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Environmental factors, mucosal permeability and defective immunoregulation drive overactive immunity to a subset of resident intestinal bacteria that mediate multiple inflammatory conditions. GUT-103 and GUT-108, live biotherapeutic products rationally designed to complement missing or underrepresented functions in the dysbiotic microbiome of IBD patients, address upstream targets, rather than targeting a single cytokine to block downstream inflammation responses. GUT-103, composed of 17 strains that synergistically provide protective and sustained engraftment in the IBD inflammatory environment, prevented and treated chronic immune-mediated colitis. Therapeutic application of GUT-108 reversed established colitis in a humanized chronic T cell-mediated mouse model. It decreased pathobionts while expanding resident protective bacteria; produced metabolites promoting mucosal healing and immunoregulatory responses; decreased inflammatory cytokines and Th-1 and Th-17 cells; and induced interleukin-10-producing colonic regulatory cells, and IL-10-independent homeostatic pathways. We propose GUT-108 for treating and preventing relapse for IBD and other inflammatory conditions characterized by unbalanced microbiota and mucosal permeability. Fecal microbiota transplantation and probiotics have been tested/used as potential therapeutics against inflammatory bowel diseases (IBD). Here the authors use a bottom-up rational consortium design approach that combines well-characterized strains isolated from healthy human stool samples to produce two consortia of metabolically interdependent strains for the treatment of IBD.

Based on reanalysis datasets and as many as 35 CMIP5 models, this study evaluates the capability of climate models to simulate the spatiotemporal features of Pacific-North American teleconnection (PNA) and North Pacific Oscillation (NPO) in the twentieth century wintertime, and further investigates their responses to greenhouse warming in the twenty-first century. Analysis reveals that while the majority (80%) of models reasonably simulate either the geographical distribution or the amplitude of PNA/NPO pattern, only half of models can well capture both features in space. As for the temporal features, variabilities of PNA and NPO in most models are biased toward higher amplitude. Additionally, most models simulate the interannual variabilities of PNA and NPO, qualitatively consistent with the observation, whereas models generally lack the capability to reproduce the decadal (20–25 years) variability of PNA. As the climate warms under the strongest future warming scenario, the PNA intensity is found to be strengthened, whereas there is no consensus on the direction of change in the NPO intensity among models. The intensification of positive PNA is primarily manifested in the large deepening of the North Pacific trough, which is robust as it is 2.3 times the unforced internal variability. By focusing on the tropical Pacific Ocean, we find that the multidecadal evolution of the North Pacific trough intensity (dominating the PNA intensity evolution) is closely related to that of the analogous trough in the PNA-like teleconnection forced by sea surface temperature anomalies (SSTa) in the tropical central Pacific (CP) rather than the tropical eastern Pacific (EP). Such association is also found to act under greenhouse warming: that is, the strengthening of the PNA-like teleconnection induced by the CP SSTa rather than the EP SSTa is a driving force for the intensification of PNA. This is in part owing to the robust enhancement of the tropical precipitation response to the CP SST variation. Indeed, further inspection suggests that models with stronger intensification of the CP SST variability and its related tropical precipitation response tend to have larger deepening magnitude of the North Pacific trough associated with the PNA variability.

Background Amplification of chromosome 7q21-7q31 is associated with tumor recurrence and multidrug resistance, and several genes in this region are powerful drivers of hepatocellular carcinoma (HCC). We aimed to investigate the key circular RNAs (circRNAs) in this region that regulate the initiation and development of HCC. Methods We used qRT-PCR to assess the expression of 43 putative circRNAs in this chromosomal region in human HCC and matched nontumor tissues. In addition, we used cultured HCC cells to modify circRNA expression and assessed the effects in several cell-based assays as well as gene expression analyses via RNA-seq. Modified cells were implanted into immunocompetent mice to assess the effects on tumor development. We performed additional experiments to determine the mechanism of action of these effects. Results circMET (hsa_circ_0082002) was overexpressed in HCC tumors, and circMET expression was associated with survival and recurrence in HCC patients. By modifying the expression of circMET in HCC cells in vitro, we found that circMET overexpression promoted HCC development by inducing an epithelial to mesenchymal transition and enhancing the immunosuppressive tumor microenvironment. Mechanistically, circMET induced this microenvironment through the miR-30-5p/Snail/ dipeptidyl peptidase 4(DPP4)/CXCL10 axis. In addition, the combination of the DPP4 inhibitor sitagliptin and anti-PD1 antibody improved antitumor immunity in immunocompetent mice. Clinically, HCC tissues from diabetic patients receiving sitagliptin showed higher CD8 + T cell infiltration than those from HCC patients with diabetes without sitagliptin treatment. Conclusions circMET is an onco-circRNA that induces HCC development and immune tolerance via the Snail/DPP4/CXCL10 axis. Furthermore, sitagliptin may enhance the efficacy of anti-PD1 therapy in a subgroup of patients with HCC.

Social deficit is a core clinical feature of autism spectrum disorder (ASD) but the underlying neural mechanisms remain largely unclear. We demonstrate that structural and functional impairments occur in glutamatergic synapses in the pyramidal neurons of the anterior cingulate cortex (ACC) in mice with a mutation in Shank3, a high-confidence candidate ASD gene. Conditional knockout of Shank3 in the ACC was sufficient to generate excitatory synaptic dysfunction and social interaction deficits, whereas selective enhancement of ACC activity, restoration of SHANK3 expression in the ACC, or systemic administration of an α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor-positive modulator improved social behavior in Shank3 mutant mice. Our findings provide direct evidence for the notion that the ACC has a role in the regulation of social behavior in mice and indicate that ACC dysfunction may be involved in social impairments in ASD.

This work focuses on the problem of multi-label learning with missing labels (MLML), which aims to label each test instance with multiple class labels given training instances that have an incomplete/partial set of these labels (i.e., some of their labels are missing). The key point to handle missing labels is propagating the label information from the provided labels to missing labels, through a dependency graph that each label of each instance is treated as a node. We build this graph by utilizing different types of label dependencies. Specifically, the instance-level similarity is served as undirected edges to connect the label nodes across different instances and the semantic label hierarchy is used as directed edges to connect different classes. This base graph is referred to as the mixed dependency graph, as it includes both undirected and directed edges. Furthermore, we present another two types of label dependencies to connect the label nodes across different classes. One is the class co-occurrence, which is also encoded as undirected edges. Combining with the above base graph, we obtain a new mixed graph, called mixed graph with co-occurrence (MG-CO). The other is the sparse and low rank decomposition of the whole label matrix, to embed high-order dependencies over all labels. Combining with the base graph, the new mixed graph is called as MG-SL (mixed graph with sparse and low rank decomposition). Based on MG-CO and MG-SL, we further propose two convex transductive formulations of the MLML problem, denoted as MLMG-CO and MLMG-SL respectively. In both formulations, the instance-level similarity is embedded through a quadratic smoothness term, while the semantic label hierarchy is used as a linear constraint. In MLMG-CO, the class co-occurrence is also formulated as a quadratic smoothness term, while the sparse and low rank decomposition is incorporated into MLMG-SL, through two additional matrices (one is assumed as sparse, and the other is assumed as low rank) and an equivalence constraint between the summation of this two matrices and the original label matrix. Interestingly, two important applications, including image annotation and tag based image retrieval, can be jointly handled using our proposed methods. Experimental results on several benchmark datasets show that our methods lead to significant improvements in performance and robustness to missing labels over the state-of-the-art methods.

Inflammation alters host physiology to promote cancer, as seen in colitis-associated colorectal cancer (CRC). Here, we identify the intestinal microbiota as a target of inflammation that affects the progression of CRC. High-throughput sequencing revealed that inflammation modifies gut microbial composition in colitis-susceptible interleukin-10—deficient (Il10⁻ / ⁻) mice. Monocolonization with the commensal Escherichia coli NC101 promoted invasive carcinoma in azoxymethane (AOM)—treated Il10⁻ / ⁻ mice. Deletion of the polyketide synthase (pks) genotoxic island from E. coli NC101 decreased tumor multiplicity and invasion in AOM/Il10⁻ / ⁻ mice, without altering intestinal inflammation. Mucosa-associated pks⁺ E. coli were found in a significantly high percentage of inflammatory bowel disease and CRC patients. This suggests that in mice, colitis can promote tumorigenesis by altering microbial composition and inducing the expansion of microorganisms with genotoxic capabilities.

Under transient greenhouse warming, El Niño-Southern Oscillation (ENSO) is projected to increase pre-2100, accompanied by an easier establishment of atmospheric convection in the equatorial eastern Pacific, where sea surface temperature (SST) warms faster than surrounding regions. After 2100, how ENSO variability may change remains unknown. Here we find that under a high emission scenario, ENSO variability post-2100 reverses from the initial increase to an amplitude far smaller than that of the 20 th century. The fast eastern warming persists and shrinks the equatorial Pacific non-convective area, such that establishing convection in the non-convective area, as during an El Niño, requires smaller convective anomaly, inducing weaker wind anomalies leading to reduced ENSO SST variability. The nonlinear ENSO response is thus a symptom of the persistent El Niño-like warming pattern. Therefore, the oscillatory ENSO impact could be replaced by that from the permanent El Niño-like mean condition with cumulative influences on affected regions. The authors find a reversal in El Niño sea surface temperature variability under persistent greenhouse warming, from an increase pre-2100 to a reduction post-2100 amid the development of a permanent El Niño-like warming pattern.

Liver cancer is the fourth most prevalent and the second most lethal cancer in China. Hepatitis B virus (HBV) infection represents a major risk factor for hepatocellular carcinoma (HCC). Liver ultrasonography plus alpha-fetoprotein every 6 months continues to be the predominant surveillance modality. The age-Male-ALBI-Platelets score was recommended in the recent 2022 Chinese guidelines to predict HCC occurrence. The Chinese liver cancer (CNLC) staging system proposed in the 2017 guidelines continues to be the standard model for staging with modifications in the treatment allocations. Considering the aggressive nature of HBV-associated HCC, multimodal and high-intensity strategies like the addition of immunotherapy-based systemic treatment to local therapies, including resection, ablation, and intra-arterial therapies, have been adopted in real-life practices in China. The latest Chinese guidelines recommend atezolizumab plus bevacizumab, suntilimab plus a bevacizumab analog, lenvatinib, sorafenib, donafenib, and FOLFOX (folinic acid, fluorouracil, and oxaliplatin) chemotherapy as first-line treatment without priority. Regorafenib, apatinib, camrelizumab, and tislelizumab have been added as second-line systemic therapies for patients who progressed on sorafenib. Systemic therapies adopted in real-life practice are sophisticated with various combination modalities and different sequences.

Background Both serum uric acid (SUA) levels and body mass index (BMI) are recognized as important risk factors for hypertension. The current study aimed to investigate the interaction effects between SUA levels and overweight (defined as BMI ≥ 24 kg/m 2 in Chinese) on the incidence of hypertension among Chinese adults. Methods 1124 hypertensive participants and 7283 non-hypertensive participants, extracted from the China Health and Nutrition Survey (CHNS), were analyzed. Participants were categorized based on their SUA levels and BMI, to investigate the interaction effects between SUA levels and overweight on hypertension. Results In comparison with the reference group (BMI < 24 kg/m 2 and in the 1st quintile of SUA), multivariable adjusted analysis demonstrated that the odds ratio (OR) (95% confidence interval, 95% CI) of hypertension for participants with overweight alone was 2.18 (1.41–3.37); for elevated SUA levels alone, the ORs (95% CIs) were 1.57 (1.08–2.30), 1.84 (1.24–2.74), 2.21 (1.47–3.32), and 2.48 (1.55–3.96) across SUA quintiles; and for the combined effect of higher SUA levels and overweight, the ORs (95% CIs) were 3.25 (2.19–4.82), 3.73 (2.51–5.55), 5.17 (3.42–7.80), and 6.21 (4.01–9.60). The relative excess risk due to interaction (RERI) was 3.26 (1.43–5.09) at the 5th quintile of SUA, indicating the presence of additive interaction between overweight and SUA levels on hypertension. Conclusion Interaction between SUA levels and overweight on hypertension exists specifically at the highest quintile (Q5, > 6.39 mg/dL) of SUA among Chinese adults. Therefore, strategies to lower SUA levels could be considered as a potential approach to mitigate hypertension risk in overweight individuals within this specific subgroup.

Background Recently, the dysregulation of circular RNA (circRNA) have been shown to have important regulatory roles in cancer development and progression, including hepatocellular carcinoma (HCC). However, the roles of most circRNAs in HCC are still unknown. Methods The expression of circular tripartite motif containing 33–12 (circTRIM33–12) in HCC tissues and cell lines was detected by qRT-PCR. The role of circTRIM33–12 in HCC progression was assessed by western blotting, CCK-8, flow cytometry, transwell and a subcutaneous tumor mouse assays both in vitro and in vivo. In vivo circRNA precipitation, RNA immunoprecipitation, luciferase reporter assays were performed to evaluate the interaction between circTRIM33–12 and miR-191. Results Here, we found that circTRIM33–12, is downregulated in HCC tissues and cell lines. The downregulation of circTRIM33–12 in HCC was significantly correlated with malignant characteristics and served as an independent risk factor for the overall survival (OS) and recurrence-free survival (RFS) of patients with HCC after surgery. The reduced expression of circTRIM33–12 in HCC cells increases tumor proliferation, migration, invasion and immune evasion. Mechanistically, we demonstrated that circTRIM33–12 upregulated TET1 expression by sponging miR-191, resulting in significantly reduced 5-hydroxymethylcytosine (5hmC) levels in HCC cells. Conclusions These results reveal the important role of circTRIM33–12 in the proliferation, migration, invasion and immune evasion abilities of HCC cells and provide a new perspective on circRNAs in HCC progression.