The roles of phosphatidylserine and phosphatidylethanolamine in Candida albicans cell wall maintenance and mitochondrial function

Enzymes involved in phospholipid biosynthesis have been suggested as possible drug targets to treat Candida albicans infections because several key enzymes, such as phosphatidylserine synthase, differ from those of the human host.We have found that phosphatidylserine synthase of C. albicans is required for virulence in a mouse model of systemic Candida infection.In addition, the C. albicans phosphatidylserine synthase mutant (cho1∆/∆) has no detectable phosphatidylserine and loss of phosphatidylserine causes alterations in the fungal cell wall. The cho1∆/∆ mutants’ cell wall defects include altered calcofluor white staining, resistance to the cell wall perturbing drug Caspofungin, and an altered physical appearance by transmission electron microscopy..We are using lipidomic analysis and transcriptomics of phosphatidylserine and phosphatidylethanolamine biosynthesis mutants to understand the role that phosphatidylserine and phosphatidylethanolamine play in controlling the cell wall in C. albicans.The elucidation of downstream effects of disruption of pathways involved in biosynthesis of phospholipids in C. albicans may validate these phospholipid biosynthesis enzymes as plausible anti-fungal drug targets. The role of phosphatidylserine and phosphatidylethanolamine in the maintenance of the fungal cell wall will also be of interest in determining how phospholipids impact signaling pathways and affect cell wall composition and architecture

White blood cell count and C-reactive protein together remain useful for diagnosis and staging of acute appendicitis in children

Background. Acute appendicitis (AA) is the most common acute surgical condition of the abdomen, and the most commonly misdiagnosed.Objective. To analyse the white blood cell count (WBCC) and C-reactive protein (CRP) contribution to the diagnosis of AA in children.Methods. This was a retrospective study of 943 consecutive patients operated on with the preoperative diagnosis of AA, in whom preoperative WBCC and CRP had both been measured. Postoperatively, the patients were divided into three groups: normal appendix (no AA), simple AA and complicated AA.Results. Of the 943 patients, 616 (65.3%) had simple AA. The mean (standard deviation (SD)) age for this group was 9.8 (3.2) years (p<0.01 v. complicated AA), the mean WBCC was 16.5 (5.0) × 109/L (p<0.01 v. complicated AA and no AA), and the mean CRP level was 304.8 (409.5) nmol/L (p<0.01 v. complicated AA). The mean age of the patients with complicated AA (283/943, 30.0%) was 7.9 (3.7) years, the mean WBCC was 17.7 (6.2) × 109/L (p<0.01 v. no AA) and the mean CRP level was 1 076.2 (923.8) nmol/L (p<0.01 v. no AA). The mean age of the patients with no AA (44/943, 4.7%) was 8.8 (3.2) years, the mean WBCC was 13.1 (5.3) × 109/L and the mean CRP was 361.9 (447.6) nmol/L. The WBCC was normal in 113/899 patients with appendicitis (12.6%) and CRP in 139 (15.5%). Both the WBCC and CRP were normal in 17 patients with appendicitis (1.9%). The best receiver operating characteristic (ROC) curve was obtained for WBCC when comparing all AA with no AA: cut-off point 15.0 × 109/L, sensitivity 65%, specificity 68%, area under the curve 0.70. The best ROC curve for CRP was obtained when comparing simple AA with complicated AA: cut-off point 361.9 nmol/L, sensitivity 74%, specificity 74%, area under the curve 0.81.Conclusions. The WBCC is helpful in diagnosing simple AA and CRP in diagnosing complicated AA. If both are normal, AA is very unlikely. Together the WBCC and CRP are useful tools in diagnosing and staging AA

Co-construcción en proyectos de generación distribuida con energía solar: participación de la comunidad en el proyecto Ayllu Solar

The level of participation of communities in distributed generation projects is a fundamental challenge for energy transition processes. Based on the experience of the Ayllu Solar project in the implementation of the co-construction methodology, this article debate on the participation of the communities in the development of energy projects, identifying learning and challenges. In this context, it is emphasized that for the success of the participatory processes it is necessary to have a thorough diagnosis of the territory; develop a proposal with sociocultural relevance; establish clear rules for the operation of work teams; work with organizations previously constituted, among others key aspects. In turn, it was possible to identify four types of barriers for the implementation of the Methodology in the territory: temporal, territorial, educational and sociocultural. Finally. two critical aspects were identified for the development of projects of this type: the tension caused by the existence of several understandings in the multidisciplinary teams on the scope of local participation, on the other hand, the contradictions and difficulties marked by the distrust generated by projects that are promoted local development, but based on the development of extractive industry. Both aspects pose great challenges for the participation and sustainability of this type of projects.El nivel participativo de las comunidades en proyectos de generación distribuida es un desafío fundamental para los procesos de transición energética. A partir de la experiencia del proyecto Ayllu Solar en la implementación de la metodología de co-construcción, el presente artículo reflexiona sobre la participación de las comunidades en el desarrollo de proyectos energéticos, identificando aprendizajes y desafíos. Así, se destaca que para el éxito de los procesos participativos es necesario contar con un diagnóstico acabado del territorio; desarrollar una propuesta con pertinencia sociocultural; establecer reglas claras para el funcionamiento de los equipos de trabajo; trabajar con líderes y organizaciones constituidas, entre otros aspectos. A su vez, fue posible reconocer cuatro tipos de barreras para la implementación de la metodología en el territorio: temporal, territorial, educacional y sociocultural. Se identifican dos aspectos críticos para el desarrollo de proyectos de este tipo: la tensión causada por la existencia de diversos entendimientos en los equipos multidisciplinarios sobre el alcance de la participación local, y las contradicciones y dificultades marcadas por la desconfianza que generan proyectos que promueven el desarrollo local, pero reciben financiamiento desde compañías basadas en la industria extractiva. Ambos aspectos plantean grandes desafíos para la participación y sustentabilidad de este tipo de proyectos

Congenital diaphragmatic hernia and retinoids: searching for an etiology

Congenital diaphragmatic hernia (CDH) is a major life-threatening cause of respiratory failure in the newborn. Recent data reveal the role of a retinoid-signaling pathway disruption in the pathogenesis of CDH. We describe the epidemiology and pathophysiology of human CDH, the metabolism of retinoids and the implications of retinoids in the development of the diaphragm and lung. Finally, we describe the existing evidence of a disruption of the retinoid-signaling pathway in CDH

Conditional deletion of WT1 in the septum transversum mesenchyme causes congenital diaphragmatic hernia in mice

Congenital diaphragmatic hernia (CDH) is a severe birth defect. Wt1-null mouse embryos develop CDH but the mechanisms regulated by WT1 are unknown. We have generated a murine model with conditional deletion of WT1 in the lateral plate mesoderm, using the G2 enhancer of the Gata4 gene as a driver. 80% of G2-Gata4Cre;Wt1fl/fl embryos developed typical Bochdalek-type CDH. We show that the posthepatic mesenchymal plate coelomic epithelium gives rise to a mesenchyme that populates the pleuroperitoneal folds isolating the pleural cavities before the migration of the somitic myoblasts. This process fails when Wt1 is deleted from this area. Mutant embryos show Raldh2 downregulation in the lateral mesoderm, but not in the intermediate mesoderm. The mutant phenotype was partially rescued by retinoic acid treatment of the pregnant females. Replacement of intermediate by lateral mesoderm recapitulates the evolutionary origin of the diaphragm in mammals. CDH might thus be viewed as an evolutionary atavismEspaña, Ministerio de Economía BFU2014- 52299-PJunta de Andalucía P11-CTS-0756

Lower NPAS3 expression during the later stages of abnormal lung development in rat congenital diaphragmatic hernia

Purpose Congenital diaphragmatic hernia (CDH) is characterized by a developmental defect in the diaphragm, pulmonary hypoplasia and pulmonary hypertension. NPAS3 is a PAS domain transcription factor regulating Drosophila tracheogenesis. NPAS3 null mice develop pulmonary hypoplasia in utero and die after birth due to respiratory failure. We aimed to evaluate NPAS3 expres- sion during normal and abnormal lung development due to CDH. Methods CDH was induced by administering 100 mg/ml nitrofen to time-pregnant dams on embryonic day (E) 9 of gestation. Lungs were isolated on E15, E18 and E21 and NPAS3 localization was determined by immunohisto- chemistry and quantified using Western blotting. Results We found that only E21 hypoplastic CDH lungs have reduced expression of NPAS3 in the terminal sac- cules. Western blotting confirmed the down-regulation of NPAS3 protein in the nitrofen-induced hypoplastic lungs. Conclusions We demonstrate for the first time that ni- trofen-induced hypoplastic CDH lungs have reduced NPAS3 expression in the terminal saccules during the later stages of abnormal lung development. Our findings suggest that NPAS3 is associated with pulmonary hypoplasia in CDH.Supported by the Children’s Hospital Research Institute of Manitoba; RK is the recipient of a Career Enhancement Award from the Canadian Child Health Clinician Scientist Program and a New Investigator Salary Award from the Canadian Institutes of Health Research, Manitoba Lung Association and the Children’s Hospital Research Institute

Hereditary renal adysplasia, pulmonary hypoplasia and Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome: a case report

<p>Abstract</p> <p>Background</p> <p>Hereditary renal adysplasia is an autosomal dominant trait with incomplete penetrance and variable expression that is usually associated with malformative combinations (including Müllerian anomalies) affecting different mesodermal organs such as the heart, lung, and urogenital system.</p> <p>Case report</p> <p>A case showing pulmonary hypoplasia, hip dysplasia, hereditary renal adysplasia, and Mayer-Rokitansky-Kuster-Hauser syndrome in adulthood is reported here. The i.v. pyelography showed right renal agenesis with a normal left kidney and ureter. Ultrasound and Magnetic Resonance Imaging also showed right renal agenesis with multicystic embryonary remnants in the right hemipelvis probably corresponding to a dysgenetic kidney. An uretrocystoscopy showed absence of ectopic ureter and of the right hemitrigone. She was scheduled for a diagnostic laparoscopy and creation of a neovagina according to the McIndoe technique with a prosthesis and skin graft. Laparoscopy confirmed the absence of the uterus. On both sides, an elongated, solid, rudimentary uterine horn could be observed. Both ovaries were also elongated, located high in both abdominal flanks and somewhat dysgenetics. A conventional cytogenetic study revealed a normal female karyotype 46, XX at a level of 550 GTG bands. A CGH analysis was performed using a 244K oligoarray CGH detecting 11 copy number variants described as normal variants in the databases. The 17q12 and 22q11.21 microdeletions described in other MRKH patients were not present in this case. Four years after operation her evolution is normal, without symptoms and the neovagina is adequately functional. The geneticists have studied her family history and the pedigree of the family is shown.</p> <p>Conclusions</p> <p>We suggest that primary damage to the mesoderm (paraaxil, intermediate, and lateral) caused by mutations in a yet unidentified gene is responsible for: 1) skeletal dysplasia, 2) inappropriate interactions between the bronchial mesoderm and endodermal lung bud as well as between the blastema metanephric and ureteric bud, and eventually 3) Müllerian anomalies (peritoneal mesothelium) at the same level. These anomalies would be transmitted as an autosomal dominant trait with incomplete penetrance and variable expressivity.</p

The desirability of transitions in demand: Incorporating behavioural and societal transformations into energy modelling

Quantitative systems modelling in support of climate policy has tended to focus more on the supply side in assessing interactions among technology, economy, environment, policy and society. By contrast, the demand side is usually underrepresented, often emphasising technological options for energy efficiency improvements. In this perspective, we argue that scientific support to climate action is not only about exploring capacity of "what", in terms of policy and outcome, but also about assessing feasibility and desirability, in terms of "when", "where" and especially for "whom". Without the necessary behavioural and societal transformations, the world faces an inadequate response to the climate crisis challenge. This could result from poor uptake of low-carbon technologies, continued high-carbon intensive lifestyles, or economy-wide rebound effects. For this reason, we propose a framing for a holistic and transdisciplinary perspective on the role of human choices and behaviours in influencing the low-carbon transition, starting from the desires of individuals and communities, and analysing how these interact with the energy and economic landscape, leading to systemic change at the macro-level. In making a case for a political ecology agenda, we expand our scope, from comprehending the role of societal acceptance and uptake of end-use technologies, to co-developing knowledge with citizens from non-mainstream and marginalised communities, and to defining the modelling requirements to assess the decarbonisation potential of shifting lifestyle patterns in climate change and action