Oral lichen planus (OLP) is a T cell–mediated chronic inflammatory disease with uncertain aetiology. Exosomes are nanosized particles with biological capacities. Here, we aimed to study the effects ...of T cell–derived exosomes (T‐exos) on the pathogenesis of OLP and its mechanism. T‐exos were incubated with Jurkat cells for 48 hours, and 26 cytokines in the supernatant were measured by luminex assay. The expression of macrophage inflammatory protein (MIP)‐1α/β was detected using immunohistochemistry and ELISA; that of CCR1/3/5 on peripheral T cells was determined by flow cytometry. Transwell assay was performed to investigate the chemotactic effect of MIP‐1α/β, and cells in the lower chambers were examinated by flow cytometry. As a result, OLP T‐exos elevated the production of MIP‐1α/β, which were highly expressed in OLP tissues and plasma. CCR1/5 were markedly expressed on OLP peripheral T cells, and the majority of CCR1/5+ T cells were CD8+ T cells. Besides, MIP‐1α/β promoted the migration of OLP mononuclear cells, while inhibiting CCR1/5 significantly decreased the trafficking of mononuclear cells, especially that of CD8+ T cells. Conclusively, OLP T‐exos‐induced MIP‐1α/β may drive the trafficking of CD8+ T cells after binding with CCR1/5 in OLP, contributing to the development of OLP.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Currently, there is no strong evidence of the well-established biomarkers for immune checkpoint inhibitors (ICIs) in nasopharyngeal carcinoma (NPC). Here, we aimed to reveal the heterogeneity of ...tumour microenvironment (TME) through virtual microdissection of gene expression profiles. An immune-enriched subtype was identified in 38% (43/113) of patients, which was characterized by significant enrichment of immune cells or immune responses. The remaining patients were therefore classified as a non-Immune Subtype (non-IS), which exhibited highly proliferative features. Then we identified a tumour immune evasion state within the immune-enriched subtype (18/43, 42%), in which high expression of exclusion- and dysfunction-related signatures was observed. These subgroups were designated the Evaded and Active Immune Subtype (E-IS and A-IS), respectively. We further demonstrated that A-IS predicted favourable survival and improved ICI response as compared to E-IS and non-IS. In summary, this study introduces the novel immune subtypes and demonstrates their feasibility in tailoring immunotherapeutic strategies.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Individual free fatty acids (FAs) play important roles in metabolic homeostasis, many through engagement with more than 40G protein-coupled receptors. Searching for receptors to sense beneficial ...omega-3 FAs of fish oil enabled the identification of GPR120, which is involved in a spectrum of metabolic diseases. Here, we report six cryo-electron microscopy structures of GPR120 in complex with FA hormones or TUG891 and G
or G
trimers. Aromatic residues inside the GPR120 ligand pocket were responsible for recognizing different double-bond positions of these FAs and connect ligand recognition to distinct effector coupling. We also investigated synthetic ligand selectivity and the structural basis of missense single-nucleotide polymorphisms. We reveal how GPR120 differentiates rigid double bonds and flexible single bonds. The knowledge gleaned here may facilitate rational drug design targeting to GPR120.
People with serious mental illness are at great risk of suicide, but little is known about the suicide rates among this population. We aimed to quantify the suicide rates among people with serious ...mental illness (bipolar disorder, major depression, or schizophrenia).
PubMed and Web of Science were searched to identify studies published from 1 January 1975 to 10 December 2020. We assessed English-language studies for the suicide rates among people with serious mental illness. Random-effects meta-analysis was used. Changes in follow-up time and the suicide rates were presented by a locally weighted scatter-plot smoothing (LOESS) curve. Suicide rate ratio was estimated for assessments of difference in suicide rate by sex.
Of 5014 identified studies, 41 were included in this analysis. The pooled suicide rate was 312.8 per 100 000 person-years (95% CI 230.3-406.8). Europe was reported to have the highest pooled suicide rate of 335.2 per 100 000 person-years (95% CI 261.5-417.6). Major depression had the highest suicide rate of 534.3 per 100 000 person-years (95% CI 30.4-1448.7). There is a downward trend in suicide rate estimates over follow-up time. Excess risk of suicide in males was found 1.90 (95% CI 1.60-2.25). The most common suicide method was poisoning 21.9 per 100 000 person-years (95% CI 3.7-50.4).
The suicide rates among people with serious mental illness were high, highlighting the requirements for increasing psychological assessment and monitoring. Further study should focus on region and age differences in suicide among this population.
Major depressive disorder (MDD) is one of the most common mental disorders. We designed a fast-onset antidepressant that works by disrupting the interaction between the serotonin transporter (SERT) ...and neuronal nitric oxide synthase (nNOS) in the dorsal raphe nucleus (DRN). Chronic unpredictable mild stress (CMS) selectively increased the SERT-nNOS complex in the DRN in mice. Augmentation of SERT-nNOS interactions in the DRN caused a depression-like phenotype and accounted for the CMS-induced depressive behaviors. Disrupting the SERT-nNOS interaction produced a fast-onset antidepressant effect by enhancing serotonin signaling in forebrain circuits. We discovered a small-molecule compound, ZZL-7, that elicited an antidepressant effect 2 hours after treatment without undesirable side effects. This compound, or analogous reagents, may serve as a new, rapidly acting treatment for MDD.
Herein, we designed a dual 3D DNA nanomachine (DDNM)-mediated catalytic hairpin assembly (DDNM-CHA) to construct an electrochemical biosensor for ultrasensitive detection of miRNA, which possesses ...quite a faster reaction rate and much higher amplification efficiency than those of traditional catalytic hairpin assembly (CHA). Impressively, since the DDNM skillfully increases the local concentration of reactants and decreases the steric hindrance of substrates simultaneously, the DDNM-CHA could be endowed with higher collision efficiency and more effective reaction compared with traditional CHA, resulting in a hyper conversion efficiency up to 2.78 × 107 only in 25 min. This way, the developed DDNM-CHA could easily conquer the main predicaments: long reaction time and low efficiency. As a proof of the concept, we adopt the gold nanoparticles (AuNPs) and the magnetic nanoparticle (Fe3O4) as the kernel of DNM-A and DNM-B, respectively, and harness the magnetic electrode to directly adsorb the products H1–H2/Fe3O4 for constructing an immobilization-free biosensor for high-speed and ultrasensitive detection of miRNA with a detection limit of 0.14 fM. As a result, the DDNM-CHA we developed carves out a new insight to design a functional DNA nanomachine and evolve the analysis method for practical amplification in the sensing area and promotes the deeper exploration of the nucleic acid signal amplification strategy and DNA nanobiotechnology.
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IJS, KILJ, NUK, PNG, UL, UM
Abstract
Aims
Positive associations between periodontitis (PD) and atherosclerosis have been established, but the causality and mechanisms are not clear. We aimed to explore the causal roles of PD in ...atherosclerosis and dissect the underlying mechanisms.
Methods and results
A mouse model of PD was established by ligation of molars in combination with application of subgingival plaques collected from PD patients and then combined with atherosclerosis model induced by treating atheroprone mice with a high-cholesterol diet (HCD). PD significantly aggravated atherosclerosis in HCD-fed atheroprone mice, including increased en face plaque areas in whole aortas and lesion size at aortic roots. PD also increased circulating levels of triglycerides and cholesterol, hepatic levels of cholesterol, and hepatic expression of rate-limiting enzymes for lipogenesis. Using 16S ribosomal RNA (rRNA) gene sequencing, Fusobacterium nucleatum was identified as the most enriched PD-associated pathobiont that is present in both the oral cavity and livers. Co-culture experiments demonstrated that F. nucleatum directly stimulated lipid biosynthesis in primary mouse hepatocytes. Moreover, oral inoculation of F. nucleatum markedly elevated plasma levels of triglycerides and cholesterol and promoted atherogenesis in HCD-fed ApoE−/− mice. Results of RNA-seq and Seahorse assay indicated that F. nucleatum activated glycolysis, inhibition of which by 2-deoxyglucose in turn suppressed F. nucleatum-induced lipogenesis in hepatocytes. Finally, interrogation of the molecular mechanisms revealed that F. nucleatum-induced glycolysis and lipogenesis by activating PI3K/Akt/mTOR signalling pathway in hepatocytes.
Conclusions
PD exacerbates atherosclerosis and impairs lipid metabolism in mice, which may be mediated by F. nucleatum-promoted glycolysis and lipogenesis through PI3K/Akt/mTOR signalling in hepatocytes. Treatment of PD and specific targeting of F. nucleatum are promising strategies to improve therapeutic effectiveness of hyperlipidaemia and atherosclerosis.
Graphical Abstract
Graphical Abstract
Herein, a programmable dual‐catalyst hairpin assembly (DCHA) for realizing the synchronous recycle of two catalysts is developed, displaying high reaction rate and outstanding conversion efficiency ...beyond traditional nucleic acid signal amplifications (NASA). Once catalyst I interacts with the catalyst II, the DCHA can be triggered to realize the simultaneous recycle of catalysts I and II to keep the highly concentrated intermediate product duplex I‐II instead of the steadily decreased one in typical NASA, which can accomplish in about only 16 min and achieves the outstanding conversion efficiency up to 4.54 × 108, easily conquering the main predicaments of NASA: time‐consuming and low‐efficiency. As a proof of the concept, the proposed DCHA as a high‐speed and hyper‐efficiency DNA signal magnifier is successfully applied in the rapid and ultrasensitive detection of miRNA‐21 in cancer cell lysates, which exploits the new generation of universal strategy for the applications in biosensing assay, clinic diagnose, and DNA nanobiotechnology.
Unlike the conventional catalytic hairpin assembly, the programmable dual‐catalyst hairpin assembly carved out achieves the coinstantaneous regeneration of double reactants (catalyst I and II) by introducing a well‐designed DNA as motivator, possessing spectacular reaction rate, and incredible conversion efficiency.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
In this work, an original rolling-circle strand displacement amplification (RC-SDA) was developed by introducing a circle DNA with two recognition domains as a template instead of the limited liner ...DNA template in traditional strand displacement amplification (SDA), which displayed much shorter reaction time down to 30 min and quite higher conversion efficiency of more than 1.77 × 108 compared with those of traditional strand displacement amplification (SDA) and could be applied to construct a label-free biosensor for ultrasensitive detection of an HIV DNA fragment. Once the target HIV DNA fragment interacts with the template circle DNA, the RC-SDA could be activated to dramatically output amounts of mimic target DNA with the assistance of the Phi29 DNA polymerase and Nb.BbvCI enzyme. In application, while the output products were captured by the DNA tetrahedral nanoprobe (DTNP) modified electrode, the electrochemical tag silver nanoclusters (AgNCs) on DTNP would be released from the electrode surface, accompanied with an obviously decreased electrochemical signal. This way, the developed signal-off biosensor was successfully applied to realize the rapid and ultrasensitive detection of target HIV DNA fragment with a detection limit down to 0.21 fM, which exploits the new generation of a universal strategy beyond the traditional ones for applications in biosensing assay, clinic diagnosis, and DNA nanobiotechnology.
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IJS, KILJ, NUK, PNG, UL, UM
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