Modelling seasonal household variation in harvested rainwater availability:a case study in Siaya County, Kenya

Rainwater harvesting reliability, the proportion of days annually when rainwater demand is fully met, is challenging to estimate from cross-sectional household surveys that underpin international monitoring. This study investigated the use of a modelling approach that integrates household surveys with gridded precipitation data to evaluate rainwater harvesting reliability, using two local-scale household surveys in rural Siaya County, Kenya as an illustrative case study. We interviewed 234 households, administering a standard questionnaire that also identified the source of household stored drinking water. Logistic mixed effects models estimated stored rainwater availability from household and climatological variables, with random effects accounting for unobserved heterogeneity. Household rainwater availability was significantly associated with seasonality, storage capacity, and access to alternative improved water sources. Most households (95.1%) that consumed rainwater faced insufficient supply of rainwater available for potable needs throughout the year, with intermittencies during the short rains for most households with alternative improved sources. Although not significant, stored rainwater lasts longer for households whose only improved water source was rainwater (301.8 ± 40.2 days) compared to those having multiple improved sources (144.4 ± 63.7 days). Such modelling analysis could enable rainwater harvesting reliability estimation, and thereby national/international monitoring and targeted follow-up fieldwork to support rainwater harvesting

Silver eel downstream migration in fragmented rivers: use of a Bayesian model to track movements triggering and duration

Obstacles in rivers are considered to be one of the main threats to diadromous fish. As a result of the recent collapse of the European eel, the European Commission introduced a Regulation, requiring to reduce all sources of anthropogenic mortality, including those caused by passing through hydropower turbines. Improving knowledge about migration triggers and processes is crucial to assess and mitigate the impact of obstacles. In our study, we tracked 97 tagged silver eels in a fragmented river situated in the Western France (the River Dronne). Using the movement ecology framework, and implementing a Bayesian state-space model, we confirmed the influence of river discharge on migration triggering and he distance travelled by fish. We also demonstrated that, in our studied area, there is a small window of opportunity for migration. Moreover, we found that obstacles have a significant impact on distance travelled. Combined with the small window, this suggests that assessment of obstacles impact on downstream migration should not be limited to quantifying mortality at hydroelectric facilities, but should also consider the delay induced by obstacles, and its effects on escapement. The study also suggests that temporary turbines shutdown may mitigate the impacts of hydropower facilities in rivers with migration process similar to those observed here

MSH3 polymorphisms and protein levels affect CAG repeat instability in huntington's disease mice

Expansions of trinucleotide CAG/CTG repeats in somatic tissues are thought to contribute to ongoing disease progression through an affected individual's life with Huntington's disease or myotonic dystrophy. Broad ranges of repeat instability arise between individuals with expanded repeats, suggesting the existence of modifiers of repeat instability. Mice with expanded CAG/CTG repeats show variable levels of instability depending upon mouse strain. However, to date the genetic modifiers underlying these differences have not been identified. We show that in liver and striatum the R6/1 Huntington's disease (HD) (CAG)~100 transgene, when present in a congenic C57BL/6J (B6) background, incurred expansion-biased repeat mutations, whereas the repeat was stable in a congenic BALB/cByJ (CBy) background. Reciprocal congenic mice revealed the Msh3 gene as the determinant for the differences in repeat instability. Expansion bias was observed in congenic mice homozygous for the B6 Msh3 gene on a CBy background, while the CAG tract was stabilized in congenics homozygous for the CBy Msh3 gene on a B6 background. The CAG stabilization was as dramatic as genetic deficiency of Msh2. The B6 and CBy Msh3 genes had identical promoters but differed in coding regions and showed strikingly different protein levels. B6 MSH3 variant protein is highly expressed and associated with CAG expansions, while the CBy MSH3 variant protein is expressed at barely detectable levels, associating with CAG stability. The DHFR protein, which is divergently transcribed from a promoter shared by the Msh3 gene, did not show varied levels between mouse strains. Thus, naturally occurring MSH3 protein polymorphisms are modifiers of CAG repeat instability, likely through variable MSH3 protein stability. Since evidence supports that somatic CAG instability is a modifier and predictor of disease, our data are consistent with the hypothesis that variable levels of CAG instability associated with polymorphisms of DNA repair genes may have prognostic implications for various repeat-associated diseases

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

A mixed methods study to evaluate participatory mapping for rural water safety planning in western Kenya

Water safety planning is an approach to ensure safe drinking-water access through comprehensive risk assessment and water supply management from catchment to consumer. However, its uptake remains low in rural areas. Participatory mapping, the process of map creation for resource management by local communities, has yet to be used for rural water safety planning. In this mixed methods study, to evaluate the validity of participatory mapping outputs for rural water safety planning and assess community understanding of water safety, 140 community members in Siaya County, Kenya, attended ten village-level participatory mapping sessions. They mapped drinking-water sources, ranked their safety and mapped potential contamination hazards. Findings were triangulated against a questionnaire survey of 234 households, conducted in parallel. In contrast to source type ranking for international monitoring, workshop participants ranked rainwater’s safety above piped water and identified source types such as broken pipes not explicitly recorded in water source typologies often used for formal monitoring. Participatory mapping also highlighted the overlap between livestock grazing areas and household water sources. These findings were corroborated by the household survey and subsequent participatory meetings. However, comparison with household survey data suggested participatory mapping outputs omitted some water sources and landscape-scale contamination hazards, such as open defecation areas or flood-prone areas. In follow-up visits, participant groups ranked remediation of rainwater harvesting systems as the most acceptable intervention to address hazards. We conclude that participatory mapping can complement other established approaches to rural water safety planning by capturing informally managed source use and facilitating community engagement

Protein palmitoylation in bovine ovarian follicle

International audienceProtein palmitoylation is a reversible post-translational modification by fatty acids (FA), mainly a palmitate (C16:0). Palmitoylation allows protein shuttling between the plasma membrane and cytosol to regulate protein stability, sorting and signaling activity and its deficiency leads to diseases. We aimed to characterize the palmitoyl-proteome of ovarian follicular cells and molecular machinery regulating protein palmitoylation within the follicle. For the first time, 84 palmitoylated proteins were identified from bovine granulosa cells (GC), cumulus cells (CC) and oocytes by acyl-biotin exchange proteomics. Of these, 32 were transmembrane proteins and 27 proteins were detected in bovine follicular fluid extracellular vesicles (ffEVs). Expression of palmitoylation and depalmitoylation enzymes as palmitoyltransferases (ZDHHCs), acylthioesterases (LYPLA1 and LYPLA2) and palmitoylthioesterases (PPT1 and PPT2) were analysed using transcriptome and proteome data in oocytes, CC and GC. By immunofluorescence, ZDHHC16, PPT1, PPT2 and LYPLA2 proteins were localized in GC, CC and oocyte. In oocyte and CC, abundance of palmitoylation-related enzymes significantly varied during oocyte maturation. These variations and the involvement of identified palmitoyl-proteins in oxidation-reduction processes, energy metabolism, protein localization, vesicle-mediated transport, response to stress, G-protein mediated and other signaling pathways suggests that protein palmitoylation may play important roles in oocyte maturation and ffEV-mediated communications within the follicle