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Threats to coastal wetlands, including sea-level rise and subsidence, led the National Wildlife Refuge (NWR) System to protect over 500,000 hectares of coastal wetlands during the twentieth century, with approximately 20% occurring in the South Atlantic geography. This effort has involved systematic long-term monitoring of changes in marsh elevation using surface elevation tables and marker horizons at 20 sites across 19 NWRs in the southeastern coastal USA. From 2012 to 2021, the rates of change in surface elevation (−9.3 to 7.1 mm/year), accretion (−0.3 to 17.5 mm/year), and net vertical elevation change (−14.3 to 3.1 mm/year) were highly variable among monitoring sites and varied with coastal wetland type (oligohaline marsh, salt marsh, pocosin, or forested wetland), land surface elevation, and estuarine salinity and geomorphology (i.e., tidally influenced or embayed). Of 20 sites included in our study, only six were gaining elevation at a rate that was equal to or greater than the long-term rates of sea-level rise and therefore considered resilient. Only Waccamaw and Currituck NWRs, both located in oligohaline marshes, were gaining elevation at a rate that exceeded sea-level rise by 1 mm/year. These results support the mounting evidence that many coastal wetlands, particularly in the South Atlantic geography of the USA, will undergo ecological transformations in the next several decades. The NWR System and other coastal management entities will need to use strategic decision-making frameworks to identify management actions that can mitigate the loss of coastal wetlands to support the conservation of coastal wetland–dependent and obligate species. [ABSTRACT FROM AUTHOR]

The US Federal Reserve has been using quantitative easing as an unconventional monetary policy tool for providing liquidity and credit-market facilities to banks, and undertaking large-scale asset purchases in periods of crisis. This study carefully examines whether the US stock market has been responsive to the use of quantitative easing over time. A major contribution of this study to the extant literature is the introduction of the novel rolling windows nonparametric causality-in-quantiles approach to studying the reaction of the stock market to quantitative easing. This approach provides a means of investigating the time-varying causality between the variables across quantiles. The standard nonparametric causality-in-quantiles test results show that stock market performance is significantly predicted by quantitative easing, except at very low and very high levels of stock returns (volatility). The rolling windows nonparametric causality-in-quantiles test results indicate that the causal effect of quantitative easing on stock market volatility and returns becomes pronounced during periods of crisis. The reactions are most significant in periods corresponding to the Asian financial crisis, the global financial crisis and the COVID-19 pandemic outbreak. Overall, the causal effect of quantitative easing on both stock market returns and volatility changes through time; the effect on stock market returns is also greater than on stock market volatility. [ABSTRACT FROM AUTHOR]

Purpose: The SCOFF questionnaire was designed as a simple, memorable screening tool to raise suspicion that a person might have an eating disorder. It is over 20 years since the creation of the SCOFF, during which time it has been widely used. Considering this, we wish to review the use of the SCOFF in peer-reviewed scientific journals, and to assess whether it is being used appropriately in the manner in which it was originally devised and tested. Methods: The Preferred Reporting Items for a Systematic Review and Meta-analysis (PRISMA) guidelines were followed, and all search strategies and methods were determined before the onset of the study. PubMed and Wiley Online Library were searched using the terms SCOFF and eating. Two reviewers were involved in the reviewing process. Criteria for appropriate use of the SCOFF were formalised with the tool's original authors. Results: 180 articles were included in the final review. 48 articles had used the SCOFF appropriately, 117 articles inappropriately and 15 articles had been mixed in the appropriateness of their use. Conclusion: This systematic review highlights the inappropriate use of the SCOFF in diverse languages and settings. When used correctly the SCOFF has made a significant contribution to the understanding of eating disorders and its simplicity has been applauded and led to widespread use. However in over two-thirds of studies, the use of the SCOFF was inappropriate and the paper highlights how and in what way it was misused, Guidelines for the appropriate use of the SCOFF are stated. Future validation and avenues of research are suggested. Level of evidence: Level I. [ABSTRACT FROM AUTHOR]

Small molecule drugs that covalently bind irreversibly to their target proteins have several advantages over conventional reversible inhibitors. They include increased duration of action, less-frequent drug dosing, reduced pharmacokinetic sensitivity, and the potential to target intractable shallow binding sites. Despite these advantages, the key challenges of irreversible covalent drugs are their potential for off-target toxicities and immunogenicity risks. Incorporating reversibility into covalent drugs would lead to less off-target toxicity by forming reversible adducts with off-target proteins and thus reducing the risk of idiosyncratic toxicities caused by the permanent modification of proteins, which leads to higher levels of potential haptens. Herein, we systematically review electrophilic warheads employed during the development of reversible covalent drugs. We hope the structural insights of electrophilic warheads would provide helpful information to medicinal chemists and aid in designing covalent drugs with better on-target selectivity and improved safety. [ABSTRACT FROM AUTHOR]

This study aims to shed light on the effects of financial development and accumulation of capital on the productivity of labor in the sub-Sahara African region within the period of 1990–2018. In this work, we used the (dynamic) common correlated effects estimator-mean group and additional techniques such as cross-section autoregressive distributed lag to calibrate the sample into the African subregion to ensure robustness. The findings reveal that financial progress in the region over time leads to an increase in productivity of labor and also the accumulation of capital. Furthermore, financial markets have a progressive impact on the productivity of labor within sub-Saharan African regions. We extend the very limited literature on the nexus between financial development and labor productivity by incorporating capital accumulation into our model which has not been previously studied. [ABSTRACT FROM AUTHOR]

Ribbed mussels, Geukensia demissa, are marsh fauna that are used in coastal management and restoration due to the ecosystem services they provide. Ribbed mussel restoration efforts may be improved with a greater understanding of the environmental drivers of ribbed mussel distribution at multiple spatial scales to predict areas where restoration could be successful. This study sought to estimate the effects of within-marsh (4 m) and landscape (500 m) factors on ribbed mussel distribution. Ribbed mussel densities were surveyed at 11 sites along the coast of Georgia, USA, and overlaid with spatial data for within-marsh factors (elevation, distance to marsh features, slope) as well as landscape factors (percent cover by subtidal creek, forest, and development within a 500-m radius). The distribution model was then validated using three previously unsurveyed marshes and explained 55% of the variance in ribbed mussel abundance. Ribbed mussel abundances and occupancy were most sensitive to changes in within-marsh factors (elevation and distance to subtidal creeks, bodies of water inundated during the full tidal cycle) but were also sensitive to landscape features (percent landcover of forests and development). The highest ribbed mussel densities were found in mid-elevation areas (~ 0.7 m NAVD88), far from subtidal creeks, and in marshes surrounded with forest and development. These results contrast with distributions in the northeastern USA, where ribbed mussels are distributed along subtidal creek banks. This work suggests that restoration may be most effective when focused on appropriate elevations and at locations away from the marsh-creek ecotone. [ABSTRACT FROM AUTHOR]

The rapid development of effective vaccines to combat the SARS-CoV-2 virus has been an effective counter measure to decrease hospitalization and the mortality rate in many countries. However, with the risk of mutated strains decreasing the efficacy of the vaccine, there has been an increasing demand for antivirals to treat COVID-19. While antivirals, such as remdesivir, have had some success treating COVID-19 patients in hospital settings, there is a need for orally bioavailable, cost-effective antivirals that can be administered in outpatient settings to minimize COVID-19-related hospitalizations and death. Nirmatrelvir (PF-07321332) is an orally bioavailable Mpro (also called 3CLpro) inhibitor developed by Pfizer. It is administered in combination with ritonavir, a potent CYP3A4 inhibitor that decreases the metabolism of nirmatrelvir. This review seeks to outline the history of the rational design, the target selectivity, synthesis, drug resistance, and future perspectives of nirmatrelvir. [ABSTRACT FROM AUTHOR]

Positive single-strand RNA (+ RNA) viruses can remodel host cell membranes to induce a replication organelle (RO) isolating the replication of their genome from innate immunity mechanisms. Some of these viruses, including severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), induce double-membrane vesicles (DMVs) for this purpose. Viral non-structural proteins are essential for DMV biogenesis, but they cannot form without an original membrane from a host cell organelle and a significant supply of lipids. The endoplasmic reticulum (ER) and the initial mechanisms of autophagic processes have been shown to be essential for the biogenesis of SARS-CoV-2 DMVs. However, by analogy with other DMV-inducing viruses, it seems likely that the Golgi apparatus, mitochondria and lipid droplets are also involved. As for hepatitis C virus (HCV), pores crossing both membranes of SARS-CoV-2-induced DMVs have been identified. These pores presumably allow the supply of metabolites essential for viral replication within the DMV, together with the export of the newly synthesized viral RNA to form the genome of future virions. It remains unknown whether, as for HCV, DMVs with open pores can coexist with the fully sealed DMVs required for the storage of large amounts of viral RNA. Interestingly, recent studies have revealed many similarities in the mechanisms of DMV biogenesis and morphology between these two phylogenetically distant viruses. An understanding of the mechanisms of DMV formation and their role in the infectious cycle of SARS-CoV-2 may be essential for the development of new antiviral approaches against this pathogen or other coronaviruses that may emerge in the future. [ABSTRACT FROM AUTHOR]

The emergence of severe acute syndrome coronavirus 2 (SARS-CoV-2) in December 2019 has led to the global COVID-19 pandemic. Although the symptoms of most COVID-19 patients are mild or self-curable, most of severe patients have sepsis caused by cytokine storms, which greatly increases the case fatality rate. Moreover, there is no effective drug that can limit the novel coronavirus thus far, so it is more needed to develop antiviral drugs for the SARS-CoV-2. In our research, we employed the techniques of molecular docking to screen 35 flavonoid compounds among which 29 compounds have Z-scores lower than − 6. Then, (−)-gallocatechin gallate, (+)-gallocatechin and baicalein were identified to have potent inhibitory activity against SARS-CoV-2 Mpro with IC50 values of 5.774 ± 0.805 μM, 13.14 ± 2.081 μM and 5.158 ± 0.928 μM respectively by FRET assay. Molecular docking results also showed that (−)-gallocatechin gallate, (+)-gallocatechin and baicalein can non-covalently bind to Mpro through π-π stacking and hydrogen bonds in the Cys145 catalytic site. We further evaluated the effect of (−)-gallocatechin gallate and baicalein on cytokine storms using a mouse model of sepsis. (−)-Gallocatechin gallate and baicalein significantly reduced sepsis of mouse models on weight, murine sepsis score, and survival rate and reduced the inflammatory factor levels, such as TNF-α, IL-1α, IL-4, and IL-10. Overall, (−)-gallocatechin gallate and baicalein show certain potential of treatment against COVID-19. [ABSTRACT FROM AUTHOR]

Nano-silver conductive ink meets the development demands of the flexible printed electronic products. The size of silver nanoparticles (AgNPs) was closely connected with the conductivity of the printed pattern. In this study, AgNPs were prepared, correlated with its conductivity. AgNPs were characterized by SEM, HR-TEM, UV–Vis, and XPS. The sintering methods of AgNPs were compared. The results showed that the optimum conditions of AgNPs with high conductivity were as follows: the molar ratio of polyvinylpyrrolidone to silver nitrate was 1.8:1, the concentration of silver nitrate was 0.05 mol/L, and the concentration of hydrazine hydrate was 2 mol/L. The particle size of AgNPs with a face-centred cubic structure was around 60 nm. Using sodium chloride as sintering agent at room temperature, AgNPs could get close to each other and sinter faster in comparison with the sintering at high temperature, and the sheet resistance of nano-silver film arrived at 1.2 × 10–5 Ω m. [ABSTRACT FROM AUTHOR]

We investigate the response of UK asset prices to a large set of domestic scheduled macroeconomic announcements using data at a daily frequency from 1998 to 2017. Our results are mostly consistent with economic theory and follow two general patterns: (1) a stronger-than-expected economy raises stock returns, causes the home currency to appreciate, makes the yield curve steeper, and lowers the corporate credit quality spread; (2) higher-than-anticipated inflation leads to an appreciation of the domestic currency and raises the slope of the yield curve. Surprises about retail sales, claimant count rate, GDP, and industrial production have the most prevalent effects across the four asset classes in our data set. A large number of macroeconomic announcements increase trading activity in the stock market, whereas there is barely any (only minor) evidence that announcements (surprises) affect the volatility of asset prices. We also document that the effects of macroeconomic surprises are contingent not only upon the state of the economy but also on the state of the stock market (bull vs. bear). [ABSTRACT FROM AUTHOR]

Inflation expectations (IEs) are often considered to be an important determinant of actual inflation in modern economic theory. This paper studies IE estimates across several European countries, focusing particularly on the key factors that determine the IE dynamics. We first use an arbitrage-free term structure model with both nominal and inflation-indexed bond yields to efficiently obtain the estimates for country-specific IEs. Second, we study the common and specific components of IE estimates in a multi-country factor model framework. We find that the estimated common IE component is an important driver for each country of interest especially for those EMU countries and can be used by central banks as a tool to help anchor IEs and enhance the conduct of monetary policy. [ABSTRACT FROM AUTHOR]

STAT2 is distinguished from other STAT family members by its exclusive involvement in type I and III interferon (IFN-I/III) signaling pathways, and its unique behavior as both positive and negative regulator of IFN-I signaling. The clinical relevance of these opposing STAT2 functions is exemplified by monogenic diseases of STAT2. Autosomal recessive STAT2 deficiency results in heightened susceptibility to severe and/or recurrent viral disease, whereas homozygous missense substitution of the STAT2-R148 residue is associated with severe type I interferonopathy due to loss of STAT2 negative regulation. Here we review the clinical presentation, pathogenesis, and management of these disorders of STAT2. [ABSTRACT FROM AUTHOR]

Introduction: Tuberculous Spondylodiscitis is the most common form of musculoskeletal tuberculosis. Molecular techniques on fresh tissues are proved to improve the diagnosis of tuberculous spondylodiscitis and to allow a rapid diagnosis to initiate the treatment and prevent neurological complications. Objectives: The objective of the present study was to assess the diagnostic performances of single tube nested PCR and GeneXpert ultra in the diagnosis of tuberculous spondylodiscitis on formalin fixed paraffin embedded tissues. Methods: This study included 63 tuberculous spondylodiscitis cases collected from June 2014 to January 2020 and corresponding to 27 definite tuberculous spondylodiscitis with positive microbiology, and 36 probable tuberculous spondylodiscitis, with histopathological, clinical and radiological findings consistent with tuberculous spondylodiscitis but with negative microbiology. The sensitivity, specificity, positive predictive value and negative predictive value of nested PCR and GeneXpert ultra were determined with reference to microbiology. Results: Nested PCR was positive in 47 (75%) cases: 26/27 definite tuberculous spondylodiscitis and 21/36 probable tuberculous spondylodiscitis. GeneXpert ultra was positive in only 6 (10%) cases corresponding to definite tuberculous spondylodiscitis. The sensitivity, specificity, positive predictive value and negative predictive value of nested PCR on formalin fixed paraffin embedded tissues were 96%, 100%, 100%, 83% respectively. For GeneXpert ultra, these rates were 22%, 100%, 100% and 25% respectively. Conclusion: Nested PCR and GeneXpert ultra on formalin fixed paraffin embedded tissues are useful tools for the diagnosis of tuberculous spondylodiscitis, especially for cases where microbiological investigations were not carried out. Both techniques have excellent specificity but single tube nested PCR is more sensitive. Key Points • Molecular techniques are routinely performed on fresh tissues • GeneXpert and nested PCR on formalin fixed paraffin embedded tissues are reliable for the diagnosis of tuberculous spondylodiscitis • Nested PCR is more sensitive than Genexpert for diagnosing tuberculous spondylodiscitis [ABSTRACT FROM AUTHOR]

Many studies on SARS-CoV-2 have been performed over short-time scale, but few have focused on the ultrastructural characteristics of infected cells. We used TEM to perform kinetic analysis of the ultrastructure of SARS-CoV-2-infected cells. Early infection events were characterized by the presence of clusters of single-membrane vesicles and stacks of membrane containing nuclear pores called annulate lamellae (AL). A large network of host cell-derived organelles transformed into virus factories was subsequently observed in the cells. As previously described for other RNA viruses, these replication factories consisted of double-membrane vesicles (DMVs) located close to the nucleus. Viruses released at the cell surface by exocytosis harbored the typical crown of spike proteins, but viral particles without spikes were also observed in intracellular compartments, possibly reflecting incorrect assembly or a cell degradation process. [ABSTRACT FROM AUTHOR]

The use of gamma-irradiated influenza A virus (γ-Flu), retains most of the viral structural antigens, represent a promising option for vaccine development. However, despite the high effectiveness of γ-Flu vaccines, the need to incorporate an adjuvant to improve vaccine-mediated protection seems inevitable. Here, we examined the protective efficacy of an intranasal gamma-irradiated HIN1 vaccine co-administered with a plasmid encoding mouse interleukin-28B (mIL-28B) as a novel adjuvant in BALB/c mice. Animals were immunized intranasally three times at one-week intervals with γ-Flu, alone or in combination with the mIL-28B adjuvant, followed by viral challenge with a high lethal dose (10 LD50) of A/PR/8/34 (H1N1) influenza virus. Virus-specific antibody, cellular and mucosal responses, and the balance of cytokines in the spleen IFN-γ, IL-12, and IL-4) and in lung homogenates (IL-6 and IL-10) were measured by ELISA. The lymphoproliferative activity of restimulated spleen cells was also determined by MTT assay. Furthermore, virus production in the lungs of infected mice was estimated using the Madin-Darby canine kidney (MDCK)/hemagglutination assay (HA). Our data showed that intranasal immunization with adjuvanted γ-Flu vaccine efficiently promoted humoral, cellular, and mucosal immune responses and efficiently decreased lung virus titers, all of which are associated with protection against challenge. This combination also reduced IL-6 and IL-10 levels in lung homogenates. The results suggest that IL-28B can enhance the ability of the vaccine to elicit virus-specific immune responses and could potentially be used as an effective adjuvant. [ABSTRACT FROM AUTHOR]

18F-FDG PET/CT has been used as an indicator of chemotherapy effects, but cancer cells can remain even when no FDG uptake is detected, indicating the importance of exploring other metabolomic pathways. Therefore, we explored the amino acid metabolism, including L-type amino acid transporter-1 (LAT1), in breast cancer tissues and clarified the role of LAT1 in therapeutic resistance and clinical outcomes of patients. We evaluated LAT1 expression before and after neoadjuvant chemotherapy and examined the correlation of glucose uptake using FDG-PET with the pathological response of patients. It revealed that LAT1 levels correlated with proliferation after chemotherapy, and amino acid and glucose metabolism were closely correlated. In addition, LAT1 was considered to be involved in treatment resistance and sensitivity only in luminal type breast cancer. Results of in vitro analyses revealed that LAT1 promoted amino acid uptake, which contributed to energy production by supplying amino acids to the TCA cycle. However, in MCF-7 cells treated with chemotherapeutic agents, oncometabolites and branched-chain amino acids also played a pivotal role in energy production and drug resistance, despite decreased glucose metabolism. In conclusion, LAT1 was involved in drug resistance and could be a novel therapeutic target against chemotherapy resistance in luminal type breast cancer. [ABSTRACT FROM AUTHOR]

Objective: To enhance adipic acid production, a computer-aided approach was employed to engineer the adipyl-CoA synthetase from Thermobifida fusca by combining sequence analysis, protein structure modeling, in silico site-directed mutagenesis, and molecular dynamics simulation. Results: Two single mutants of T. fusca adipyl-CoA synthetase, E210βN and E210βQ, achieved a specific enzyme activity of 1.95 and 1.84 U/mg, respectively, which compared favorably with the 1.48 U/mg for the wild-type. The laboratory-level fermentation experiments showed that E210βN and E210βQ achieved a maximum adipic acid titer of 0.32 and 0.3 g/L. In contrast, the wild-type enzyme yielded a titer of 0.15 g/L under the same conditions. Molecular dynamics (MD) simulations revealed that the mutants (E210βN and E210βQ) could accelerate the dephosphorylation process in catalysis and enhance enzyme activity. Conclusions: The combined computational-experimental approach provides an effective strategy for enhancing enzymatic characteristics, and the mutants may find a useful application for producing adipic acid. [ABSTRACT FROM AUTHOR]

Lipids form an integral, structural, and functional part of all life forms. They play a significant role in various cellular processes such as membrane fusion, fission, endocytosis, protein trafficking, and protein functions. Interestingly, recent studies have revealed their more impactful and critical involvement in infectious diseases, starting with the manipulation of the host membrane to facilitate pathogenic entry. Thereafter, pathogens recruit specific host lipids for the maintenance of favorable intracellular niche to augment their survival and proliferation. In this review, we showcase the lipid-mediated host pathogen interplay in context of life-threatening viral and bacterial diseases including the recent SARS-CoV-2 infection. We evaluate the emergent lipid-centric approaches adopted by these pathogens, while delineating the alterations in the composition and organization of the cell membrane within the host, as well as the pathogen. Lastly, crucial nexus points in their interaction landscape for therapeutic interventions are identified. Lipids act as critical determinants of bacterial and viral pathogenesis by altering the host cell membrane structure and functions. [ABSTRACT FROM AUTHOR]

The existence of more than 30 strains of transmissible spongiform encephalopathy (TSE) and the paucity of infectivity of purified PrPSc, as well as considerations of PrP structure, are inconsistent with the protein-only (prion) theory of TSE. Nucleic acid is a strong contender as a second component. We juxtapose two key findings: (i) PrP is a nucleic-acid-binding antimicrobial protein that is similar to retroviral Gag proteins in its ability to trigger reverse transcription. (ii) Retroelement mobilization is widely seen in TSE disease. Given further evidence that PrP also mediates nucleic acid transport into and out of the cell, a strong case is to be made that a second element – retroelement nucleic acid – bound to PrP constitutes the second component necessary to explain the multiple strains of TSE. [ABSTRACT FROM AUTHOR]

An amendment to this paper has been published and can be accessed via a link at the top of the paper. [ABSTRACT FROM AUTHOR]

A museum exhibit that enables direct full-body interactions with living microbes immerses human visitors into the microscopic world and could inform the design of future educational life-science technologies. [ABSTRACT FROM AUTHOR]

Membrane fusion, one of the most essential processes in the life of eukaryotes, occurs when two separate lipid bilayers merge into a continuous bilayer and internal contents of two separated membranes mingle. There is a certain class of proteins that assist the binding of the viral envelope to the target host cell and catalyzing fusion. All class I viral fusion proteins contain a highly conserved 20-25 amino-acid amphipathic peptide at the N-terminus, which is essential for fusion activity and is termed as the 'fusion peptide'. It has been shown that insertion of fusion peptides into the host membrane and the perturbation in the membrane generated thereby is crucial for membrane fusion. Significant efforts have been given in the last couple of decades to understand the lipid-dependence of structure and function of the fusion peptide in membranes to understand the role of lipid compositions in membrane fusion. In addition, the lipid compositions further change the membrane physical properties and alter the mechanism and extent of membrane fusion. Therefore, lipid compositions modulate membrane fusion by changing membrane physical properties and altering structure of the fusion peptide. [ABSTRACT FROM AUTHOR]

Background and Aims: The clinical course and responsiveness to antiviral treatments differs among hepatitis B virus (HBV) genotypes. However, the cause of these differences is unclear. In the present study, we compared mRNA expression profiles in human hepatocyte chimeric mice infected with HBV genotypes A and C.Methods: Fifteen chimeric mice were prepared and divided into the following three groups: uninfected control mice, HBV genotype A-infected mice, and HBV genotype C-infected mice. Human hepatocytes were collected from these mouse livers and gene expression analyses were performed using next-generation RNA sequencing.Results: Although similar pathways were influenced by HBV infection, including inflammation mediated by chemokine and cytokine signaling, p53, and integrin signaling pathways, expression levels of up-regulated genes by HBV genotype A or C infection were quite different. In HBV genotype A-infected hepatocytes, 172 genes, including KRT23 and C10orf54, were significantly more highly expressed than in HBV genotype C-infected cells, whereas 10 genes, including SPX and IER3, were expressed at significantly lower levels. Genes associated with the p53 pathway and the inflammation mediated by chemokine and cytokine signaling pathway were more highly expressed in cells with HBV genotype A infection, whereas genes associated with CCKR signaling map and oxidative stress response were more highly expressed in cells with HBV genotype C infection.Conclusion: Several differences in gene expression with respect to HBV genotype A and C infection were detected in human hepatocytes. These differences might be associated with genotypic difference in the clinical course or responsiveness to treatment. [ABSTRACT FROM AUTHOR]

Herpes simplex virus type-1 (HSV-1) is a ubiquitous pathogen that infects a large majority of the human population worldwide. It is also a leading cause of infection-related blindness in the developed world. HSV-1 infection of the cornea begins with viral entry into resident cells via a multistep process that involves interaction of viral glycoproteins and host cell surface receptors. Once inside, HSV-1 infection induces a chronic immune-inflammatory response resulting in corneal scarring, thinning and neovascularization. This leads to development of various ocular diseases such as herpes stromal keratitis, resulting in visual impairment and eventual blindness. HSV-1 can also invade the central nervous system and lead to encephalitis, a relatively common cause of sporadic fetal encephalitis worldwide. In this review, we discuss the pathological processes activated by corneal HSV-1 infection and existing antiviral therapies as well as novel therapeutic options currently under development. [ABSTRACT FROM AUTHOR]

Viral infections cause at least 10%-15% of all human carcinomas. Over the last century, the elucidation of viral oncogenic roles in many cancer types has provided fundamental knowledge on carcinogenetic mechanisms and established a basis for the early intervention of virus-related cancers. Meanwhile, rapidly evolving genome-editing techniques targeting viral DNA/RNA have emerged as novel therapeutic strategies for treating virus-related carcinogenesis and have begun showing promising results. This review discusses the recent advances of genome-editing tools for treating tumorigenic viruses and their corresponding cancers, the challenges that must be overcome before clinically applying such genome-editing technologies, and more importantly, the potential solutions to these challenges. [ABSTRACT FROM AUTHOR]

During the recent financial crisis, the Bank of England has taken quantitative easing (QE) measures by buying public as well as private assets in order to strengthen the economy via liquidity injections. This paper investigates the dynamic relationship between unconventional policy measures reflected in central bank’s assets, and government versus commercial bank liability curves in a non-linear framework. By adopting a threshold cointegration methodology we provide evidence against linearity in gilt and commercial banks’ yield responses to asset purchase facility (APF) activity with policy rate being near the zero lower bound (ZLB). By estimating a momentum-TART model, evidence for a uni-directional long run causality from the Bank of England’s assets to both curves are present. [ABSTRACT FROM AUTHOR]

Although current therapies can be successful at suppressing hepatitis B viral load, long-term viral cure is not within reach. Subsequent strategies combining pegylated interferon alfa with nucleoside/nucleotide analogues have not resulted in any major paradigm shift. An improved understanding of the hepatitis B virus (HBV) lifec ycle and virus-induced immune dysregulation has, however, revealed many potential therapeutic targets, and there are hopes that treatment of hepatitis B could soon be revolutionized. This review summarizes the current developments in HBV therapeutics-both virus directed and host directed. [ABSTRACT FROM AUTHOR]

The mechanism of how chronic hepatitis C virus (HCV) infection leads to such a high rate of hepatocellular carcinoma (HCC) is unknown. We found that the PERK axis of endoplasmic reticulum (ER) stress elicited prominent nuclear translocation of Nrf2 in 100% of HCV infected hepatocytes. The sustained nuclear translocation of Nrf2 in chronically infected culture induces Mdm2-mediated retinoblastoma protein (Rb) degradation. Silencing PERK and Nrf2 restored Mdm2-mediated Rb degradation, suggesting that sustained activation of PERK/Nrf2 axis creates oncogenic stress in chronically infected HCV culture model. The activation of Nrf2 and its nuclear translocation were prevented by ER-stress and PERK inhibitors, suggesting that PERK axis is involved in the sustained activation of Nrf2 signaling during chronic HCV infection. Furthermore, we show that HCV clearance induced by interferon-α based antiviral normalized the ER-stress response and prevented nuclear translocation of Nrf2, whereas HCV clearance by DAAs combination does neither. In conclusion, we report here a novel mechanism for how sustained activation of PERK axis of ER-stress during chronic HCV infection activates oncogenic Nrf2 signaling that promotes hepatocyte survival and oncogenesis by inducing Mdm2-mediated Rb degradation. [ABSTRACT FROM AUTHOR]

With the development of China's economy, the problem of environmental pollution has become increasingly more serious, affecting the sustained and healthy development of Chinese cities and the willingness of residents to invest in fixed assets. In this paper, a panel data set of 70 of China's key cities from 2003 to 2014 is used to study the effect of environmental pollution on home prices in China's key cities. In addition to the static panel data regression model, this paper uses the generalized method of moments (GMM) to control for the potential endogeneity and introduce the dynamics. To ensure the robustness of the research results, this paper uses four typical pollutants: per capita volume of SO emissions, industrial soot (dust) emissions, industrial wastewater discharge, and industrial chemical oxygen demand discharge. The analysis shows that environmental pollution does have a negative impact on home prices, and the magnitude of this effect is dependent on the level of economic development. When GDP per capita increases, the size of the negative impact on home prices tends to reduce. Industrial soot (dust) has the greatest impact, and the impact of industrial wastewater is relatively small. It is also found that some other social and economic factors, including greening, public transport, citizen income, fiscal situation, loans, FDI, and population density, have positive effects on home prices, but the effect of employment on home prices is relatively weak. [ABSTRACT FROM AUTHOR]

Background: Labelling proteins with gallium-68 using bifunctional chelators is often problematic because of unsuitably harsh labelling conditions such as low pH or high temperature and may entail post-labelling purification. To determine whether tris(hydroxypyridinone) (THP) bifunctional chelators offer a potential solution to this problem, we have evaluated the labelling and biodistribution of a THP conjugate with a new single-chain antibody against the prostate-specific membrane antigen (PSMA), an attractive target for staging prostate cancer (PCa). A single-chain variable fragment (scFv) of J591, a monoclonal antibody that recognises an external epitope of PSMA, was prepared in order to achieve biokinetics matched to the half-life of gallium-68. The scFv, J591c-scFv, was engineered with a C-terminal cysteine. Results: J591c-scFv was produced in HEK293T cells and purified by size-exclusion chromatography. A maleimide THP derivative (THP-mal) was coupled site-specifically to the C-terminal cysteine residue. The THP-mal-J591c-scFv conjugate was labelled with ammonium acetate-buffered gallium-68 from a Ge/Ga generator at room temperature and neutral pH. The labelled conjugate was evaluated in the PCa cell line DU145 and its PSMA-overexpressing variant in vitro and xenografted in SCID mice. J591c-scFv was produced in yields of 4-6 mg/l culture supernatant and efficiently coupled with the THP-mal bifunctional chelator. Labelling yields > 95% were achieved at room temperature following incubation of 5 μg conjugate with gallium-68 for 5 min without post-labelling purification. Ga-THP-mal-J591c-scFv was stable in serum and showed selective binding to the DU145-PSMA cell line, allowing an IC50 value of 31.5 nM to be determined for unmodified J591c-scFv. Serial PET/CT imaging showed rapid, specific tumour uptake and clearance via renal elimination. Accumulation in DU145-PSMA xenografts at 90 min post-injection was 5.4 ± 0.5%ID/g compared with 0.5 ± 0.2%ID/g in DU145 tumours ( n = 4). Conclusions: The bifunctional chelator THP-mal enabled simple, rapid, quantitative, one-step room temperature radiolabelling of a protein with gallium-68 at neutral pH without a need for post-labelling purification. The resultant gallium-68 complex shows high affinity for PSMA and favourable in vivo targeting properties in a xenograft model of PCa. [ABSTRACT FROM AUTHOR]

Acute lymphoblastic leukemia (ALL) is believed to be resistant to NK cell-mediated killing. To overcome this resistance, we developed an innovative approach based on NK cell stimulation with Toll-like receptor (TLR)-activated plasmacytoid dendritic cells (pDC). The translation of this approach into the clinic requires the production of high numbers of human pDC. Herein, we show that in vitro differentiation of cord blood CD34 progenitors in the presence of aryl hydrocarbon receptor antagonists gives rise to clinically relevant numbers of pDC, as about 10 pDC can be produced from a typical cord blood unit. Blocking the aryl hydrocarbon receptor (AHR) pathway significantly increased the yield of pDC. When compared to pDC isolated from peripheral blood, in vitro differentiated pDC (ivD-pDC) exhibited an increased capacity to induce NK cell-mediated killing of ALL. Although ivD-pDC produced lower amounts of IFN-α than peripheral blood pDC upon TLR activation, they produced more IFN-λ2, known to play a critical role in the induction of anti-tumoral NK cell functions. Both TLR-9 and TLR-7 ligands triggered pDC-induced NK cell activation, offering the possibility to use any clinical-grade TLR-7 or TLR-9 ligands in future clinical trials. Finally, adoptive transfer of ivD-pDC cultured in the presence of an AHR antagonist cured humanized mice with minimal ALL disease. Collectively, our results pave the way to clinical-grade production of sufficient numbers of human pDC for innate immunotherapy against ALL and other refractory malignancies. [ABSTRACT FROM AUTHOR]

Viral myocarditis is a common cardiovascular disease, which seriously endangers the health of people and even leads to sudden unexpected death. MicroRNAs play very important roles in various physical and pathological processes including cardiogenesis and heart diseases. In recent years, miR-20b has been implicated in various diseases such as breast cancer, gastric cancer, hepatocellular carcinoma, cardiovascular diseases. However, the function of miR-20b in the pathological progress of viral myocarditis has not been reported. In this study, we found that miR-20b was up-regulated in mouse heart tissues post Coxsackievirus B3 (CVB3) infection. Bioinformatics analysis identified ZFP-148, a transcription factor that plays essential roles in the regulation of virus replication, is one of the predicted targets of miR-20b. MiR-20b expression was found to be up-regulated and ZFP-148 protein level was markedly repressed during viral myocarditis. Further studies demonstrated that miR-20b directly binds to the 3′-UTR of ZFP-148 and suppresses its translation. Moreover, aberrant expression of miR-20b promoted the expression of anti-apoptosis proteins Bcl-2 and Bcl-xL, suggesting that altered gene expression might promote cardiomyocytes survival in viral myocarditis. Our findings indicated that miR-20b might be a potential therapeutic target for CVB3-induced viral myocarditis and a useful marker for the diagnosis of viral myocarditis. [ABSTRACT FROM AUTHOR]

Despite the discovery of an effective vaccine over 30 years ago, hepatitis B virus (HBV) infection remains a significant cause of global mortality and morbidity affecting over 250 million individuals. Fortunately, many new antiviral agents targeting different steps of the HBV lifecycle are currently being developed marking a true shift in the treatment paradigm. It is hopeful these new therapies will provide a functional and durable cure from HBV infection from a finite duration of treatment. [ABSTRACT FROM AUTHOR]

Although the availability of effective oral therapies for hepatitis B virus (HBV) infection has reduced the need for liver transplantation (LT) for decompensated cirrhosis due to chronic infection, HBV remains an important cause of hepatocellular carcinoma and acute liver failure. Recurrent HBV infection occurs almost invariably post-LT in the absence of prophylaxis if viremia was detectable pre-LT, so prophylaxis remains necessary to prevent graft reinfection. Current approaches include the use of nucleos(t)ide analogues pre- and post-LT and hepatitis B immune globulin, but several novel antiviral agents are currently under investigation in non-transplant populations and may potentially prove to be useful in the LT setting in the future. [ABSTRACT FROM AUTHOR]

In this study, the relationship between physiological conditions, including oogenesis and gravidity, and attraction to carcass odors was examined in order to discover how the attractivity of volatile organic compounds (VOCs) varied in females of the necrophagous fly Lucilia caesar (Linnaeus, 1758) (Diptera: Calliphoridae). Thus we want to shed some light on settlement behavior of scavenger flies. In bioassays with a decomposed mouse ( Mus musculus), mixtures of synthetic compounds and flies of several physiological states, we observed rates of attraction and found compound classes that attract the different physiological stages. We found that a protein-poor diet increased the attraction to a carcass, especially between the age of 3 and 7 days. 7-day old females were attracted to cyclic compounds when mated and after exposure to a protein-poor nutrition, whereas they responded to fatty acids when mated after exposure to a protein-enriched diet. Furthermore we found that only with a protein-rich diet did the gonadal development complete with mature eggs in the Xth stadium between seven and 10 days and an overlapping second cycle with eggs in the Vth stadium at day 10. [ABSTRACT FROM AUTHOR]

Mutations in SUCLA2, encoding the ß-subunit of succinyl-CoA synthetase of Krebs cycle, are one cause of mitochondrial DNA depletion syndrome. Patients have been reported to have severe progressive childhood-onset encephalomyopathy, and methylmalonic aciduria, often leading to death in childhood. We studied two families, with children manifesting with slowly progressive mitochondrial encephalomyopathy, hearing impairment and transient methylmalonic aciduria, without mtDNA depletion. The other family also showed dominant inheritance of bilateral retinoblastoma, which coexisted with mitochondrial encephalomyopathy in one patient. We found a variant in SUCLA2 leading to Asp333Gly change, homozygous in one patient and compound heterozygous in one. The latter patient also carried a deletion of 13q14 of the other allele, discovered with molecular karyotyping. The deletion spanned both SUCLA2 and RB1 gene regions, leading to manifestation of both mitochondrial disease and retinoblastoma. We made a homology model for human succinyl-CoA synthetase and used it for structure-function analysis of all reported pathogenic mutations in SUCLA2. On the basis of our model, all previously described mutations were predicted to result in decreased amounts of incorrectly assembled protein or disruption of ADP phosphorylation, explaining the severe early lethal manifestations. However, the Asp333Gly change was predicted to reduce the activity of the otherwise functional enzyme. On the basis of our findings, SUCLA2 mutations should be analyzed in patients with slowly progressive encephalomyopathy, even in the absence of methylmalonic aciduria or mitochondrial DNA depletion. In addition, an encephalomyopathy in a patient with retinoblastoma suggests mutations affecting SUCLA2. [ABSTRACT FROM AUTHOR]

Purpose: Given the bone tropism of prostate cancer, conventional imaging modalities poorly identify or quantify metastatic disease. Zr-huJ591 positron emission tomography (PET) imaging was performed in patients with metastatic prostate cancer to analyze and validate this as an imaging biomarker for metastatic disease. The purpose of this initial study was to assess safety, biodistribution, normal organ dosimetry, and optimal imaging time post-injection for lesion detection. Methods: Ten patients with metastatic prostate cancer received 5 mCi of Zr-huJ591. Four whole-body scans with multiple whole-body count rate measurements and serum activity concentration measurements were obtained in all patients. Biodistribution, clearance, and lesion uptake by Zr-huJ591 immuno-PET imaging was analyzed and dosimetry was estimated using MIRD techniques. Initial assessment of lesion targeting of Zr-huJ591 was done. Optimal time for imaging post-injection was determined. Results: The dose was well tolerated with mild chills and rigors seen in two patients. The clearance of Zr-huJ591 from serum was bi-exponential with biological half-lives of 7 ± 4.5 h (range 1.1-14 h) and 62 ± 13 h (range 51-89 h) for initial rapid and later slow phase. Whole-body biological clearance was 219 ± 48 h (range 153-317 h). The mean whole-body and liver residence time was 78.7 and 25.6 h, respectively. Dosimetric estimates to critical organs included liver 7.7 ± 1.5 cGy/mCi, renal cortex 3.5 ± 0.4 cGy/mCi, and bone marrow 1.2 ± 0.2 cGy/mCi. Optimal time for patient imaging after injection was 7 ± 1 days. Lesion targeting of bone or soft tissue was seen in all patients. Biopsies were performed in 8 patients for a total 12 lesions, all of which were histologically confirmed as metastatic prostate cancer. One biopsy-proven lesion was not positive on Zr-huJ591, while the remaining 11 lesions were Zr-huJ591 positive. Two biopsy-positive nodal lesions were noted only on Zr-huJ591 study, while the conventional imaging modality was negative. Conclusion: Zr-huJ591 PET imaging of prostate-specific membrane antigen expression is safe and shows good localization of disease in prostate cancer patients. Liver is the critical organ for dosimetry, and 7 ± 1 days is the optimal imaging time. A larger study is underway to determine lesion detection in an expanded cohort of patients with metastatic prostate cancer. [ABSTRACT FROM AUTHOR]

To identify perceived roles with regard to care for women with gestational diabetes mellitus (GDM) history and resources for improving care among women with a history of GDM from the perspective of obstetrician/gynecologists (OB/GYNs), certified nurse midwives (CNM), family practitioners, and internists. In 2010, a survey was sent to a random sample of OB/GYNs, CNM, family practitioners, and internists (n = 2,375) in Ohio to assess knowledge, attitudes, and postpartum practices regarding diabetes prevention for women with a history of GDM. A total of 904 practitioners completed the survey (46 %). Over 70 % of CNMs strongly agreed it is part of their job to help women with GDM history improve diet and increase exercise, compared with 60 % of family practitioners/internists and 55 % of OB/GYNs ( p < 0.001). More OB/GYNs and CNMs identified a need for more local nutrition specialists and patient education materials, compared with family practitioners/ internists. Between 60 and 70 % of OB/GYNs and CNMs reported lifestyle modification programs and corresponding reimbursement would better support them to provide improved care. Health care providers giving care to women with GDM history have varying perceptions of their roles, however, there was agreement on resources needed to improve care. [ABSTRACT FROM AUTHOR]

Infecting ducks with duck hepatitis B virus (DHBV) is widely accepted as a relevant model for studying aspects of human HBV infection. However, efficient and sensitive diagnostic methods for the various infection models are limited. In order to provide a more simple and convenient method for serologic diagnosis, we improved the production of recombinant DHBV viral capsid protein (core protein) and then used it to develop an indirect enzyme-linked immunosorbent assay (ELISA) for detecting anti-DHBc antibodies (DHBcAg ELISA) in DHBV-infected ducks. Given the positive/negative cut-off value, the maximum dilution of duck sera in which anti-DHBc antibodies could be detected was 1:12,800. In addition, the DHBcAg ELISA displayed no cross reactivity with duck antisera against duck circovirus (DuCV), duck plague virus (DPV), duck hepatitis virus (DHV), duck swollen head septicemia virus (DSHSV), avian influenza virus (AIV), Riemerella anatipestifer, Salmonella anatum, or Escherichia coli. Furthermore, the coefficients of variation (CVs) of inter-assay and intra-assay experiments were both below than 10 %. When compared to PCR for accuracy on clinical samples from cases of suspected DHBV infection, the DHBcAg showed 95.45 % coincidence with PCR. In conclusion, recombinant DHBc was readily produced and used to establish a simple DHBcAg ELISA that provided a highly specific and sensitive method for analysis of clinical samples. [ABSTRACT FROM AUTHOR]

We report a case of repeat hepatectomies for hepatic malignant lymphoma and hepatocellular carcinoma (HCC). A 75-year-old man with chronic hepatitis C underwent partial hepatectomy for a 25 mm hepatic tumor in S5. The histological diagnosis was diffuse large B-cell malignant lymphoma and as postoperative F-fluorodeoxyglucose-positron emission tomography showed no hot spots, the mass was presumed to be primary hepatic lymphoma. Thus, adjuvant systemic chemotherapy was given following the hepatectomy. Abdominal ultrasonography, done 12 months after the hepatectomy, showed a hepatic tumor in S6 and repeat partial hepatectomy was performed. This tumor was histologically diagnosed as HCC. [ABSTRACT FROM AUTHOR]

The ascomycetous fungus Monascus ruber is one of the most well-known species widely used to produce Monascus-fermentation products for natural food colorants and medicine. Our previous research on the Gα subunit Mga1 and the regulator of G protein signaling MrflbA indicated that heterotrimeric G protein signaling pathways were involved in aspects of growth, sporulation and secondary metabolite production in M. ruber. To better understand the G protein signaling pathways in this fungus, a Gβ subunit gene ( Mgb1) and a GΓ subunit gene ( Mgg1) were cloned and investigated in the current study. The predicted Mgb1 protein consisted of 353 amino acids and Mgg1 consisted of 94 amino acids, sharing marked similarity with Aspergillus Gβ and GΓ subunits, respectively. Targeted deletion (Δ) of Mgb1 or Mgg1 resulted in phenotypic alterations similar to those resulting from Δ Mga1, i.e., restricted vegetative growth, lowered asexual sporulation, impaired cleistothecial formation, and enhanced citrinin and pigment production. Moreover, deletion of Mgg1 suppressed the defects in asexual development and in biosynthesis of citrinin and pigment caused by the absence of MrflbA function. These results provide evidence that Mgb1 and Mgg1 form a functional GβΓ dimer and the dimer interacts with Mga1 to mediate signaling pathways, which are negatively controlled by MrflbA, for growth, reproduction and citrinin and pigment biosynthesis in M. ruber. [ABSTRACT FROM AUTHOR]