A participatory epidemiological and One Health approach to explore the community’s capacity to detect emerging zoonoses and surveillance network opportunities in the forest region of Guinea

The Ebola virus disease epidemic that threatened West Africa between 2013 and 2016 was of unprecedented health magnitude. After this health crisis, studies highlighted the need to introduce community-based surveillance systems and to adopt a One Health approach. This study aimed to provide preparatory insights for the definition of a community-based surveillance system for emerging zoonoses such as viral hemorrhagic fevers in Guinea. The objective was to explore the disease detection capacity and the surveillance network opportunities at the community level in two pilot areas in the forest region of Guinea, where the epidemic emerged. Based on a participatory epidemiological and One Health approach, we conducted Focus Group Discussions with human, animal and ecosystem health actors. We used a range of participatory tools, included semi-structured interviews, ranking, scoring and flow diagram, to estimate the local knowledge and perception of diseases and clinical signs and to investigate the existing health information exchange network and its related strengths and weaknesses. The results showed that there is heterogeneity in knowledge of diseases and perception of the clinical signs among actors and that there are preferred and more effective health communication channels opportunities. This preparatory study suggests that it is necessary to adapt the case definitions and the health communication channels to the different actors who can play a role in a future community-based surveillance system and provides recommendations for future surveillance activities to be carried out in West Africa.     

MAPK Signaling Drives Inflammation in LPS-Stimulated Cardiomyocytes: The Route of Crosstalk to G-Protein-Coupled Receptors

Profound cardiovascular dysfunction is an important cause of mortality from septic shock. The molecular underpinnings of cardiac dysfunction during the inflammatory surge of early sepsis are not fully understood. MAPKs are important signal transducers mediating inflammation whereas G-protein signaling pathways modulate the cardiac response to stress. Using H9c2 cardiomyocytes, we investigated the interaction of MAPK and G-protein signaling in a sepsis model to test the hypothesis that the cardiomyocyte inflammatory response is controlled by MAPKs via G-protein-mediated events. We found that LPS stimulated proinflammatory cytokine production was markedly exacerbated by siRNA knockdown of the MAPK negative regulator Mkp-1. Cytokine production was blunted when cells were treated with p38 inhibitor. Two important cellular signaling molecules typically regulated by G-protein-coupled receptors, cAMP and PKC activity, were also stimulated by LPS and inflammatory cytokines TNF-α and IL-6, through a process regulated by Mkp-1 and p38. Interestingly, neutralizing antibodies against Gα_s and Gα_q blocked the increase in cellular cAMP and PKC activation, respectively, in response to inflammatory stimuli, indicating a critical role of G-protein coupled receptors in this process. LPS stimulation increased COX-2 in H9c2 cells, which also express prostaglandin receptors. Blockade of G-protein-coupled EP4 prostaglandin receptor by AH 23848 prevented LPS-induced cAMP increase. These data implicate MAPKs and G-proteins in the cardiomyocyte inflammatory response to LPS as well as crosstalk via COX-2-generated PGE₂. These data add to our understanding of the pathogenesis of septic shock and have the potential to guide the selection of future therapeutics.     

Product analysis of RNA generated de novo by Qβ replicase

Q_β replicase synthesizes self-replicating RNA in the absence of exogenous template after a certain lag time (“template-free synthesis”). The products of the template-free RNA synthesis have been investigated by gel electrophoresis and fingerprinting techniques. It has been found that a multitude of self-replicating RNA species appears in the early phases of reaction with variable lengths and sequences. Template-free synthesis in different samples under completely identical conditions yields RNA products with very different and unrelated fingerprints. The early products rapidly undergo an evolution process that alters the phenotypic properties of the self-replicating RNA, and leads to a concomitant increase of replication efficiency. Fingerprints and electrophoretic mobilities of the self-replicating RNA species are altered discontinuously during the evolution process. The evolution process ends with the selection of optimized self-replicating RNA species, whose phenotypes are conserved even after many serial transfers. Some optimized RNA species and midivariant RNA apparently have related sequences, since they contain many identical spots in their fingerprints. The properties of the RNA species produced by template-free synthesis match those of 6 S RNA found in Q_β-infected Escherichia coli cells. The results are in full agreement with the finding of Sumper & Luce (1975), who have presented evidence that Q_β replicase synthesized RNA de novo in the absence of exogenous template.     

Split-thickness skin grafting of the myelomeningocele defect: a subset at risk for late ulceration

The appropriate method and timing of the management of the myelomeningocele defect have prompted considerable discussion. Use of split-thickness skin grafts acutely has accomplished wound closure with low morbidity and mortality. This study was designed to address the question of long-term suitability of the technique of split-thickness skin grafting of the myelomeningocele patient. The incidence of late and/or severe skin ulceration and the presence of gibbus deformity were correlated with the method of skin closure. Long-term follow-up revealed a higher incidence of chronic skin ulceration in the split-thickness skin graft group as compared with the primary closure group. All skin breakdowns appeared in the presence of a gibbus deformity, and gibbus deformity was more prevalent in the split-thickness skin graft group. The incidence of skin ulceration and gibbus deformity was site-dependent. A thoracic or thoracolumbar myelomeningocele repair with split-thickness skin graft was significantly more likely to be complicated by skin problems than the defect in the lumbar, lumbosacral, or sacral region. This relationship was secondary to the frequency of gibbus deformity in the more cephalad defects than defects caudad. A treatment plan is outlined that is based on the primary variable of the location of the myelomeningocele and secondarily by defect size.     

Noncovalent binding of some new lipophilic gadolinium DTPA complexes to human serum albumin. A structure-affinity relationship

Four Gadolinium?DTPA complexes bearing long lipophilic alkyl chains were synthesized: two bis[amide] and two 4‐substituted derivatives. In two of them (one bis[amide] and one 4‐substituted), the alkyl chain ends with a carboxylate function. Their relaxometric properties in H₂O show the self aggregation of Gd?DTPA‐BdodecylAmide, the better stability of the 4‐substituted derivatives vs. Zn transmetallation, and the very good stability of Gd?(4‐(carboxyundecylisothiourea‐Bz)DTPA). Amongst the four compounds, only Gd?(4‐(carboxyundecylisothiourea‐Bz)DTPA) shows a strong interaction with human serum albumin (HSA) as demonstrated by proton relaxometry and ESI mass spectrometry. These data highlight the importance of the negative charge on the alkyl chain in the context of the interaction of Gd?(4‐substituted DTPA) derivatives with HSA.     

The maize Ab10 meiotic drive system maps to supernumerary sequences in a large complex haplotype

The meiotic drive system on maize abnormal chromosome 10 (Ab10) is contained within a terminal domain of chromatin that extends the long arm of Ab10 to approximately 1.3 times the size of normal chromosome 10L. Ab10 type I (Ab10-I) does not recombine with normal chromosome 10 (N10) over an approximately 32-cM terminal region of the long arm. Comparative RFLP mapping demonstrates that multiple independent rearrangements are responsible for the current organization of Ab10-I, including a set of nested inversions and at least one long supernumerary segment at the end of the chromosome. Four major meiotic drive functions, i.e., the recombination effect, smd3, 180-bp neocentromere activity, and the distal tip function, all map to the distal supernumerary segment. TR-1-mediated neocentromere activity (the fifth known drive function) is nonessential in the type II variant of Ab10 and maps to a central region that may include a second supernumerary insertion. Both neocentromere activity and the recombination effect behave as dominant gain-of-function mutations, consistent with the view that meiotic drive involves new or alien gene products. These and other data suggest that the Ab10 meiotic drive system was initially acquired from a related species and that a complex haplotype evolved around it.     

eIF4E is a central node of an RNA regulon that governs cellular proliferation

This study demonstrates that the eukaryotic translation initiation factor eIF4E is a critical node in an RNA regulon that impacts nearly every stage of cell cycle progression. Specifically, eIF4E coordinately promotes the messenger RNA (mRNA) export of several genes involved in the cell cycle. A common feature of these mRNAs is a structurally conserved, approximately 50-nucleotide element in the 3' untranslated region denoted as an eIF4E sensitivity element. This element is sufficient for localization of capped mRNAs to eIF4E nuclear bodies, formation of eIF4E-specific ribonucleoproteins in the nucleus, and eIF4E-dependent mRNA export. The roles of eIF4E in translation and mRNA export are distinct, as they rely on different mRNA elements. Furthermore, eIF4E-dependent mRNA export is independent of ongoing RNA or protein synthesis. Unlike the NXF1-mediated export of bulk mRNAs, eIF4E-dependent mRNA export is CRM1 dependent. Finally, the growth-suppressive promyelocytic leukemia protein (PML) inhibits this RNA regulon. These data provide novel perspectives into the proliferative and oncogenic properties of eIF4E.