Modulation of immune response is important in cancer immunotherapy, vaccine adjuvant development and inflammatory or immune disease therapy. Here we report the development of new immunomodulators via control of shape transition among RNA triangle, square and pentagon. Changing one RNA strand in polygons automatically induced the stretching of the interior angle from 60° to 90° or 108°, resulting in self-assembly of elegant RNA triangles, squares and pentagons. When immunological adjuvants were incorporated, their immunomodulation effect for cytokine TNF-α and IL-6 induction was greatly enhanced in vitro and in animals up to 100-fold, while RNA polygon controls induced unnoticeable effect. The RNA nanoparticles were delivered to macrophages specifically. The degree of immunostimulation greatly depended on the size, shape and number of the payload per nanoparticles. Stronger immune response was observed when the number of adjuvants per polygon was increased, demonstrating the advantage of shape transition from triangle to pentagon.

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In the CNS, no pathway dedicated to immune surveillance has been characterized for preventing the anti-CNS immune responses that develop in autoimmune neuroinflammatory disease. Here, we identified a pathway for immune cells to traffic from the brain that is associated with the rostral migratory stream (RMS), which is a forebrain source of newly generated neurons. Evaluation of fluorescently labeled leukocyte migration in mice revealed that DCs travel via the RMS from the CNS to the cervical LNs (CxLNs), where they present antigen to T cells. Pharmacologic interruption of immune cell traffic with the mononuclear cell-sequestering drug fingolimod influenced anti-CNS T cell responses in the CxLNs and modulated experimental autoimmune encephalomyelitis (EAE) severity in a mouse model of multiple sclerosis (MS). Fingolimod treatment also induced EAE in a disease-resistant transgenic mouse strain by altering DC-mediated Treg functions in CxLNs and disrupting CNS immune tolerance. These data describe an immune cell pathway that originates in the CNS and is capable of dampening anti-CNS immune responses in the periphery. Furthermore, these data provide insight into how fingolimod treatment might exacerbate CNS neuroinflammation in some cases and suggest that focal therapeutic interventions, outside the CNS have the potential to selectively modify anti-CNS immunity.

There were only two studies that described the appropriateness of outpatient antibiotic prescriptions in multiple provinces of China. One study estimated that in primary health care settings in China, more than 60% of antibiotic prescriptions were inappropriate by using a sample of only 7311 outpatient visits from six provinces. The other study reported the appropriateness of antibiotic prescriptions in tertiary-level hospitals in 25 provinces of Mainland China, with 0•45 million prescriptions. Both studies were conducted through manual prescription review, of which the review scheme was not clearly described and validated. No study investigated the antibiotic prescription rates for various diagnoses at the national level in China. Added value of this studyWe analyzed a prescription data of 173 million outpatient visits from 28 provinces collected during October 2014 and April 2018 in China. Using a well established and validated approach, we established the baseline of outpatient antibiotic prescription rates for various diagnoses and the proportion of inappropriate antibiotic prescribing, and our results suggested that over 50% of outpatient antibiotic prescribing in China was inappropriate. To the best of our knowledge, no previous studies analyzed such a big prescription data to investigate antibiotic prescribing in China. This study provides the most recent and comprehensive evaluation of the appropriateness of outpatient antibiotic prescriptions in China, which can be benchmark for future studies to assess the progress of China curbing antibiotic misuse and overuse. Implications of all the available evidenceAlthough years of efforts to curb antibiotic use have significantly reduced antibiotic prescription rate, the inappropriate antibiotic prescribing is still prevalent in China. Our findings inform policy makers in China, as well as other countries with high prevalence of inappropriate antibiotic prescribing, carrying out more in-depth antibiotic stewardship programs focusing on reducing inappropriate antibiotic prescribing to achieve the goals of optimizing antibiotic use and curbing antimicrobial resistance. This study also provides a precedent for the use of large-scale prescription data and a wellestablished methodological framework to evaluate the appropriateness of antibiotic prescriptions in China. Future studies focusing on antibiotic use in China can apply our methods to evaluate the appropriateness of antibiotic prescribing by using big electric medical records or administrative data. Summary BackgroundInappropriate antibiotic use greatly accelerates antimicrobial resistance. The appropriateness of antibiotic prescriptions is well evaluated, using big observational data, in some high-income countries (HICs), whereas the evidence of this appropriateness is very limited in China. We aimed to assess the appropriateness of antibiotic prescriptions in China ambulatory care settings. MethodsWe used a data from the Beijing Data Center for Rational Use of Drugs, which was a national database designed for...

Diabetic cardiomyopathy (DCM) is a vital cause of fatalities in diabetic patients. The programmed death of cardiomyocytes and inflammation critically contribute to cardiac hypertrophy and fibrosis in DCM. Furthermore, circular RNA (circRNA) is a key regulator of various diseases. However, the role of circRNAs in DCM remains to be elucidated. Our previous study found that pyroptosis was markedly activated in the cardiomyocytes subjected to high-glucose conditions, and miR-214-3p regulated the expression of caspase-1. The aim of this study was to elucidate whether circRNA is involved in DCM pyroptosis via the miR-214-3p/caspase-1 pathway. Herein, we identified that hsa_circ_0076631, named caspase-1-associated circRNA (CACR), was increased both in high-glucose-treated cardiomyocytes and in the serum of diabetic patients. CACR also sponged an endogenous miR-214-3p to sequester and inhibit its expression. CACR knockdown in cardiomyocytes counteracted highglucose-induced caspase-1 activation. Conversely, miR-214-3p knockdown partially abolished the beneficial effects of CACR silencing on pyroptosis in cardiomyocytes. Therefore, this study elucidated that CACR might be a novel therapeutic target via the CACR/miR-214-3p/caspase-1 pathway in DCM.

Curcumin potently inhibits the activation of NLRP3 inflammasome which may contribute to its anti-inflammatory activity. Our finding offers a mechanistic basis for the therapeutic potential of curcumin in septic shock and other NLRP3 inflammasome-driven diseases.