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tance contributes to the pathophysiology of diabetes and is a hallmark of obesity, metabolic syndrome, and many cardiovascular diseases. Therefore, quantifying insulin sensitivity/resistance in humans and animal models is of great importance for epidemiological studies, clinical and basic science investigations, and eventual use in clinical practice. Direct and indirect methods of varying complexity are currently employed for these purposes. Some methods rely on steady-state analysis of glucose and insulin, whereas others rely on dynamic testing. Each of these methods has distinct advantages and limitations. Thus, optimal choice and employment of a specific method depends on the nature of the studies being performed. Established direct methods for measuring insulin sensitivity in vivo are relatively complex. The hyperinsulinemic euglycemic glucose clamp and the insulin suppression test directly assess insulin-mediated glucose utilization under steady-state conditions that are both labor and time intensive. A slightly less complex indirect method relies on minimal model analysis of a frequently sampled intravenous glucose tolerance test. Finally, simple surrogate indexes for insulin sensitivity/ resistance are available (e.g., QUICKI, HOMA, 1/insulin, Matusda index) that are derived from blood insulin and glucose concentrations under fasting conditions (steady state) or after an oral glucose load (dynamic). In particular, the quantitative insulin sensitivity check index (QUICKI) has been validated extensively against the reference standard glucose clamp method. QUICKI is a simple, robust, accurate, reproducible method that appropriately predicts changes in insulin sensitivity after therapeutic interventions as well as the onset of diabetes. In this Frontiers article, we highlight merits, limitations, and appropriate use of current in vivo measures of insulin sensitivity/resistance. glucose clamp; quantitative insulin sensitivity check index; minimal model; homeostatis model assessment INSULIN IS AN ESSENTIAL PEPTIDE HORMONE whose metabolic actions maintain whole body glucose homeostasis and promote efficient glucose utilization (3). Insulin stimulates increased glucose disposal in skeletal muscle and adipose tissue, whereas it inhibits gluconeogenesis in liver to help regulate glucose homeostasis. In addition to these classical insulin target tissues, there are many other important physiological targets of insulin, including the brain, pancreatic ␤-cells, heart, and vascular endothelium, that help to coordinate and couple metabolic and cardiovascular homeostasis under healthy conditions (3,54,72,79). Insulin has concentration-dependent saturable actions to increase whole body glucose disposal. The maximal effect of insulin defines "insulin responsiveness," whereas the insulin concentration required for a half-maximal response defines "insulin sensitivity" (Fig. 1A).Insulin resistance is typically defined as decreased sensitivity or responsiveness to metabolic actions of insulin, such as insulin-mediated glucose d...

s u m m a r yBackground: Since the first case of a novel coronavirus infection pneumonia was detected in Wuhan, China, a series of confirmed cases of the COVID-19 were found in Beijing. We analyzed the data of 262 confirmed cases to determine the clinical and epidemiological characteristics of COVID-19 in Beijing. Methods: We collected patients who were transferred by Beijing Emergency Medical Service to the designated hospitals. The information on demographic, epidemiological, clinical, laboratory test for the COVID-19 virus, diagnostic classification, cluster case and outcome were obtained. Furthermore we compared the characteristics between severe and common confirmed cases which including mild cases, no-pneumonia cases and asymptomatic cases, and we also compared the features between COVID-19 and 2003 SARS. Findings: By Feb 10, 2020, 262 patients were transferred from the hospitals across Beijing to the designated hospitals for special treatment of the COVID-19 infected by Beijing emergency medical service. Among of 262 patients, 46 (17.6%) were severe cases, 216 (82.4%) were common cases, which including 192 (73.3%) mild cases, 11(4.2%) non-pneumonia cases and 13 (5.0%) asymptomatic cases respectively. The median age of patients was 47.5 years old and 48.5% were male. 192 (73.3%) patients were residents of Beijing, 50 (26.0%) of which had been to Wuhan, 116 (60.4%) had close contact with confirmed cases, 21 (10.9%) had no contact history. The most common symptoms at the onset of illness were fever (82.1%), cough (45.8%), fatigue (26.3%), dyspnea (6.9%) and headache (6.5%). The median incubation period was 6.7 days, the interval time from between illness onset and seeing a doctor was 4.5 days. As of Feb 10, 17.2% patients have discharged and 81.7% patients remain in hospital in our study, the fatality of COVID-19 infection in Beijing was 0.9%. Interpretation: On the basis of this study, we provided the ratio of the COVID-19 infection on the severe cases to the mild, asymptomatic and non-pneumonia cases in Beijing. Population was generally susceptible, and with a relatively low fatality rate. The measures to prevent transmission was very successful at early stage, the next steps on the COVID-19 infection should be focused on early isolation of patients and quarantine for close contacts in families and communities in Beijing.

Adiponectin is secreted by adipose cells and mimics many metabolic actions of insulin. However, mechanisms by which adiponectin acts are poorly understood. The vascular action of insulin to stimulate endothelial production of nitric oxide (NO), leading to vasodilation and increased blood flow is an important component of insulin-stimulated whole body glucose utilization. Therefore, we hypothesized that adiponectin may also stimulate

With the dramatic increase of confirmed cases of coronavirus disease (COVID-19) and the increasing death toll in China, timely and effective management of severely and critically ill patients appears to be particularly important. Previous studies on COVID-19 mainly described the general features of patients (1). However, little attention has been paid to clinical characteristics and outcomes of intensive care patients, data on whom are scarce but are of paramount importance to reduce mortality. Some of the results of these studies have been previously reported in the form of an abstract (2). Methods This study enrolled 344 severely and critically ill patients (intensive care patients) who were diagnosed with COVID-19 according to World Health Organization interim guidance by positive result of an RT-PCR assay of nasal and/or throat-swab specimens, and were hospitalized in eight intensive care wards (totaling approximately 330 beds) in Tongji hospital from January 25, 2020, through February 25, 2020. The intensive care wards staff intensivists and specialist nurses in intensive care and were equipped with continuous vital signs monitoring and respiratory support, including noninvasive and invasive ventilators, high-flow nasal cannula (HFNC) oxygen therapy, and extracorporeal membrane oxygenation. We collected demographic, clinical, laboratory, and radiologic findings, and treatment and outcome data from electronic medical records. The illness severity of COVID-19 was defined according to the Chinese management guideline for COVID-19 (version 6.0) (3). Cytokines were measured by a chemiluminescent immunometric assay (Immulite 1000; Diagnostic Products). Acute respiratory distress syndrome (ARDS) was diagnosed according to the Berlin definition, and septic shock was defined according to the 2016 Third International Consensus definition (4, 5). Disseminated intravascular coagulation was

The complement system as well as the coagulation system has fundamental clinical implications in the context of life-threatening tissue injury and inflammation. Associations between both cascades have been proposed, but the precise molecular mechanisms remain unknown. The current study reports multiple links for various factors of the coagulation and fibrinolysis cascades with the central complement components C3 and C5 in vitro and ex vivo. Thrombin, human coagulation factors (F) XIa, Xa, and IXa, and plasmin were all found to effectively cleave C3 and C5. Mass spectrometric analyses identified the cleavage products as C3a and C5a, displaying identical molecular weights as the native anaphylatoxins C3a and C5a. Cleavage products also exhibited robust chemoattraction of human mast cells and neutrophils, respectively. Enzymatic activity for C3 cleavage by the investigated clotting and fibrinolysis factors is defined in the following order: FXa > plasmin > thrombin > FIXa > FXIa > control. Furthermore, FXa-induced cleavage of C3 was significantly suppressed in the presence of the selective FXa inhibitors fondaparinux and enoxaparin in a concentration-dependent manner. Addition of FXa to human serum or plasma activated complement ex vivo, represented by the generation of C3a, C5a, and the terminal complement complex, and decreased complement hemolytic serum activity that defines exact serum concentration that results in complement-mediated lysis of 50% of sensitized sheep erythrocytes. Furthermore, in plasma from patients with multiple injuries (n = 12), a very early appearance and correlation of coagulation (thrombin–antithrombin complexes) and the complement activation product C5a was found. The present data suggest that coagulation/fibrinolysis proteases may act as natural C3 and C5 convertases, generating biologically active anaphylatoxins, linking both cascades via multiple direct interactions in terms of a complex serine protease system.

APOBEC3 proteins constitute a family of cytidine deaminases that provide intracellular resistance to retrovirus replication and transposition of endogenous retroelements. One family member, APOBEC3A (hA3A), is an orphan, without any known antiviral activity. We show that hA3A is catalytically active and that it, but none of the other family members, potently inhibits replication of the parvovirus adeno-associated virus (AAV). hA3A was also a potent inhibitor of the endogenous LTR retroelements, MusD, IAP, and the non-LTR retroelement, LINE-1. Its function was dependent on the conserved amino acids of the hA3A active site, consistent with a role for cytidine deamination, although mutations in retroelement sequences were not found. These findings demonstrate the potent activity of hA3A, an APOBEC3 family member with no previously identified function. They also highlight the functional differences between APOBEC3 proteins. The APOBEC3 family members have distinct functions and may have evolved to resist various classes of genetic elements.

Reactivity principles based on orbital overlap and bonding/antibonding interactions are well established to describe the reactivity of organic species, and atomic structures are typically predicted by Hund's rules to have maximum single-electron occupancy of degenerate orbitals in the ground state. Here, we extend the role of exchange to transition states and discuss how, for reactions and kinetics of bioinorganic species, the analogue of Hund's rules is exchange-controlled reactivity. Pathways that increase the number of unpaired and spin-identical electrons on a metal centre will be favoured by exchange stabilization. Such exchange-enhanced reactivity endows transition states with a stereochemistry different from that observed in cases that are not exchange-enhanced, and is in good agreement with the reactivity observed for iron-based enzymes and synthetic analogues. We discuss the interplay between orbital- and exchange-controlled principles, and how this depends on the identity of the transition metal, its oxidation number and its coordination sphere.