Spontaneous Chelation-Driven Reduction of the Neptunyl Cation in Aqueous Solution.

Octadentate hydroxypyridinone (HOPO) and catecholamide (CAM) siderophore analogues are known to be efficacious chelators of the actinide cations, and these ligands are also capable of facilitating both activation and reduction of actinyl species. Utilizing X-ray absorption near edge structure (XANES) and extended X-ray absorption fine structure (EXAFS) spectroscopies, as well as cyclic voltammetry measurements, herein, we elucidate chelation-based mechanisms for driving reactivity and initiating redox processes in a family of neptunyl-HOPO and CAM complexes. Based on the selected chelator, the ability to control the oxidation state of neptunium and the speed of reduction and concurrent oxo group activation was demonstrated. Most notably, reduction kinetics for the NpV O2 +/ /NpIV redox couple upon chelation by the ligands 3,4,3-LI(1,2-HOPO) and 3,4,3-LI(CAM)2 (1,2-HOPO)2 was observed to be faster than ever reported, and in fact quicker than we could measure using either X-ray absorption spectroscopy or electrochemical techniques

The Continuing Professional Development of School Psychologists in Georgia: A Comparison to National Practices and Preferences

The current study investigated Georgia school psychologists’ continuing professional development (CPD) practices and preferences for comparison to a national study of school psychology professional development by Armistead, Castillo, Curtis, Chappel, and Cunningham (2013). Utilizing the same instrument as Armistead et al., a survey was emailed to 442 members of the Georgia Association of School Psychologists (GASP). Ninety-five surveys were completed at a 21.5% response rate. Both Georgia school psychologists and national school psychologists reported receiving a median of approximately 40 hours of professional development in the previous year. Georgia school psychologists differed from the national sample with a higher percentage expressing satisfaction with the amount of professional development provided by their state professional association, with lower personal costs associated with CPD, and with greater participation in online professional development opportunities

Role of Sequence and Structure of the Hendra Fusion Protein Fusion Peptide in Membrane Fusion

Viral fusion proteins are intriguing molecular machines that undergo drastic conformational changes to facilitate virus-cell membrane fusion. During fusion a hydrophobic region of the protein, termed the fusion peptide (FP), is inserted into the target host cell membrane, with subsequent conformational changes culminating in membrane merger. Class I fusion proteins contain FPs between 20 and 30 amino acids in length that are highly conserved within viral families but not between. To examine the sequence dependence of the Hendra virus (HeV) fusion (F) protein FP, the first eight amino acids were mutated first as double, then single, alanine mutants. Mutation of highly conserved glycine residues resulted in inefficient F protein expression and processing, whereas substitution of valine residues resulted in hypofusogenic F proteins despite wild-type surface expression levels. Synthetic peptides corresponding to a portion of the HeV F FP were shown to adopt an α-helical secondary structure in dodecylphosphocholine micelles and small unilamellar vesicles using circular dichroism spectroscopy. Interestingly, peptides containing point mutations that promote lower levels of cell-cell fusion within the context of the whole F protein were less α-helical and induced less membrane disorder in model membranes. These data represent the first extensive structure-function relationship of any paramyxovirus FP and demonstrate that the HeV F FP and potentially other paramyxovirus FPs likely require an α-helical structure for efficient membrane disordering and fusion

Unfolding dynamics of proteins under applied force

Understanding the mechanisms of protein folding is a major challenge that is being addressed effectively by collaboration between researchers in the physical and life sciences. Recently, it has become possible to mechanically unfold proteins by pulling on their two termini using local force probes such as the atomic force microscope. Here, we present data from experiments in which synthetic protein polymers designed to mimic naturally occurring polyproteins have been mechanically unfolded. For many years protein folding dynamics have been studied using chemical denaturation, and we therefore firstly discuss our mechanical unfolding data in the context of such experiments and show that the two unfolding mechanisms are not the same, at least for the proteins studied here. We also report unexpected observations that indicate a history effect in the observed unfolding forces of polymeric proteins and explain this in terms of the changing number of domains remaining to unfold and the increasing compliance of the lengthening unstructured polypeptide chain produced each time a domain unfolds

Effector memory differentiation increases detection of replication-competent HIV-l in resting CD4+ T cells from virally suppressed individuals.

Studies have demonstrated that intensive ART alone is not capable of eradicating HIV-1, as the virus rebounds within a few weeks upon treatment interruption. Viral rebound may be induced from several cellular subsets; however, the majority of proviral DNA has been found in antigen experienced resting CD4+ T cells. To achieve a cure for HIV-1, eradication strategies depend upon both understanding mechanisms that drive HIV-1 persistence as well as sensitive assays to measure the frequency of infected cells after therapeutic interventions. Assays such as the quantitative viral outgrowth assay (QVOA) measure HIV-1 persistence during ART by ex vivo activation of resting CD4+ T cells to induce latency reversal; however, recent studies have shown that only a fraction of replication-competent viruses are inducible by primary mitogen stimulation. Previous studies have shown a correlation between the acquisition of effector memory phenotype and HIV-1 latency reversal in quiescent CD4+ T cell subsets that harbor the reservoir. Here, we apply our mechanistic understanding that differentiation into effector memory CD4+ T cells more effectively promotes HIV-1 latency reversal to significantly improve proviral measurements in the QVOA, termed differentiation QVOA (dQVOA), which reveals a significantly higher frequency of the inducible HIV-1 replication-competent reservoir in resting CD4+ T cells

Extracorporeal Membrane Oxygenation for COVID-19-Associated Multisystem Inflammatory Syndrome in a 5-year-old

Severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) is associated with multisystem inflammatory syndrome in children (MIS-C) that ranges from mild symptoms to cardiopulmonary collapse. A 5-year-old girl presented with shock and a rapid decline in left ventricular function requiring intubation. SARS-CoV-2 was diagnosed by viral Polymerase Chain Reaction (PCR), and she received remdesivir and COVID-19 convalescent plasma. Initial echocardiogram (ECHO) demonstrated low normal left ventricular function and mild left anterior descending coronary artery dilation. She remained hypotensive, despite high-dose epinephrine and norepinephrine infusions as well as stress-dose hydrocortisone. Admission SARS-CoV-2 IgG assay was positive, meeting the criteria for MIS-C. An ECHO 9 hours after admission demonstrated a severe decline in left ventricular function. Due to severe cardiogenic shock, she was cannulated for venoarterial extracorporeal support (ECMO). During her ECMO course, she was treated with remdesivir, intravenous methylprednisolone, intravenous immunoglobulin, and anakinra. She was decannulated on ECMO day 7, extubated the following day, and discharged home 2 weeks later without respiratory or cardiac support. The use of ECMO for cardiopulmonary support for pediatric patients with MIS-C is feasible and should be considered early as part of the treatment algorithm for patients with severe cardiopulmonary dysfunction

Farmers Markets and the Local Food System: The Case of Gettysburg, Pennsylvania

In order to examine and obtain a better understanding of the local food system within Adams County, Pennsylvania, this study explores the characteristics and perspectives of the customers and vendors at the farmers markets in Gettysburg, Pennsylvania. Survey findings from the Gettysburg Farmers Market and the three Adams County Farmers Markets include customer demographic information, perspectives and shopping behavior as well as vendor product information, farm size and location and preference for market management. Introductory background information on the Farm Bill and the influence of agricultural practices on the environment, human health and nutrition and the relationship between farmers markets and the local economy are offered in order to emphasize the value of a well-managed local food system. Conclusions provide evidence that lower income and lower education levels are not sufficiently represented at all the markets and food stamp programs are being underutilized. This study suggests employing additional marketing to target underrepresented demographic groups, public transportation to potentially inaccessible market locations and increased advertisement and encouragement of food stamp programs at all markets in order to expand the customer base and increase access to healthy, local foods for less advantaged citizens. The results from this study are intended to offer evidence that will promote and facilitate market management, strengthen customer/vendor relationships and encourage better ties between the local community and local food systems at the farmers markets within Gettysburg in Adams County, Pennsylvania

Increased attenuation but decreased immunogenicity by deletion of multiple vaccinia virus immunomodulators.

Vaccinia virus (VACV)-derived vectors are popular candidates for vaccination against diseases such as HIV-1, malaria and tuberculosis. However, their genomes encode a multitude of proteins with immunomodulatory functions, several of which reduce the immunogenicity of these vectors. Hitherto only limited studies have investigated whether the removal of these immunomodulatory genes in combination can increase vaccine efficacy further. To this end we constructed viruses based on VACV strain Western Reserve (WR) lacking up to three intracellular innate immunomodulators (N1, C6 and K7). These genes were selected because the encoded proteins had known functions in innate immunity and the deletion of each gene individually had caused a decrease in virus virulence in the murine intranasal and intradermal models of infection and an increase in immunogenicity. Data presented here demonstrate that deletion of two, or three of these genes in combination attenuated the virus further in an incremental manner. However, when vaccinated mice were challenged with VACV WR the double and triple gene deletion viruses provided weaker protection against challenge. This was accompanied by inferior memory CD8(+) T cell responses and lower neutralising antibody titres. This study indicates that, at least for the three genes studied in the context of VACV WR, the single gene deletion viruses are the best vaccine vectors, and that increased attenuation induced by deletion of additional genes decreased immunogenicity. These data highlight the fine balance and complex relationship between viral attenuation and immunogenicity. Given that the proteins encoded by the genes examined in this study are known to affect specific aspects of innate immunity, the set of viruses constructed here are interesting tools to probe the role of the innate immune response in influencing immune memory and vaccine efficacy.Medical Research Council, Wellcome TrustThis is the final version of the article. It first appeared from Elsevier via http://dx.doi.org/10.1016/j.vaccine.2016.08.00