Structural determination and characterization of the envelope proteins of shrimp white spot syndrome virus (WSSV)

Ph.DDOCTOR OF PHILOSOPH

Hepcidin as a key iron regulator mediates glucotoxicity-induced pancreatic β-cell dysfunction

It has been well established that glucotoxicity induces pancreatic β-cells dysfunction; however, the precise mechanism remains unclear. Our previous studies demonstrated that high glucose concentrations are associated with decreased hepcidin expression, which inhibits insulin synthesis. In this study, we focused on the role of low hepcidin level-induced increased iron deposition in β-cells and the relationship between abnormal iron metabolism and β-cell dysfunction. Decreased hepcidin expression increased iron absorption by upregulating transferrin receptor 1 (TfR1) and divalent metal transporter 1 (DMT1) expression, resulting in iron accumulation within cells. Prussia blue stain and calcein-AM assays revealed greater iron accumulation in the cytoplasm of pancreatic tissue isolated from db/db mice, cultured islets and Min6 cells in response to high glucose stimulation. Increased cytosolic iron deposition was associated with greater Fe2+ influx into the mitochondria, which depolarized the mitochondria membrane potential, inhibited ATP synthesis, generated excessive ROS and induced oxidative stress. The toxic effect of excessive iron on mitochondrial function eventually resulted in impaired insulin secretion. The restricted iron content in db/db mice via reduced iron intake or accelerated iron clearance improved blood glucose levels with decreased fasting blood glucose (FBG), fasting blood insulin (FIns), HbA1c level, as well as improved intraperitoneal glucose tolerance test (IPGTT) results. Thus, our study may reveal the mechanism involved in the role of hepcidin in the glucotoxcity impaired pancreatic β cell function pathway

Modifying the Substrate Specificity of Carcinoscorpius rotundicauda Serine Protease Inhibitor Domain 1 to Target Thrombin

Protease inhibitors play a decisive role in maintaining homeostasis and eliciting antimicrobial activities. Invertebrates like the horseshoe crab have developed unique modalities with serine protease inhibitors to detect and respond to microbial and host proteases. Two isoforms of an immunomodulatory two-domain Kazal-like serine protease inhibitor, CrSPI-1 and CrSPI-2, have been recently identified in the hepatopancreas of the horseshoe crab, Carcinoscorpius rotundicauda. Full length and domain 2 of CrSPI-1 display powerful inhibitory activities against subtilisin. However, the structure and function of CrSPI-1 domain-1 (D1) remain unknown. Here, we report the crystal structure of CrSPI-1-D1 refined up to 2.0 Å resolution. Despite the close structural homology of CrSPI-1-D1 to rhodniin-D1 (a known thrombin inhibitor), the CrSPI-1-D1 does not inhibit thrombin. This prompted us to modify the selectivity of CrSPI-1-D1 specifically towards thrombin. We illustrate the use of structural information of CrSPI-1-D1 to modify this domain into a potent thrombin inhibitor with IC50 of 26.3 nM. In addition, these studies demonstrate that, besides the rigid conformation of the reactive site loop of the inhibitor, the sequence is the most important determinant of the specificity of the inhibitor. This study will lead to the significant application to modify a multi-domain inhibitor protein to target several proteases

Structural basis of suppression of host translation termination by Moloney Murine Leukemia Virus

Retroviral reverse transcriptase (RT) of Moloney murine leukemia virus (MoMLV) is expressed in the form of a large Gag–Pol precursor protein by suppression of translational termination in which the maximal efficiency of stop codon read-through depends on the interaction between MoMLV RT and peptidyl release factor 1 (eRF1). Here, we report the crystal structure of MoMLV RT in complex with eRF1. The MoMLV RT interacts with the C-terminal domain of eRF1 via its RNase H domain to sterically occlude the binding of peptidyl release factor 3 (eRF3) to eRF1. Promotion of read-through by MoMLV RNase H prevents nonsense-mediated mRNA decay (NMD) of mRNAs. Comparison of our structure with that of HIV RT explains why HIV RT cannot interact with eRF1. Our results provide a mechanistic view of how MoMLV manipulates the host translation termination machinery for the synthesis of its own proteins

Dimerization of Hepatitis E Virus Capsid Protein E2s Domain Is Essential for Virus–Host Interaction

Hepatitis E virus (HEV), a non-enveloped, positive-stranded RNA virus, is transmitted in a faecal-oral manner, and causes acute liver diseases in humans. The HEV capsid is made up of capsomeres consisting of homodimers of a single structural capsid protein forming the virus shell. These dimers are believed to protrude from the viral surface and to interact with host cells to initiate infection. To date, no structural information is available for any of the HEV proteins. Here, we report for the first time the crystal structure of the HEV capsid protein domain E2s, a protruding domain, together with functional studies to illustrate that this domain forms a tight homodimer and that this dimerization is essential for HEV–host interactions. In addition, we also show that the neutralizing antibody recognition site of HEV is located on the E2s domain. Our study will aid in the development of vaccines and, subsequently, specific inhibitors for HEV

Pneumonia Incidence and Mortality in Mainland China: Systematic Review of Chinese and English Literature, 1985–2008

BACKGROUND: Pneumonia is a leading infectious disease killer worldwide, yet the burden in China is not well understood as much of the data is published in the non-English literature. METHODOLOGY/PRINCIPAL FINDINGS: We systematically reviewed the Chinese- and English-language literature for studies with primary data on pneumonia incidence and mortality in mainland China. Between 1985 and 2008, 37 studies met the inclusion criteria. The quality of the studies was highly variable. For children <5 years, incidence ranged from 0.06-0.27 episodes per person-year and mortality ranged from 184-1,223 deaths per 100,000 population. Overall incidence and mortality were stable or decreased over the study period and were higher in rural compared to urban areas. CONCLUSIONS/SIGNIFICANCE: Pneumonia continues to be a major public health challenge in young children in China, and estimates of pneumonia incidence and mortality vary widely. Reliable surveillance data and new prevention efforts may be needed to achieve and document additional declines, especially in areas with higher incidence and mortality such as rural settings

Rizzi, Andrea; Lang, Birgit & Pym, Anthony (2019): What is Translation History? A Trust-Based Approach. Cham: Palgrave Macmillan, 140pp, ISBN 978-3-030-20099-2

Eine Rezension folgender Publikation: Rizzi, Andrea; Lang, Birgit &amp; Pym, Anthony (2019): What is Translation History? A Trust-Based Approach. Cham: Palgrave Macmillan, 140pp, ISBN 978-3-030-20099-2A review of: Rizzi, Andrea; Lang, Birgit &amp; Pym, Anthony (2019): What is Translation History? A Trust-Based Approach. Cham: Palgrave Macmillan, 140pp, ISBN 978-3-030-20099-

The Value of Neutrophil/Lymphocyte Ratio Combined with Red Blood Cell Distribution Width in Evaluating the Prognosis of Emergency Patients with Sepsis

Sepsis is a dysfunction of various organs caused by a dysfunctional host response induced by infection. In recent years, the mortality rate of sepsis patients, especially the mortality rate of septic shock patients still remains high. Due to the complexity and heterogeneity of sepsis, there is currently a lack of clinical biomarkers that can be widely used for the early assessment of sepsis. In order to find more concise and accurate biomarkers for timely and adequate intervention in sepsis, we explored the value of neutrophil/lymphocyte ratio (NLR) combined with red blood cell distribution width (RDW) in assessing the prognosis of emergency sepsis patients. The results showed that NLR and RDW were closely related to the prognosis of emergency sepsis patients. The combination of the two can evaluate the prognosis of patients with emergency sepsis, which deserves close attention from clinicians

RNase AS versus RNase T: Similar yet Different

In this issue of Structure, Romano and colleagues show that RNase AS specifically hydrolyses adenylate-containing RNA and affects mycobacterial virulence. This study reveals the structural basis underlying the substrate specificity of this enzyme