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Increasing the operating lifetime of green phosphorescent OLEDs by inserting a thin layer of TCTA to reduce charge accumulation at the interface is reported.

While crop yields have historically increased, drought resistance has become a major concern in the context of global climate change. The trade-off between crop yield and drought resistance is a common phenomenon; however, the underlying molecular modulators remain undetermined. Through genome-wide association study, we revealed that three non-synonymous variants in a drought-resistant allele of ZmSRO1d-R resulted in plasma membrane localization and enhanced mono-ADP-ribosyltransferase activity of ZmSRO1d toward ZmRBOHC, which increased reactive oxygen species (ROS) levels in guard cells and promoted stomatal closure. ZmSRO1d-R enhanced plant drought resilience and protected grain yields under drought conditions, but it led to yield drag under favorable conditions. In contrast, loss-of-function mutants of ZmRBOHC showed remarkably increased yields under well-watered conditions, whereas they showed compromised drought resistance. Interestingly, by analyzing 189 teosinte accessions, we found that the ZmSRO1d-R allele was present in teosinte but was selected against during maize domestication and modern breeding. Collectively, our work suggests that the allele frequency reduction of ZmSRO1d-R in breeding programs may have compromised maize drought resistance while increased yields. Therefore, introduction of the ZmSRO1d-R allele into modern maize cultivars would contribute to food security under drought stress caused by global climate change.

The cannabinoid receptor 2 (CB2) is a receptor mainly expressed in immune cells and believed to be immunosuppressive in infective or inflammatory models. However, its role in sepsis has not been fully elucidated. In this study, we delineate the function and mechanism of CB2 in the cecal ligation and puncture–induced septic model in mice. The activation of CB2 signaling with HU308 led to decreased survival rates and more severe lung injury in septic mice, and lower IL-10 levels in peritoneal lavage fluid were observed in the CB2 agonist group. The mice with conditional knockout of CB2-encoding gene CNR2 in CD4+ T cells (CD4 Cre CNR2fl/fl) improved survival, enhanced IL-10 production, and ameliorated pulmonary damage in the sepsis model after CB2 activation. In addition, double-knockout of the CNR2 gene (Lyz2 Cre CD4 Cre CNR2fl/fl) decreased the susceptibility to sepsis compared with Lyz2 Cre CNR2fl/fl mice. Mechanistically, the blockade of IL-10 with the anti–IL-10 Ab abolished its protection in CD4 Cre CNR2fl/fl mice. In accordance with the animal study, in vitro results revealed that the lack of CNR2 in CD4+ cells elevated IL-10 production, and CB2 activation inhibited CD4+ T cell–derived IL-10 production. Furthermore, in the clinical environment, septic patients expressed enhanced CB2 mRNA levels compared with healthy donors in PBMCs, and their CB2 expression was inversely correlated with IL-10. These results suggested that the activation of CD4+ T cell–derived CB2 increased susceptibility to sepsis through inhibiting IL-10 production.

Contactin 4 (CNTN4) is a crucial synaptic adhesion protein that belongs to the contactin superfamily. Evidence from both human genetics and mouse models suggests that synapse formation and structural deficits strongly correlate with neurodevelopmental disorders, including autism. In addition, several lines of evidence suggest that CNTN4 is associated with the risk of autism. However, the biological functions of CNTN4 in neural development and disease pathogenesis are poorly understood. In this study, we investigated whether and how CNTN4 is autonomously involved in the development of dendrites and dendritic spines in cortical neurons. Disruption of Cntn4 decreased the number of excitatory synapses, which led to a reduction in neural activity. Truncated proteins lacking the signal peptide, FnIII domains or GPI domain lacked the ability to regulate dendritic spine formation, indicating that CNTN4 regulates dendritic spine density through a mechanism dependent on FnIII domains. Importantly, we revealed that autism-related variants lacked the ability to regulate spine density and neural activity. In conclusion, our study suggests that CNTN4 is essential for promoting dendrite growth and dendritic spine formation and that disruptive variants of CNTN4 interfere with abnormal synapse formation and may increase the risk of autism.

High myopia is one of the leading causes of visual impairment worldwide with high heritability. We have previously identified the genetic contribution of SLC39A5 to nonsyndromic high myopia and demonstrated that disease‐related mutations of SLC39A5 dysregulate the TGF‐β pathway. In this study, the mechanisms underlying SLC39A5 involvement in the pathogenesis of high myopia are determined. We observed the morphogenesis and migration abnormalities of the SLC39A5 knockout (KO) human embryonic kidney cells (HEK293) and found a significant injury of ECM constituents. RNA‐seq and qRT‐PCR revealed the transcription decrease in COL1A1, COL2A1, COL4A1, FN1 and LAMA1 in the KO cells. Further, we demonstrated that TGF‐β signalling, the regulator of ECM, was inhibited in SLC39A5 depletion situation, wherein the activation of receptor Smads (R‐Smads) via phosphorylation was greatly blocked. SLC39A5 re‐expression reversed the phenotype of TGF‐β signalling and ECM synthesis in the KO cells. The fact that TGF‐β signalling was zinc‐regulated and that SLC39A5 was identified as a zinc transporter urged us to check the involvement of intracellular zinc in TGF‐β signalling impairment. Finally, we determined that insufficient zinc chelation destabilized Smad proteins, which naturally inhibited TGF‐β signalling. Overall, the SLC39A5 depletion–induced zinc deficiency destabilized Smad proteins, which inhibited the TGF‐β signalling and downstream ECM synthesis, thus contributing to the pathogenesis of high myopia. This discovery provides a deep insight into myopic development.

We aimed to detect the causative gene in five unrelated families with recessive inheritance pattern neurological disorders involving the central nervous system, and the potential function of the NEMF gene in the central nervous system. Exome sequencing (ES) was applied to all families and linkage analysis was performed on family 1. A minigene assay was used to validate the splicing effect of the relevant discovered variants. Immunofluorescence (IF) experiment was performed to investigate the role of the causative gene in neuron development. The large consanguineous family confirms the phenotype-causative relationship with homozygous frameshift variant (NM_004713.6:c.2618del) as revealed by ES. Linkage analysis of the family showed a significant single-point LOD of 4.5 locus. Through collaboration in GeneMatcher, four additional unrelated families' likely pathogenic NEMF variants for a spectrum of central neurological disorders, two homozygous splice-site variants (NM_004713.6:c.574+1G>T and NM_004713.6:c.807-2A>C) and a homozygous frameshift variant (NM_004713.6: c.1234_1235insC) were subsequently identified and segregated with all affected individuals. We further revealed that knockdown (KD) of Nemf leads to impairment of axonal outgrowth and synapse development in cultured mouse primary cortical neurons. Our study demonstrates that disease-causing biallelic NEMF variants result in central nervous system impairment and other variable features. NEMF is an important player in mammalian neuron development.

Background The immunity of moso bamboo (Phyllostachys heterocycle) to insect defoliator outbreaks differs between on-years to off-years; however, the underlying genetic mechanisms remain unknown. In this study, the genetic relationships of functional genes conferring pest resistance were investigated. Results PhJAZ1 (Phyllostachys heterocycla JASMONATE ZIM-domain protein 1) exhibited the highest enrichment and was expressed at higher levels in the leaves of on-year bamboo plants compared with off-year, whereas the expression of PhSPL17 (Phyllostachys heterocycla SQUAMOSA Promoter binding protein-Like 17) showed the reverse pattern. The expression pattern of PhJAZ1 differed in on- and off-year bamboo (i.e., decreasing in the off-year with no obvious change in the on-year) after feeding by Pantana phyllostachysae (lepidopteran caterpillar of moso bamboo). Due to the lack of a genetic transformation system, the model plant Arabidopsis was used for the investigation of the genetic relationships between PhJAZ1 and PhSPL17. Overexpression of the PhJAZ1 protein in Arabidopsis showed a negative impact on the survival ratio and weight of third-instar Helicoverpa armigera (Arabidopsis leaf-feeding lepidopteran caterpillar). Transcriptional suppression of PhJAZ1 by PhSPL17 was observed, which was able to reveal the reverse expression pattern of PhJAZ1 and PhSPL17. Conclusion Together, these results suggest that on- and off-years (leaf age) regulate the expression of PhSPL17, which negatively regulates the expression of PhJAZ1 to generate differential response to Jasmonate. This study is the first to detail the genetic connection between leaf age and Jasmonate response in moso bamboo and provides a foundation for further pest control via the genetic breeding of moso bamboo. © 2019 Society of Chemical Industry.

The cannabinoid receptor 2 (CB2) is a receptor mainly expressed in immune cells and believed to be immunosuppressive in infective or inflammatory models. However, its role in sepsis has not been fully elucidated. In this study, we delineate the function and mechanism of CB2 in the cecal ligation and puncture-induced septic model in mice. The activation of CB2 signaling with HU308 led to decreased survival rates and more severe lung injury in septic mice, and lower IL-10 levels in peritoneal lavage fluid were observed in the CB2 agonist group. The mice with conditional knockout of CB2-encoding gene CNR2 in CD4

Low circulating 25-hydroxyvitamin D (25(OH)D) levels associate with obesity, diabetes, and hyperlipidemia, but the underlying mechanisms remain uncertain. As energy-dense diet contributes to these disorders, this study investigates whether diet could impair vitamin D metabolism.Compared with control chow-fed mice, high fat diet (HFD)-fed mice show lower serum 25(OH)DThese findings suggest that diet-induced elevation of circulating cholesterol, glucose, and insulin reduces serum 25(OH)D

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Objective Heat shock factor 1 (HSF1), a transcriptional regulator of heat shock proteins (HSPs), is an attractive therapeutic target for cancer. However, only a few HSF1 inhibitors have been identified so far.Methods The mRNA and protein levels of HSF1, HSPs, cleaved PARP, and phosphorylated HSF1 were examined by real-time PCR and Western blot. Forced expression, RNA interference, and immunofluorescence assay were used for mechanistic studies. Cell viability and apoptosis were measured by WST-8 assay and flow cytometry, respectively. Xenograft studies were performed in nude mice to evaluate the effect of dorsomorphin and an HSP90 inhibitor on tumor growth.Results Dorsomorphin suppressed multiple stimuli-induced and constitutive HSPs expression in cancer cells. Mechanistic studies revealed that dorsomorphin reduced heat-induced HSP expression independent of adenosine monophosphate activated protein kinase. Dorsomorphin reduced heat-stimulated HSF1 Ser320 phosphorylation and nuclear translocation, as well as resting nuclear HSF1 levels in cancer cells. Dorsomorphin induced cancer cell apoptosis by inhibiting HSF1 expression. A structure-activity study revealed that the 4-pyridyl at the 3-site of the pyrazolo [1, 5-a]pyrimidine ring is critical for the anti-HSF1 activities of dorsomorphin. Dorsomorphin sensitized cancer cells to HSP90 and proteasome inhibitors and inhibited HSP70 expression induced by these inhibitors in vitro. In tumor-bearing nude mice, dorsomorphin enhanced HSP90 inhibitor-induced cancer cell apoptosis, tumor growth inhibition, and HSP70 expression.Conclusions Dorsomorphin is an HSF1 inhibitor. It induces cancer cell apoptosis, sensitizes cancer cells to both HSP90 and proteasome inhibitors, and suppresses HSP upregulation by these drugs, which may prevent the development of drug resistance. Hence, dorsomorphin and its derivates may serve as potential precursors for developing drugs against cancer.

Excess de novo likely gene-disruptive and missense variants within dozens of genes have been identified in autism spectrum disorder (ASD) and other neurodevelopmental disorders. However, many rare inherited missense variants of these high-risk genes have not been thoroughly evaluated. In this study, we analyzed the rare missense variant burden of POGZ in a large cohort of ASD patients from the Autism Clinical and Genetic Resources in China (ACGC) and further dissected the functional effect of disease-associated missense variants on neuronal development. Our results showed a significant burden of rare missense variants in ASD patients compared to the control population (P = 4.6 × 10−5, OR = 3.96), and missense variants in ASD patients showed more severe predicted functional outcomes than those in controls. Furthermore, by leveraging published large-scale sequencing data of neurodevelopmental disorders (NDDs) and sporadic case reports, we identified 8 de novo missense variants of POGZ in NDD patients. Functional analysis revealed that two inherited, but not de novo, missense variants influenced the cellular localization of POGZ and failed to rescue the defects in neurite and dendritic spine development caused by Pogz knockdown in cultured mouse primary cortical neurons. Significantly, L1CAM, an autism candidate risk gene, is differentially expressed in POGZ deficient cell lines. Reduced expression of L1cam was able to partially rescue the neurite length defects caused by Pogz knockdown. Our study showed the important roles of rare inherited missense variants of POGZ in ASD risk and neuronal development and identified the potential downstream targets of POGZ, which are important for further molecular mechanism studies.

Background Disseminated superficial actinic porokeratosis (DSAP) is a rare autosomal dominant disease. In our previous research, we found that a linkage region of DSAP in a large family is located at 12q23·2-q24·1. Subsequently, the mevalonate kinase gene (MVK) was shown to be pathogenic in DSAP. Objectives To elucidate the mechanism by which MVK mutations lead to keratinocyte apoptosis and DSAP, and to report a new missense mutation, c.566 C>T (p.A189V), in MVK in a Chinese DSAP pedigree. Methods The half-life of wild-type (WT) MVK protein and mutants was assessed using cycloheximide treatment of cells. Dimerization of MVK was analysed by coimmunoprecipitation and glutathione S transferase pull-down assay. MVK kinase activity, production of cell cholesterol, mitochondrial complex activity and apoptosis were detected, using the corresponding commercial kits, in cells overexpressing MVK WT and mutants. Results Mechanically, we demonstrated that both the pathogenic p.A189V mutant and a sporadic mutation p.H312R (c.935A>G), which we reported previously, have rapid degradation, decreased kinase activity and reduced production of cell cholesterol. Also, we found the p.H312R mutation confers on the MVK protein an inability to dimerize. Further, we demonstrated that the mutants are impaired in mitochondrial function and lead to increased apoptosis. Conclusions Our results provide an important basis for elucidating the mechanism by which MVK missense mutations contribute to DSAP.

Obesity and related inflammation are critical for the pathogenesis of insulin resistance, but the underlying mechanisms are not fully understood. Formyl peptide receptor 2 (FPR2) plays important roles in host immune responses and inflammation-related diseases. We found that Fpr2 expression was elevated in the white adipose tissue of high-fat diet (HFD)–induced obese mice and db/db mice. The systemic deletion of Fpr2 alleviated HFD-induced obesity, insulin resistance, hyperglycemia, hyperlipidemia, and hepatic steatosis. Furthermore, Fpr2 deletion in HFD-fed mice elevated body temperature, reduced fat mass, and inhibited inflammation by reducing macrophage infiltration and M1 polarization in metabolic tissues. Bone marrow transplantations between wild-type and Fpr2−/− mice and myeloid-specific Fpr2 deletion demonstrated that Fpr2-expressing myeloid cells exacerbated HFD-induced obesity, insulin resistance, glucose/lipid metabolic disturbances, and inflammation. Mechanistic studies revealed that Fpr2 deletion in HFD-fed mice enhanced energy expenditure probably through increasing thermogenesis in skeletal muscle; serum amyloid A3 and other factors secreted by adipocytes induced macrophage chemotaxis via Fpr2; and Fpr2 deletion suppressed macrophage chemotaxis and lipopolysaccharide-, palmitate-, and interferon-γ–induced macrophage M1 polarization through blocking their signals. Altogether, our studies demonstrate that myeloid Fpr2 plays critical roles in obesity and related metabolic disorders via regulating muscle energy expenditure, macrophage chemotaxis, and M1 polarization.

For the sustainable development of aquaculture, vegetable ingredients have been used to replace the traditional ingredients fishmeal and fish oil in aquafeeds. On the other hand, selective breeding has also been implemented at research level to obtain strains that are adapted to feeding on the plant-based diet. To better understand the underlying mechanisms prompting the adaptation to plant-based diets in fish, we investigated the hepatic expression of several microRNAs (miRNAs) that are involved in the post-transcriptional regulation of cholesterol and lipid metabolism at 8 h and 16 h after the last meal in two lines of rainbow trout: one selected for better adaptation to plant-based diets and the corresponding control line. Both groups were fed either a fishmeal and fish oil based diet or a 100% plant-based diet. Results showed that the expression of miR-33a in liver was greatly elevated in trout fed the plant-based diet, while the expression of miR-122 and miR-128 was much higher in the selected line at 8 h after the last meal regardless of the diet. Furthermore, our results indicated that some genes involved in immune processes (caspase 6 apoptosis-related cysteine peptidase like 2, casp6l2) and cAMP signal transduction (phosphodiesterase 4B cAMP-specific a, pde4ba) were also potentially regulated by miRNAs. They were newly identified as putative direct targets of miRNAs and affected in trout fed the plant-based diet. Though further investigations are still needed to establish a valid relationship between miRNAs and their target genes, our study found miR-33a, miR-122 and miR-128 as potential candidates for further study and provided new perspectives to understand the role of miRNAs in the selective breeding for adaptation to the plant-based diets.

Dietary phospholipids play important roles in growth and nutrition metabolism in fish. Previous studies showed that moderate dietary cholesterol supplementation improved the growth performance of juvenile turbot fed plant-based or defatted fishmeal diets. Therefore, we examined the effect of dietary cholesterol and phospholipids on feed intake, growth performance and cholesterol metabolism in juvenile turbot (Scophthalmus maximus L.) (initial body weight 5.18 ± 0.01 g) during a 10-week period. Nine isonitrogenous and isolipidic diets were formulated to contain 0.0, 1.0 and 2.0% cholesterol (LC, MC and HC), and each with 0.0, 2.0 and 4.0% phospholipids (LP, MP and HP), respectively. A significant interaction between dietary cholesterol and phospholipids on weight gain rate was shown in the present study (P = 0.049). However, no significant interaction between dietary cholesterol and phospholipids was found in feed intake (P = 0.332) though the expression of the orexigenic factor ghrelin in the intestine was significantly affected by the interaction (P = 0.011). Except for total cholesterol, free cholesterol and cholesterol ester, both high-density lipoprotein cholesterol (HDL-C) (P = 0.012) and low-density lipoprotein cholesterol (LDL-C) (P = 0.002) in serum were significantly affected by the interaction between dietary cholesterol and phospholipids. Regarding the key genes involved in cholesterol and bile acid synthesis, no interaction between dietary cholesterol and phospholipids was found in the expression of 3-hydroxy-3-methylglutaryl-CoA reductase (hmgcr) (P = 0.380) and cholesterol 7α-hydroxylase (cyp7a1) (P = 0.587) in liver. In conclusion, there is a significant interaction between dietary cholesterol and phospholipids on the growth performance and the HDL-C and LDL-C involved in cholesterol transport, while no significant interaction was found on the feed intake in juvenile turbot.

Listeria monocytogenes (Lm) is zoonotic pathogen that can cause listeriosis, and vaccine is one of the effective methods to prevent this pathogen infection. In this study, we developed a novel vaccine that is a mixture of inactivated bacteria and Montanide™ ISA 61 VG, a mineral oil adjuvant, and evaluated the safety and immune response characteristics of this vaccine. The mice immunized with the ISA 61 VG adjuvant had high safety, and it could induce significantly higher titer of anti-listeriolysin O (LLO) antibody and higher value of IgG2a/IgG1 ratio compared with the group without the adjuvant. In particular, it could provide 100% immune protection against lethal doses of Lm challenge in mice. In summary, ISA 61VG adjuvant significantly enhanced the ability of inactivated listeria vaccine to induce humoral and cellular immune responses, thereby enhanced the protective immune response in the host, and it is a potential vaccine candidate for the prevention of Lm infection in humans and animals.单核细胞增生李斯特氏菌 (Listeria monocytogenes，Lm) 是重要的人兽共患李斯特氏菌病的致病菌，疫苗免疫是预防该病原菌感染的有效手段之一。本研究研制了添加矿物油佐剂Montanide™ ISA 61 VG 的新型灭活细菌疫苗，并对其安全性和免疫应答特性进行了研究。结果表明，ISA 61 VG 佐剂疫苗具有较好的安全性；诱导小鼠产生的抗李斯特氏菌溶血素O 抗体滴度以及IgG2a/IgG1 比值显著高于无佐剂免疫组；在致死剂量Lm 攻毒下，能对小鼠提供100%的免疫保护。因此，ISA 61VG 佐剂能显著增强灭活疫苗诱导宿主产生体液免疫和细胞免疫应答的能力，从而提高灭活疫苗的保护性免疫应答作用，是预防人和动物Lm 感染的潜在疫苗候选株。.

Various medical treatments for COVID-19 are attempted. After patients are discharged, SARS-CoV-2 recurring cases are reported and the recurrence could profoundly impact patient healthcare and social economics. To date, no data on the effects of medical treatments on recurrence has been published. We analyzed the treatment data of combinations of ten different drugs for the recurring cases in a single medical center, Shenzhen, China. A total of 417 patients were considered and 414 of them were included in this study (3 deaths) with mild-to-critical COVID-19. Patients were treated by 10 different drug combinations and followed up for recurrence for 28 days quarantine after being discharged from the medical center between February and May, 2020. We applied the Synthetic Minority Oversampling Technique (SMOTE) to overcome the rare recurring events in certain age groups and performed Virtual Twins (VT) analysis facilitated by random forest regression for medical treatment-recurrence classification. Among those drug combinations, Methylprednisolone/Interferon/Lopinavir/Ritonavir/Arbidol led to the lowest recurring rate (0.133) as compared to the average recurring rate (0.203). For the younger group (age 20-27) or the older group (age 60-70), the optimal drug combinations are different, but the above combination is still the second best. For obese patients, the combination of Ribavirin/Interferon/Lopinavir/Ritonavir/Arbidol led to the lowest recurring rate for age group of 20-50, whereas the combination of Interferon/Lopinavir/Ritonavir/Arbidol led to lowest recurring rate for age group of 50-70. The insights into combinatorial therapy we provided here shed lights on the use of a combination of (biological and chemical) anti-virus therapy and/or anti-cytokine storm as a potentially effective therapeutic treatment for COVID-19.

IMPORTANCEHow to appropriately care for patients who become PCR-negative for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is still not known. Patients who have recovered from coronavirus disease 2019 (COVID-19) could profoundly impact the health care system if a subset were to be PCR-positive again with reactivated SARS-CoV-2.OBJECTIVETo characterize a single center COVID-19 cohort with and without recurrence of PCR positivity, and develop an algorithm to identify patients at high risk of retest positivity after discharge to inform health care policy and case management decision-making.DESIGN, SETTING, AND PARTICIPANTSA cohort of 414 patients with confirmed SARS-CoV-2 infection, at The Second Affiliated Hospital of Southern University of Science and Technology in Shenzhen, China from January 11 to April 23, 2020.EXPOSURESPolymerase chain reaction (PCR) and IgM-IgG antibody confirmed SARS-CoV-2 infection.MAIN OUTCOMES AND MEASURESUnivariable and multivariable statistical analysis of the clinical, laboratory, radiologic image, medical treatment, and clinical course of admission/quarantine/readmission data to develop an algorithm to predict patients at risk of recurrence of PCR positivity.RESULTS16.7% (95CI: 13.0%-20.3%) patients retest PCR positive 1 to 3 times after discharge, despite being in strict quarantine. The driving factors in the recurrence prediction model included: age, BMI; lowest levels of the blood laboratory tests during hospitalization for cholinesterase, fibrinogen, albumin, prealbumin, calcium, eGFR, creatinine; highest levels of the blood laboratory tests during hospitalization for total bilirubin, lactate dehydrogenase, alkaline phosphatase; the first test results during hospitalization for partial pressure of oxygen, white blood cell and lymphocyte counts, blood procalcitonin; and the first test episodic Ct value and the lowest Ct value of the nasopharyngeal swab RT PCR results. Area under the ROC curve is 0.786.CONCLUSIONS AND RELEVANCEThis case series provides clinical characteristics of COVID-19 patients with recurrent PCR positivity, despite strict quarantine, at a 16.7% rate. Use of a recurrence prediction algorithm may identify patients at high risk of PCR retest positivity of SARS-CoV-2 and help modify COVID-19 case management and health policy approaches.Key PointsQuestionWhat are the characteristics, clinical presentations, and outcomes of COVID-19 patients with PCR retest positivity after resolution of the initial infection and consecutive negative tests? Can we identify recovered patients, prior to discharge, at risk of the recurrence of SARS-CoV-2 PCR positivity?FindingsIn this series of 414 COVID-19 inpatients discharged to a designated quarantine center, 69 retest positive (13 with 2 readmissions, and 3 with 3 readmissions). A multivariable model was developed to predict the risk of the recurrence of SARS-CoV-2 PCR positivity.MeaningRate and timing of the recurrence of PCR positivity following strict quarantine were characterized. Our prediction algorithm may have implications for COVID-19 clinical treatment, patient management, and health policy.

International audience; Cholesterol metabolism is greatly affected in fish fed plant-based diet. The regulation of cholesterol metabolism is mediated by both transcriptional factors such as sterol regulatory element binding proteins (SREBPs) and liver X receptors (LXRs), and posttranscriptional factors including miRNAs. In mammals, SREBP-2 and LXRα are involved in the transcrip-tional regulation of cholesterol synthesis and elimination, respectively. In mammals, miR-33a is reported to directly target genes involved in cholesterol catabolism. The present study aims to investigate the regulation of cholesterol metabolism by SREBP-2 and LXRα and miR-33a in rainbow trout using in vivo and in vitro approaches. In vivo, juvenile rainbow trout of~72 g initial body weight were fed a total plant-based diet (V) or a marine diet (M) containing fishmeal and fish oil. In vitro, primary cell culture hepatocytes were stimulated by graded concentrations of 25-hydroxycholesterol (25-HC). The hepatic expression of cholesterol synthetic genes, srebp-2 and miR-33a as well as miR-33a level in plasma were increased in fish fed the plant-based diet, reversely, their expression in hepatocytes were inhibited with the increasing 25-HC in vitro. However, lxrα was not affected neither in vivo nor in vitro. Our results suggest that SREBP-2 and miR-33a synergistically enhance the expression of cholesterol synthetic genes but do not support the involvement of LXRα in the regulation of cholesterol elimination. As plasma level of miR-33a appears as potential indicator of cholesterol synthetic capacities, this study also highlights circulating miRNAs as promising noninvasive biomarker in aquaculture.

BACKGROUND: Recurrence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positive detection in infected but recovered individuals has been reported. Patients who have recovered from coronavirus disease 2019 (COVID-19) could profoundly impact the health care system if a subset were to be polymerase chain reaction (PCR)-positive again with reactivated SARS-CoV-2. We sought to define the kinetics and relevance of PCR-positive recurrence during recovery from acute COVID-19 to better understand risks for prolonged infectivity and reinfection. METHODS: A series of COVID-19 414 patients, at The Second Affiliated Hospital of Southern University of Science and Technology in Shenzhen, China from January 11 to April 23, 2020. Univariable and multivariable statistical analysis of inpatient data were performed to develop an algorithm to predict patients at risk of recurrence of PCR positivity. FINDINGS: 16·7% recovered patients with PCR positive recurring one to three times, despite being in strict quarantine. Younger patients with mild pulmonary respiratory syndrome had higher risk of PCR positivity recurrence. The recurrence prediction model had an area under the ROC curve of 0·786. INTERPRETATION: This case series provides clinical characteristics of recovered COVID-19 patients with recurrent SARS-CoV-2 positivity, despite strict quarantine, at a 16·7% rate. Use of a recurrence prediction algorithm may identify patients at high risk of recurrent SARS-CoV-2 positivity and help understand reactivation and reinfection possibilities to establish protocols for health policy. FUNDING STATEMENT: This work was supported by grants from Sanming Project of Medicine in Shenzhen (Jia Huang, No. SZSM201812065); Bill & Melinda Gates Foundations (Lei Liu); and from National Natural Science Foundation of China (Jia Huang, No. 81501651) DECLARATION OF INTERESTS: The authors declare no competing interests. ETHICS APPROVAL STATEMENT: This study was approved by the Ethics Committee of the Second Affiliated Hospital of Southern University of Science and Technology. Written informed consent was obtained from all patients.

Fragile X syndrome (FXS) is the leading inherited cause of intellectual disability, resulting from the lack of functional fragile X mental retardation protein (FMRP), an mRNA binding protein mainly serving as a translational regulator. Loss of FMRP leads to dysregulation of target mRNAs. The Drosophila model of FXS show an abnormal circadian rhythm with disruption of the output pathway downstream of the clock network. Yet the FMRP targets involved in circadian regulation have not been identified. Here, we identified collapsing response mediator protein (CRMP) mRNA as a target of FMRP. Knockdown of pan-neuronal CRMP expression ameliorated the circadian defects and abnormal axonal structures of clock neurons (ventral lateral neurons) in dfmr1 mutant flies. Furthermore, specific reduction of CRMP in the downstream output insulin-producing cells attenuated the aberrant circadian behaviors. Molecular analyses revealed that FMRP binds with CRMP mRNA and negatively regulates its translation. Our results indicate that CRMP is an FMRP target and establish an essential role for CRMP in the circadian output in FXS Drosophila. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12264-021-00682-z.

β2-adrenoceptor (β2AR) agonists can stimulate skeletal muscle growth. Their illegal use in food-producing animals, human athletes and bodybuilders causes adverse health effects. In the present study, we developed 3D-QSAR models for predicting the activity of chemicals which can stimulate skeletal muscle growth through β2AR. The activity of 25 β2AR agonists was measured by β2AR-cAMP response element (CRE) –luciferase (Luc) reporter assay. The 3D-QSAR models were built using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). The CoMFA and CoMSIA models displayed high external predictability (R2 0.996 and 0.992, respectively) and good statistical robustness, and revealed that electrostatic effects were the most prominent forces influencing the activity of β2AR agonists. The CoMFA and CoMSIA contour plots provided clues regarding the main chemical features responsible for the activity variations and also resulted in predictions which correlate very well with the observed activity. In vitro study with differentiated myotubes showed that the potency orders of β2AR agonists in activating the β2AR-CRE-Luc reporter and in upregulating CREB target genes related to muscle growth were consistent. These 3D-QSAR models provide tools for predicting the activity of chemicals which might be illegally used in livestock or humans to stimulate skeletal muscle growth.