Depletion of a putatively druggable class of phosphatidylinositol kinases inhibits growth of p53-null tumors.

Here, we show that a subset of breast cancers express high levels of the type 2 phosphatidylinositol-5-phosphate 4-kinases α and/or ß (PI5P4Kα and ß) and provide evidence that these kinases are essential for growth in the absence of p53. Knocking down PI5P4Kα and ß in a breast cancer cell line bearing an amplification of the gene encoding PI5P4K ß and deficient for p53 impaired growth on plastic and in xenografts. This growth phenotype was accompanied by enhanced levels of reactive oxygen species (ROS) leading to senescence. Mice with homozygous deletion of both TP53 and PIP4K2B were not viable, indicating a synthetic lethality for loss of these two genes. Importantly however, PIP4K2A(-/-), PIP4K2B(+/-), and TP53(-/-) mice were viable and had a dramatic reduction in tumor formation compared to TP53(-/-) littermates. These results indicate that inhibitors of PI5P4Ks could be effective in preventing or treating cancers with mutations in TP53.

Declined terrestrial ecosystem resilience.

Terrestrial ecosystem resilience is crucial for maintaining the structural and functional stability of ecosystems following disturbances. However, changes in resilience over the past few decades and the risk of future resilience loss under ongoing climate change are unclear. Here, we identified resilience trends using two remotely sensed vegetation indices, analyzed the relative importance of potential driving factors to resilience changes, and finally assessed the risk of future resilience loss based on the output data of eight models from CMIP6. The results revealed that more than 60% of the ecosystems experienced a conversion from an increased trend to a declined trend in resilience. Attribution analysis showed that the most important driving factors of declined resilience varied regionally. The declined trends in resilience were associated with increased precipitation variability in the tropics, decreased vegetation cover in arid region, increased temperature variability in temperate regions, and increased average temperature in cold regions. CMIP6 reveals that terrestrial ecosystems under SPP585 are expected to experience more intense declines in resilience than those under SSP126 and SSP245, particularly in cold regions. These results highlight the risk of continued degradation of ecosystem resilience in the future and the urgency of climate mitigation actions.

Thermally Activated Delayed Fluorescent Binuclear Copper(I) Alkynyl Complexes with Cuprophilic Interactions.

Copper(I)-based thermally activated delayed fluorescence (TADF) emitters have been conceived to be promising candidates for display and lighting applications because of their multifarious structures and strong photoluminescence. Herein a string of binuclear Cu(I) complexes bearing pronounced cuprophilic interactions have been designed and synthesized. [Cu2(dppb)2(µ2-η1-C≡C-Ph)2] (1 a) and [Cu2(dppb)2(µ2-η1-C≡C-PPXZ)2] (1 b) display photoluminescence quantum yields of up to 67 % in doped films and solid states via TADF and exhibit reversible bicolor luminescence switching upon mechanical stimuli. Computational studies manifest that the metal-to-ligand charge transfer predominant transitions ensure a small energy splitting (ΔEST) between the lowest singlet (S1) and triplet (T1) excited states and cuprophilic interactions promote the spin-orbit coupling (SOC), favoring the reverse intersystem crossing (RISC) process. This study provides a new strategy for the construction of stimuli-responsive metal-based TADF materials.

Requirement of RORα for maintenance and antitumor immunity of liver-resident natural killer cells/ILC1s.

BACKGROUD AND AIMS: Liver type 1 innate lymphoid cells (ILC1s), also known as liver-resident natural killer (LrNK) cells, comprise a high proportion of total hepatic ILCs. However, factors regulating their maintenance and function remain unclear. APPROACH AND RESULTS: In this study, we found high expression of retinoid-related orphan nuclear receptor alpha (RORα) in LrNK cells/ILC1s. Mice with conditional ablation of retinoid-related orphan nuclear receptor alpha (Rorα) in LrNK cells/ILC1s and conventional natural killer (cNK) cells had decreased LrNK cells/ILC1s but normal numbers of cNK cells. RORα-deficient LrNK cells/ILC1s displayed increased apoptosis and significantly altered transcriptional profile. Using a murine model of colorectal cancer liver metastasis, we found that RORα conditional deficiency resulted in more aggressive liver tumor progression and impaired effector molecule expression in LrNK cells/ILC1s. Consequently, treatment with the RORα agonist efficiently limited liver metastases and promoted effector molecule expression of LrNK cells/ILC1s. CONCLUSIONS: This study reveals a role of RORα in LrNK cell/ILC1 maintenance and function, providing insights into the harnessing of LrNK cell/ILC1 activity in the treatment of liver cancer.

Soil moisture determines the recovery time of ecosystems from drought.

Recovery time, the time it takes for ecosystems to return to normal states after experiencing droughts, is critical for assessing the response of ecosystems to droughts; however, the spatial dominant factors determining recovery time are poorly understood. We identify the global patterns of terrestrial ecosystem recovery time based on remote sensed vegetation indices, analyse the affecting factors of recovery time using random forest regression model, and determine the spatial distribution of the dominant factors of recovery time based on partial correlation. The results show that the global average recovery time is approximately 3.3 months, and that the longest recovery time occurs in mid-latitude drylands. Analysis of affecting factors of recovery time suggests that the most important environmental factor affecting recovery time is soil moisture during the recovery period, followed by temperature and vapour pressure deficit (VPD). Recovery time shortens with increasing soil moisture and prolongs with increasing VPD; however, the response of recovery time to temperature is nonmonotonic, with colder or hotter temperatures leading to longer recovery time. Soil moisture dominates the drought recovery time over 58.4% of the assessed land area, mostly in the mid-latitudes. The concern is that soil moisture is projected to decline in more than 65% regions in the future, which will lengthen the drought recovery time and exacerbate drought impacts on terrestrial ecosystems, especially in southwestern United States, the Mediterranean region and southern Africa. Our research provides methodological insights for quantifying recovery time and spatially identifies dominant factors of recovery time, improving our understanding of ecosystem response to drought.

Synthesis of Low-Cost and High-Performance Dual-Atom Doped Carbon-Based Materials with a Simple Green Route as Anodes for Sodium-Ion Batteries.

Sodium-ion batteries (SIBs) are promising alternatives to replace lithium-ion batteries as future energy storage batteries because of their abundant sodium resources, low cost, and high charging efficiency. In order to match the high energy capacity and density, designing an atomically doped carbonous material as the anode is presently one of the important strategies to commercialize SIBs. In this work, we report the preparation of high-performance dual-atom-doped carbon (C) materials using low-cost corn starch and thiourea (CH4N2S) as the precursors. The electronegativity and radii of the doped atoms and C are different, which can vary the embedding properties of sodium ions (Na+) into/on C. As sulfur (S) can effectively expand the layer spacing, it provides more channels for embedding and de-embedding Na+. The synergistic effect of N and S co-doping can remarkably boost the performance of SIBs. The capacity is preserved at 400 mAh g -1 after 200 cycles at 500 mA g-1; more notably, the initial Coulombic efficiency is 81%. Even at a high rate of high current of 10 A g-1, the cell capacity can still reach 170 mAh g-1. More importantly, after 3000 cycles at 1 A g-1, the capacity decay is less than 0.003% per cycle, which demonstrates its excellent electrochemical performance. These results indicate that high-performance carbon materials can be prepared using low-cost corn starch and thiourea.

Level of N6-Methyladenosine in Peripheral Blood RNA: A Novel Predictive Biomarker for Gastric Cancer.

BACKGROUND: Dysregulation of N6-methyladenosine (m6A) is associated with various human diseases including cancer. This study aimed to evaluate the level of m6A as a biomarker for gastric cancer (GC) diagnosis. METHODS: Peripheral blood samples were collected from 100 GC patients, 30 benign gastric disease (BGD) patients, and 75 healthy controls (HCs). Levels of m6A in total RNA and expression of m6A-related proteins were analyzed. RESULTS: The m6A levels in peripheral blood RNA were significantly increased in the GC group compared with those in the BGD or HC groups; moreover, levels increased with the progression and metastasis of GC and decreased in GC patients after surgery. The area under the curve (AUC) for m6A in the GC group was 0.929 (95% CI, 0.88-0.96), which is markedly greater than the AUCs for carcinoembryonic antigen (CEA; 0.694) and carbohydrate antigen 199 (CA199; 0.603). The combination of CEA and CA199 with m6A improved the AUC to 0.955 (95% CI, 0.91-0.98). The expressions of m6A demethylases ALKBH5 and FTO were significantly downregulated in the GC group compared with the HC group. Coculture with GC cells increased the m6A of RNA in promyelocytic (HL-60) and monocytic (THP-1) leukemia cells and nontumorigenic human peripheral blood B lymphocyte cells (PENG-EBV). Furthermore, a xenograft model enhanced the m6A in peripheral blood RNA of mice. Accordingly, expressions of ALKBH5 and FTO were decreased both in vitro and in vivo. CONCLUSIONS: Level of m6A in peripheral blood RNA is a promising noninvasive diagnostic biomarker for GC patients.

Screening the expression of several miRNAs from TaqMan Low Density Array in traumatic brain injury: miR-219a-5p regulates neuronal apoptosis by modulating CCNA2 and CACUL1.

Circulating microRNAs (miRNAs) have emerged as diagnostic and prognostic biomarkers for traumatic brain injury (TBI). However, a comprehensive characterization of the serum miRNA profile in patients with TBI and the roles of these potential markers in neuronal regulation have rarely been reported. In this study, the levels of 754 serum miRNAs were initially determined in two pooled samples of 15 severe traumatic brain injury (sTBI) patients and 15 healthy controls using a TaqMan Low Density Array. The markedly upregulated miRNAs in sTBI patients were subsequently validated individually by quantitative reverse-transcription PCR (RT-qPCR) in another larger cohort consisting of 81 sTBI patients, 81 mild traumatic brain injury (mTBI) patients and 82 age/sex-matched healthy controls. Seven miRNAs, including miR-103a-3p, miR-219a-5p, miR-302d-3p, miR-422a, miR-518f-3p, miR-520d-3p and miR-627, were significantly upregulated in both sTBI and mTBI patients compared with their expression in controls. Among these miRNAs, miR-219a-5p not only discriminated sTBI and mTBI patients from controls but also discriminated between sTBI and mTBI patients. We further show here that in the neuronal cell injury model, upregulated miR-219a-5p inhibits the expression of CCNA2 and CACUL1 and further regulates akt/Foxo3a and p53/Bcl-2 signaling pathways, causing a notable change in the expression of cleaved caspase-3, thereby inducing neuronal apoptosis. These results indicate that these seven selected miRNAs could serve as novel biomarkers for TBI. In particular, miR-219a-5p is a potentially valuable indicator of the diagnosis, prognosis of TBI and appears to regulate neuronal apoptosis and death.

Single-molecule protein sensing in a nanopore: a tutorial.

Proteins are the structural elements and machinery of cells responsible for a functioning biological architecture and homeostasis. Advances in nanotechnology are catalyzing key breakthroughs in many areas, including the analysis and study of proteins at the single-molecule level. Nanopore sensing is at the forefront of this revolution. This tutorial review provides readers a guidebook and reference for detecting and characterizing proteins at the single-molecule level using nanopores. Specifically, the review describes the key materials, nanoscale features, and design requirements of nanopores. It also discusses general design requirements as well as details on the analysis of protein translocation. Finally, the article provides the background necessary to understand current research trends and to encourage the identification of new biomedical applications for protein sensing using nanopores.

Association of decreased expression of the macrophage scavenger receptor MARCO with tumor progression and poor prognosis in human hepatocellular carcinoma.

BACKGROUND AND AIM: The macrophage receptor with collagenous structure (MARCO) belongs to the scavenger receptor family; however, few studies have assessed their potentials in modulating inflammatory signaling other than the typical function of pattern recognition and phagocytic clearance. Interestingly, RNA-Seq analyses of hepatocellular carcinoma (HCC) have identified MARCO as one of the top 30 differentially expressed genes between cancerous and adjacent noncancerous tissues. However, no research has been performed to study MARCO in liver cancer. METHODS: MARCO protein expression was evaluated by immunostaining liver tissue specimens collected from 88 HCC patients, 10 liver cirrhosis patients, 6 metastatic patients, and 5 healthy controls. All sections were reviewed by blinded observers followed by the interpretation of integral optical density per area as a measure of protein intensity. RESULTS: We observed significantly decreased expression of MARCO in intratumoral tissues of HCC compared with expression in peritumoral tissues. The expression of MARCO declined progressively as the disease condition was aggravated, with the highest expression found in healthy controls and the lowest found in patients with HCC metastasis. Furthermore, MARCO expression decreased along with tumor progression. MARCO+ cells co-localized with CD68+ cells, indicating predominant expression on macrophages. The overall survival rate was significantly increased in patients with high intratumoral MARCO expression compared with that of patients with low intratumoral MARCO expression. CONCLUSIONS: Our study is the first to demonstrate an association between MARCO expression and the progression and prognosis of HCC.

Elevated levels of preß1-high-density lipoprotein are associated with cholesterol ester transfer protein, the presence and severity of coronary artery disease.

BACKGROUND: Preß1-high-density lipoprotein (preß1-HDL), plays an important role in reverse cholesterol transport and exhibits potent risk for coronary artery disease (CAD). However, the association of plasma preß1-HDL and cholesterol ester transfer protein (CETP) levels in CAD patients and the relationship of preß1-HDL with extent of CAD are debatable. METHODS: Preß1-HDL and CETP levels were measured by enzymed-linked immunosorbent assay (ELISAs) in 88 acute coronary syndromes (ACS), 79 stable coronary artery disease (SCAD) patients and 85 control subjects. The correlation analyses, multiple linear regression analyses and logistic regression analyses were performed, respectively. RESULTS: The preß1-HDL and CETP levels in ACS patients were significantly higher than those in SCAD patients and both of them were higher than controls'. Preß1-HDL levels were positively associated with CETP (R = 0.348, P = 0.000), the diameter of stenosis (R = 0.253, P = 0.005), the number of vessel disease (R = 0.274, P = 0.002) and Gensini score (R = 0.227, P = 0.009) in CAD patients. Stepwise multiple linear regression analyses showed that CETP was one of the determinants of preß1-HDL levels. Logistic regression analysis revealed that elevated preß1-HDL and CETP were potential risk factors for both ACS and SCAD. CONCLUSION: The elevated preß1-HDL levels may change with CETP concentrations in CAD patients and were related to the presence and severity of CAD.

Elevated serum miR-93, miR-191, and miR-499 are noninvasive biomarkers for the presence and progression of traumatic brain injury.

The levels of miR-93, miR-191, and miR-499 have been reported to be up-regulated in the tissues of experimental traumatic brain injury (TBI) rat models. However, the clinical diagnostic and prognostic values of the serum signatures of these 3 miRNAs in TBI remain unclear. The purpose of this study was to determine the expression levels of these 3 microRNAs (miRNAs) in the sera of TBI patients and to evaluate their relationships with the severity and clinical outcome of TBI. The serum levels of these miRNAs were assessed in TBI patients (n = 76) and healthy controls (n = 38) by quantitative reverse-transcription PCR. The severities and clinical outcomes of the TBI patients were evaluated with the Glasgow coma scale and the Glasgow outcome scale. The serum miR-93, miR-191, and miR-499 levels were significantly increased in the TBI patients compared with the controls at all examined time points, and these levels were significantly higher in the patients with severe TBI than in those with moderate or mild TBI (p < 0.05). The serum miR-93, miR-191, and miR-499 levels were significantly higher in the patients with a poor outcome than in those with a good outcome (p < 0.05). The AUCs of miR-93, miR-191, and miR-499 for distinguishing the TBI patients from the healthy controls were 1.000 (p < 0.001), 0.727 (p < 0.001) and 0.801 (p < 0.001), respectively. Interestingly, the AUCs of miR-93, miR-191, and miR-499 for distinguishing the mild TBI patients from the healthy controls were 1.000 (p < 0.001), 0.742 (p < 0.001) and 0.819 (p < 0.001), respectively. Taken together, these results indicate that miR-93, miR-191, and miR-499 are potentially valuable indicators of the diagnosis, severity, and prognosis of TBI. Our study showed that the serum levels of miR-93, miR-191, and miR-499 are all increased in traumatic brain injury (TBI) patients. Their serum levels are associated with TBI severity and outcome, which suggest that these miRNAs play important roles in the pathogenesis and progression of TBI. We think these findings should provide a new strategy for the diagnostic, prognostic, and treatment of TBI.

p63-expressing cells are the stem cells of developing prostate, bladder, and colorectal epithelia.

The tumor protein p63 (p63), and more specifically the NH2-terminal truncated (ΔN) p63 isoform, is a marker of basal epithelial cells and is required for normal development of several epithelial tissues, including the bladder and prostate glands. Although p63-expressing cells are proposed to be the stem cells of the developing prostate epithelium and bladder urothelium, cell lineages in these endoderm-derived epithelia remain highly controversial, and rigorous lineage tracing studies are warranted. Here, we generated knock-in mice expressing Cre recombinase (Cre) under the control of the endogenous ΔNp63 promoter. Heterozygote ΔNp63(+/Cre) mice were phenotypically normal and fertile. Cre-mediated recombination in ΔNp63(+/Cre);ROSA26(EYFP) reporter mice faithfully recapitulated the pattern of ΔNp63 expression and were useful for genetic lineage tracing of ΔNp63-expressing cells of the caudal endoderm in vivo. We found that ΔNp63-positive cells of the urogenital sinus generated all epithelial lineages of the prostate and bladder, indicating that these cells represent the stem/progenitor cells of those epithelia during development. We also observed ΔNp63 expression in caudal gut endoderm and the contribution of ΔNp63-positive cells to the stem/progenitor compartment of adult colorectal epithelium. Because p63 is a master regulator of stratified epithelial development, this finding provides a unique developmental insight into the cell of origin of squamous cell metaplasia and squamous cell carcinoma of the colon.

Phase 2 trial of sunitinib and gemcitabine in patients with sarcomatoid and/or poor-risk metastatic renal cell carcinoma.

BACKGROUND: Sarcomatoid renal cell carcinoma (RCC) is associated with an aggressive biology and a poor prognosis. Poor-risk RCC is defined by clinical prognostic factors and demonstrates similarly aggressive behavior. No standard treatment exists for patients with sarcomatoid RCC, and treatment options for patients with poor-risk disease are of limited benefit. The objective of this study was to investigate the efficacy of antiangiogenic therapy in combination with cytotoxic chemotherapy in clinically aggressive RCC. METHODS: This was a phase 2, single-arm trial of sunitinib and gemcitabine in patients with sarcomatoid or poor-risk RCC. The primary endpoint was the objective response rate (ORR). Secondary endpoints included the time to progression (TTP), overall survival (OS), safety, and biomarker correlatives. RESULTS: Overall, 39 patients had sarcomatoid RCC, and 33 had poor-risk RCC. The ORR was 26% for patients with sarcomatoid RCC and 24% for patients with poor-risk RCC. The median TTP and OS for patients with sarcomatoid RCC were 5 and 10 months, respectively. For patients with poor-risk disease, the median TTP and OS were 5.5 and 15 months, respectively. Patients whose tumors had >10% sarcomatoid histology had a higher clinical benefit rate (ORR plus stable disease) than those with ≤10% sarcomatoid histology (P = .04). The most common grade 3 or higher treatment-related adverse events included neutropenia (n = 20), anemia (n = 10), and fatigue (n = 7). CONCLUSIONS: These results suggest that antiangiogenic therapy and cytotoxic chemotherapy are an active and well-tolerated combination for patients with aggressive RCC. The combination may be more efficacious than either therapy alone and is currently under further investigation.

A sensitive chemiluminescence imaging immunoassay for simultaneous detection of serum oxidized lipoprotein(a) and low density lipoprotein.

BACKGROUND: Oxidized lipoprotein(a) [ox-Lp(a)] and oxidized low density lipoprotein (ox-LDL) levels have been reported to be useful predictors of cardiovascular events. The study developed a chemiluminescence (CL) imaging immunoassay method for simultaneously detecting serum concentrations of ox-Lp(a) and ox-LDL. METHODS: Ox-Lp(a) and ox-LDL levels were measured by CL imaging immunoassay using a disposable immunosensor array as the carrier and a charge-coupled device as the detector, and were studied in 46 acute coronary syndromes (ACS) patients, 58 stable coronary artery disease (CAD) and 61 control subjects. RESULTS: This method showed good linear relations (R²>0.99) in the concentration range of 2.00×10⁻5-2.00×10⁻¹ and 2.40×10⁻4-2.40 U/mL for ox-Lp(a) and ox-LDL, respectively. The detection limits for ox-Lp(a) and ox-LDL were 2.40×10⁻6 and 3.00×10⁻5 U/mL, respectively. The intra- and inter-assay coefficients of variation (CV) were 4.90%-6.76% and 7.11%-10.06% for ox-Lp(a), and 5.01%-6.04% and 5.47%-9.77% for ox-LDL, respectively. The mean recovery was 99.31% for ox-Lp(a) and 99.57% for ox-LDL, respectively. Significant correlations were observed between ox-Lp(a) levels detected by CL imaging immunoassay and ELISA, and between ox-LDL levels detected by the two methods, respectively. Furthermore, ox-Lp(a) and ox-LDL levels increased in stable CAD, and especially in ACS. CONCLUSIONS: The CL imaging immunoassay provided a simple, sensitive and reliable method for the simultaneous determination of serum ox-Lp(a) and ox-LDL. The clinical monitoring ox-Lp(a) and ox-LDL levels may possess distinctly clinical value for assessment of CAD risk.

Interannual precipitation variability dominates the growth of alpine grassland above-ground biomass at high elevations on the Tibetan Plateau.

The impact of global climate change on mountainous regions with significant elevational gaps is complex and often unpredictable. In particular, alpine grassland ecosystems, are experiencing changes in their spatial patterns along elevational gradients, which increases their vulnerability to degradation. Therefore, a more detailed understanding of spatiotemporal changes in alpine grassland productivity along elevational gradients and an elevation-dependent characterization of the effects of climatic variables on grassland productivity dynamics are essential. Thus, we conducted a study in the Tibetan Plateau, where we collected 2251 above-ground biomass (AGB) observations collected from 1986 to 2020. Mean annual temperature (TMP), annual precipitation (PRE), interannual precipitation variability (CVP), and snowmelt (SNMM) were chosen as influential variables. Using the Random Forest algorithm, we generated an AGB raster dataset covering the period 1989-2020 based on earth observation data at 30 m resolution to examine the dynamics of alpine grasslands and their response to climate change with respect to elevation. The results showed that the AGB of alpine grassland on the Tibetan Plateau was 49.17 g/m2. We observed an increasing trend in grassland AGB at high elevations, with a growth rate of about 0.28 g/m2 per year within the interval of 3100-4800 m. However, above the elevation of approximately 4400-4600 m, we observed a decoupling trend between grassland AGB and TMP. Moreover, at most elevations, the proportion of maximum partial correlation coefficients for CVP, PRE, and SNMM surpassed that of TMP. We found the dominant role of precipitation variability on grassland AGB dynamics, with 22.80 % and 18.86 % for CVP+ and CVP-, respectively. The proportion of CVP+ did not vary much at different elevations, whereas the proportion of CVP- increased with elevation, varying between 12.85 and 30.25 %. In the future, precipitation on the Tibetan plateau is expected to increase, potentially reversing its original positive impact.

Mettl3-Mediated m6A Methylation Controls Pancreatic Bipotent Progenitor Fate and Islet Formation.

The important role of m6A RNA modification in ß-cell function has been established; however, how it regulates pancreatic development and endocrine differentiation remains unknown. Here, we generated transgenic mice lacking RNA methyltransferase-like 3 (Mettl3) specifically in Pdx1+ pancreatic progenitor cells and found the mice with the mutation developed hyperglycemia and hypoinsulinemia at age 2 weeks, along with an atrophic pancreas, reduced islet mass, and abnormal increase in ductal formation. At embryonic day 15.5, Mettl3 deletion had caused a significant loss of Ngn3+ endocrine progenitor cells, which was accompanied by increased Sox9+ ductal precursor cells. We identified histone deacetylase 1 (Hdac1) as the critical direct m6A target in bipotent progenitors, the degeneration of which caused abnormal activation of the Wnt/Notch signaling pathway and blocked endocrine differentiation. This transformation could be manipulated in embryonic pancreatic culture in vitro through regulation of the Mettl3-Hdac1-Wnt/Notch signaling axis. Our finding that Mettl3 determines endocrine lineage by modulating Hdac1 activity during the transition of bipotent progenitors might help in the development of targeted endocrine cell protocols for diabetes treatment.

Bile acids metabolism involved in the beneficial effects of Danggui Shaoyao San via gut microbiota in the treatment of CCl4 induced hepatic fibrosis.

ETHNOPHARMACOLOGICAL RELEVANCE: Danggui Shaoyao San (DSS) is a traditional Chinese medicine (TCM) first recorded in the Synopsis of the Golden Chamber. DSS has proven efficacy in treating hepatic fibrosis (HF). However, the effects and mechanisms of DSS on HF are not clear. AIM OF THE STUDY: To investigate the effect of DSS on HF via gut microbiota and its metabolites (SCFAs, BAs). MATERIALS AND METHODS: HF rats were induced with CCl4 and treated with DSS. Firstly, the therapeutic efficacy of DSS in HF rats and the protection of gut barrier were assessed. Then, 16S rRNA gene sequencing and untargeted fecal metabolomics preliminarily explored the mechanism of DSS in treating HF, and identified different microbiota and metabolic pathways. Finally, targeted metabolomics and RT-qPCR were used to further validate the mechanism of DSS for HF based on the metabolism of SCFAs and BAs. RESULTS: After 8 weeks of administration, DSS significantly reduced the degree of HF. In addition, DSS alleviated inflammation in the ileum and reduced the levels of LPS and D-lactate. Furthermore, DSS altered the structure of gut microbiota, especially Veillonella, Romboutsia, Monoglobus, Parabacteroides, norank_f_Coriobacteriales_Incertae_Sedis. These bacteria have been linked to the production of SCFAs and the metabolism of BAs. Untargeted metabolomics suggested that DSS may play a role via BAs metabolism. Subsequently, targeted metabolomics and RT-qPCR further confirmed the key role of DSS in increasing SCFAs levels and regulating BAs metabolism. CONCLUSIONS: DSS can alleviate CCl4-induced HF and protect the gut barrier. DSS may exert its beneficial effects on HF by affecting the gut microbiota and its metabolites (SCFAs, BAs).

RORα is required for expansion and memory maintenance of ILC1s via a lymph node-liver axis.

Type 1 innate lymphoid cells (ILC1s) possess adaptive immune features, which confer antigen-specific memory responses against haptens and viruses. However, the transcriptional regulation of memory ILC1 responses is currently not known. We show that retinoic acid receptor-related orphan receptor alpha (RORα) has high expression in memory ILC1s in murine contact hypersensitivity (CHS) models. RORα deficiency diminishes ILC1-mediated CHS responses significantly but has no effect on memory T cell-mediated CHS responses. During sensitization, RORα promotes sensitized-ILC1 expansion by suppressing expression of cell-cycle repressors in draining lymph nodes. RORα programs gene-expression patterns related to cell survival and is required for the long-term maintenance of memory ILC1s in the liver. Our findings reveal RORα to be a key transcriptional factor for sensitized-ILC1 expansion and long-term maintenance of memory ILC1s.