Deacetylase Sirtuin 1 mitigates type I IFN- and type II IFN-induced signaling and antiviral immunity.

Type I and type II IFNs are important immune modulators in both innate and adaptive immunity. They transmit signaling by activating JAK-STAT pathways. Sirtuin 1 (SIRT1), a class III NAD+-dependent deacetylase, has multiple functions in a variety of physiological processes. Here, we characterized the novel functions of SIRT1 in the regulation of type I and type II IFN-induced signaling. Overexpression of SIRT1 inhibited type I and type II IFN-induced interferon-stimulated response element activation. In contrast, knockout of SIRT1 promoted type I and type II IFN-induced expression of ISGs and inhibited viral replication. Treatment with SIRT1 inhibitor EX527 had similar positive effects. SIRT1 physically associated with STAT1 or STAT3, and this interaction was enhanced by IFN stimulation or viral infection. By deacetylating STAT1 at K673 and STAT3 at K679/K685/K707/K709, SIRT1 downregulated the phosphorylation of STAT1 (Y701) and STAT3 (Y705). Sirt1+/- primary peritoneal macrophages and Sirt1+/- mice exhibited enhanced IFN-induced signaling and antiviral activity. Thus, SIRT1 is a novel negative regulator of type I and type II IFN-induced signaling through its deacetylase activity.IMPORTANCESIRT1 has been reported in the precise regulation of antiviral (RNA and DNA) immunity. However, its functions in type I and type II IFN-induced signaling are still unclear. In this study, we deciphered the important functions of SIRT1 in both type I and type II IFN-induced JAK-STAT signaling and explored the potential acting mechanisms. It is helpful for understanding the regulatory roles of SIRT1 at different levels of IFN signaling. It also consolidates the notion that SIRT1 is an important target for intervention in viral infection, inflammatory diseases, or even interferon-related therapies.

Glycaemia risk index uncovers distinct glycaemic variability patterns associated with remission status in type 1 diabetes.

AIMS/HYPOTHESIS: The aim of this work was to define a unique remission status using glycaemia risk index (GRI) and other continuous glucose monitoring (CGM) metrics in individuals with type 1 diabetes for improved phenotyping. METHODS: A group of 140 individuals with type 1 diabetes were recruited for a cross-sectional study. The participants were categorised into four groups based on their remission status, which was defined as insulin-dose-adjusted A1c (IDAA1c) <9 or C-peptide ≥300 pmol/l: new-onset (n=24); mid-remission (n=44); post-remission (n=44); and non-remission (individuals who did not experience remission, n=28). Participants in the remission phase were referred to as 'remitters', while those who were not in the remission phase were referred to as 'non-remitters', the latter group including new-onset, post-remission and non-remission participants. Clinical variables such as HbA1c, C-peptide and insulin daily dose, as well as IDAA1C and CGM data, were collected. The patterns of CGM metrics were analysed for each group using generalised estimating equations to investigate the glycaemic variability patterns associated with remission status. Then, unsupervised hierarchical clustering was used to place the participants into subgroups based on GRI and other CGM core metrics. RESULTS: The glycaemic variability patterns associated with remission status were found to be distinct based on the circadian CGM metrics. Remitters showed improved control of blood glucose levels over 14 days within the range of 3.9-10 mmol/l, and lower GRI compared with non-remitters (p<0.001). Moreover, GRI strongly correlated with IDAA1C (r=0.62; p<0.001) and was sufficient to distinguish remitters from non-remitters. Further, four subgroups demonstrating distinct patterns of glycaemic variability associated with different remission status were identified by clustering on CGM metrics: remitters with low risk of dysglycaemia; non-remitters with high risk of hypoglycaemia; non-remitters with high risk of hyperglycaemia; and non-remitters with moderate risk of dysglycaemia. CONCLUSIONS/INTERPRETATION: GRI, an integrative index, together with other traditional CGM metrics, helps to identify different glycaemic variability patterns; this might provide specifically tailored monitoring and management strategies for individuals in the various subclusters.

TiO2 Nanotube Arrays Inside Ultrafine Ti Tubes with an Aspect Ratio of 2500 for Sensing Needles: The Bubble Effect in a Confined Space.

Capillary metal tubes have attracted considerable interest for flexible electronics, portable devices, trace sampling, and detection. Tailoring the microstructure and wettability inside the capillary tubes is of paramount importance, yet it presents great difficulty because of the spatial confinement. Here, the coupling effect is revealed between the fluidic and electric field induced by bubble motion in a confined space during anodic oxidation. By controlling the bubble regeneration and flow rate, uniform and superhydrophilic TiO2 nanotube arrays are developed throughout the inner surface of an ultrafine Ti tube with a diameter of 0.4 mm and length of 1000 mm, equivalent to an aspect ratio of 2500 that is the largest value being ever reported. The inner surface of a capillary tube is further coated with a polytetrafluoroethylene layer and explored as a sensing needle for liquid detection in terms of concentration and species. This study provides an innovative approach to tailor the microstructure and wettability in a confined space for functional capillary tubes.

Thiocarbonyl-Based Hole Transport Materials with Enhanced Defect Passivation Ability for Efficient and Stable Perovskite Solar Cells.

Organic hole transporting materials (HTMs) are extensively studied in perovskite solar cells (PSCs). The HTMs directly contact the underlying perovskite material, and they play additional roles apart from hole transporting. Developing organic HTMs with defect passivation function has been proved to be an efficient strategy to construct efficient and stable PSCs. In this work, new organic molecules with thiocarbonyl (C═S) and carbonyl (C═O) functional groups are synthesized and applied as HTMs (named FN-S and FN-O). FN-S with C═S can be facilely obtained from FN-O containing C═O. Notably, the C═S in FN-S results in superior defect passivation ability compared to FN-O. Moreover, FN-S exhibits excellent hole extraction/transport capability. Conventional PSCs using FN-S as HTM show an impressive power conversion efficiency (PCE) of 23.25%, with excellent long-term stability and operational stability. This work indicates that simply converting C═O to C═S is an efficient way to improve the device performance by strengthening the defect passivation functionality.

Ferroptosis-related lncRNA pairs to predict the clinical outcome and molecular characteristics of pancreatic ductal adenocarcinoma.

Ferroptosis is a form of regulated cell death initiated by oxidative perturbations that can be blocked by iron chelators and lipophilic antioxidants, and ferroptosis may be the silver bullet treatment for multiple cancers, including immunotherapy- and chemotherapy-insensitive cancers such as pancreatic ductal adenocarcinoma (PDAC). Numerous studies have noted that long non-coding RNAs (lncRNAs) regulate the biological behaviour of cancer cells by binding to DNA, RNA and protein. However, few studies have reported the role of lncRNAs in ferroptosis processes and the function of ferroptosis-associated lncRNAs. The primary objective of the present study was to identify ferroptosis-related lncRNAs using bioinformatic approaches combined with experimental validation. The second objective was to construct a prognostic model to predict the overall survival of patients with PDAC. The present study identified ferroptosis-related lncRNAs using a bioinformatic approach and validated them in an independent pancreatic cancer cohort from Fudan University Shanghai Cancer Center. The lncRNA SLCO4A1-AS1 was identified as a novel molecule mediating ferroptosis resistance in vitro. A novel algorithm was used to construct a '0 or 1' matrix-based prognosis model, which showed promising diagnostic accuracy for potential clinical translation (area under the curve = 0.89 for the 2-year survival rate). Notably, molecular subtypes classified by the risk scores of the model did not belong to any previously reported subtypes of PDAC. The immune microenvironment, metabolic activities, mutation landscape and ferroptosis sensitivity were significantly distinct between patients with different risk scores. Sensitivity (IC50) to 30 common anticancer drugs was analysed between patients with different risks, and imatinib and axitinib were found to be potential drugs for the treatment of patients with lower risk scores. Overall, we developed an accurate prognostic model based on the expression patterns of ferroptosis lncRNAs, which may contribute greatly to the evaluation of patient prognosis, molecular characteristics and treatment modalities and could be further translated into clinical applications.

CXCL12-CXCR4 mediates CD57+ CD8+ T cell responses in the progression of type 1 diabetes.

CD57+ CD8+ T cells, also referred as effector memory cells, are implicated in various conditions including tumor immunity, virus immunity, and most recently with autoimmunity. However, their roles in the progression and remission of T1D are still unclear. Here, we noted an increase in peripheral CD57+ CD8+ T cells in a T1D patient harboring an activator of transcription 3 (STAT3) mutation. Our in-depth study on the role of CD57+ CD8+ T cells within a T1D patient cohort revealed that these cells undergo significant compositional shifts during the disease's progression. Longitudinal cohort data suggested that CD57+ CD8+ T cell prevalence may be a harbinger of ß-cell function decline in T1D patients. Characterized by robust cytotoxic activity, heightened production of pro-inflammatory cytokines, and increased intracellular glucose uptake, these cells may be key players in the pathophysiology of T1D. Moreover, in vitro assays showed that the CXCL12-CXCR4 axis promotes the expansion and function of CD57+ CD8+ T cells via Erk1/2 signaling. Notably, the changes of serum CXCL12 concentrations were also found in individuals during the peri-remission phase of T1D. Furthermore, treatment with the CXCR4 antagonist LY2510924 reduced the immunological infiltration of CD57+ CD8+ T cells and mitigated hyperglycemia in a STZ-induced T1D mouse model. Taken together, our work has uncovered a novel role of the CXCL12-CXCR4 axis in driving CD57+ CD8+ T cells responses in T1D, and presented a promising therapeutic strategy for delaying the onset and progression of diabetes.

NUSAP1 promotes pancreatic ductal adenocarcinoma progression by drives the epithelial-mesenchymal transition and reduces AMPK phosphorylation.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, and its molecular mechanisms are unclear. Nucleolar and spindle-associated protein 1 (NUSAP1), an indispensable mitotic regulator, has been reported to be involved in the development of several types of tumors. The biological function and molecular mechanism of NUSAP1 in PDAC remain controversial. This study explored the effects and mechanism of NUSAP1 in PDAC. METHODS: Differentially expressed genes (DEGs) were screened. A protein‒protein interaction (PPI) network was constructed to identify hub genes. Experimental studies and tissue microarray (TMA) analysis were performed to investigate the effects of NUSAP1 in PDAC and explore its mechanism. RESULTS: Network analysis revealed that NUSAP1 is an essential hub gene in the PDAC transcriptome. Genome heterogeneity analysis revealed that NUSAP1 is related to tumor mutation burden (TMB), loss of heterozygosity (LOH) and homologous recombination deficiency (HRD) in PDAC. NUSAP1 is correlated with the levels of infiltrating immune cells, such as B cells and CD8 T cells. High NUSAP1 expression was found in PDAC tissues and was associated with a poor patient prognosis. NUSAP1 promoted cancer cell proliferation, migration and invasion, drives the epithelial-mesenchymal transition and reduces AMPK phosphorylation. CONCLUSIONS: NUSAP1 is an essential hub gene that promotes PDAC progression and leads to a dismal prognosis by drives the epithelial-mesenchymal transition and reduces AMPK phosphorylation.

Three Fe(III)-reducing and nitrogen-fixing bacteria, Anaeromyxobacter terrae sp. nov., Anaeromyxobacter oryzisoli sp. nov. and Anaeromyxobacter soli sp. nov., isolated from paddy soil.

Three microaerophilic bacterial strains, designated SG22T, SG63T and SG29T were isolated from paddy soils in PR China. Cells of these strains were Gram-staining-negative and long rod-shaped. SG22T, SG63T and SG29T showed the highest 16S rRNA gene sequence similarities with the members of the genus Anaeromyxobacter. The results of phylogenetic and phylogenomic analysis also indicated that these strains clustered with members of the genus Anaeromyxobacter. The main respiratory menaquinone of SG22T, SG63T and SG29T was MK-8 and the major fatty acids were iso-C15 : 0, iso-C17 : 0 and C16 : 0. SG22T, SG29T and SG63T not only possessed iron reduction ability but also harboured genes (nifHDK) encoding nitrogenase. The genomic DNA G+C contents of SG22T, SG63T and SG29T ranged from 73.3 to 73.5 %. The average nucleotide identity (ANI) and digital DNA-DNA hybridisation (dDDH) values between SG22T, SG63T and SG29T and the closely related species of the genus Anaeromyxobacter were lower than the cut-off values (dDDH 70 % and ANI 95-96 %) for prokaryotic species delineation. On the basis of these results, strains SG22T, SG63T and SG29T represent three novel species within the genus Anaeromyxobacter, for which the names Anaeromyxobacter terrae sp. nov., Anaeromyxobacter oryzisoli sp. nov. and Anaeromyxobacter soli sp. nov., are proposed. The type strains are SG22T (= GDMCC 1.3185T = JCM 35581T), SG63T (= GDMCC 1.2914T = JCM 35124T) and SG29T (= GDMCC 1.2911T = JCM 35123T).

Enhancement of hydrogenotrophic methanogenesis for methane production by nano zero-valent iron in soils.

Nanoscale zero-valent iron (nZVI) is attracting increasing attention as the most commonly used environmental remediation material. However, given the high surface area and strong reducing capabilities of nZVI, there is a lack of understanding regarding its effects on the complex anaerobic methane production process in flooded soils. To elucidate the mechanism of CH4 production in soil exposed to nZVI, paddy soil was collected and subjected to anaerobic culture under continuous flooding conditions, with various dosages of nZVI applied. The results showed that the introduction of nZVI into anaerobic flooded rice paddy systems promoted microbial utilization of acetate and carbon dioxide as carbon sources for methane production, ultimately leading to increased methane production. Following the introduction of nZVI into the soil, there was a rapid increase in hydrogen levels in the headspace, surpassing that of the control group. The hydrogen levels in both the experimental and control groups were depleted by the 29th day of culture. These findings suggest that nZVI exposure facilitates the enrichment of hydrogenotrophic methanogens, providing them with a favorable environment for growth. Additionally, it affected soil physicochemical properties by increasing pH and electrical conductivity. The metagenomic analysis further indicates that under exposure to nZVI, hydrogenotrophic methanogens, particularly Methanobacteriaceae and Methanocellaceae, were enriched. The relative abundance of genes such as mcrA and mcrB associated with methane production was increased. This study provides important theoretical insights into the response of key microbes, functional genes, and methane production pathways to nZVI during anaerobic methane production in rice paddy soils, offering fundamental insights into the long-term fate and risks associated with the introduction of nZVI into soils.

Two novel Fe(III)-reducing bacteria, Geothrix campi sp. nov. and Geothrix mesophila sp. nov., isolated from paddy soils.

In this research, two novel Fe(III)-reducing bacteria, SG10T and SG198T of genus Geothrix, were isolated from the rice field of Fujian Agriculture and Forestry University in Fuzhou, Fujian Province, China. Strains SG10T and SG198T were strictly anaerobic, rod-shaped and Gram-stain-negative. The two novel strains exhibited iron reduction ability, utilizing various single organic acid as the elector donor and Fe(III) as a terminal electron acceptor. Strains SG10T and SG198T showed the highest 16S rRNA sequences similarities to the type strains of Geothrix oryzisoli SG189T (99.0-99.5%) and Geothrix paludis SG195T (99.0-99.7%), respectively. The phylogenetic trees based on the 16S rRNA gene and genome 120 conserved core genes showed that strains SG10T and SG198T belong to the genus Geothrix. Average nucleotide identity (ANI) and digital DNA-DNA hybridization (dDDH) values between the phylogenetic neighbors and the two isolated strains were 86.1-94.3% and 30.7-59.5%, respectively. The major fatty acids were iso-C15:0, anteiso-C15:0, C16:0 and iso-C13:0 3OH, and MK-8 was the main respiratory quinone. According to above results, the two strains were assigned to the genus Geothrix with the names Geothrix campi sp. nov. and Geothrix mesophila sp. nov. Type strains are SG10T (= GDMCC 1.3406 T = JCM 39331 T) and SG198T (= GDMCC 62910 T = KCTC 25635 T), respectively.

Azotosporobacter soli gen. nov., sp. nov., a novel nitrogen-fixing bacterium isolated from paddy soil.

A nitrogen-fixing strain designated SG130T was isolated from paddy soil in Fujian Province, China. Strain SG130T was Gram-staining-negative, rod-shaped, and strictly anaerobic. Strain SG130T showed the highest 16S rRNA gene sequence similarities with the type strains Dendrosporobacter quercicolus DSM 1736T (91.7%), Anaeroarcus burkinensis DSM 6283T (91.0%) and Anaerospora hongkongensis HKU 15T (90.9%). Furthermore, the phylogenetic and phylogenomic analysis also suggested strain SG130T clustered with members of the family Sporomusaceae and was distinguished from other genera within this family. Growth of strain SG130T was observed at 25-45 °C (optimum 30 °C), pH 6.0-9.5 (optimum 7.0) and 0-1% (w/v) NaCl (optimum 0.1%). The quinones were Q-8 and Q-9. The polar lipids were phosphatidylserine (PS), phosphatidylethanolamine (PE), glycolipid (GL), phospholipid (PL) and an unidentified lipid (UL). The major fatty acids (> 10%) were iso-C13:0 3OH (26.6%), iso-C17:1 (15.6%) and iso-C15:1 F (11.4%). The genomic DNA G + C content was 50.7%. The average nucleotide identity (ANI) and digital DNA-DNA hybridization (dDDH) values between strain SG130T and the most closely related type strain D. quercicolus DSM 1736T (ANI 68.0% and dDDH 20.3%) were both below the cut-off level for species delineation. The average amino acid identity (AAI) between strain SG130T and the most closely related type strain D. quercicolus DSM 1736T was 63.2%, which was below the cut-off value for bacterial genus delineation (65%). Strain SG130T possessed core genes (nifHDK) involved in nitrogen fixation, and nitrogenase activity (106.38 µmol C2H4 g-1 protein h-1) was examined using the acetylene reduction assay. Based on the above results, strain SG130T is confirmed to represent a novel genus of the family Sporomusaceae, for which the name Azotosporobacter soli gen. nov., sp. nov. is proposed. The type strain is SG130T (= GDMCC 1.3312T = JCM 35641T).

Use of cardiac contractility modulation combined with left bundle branch pacing CRT-P in a female with a 22-year history of non-ischemic dilated cardiomyopathy: A case report.

Cardiac contractility modulation (CCM) is a novel device-based therapy used to treat patients with heart failure with reduced ejection fraction (HFrEF). In both randomized clinical trials and real-life studies, CCM has been shown to improve exercise tolerance and quality of life, reverse left ventricular remodeling, and reduce hospitalization in patients with HFrEF. In this case report, we describe for the first time the use of CCM combined with left bundle branch pacing (LBBP) cardiac resynchronization therapy pacemaker (CRT-P) implantation therapy in a female with a 22-year history of non-ischemic dilated cardiomyopathy. With the optimal medical therapy and cardiac resynchronization therapy (CRT) strategies, the patient's quality of life initially recovered to some extent, but began to deteriorate in the past year. Additionally, heart transplantation was not considered due to economic reasons and late stage systolic heart failure. This is the first case of CCM implantation in Fujian Province and the first report of a combined CCM and left bundle branch pacing CRT-P implantation strategy in a patient with non-ischemic etiology dilated cardiomyopathy in China.

Bulked Segregant RNA-Seq Reveals Different Gene Expression Patterns and Mutant Genes Associated with the Zigzag Pattern of Tea Plants (Camellia sinensis).

The unique zigzag-patterned tea plant is a rare germplasm resource. However, the molecular mechanism behind the formation of zigzag stems remains unclear. To address this, a BC1 genetic population of tea plants with zigzag stems was studied using histological observation and bulked segregant RNA-seq. The analysis revealed 1494 differentially expressed genes (DEGs) between the upright and zigzag stem groups. These DEGs may regulate the transduction and biosynthesis of plant hormones, and the effects on the phenylpropane biosynthesis pathways may cause the accumulation of lignin. Tissue sections further supported this finding, showing differences in cell wall thickness between upright and curved stems, potentially due to lignin accumulation. Additionally, 262 single-nucleotide polymorphisms (SNPs) across 38 genes were identified as key SNPs, and 5 genes related to zigzag stems were identified through homologous gene function annotation. Mutations in these genes may impact auxin distribution and content, resulting in the asymmetric development of vascular bundles in curved stems. In summary, we identified the key genes associated with the tortuous phenotype by using BSR-seq on a BC1 population to minimize genetic background noise.

Assistive device utilization among disabled elderly in China: A cross-sectional study.

OBJECTIVE: This study aimed to examine the characteristics of assistive device users and influencing factors among disabled elderly in China. METHODS: A total of 13,510 disabled elderly in Sichuan Province were surveyed. Disability was assessed using the Barthel Activities of Daily Living Scale, mental status, sensory perception, and social engagement evaluation. Univariate analysis and logistic regression analysis were employed to identify the impact factors. RESULTS: The prevalence of assistive device utilization among participants was 79.2% (10,700/13,510, 95% CI 78.5%-79.9%), with the wheelchair being the most commonly used device. Various factors were found to influence the usage of the device, including disability level, somatic disability, age, caregivers, income, caregiver fees, and living situation (p < .05). Additionally, several factors were identified associated with the frequency of device usage, such as somatic disability, education background, income, caregiver fees, living situation, access to acquire assistive devices, duration of assistive device usage, education on assistive devices, and satisfaction level (p < .05). CONCLUSIONS: The use of assistive devices among elderly individuals in China is prevalent. There are many factors that affect the use of assistive devices, which can provide a reference for the formulation of policies in the field of assistive devices.

Environmental Impact Assessment for the Use of an Orally Aerosolized Adenovirus Type-5 Vector-Based COVID-19 Vaccine in Randomized Clinical Trials.

BACKGROUND: An orally aerosolized adenovirus type-5 vector-based coronavirus disease 2019 (COVID-19) vaccine (Ad5-nCoV) has recently been authorized for boosting immunization in China. Our study aims to assess the environmental impact of the use of aerosolized Ad5-nCoV. METHODS: We collected air samples from rooms, swabs from the desks on which the vaccine nebulizer was set, mask samples from participants, and blood samples of nurses who administered the inoculation in the clinical trials. The viral load of adenovirus type-5 vector in the samples and the antibody levels against the wild-type severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strain in serum were detected. RESULTS: Only one (4.00%) air sample collected before initiation of vaccination was positive and most air samples collected during and after vaccination were positive (97.96%, 100%, respectively). All nurses in trial A showed at least 4-fold increase of the neutralizing antibody against SARS-CoV-2 after initiation of the study. In trial B, the proportion of positive mask samples was 72.97% at 30 minutes after vaccination, 8.11% at day 1, and 0% at days 3, 5, and 7. CONCLUSIONS: Vaccination with the orally aerosolized Ad5-nCoV could result in some spillage of the vaccine vector viral particles in the environment and cause human exposure. Clinical Trials Registration. NCT04840992 and NCT05303584.

Stabilizing Zn/electrolyte Interphasial Chemistry by a Sustained-Release Drug Inspired Indium-Chelated Resin Protective Layer for High-Areal-Capacity Zn//V2O5 Batteries.

For zinc-metal batteries, the instable chemistry at Zn/electrolyte interphasial region results in severe hydrogen evolution reaction (HER) and dendrite growth, significantly impairing Zn anode reversibility. Moreover, an often-overlooked aspect is this instability can be further exacerbated by the interaction with dissolved cathode species in full batteries. Here, inspired by sustained-release drug technology, an indium-chelated resin protective layer (Chelex-In), incorporating a sustained-release mechanism for indium, is developed on Zn surface, stabilizing the anode/electrolyte interphase to ensure reversible Zn plating/stripping performance throughout the entire lifespan of Zn//V2O5 batteries. The sustained-release indium onto Zn electrode promotes a persistent anticatalytic effect against HER and fosters uniform heterogeneous Zn nucleation. Meanwhile, on the electrolyte side, the residual resin matrix with immobilized iminodiacetates anions can also repel detrimental anions (SO4 2- and polyoxovanadate ions dissolved from V2O5 cathode) outside the electric double layer. This dual synergetic regulation on both electrode and electrolyte sides culminates a more stable interphasial environment, effectively enhancing Zn anode reversibility in practical high-areal-capacity full battery systems. Consequently, the bio-inspired Chelex-In protective layer enables an ultralong lifespan of Zn anode over 2800 h, which is also successfully demonstrated in ultrahigh areal capacity Zn//V2O5 full batteries (4.79 mAh cm-2).

CRIP1 fosters MDSC trafficking and resets tumour microenvironment via facilitating NF-κB/p65 nuclear translocation in pancreatic ductal adenocarcinoma.

OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) is among the most immunosuppressive tumour types. The tumour immune microenvironment (TIME) is largely driven by interactions between immune cells and heterogeneous tumour cells. Here, we aimed to investigate the mechanism of tumour cells in TIME formation and provide potential combination treatment strategies for PDAC patients based on genotypic heterogeneity. DESIGN: Highly multiplexed imaging mass cytometry, RNA sequencing, mass cytometry by time of flight and multiplex immunofluorescence staining were performed to identify the pro-oncogenic proteins associated with low immune activation in PDAC. An in vitro coculture system, an orthotopic PDAC allograft tumour model, flow cytometry and immunohistochemistry were used to explore the biological functions of cysteine-rich intestinal protein 1 (CRIP1) in tumour progression and TIME formation. RNA sequencing, mass spectrometry and chromatin immunoprecipitation were subsequently conducted to investigate the underlying mechanisms of CRIP1. RESULTS: Our results showed that CRIP1 was frequently upregulated in PDAC tissues with low immune activation. Elevated CRIP1 expression induced high levels of myeloid-derived suppressor cell (MDSC) infiltration and fostered an immunosuppressive tumour microenvironment. Mechanistically, we primarily showed that CRIP1 bound to nuclear factor kappa-B (NF-κB)/p65 and facilitated its nuclear translocation in an importin-dependent manner, leading to the transcriptional activation of CXCL1/5. PDAC-derived CXCL1/5 facilitated the chemotactic migration of MDSCs to drive immunosuppression. SX-682, an inhibitor of CXCR1/2, blocked tumour MDSC recruitment and enhanced T-cell activation. The combination of anti-PD-L1 therapy with SX-682 elicited increased CD8+T cell infiltration and potent antitumor activity in tumour-bearing mice with high CRIP1 expression. CONCLUSIONS: The CRIP1/NF-κB/CXCL axis is critical for triggering immune evasion and TIME formation in PDAC. Blockade of this signalling pathway prevents MDSC trafficking and thereby sensitises PDAC to immunotherapy.

Recovery of intracellular glucose uptake in T cells during partial remission of type 1 diabetes.

AIMS/HYPOTHESIS: Notwithstanding the irreversible beta cell failure seen in type 1 diabetes, some individuals may experience a special phase named 'partial remission' or 'the honeymoon period', in which there is a transient recovery of beta cell function. Importantly, this stage of partial remission shows spontaneous immune downregulation, although the exact mechanisms are unclear. Intracellular energy metabolism is crucial for the differentiation and function of T cells, and provides promising targets for immunometabolic intervention strategies, but its role during partial remission is unknown. In this study, we aim to investigate the association between T cell intracellular glucose and fatty acid metabolism and the partial remission phase. METHODS: This is a cross-sectional study with a follow-up component. Intracellular uptake of glucose and fatty acids by T cells was detected in participants with either new-onset type 1 diabetes or type 1 diabetes that was already in partial remission, and compared with heathy individuals and participants with type 2 diabetes. Subsequently, the participants with new-onset type 1 diabetes were followed up to determine whether they experienced a partial remission (remitters) or not (non-remitters). The trajectory of changes in T cell glucose metabolism was observed in remitters and non-remitters. Expression of programmed cell death-1 (PD-1) was also analysed to investigate possible mechanisms driving altered glucose metabolism. Partial remission was defined when patients had convalescent fasting or 2 h postprandial C-peptide >300 pmol/l after insulin treatment. RESULTS: Compared with participants with new-onset type 1 diabetes, intracellular glucose uptake by T cells decreased significantly in individuals with partial remission. The trajectory of these changes during follow-up showed that intracelluar glucose uptake in T cells fluctuated during different disease stages, with a decreased uptake during partial remission that rebounded after remission. This dynamic in T cell glucose uptake was only detected in remitters and not in non-remitters. Further analysis demonstrated that changes of intracellular glucose uptake were found in subsets of CD4+ and CD8+ T cells, including Th17, Th1, CD8+ naive T cells (Tn) and CD8+ terminally differentiated effector memory T cells (Temra). Moreover, glucose uptake in CD8+ T cells was negatively related to PD-1 expression. The intracellular metabolism of fatty acids was not found to be different between new-onset participants and those in partial remission. CONCLUSIONS/INTERPRETATION: Intracellular glucose uptake in T cells was specifically decreased during partial remission in type 1 diabetes and may be related to PD-1 upregulation, which may be involved in the down-modulation of immune responses during partial remission. This study suggests that altered immune metabolism could be a target for interventions at the point of diagnosis of type 1 diabetes.

OsTKPR2 is part of a sporopollenin-producing metabolon required for exine formation in rice.

The sporopollenin polymer is a major component of the pollen exine. Fatty acid derivatives synthesized in the tapetum are among the precursors of sporopollenin. Progress has been made to understand sporopollenin metabolism in rice; however, the underlying molecular mechanisms remain elusive. We found that OsTKPR2 and OsTKPR1 share a similar expression pattern, and their coding proteins have a similar subcellular localization and enzyme activities towards reduced tetraketide α-pyrone and hydroxylated tetraketide α-pyrone. Unexpectedly, OsTKPR1pro:OsTKPR2-eGFP could not rescue the phenotype of ostkpr1-4. Three independent ostkpr2 mutant lines generated by CRISPR/Cas9 displayed reduced male fertility to various extents which were correlated with the severity of gene disruptions. Notably, the anther cuticle, Ubisch bodies, and pollen development were affected in the ostkpr2-1 mutant, where a thinner pollen exine was noticed. OsTKPR1 and OsTKPR2 were integrated into a metabolon including OsACOS12 and OsPKS2, which resulted in a significant increased enzymatic efficiency when both OsTKPR1 and OsTKPR2 were present, indicating the mutual dependence of OsTKPR2 and OsTKPR1 for their full biochemical activities. Thus, our results demonstrated that OsTKPR2 is required for anther and pollen development where an OsTKPR2-containing metabolon is functional during rice sporopollenin synthesis. Furthermore, the cooperation and possible functional divergence between OsTKPR2 and OsTKPR1 is also discussed.

A novel sulfate-reducing and nitrogen-fixing bacterium Fundidesulfovibrio soli sp. nov., isolated from paddy soils.

A strictly anaerobic sulfate-reducing strain, designated SG60T, was isolated from paddy soil collected in Fujian Province, China. Growth of strain SG60T was observed at 20-37 °C, pH 5.5-10.0 and 0-0.7% (w/v) NaCl. Strain SG60T showed the highest 16S rRNA sequence similarities to the type strains of Fundidesulfovibrio magnetotacticus FSS-1T (97.2%) and Fundidesulfovibrio putealis DSM 16056T (96.4%). Phylogenetic trees based on the16S rRNA sequence and genome-based phylogenomic tree constructed using 120 core genes showed that strain SG60T clustered with members of the genus Fundidesulfovibrio. The average nucleotide identity (ANI) and digital DNA-DNA hybridization (dDDH) values between strain SG60T and the most closely related type strain F. magnetotacticus were 78.2% and 21.6%, respectively. Strain SG60T contained MK-7 as the main respiratory quinone and anteiso-C15:0, anteiso-C17:1 ω9c, iso-C16:0 and iso-C16:1 H as the major fatty acids. Strain SG60T produced desulfoviridin and possessed genes (nifHDK) encoding functions involved in nitrogen fixation. The genomic DNA G + C content was 65.5%. Based on the observed physiological properties, chemotaxonomic characteristics and ANI and dDDH values, strain SG60T represents a novel species of the genus Fundidesulfovibrio, for which the name Fundidesulfovibrio soli sp. nov. is proposed. The type strain is SG60T (= GDMCC 1.3310T = JCM 35676T).