for the prediction of intermediate coronary lesions function by referencing quantitative fraction ratio (QFR) ≤ 0.80 (vs. > 0.80). METHODS: Eighty four cases with 92 intermediate coronary lesions in vessels with a diameter ≥ 2.50 mm were enrolled. Paired assessment of IVUS and cQFR was available, and vessels with cQFR ≤ 0.8 were considered the positive reference standard. Logistic regression was used to select model variables by a maximum partial likelihood estimation test and receiver operating characteristic curve (ROC) analysis to evaluate the diagnostic value of different indices. RESULTS: Plaque burden (PB) and lesion length (LL) of IVUS were independent risk factors for the function of coronary lesions. The predictive probability P was derived from the combined PB and LL model. The area under the curve (AUC) of PB, (minimum lumen area) MLA, and LL and the predicted probability P are 0.789,0.732,0731, and 0.863, respectively (P < 0.01). The AUC of the predicted probability P was the biggest among them; the prediction accuracy of cQFR ≤ 0.8 was 84.8%, and the sensitivity of the diagnostic model was 0.826, specificity was 0. 725, and P < 0.01. CONCLUSION: PB and LL of IVUS were independent risk factors influencing the function of intermediate coronary lesions. The model combining the PB and LL may predict coronary artery function better than any other single parameter.

Association of air pollution and genetic risks with incidence of elderly-onset atopic dermatitis: A prospective cohort study.

BACKGROUND: Elderly-onset atopic dermatitis (AD) is a remarkable subtype and has been put on the agenda owing to its difficulty to control. Understanding the influence of genetic and environmental exposures is crucial to preventing elderly-onset AD. OBJECTIVES: To explore the association between genes and air pollution on incident elderly-onset AD. MATERIAL AND METHODS: This study was based on UK Biobank that recruited over 500,000 participants. The genetic risks were categorized into low, intermediate, and high groups according to tertiles of polygenic risk scores. Mixed exposure to various air pollutants was assessed using the weighted quantile sum (WQS) and also categorized based on tertiles. Within each genetic risk group, whether air pollutant mixture was associated with incident elderly-onset AD was estimated. RESULTS: 337,910 participants were included in the final analysis, and the mean age was 57.1. The median years for follow-up were 12.0, and the incident cases of AD were 2545. The medium and high air pollution mixture was significantly associated with incident AD compared with the low pollution group, with HRs of 1.182 (P = 0.003) and 1.359 (P < 0.001), respectively. In contrast, HR for medium and high genetic susceptibility was only 1.065 (P = 0.249) and 1.153 (P = 0.008). The population-attributable fraction of air pollution and genetic risk was 15.5 % (P < 0.001) and 6.4 % (P = 0.004). Additionally, compared with low genetic risk and low air pollution, high genetic risk and high air pollution was significantly associated with the incidence of elderly-onset AD with a HR of up to 1.523 (P < 0.001). There were no interactive effects between each group of genetic risks and air pollution. When grouped by sex, females could observe a stronger effect by genetic and air pollutant mixture exposure. CONCLUSION: Air pollution and genetics both independently enhance the risk of newly developed AD, and the effect of air pollutants is stronger than the investigated genes.

Regulation of gut bacteria in silkworm (Bombyx mori) after exposure to endogenous cadmium-polluted mulberry leaves.

Soil cadmium (Cd) pollution presents a severe pollution burden to flora and fauna due to its non-degradability and transferability. The Cd in the soil is stressing the silkworm (Bombyx mori) out through a soil-mulberry-silkworm system. The gut microbiota of B.mori are reported to shape host health. However, earlier research had not reported the effect of endogenous Cd-polluted mulberry leaves on the gut microbiota of B.mori. In the current research, we compared the phyllosphere bacteria of endogenous Cd-polluted mulberry leaves at different concentrations. The investigation of the gut bacteria of B.mori fed with the mulberry leaves was done to evaluate the impact of endogenous Cd- polluted mulberry leaves on the gut bacteria of the silkworm. The results revealed a dramatic change in the gut bacteria of B.mori whereas, the changes in the phyllosphere bacteria of mulberry leaves in response to an increased Cd concentration were insignificant. It also increased the α-diversity and altered the gut bacterial community structure of B. mori. A significant change in the abundance of dominant phyla of gut bacteria of B.mori was recorded. At the genus level, the abundance of Enterococcus, Brachybacterium and Brevibacterium group related to disease resistance, and the abundance of Sphingomonas, Glutamicibacter and Thermus related to metal detoxification was significantly increased after Cd exposure. Meanwhile, there was a significant decrease in the abundance of the pathogenic bacteria Serratia and Enterobacter. The results demonstrated that endogenous Cd-polluted mulberry leaves caused perturbations in the gut bacterial composition of B.mori, which may driven by Cd content rather than phyllosphere bacteria. A significant variation in the specific bacterial community indicated the adaptation of B. mori gut for its role in heavy metal detoxification and immune function regulation. The results of this study help to understand the bacterial community associated with endogenous Cd-polluted resistance in the gut of B.mori, which proves to be a novel addition in describing its response in activating the detoxification mechanism and promoting its growth and development. This research work will help to explore the other mechanisms and microbiota associated with the adaptations to mitigate the Cd pollution problems.

Character and Distribution of Geometrically Necessary Dislocations in Polycrystalline Tantalum.

Geometrically necessary dislocations (GNDs) play a key role in accommodating strain incompatibility between neighboring grains in polycrystalline materials. One critical step toward accurately capturing GNDs in deformation models involves studying the microstructural features that promote GND accumulation and the resulting character of GND fields. This study utilizes high-resolution electron backscatter diffraction to map GND populations in a large polycrystalline sample of pure tantalum, under simple tension. A total of 1,989 grains, 3,518 grain boundaries (GBs), and 3,207 triple junctions (TJs) were examined in a subsurface region of the sample. Correlations between GND density and GB character, and to some extent, TJ character, are investigated. Statistical geometrical relationships between these entities are quantified, and also visualized, using a novel application of two-point statistics. The nature of GNDs across the sample is also visualized and assessed using a recently developed method of mapping the local net Burgers vectors. The different approaches to characterizing GND distribution are compared in terms of how they quantify the size of near boundary gradient zones.

CCHCR1-astrin interaction promotes centriole duplication through recruitment of CEP72.

BACKGROUND: The centrosome is one of the most important non-membranous organelles regulating microtubule organization and progression of cell mitosis. The coiled-coil alpha-helical rod protein 1 (CCHCR1, also known as HCR) gene is considered to be a psoriasis susceptibility gene, and the protein is suggested to be localized to the P-bodies and centrosomes in mammalian cells. However, the exact cellular function of HCR and its potential regulatory role in the centrosomes remain unexplored. RESULTS: We found that HCR interacts directly with astrin, a key factor in centrosome maturation and mitosis. Immunoprecipitation assays showed that the coiled-coil region present in the C-terminus of HCR and astrin respectively mediated the interaction between them. Astrin not only recruits HCR to the centrosome, but also protects HCR from ubiquitin-proteasome-mediated degradation. In addition, depletion of either HCR or astrin significantly reduced centrosome localization of CEP72 and subsequent MCPH proteins, including CEP152, CDK5RAP2, and CEP63. The absence of HCR also caused centriole duplication defects and mitotic errors, resulting in multipolar spindle formation, genomic instability, and DNA damage. CONCLUSION: We conclude that HCR is localized and stabilized at the centrosome by directly binding to astrin. HCR are required for the centrosomal recruitment of MCPH proteins and centriolar duplication. Both HCR and astrin play key roles in keeping normal microtubule assembly and maintaining genomic stability.

Trichosanthin Promotes Anti-Tumor Immunity through Mediating Chemokines and Granzyme B Secretion in Hepatocellular Carcinoma.

Trichosanthin (TCS) is a type I ribosome-inactivating protein extracted from the tuberous root of the plant Trichosanthes. TCS shows promising potential in clinical drug abortion, anti-tumor and immunological regulation. However, the molecular mechanisms of its anti-tumor and immune regulation properties are still not well discovered. In the present study, we investigated the anti-tumor activity of TCS in hepatocellular carcinoma (HCC), both in vitro and in vivo. Both HCC cell lines and xenograft tumor tissues showed considerable growth inhibition after they were treated with TCS. TCS provoked caspase-mediated apoptosis in HCC cells and xenograft tumor tissues. The recruitment of CD8+ T cells to HCC tissues and the expression of chemokines, CCL2 and CCL22, were promoted upon TCS treatment. In addition, TCS induced an upregulation of Granzyme B (GrzB), TNF-α and IFN-γ in HCC tissues, which are the major cytotoxic mediators produced by T cells. Furthermore, TCS also resulted in an increase of mannose-6-phosphate receptor (M6PR), the major receptor of GrzB, in HCC tissues. In summary, these results suggest that TCS perhaps increases T-cell immunity via promoting the secretion of chemokines and accelerating the entry of GrzB to HCC cells, which highlights the potential role of TCS in anti-tumor immunotherapy.

Core-Shell Structure Trimetallic Sulfide@N-Doped Carbon Composites as Anodes for Enhanced Lithium-Ion Storage Performance.

The high specific capacity of transition metal sulfides (TMSs) opens up a promising new development direction for lithium-ion batteries with high energy storage. However, the poor conductivity and serious volume expansion during charge and discharge hinder their further development. In this work, trimetallic sulfide Zn-Co-Fe-S@nitrogen-doped carbon (Zn-Co-Fe-S@N-C) polyhedron composite with a core-shell structure is synthesized through a simple self-template method using ZnCoFe-ZIF as precursor, followed by a dopamine surface polymerization process and sulfidation during high-temperature calcination. The obvious space between the internal core and the external shell of the Zn-Co-Fe-S@N-C composites can effectively alleviate the volume expansion and shorten the diffusion path of Li ions during charge and discharge cycles. The nitrogen-doped carbon shell not only significantly improves the electrical conductivity of the material, but also strengthens the structural stability of the material. The synergistic effect between polymetallic sulfides improves the electrochemical reactivity. When used as an anode in lithium-ion batteries (LIBs), the prepared Zn-Co-Fe-S@N-C composite exhibits a high specific capacity retention (966.6 mA h g-1 after 100 cycles at current rate of 100 mA g-1) and good cyclic stability (499.17 mA h g-1 after 120 cycles at current rate of 2000 mA g-1).

Does Plant Identity Affect the Dispersal of Resistomes Above and Below Ground?

Resistomes are ubiquitous in natural environments. Previous studies have shown that both the plant phyllosphere and soil-borne nematodes were reservoirs of above- and below-ground resistomes, respectively. However, the influence of plant identity on soil, nematode, and phyllosphere resistomes remains unclear. Here, a microcosm experiment was used to explore the characteristics of bacterial communities and resistomes in soil, nematode, and phyllosphere associated with six different plant identities (Lactuca sativa, Cichorium endivia, Allium fistulosum, Coriandrum sativum, Raphanus sativus, and Mesembryanthemum crystallinum). A total of 222 antibiotic resistance genes (ARGs) and 7 mobile genetic elements (MGEs) were detected by high-throughput quantitative PCR from all samples. Plant identity not only significantly affected the diversity of resistomes in soil, nematode, and phyllosphere but also influenced the abundance of resistomes in nematodes. Shared bacteria and resistomes indicated a possible pathway of resistomes transfer through the soil-nematode-phyllosphere system. Structural equation models revealed that plant identity had no direct effect on phyllosphere ARGs, but altered indirectly through complex above- and below-ground interactions (soil-plant-nematode trophic transfer). Results also showed that bacteria and MGEs were key factors driving the above- and below-ground flow of resistomes. The study extends our knowledge about the top-down and bottom-up dispersal patterns of resistomes.

Development and validation of a novel nomogram to predict overall survival of patients with moderate to severe chronic kidney disease.

INTRODUCTION: The risk of death significantly increased from stage 3 chronic kidney disease (CKD) onward. We aimed to construct a novel nomogram to predict the overall survival (OS) of patients afflicted with CKD from stage 3-5. METHODS: A total of 882 patients with stage 3-5 CKD were enrolled from the NHANES 2001-2004 survey. Data sets from the 2003-2004 survey population were used to develop a nomogram that would predict the risk of OS. The 2001-2002 survey population was used to validate the nomogram. Least absolute shrinkage and selection operator (Lasso) regression was conducted to screen the significant predictors relative to all-cause death. The multivariate Cox regression based on the screened factors was applied to effectively construct the nomogram. The performance of the nomogram was evaluated according to the C-index, the area under the receiver operating characteristic curve (AUC), and the calibration curve with 1000 bootstraps resample. Kaplan-Meier's curves were used for testing the discrimination of the prediction model. RESULTS: Five variables (age, urinary albumin-to-creatinine ratio (UACR), potassium, cystatin C (Cys C), and homocysteine) were screened by the Lasso regression. The nomogram was constructed using these factors, as well as the CKD stage. The included factors (age, CKD stage, UACR, potassium, Cys C, and homocysteine) were all significantly related to the death of CKD patients, according to the multivariate Cox regression analysis. The internal validation showed that this nomogram demonstrates good discrimination and calibration (adjusted C-index: 0.70; AUC of 3-, 5-, and 10-year OS were 0.75, 0.78, and 0.77, respectively). External validation also demonstrated exceedingly similar results (C-index: 0.72, 95% CI: 0.69-0.76; AUC of 3-, 5-, and 10-year OS were 0.76, 0.79, and 0.80, respectively). CONCLUSIONS: This study effectively constructed a novel nomogram that incorporates CKD stage, age, UACR, potassium, Cys C, and homocysteine, which can be conveniently used to facilitate the individualized prediction of survival probability in patients with stage 3-5 CKD. It displays valuable potential for clinical application.