Damage to Drosophila melanogaster imaginal discs activates a regeneration checkpoint that (1) extends larval development and (2) coordinates the regeneration of the damaged disc with the growth of undamaged discs. These two systemic responses to damage are both mediated by Dilp8, a member of the insulin/insulin-like growth factor/relaxin family of peptide hormones, which is released by regenerating imaginal discs. Growth coordination between regenerating and undamaged imaginal discs is dependent on Dilp8 activation of nitric oxide synthase (NOS) in the prothoracic gland (PG), which slows the growth of undamaged discs by limiting ecdysone synthesis. Here we demonstrate that the Drosophila relaxin receptor homolog Lgr3, a leucine-rich repeat-containing G-protein-coupled receptor, is required for Dilp8-dependent growth coordination and developmental delay during the regeneration checkpoint. Lgr3 regulates these responses to damage via distinct mechanisms in different tissues. Using tissue-specific RNA-interference disruption of Lgr3 expression, we show that Lgr3 functions in the PG upstream of NOS, and is necessary for NOS activation and growth coordination during the regeneration checkpoint. When Lgr3 is depleted from neurons, imaginal disc damage no longer produces either developmental delay or growth inhibition. To reconcile these discrete tissue requirements for Lgr3 during regenerative growth coordination, we demonstrate that Lgr3 activity in both the CNS and PG is necessary for NOS activation in the PG following damage. Together, these results identify new roles for a relaxin receptor in mediating damage signaling to regulate growth and developmental timing. KEYWORDS Lgr3; checkpoint; growth coordination; regeneration G ROWTH rate and developmental time must be regulated in concert to ensure that organs develop to the correct size and proportion. Following damage to imaginal discs, Drosophila larvae activate a regeneration checkpoint that delays development and slows the growth of undamaged imaginal discs. These systemic responses to damage may function to coordinate regeneration with the growth and development of undamaged tissues (Stieper et al. 2008;Halme et al. 2010;Parker and Shingleton 2011;Jaszczak et al. 2015). The peptide Dilp8 is required for both delay and growth coordination and is secreted by regenerating imaginal discs to activate the regeneration checkpoint (Colombani et al. 2012;Garelli et al. 2012). Dilp8 induces developmental delay by inhibiting production of the neuropeptide prothoracicotropic hormone (PTTH) in the central nervous system (CNS) (Halme et al. 2010;Colombani et al. 2012), whereas Dilp8 inhibits growth of the undamaged imaginal discs by reducing biosynthesis of the steroid hormone ecdysone through activation of nitric oxide synthase (NOS) in the prothoracic gland (PG) (Jaszczak et al. 2015).Dilp8 has been classified as a member of the insulin/ insulin-like growth factor/relaxin family of peptide hormones (Garelli et al. 2012). Relaxin receptors in mammals belong to a l...

Modern contraceptives are highly effective and proven means of preventing unintended pregnancy and reducing maternal mortality. Social and economic characteristics are some of the key determinants of health and utilization family planning. However, studies examining the factors associated with utilization of long acting reversible contraception (LARC) are limited in Nepal. This study assessed the factors associated with utilization of LARC methods among married women of reproductive age in Nepal. Secondary data analysis was conducted using the 2016 Nepal Demographic and Health Survey (NDHS). A logistic regression model examined the association of socioeconomic, demographic, or fertility related characteristics with the use of LARCs among 9875 ever married women of reproductive age. The overall utilization rate of LARC in this study was 4.7%. Women in the age group of <25 years (AOR: 0.65, 95% CI: 0.45–0.92) and 25–35 years (AOR: 0.70, 95% CI: 0.56–0.89), having husbands with primary education (AOR:0.71; 95%CI: 0.64–0.84) and no education (AOR: 0.54; 95%CI: 0.38–0.73), belonging to Janajatis (AOR: 0.55; 95%CI: 0.42–0.71) and Newars (AOR: 0.29; 95%CI: 0.19–42), poor wealth quintile (AOR: 0.60; 95% CI: 0.45–0.86) had negative association with LARC use. On the other hand, women having their husband as a skilled worker (AOR: 1.49; 95%CI: 1.10–2), having two or less than two children (AOR: 1.46; 95% CI: 1.15–1.186), and having desire for children in future (AOR: 3.24; 95% CI: 2.29–4.57) had positive association with the use of LARC. In this study, younger women’s age, low or no husband’s education, from indigenous community such as Janajati and Newer, being in lowest wealth quintile negatively influenced the use of LARC. Conversely, women having her husband as skilled worker, parity less than two, and desire of having future children, positively influenced the use of LARC. The study highlights the need to reach women who were in the lower socioeconomic background to improve LARC use.

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To achieve elimination of hepatitis C (HCV), a critical group to prioritise for diagnosis and treatment is the prison population, where HCV prevalence is high. A universal offer of blood‐borne virus testing (UOBBVT) programme and a new treatment pathway were introduced to seven North East England (NEE) Prisons. Our aim was to assess: (a) the proportion of individuals with active HCV commencing direct‐acting antivirals (DAAs); (b) the outcomes following DAA treatment; (3) the reinfection rate following sustained virological response (SVR). Data were collected prospectively on BBVT uptake, HCV positivity, HCV treatment outcomes and reinfection from March 2016 onwards. 8538 individuals had BBV testing. In total, 612 (7.2%) and 374 (4.4%) were HCV antibody positive and HCV RNA positive, respectively. Ultimately, 266 (71%) individuals commenced DAAs. Overall 111 achieved a documented SVR (42%), 17 (6%) failed treatment, 30 (11%) were still on treatment or had not reached 12 weeks post‐treatment at time of analysis, and 108 (41%) were lost to follow‐up. In those with a known outcome (n = 128), 87% achieved SVR. Worryingly, of those who achieved SVR, 21 (19%) were subsequently identified as having been reinfected (median time from SVR to documented reinfection 13 (range 7‐25) months). The reinfection rate was 0.406 cases per person‐year follow‐up. In conclusion, Implementation of a UOBBVT programme and new treatment pathway resulted in increased diagnosis and treatment of HCV in the NEE prison population. However, the high HCV reinfection rate suggests a need to improve harm reduction approaches.

the tumor microenvironment (tMe) is an essential contributor to the development and progression of malignancy. Within the tMe, tumor associated macrophages (tAMs) mediate angiogenesis, metastasis, and immunosuppression, which inhibits infiltration of tumor-specific cytotoxic CD8+ t cells. in previous work, we demonstrated that the synthetic triterpenoid cDDo-methyl ester (cDDo-Me) converts breast tAMs from a tumor-promoting to a tumor-inhibiting activation state in vitro. We show now that CDDO-Me remodels the breast TME, redirecting TAM activation and T cell tumor infiltration in vivo. We demonstrate that CDDO-Me significantly attenuates IL-10 and VEGF expression but stimulates TNF production, and reduces surface expression of CD206 and CD115, markers of immunosuppressive TAMs. CDDO-Me treatment redirects the TAM transcriptional profile, inducing signaling pathways associated with immune stimulation, and inhibits TAM tumor infiltration, consistent with decreased expression of CCL2. In CDDO-Me-treated mice, both the absolute number and proportion of splenic CD4 + t cells were reduced, while the proportion of CD8 + T cells was significantly increased in both tumors and spleen. Moreover, mice fed CDDO-Me demonstrated significant reductions in numbers of CD4 + Foxp3 + regulatory T cells within tumors. These results demonstrate for the first time that CDDO-Me relieves immunosuppression in the breast tMe and unleashes host adaptive anti-tumor immunity.The tumor microenvironment (TME) provides the interface for communication between malignant and immune cells. As cells accumulate genetic and epigenetic aberrations, they recruit immune and other cellular mediators that collectively establish chronic inflammation in the TME. Mounting evidence demonstrates that interaction between tumor cells and immune cells in the TME facilitates tumor immune evasion by redirecting immune cell activation from a state of immune stimulation to immune suppression.The activation state and effector function of tumor-associated lymphoid and myeloid cells are profoundly influenced by the local TME, and these cells are likely an essential component of most tumors, regardless of tumorigenic trigger 1,2 . Tumor associated macrophages (TAMs) are key orchestrators of tumor cell survival and metastasis and shape adaptive immune responses via interaction with CD4 + and CD8 + T cell populations, among others 3 . TAMs recruit monocytes to the TME by secreting chemokines including CCL2, and promote angiogenesis through production of vascular endothelial growth factor (VEGF) 4,5 , transforming growth factor β (TGF-β) and matrix metalloproteinases (MMPs) 6 . Immunosuppression in the TME is mediated by TAMs through production of TGF-β, IL-10, and arginase 1 7 , which inhibit T cell activation and survival.TAMs can account for up to 50% of the tumor mass in breast cancer and genetic depletion of TAMs results in delayed tumor progression 8 , indicating that these cells play a non-redundant role. High TAM volumes are associated with poor clinical outcome for s...

Objective The development of precision therapeutics for systemic sclerosis (SSc) has been hindered by the lack of models that accurately mimic the disease in vitro. This study was undertaken to design and test a self‐assembled skin equivalent (saSE) system that recapitulates the cross‐talk between macrophages and fibroblasts in cutaneous fibrosis. Methods SSc‐derived dermal fibroblasts (SScDFs) and normal dermal fibroblasts (NDFs) were cultured with CD14+ monocytes from SSc patients or healthy controls to allow de novo stroma formation. Monocyte donor–matched plasma was introduced at week 3 prior to seeding keratinocytes to produce saSE with a stratified epithelium. Tissue was characterized by immunohistochemical staining, atomic force microscopy, enzyme‐linked immunosorbent assay, and quantitative reverse transcriptase–polymerase chain reaction. Results Stroma synthesized de novo from NDFs and SScDFs supported a fully stratified epithelium to form saSE. A thicker and stiffer dermis was generated by saSE with SScDFs, and more interleukin‐6 and transforming growth factor β (TGFβ) was secreted by saSE with SScDFs compared to saSE with NDFs, regardless of the inclusion of monocytes. Tissue with SSc monocytes and plasma had amplified dermal thickness and stiffness relative to control tissue. Viable CD163+ macrophages were found within the stroma of saSE 5 weeks after seeding. Additionally, SSc saSE contained greater numbers of CD163+ and CD206+ macrophages compared to control saSE. TGFβ blockade inhibited stromal stiffness to a greater extent in SSc saSE compared to control saSE. Conclusion These data suggest reciprocal activation between macrophages and fibroblasts that increases tissue thickness and stiffness, which is dependent in part on TGFβ activation. The saSE system may serve as a platform for preclinical therapeutic testing and for molecular characterization of SSc skin pathology through recapitulation of the interactions between macrophages and fibroblasts.

In Drosophila melanogaster, loss of regenerative capacity in wing imaginal discs coincides with an increase in systemic levels of the steroid hormone ecdysone, a key coordinator of their developmental progression. Regenerating discs release the relaxin hormone Dilp8 (Drosophila insulin-like peptide 8) to limit ecdysone synthesis and extend the regenerative period. Here, we describe how regenerating tissues produce a biphasic response to ecdysone levels: lower concentrations of ecdysone promote local and systemic regenerative signaling, whereas higher concentrations suppress regeneration through the expression of broad splice isoforms. Ecdysone also promotes the expression of wingless during both regeneration and normal development through a distinct regulatory pathway. This dual role for ecdysone explains how regeneration can still be completed successfully in dilp8−mutant larvae: higher ecdysone levels increase the regenerative activity of tissues, allowing regeneration to reach completion in a shorter time. From these observations, we propose that ecdysone hormone signaling functions to coordinate regeneration with developmental progression.

Background: Severe acute malnutrition is an excessive loss of weight due to the acute shortage of food or illness. It is one of the major public health problems in developing countries including Nepal. According to multiple indicator cluster survey (MICS) 2014, 2.6% severely malnourished in Nepal and 4.4% are severely malnourished in Kavre district. However, there are limited studies about predictors of severe acute malnutrition in Nepal. Thus, this study was aimed to identify the predictors of severe acute malnutrition in Kavre district of Nepal.Methods: Health facility based matched case control study was conducted among 210 (70 cases and 140 controls) children aged 6-59 months from November 2015 to April 2016. Data was collected through face to face interview with mother of eligible children using structured questionnaires. Multivariate analysis was applied to estimate adjusted odds ratio along with 95% confidence interval.Results: Children with severe acute malnutrition were 11.32 times more likely than control to have recurrent diarrhea in past six months (95% CI=4.64-28.21). Similarly, severe acute malnutrition was associated with female sex (AOR=2.44, 95% CI=1.88-6.78), fathers occupation daily labor (AOR=4.69, 95% CI=1.17-13.76) and agriculture (AOR=6.850, 95%CI=3.81-12.93), improper exclusive breast feeding (AOR=6.646, 95%CI=2.11-20.90), not feeding colostrum (AOR=3.89, 95% CI=2.88-11.21), severe food insecurity access (AOR=3.55, 95% CI=1.85-9.77) and monthly income less than average level (AOR=8.214, 95% CI=1. 43-22.16). Conclusion:Severe acute malnutrition was independently associated with sex of child, occupation of father, monthly household income, not feeding colostrum, improper exclusive breast feeding, severe household food insecurity access and recurrent diarrhea.