South-to-south mentoring as a vehicle for implementing sustainable health security in Africa.

BACKGROUND: While sustainability has become a universal precept in the development of global health security systems, supporting policies often lack mechanisms to drive policies into regular practice. 'On-paper' norms and regulations are to a great extent upheld by frontline workers who often lack the opportunity to communicate their first-hand experiences to decisionmakers; their role is an often overlooked, yet crucial, aspect of a sustainable global health security landscape. Initiatives and programs developing transdisciplinary professional skills support the increased bidirectional dialogue between these frontline workers and key policy- and decisionmakers which may sustainably narrow the gap between global health security policy design and implementation. METHODS: The International Federation of Biosafety Associations' (IFBA) Global Mentorship Program recruits biosafety and biosecurity champions across Africa to provide local peer mentorship to developing professionals in their geographic region. Mentors and mentees complete structured one year program cycles, where they are provided with written overviews of monthly discussion topics, and attend optional virtual interactive activities. Feedback from African participants of the 2019-2020 program cycle was collected using a virtual Exit Survey, where aspects of program impact and structure were assessed. RESULTS: Following its initial call for applications, the IFBA Global Mentorship Program received considerable interest from professionals across the African continent, particularly in East and North Africa. The pilot program cycle matched a total of 62 individuals from an array of professional disciplines across several regions, 40 of which were located on the African continent. The resulting mentorship pairs shared knowledge, skills, and experiences towards translating policy objectives to action on the front lines. Mentorship pairs embraced multidisciplinary approaches to harmonize health security strategies across the human and animal health sectors. South-to-South mentorship therefore provided mentees with locally relevant support critical to translation of best technical practices to local capacity and work. CONCLUSION: The IFBA's South-to-South Global Mentorship Program has demonstrated its ability to form crucial links between frontline biosafety professionals, laboratory workers, and policy- and decision-makers across several implicated sectors. By supporting regionally relevant peer mentorship programs, the gap between health security policy development and implementation may be narrowed.

Qualitative Behavioral Assessment in Juvenile Farmed Atlantic Salmon (Salmo salar): Potential for On-Farm Welfare Assessment.

There is a growing scientific and legislative consensus that fish are sentient, and therefore have the capacity to experience pain and suffering. The assessment of the welfare of farmed fish is challenging due to the aquatic environment and the number of animals housed together. However, with increasing global production and intensification of aquaculture comes greater impetus for developing effective tools which are suitable for the aquatic environment to assess the emotional experience and welfare of farmed fish. This study therefore aimed to investigate the use of Qualitative Behavioral Assessment (QBA), originally developed for terrestrial farmed animals, in farmed salmon and evaluate its potential for use as a welfare monitoring tool. QBA is a "whole animal" approach based on the description and quantification of the expressive qualities of an animal's dynamic style of behaving, using descriptors such as relaxed, agitated, lethargic, or confident. A list of 20 qualitative descriptors was generated by fish farmers after viewing video-footage showing behavior expressions representative of the full repertoire of salmon in this context. A separate, non-experienced group of 10 observers subsequently watched 25 video clips of farmed salmon, and scored the 20 descriptors for each clip using a Visual Analog Scale (VAS). To assess intra-observer reliability each observer viewed the same 25 video clips twice, in two sessions 10 days apart, with the second clip set presented in a different order. The observers were unaware that the two sets of video clips were identical. Data were analyzed using Principal Component (PC) Analysis (correlation matrix, no rotation), revealing four dimensions that together explained 79% of the variation between video clips, with PC1 (Tense/anxious/skittish-Calm/mellow/relaxed) explaining the greatest percentage of variation (56%). PC1 was the only dimension to show acceptable inter- and intra-observer reliability, and mean PC1 scores correlated significantly to durations of slow and erratic physical movements measured for the same 25 video clips. Further refinements to the methodology may be necessary, but this study is the first to provide evidence for the potential of Qualitative Behavioral Assessment to serve as a time-efficient welfare assessment tool for juvenile salmon under farmed conditions.

Accelerating Action in Global Health Security: Global Biosecurity Dialogue as a Model for Advancing the Global Health Security Agenda.

Biosecurity and biosafety measures are designed to mitigate intentional and accidental biological risks that pose potentially catastrophic consequences to a country's health system, security, and political and economic stability. Unfortunately, biosecurity and biosafety are often under-prioritized nationally, regionally, and globally. Security leaders often deemphasize accidental and deliberate biological threats relative to other challenges to peace and security. Given emerging biological risks, including those associated with rapid technological advances and terrorist and state interest in weapons of mass destruction, biosecurity deserves stronger emphasis in health and security fora. The Global Biosecurity Dialogue (GBD) was initiated to align national and regional donor initiatives toward a common set of measurable targets. The GBD was launched by the Nuclear Threat Initiative (NTI), with support from Global Affairs Canada's Weapons Threat Reduction Program and the Open Philanthropy Project, and in coordination with the government of The Netherlands as the 2018-19 Chair of the Global Health Security Agenda (GHSA) Action Package Prevent-3 (APP3) on Biosafety and Biosecurity. The GBD provides a multisectoral forum for sharing models, enabling new actions to achieve biosecurity-related targets, and promoting biosecurity as an integral component of health security. The GBD has contributed to new national and continent-wide actions, including the African Union and Africa Centres for Disease Control and Prevention's new regional Initiative to Strengthen Biosafety and Biosecurity in Africa. Here we present the GBD as a model for catalyzing action within APP3. We describe how the benefits of this approach could expand to other GHSA Action Packages and international health security initiatives.

RhoA regulation of NF-kappaB activation is mediated by COX-2-dependent feedback inhibition of IKK in kidney epithelial cells.

Numerous studies have demonstrated a central role of renal tubular epithelial cells in the etiology of kidney injury and disease through the elaboration of inflammatory mediators. However, little is known about the cellular signaling mechanisms involved in this process. In this study we employed normal rat kidney epithelial (NRK52E) cells to identify a novel LPS-induced signaling pathway in which RhoA-mediated AP-1 activity promotes expression of cyclooxygenase-2 (COX-2) with consequent feedback inhibition of NF-kappaB activation through IKKbeta. Inhibition of RhoA signaling using either the RhoA kinase inhibitor Y-27632 or a dominant negative mutant of RhoA (RhoA-DN) dramatically extended the duration of p65-DNA binding, IkappaBalpha phosphorylation, and IKKbeta activity following LPS treatment. Prolongation of events associated with NF-kappaB activation was also observed in cells pretreated and/or cotransfected with the JNK inhibitor SP600125 or deletion mutants of MEKK1 (MEKK1-KD) or Jun (Jun-DN). Conversely, constitutive expression of RhoA prevented NF-kappaB activation by LPS, and this effect was reversed by cotransfection with MEKK1-KD. In addition, we found that the RhoA/AP-1 signaling axis plays a necessary role in COX-2 expression by LPS and that this effect is independent of NF-kappaB activation. Moreover, inhibition of COX-2 activity results in persistent p65-DNA binding, IkappaBalpha phosphorylation, and IKKbeta activity, similar to that observed after prevention of RhoA/AP-1 axis signaling. These findings suggest that COX-2 links the RhoA/AP-1 signaling cascade to NF-kappaB activation, thereby defining a novel integrated model for regulation of the inflammatory response of kidney epithelial cells to LPS and potentially other external stimuli.

Electrical and optical measurements on the first SCUBA-2 prototype 1280 pixel submillimeter superconducting bolometer array.

SCUBA-2 is a submillimeter camera being built for the James Clerk Maxwell Telescope in Hawaii. Bringing CCD style imaging to the submillimeter for the first time, with over 10000 pixels, it will provide a revolutionary improvement in sensitivity and mapping speed. We present results of the first tests on a prototype 1280 pixel SCUBA-2 subarray; the full instrument will be made up of eight such subarrays. The array is made up of transition edge sensor (TES) detectors, with Mo/Cu bilayers as the sensing element. To keep the number of wires reasonable, a multiplexed readout is used. Unlike previous TES arrays, an in-focal plane multiplexer configuration is used, in which the multiplexing elements are located beneath each pixel. To achieve the required performance, the detectors are operated at a temperature of approximately 120 mK. We describe the results of a basic electrical and optical characterization of the array, demonstrating that it is fully operational. Noise measurements were made on several pixels and gave a noise equivalent power below 2.5 x 10(-17) W HZ(-0.5), within the requirements for SCUBA-2. The construction of the testbed used to carry out these measurements is also described.

Nuclear factor kappaB activity determines the sensitivity of kidney epithelial cells to apoptosis: implications for mercury-induced renal failure.

Nuclear factor kappa B (NF-kappaB) is a thiol-dependent transcriptional factor that promotes cell survival and protects cells from apoptotic stimuli. Numerous studies have demonstrated increased sensitivity to apoptosis associated with inhibition of NF-kappaB activation in various cell types. We have previously demonstrated that mercuric ion (Hg(2+)), one of the strongest thiol-binding agents known, impairs NF-kappaB activation and DNA binding at low microM concentrations in kidney epithelial cells. In the present studies we investigated the hypothesis that inhibition of NF-kappaB activation by Hg(2+) and other selective NF-kappaB inhibitors would increase the sensitivity of kidney epithelial (NRK52E) cells to apoptogenic agents to which these cells are normally resistant. Fewer than 10% of untreated cells in culture were found to be apoptotic when evaluated by DNA fragmentation (TUNEL) assay. Treatment of cells with Hg(2+) in concentrations up to 5 microM or with tumor necrosis factor-alpha (TNF) (300 units/ml) did not significantly increase the proportion of apoptotic cells, compared with untreated controls. However, when TNF was given following Hg(2+) pretreatment (0.5 to 5 microM for 30 min), the proportion of cells undergoing apoptosis increased by 2- to 6-fold over that seen in untreated controls. Kidney cells pretreated with specific NF-kappaB inhibitors (Bay11-7082 or SN50) prior to TNF also showed a significant increase in apoptosis. Increased sensitivity to apoptotic cell death following these treatments was significantly attenuated in cells transfected with a p65 expression vector. In studies in vivo, rats pretreated by intraperitoneal injection with Hg(2+) (0.75 mg/kg) 18 h prior to administration of bacterial lipopolysaccharide (LPS) (10 mg/kg) displayed impaired NF-kappaB activation and an increased mitochondrial cytochrome c release in kidney cortical cells. These findings are consistent with the view that prevention of NF-kappaB activity in vitro or in vivo enhances the sensitivity of kidney cells to apoptotic stimuli to which these cells are otherwise resistant. Since apoptosis is known to play a seminal role in the pathogenesis of renal failure caused by toxicant injury to tubular cells, the present findings suggest that inhibition of NF-kappaB activity may define a molecular mechanism underlying the pathogenesis of Hg(2+) toxicity in kidney cells.

Attenuation of nuclear factor kappa B (NF-kappaB) promotes apoptosis of kidney epithelial cells: a potential mechanism of mercury-induced nephrotoxicity.

Nuclear factor kappa B (NF-kappaB), a pleiotropic transcriptional factor that promotes cell survival and protects cells from apoptosis, requires reduced thiols at critical steps in its activation pathway. Mercuric ion (Hg(2+)), one of the strongest thiol-binding agents known, impairs NF-kappaB activation and transcriptional activity in normal rat kidney epithelial (NRK52E) cells at concentrations as low as 0.5 microM by binding to specific reduced thiol moieties in the NF-kappaB activation pathway. We hypothesized that prevention of NF-kappaB activation by Hg(2+) will increase the sensitivity of kidney cells to the apoptosis-inducing effects of other toxicants to which these cells are otherwise resistant by virtue of their NF-kappaB-activating capacity. Fewer than 5% of untreated kidney cells in culture (70-90% confluent) were found to be apoptotic when evaluated by DNA fragmentation (terminal deoxynucleotide transferase-mediated dUTP nick-end labeling) or flow cytometric DNA profile analyses. Hg(2+) (5 microM) treatment for 24 hr increased this proportion by 1.5- to 2-fold. Neither lipopolysaccharide (LPS) (1 microg/mL) nor tumor necrosis factor-alpha (TNF-alpha; 300 U/mL), both potent activators of NF-kappaB in kidney cells, significantly altered the proportion of apoptotic cells, compared with untreated controls, when applied without Hg(2+) pretreatment. However, when LPS or TNF-alpha was administered after Hg(2+) pretreatment (5 microM for 30 min), the proportion of cells undergoing apoptosis 22 hr later increased by 4- to 6-fold compared with untreated controls. In contrast, Hg(2+) pretreatment did not increase the amount of apoptosis caused by apoptosis-inducing agents that do not activate NF-kappaB (staurosporine, Fas ligand). These findings suggest that Hg(2+) enhances the sensitivity of kidney cells to apoptotic stimuli as a consequence of inhibition of NF-kappaB activity. Because apoptosis is known to play a key role in the pathogenesis of renal failure resulting from toxicant injury to proximal tubular cells, promotion of apoptosis via inhibition of NF-kappaB activity may define a novel molecular mechanism by which Hg(2+) toxicity is initiated in kidney cells.