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Previous studies have been indicated that tumor necrosis factor receptor-associated factor 6 (TRAF6)-induced inflammation leads to acute kidney injury (AKI). How microRNA (miR) contributes to this process is poorly defined. The aim of this study was to investigate whether miR-590-3p regulated lipopolysaccharide (LPS)-induced inflammatory response by inhibiting TRAF6. LPS-induced septic mice were treated with adenovirus expressing miR-590-3p (ad-miR-590-3p) via tail-vein injection. AKI was evaluated by examining serum cystatin C (CysC), serum β2-microglobulin (β2-MG), and blood urea nitrogen (BUN). The mRNA and protein levels were assayed by RT-qPCR and western blotting, respectively. The proliferation of podocytes was monitored using the MTT assay. Cell apoptosis was analyzed by flow cytometry. Survival outcomes in ad-miR-590-3p-transfected septic mice were markedly improved compared with mice with LPS-induced sepsis. Ad-miR-590-3p transfection significantly attenuated LPS-induced AKI, which was reflected by an improved glomerular filtration rate (GFR) as determined by measuring CysC, β2-MG, and BUN. Moreover, we observed that miR-590-3p was a novel regulator of TRAF6, binding to its 3′-untranslated regions (3′-UTRs). In vitro, a miR-590-3p gain-of-function mutation blocked LPS-induced podocyte growth inhibition and apoptosis, as well as overactivation of the inflammatory response. miR-590-3p has the ability to suppress LPS-induced AKI and podocyte apoptosis by targeting TRAF6. This might provide a novel strategy for the treatment of LPS-induced renal injuries.

Objectives This study aims to determine the protection provided by Shenfu injection (a traditional Chinese medicine) against development of organ dysfunction in critically ill patients with coronavirus disease 2019 (COVID-19). Trial design This study is a multicenter, randomized, controlled, open-label, two-arm ratio 1:1, parallel group clinical trial. Participants The patients, who are aged from 18 to 75 years old, with a confirmed or suspected diagnosis of severe or critical COVID-19, will be consecutively recruited in the study, according to the guideline on diagnosis and treatment of COVID-19 (the 7 th version) issued by National Health Commission of the People’s Republic of China. Exclusion criteria include pregnant and breastfeeding women, atopy or allergies to Shenfu Injection (SFI), severe underlying disease (malignant tumor with multiple metastases, uncontrolled hemopathy, cachexia, severe malnutrition, HIV), active bleeding, obstructive pneumonia caused by lung tumor, severe pulmonary interstitial fibrosis, alveolar proteinosis and allergic alveolitis, continuous use of immunosuppressive drugs in last 6 months, organ transplantation, expected death within 48 hours, the patients considered unsuitable for this study by researchers. The study is conducted in 11 ICUs of designated hospitals for COVID-19, located in 5 cities of China. Intervention and comparator The enrolled patients will randomly receive 100 ml SFI (study group) or identical volume of saline (control group) twice a day for seven consecutive days. Patients in the both groups will be given usual care and the necessary supportive therapies as recommended by the latest edition of the management guidelines for COVID-19 (the 7 th version so far). Main outcomes The primary endpoint is a composite of newly developed or exacerbated organ dysfunction. This is defined as an increase in the sequential organ failure assessment (SOFA) score of two or more, indicating sepsis and involvement of at least one organ. The SOFA score will be measured for the 14 days after enrolment from the baseline (the score at randomization). The secondary endpoints are shown below: • SOFA score in total • Pneumonia severity index score • Dosage of vasoactive drugs • Ventilation free days within 28 days • Length of stay in intensive care unit • Total hospital costs to treat the patient • 28-day mortality • The incidence of adverse drug events related to SFI Randomisation The block randomization codes were generated by SAS V.9.1 for allocation of participants in this study. The ratio of random distribution is 1:1. The sealed envelope method is used for allocation concealment. Blinding (masking) The patients and statistical personnel analyzing study data are both blinded. The blinding of group assignment is not adopted for the medical staff. Numbers to be randomised (sample size) This study is expected to recruit 300 patients with COVID-19, (150 in each group). Trial Status Protocol version 2.0, February 15, 2020. Patient recruitment started on February 25, and will end on August 31, 2020. Trial registration Chinese Clinical Trial Registry: ChiCTR2000030043. Registered February 21, 2020, http://www.chictr.org.cn/showprojen.aspx?proj=49866 Full protocol The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1 ). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this letter serves as a summary of the key elements of the full protocol.

Myocardial ischemia-reperfusion injury is a medical problem occurring as damage to the myocardium following blood flow restoration after a critical period of coronary occlusion. Oxygen free radicals (OFR) are implicated in reperfusion injury after myocardial ischemia. The antioxidant enzyme, Cu, Zn-superoxide dismutase (Cu, Zn-SOD, also called SOD1) is one of the major means by which cells counteract the deleterious effects of OFR after ischemia. Recently, we reported that a PEP-1-SOD1 fusion protein was efficiently delivered into cultured cells and isolated rat hearts with ischemia-reperfusion injury. In the present study, we investigated the protective effects of the PEP-1-SOD1 fusion protein after ischemic insult. Immunofluorescecnce analysis revealed that the expressed and purified PEP-1-SOD1 fusion protein injected into rat tail veins was efficiently transduced into the myocardium with its native protein structure intact. When injected into Sprague-Dawley rat tail veins, the PEP-1-SOD1 fusion protein significantly attenuated myocardial ischemia-reperfusion damage; characterized by improving cardiac function of the left ventricle, decreasing infarct size, reducing the level of malondialdehyde (MDA), decreasing the release of creatine kinase (CK) and lactate dehydrogenase (LDH), and relieving cardiomyocyte apoptosis. These results suggest that the biologically active intact forms of PEP-1-SOD1 fusion protein will provide an efficient strategy for therapeutic delivery in various diseases related to SOD1 or to OFR.

Cushing＇s disease, also known as adrenocorticotropic hormone （ACTH）-secreting pituitary adenomas （PAs） that cause excess cortisol production, accounts for up to 85% of corticotrophin-dependent Cushing＇s syndrome cases. However, the genetic alterations in this disease are unclear. Here, we performed whole-exome sequencing of DNA derived from 12 ACTH-secreting PAs and matched blood samples, which revealed three types of somatic mutations in a candidate gene, USP8 （encoding ubiquitin-specific protease 8）, exclusively in exon 14 in 8 of 12 ACTH-secreting PAs. We further evaluated somatic USP8 mutations in additional 258 PAs by Sanger sequencing. Targeted sequenc- ing further identified a total of 17 types of USP8 variants in 67 of 108 ACTH-secreting PAs （62.04%）. However, none of these mutations was detected in other types of PAs （n = 150）. These mutations aggregate within the 14-3-3 binding motif of USP8 and disrupt the interaction between USP8 and 14-3-3 protein, resulting in an elevated capacity to pro- tect EGFR from lysosomal degradation. Accordingly, PAs with mutated USP8 display a higher incidence of EGFR expression, elevated EGFR protein abundance and mRNA expression levels of POMC, which encodes the precursor of ACTH. PAs with mutated USP8 are significantly smaller in size and have higher ACTH production than wild- type PAs. In surgically resected primary USP8-mutated tumor cells, USP8 knockdown or blocking EGFR effectively attenuates ACTH secretion. Taken together, somatic gain-of-function USP8 mutations are common and contribute to ACTH overproduction in Cushing＇s disease. Inhibition of USP8 or EGFR is promising for treating USP8-mutated corticotrophin adenoma. Our study highlights the potentially functional mutated gene in Cushing＇s disease and pro- vides insights into the therapeutics of this disease.

Background： Coarctation of the aorta （CoA） with aortic arch hypoplasia （AAH） is a relatively common congenital heart disease in clinical practice. Nonetheless, the corrective surgical technique for infants and children is a clinical problem that remains controversial. In this study, we sought to evaluate the surgical effects of aortic arch （AA） reconstruction with coarctation resection and aortoplasty with autologous pulmonary artery patch for infants and young children with CoA and AAH. Methods： Between January 2009 and December 2015, a total of 22 infants and young children with CoA and AAH who underwent coarctation resection and aortoplasty with autologous pulmonary artery patch were enrolled in this study. The median age of patients was 4.5 （Q1, Q3： 2.0, 14.0） months and the median body weight was 5.75 （Q1, Q3： 4.10, 9.38） kg. All patients were diagnosed with CoA and AAH, and concomitant cardiac anomalies were corrected in one stage. Perioperative and postoperative data were collected and analyzed using the paired sample t-test. Results： No perioperative deaths occurred. No residual obstruction was detected by echocardiography. The postoperative pressure difference across the repaired segment of CoA was 14.05 ± 4.26 mmHg （1 mmHg = 0.133 kPa）, which was smaller than the preoperative pressure difference （48.30 ± 15.73 mmHg; t = -10.119, P 〈 0.001）. The median follow-up time was 29.0 （Q1, Q3： 15.5, 57.3） months. There was no death during the follow-up period, and all patients experienced obvious clinical improvement. Only one child underwent subsequent aortic balloon angioplasty due to restenosis. Computed tomography angiography showed that the AA morphology was smooth, with no aortic aneurysm or angulation deformity. Conclusion： AA reconstruction with coarctation resection and aortoplasty with autologous pulmonary artery patch could effectively correct CoA with AAH, and the rate of reintervention for restenosis is low.

Recently, radiation pressure acceleration （RPA） has been proposed and extensively studied, which shows that circularly polarized （CP） laser pulses can accelerate mono-energetic ion bunches in a phase-stable-acceleration （PSA） way from ultrathin foils. It is found that self-orgizing proton beam can be stably accelerated to GeV in the interaction of a CP laser with a planar target at 1022 W/cm2. A project called Compact LAser Plasma proton Accelerator （CLAPA） is approved by MOST in China recently. A prototype of laser driven proton accelerator （1 to 15 MeV/1 Hz） based on the PSA mechanism and plasma lens is going to be built at Peking University in the next five years. It will be upgraded to 200 MeV later for applications such as cancer therapy, plasma imaging and fast ignitiou for inertial confine fusion.