Resurrection of 2'-5'-oligoadenylate synthetase 1 (OAS1) from the ancestor of modern horseshoe bats blocks SARS-CoV-2 replication.

The prenylated form of the human 2'-5'-oligoadenylate synthetase 1 (OAS1) protein has been shown to potently inhibit the replication of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the virus responsible for the Coronavirus Disease 2019 (COVID-19) pandemic. However, the OAS1 orthologue in the horseshoe bats (superfamily Rhinolophoidea), the reservoir host of SARS-related coronaviruses (SARSr-CoVs), has lost the prenylation signal required for this antiviral activity. Herein, we used an ancestral state reconstruction approach to predict and reconstitute in vitro, the most likely OAS1 protein sequence expressed by the Rhinolophoidea common ancestor prior to its prenylation loss (RhinoCA OAS1). We exogenously expressed the ancient bat protein in vitro to show that, unlike its non-prenylated horseshoe bat descendants, RhinoCA OAS1 successfully blocks SARS-CoV-2 replication. Using protein structure predictions in combination with evolutionary hypothesis testing methods, we highlight sites under unique diversifying selection specific to OAS1's evolution in the Rhinolophoidea. These sites are located near the RNA-binding region and the C-terminal end of the protein where the prenylation signal would have been. Our results confirm that OAS1 prenylation loss at the base of the Rhinolophoidea clade ablated the ability of OAS1 to restrict SARSr-CoV replication and that subsequent evolution of the gene in these bats likely favoured an alternative function. These findings can advance our understanding of the tightly linked association between SARSr-CoVs and horseshoe bats.

Omega­3 polyunsaturated fatty acids inhibit IL­11/STAT3 signaling in hepatocytes during acetaminophen hepatotoxicity.

Omega­3 polyunsaturated fatty acids (n­3 PUFAs) exert a negative effect on IL­6 production in several liver disorders, including cirrhosis, acute liver failure and fatty liver disease. However, its effect on the production of IL­11, another important IL­6 family cytokine, remains unclear. IL­11 was found to be significantly elevated in acetaminophen (APAP)­induced liver damage. The aim of the present study was to investigate whether and how n­3 PUFAs modulate IL­11 production during APAP­induced liver injury. For that purpose, wild­type (WT) and fat­1 transgenic mice were intraperitoneally injected with APAP to induce liver injury. Serum was collected for ELISA and alanine aminotransferase assay. The hepatocytes of APAP­injected mice were isolated for reverse transcription­quantitative PCR and western blot analyses. For the in vitro study, primary hepatocytes isolated from WT or fat­1 mice were stimulated with APAP. The results revealed that both endogenous and exogenous n­3 PUFAs significantly aggravated APAP­induced liver damage via the downregulation of STAT3 signaling. Notably, n­3 PUFAs inhibited IL­11 expression, but not IL­6 expression in hepatocytes during the APAP challenge. Furthermore, it was demonstrated that limited phosphorylation of ERK1/2 and Fos­â€‹like­1 (Fra­1) expression are responsible for the n­3 PUFA­mediated inhibitory effect on IL­11 production in APAP­treated hepatocytes. It was concluded that n­3 PUFAs inhibit IL­11 production and further STAT3 activation in hepatocytes during APAP­induced liver injury. Therefore, ERK1/2­mediated Fra­1 expression is responsible for the effect of n­3 PUFAs on IL­11 expression.

Strategies for Vaccine Prioritization and Mass Dispensing.

We propose a system that helps decision makers during a pandemic find, in real time, the mass vaccination strategies that best utilize limited medical resources to achieve fast containments and population protection. Our general-purpose framework integrates into a single computational platform a multi-purpose compartmental disease propagation model, a human behavior network, a resource logistics model, and a stochastic queueing model for vaccination operations. We apply the modeling framework to the current COVID-19 pandemic and derive an optimal trigger for switching from a prioritized vaccination strategy to a non-prioritized strategy so as to minimize the overall attack rate and mortality rate. When vaccine supply is limited, such a mixed vaccination strategy is broadly effective. Our analysis suggests that delays in vaccine supply and inefficiencies in vaccination delivery can substantially impede the containment effort. Employing an optimal mixed strategy can significantly reduce the attack and mortality rates. The more infectious the virus, the earlier it helps to open the vaccine to the public. As vaccine efficacy decreases, the attack and mortality rates rapidly increase by multiples; this highlights the importance of early vaccination to reduce spreading as quickly as possible to lower the chances for further mutations to evolve and to reduce the excessive healthcare burden. To maximize the protective effect of available vaccines, of equal importance are determining the optimal mixed strategy and implementing effective on-the-ground dispensing. The optimal mixed strategy is quite robust against variations in model parameters and can be implemented readily in practice. Studies with our holistic modeling framework strongly support the urgent need for early vaccination in combating the COVID-19 pandemic. Our framework permits rapid custom modeling in practice. Additionally, it is generalizable for different types of infectious disease outbreaks, whereby a user may determine for a given type the effects of different interventions including the optimal switch trigger.

M2 Macrophages Serve as Critical Executor of Innate Immunity in Chronic Allograft Rejection.

Allograft functional failure due to acute or chronic rejection has long been a major concern in the area of solid organ transplantation for decades. As critical component of innate immune system, the macrophages are unlikely to be exclusive for driving acute or chronic sterile inflammation against allografts. Traditionally, macrophages are classified into two types, M1 and M2 like macrophages, based on their functions. M1 macrophages are involved in acute rejection for triggering sterile inflammation thus lead to tissue damage and poor allograft survival, while M2 macrophages represent contradictory features, playing pivotal roles in both anti-inflammation and development of graft fibrosis and resulting in chronic rejection. Macrophages also contribute to allograft vasculopathy, but the phenotypes remain to be identified. Moreover, increasing evidences are challenging traditional identification and classification of macrophage in various diseases. Better understanding the role of macrophage in chronic rejection is fundamental to developing innovative strategies for preventing late graft loss. In this review, we will update the recent progress in our understanding of diversity of macrophage-dominated innate immune response, and reveal the roles of M2 macrophages in chronic allograft rejection as well.

The role of circulating microRNAs for the diagnosis of hepatitis B virus-associated hepatocellular carcinoma with low alpha-fetoprotein level: a systematic review and meta-analysis.

BACKGROUND: Alpha-fetoprotein (AFP) has been widely used for many years as a serum marker for hepatocellular carcinoma (HCC). However, AFP has been recognized as having poor sensitivity. More and more studies have concluded that circulating microRNAs (miRNAs) might be a promising biomarker that could complement AFP. However, the diagnostic ability of circulating miRNAs has varied among the studies. Therefore, we performed the present meta-analysis to appraise the diagnostic performance of circulating miRNAs as a biomarker for hepatitis B virus-associated HCC (HBV-HCC) patients with low AFP levels. METHODS: We performed a systematic review and meta-analysis of the published literature to assess the diagnostic accuracy of circulating miRNAs in differentiating HBV-HCC patients with low AFP levels from non-HCC controls. RESULTS: Circulating miRNAs showed promising potential in the diagnosis of HBV-HCC patients with low AFP levels. In the low-AFP HBV-HCC patients, the area under the curve (AUC) was 0.88 (95% confidence interval [CI]: 0.84-0.90). The pooled sensitivity and specificity were 0.84 (95% CI: 0.78-0.88) and 0.76 (95% CI: 0.69-0.83), respectively. CONCLUSIONS: The detection of circulating miRNAs provides a valuable method for the diagnosis of HBV-HCC in patients with low AFP levels.

Surgical treatment of a massive neurofibroma of the head and neck in a patient with neurofibromatosis type 1: a case report / Tratamiento quirúrgico de un neurofibroma masivo de cabeza y cuello en un paciente con neurofibromatosis tipo 1: reporte de un caso

SUMMARY: Neurofibromatosis type 1 (NF1) is a rare autosomal dominant neurogenetic disease with variable clinical manifestations, which are primarily manifested as neurofibromas, café-au-lait macules (CALMs) and skeletal deformities. Although generally benign, expansile neurofibromas that are characteristic of NF1 readily lead to disturbing deformities. It is often difficult to surgically extirpate a tumor that involves these important tissues or organs. We report a rare case of a patient with neurofibromatosis Type 1. The patient presented with a congenital giant scalp neurofibroma and CALMs in the occipito-cervical region, in addition to ear and occipital deformities. We performed a challenging surgical intervention (a near-total resection) to reduce the tumor burden and rehabilitate the appearance and function of the patient while preserving the intracranial tissue structure. Here, we review this case and analyze the clinical manifestations, diagnosis and management of NF1.

RESUMEN: La neurofibromatosis tipo 1 (NF1) es una rara enfermedad neurogenética autosómica dominante, con manifestaciones clínicas variables, que se manifiestan principalmente como neurofibromas, máculas café con leche (CALM) y deformidades esqueléticas. Generalmente los neurofibromas expansivos benignos que son característicos de NF1 conducen fácilmente a deformidades exageradas. A menudo es difícil extirpar quirúrgicamente un tumor que involucra estos tejidos u órganos importantes. Presentamos un caso raro de un paciente con neurofibromatosis tipo 1. La paciente presentó un neurofibroma congénito gigante del cuero cabelludo y CALM en la región occipitocervical, además de deformidades del oido y región occipital. Realizamos una intervención quirúrgica desafiante (una resección casi total) para reducir la carga tumoral y rehabilitar la apariencia y función de la paciente mientras se preservó la estructura del tejido intracraneal. Aquí, revisamos este caso y analizamos las manifestaciones clínicas, el diagnóstico y el tratamiento de NF1.

The curative effect of liposuction curettage in the treatment of bromhidrosis: A meta-analysis.

BACKGROUND: We aimed to understand the curative effect of liposuction curettage (LC) in the treatment of bromhidrosis. METHODS: Relevant studies published before January 2017were searched from the PubMed, Embase, Cochrane Library, Wanfang, VIP, and China National Knowledge Infrastructure databases. Parameters including recurrence, complications, complete response, and overall response were assessed. Meta-analysis was performed using the R 3.12 statistical package. Odds ratio (OR) and 95% confidence interval (95% CI) were used for dichotomous data. Heterogeneity was assessed using Cochran's Q-statistic and I test. In addition, Egger's test was conducted to detect publication bias. RESULTS: Ten studies with a total of 1124 participants (545 cases and 579 controls) were included. There was no statistical difference in recurrence (OR = 1.19, 95% CI: 0.51-2.74), complete response (OR = 0.66, 95% CI: 0.25-1.74), or overall response (OR = 0.63, 95% CI: 0.21-1.87) between the case and control groups. The incidence of complications in the case group was lower than that in the control group (OR = 0.24, 95% CI: 0.08-0.67) and open excision group (OR = 0.11, 95% CI: 0.07-0.19). Publication bias existed for the recurrence index in the open excision group (t = 3.3979, P = .04), but no publication bias was found in other subgroups, indicating stable results. CONCLUSIONS: LC, which has fewer complications, can be considered the primary choice in the treatment of patients with bromhidrosis compared with other surgical procedures.

Oxidative Stress and Liver Cancer: Etiology and Therapeutic Targets.

Accumulating evidence has indicated that oxidative stress (OS) is associated with the development of hepatocellular carcinoma (HCC). However, the mechanisms remain largely unknown. Normally, OS occurs when the body receives any danger signal-from either an internal or external source-and further induces DNA oxidative damage and abnormal protein expression, placing the body into a state of vulnerability to the development of various diseases such as cancer. There are many factors involved in liver carcinogenesis, including hepatitis B virus (HBV) and hepatitis C virus (HCV) infection, alcohol abuse, and nonalcoholic fatty liver disease (NAFLD). The relationship between OS and HCC has recently been attracting increasing attention. Therefore, elucidation of the impact of OS on the development of liver carcinogenesis is very important for the prevention and treatment of liver cancer. This review focuses mainly on the relationship between OS and the development of HCC from the perspective of cellular and molecular mechanisms and the etiology and therapeutic targets of HCC.

The Protective Effects of Trypsin Inhibitor on Hepatic Ischemia-Reperfusion Injury and Liver Graft Survival.

The aim of this study was to explore the protective effects of ulinastatin (urinary trypsin inhibitor, UTI) on liver ischemia-reperfusion injury (IRI) and graft survival. We employed mouse liver cold IRI and orthotopic liver transplantation (OLTx) models. UTI was added to lactated Ringer's (LR) solution for liver perfusion and preservation in vitro or combined with UTI injection intraperitoneally to the liver graft recipient. Our results indicated that UTI supplementation protected the liver from cold IRI in a dose-dependent manner and prolonged liver graft survival from extended cold preserved liver donors significantly. The underlying mechanism of UTI on liver IRI may be mediated by inhibition of proinflammatory cytokine release, increasing the expression of the antiapoptotic gene Bcl-2 and decreasing the expression of the proapoptosis genes of Caspase-3 and Bax, and further protects hepatocytes from apoptotic death and improves liver function.

Mechanisms of hepatic ischemia-reperfusion injury and protective effects of nitric oxide.

Hepatic ischemia-reperfusion injury (IRI) is a pathophysiological event post liver surgery or transplantation and significantly influences the prognosis of liver function. The mechanisms of IRI remain unclear, and effective methods are lacking for the prevention and therapy of IRI. Several factors/pathways have been implicated in the hepatic IRI process, including anaerobic metabolism, mitochondria, oxidative stress, intracellular calcium overload, liver Kupffer cells and neutrophils, and cytokines and chemokines. The role of nitric oxide (NO) in protecting against liver IRI has recently been reported. NO has been found to attenuate liver IRI through various mechanisms including reducing hepatocellular apoptosis, decreasing oxidative stress and leukocyte adhesion, increasing microcirculatory flow, and enhancing mitochondrial function. The purpose of this review is to provide insights into the mechanisms of liver IRI, indicating the potential protective factors/pathways that may help to improve therapeutic regimens for controlling hepatic IRI during liver surgery, and the potential therapeutic role of NO in liver IRI.

Mechanisms of murine spontaneous liver transplant tolerance.

Liver transplant is associated with the induction of peripheral immune tolerance. Liver allografts are accepted spontaneously in most combinations of mismatch in major histocompatibility complex, without any requirements for immunosuppression. Liver nonparenchymal cells (especially dendritic cells and Kupffer cells), costimulatory pathways, and activated T-cell apoptosis may contribute to the induction of liver tolerance. Therefore, liver tolerance is an active process that includes T-cell activation, proliferation, infiltration of the allograft, and T-cell apoptosis. Liver dendritic cells may modulate the amount of alloreactive T cells in liver graft recipients by expressing the coinhibitory molecule programmed death-ligand 1 and the immunosuppressive enzyme indoleamine 2,3-dioxygenase. Liver dendritic cells also may induce activated T-cell apoptosis and Foxp3+ regulatory T cells. Future studies may clarify the precise function of liver nonparenchymal cells, the interactions between programmed death-ligand 1 and other costimulatory signals, and the contribution of the liver microenvironment to the induction and expansion of Foxp 3 regulatory T cells.

Amine modified graphene as reversed-dispersive solid phase extraction materials combined with liquid chromatography-tandem mass spectrometry for pesticide multi-residue analysis in oil crops.

Amine modified graphene is successfully synthesized via a one-pot solvothermal reaction between graphene oxide and ammonia water, methylamine or n-butyl amine. The presence of amine groups in graphene is identified by Fourier-transform infrared spectrometry, X-ray photoelectron spectroscopy and an X-ray diffractometer. The ability of amine modified graphene to cleanup fatty acids and other interfering substances from acetonitrile extracts of oil crops has been evaluated. It is found that the resulting CH3NH-G exhibits the best performance in interfering substances removal. Meanwhile, a multi-residue method is validated on 28 representative pesticide residues in four oil crops (rapeseed, peanut, sesame seeds and soybean). This method is based on modified QuEChERS sample preparation with CH3NH-G as reversed-dispersive solid phase extraction material and liquid chromatography-tandem mass spectrometry. Use of matrix-matched standards provides acceptable results for most pesticides with overall average recoveries between 70.5 and 100% and consistent RSDs<13%, except for pymetrozine, thidiazuron and diuron. In any case, this method still meets the 0.1-8.3 µg/kg detection limit needs for most pesticides and may be used for qualitative screening applications, in which any identified pesticides can be quantified and confirmed by a more intensive method that achieves >70% recovery.

Determination and study on residue and dissipation of florasulam in wheat and soil under field conditions.

The residue and dissipation of florasulam in wheat and soil were determined by high performance liquid chromatography-tandem mass spectrometry. The dissipation half-lives for florasulam in soil were 0.66 days in Zhejiang and 0.64 days in Hebei. In wheat plant, half-lives of florasulam were 5.16 days in Zhejiang and 2.07 days in Hebei. The residues of florasulam in wheat grain, wheat straw and soil were below the detection limit (i.e., 0.01 mg/kg, the maximum residue level of florasulam). These results would be helpful in setting MRL guidance of florasulam in wheat in China.