Cellular and molecular effects of fibroblast growth factors 2 and 4 on human umbilical veinal endothelial cells

Fibroblast growth factors (FGFs), encompasses a family of 22 related polypeptide. There are 18 different biologically active FGF proteins. They influence a wide array of biological and physiological responses such as migration, proliferation, tissue homeostasis, and wound healing. Most FGF are secreted and bind to heparin sulphate binding proteins (HPSG) in the extra cellular matrix (ECM). FGF-binding protein (FGF-BP) is a chaperon protein that binds to FGF releasing from the ECM and chaperoning it to bind to FGF receptors (FGFRs). FGFR dimerize when bound to FGF and starts series of a signal cascade that ultimately leads to the activation of MAPK. FGF2 and FGF4 are selected from the pool of 18 different FGF to be studied in this investigation. Both FGF2 and FGF4 have been reported to be critical for development during embryogenesis. De-regulation of these proteins could lead to various pathologies including different types of cancers. Hence we attempt to investigate the cellular and molecular role of these proteins and their implication on cells in an attempt to set up a foundational understanding for further studies that will include FGF-BPs and FGFRs. To do so, we used HUVECs to examine FGF2 and FGF4 activity through Western Blot analysis. We also investigated their effect on migration using the ECIS Migration Assays, on wound healing by the ECIS Wound Healing Assays and captured wound healing images through Incucyte. Data from these experiments indicated that both, FGF2 and FGF4, have a role in cellular migration and wound healing. They also show they have a dose response on these cells. As a result, we can use these models to further investigate FGF2 and FGF4 modulation by FGF-BP1 and FGF-BP3 and the affects cellular response

Mapping of southern security and justice civil society organisations and networks

The purpose of this mapping study is to provide the UK Department for International Development (DFID) with a quantitative and qualitative snapshot of security and justice civil society organisations (CSOs) and networks working in and across the countries investigated. CSO engagement on issues of security and justice is inherently difficult in many countries due to the nature of their governing regimes (such as where the state has authoritarian tendencies or where military regimes preside). In some cases the political space for CSOs to engage in issues of security and justice is being increasingly suppressed. Consequently, the success of donor support for security and justice CSOs often depends to a great extent on the political will of respective governments to enable CSOs to work freely. Furthermore, donors who wish to support security and justice CSOs need to take account of the extent to which donor interactions with government security and justice structures may influence the extent and quality of donor interaction with CSOs. In many countries, an understanding of security and justice as conceptualised and defined by donors is lacking amongst civil society – and an understanding of these issues as conceptualised by civil society is often lacking among donors and governments. This scenario even holds true in those countries where civil society as a whole is otherwise vibrant. Consequently, there is a need to increase the basic level of understanding on security and justice matters (both within CSOs and governments), to broaden the strategic community (those working in think tanks or engaged in policy analysis), and to support the development of research capacity and expertise in security and justice areas. Joined up approaches to security and justice work are rare in almost all contexts and common/collaborative/networking fora do not exist. Recommendations were made in almost all sub-regions stating that donor approaches should encourage collaboration at the outset between security and justice CSOs and devise schemes that reward or encourage joined up working

Non-alcoholic fatty liver disease is associated with greater risk of 30-day hospital readmission in the United States (U.S.)

Introduction and Objectives: Data about 30-day readmission for patients with chronic liver disease (CLD) and their contribution to CLD healthcare burden are sparse. Patterns, diagnoses, timing and predictors of 30-day readmissions for CLD from 2010-2017 were assessed. Materials and Methods: Nationwide Readmission Database (NRD) is an all-payer, all-ages, longitudinal administrative database, representing 35 million discharges in the US population yearly. We identified unique patients discharged with CLD including hepatitis B (HBV) and C (HCV), alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) from 2010 through 2017. Survey-weight adjusted multivariable analyses were used. Results: From 2010 to 2017, the 30-day readmission rate for CLD decreased from 18.4% to 17.8% (p=.008), while increasing for NAFLD from 17.0% to 19. 9% (p<.001). Of 125,019 patients discharged with CLD (mean age 57.4 years, male 59.0%) in 2017, the most common liver disease was HCV (29.2%), followed by ALD (23.5%), NAFLD (17.5%), and HBV (4.3%). Readmission rates were 20.5% for ALD, 19.9% for NAFLD, 16.8% for HCV and 16.7% for HBV. Compared to other liver diseases, patients with NAFLD had significantly higher risk of 30-day readmission in clinical comorbidities adjusted model (Hazard ratio [HR]=1.08 [95% confidence interval 1.03-1.13]). In addition to ascites, hepatic encephalopathy, higher number of coexisting comorbidities, comorbidities associated with higher risk of 30-day readmission included cirrhosis for NALFD and HCV; acute kidney injury for NAFLD, HCV and ALD; HCC for HCV, and peritonitis for ALD. Cirrhosis and cirrhosis-related complications were the most common reasons for 30-day readmission, followed by sepsis. However, a large proportion of patients (43.7% for NAFLD; 28.4% for HCV, 39.0% for HBV, and 29.1% for ALD) were readmitted for extrahepatic reasons. Approximately 20% of those discharged with CLD were readmitted within 30 days but the majority of readmissions occurred within 15 days of discharge (62.8% for NAFLD, 63.7% for HCV, 74.3% for HBV, and 72.9% for ALD). Among readmitted patients, patients with NAFLD or HCV readmitted ≤30-day had significantly higher costs and risk of in-hospital mortality (NAFLD +5.69% change [95% confidence interval, 2.54%-8.93%] and odds ratio (OR)=1.58 [1.28-1.95]; HCV +9.85% change [95%CI:6.96%-12.82%] and OR=1.31, 1.08-1.59). Conclusions: Early readmissions for CLD are prevalent causing economic and clinical burden to the US healthcare system, especially NAFLD readmissions. Closer surveillance and attention to both liver and extrahepatic medical conditions immediately after CLD discharge is encouraged

Future of an "Asymptomatic" T-cell Epitope-Based Therapeutic Herpes Simplex Vaccine

SummaryConsidering the limited success of the recent herpes clinical vaccine trial [1], new vaccine strategies are needed. Infections with herpes simplex virus type 1 and type 2 (HSV-1 &amp; HSV-2) in the majority of men and women are usually asymptomatic and results in lifelong viral latency in neurons of sensory ganglia (SG). However, in a minority of men and women HSV spontaneous reactivation can cause recurrent disease (i.e., symptomatic individuals). Our recent findings show that T cells from symptomatic and asymptomatic men and women (i.e. those with and without recurrences, respectively) recognize different herpes epitopes. This finding breaks new ground and opens new doors to assess a new vaccine strategy: mucosal immunization with HSV-1 &amp; HSV-2 epitopes that induce strong in vitro CD4 and CD8 T cell responses from PBMC derived from asymptomatic men and women (designated here as “asymptomatic” protective epitopes”) could boost local and systemic “natural” protective immunity, induced by wild-type infection. Here we highlight the rationale and the future of our emerging “asymptomatic” T cell epitope-based mucosal vaccine strategy to decrease recurrent herpetic disease

Future of an "Asymptomatic" T-cell Epitope-Based Therapeutic Herpes Simplex Vaccine

SummaryConsidering the limited success of the recent herpes clinical vaccine trial [1], new vaccine strategies are needed. Infections with herpes simplex virus type 1 and type 2 (HSV-1 &amp; HSV-2) in the majority of men and women are usually asymptomatic and results in lifelong viral latency in neurons of sensory ganglia (SG). However, in a minority of men and women HSV spontaneous reactivation can cause recurrent disease (i.e., symptomatic individuals). Our recent findings show that T cells from symptomatic and asymptomatic men and women (i.e. those with and without recurrences, respectively) recognize different herpes epitopes. This finding breaks new ground and opens new doors to assess a new vaccine strategy: mucosal immunization with HSV-1 &amp; HSV-2 epitopes that induce strong in vitro CD4 and CD8 T cell responses from PBMC derived from asymptomatic men and women (designated here as “asymptomatic” protective epitopes”) could boost local and systemic “natural” protective immunity, induced by wild-type infection. Here we highlight the rationale and the future of our emerging “asymptomatic” T cell epitope-based mucosal vaccine strategy to decrease recurrent herpetic disease

The herpes simplex virus type 1 latency-associated transcript inhibits phenotypic and functional maturation of dendritic cells.

We recently found that the herpes simplex virus-1 (HSV-1) latency-associated transcript (LAT) results in exhaustion of virus-specific CD8⁺ T cells in latently-infected trigeminal ganglia (TG). In this study we sought to determine if this impairment may involve LAT directly and/or indirectly interfering with DC maturation. We found that a small number of HSV-1 antigen-positive DCs are present in the TG of latently-infected CD11c/eYFP mice; however, this does not imply that these DCs are acutely or latently infected. Some CD8⁺ T cells are adjacent to DCs, suggesting possible interactions. It has previously been shown that wild-type HSV-1 interferes with DC maturation. Here we show for the first time that this is associated with LAT expression, since compared to LAT⁻ virus: (1) LAT⁺ virus interfered with expression of MHC class I and the co-stimulatory molecules CD80 and CD86 on the surface of DCs; (2) LAT⁺ virus impaired DC production of the proinflammatory cytokines IL-6, IL-12, and TNF-α; and (3) DCs infected in vitro with LAT⁺ virus had significantly reduced the ability to stimulate HSV-specific CD8⁺ T cells. While a similar number of DCs was found in LAT⁺ and LAT⁻ latently-infected TG of CD11c/eYFP transgenic mice, more HSV-1 Ag-positive DCs and more exhausted CD8 T cells were seen with LAT⁺ virus. Consistent with these findings, HSV-specific cytotoxic CD8⁺ T cells in the TG of mice latently-infected with LAT⁺ virus produced less IFN-γ and TNF-α than those from TG of LAT⁻-infected mice. Together, these results suggest a novel immune-evasion mechanism whereby the HSV-1 LAT increases the number of HSV-1 Ag-positive DCs in latently-infected TG, and interferes with DC phenotypic and functional maturation. The effect of LAT on TG-resident DCs may contribute to the reduced function of HSV-specific CD8⁺ T cells in the TG of mice latently infected with LAT⁺ virus

The Herpes Simplex Virus Type 1 Latency-Associated Transcript Inhibits Phenotypic and Functional Maturation of Dendritic Cells

We recently found that the herpes simplex virus-1 (HSV-1) latency-associated transcript (LAT) results in exhaustion of virus-specific CD8+ T cells in latently-infected trigeminal ganglia (TG). In this study we sought to determine if this impairment may involve LAT directly and/or indirectly interfering with DC maturation. We found that a small number of HSV-1 antigen-positive DCs are present in the TG of latently-infected CD11c/eYFP mice; however, this does not imply that these DCs are acutely or latently infected. Some CD8+ T cells are adjacent to DCs, suggesting possible interactions. It has previously been shown that wild-type HSV-1 interferes with DC maturation. Here we show for the first time that this is associated with LAT expression, since compared to LAT(−) virus: (1) LAT(+) virus interfered with expression of MHC class I and the co-stimulatory molecules CD80 and CD86 on the surface of DCs; (2) LAT(+) virus impaired DC production of the proinflammatory cytokines IL-6, IL-12, and TNF-α; and (3) DCs infected in vitro with LAT(+) virus had significantly reduced the ability to stimulate HSV-specific CD8+ T cells. While a similar number of DCs was found in LAT(+) and LAT(−) latently-infected TG of CD11c/eYFP transgenic mice, more HSV-1 Ag-positive DCs and more exhausted CD8 T cells were seen with LAT(+) virus. Consistent with these findings, HSV-specific cytotoxic CD8+ T cells in the TG of mice latently-infected with LAT(+) virus produced less IFN-γ and TNF-α than those from TG of LAT(−)-infected mice. Together, these results suggest a novel immune-evasion mechanism whereby the HSV-1 LAT increases the number of HSV-1 Ag-positive DCs in latently-infected TG, and interferes with DC phenotypic and functional maturation. The effect of LAT on TG-resident DCs may contribute to the reduced function of HSV-specific CD8+ T cells in the TG of mice latently infected with LAT(+) virus