Fatal swine acute diarrhoea syndrome caused by an HKU2-related coronavirus of bat origin.

Cross-species transmission of viruses from wildlife animal reservoirs poses a marked threat to human and animal health 1 . Bats have been recognized as one of the most important reservoirs for emerging viruses and the transmission of a coronavirus that originated in bats to humans via intermediate hosts was responsible for the high-impact emerging zoonosis, severe acute respiratory syndrome (SARS) 2-10 . Here we provide virological, epidemiological, evolutionary and experimental evidence that a novel HKU2-related bat coronavirus, swine acute diarrhoea syndrome coronavirus (SADS-CoV), is the aetiological agent that was responsible for a large-scale outbreak of fatal disease in pigs in China that has caused the death of 24,693 piglets across four farms. Notably, the outbreak began in Guangdong province in the vicinity of the origin of the SARS pandemic. Furthermore, we identified SADS-related CoVs with 96-98% sequence identity in 9.8% (58 out of 591) of anal swabs collected from bats in Guangdong province during 2013-2016, predominantly in horseshoe bats (Rhinolophus spp.) that are known reservoirs of SARS-related CoVs. We found that there were striking similarities between the SADS and SARS outbreaks in geographical, temporal, ecological and aetiological settings. This study highlights the importance of identifying coronavirus diversity and distribution in bats to mitigate future outbreaks that could threaten livestock, public health and economic growth.

1,6-Hydride Transfer-Enabled [6 + 1] Annulation to Access Polycyclic 3,4-Fused Azepinoindoles.

A [6 + 1] annulation reaction via cascade 1,6-hydride transfer/cyclization is reported to construct a polycyclic 3,4-fused azepinoindole skeleton. The newly designed 4-amino-indole-3-carbaldehyde is applied as a novel six-atom synthon, interacting with arylamines and malononitrile to achieve the [6 + 1] annulation. Notably, the reaction proceeds smoothly under redox-neutral and metal-free conditions, providing a wide range of azepinoindoles in up to 94% yields, with water as the only byproduct. Besides, the advantage of high step- and atom-economy further highlights the practicality of this methodology.

CD206+CD68+ mono-macrophages and serum soluble CD206 level are increased in antineutrophil cytoplasmic antibodies associated glomerulonephritis.

BACKGROUND: Antineutrophil Cytoplasmic Antibodies (ANCA) associated glomerulonephritis (AGN) is a group of autoimmune diseases and mono-macrophages are involved in its glomerular injuries. In this study, we aim to investigate the role of CD206+ mono-macrophages in AGN. METHODS: 27 AGN patients (14 active AGN, 13 remissive AGN) together with healthy controls (n = 9), disease controls (n = 6) and kidney function adjusted controls (n = 9) from Department of Nephrology, Ruijin hospital were recruited. Flow cytometry was used to study proportion of CD206+ cells in peripheral blood. Immunohistochemistry for CD206 staining was performed and CD206 expression was scored in different kidney regions. Serum soluble CD206 (sCD206) was measured by enzyme-linked immunosorbent assay (ELISA). We also generated murine myeloperoxidase (MPO) (muMPO) ANCA by immunizing Mpo-/- mice. Mouse bone marrow-derived macrophages (BMDMs) from wild C57BL/6 mice and peripheral blood mononuclear cell (PBMC) derived macrophages from healthy donors were treated with MPO ANCA with or without its inhibitor AZD5904 to investigate the effects of MPO-ANCA on CD206 expression. RESULTS: The proportion of peripheral CD206+CD68+ cells in active AGN patients were significantly higher than that in remissive patients (p < 0.001), healthy controls (p < 0.001) and kidney function adjusted controls (p < 0.001). Serum sCD206 level in active AGN patients was higher than that in healthy controls (p < 0.05) and remissive patients (p < 0.01). Immunohistochemistry showed CD206 was highly expressed in different kidney regions including fibrinoid necrosis or crescent formation, glomeruli, periglomerular and tubulointerstitial compartment in active AGN patients in comparison with disease controls. Further studies showed MPO ANCA could induce CD206 expression in BMDMs and PBMC derived macrophages and such effects could be reversed by its inhibitor AZD5904. CONCLUSION: ANCA could induce CD206 expression on mono-macrophages and CD206+ mono-macrophages are activated in AGN. CD206 might be involved in the pathogenesis of AAV and may be a potential target for the disease.

Diffusion-Coefficient Power Laws and Defect-Driven Glassy Dynamics in Swap Acceleration.

Particle swaps can drastically accelerate dynamics in glass. The mechanism is expected to be vital for a fundamental understanding of glassy dynamics. To extract defining features, we propose a partial swap model with a fraction ϕ_{s} of swap-initiating particles, which can only swap locally with each other or with regular particles. We focus on the swap-dominating regime. At all temperatures studied, particle diffusion coefficients scale with ϕ_{s} in unexpected power laws with temperature-dependent exponents, consistent with the kinetic picture of glassy dynamics. At small ϕ_{s}, swap initiators, becoming defect particles, induce remarkably typical glassy dynamics of regular particles. This supports defect models of glass.

Dihydroartemisinin suppresses renal fibrosis in mice by inhibiting DNA-methyltransferase 1 and increasing Klotho.

Renal fibrosis is an unavoidable end result of all forms of progressive chronic kidney diseases (CKD). Discovery of efficacious drugs against renal fibrosis is in crucial need. In a preliminary study we found that a derivative of artemisinin, dihydroartemisinin (DHA), exerted strong renoprotection, and reversed renal fibrosis in adenine-induced CKD mouse model. In this study we investigated the anti-fibrotic mechanisms of DHA, particularly its specific target in renal cells. Renal fibrosis was induced in mice by unilateral ureteral obstruction (UUO) or oral administration of adenine (80 mg · kg-1), the mice received DHA (30 mg · kg-1 · d-1, i.g.) for 14 or 21 days, respectively. We showed that DHA administration markedly attenuated the inflammation and fibrotic responses in the kidneys and significantly improved the renal function in both the renal fibrosis mouse models. In adenine-treated mice, DHA was more effective than 5-azacytidine against renal fibrosis. The anti-fibrotic effects of DHA were also observed in TGF-ß1-treated HK-2 cells. In order to determine the target protein of DHA, we conducted pull-down technology coupled with shotgun proteomics using a small-molecule probe based on the structure of DHA (biotin-DHA). As a results, DNA methyltransferase 1 (DNMT1) was identified as the anti-fibrotic target of DHA in 3 different types of renal cell lines (HK-2, HEK293 and 3T3). We demonstrated that DHA directly bound to Asn 1529 and Thr 1528 of DNMT1 with a Kd value of 8.18 µM. In primary mouse renal tubular cells, we showed that DHA (10 µM) promoted DNMT1 degradation via the ubiquitin-proteasome pathway. DHA-reduced DNMT1 expression effectively reversed Klotho promoter hypermethylation, which led to the reversal of Klotho protein loss in the kidney of UUO mice. This subsequently resulted in inhibition of the Wnt/ß-catenin and TGF-ß/Smad signaling pathways and consequently conferred renoprotection in the animals. Knockdown of Klotho abolished the renoprotective effect of DHA in UUO mice. Our study reveals a novel pharmacological activity for DHA, i.e., renoprotection. DHA exhibits this effect by targeting DNMT1 to reverse Klotho repression. This study provides an evidence for the possible clinical application of DHA in the treatment of renal fibrosis.

Purification of Polysaccharides from Orostachys cartilaginous Cell Cultures by Macroporous Resin Absorption and Bioactivities of the Purified Polysaccharides.

Orostachys cartilaginous is a traditional herbal medicine and its cell cultures contain large amounts of polysaccharides. To utilize the cultured O. cartilaginous cells, this study purified the crude polysaccharides of O. cartilaginous cells by macroporous resin absorption and optimized the purification process in the experiment of orthogonal design with four factors (sample concentration and volume, and eluent concentration and volume) and three levels; the antibacterial and anti-cancer effects of the purified polysaccharides (OTP) were further examined. The results showed that polysaccharide purity reached 95 % in the optimized group, i. e., 1.6 mg/mL of sample (crude polysaccharides) concentration, 3.0 bed volume (BV) of sample volume, 65 % eluent (ethanol) concentration, and 3.0 BV of eluent volume. In the antibacterial experiment, the growth of three bacterial species, i. e., Pseudomonas aeruginosa, Staphylococcus aureus, and Bacillus subtilis was inhibited by OTP, whereas that of Escherichia coli was not affected; the largest diameter of the inhibitory zone was found on B. subtilis; the extracellular alkaline phosphatase activity and the electrical conductivity, nucleic acid, and protein levels of B. subtilis increased after OTP treatment, indicating that the inhibition of B. subtilis growth was caused by the leakage of cell contents. In the anti-cancer experiment, OTP decreased the cell viabilities of the tested human cancer cells, i. e., AGS (gastric cancer), HCT116 (colon cancer), HepG2 (liver cancer), and HeLa (cervical cancer), and the highest inhibitory effect was on HCT116. OTP promoted HCT116 apoptosis and affected the expression of apoptosis-related proteins, i. e., the expression of B-cell lymphoma-2 decreased and that of bcl-2 associated X protein, cytochrome c, caspase 9 and caspase 3 increased. The findings of the present study suggest that O. cartilaginous cell cultures have a potential application in food or drug production.

[Visual analysis of exosomes in traditional Chinese medicine research and application status based on CiteSpace knowledge map].

In this study, CiteSpace was used to conduct bibliometric statistics and visualization of the research papers on the exosomes in traditional Chinese medicine(TCM) and application status in CNKI, Wanfang, VIP, and Web of Science. The authors, research institutions, and keywords of the relevant papers were analyzed to summarize the research status, hotspots, and development trends of TCM application of exosomes, thereby providing references for future research. A total of 340 Chinese papers and 9 English papers were included. In Chinese papers, GUO Hai-dong is the author with the largest amount of research papers, and his research interest is the mechanism of electroacupuncture in promoting functional recovery after sciatic nerve injury by regulating the release of exosomes. Shanghai University of Traditional Chinese Medicine is the research institution with the largest amount of papers, followed by Nanjing University of Chinese Medicine and Hunan University of Chinese Medicine. There was less cooperation among these research institutions, and cooperation between teams and agencies should be strengthened. The overall volume of publications in English was comparatively small, and the connections between the authors were weak. The publishing organizations were mostly distributed in medical schools, hospitals, comprehensive universities, and the cooperation between institutions was scattered. The main keywords in Chinese papers include microRNA, mesenchymal stem cells, bone marrow mesenchymal stem cells, mechanism of action, and extracellular vesicles. The research of exosomes in TCM is increasing in recent years. The research hotspot is that exosomes can both serve as biomarkers for the diagnosis and prognosis of certain diseases in TCM and drug carriers of Chinese medicine for targeted treatment of diseases. Keyword prominence suggested that exosomes derived from osteoblasts and macrophages in the treatment of diseases might still be a future research trend.

Exploration of the lactation function of protein phosphorylation sites in goat mammary tissues by phosphoproteome analysis.

BACKGROUND: Protein phosphorylation plays an important role in lactation. Differentially modified phosphorylation sites and phosphorylated proteins between peak lactation (PL, 90 days postpartum) and late lactation (LL, 280 days postpartum) were investigated using an integrated approach, namely, liquid chromatography with tandem mass spectrometry (LC-MS/MS) and tandem mass tag (TMT) labeling, to determine the molecular changes in the mammary tissues during the different stages of goat lactation. RESULTS: A total of 1,938 (1,111 upregulated, 827 downregulated) differentially modified phosphorylation sites of 1,172 proteins were identified (P values < 0.05 and fold change of phosphorylation ratios > 1.5). Multiple phosphorylation sites of FASN, ACACA, mTOR, PRKAA, IRS1, RPS6KB, EIF4EBP1, JUN, and TSC2 were different in PL compared with LL. In addition, the Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis showed that the calcium signaling pathway, oxytocin signaling pathway and MAPK signaling pathway were enriched. The western blot results showed that the phosphorylation levels of ACACA (Ser80), EIF4EBP1 (Thr46) and IRS1 (Ser312) increased and JUN (Ser63) decreased in PL compared with LL. These results were consistent with the phosphoproteome results. CONCLUSIONS: In this study, we identified for the first time the differentially modified phosphorylation sites in goat mammary tissues between PL and LL. These results indicate that the multiple differentially modified phosphorylation sites of FASN, ACACA, mTOR, PRKAA, IRS1, RPS6KB, EIF4EBP1, TSC2, and JUN and proteins involved in the calcium signaling pathway, oxytocin signaling pathway, and MAPK signaling pathway are worthy of further exploration.

Nocturnal dexmedetomidine alleviates post-intensive care syndrome following cardiac surgery: a prospective randomized controlled clinical trial.

BACKGROUND: Dexmedetomidine is a sedative agent that may have the potential to reduce the risk of post-intensive care syndrome (PICS). This study aimed to establish whether prophylactic nocturnal dexmedetomidine safely reduces postoperative PICS incidence and to develop an easy-to-use model for predicting the risk of PICS following cardiac surgery. METHODS: This was a single-center, double-blind, randomized, prospective, placebo-controlled trial. Patients undergoing cardiac surgery were randomly assigned (1:1) to dexmedetomidine or placebo (normal saline) groups between January 2019 and July 2020. Dexmedetomidine or a similar volume of saline was administered, with an infusion rate up to 1.2 µg/kg/h until the RASS remained between - 1 and 0. The primary study endpoint was PICS incidence at 6 months follow-up, as defined by cognitive, physical, or psychological impairments. RESULTS: We assessed 703 individuals for eligibility, of whom 508 were enrolled. Of these, there were 251 in the dexmedetomidine group and 257 in the placebo group that received the trial agent, forming a modified intention-to-treat population. PICS incidence at 6-month follow-up was significantly decreased in the dexmedetomidine group (54/251, 21.5%) relative to the placebo group (80/257, 31.1%) (odds ratio [OR] 0.793, 95% CI 0.665-0.945; p = 0.014). Psychological impairment was significantly reduced in the dexmedetomidine group relative to the placebo group (18.7% vs. 26.8%, OR 0.806, CI 0.672-0.967, p = 0.029). However, dexmedetomidine treatment was associated with a higher rate of hypotension. A nomogram revealed that age, education, a medical history of diabetes and smoking, dexmedetomidine treatment, postoperative atrial fibrillation, and sequential organ failure assessment scores at 8 h post-surgery were independent predictors of PICS. CONCLUSIONS: Prophylactic nocturnal dexmedetomidine administration significantly reduced PICS incidence by a marked reduction in psychological impairment within a 6-month follow-up period. TRIAL REGISTRATION: ChiCTR, ChiCTR1800014314 . Registered 5 January 2018, http://www.chictr.org.cn/index.aspx.

Comparison of Anticoagulation Regimens Following Stent Placement for Nonthrombotic Lower Extremity Venous Disease.

PURPOSE: To determine whether subtherapeutic anticoagulation regimens are noninferior to therapeutic anticoagulation regimens following stent placement for nonthrombotic lower extremity venous disease. MATERIALS AND METHODS: Fifty-one consecutive patients (88% women; mean age, 44 years) who underwent stent placement for nonthrombotic lower extremity venous disease between 2002 and 2016 were retrospectively identified. The patients were divided into 2 cohorts: those who received prophylactic enoxaparin or no anticoagulation (subtherapeutic) after the procedure and those who received therapeutic doses of anticoagulation with enoxaparin, warfarin, and/or rivaroxaban (therapeutic) after the procedure. Baseline demographic characteristics, procedure characteristics, and outcomes were compared between the 2 groups using the Student t test, Fisher exact test, and χ2 test. The subtherapeutic and therapeutic anticoagulation groups did not differ significantly in the baseline demographic characteristics (eg, sex, race, and age) or procedure characteristics (eg, number of stents placed, stent brand, stent diameter, etc). RESULTS: The mean clinical follow-up time was 4.4 years (range, 0-16.3 years). There were no thrombotic adverse events or luminal obstructions due to in-stent restenosis in either group. There were 5 minor bleeding adverse effects in the therapeutic group and no bleeding adverse effects in the subtherapeutic group (P = .051). There were no statistically significant differences in subjective symptom improvement (P = .75). CONCLUSIONS: In this retrospective cohort, the subtherapeutic and therapeutic anticoagulation regimens produced equivalent outcomes in terms of adverse event rates, reintervention rates, and symptomatic improvement, suggesting that therapeutic doses of anticoagulation do not improve outcomes compared with subtherapeutic anticoagulation regimens following nonthrombotic venous stent placement.

Evaluating renal outcome of ANCA-associated renal vasculitis: comparative study of two histopathological scoring systems.

OBJECTIVES: Renal risk score (RRS) and chronicity score (CS) are both newly proposed tools to predict end stage renal disease (ESRD) which could be applicable in antineutrophil cytoplasmic antibody (ANCA)-associated renal vasculitis patients. Their predictive value has not been fully studied and compared. METHODS: 252 patients with newly biopsy-proven ANCA-associated renal vasculitis were retrospectively studied at the Department of Nephrology, Ruijin Hospital, China. Patients were evaluated with RRS and CS for clinical factors, pathological lesions and outcome. Their predictive value of renal survival was also compared. RESULTS: The median RRS score point at diagnosis was 6 (interquartile range [IQR] 0-9) and CS score point was 4 (IQR 3-7). In accordance with severity of RRS category and CS grade, percentage of hypertensive patients, dialysis dependency, and level of proteinuria increased accordingly. Significant differences were found regarding dialysis dependency within RRS and CS groups (p<0.001 and p<0.01 respectively). The addition of RRS or CS scoring scheme to the base model of dialysis dependency significantly improved discrimination. The C statistic, integrated discrimination improvement and net reclassification improvement were significantly increased by adding either RRS/CS or both. Furthermore, RRS had better ROC. CONCLUSIONS: Among ANCA associated renal vasculitis patients, RRS and CS achieved similar discrimination, but the discrimination of RRS was superior.

Genetic diversity and evolutionary dynamics of Ebola virus in Sierra Leone.

A novel Ebola virus (EBOV) first identified in March 2014 has infected more than 25,000 people in West Africa, resulting in more than 10,000 deaths. Preliminary analyses of genome sequences of 81 EBOV collected from March to June 2014 from Guinea and Sierra Leone suggest that the 2014 EBOV originated from an independent transmission event from its natural reservoir followed by sustained human-to-human infections. It has been reported that the EBOV genome variation might have an effect on the efficacy of sequence-based virus detection and candidate therapeutics. However, only limited viral information has been available since July 2014, when the outbreak entered a rapid growth phase. Here we describe 175 full-length EBOV genome sequences from five severely stricken districts in Sierra Leone from 28 September to 11 November 2014. We found that the 2014 EBOV has become more phylogenetically and genetically diverse from July to November 2014, characterized by the emergence of multiple novel lineages. The substitution rate for the 2014 EBOV was estimated to be 1.23 × 10(-3) substitutions per site per year (95% highest posterior density interval, 1.04 × 10(-3) to 1.41 × 10(-3) substitutions per site per year), approximating to that observed between previous EBOV outbreaks. The sharp increase in genetic diversity of the 2014 EBOV warrants extensive EBOV surveillance in Sierra Leone, Guinea and Liberia to better understand the viral evolution and transmission dynamics of the ongoing outbreak. These data will facilitate the international efforts to develop vaccines and therapeutics.

A novel combined enteroscopy and laparoscopy approach to prevent urethral complications in management of rectourethral fistula.

BACKGROUND: For the last 20 years, laparoscopy management of anorectal malformations (ARM) has been challenged due to the development of postoperative urethral diverticulum or injury caused by the imprecise transection of rectourethral fistulae, particularly rectobulbar fistulae situated deep in the pelvis. We have developed a combined approach of enteroscopy and laparoscopy for intraluminal incision of a rectourethral fistula. METHODS: We retrospectively reviewed 47 ARM patients who underwent surgical corrections using the combined approach between January 2019 and June 2020. Early postoperative and subsequent follow-up results were evaluated. RESULTS: The median follow-up period was 12 months. The average age at surgery was 3.18 ± 0.64 months. The mean operative time of a single-incision laparoscopic-assisted anorectoplasty (SILAARP) was 1.19 ± 0.29 h. The time for intraluminal incision of the fistula was shortened from 14 to 2 min. No patients underwent a conversion. The average postoperative hospital stay, time to full feeds and placement of an anal tube were 10 days, 1 day, and 5 days, respectively. No urethral diverticulum, urinary injury, wound infection, rectal retraction, anal stenosis or rectal prolapse was encountered in the cohort. CONCLUSIONS: The combined enteroscopy and laparoscopy approach offers precise management of rectourethral fistulae. It could effectively obviate urethral complications, eliminating the obstacles of laparoscopy application in the management of ARMs.

Optimum dose of spinal ropivacaine with or without single intravenous bolus of S-ketamine during elective cesarean delivery: a randomized, double-blind, sequential dose-finding study.

BACKGROUND: Maternal hypotension after spinal anaesthesia occurs at a high rate during caesarean delivery and can lead to adverse maternal or foetal outcomes. The aim of this study was to determine the optimal dose of spinal ropivacaine for caesarean section with or without intravenous single bolus of S-ketamine and to observe the rates of hypotension associated with both methods. METHODS: Eighty women undergoing elective caesarean delivery were randomly allocated into either a ropivacaine only or ropivacaine with intravenous S-ketamine group. If the upper sensory level of the patient reached T6 and the visual analogue scale (VAS) scores remained below 3 points before delivery, the next patient had a 1/9th chance of receiving a lower dose or an 8/9th chance of receiving the same dose as the previous patient. If the patient had VAS scores of more than 2 points or needed an extra epidural rescue bolus before delivery, a higher dose was used for the next patient. The primary outcome was the successful use of spinal ropivacaine to maintain patient VAS score of < 3 points before delivery and the incidence of post-spinal hypotension in both groups. Secondary outcomes included the rates of hypotension-related symptoms and interventions, upper sensory level of anaesthesia, level of sedation, neonatal outcomes, Edinburgh Postnatal Depression Scale scores at admission and discharge, and post-operative analgesic effect. The 90% effective dose (ED90) and 95% confidence interval (95% CI) were estimated by isotonic regression. RESULTS: The estimated ED90 of ropivacaine was 11.8 mg (95% CI: 11.7-12.7) with and 14.7 mg (95% CI: 14.6-16.0) without intravenous S-ketamine, using biased coin up-down sequential dose-finding method. The rates of hypotension and associated symptoms were significantly lower in S-ketamine group than in the ropivacaine only group. CONCLUSIONS: A spinal dose of ropivacaine 12 mg with a single intravenous 0.15 mg/kg bolus dose of S-ketamine may significantly reduce the risk of hypotension and induce sedation before delivery. This method may be used with appropriate caution for women undergoing elective caesarean delivery and at a high risk of hypotension or experiencing extreme nervousness. TRIAL REGISTRATION: http://www.chictr.org.cn ( ChiCTR2000040375 ; 28/11/2020).

Invariances in the architecture of pride across small-scale societies.

Becoming valuable to fellow group members so that one would attract assistance in times of need is a major adaptive problem. To solve it, the individual needs a predictive map of the degree to which others value different acts so that, in choosing how to act, the payoff arising from others' valuation of a potential action (e.g., showing bandmates that one is a skilled forager by pursuing a hard-to-acquire prey item) can be added to the direct payoff of the action (e.g., gaining the nutrients of the prey captured). The pride system seems to incorporate all of the elements necessary to solve this adaptive problem. Importantly, data from western(-ized), educated, industrialized, rich, and democratic (WEIRD) societies indicate close quantitative correspondences between pride and the valuations of audiences. Do those results generalize beyond industrial mass societies? To find out, we conducted an experiment among 567 participants in 10 small-scale societies scattered across Central and South America, Africa, and Asia: (i) Bosawás Reserve, Nicaragua; (ii) Cotopaxi, Ecuador; (iii) Drâa-Tafilalet, Morocco; (iv) Enugu, Nigeria; (v) Le Morne, Mauritius; (vi) La Gaulette, Mauritius; (vii) Tuva, Russia; (viii) Shaanxi and Henan, China; (ix) farming communities in Japan; and (x) fishing communities in Japan. Despite widely varying languages, cultures, and subsistence modes, pride in each community closely tracked the valuation of audiences locally (mean r = +0.66) and even across communities (mean r = +0.29). This suggests that the pride system not only develops the same functional architecture everywhere but also operates with a substantial degree of universality in its content.

Cross-cultural invariances in the architecture of shame.

Human foragers are obligately group-living, and their high dependence on mutual aid is believed to have characterized our species' social evolution. It was therefore a central adaptive problem for our ancestors to avoid damaging the willingness of other group members to render them assistance. Cognitively, this requires a predictive map of the degree to which others would devalue the individual based on each of various possible acts. With such a map, an individual can avoid socially costly behaviors by anticipating how much audience devaluation a potential action (e.g., stealing) would cause and weigh this against the action's direct payoff (e.g., acquiring). The shame system manifests all of the functional properties required to solve this adaptive problem, with the aversive intensity of shame encoding the social cost. Previous data from three Western(ized) societies indicated that the shame evoked when the individual anticipates committing various acts closely tracks the magnitude of devaluation expressed by audiences in response to those acts. Here we report data supporting the broader claim that shame is a basic part of human biology. We conducted an experiment among 899 participants in 15 small-scale communities scattered around the world. Despite widely varying languages, cultures, and subsistence modes, shame in each community closely tracked the devaluation of local audiences (mean r = +0.84). The fact that the same pattern is encountered in such mutually remote communities suggests that shame's match to audience devaluation is a design feature crafted by selection and not a product of cultural contact or convergent cultural evolution.

MicroRNA-195 prevents hippocampal microglial/macrophage polarization towards the M1 phenotype induced by chronic brain hypoperfusion through regulating CX3CL1/CX3CR1 signaling.

BACKGROUND: Microglial polarization is a dynamic response to acute brain hypoxia induced by stroke and traumatic brain injury (TBI). However, studies on the polarization of microglia in chronic cerebral circulation insufficiency (CCCI) are limited. Our objective was to investigate the effect of CCCI on microglial polarization after chronic brain hypoperfusion (CBH) and explore the underlying molecular mechanisms. METHODS: CBH model was established by bilateral common carotid artery occlusion (2-vessel occlusion, 2VO) in rats. Using the stereotaxic injection technique, lenti-pre-miR-195 and anti-miR-195 oligonucleotide fragments (lenti-pre-AMO-miR-195) were injeted into the CA1 region of the hippocampus to construct animal models with high or low expression of miR-195. Immunofluorescence staining and flow cytometry were conducted to examine the status of microglial polarization. In vitro, Transwell co-culture system was taken to investigate the role of miR-195 on neuronal-microglial communication through CX3CL1-CX3CR1 signaling. Quantitative real-time PCR was used to detect the level of miR-195 and inflammatory factors. The protein levels of CX3CL1 and CX3CR1 were evaluated by both western blot and immunofluorescence staining. RESULTS: CBH induced by 2VO initiated microglial/macrophage activation in the rat hippocampus from 1 week to 8 weeks, as evaluated by increased ratio of (CD68+ and CD206+)/Iba-1 immunofluorescence. And the microglial/macrophage polarization was shifted towards the M1 phenotype at 8 weeks following CBH. The expression of CX3CL1 and CX3CR1 was increased in the hippocampus of 2VO rats at 8 weeks. An in vitro study in a Transwell co-culture system demonstrated that transfection of either primary-cultured neonatal rat neurons (NRNs) or microglial BV2 cells with AMO-195-induced M1 polarization of BV2 cells and increased CX3CL1 and CX3CR1 expression and that these effects were reversed by miR-195 mimics. Furthermore, the upregulation of miR-195 induced by lenti-pre-miR-195 injection prevented microglial/macrophage polarization to M1 phenotype triggered by hippocampal injection of lenti-pre-AMO-miR-195 and 2VO surgery. CONCLUSIONS: Our findings conclude that downregulation of miR-195 in the hippocampus is involved in CBH-induced microglial/macrophage polarization towards M1 phenotype by governing communication between neurons and microglia through the regulation of CX3CL1 and CX3CR1 signaling. This indicates that miR-195 may provide a new strategy for clinical prevention and treatment of CBH.

Injectable Ovalbumin-Based Composite Implant for Photothermal Tumor Therapy.

Polymeric hydrogels with three-dimensional network structures have found tremendous applications in biomedicine. Herein, we report the synthesis of a multifunctional implant based on ovalbumin (OVA) as a carrier capable of synergistically delivering a photothermal transducing agent (polydopamine, PDA) to tumors. The formation of PDA was achieved by utilizing the basicity of OVA, whereas the formation of the hydrogel implant was achieved through the in vitro/in vivo near-infrared (NIR) laser-induced hyperthermia of PDA. The as-prepared PDA@OVA implant exhibits high photothermal conversion efficiency (38.7 %). Once implanted in vivo, the OVA-based implant shows great versatility in the treatment of malignant tumors. Furthermore, a chemotherapeutic (doxorubicin, DOX) and a contrast agent (iohexol), dispersed in the OVA solution in advance, can also be firmly entrapped in the hydrogel along with the hydrogel formation. It is anticipated that the multifunctional OVA-based implant, not showing any obvious toxicity to healthy tissue, could be a promising system for synergistic cancer treatment.

MicroRNA-153 impairs presynaptic plasticity by blocking vesicle release following chronic brain hypoperfusion.

BACKGROUND: Chronic brain hypoperfusion (CBH) is closely related to Alzheimer's disease (AD) and vascular dementia (VaD). Meanwhile, synaptic pathology plays a prominent role in the initial stage of AD and VaD. However, whether and how CBH impairs presynaptic plasticity is currently unclear. METHODS: In the present study, we performed a battery of techniques, including primary neuronal culture, patch clamp, stereotaxic injection of the lentiviral vectors, morris water maze (MWM), dual luciferase reporter assay, FM1-43 fluorescence dye evaluation, qRT-PCR and western blot, to investigate the regulatory effect of miR-153 on hippocampal synaptic vesicle release both in vivo and in vitro. The CBH rat model was generated by bilateral common carotid artery ligation (2VO). RESULTS: Compared to sham rats, 2VO rats presented decreased field excitatory postsynaptic potential (fEPSP) amplitude and increased paired-pulse ratios (PPRs) in the CA3-CA1 pathway, as well as significantly decreased expression of multiple vesicle fusion-related proteins, including SNAP-25, VAMP-2, syntaxin-1A and synaptotagmin-1, in the hippocampi. The levels of microRNA-153 (miR-153) were upregulated in the hippocampi of rats following 2VO surgery, and in the plasma of dementia patients. The expression of the vesicle fusion-related proteins affected by 2VO was inhibited by miR-153, elevated by miR-153 inhibition, and unchanged by binding-site mutation or miR masks. FM1-43 fluorescence images showed that miR-153 blunted vesicle exocytosis, but this effect was prevented by either 2'-O-methyl antisense oligoribonucleotides to miR-153 (AMO-153) and miR-masking of the miR-153 binding site in the 3' untranslated region (3'UTR) of the Snap25, Vamp2, Stx1a and Syt1 genes. Overexpression of miR-153 by lentiviral vector-mediated miR-153 mimics (lenti-pre-miR-153) decreased the fEPSP amplitude and elevated the PPR in the rat hippocampus, whereas overexpression of the antisense molecule (lenti-AMO-153) reversed these changes triggered by 2VO. Furthermore, lenti-AMO-153 attenuated the cognitive decline of 2VO rats. CONCLUSIONS: Overexpression of miR-153 controls CBH-induced presynaptic vesicle release impairment by posttranscriptionally regulating the expression of four vesicle release-related proteins by targeting the 3'UTRs of the Stx1a, Snap25, Vamp2 and Syt1 genes. These findings identify a novel mechanism of presynaptic plasticity impairment during CBH, which may be a new drug target for prevention or treatment of AD and VaD. Video Abstract.

Fluorinated Alcohols: Magic Reaction Medium and Promoters for Organic Synthesis.

Fluorinated alcohols have been widely used in the synthetic organic chemistry over the past decades. The unique properties such as the strong hydrogen-bonding donor ability and low nucleophilicity allow them to promote organic reactions in the absence of any catalyst. These approaches have distinct advantages in terms of operational simplicity, practicability and environmental friendliness. Reactions promoted by fluorinated alcohols, including nucleophilic substitution reactions, annulation reactions, electrophilic reactions, dearomatization reactions, functionalization of multiple bond, epoxidation reactions and miscellaneous reactions have been summarized in this account.