Increasing evidence has confirmed that the antimicrobial and anti‐inflammatory effects of cinnamon essential oil (CEO) contribute to protection against inflammatory bowel disease (IBD). The dextran ...sodium sulfate (DSS)‐induced colitis mouse model was established to investigate the correlation between the protective effects of CEO and the regulation of intestinal microflora. The symptoms of IBD were assessed by measuring the hemoglobin content, myeloperoxidase activity, histopathological observation, cytokines, and toll‐like receptor (TLR4) expression. The alteration of the fecal microbiome composition was analyzed by 16S rRNA gene sequencing. The results indicated that the oral administration of CEO enriched with cinnamaldehyde effectively alleviated the development of DSS‐induced colitis. In contrast to the inability of antibiotics to regulate flora imbalance, the mice fed with CEO had an improved diversity and richness of intestinal microbiota, and a modified community composition with a decrease in Helicobacter and Bacteroides and an increase in Bacteroidales_S24‐7 family and short‐chain fatty acids (SCFA)‐producing bacteria (Alloprevotella and Lachnospiraceae_NK4A136_group). Moreover, the correlation analysis showed that TLR4 and tumor necrosis factor‐α was positively correlated with Helicobacter, but inversely correlated with SCFA‐producing bacteria. These findings indicated from a new perspective that the inhibitory effect of CEO on IBD was closely related to improving the intestinal flora imbalance.
The suprachiasmatic nucleus (SCN) drives circadian clock coherence through intercellular coupling, which is resistant to environmental perturbations. We report that primary cilia are required for ...intercellular coupling among SCN neurons to maintain the robustness of the internal clock in mice. Cilia in neuromedin S-producing (NMS) neurons exhibit pronounced circadian rhythmicity in abundance and length. Genetic ablation of ciliogenesis in NMS neurons enabled a rapid phase shift of the internal clock under jet-lag conditions. The circadian rhythms of individual neurons in cilia-deficient SCN slices lost their coherence after external perturbations. Rhythmic cilia changes drive oscillations of Sonic Hedgehog (Shh) signaling and clock gene expression. Inactivation of Shh signaling in NMS neurons phenocopied the effects of cilia ablation. Thus, cilia-Shh signaling in the SCN aids intercellular coupling.
We investigated the correlation between the beneficial effect of Lactobacillus acidophilus on gut microbiota composition, metabolic activities, and reducing cow's milk protein allergy. Mice ...sensitized with β‐lactoglobulin (β‐Lg) were treated with different doses of L. acidophilus KLDS 1.0738 for 4 weeks, starting 1 week before allergen induction. The results showed that intake of L. acidophilus significantly suppressed the hypersensitivity responses, together with increased fecal microbiota diversity and short‐chain fatty acids (SCFAs) concentration (including propionate, butyrate, isobutyrate, and isovalerate) when compared with the allergic group. Moreover, treatment with L. acidophilus induced the expression of SCFAs receptors, G‐protein–coupled receptors 41 (GPR41) and 43 (GPR43), in the spleen and colon of the allergic mice. Further analysis revealed that the GPR41 and GPR43 messenger RNA expression both positively correlated with the serum concentrations of transforming growth factor‐β and IFN‐γ (p < .05), but negatively with the serum concentrations of IL‐17, IL‐4, and IL‐6 in the L. acidophilus–treated group compared with the allergic group (p < .05). These results suggested that L. acidophilus protected against the development of allergic inflammation by improving the intestinal flora, as well as upregulating SCFAs and their receptors GPR41/43.
Chimeric antigen receptor (CAR) T cell therapy has demonstrated proven efficacy in some hematologic cancers. We evaluated the safety and efficacy of LCAR-B38M, a dual epitope-binding CAR T cell ...therapy directed against 2 distinct B cell maturation antigen epitopes, in patients with relapsed/refractory (R/R) multiple myeloma (MM).
This ongoing phase 1, single-arm, open-label, multicenter study enrolled patients (18 to 80 years) with R/R MM. Lymphodepletion was performed using cyclophosphamide 300 mg/m
. LCAR-B38M CAR T cells (median CAR+ T cells, 0.5 × 10
cells/kg range, 0.07 to 2.1 × 10
) were infused in 3 separate infusions. The primary objective is to evaluate the safety of LCAR-B38M CAR T cells; the secondary objective is to evaluate the antimyeloma response of the treatment based on the general guidelines of the International Myeloma Working Group.
At data cutoff, 57 patients had received LCAR-B38M CAR T cells. All patients experienced ≥ 1 adverse events (AEs). Grade ≥ 3 AEs were reported in 37/57 patients (65%); most common were leukopenia (17/57; 30%), thrombocytopenia (13/57; 23%), and aspartate aminotransferase increased (12/57; 21%). Cytokine release syndrome occurred in 51/57 patients (90%); 4/57 (7%) had grade ≥ 3 cases. One patient reported neurotoxicity of grade 1 aphasia, agitation, and seizure-like activity. The overall response rate was 88% (95% confidence interval CI, 76 to 95); 39/57 patients (68%) achieved a complete response, 3/57 (5%) achieved a very good partial response, and 8/57 (14%) achieved a partial response. Minimal residual disease was negative for 36/57 (63%) patients. The median time to response was 1 month (range, 0.4 to 3.5). At a median follow-up of 8 months, median progression-free survival was 15 months (95% CI, 11 to not estimable). Median overall survival for all patients was not reached.
LCAR-B38M CAR T cell therapy displayed a manageable safety profile and demonstrated deep and durable responses in patients with R/R MM.
ClinicalTrials.gov , NCT03090659 ; Registered on March 27, 2017, retrospectively registered.
•The experimental and computational techniques for proton-conductive MOFs are summarized.•Representative studies are reviewed on the tuning of proton conductivity of MOFs.•Perspectives toward the ...modulation on the proton conductivity of MOFs are presented.
Over the past decades, research on proton-conductive metal-organic frameworks (MOFs) has rapidly accelerated due to the importance of energy for modern society. This review mainly focuses on some representative proton-conductive MOFs reported recently, with related discussions on the underlying proton transportation mechanisms. In the first section, we give a brief introduction to the background of proton-conductive MOFs. In the following second section, a summarization on the widely used experimental characterization techniques as well as the well-established computational methods for exploring the proton transportation mechanism is given. In the third section, some representative studies in this field are reviewed from the aspect that how to tune the proton conductivity of MOFs, with emphasis on the following factors: the impact of framework and guest molecules/ions; the modification with functionalized groups and the tuning of Brønsted acidity; the influence of phase transition, defects, and amorphization. Finally, the conclusion and perspective are presented regarding the modulation on the proton conductivity of MOFs and the rational design of novel proton-conductive MOFs.
Lack of detailed knowledge of SARS-CoV-2 infection has been hampering the development of treatments for coronavirus disease 2019 (COVID-19). Here, we report that RNA triggers the liquid-liquid phase ...separation (LLPS) of the SARS-CoV-2 nucleocapsid protein, N. By analyzing all 29 proteins of SARS-CoV-2, we find that only N is predicted as an LLPS protein. We further confirm the LLPS of N during SARS-CoV-2 infection. Among the 100,849 genome variants of SARS-CoV-2 in the GISAID database, we identify that ~37% (36,941) of the genomes contain a specific trio-nucleotide polymorphism (GGG-to-AAC) in the coding sequence of N, which leads to the amino acid substitutions, R203K/G204R. Interestingly, N
exhibits a higher propensity to undergo LLPS and a greater effect on IFN inhibition. By screening the chemicals known to interfere with N-RNA binding in other viruses, we find that (-)-gallocatechin gallate (GCG), a polyphenol from green tea, disrupts the LLPS of N and inhibits SARS-CoV-2 replication. Thus, our study reveals that targeting N-RNA condensation with GCG could be a potential treatment for COVID-19.
Cancer is a major factor threatening human health and life safety, and there is a lack of safe and effective therapeutic drugs. Intervention and prevention in premalignant process are effective ways ...to reverse carcinogenesis and prevent cancer from occurring. Plant natural products are rich in sources and are a promising source for cancer chemoprevention. This article reviews the chemopreventive effects of natural products, especially focused on polyphenols, flavonoids, monoterpene and triterpenoids, sulfur compounds, and cellulose. Meanwhile, the main mechanisms include induction of apoptosis, antiproliferation and inhibition of metastasis are briefly summarized. In conclusion, this article provides evidence for natural products remaining a prominent source of cancer chemoprevention.
Cyclic GMP‐AMP synthase (cGAS) functions as a key sensor for microbial invasion and cellular damage by detecting emerging cytosolic DNA. Here, we report that GTPase‐activating protein‐(SH3 ...domain)–binding protein 1 (G3BP1) primes cGAS for its prompt activation by engaging cGAS in a primary liquid‐phase condensation state. Using high‐resolution microscopy, we show that in resting cells, cGAS exhibits particle‐like morphological characteristics, which are markedly weakened when G3BP1 is deleted. Upon DNA challenge, the pre‐condensed cGAS undergoes liquid–liquid phase separation (LLPS) more efficiently. Importantly, G3BP1 deficiency or its inhibition dramatically diminishes DNA‐induced LLPS and the subsequent activation of cGAS. Interestingly, RNA, previously reported to form condensates with cGAS, does not activate cGAS. Accordingly, we find that DNA – but not RNA – treatment leads to the dissociation of G3BP1 from cGAS. Taken together, our study shows that the primary condensation state of cGAS is critical for its rapid response to DNA.
Synopsis
Host cell encoded cGAS is a critical DNA sensor to detect invading pathogens. The stress‐granule protein G3BP1 engages cGAS in a primary condensation state to enable a rapid response to free DNA.
G3BP1 primes cGAS for its prompt activation.
G3BP1 engages cGAS in a primary condensation state.
DNA‐ but not RNA‐interaction leads to the dissociation of G3BP1 from cGAS.
Green tea compound epigallocatechin gallate (EGCG) inhibits G3BP1‐promoted cGAS phase condensation and activation.
Host cell encoded cGAS is a critical DNA sensor to detect invading pathogens. The stress‐granule protein G3BP1 engages cGAS in a primary condensation state to enable a rapid response to free DNA.
Most of the current health management products are used in medical institutions and generally do not pay enough attention to the student population. Based on this, this paper designs a ...student-oriented and functional autonomous health management system. This paper proposes a personal health management system based on a multidimensional data model based on the main social characteristics of the population with chronic diseases and the actual needs of personal health management for chronic diseases. The value of various health data for health management is deeply analyzed and mined, and a multidimensional model data warehouse is constructed according to relevant national health data standards to create a standard data platform for intelligent health warning and disease risk assessment. This paper researches and designs a closed-loop personal health management method based on the Plan-Do-Check-Action (PDCA) cycle management model, with detailed functional design in four aspects: health data collection and recording, health assessment, health planning, and tracking and execution. This paper researches health data collection, processing, and storage technologies and adopts HDFS data storage technology, html, css, Java Script, java, and other software development technologies, combined with j Query, UEditor, Date Range Picker, and other plug-ins, as well as SMS email generation interface, wireless Bluetooth transmission interface, etc. This system web and mobile application platforms are designed and developed. Relational database is used as the system database, and a snowflake-type multidimensional data model is designed. Finally, the functions and performance of this system were tested, and the development and trial run of the basic version have been completed.
Many infections and stress signals can rapidly activate the NLRP3 inflammasome to elicit robust inflammatory responses. This activation requires a priming step, which is thought to be mainly for ...upregulating NLRP3 transcription. However, recent studies report that the NLRP3 inflammasome can be activated independently of transcription, suggesting that the priming process has unknown essential regulatory steps. Here, we report that JNK1-mediated NLRP3 phosphorylation at S194 is a critical priming event and is essential for NLRP3 inflammasome activation. We show that NLRP3 inflammasome activation is disrupted in NLRP3-S194A knockin mice. JNK1-mediated NLRP3 S194 phosphorylation is critical for NLRP3 deubiquitination and facilitates its self-association and the subsequent inflammasome assembly. Importantly, we demonstrate that blocking S194 phosphorylation prevents NLRP3 inflammasome activation in cryopyrin-associated periodic syndromes (CAPS). Thus, our study reveals a key priming molecular event that is a prerequisite for NLRP3 inflammasome activation. Inhibiting NLRP3 phosphorylation could be an effective treatment for NLRP3-related diseases.
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•Phosphorylation of NLRP3 at S194 is a key priming event for inflammasome activation•JNK1 directly phosphorylates NLRP3•S194 phosphorylation facilitates the self-association of NLRP3•Inhibiting NLRP3 phosphorylation could be a treatment for NLRP3-related diseases
The NLRP3 inflammasome activation requires a priming process; however, the mechanism remains obscure. Song et al. demonstrate that JNK1-mediated NLRP3 phosphorylation is a key molecular priming event that poises NLRP3 for its self-association and inflammasome assembly. This study suggests that inhibiting NLRP3 phosphorylation could be utilized in treating NLRP3-related diseases.
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