Associations between Shared Sanitation, Stunting and Diarrhoea in Low-Income, High Density Urban Neighbourhoods of Maputo, Mozambique - a Cross-Sectional Study.

INTRODUCTION: Shared sanitation facilities are used by over 500 million people around the world. Most research evidence indicates that shared sanitation conveys higher risk than household sanitation for many adverse health outcomes. However, studies often fail to account for variation between different types of shared facilities. As informal housing development outpaces sanitation infrastructure, it is imperative to understand which components of shared facilities may mitigate the health risks of shared sanitation use. METHODS: This cross-sectional study determines whether sanitation improvement or compound hygiene were associated with stunting or diarrhoeal prevalence in children under five living in Maputo, Mozambique who rely on shared sanitation facilities. The study uses logistic and linear multivariable regression analysis to search for associations and control for potential confounding factors. RESULTS: 346 children (43.9%) in the study population were stunted. Each unit increase in sanitation score was associated with an approximate decrease of 22% in the odds of stunting (OR: 0.78, CI: 0.66, 0.92), and an increase in height of 0.23 height-for-age z-scores (CI: 0.10, 0.36). There was no evidence that the compound hygiene score was associated with height as measured by stunting (OR: 1.05, CI: 0.87, 1.26) or z-score (-0.06, CI: -0.21, 0.09). Neither sanitation nor compound hygiene score were associated with diarrhoea in the population. CONCLUSIONS: Use of an improved shared latrine is associated with decreased odds of stunting. There is no evidence of an association between latrine improvement and diarrhoea. Further investigation is necessary to isolate attributes of shared sanitation facilities that may reduce health risks.

Household-level water, sanitation and hygiene factors and interventions and the prevention of relapse after severe acute malnutrition recovery: A systematic review.

Severe acute malnutrition (SAM) is the most serious form of acute malnutrition and is associated with high mortality risk among children under 5. While the Community-based Management of Acute Malnutrition (CMAM) approach, recommended for treating cases of uncomplicated SAM, has increased treatment coverage and recovery outcomes, high relapse rates have been reported. Several risk factors for SAM relapse, such as insufficient food intake and high infectious disease burden in the community, have been identified. However, the role of household water, sanitation and hygiene (WASH) conditions remains unclear. This systematic review: (1) assesses the effectiveness of WASH interventions on preventing SAM relapse and (2) identifies WASH-related conditions associated with relapse to SAM among children aged 6-59 months discharged as recovered following SAM CMAM treatment. We performed electronic searches of six databases to identify relevant studies published between 1 January 2000 and 6 November 2023 and assessed their quality. After deduplication, 10,294 documents were screened by title and abstract, with 13 retrieved for full-text screening. We included three studies ranging from low- to medium-quality. One intervention study found that providing a WASH kit during SAM outpatient treatment did not reduce the risk of relapse to SAM. Two observational studies found inconsistent associations between household WASH conditions-unimproved sanitation and unsafe drinking water-and SAM relapse. Despite the paucity of evidence, the hypothesised causal pathways between WASH conditions and the risk of relapse remain plausible. Further evidence is needed to identify interventions for an integrated postdischarge approach to prevent relapse.

Determinants of Willingness to Pay for Fecal Sludge Management Services and Knowledge Gaps: A Scoping Review.

Achieving universal access to safely managed sanitation services is one of the Sustainable Development Goal 6 targets (SDG6.2). The cost and availability of services to ensure the safe management of on-site sanitation, such as pit latrines and septic tanks, can be major barriers for poor households. Particularly, fecal sludge emptying services have become increasingly important due to the growing urban population. This review aims to scope the literature on stated and revealed willingness to pay (WTP) for emptying on-site sanitation systems and to identify determinants of WTP and gaps in knowledge. We performed electronic searches of six databases. After deduplication, 1846 records were identified, of which 14 were included in the review. In these studies, we identified 26 distinct scenarios that reported mean or median WTP values for emptying services and their market price (i.e., price at which the services were provided). Among the 26 scenarios, 77% (n = 20) reported that WTP was lower than the market price. We identified 20 statistically significant determinants of WTP, which can be leveraged when developing or improving manual and mechanical emptying services to attract more customers. Future research should consider services that adopt flexible pricing or mobile money payment and optimize their emptying operations to increase WTP. Validating the effectiveness of such services in solving the WTP-market price imbalance is a significant knowledge gap.

Risk factors for food contamination among children discharged from community management of acute malnutrition programmes in South Sudan: A cross-sectional study and hazard analysis critical control point approach.

Children under-5 years of age are particularly vulnerable to severe acute malnutrition (SAM), and the risk factors associated with relapse to SAM are poorly understood. Possible causes are asymptomatic or symptomatic infection with enteric pathogens, with contaminated food as a critical transmission route. This cross-sectional study comprised a household survey with samples of child food (n = 382) and structured observations of food preparation (n = 197) among children aged 6-59 months that were discharged from treatment in community management of acute malnutrition (CMAM) programmes in South Sudan. We quantified Escherichia coli and total coliforms (TCs), measured in colony forming units per g of food (CFU/g), as indicators of microbial contamination of child food. A modified hazard analysis critical control point (HACCP) approach was utilised to determine critical control points (CCPs) followed by multivariate logistic regression analysis to understand the risk factors associated with contamination. Over 40% (n = 164) of samples were contaminated with E. coli (43% >0 E. coli CFU/g, 95% CI 38%-48%), and 90% (n = 343) had >10 TCs (CFU/g) (>10 TC CFU/g, 95% CI 87%-93%). Risk factors associated (p < 0.05) with child food contamination included if the child fed themselves (9.05 RR, 95% CI [3.18, 31.16]) and exposure to animals (2.63 RR, 95% CI [1.33, 5.34]). This study highlights the risk factors and potential control strategies that can support interventions that reduce food contamination exposure in young children and help further protect those that are highly vulnerable to recurrent exposure to enteric pathogens.

Recommendations for hand hygiene in community settings: a scoping review of current international guidelines.

BACKGROUND: Hand hygiene is an important measure to prevent disease transmission. OBJECTIVE: To summarise current international guideline recommendations for hand hygiene in community settings and to assess to what extent they are consistent and evidence based. ELIGIBILITY CRITERIA: We included international guidelines with one or more recommendations on hand hygiene in community settings-categorised as domestic, public or institutional-published by international organisations, in English or French, between 1 January 1990 and 15 November 2021. DATA SOURCES: To identify relevant guidelines, we searched the WHO Institutional Repository for Information Sharing Database, Google, websites of international organisations, and contacted expert organisations and individuals. CHARTING METHODS: Recommendations were mapped to four areas related to hand hygiene: (1) effective hand hygiene; (2) minimum requirements; (3) behaviour change and (4) government measures. Recommendations were assessed for consistency, concordance and whether supported by evidence. RESULTS: We identified 51 guidelines containing 923 recommendations published between 1999 and 2021 by multilateral agencies and international non-governmental organisations. Handwashing with soap is consistently recommended as the preferred method for hand hygiene across all community settings. Most guidelines specifically recommend handwashing with plain soap and running water for at least 20 s; single-use paper towels for hand drying; and alcohol-based hand rub (ABHR) as a complement or alternative to handwashing. There are inconsistent and discordant recommendations for water quality for handwashing, affordable and effective alternatives to soap and ABHR, and the design of handwashing stations. There are gaps in recommendations on soap and water quantity, behaviour change approaches and government measures required for effective hand hygiene. Less than 10% of recommendations are supported by any cited evidence. CONCLUSION: While current international guidelines consistently recommend handwashing with soap across community settings, there remain gaps in recommendations where clear evidence-based guidance might support more effective policy and investment.

The efficacy of soap against schistosome cercariae: A systematic review.

BACKGROUND: Schistosomiasis is a parasitic disease that is endemic in 78 countries and affects almost 240 million people worldwide. It has been acknowledged that an integrated approach that goes beyond drug treatment is needed to achieve control and eventual elimination of the disease. Improving hygiene has been encouraged by World Health Organisation, and one aspect of good hygiene is using soap during water-contact activities, such as bathing and doing laundry. This hygiene practice might directly reduce the skin exposure to cercariae at transmission sites. A systematic review was carried out to investigate the efficacy of soap against schistosome cercariae and to identify the knowledge gaps surrounding this topic. METHODOLOGY: Six online databases were searched between 5th and 8th July of 2021. Records returned from these databases were screened to remove duplicates, and the remaining records were classified by reading titles, abstracts, and full texts to identify the included studies. The results were categorised into two groups based on two different protective mechanisms of soap (namely, damage to cercariae and protection of skin). CONCLUSIONS: Limited research has been conducted on the efficacy of soap against schistosome cercariae and only 11 studies met the criteria to be included in this review. The review demonstrates that soap has the potential of protecting people against schistosome cercariae and there are two protective aspects: (1) soap affects cercariae adversely; (2) soap on the skin prevents cercariae from penetrating the skin, developing into adult worms and producing eggs. Both aspects of protection were influenced by many factors, but the differences in the reported experimental conditions, such as the cercarial endpoint measurement used and the cercaria numbers used per water sample, lead to low comparability between the previous studies. This review indicates that more evidence is needed to inform hygiene advice for people living in schistosomiasis endemic areas.

LXRα Regulates oxLDL-Induced Trained Immunity in Macrophages.

Reprogramming of metabolic pathways in monocytes and macrophages can induce a proatherosclerotic inflammatory memory called trained innate immunity. Here, we have analyzed the role of the Liver X receptor (LXR), a crucial regulator of metabolism and inflammation, in oxidized low-density lipoprotein (oxLDL)-induced trained innate immunity. Human monocytes were incubated with LXR agonists, antagonists, and oxLDL for 24 h. After five days of resting time, cells were restimulated with the TLR-2 agonist Pam3cys. OxLDL priming induced the expression of LXRα but not LXRß. Pharmacologic LXR activation was enhanced, while LXR inhibition prevented the oxLDL-induced inflammatory response. Furthermore, LXR inhibition blocked the metabolic changes necessary for epigenetic reprogramming associated with trained immunity. In fact, enrichment of activating histone marks at the IL-6 and TNFα promotor was reduced following LXR inhibition. Based on the differential expression of the LXR isoforms, we inhibited LXRα and LXRß genes using siRNA in THP1 cells. As expected, siRNA-mediated knock-down of LXRα blocked the oxLDL-induced inflammatory response, while knock-down of LXRß had no effect. We demonstrate a specific and novel role of the LXRα isoform in the regulation of oxLDL-induced trained immunity. Our data reveal important aspects of LXR signaling in innate immunity with relevance to atherosclerosis formation.

Force-induced changes of α-catenin conformation stabilize vascular junctions independently of vinculin.

Cadherin-mediated cell adhesion requires anchoring via the ß-catenin-α-catenin complex to the actin cytoskeleton, yet, α-catenin only binds F-actin weakly. A covalent fusion of VE-cadherin to α-catenin enhances actin anchorage in endothelial cells and strongly stabilizes endothelial junctions in vivo, blocking inflammatory responses. Here, we have analyzed the underlying mechanism. We found that VE-cadherin-α-catenin constitutively recruits the actin adaptor vinculin. However, removal of the vinculin-binding region of α-catenin did not impair the ability of VE-cadherin-α-catenin to enhance junction integrity. Searching for an alternative explanation for the junction-stabilizing mechanism, we found that an antibody-defined epitope, normally buried in a short α1-helix of the actin-binding domain (ABD) of α-catenin, is openly displayed in junctional VE-cadherin-α-catenin chimera. We found that this epitope became exposed in normal α-catenin upon triggering thrombin-induced tension across the VE-cadherin complex. These results suggest that the VE-cadherin-α-catenin chimera stabilizes endothelial junctions due to conformational changes in the ABD of α-catenin that support constitutive strong binding to actin.

SARS-Cov-2 Seroprevalence in a French Kidney Transplant Center Located Within a "High-risk" Zone.

BACKGROUND: Data on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) seroprevalence in kidney transplant recipients (KTRs) remain rare. We sought to shed further light on this issue by conducting a single-center study in a kidney transplant center located in one of the France's highest risk zone (Grand Est) for coronavirus disease 2019 (Covid-19) during the initial disease outbreak. METHODS: To this aim, we used a survey approach coupled with systematic investigation of SARS-CoV-2 serology in a cohort of 1390 KTRs. RESULTS: SARS-CoV-2 serologies were available for 780 survey respondents, among whom 48 had anti-SARS-CoV-2 antibodies (total seroprevalence: 6.2%). Thirty-five of the 48 seropositive KTRs had previously received a diagnosis of Covid-19, whereas the remaining 13 patients were not known to be infected (8 asymptomatic cases). Specifically, 18.7% of seropositive KTRs and 1.1% of the entire cohort were asymptomatic. Household exposure was found to markedly increase the risk of SARS-CoV-2 transmission. CONCLUSIONS: Our findings demonstrate that the overall SARS-CoV-2 seroprevalence in KTRs living in one of the France's highest risk zone for Covid-19 during the first French lockdown was as low as 6.3%. Rapid and strict implementation of protective measures could have significantly mitigated virus spread even in an area of high virus circulation.

Biomarkers of Cytokine Release Syndrome Predict Disease Severity and Mortality From COVID-19 in Kidney Transplant Recipients.

BACKGROUND: Data on coronavirus disease 2019 (COVID-19) in immunocompromised kidney transplant recipients (KTR) remain scanty. Although markers of inflammation, cardiac injury, and coagulopathy have been previously associated with mortality in the general population of patients with COVID-19, their prognostic impact amongst KTR with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection has not been specifically investigated. METHODS: We conducted a cohort study of 49 KTR who presented with COVID-19. Clinical and laboratory risk factors for severe disease and mortality were prospectively collected and analyzed with respect to outcomes. The study participants were divided into 3 groups: (1) mild disease manageable in an outpatient setting (n = 8), (2) nonsevere disease requiring hospitalization (n = 21), and (3) severe disease (n = 20). RESULTS: Gastrointestinal manifestations were common at diagnosis. The 30-day mortality rate in hospitalized patients was 19.5%. Early elevations of C-reactive protein (>100 mg/L) and interleukin-6 (>65 ng/L) followed by increases in high-sensitivity troponin I (>30 ng/L) and D-dimer (>960 ng/mL) were significantly associated with severe disease and mortality. Viral load did not have prognostic significance in our sample, suggesting that outcomes were chiefly driven by a cytokine release syndrome (CRS). CONCLUSIONS: Regular monitoring of CRS biomarkers in KTR with COVID-19 is paramount to improve clinical outcomes.

How state and trait versions of self-esteem and depressive symptoms affect their interplay: A longitudinal experimental investigation.

States and traits are important concepts in psychological research. They can be operationalized (a) by using measures that employ different time frames and (b) by applying statistical models that decompose the variance. However, the effects of using variations in states and traits by applying measurement and modeling approaches have yet to be merged and studied systematically. The present study addressed this topic by revisiting an intensively studied research question, namely: What is the longitudinal relation between self-esteem and depressive symptoms? To do so, we created state and trait versions of questionnaires by systematically changing the time frame ("during the last 2 weeks" vs. "in general") that was used to measure self-esteem and depressive symptoms and in addition, by using state-trait statistical models. We conducted an exploratory study (N = 683) and a confirmatory replication study (N = 1,087) with samples of university students, designed as a 2 × 2 longitudinal experiment with 4 time points spanning 1 semester. Our results indicated that first, consistently across the 2 studies, trait time frames revealed higher proportions of trait variance than state time frames. Second, across the 2 studies, the well-researched vulnerability effect, which postulates that low self-esteem predicts depressive symptoms, only held when trait time frames for self-esteem were applied and traditional cross-lagged models were used. Third, when controlling for stable trait differences, cross-lagged results were least consistent when trait time frames were used, which highlighted the interdependency involved in measuring and modeling states and traits. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Chlorination of Schistosoma mansoni cercariae.

BACKGROUND: Schistosomiasis is a water-based disease acquired through contact with cercaria-infested water. Communities living in endemic regions often rely on parasite-contaminated freshwater bodies for their daily water contact activities, resulting in recurring schistosomiasis infection. In such instances, water treatment can provide safe water on a household or community scale. However, to-date there are no water treatment guidelines that provide information on how to treat water containing schistosome cercariae. Here, we rigorously test the effectiveness of chlorine against Schistosoma mansoni cercariae. METHOD: S. mansoni cercariae were chlorinated using sodium hypochlorite under lab and field condition. The water pH was controlled at 6.5, 7.0 or 7.5, the water temperature at 20°C or 27°C, and the chlorine dose at 1, 2 or 3 mg/l. Experiments were conducted up to contact times of 45 minutes. 100 cercariae were used per experiment, thereby achieving up to 2-log10 inactivations of cercariae. Experiments were replicated under field conditions at Lake Victoria, Tanzania. CONCLUSION: A CT (residual chlorine concentration x chlorine contact time) value of 26±4 mg·min/l is required to achieve a 2-log10 inactivation of S. mansoni cercariae under the most conservative condition tested (pH 7.5, 20°C). Field and lab-cultivated cercariae show similar chlorine sensitivities. A CT value of 30 mg·min/l is therefore recommended to disinfect cercaria-infested water, though safety factors may be required, depending on water quality and operating conditions. This CT value can be achieved with a chlorine residual of 1 mg/l after a contact time of 30 minutes, for example. This recommendation can be used to provide safe water for household and recreational water activities in communities that lack safe alternative water sources.

Neural metabolic imbalance induced by MOF dysfunction triggers pericyte activation and breakdown of vasculature.

Mutations in chromatin-modifying complexes and metabolic enzymes commonly underlie complex human developmental syndromes affecting multiple organs. A major challenge is to determine how disease-causing genetic lesions cause deregulation of homeostasis in unique cell types. Here we show that neural-specific depletion of three members of the non-specific lethal (NSL) chromatin complex-Mof, Kansl2 or Kansl3-unexpectedly leads to severe vascular defects and brain haemorrhaging. Deregulation of the epigenetic landscape induced by the loss of the NSL complex in neural cells causes widespread metabolic defects, including an accumulation of free long-chain fatty acids (LCFAs). Free LCFAs induce a Toll-like receptor 4 (TLR4)-NFκB-dependent pro-inflammatory signalling cascade in neighbouring vascular pericytes that is rescued by TLR4 inhibition. Pericytes display functional changes in response to LCFA-induced activation that result in vascular breakdown. Our work establishes that neurovascular function is determined by the neural metabolic environment.

Platelets docking to VWF prevent leaks during leukocyte extravasation by stimulating Tie-2.

Neutrophil extravasation requires opening of the endothelial barrier but does not necessarily cause plasma leakage. Leaks are prevented by contractile actin filaments surrounding the diapedesis pore, keeping this opening tightly closed around the transmigrating neutrophils. We have identified the receptor system that is responsible for this. We show that silencing, or gene inactivation, of endothelial Tie-2 results in leak formation in postcapillary venules of the inflamed cremaster muscle at sites of neutrophil extravasation, as visualized by fluorescent microspheres. Leakage was dependent on neutrophil extravasation, because it was absent upon neutrophil depletion. We identified the Cdc42 GTPase exchange factor FGD5 as a downstream target of Tie-2 that is essential for leakage prevention during neutrophil extravasation. Looking for the Tie-2 agonist and its source, we found that platelet-derived angiopoietin-1 (Angpt1) was required to prevent neutrophil-induced leaks. Intriguingly, blocking von Willebrand factor (VWF) resulted in vascular leaks during transmigration, indicating that platelets interacting with endothelial VWF activate Tie-2 by secreting Angpt1, thereby preventing diapedesis-induced leakiness.

Determining the viability of Schistosoma mansoni cercariae using fluorescence assays: An application for water treatment.

BACKGROUND: Schistosome cercariae are the human-infectious stage of the Schistosoma parasite. They are shed by snail intermediate hosts living in freshwater, and penetrate the skin of the human host to develop into schistosomes, resulting in schistosomiasis infection. Water treatment (e.g. filtration or chlorination) is one way of cutting disease transmission; it kills or removes cercariae to provide safe water for people to use for activities such as bathing or laundry as an alternative to infested lakes or rivers. At present, there is no standard method for assessing the effectiveness of water treatment processes on cercariae. Examining cercarial movement under a microscope is the most common method, yet it is subjective and time-consuming. Hence, there is a need to develop and verify accurate, high-throughput assays for quantifying cercarial viability. METHOD: We tested two fluorescence assays for their ability to accurately determine cercarial viability in water samples, using S. mansoni cercariae released from infected snails in the Schistosomiasis Collection at the Natural History Museum, London. These assays consist of dual stains, namely a vital and non-vital dye; fluorescein diacetate (FDA) and Hoechst, and FDA and Propidium Iodide. We also compared the results of the fluorescence assays to the viability determined by microscopy. CONCLUSION: Both fluorescence assays can detect the viability of cercariae to an accuracy of at least 92.2% ± 6.3%. Comparing the assays to microscopy, no statistically significant difference was found between the method's viability results. However, the fluorescence assays are less subjective and less time-consuming than microscopy, and therefore present a promising method for quantifying the viability of schistosome cercariae in water samples.

LXR Activation Induces a Proinflammatory Trained Innate Immunity-Phenotype in Human Monocytes.

Objectives: The concept of trained innate immunity describes a long-term proinflammatory memory in innate immune cells. Trained innate immunity is regulated through reprogramming of cellular metabolic pathways including cholesterol and fatty acid synthesis. Here, we have analyzed the role of Liver X Receptor (LXR), a key regulator of cholesterol and fatty acid homeostasis, in trained innate immunity. Methods and Results: Human monocytes were isolated and incubated with different stimuli for 24 h, including LXR agonists, antagonists and Bacillus Calmette-Guerin (BCG) vaccine. After 5 days resting time, cells were restimulated with the TLR2-agonist Pam3cys. LXR activation did not only increase BCG trained immunity, but also induced a long-term inflammatory activation by itself. This inflammatory activation by LXR agonists was accompanied by characteristic features of trained innate immunity, such as activating histone marks on inflammatory gene promoters and metabolic reprogramming with increased lactate production and decreased oxygen consumption rate. Mechanistically, LXR priming increased cellular acetyl-CoA levels and was dependent on the activation of the mevalonate pathway and IL-1ß signaling. In contrast to mevalonate pathway inhibition, blocking fatty acid synthesis further increased proinflammatory priming by LXR. Conclusion: We demonstrate that LXR activation induces a proinflammatory trained immunity phenotype in human monocytes through epigenetic and metabolic reprogramming. Our data reveal important novel aspects of LXR signaling in innate immunity.

Ultraviolet sensitivity of WASH (water, sanitation, and hygiene) -related helminths: A systematic review.

BACKGROUND: Helminthiases are a group of disabling neglected tropical diseases that affect billions of people worldwide. Current control methods use preventative chemotherapy but reinfection is common and an inter-sectoral approach is required if elimination is to be achieved. Household and community scale water treatment can be used to provide a safe alternative water supply for contact activities, reducing exposure to WASH (water, sanitation, and hygiene) -related helminths. With the introduction of ultraviolet light emitting diodes (UV-C LEDs), ultraviolet (UV) disinfection could be a realistic option for water treatment in low-income regions in the near future, to provide safe alternative water supplies for drinking and contact activities such as handwashing, bathing, and laundry, but currently there is no guidance for the use of UV or solar disinfection against helminths. METHODOLOGY: A qualitative systematic review of existing literature was carried out to establish which WASH-related helminths are more susceptible to UV disinfection and identify gaps in research to inform future studies. The search included all species that can infect humans and can be transmitted through water or wastewater. Five online databases were searched and results were categorized based on the UV source: sunlight and solar simulators, UV-A and UV-B (long wavelength) sources, and UV-C (germicidal) sources. CONCLUSIONS: There has been very little research into the UV sensitivity of helminths; only 47 studies were included in this review and the majority were carried out before the standard protocol for UV disinfection experiments was published. Only 18 species were studied; however all species could be inactivated by UV light. Fluences required to achieve a 1-log inactivation ranged from 5 mJ/cm2 to over 800 mJ/cm2. Larval forms were generally more sensitive to UV light than species which remain as an egg in the environment. This review confirms that further research is required to produce detailed recommendations for household or community scale UV-C LED or solar disinfection (SODIS) of water for preventing helminthiases.

VE-PTP inhibition stabilizes endothelial junctions by activating FGD5.

Inhibition of VE-PTP, an endothelial receptor-type tyrosine phosphatase, triggers phosphorylation of the tyrosine kinase receptor Tie-2, which leads to the suppression of inflammation-induced vascular permeability. Analyzing the underlying mechanism, we show here that inhibition of VE-PTP and activation of Tie-2 induce tyrosine phosphorylation of FGD5, a GTPase exchange factor (GEF) for Cdc42, and stimulate its translocation to cell contacts. Interfering with the expression of FGD5 blocks the junction-stabilizing effect of VE-PTP inhibition in vitro and in vivo. Likewise, FGD5 is required for strengthening cortical actin bundles and inhibiting radial stress fiber formation, which are each stimulated by VE-PTP inhibition. We identify Y820 of FGD5 as the direct substrate for VE-PTP. The phosphorylation of FGD5-Y820 is required for the stabilization of endothelial junctions and for the activation of Cdc42 by VE-PTP inhibition but is dispensable for the recruitment of FGD5 to endothelial cell contacts. Thus, activation of FGD5 is a two-step process that comprises membrane recruitment and phosphorylation of Y820. These steps are necessary for the junction-stabilizing effect stimulated by VE-PTP inhibition and Tie-2 activation.

The effectiveness of water treatment processes against schistosome cercariae: A systematic review.

BACKGROUND: Schistosomiasis is one of the most disabling neglected tropical diseases, ranking second in terms of years lived with disability. While treatment with the drug praziquantel can have immediate beneficial effects, reinfection can occur rapidly if people are in contact with cercaria-infested water. Water treatment for schistosomiasis control seeks to eliminate viable cercariae from water, thereby providing safe alternative water supplies for recreational and domestic activities including laundry and bathing. This provision may reduce contact with infested water, which is crucial for reducing reinfection following chemotherapy and cutting schistosome transmission. METHODOLOGY: A qualitative systematic review was carried out to summarize the existing knowledge on the effectiveness of water treatment in removing or inactivating human schistosome cercariae. Four online databases were searched. Studies were screened and categorized into five water treatment processes: storage, heating, chlorination, filtration, and ultraviolet (UV) disinfection. CONCLUSIONS: All five water treatment methods can remove or inactivate cercariae in water, and hence produce cercaria-free water. However, reliable design guidelines for treating water do not exist as there are insufficient data. Overall, the review found that cercariae are inactivated when storing water for 10-72 hours (depending on temperature), or with chlorination values of 3-30 mg-min/l. UV fluences between 3-60 mJ/cm2 may significantly damage or kill cercariae, and sand filters with 0.18-0.35 mm grain size have been shown to remove cercariae. This systematic review identified 67 studies about water treatment and schistosomiasis published in the past 106 years. It highlights the many factors that influence the results of water treatment experiments, which include different water quality conditions and methods for measuring key parameters. Variation in these factors limit comparability, and therefore currently available information is insufficient for providing complete water treatment design recommendations.

Nanoscale localization of proteins within focal adhesions indicates discrete functional assemblies with selective force-dependence.

Focal adhesions (FAs) are subcellular regions at the micrometer scale that link the cell to the surrounding microenvironment and control vital cell functions. However, the spatial architecture of FAs remains unclear at the nanometer scale. We used two-color and three-color super-resolution stimulated emission depletion microscopy to determine the spatial distributions and co-localization of endogenous FA components in fibroblasts. Our data indicate that adhesion proteins inside, but not outside, FAs are organized into nanometer size units of multi-protein assemblies. The loss of contractile force reduced the nanoscale co-localization between different types of proteins, while it increased this co-localization between markers of the same type. This suggests that actomyosin-dependent force exerts a nonrandom, specific, control of the localization of adhesion proteins within cell-matrix adhesions. These observations are consistent with the possibility that proteins in cell-matrix adhesions are assembled in nanoscale particles, and that force regulates the localization of the proteins therein in a protein-specific manner. This detailed knowledge of how the organization of FA components at the nanometer scale is linked to the capacity of the cells to generate contractile forces expands our understanding of cell adhesion in health and disease.