Abstract. In 1994–1995, a child and five dogs from villages located between Jerusalem and Tel-Avi... more Abstract. In 1994–1995, a child and five dogs from villages located between Jerusalem and Tel-Aviv, Israel were diagnosed with visceral leishmaniasis (VL). Based on these findings, the distribution of VL in domestic and wild canids in central Israel was examined. In the two villages where canine index cases were identified, a substantial proportion (11.5%, 14 of 122) of the dogs examined were seropositive. However, the rate of infection in five neigh-boring villages was only 1 % (1 of 99). Parasites were cultured from 92 % (12 of 13) of the seropositive dogs biopsied and the strains were characterized as Leishmania infantum by a clamped polymorphic–polymerase chain reaction, monoclonal antibodies, and/or excreted factor serology. The discovery of VL close to major urban centers is an important public health issue. The disease appears to have emerged recently in this area, and it is unclear whether the parasite was re-introduced or was continuously present at low levels in this regio...
Asymptomatic human visceral leishmaniasis was identified in Israel by using an enzyme-linked immu... more Asymptomatic human visceral leishmaniasis was identified in Israel by using an enzyme-linked immunosorbent assay. Positive serum samples were more prevalent in visceral leishmaniasis–endemic (2.97%) compared to nonendemic (1.01%) regions (p=0.021). Parasite exposure was higher than expected, despite the small number of clinical cases, suggesting factors other than infection per se influence clinical outcome. Human visceral leishmaniasis (HVL), caused by the Leishmania donovani complex, is lethal if not promptly diagnosed and treated (1). Yet in the Mediterranean and Middle East, only a small percentage of infections progress to clinical disease (2,3). HVL in this region is primarily a disease of young children; however, its epidemiology is changing. In southern Europe, 50 % of new cases are in adults coinfected with HIV (4).
RhoB controls coordination of adult angiogenesis and lymphangiogenesis following injury by regula... more RhoB controls coordination of adult angiogenesis and lymphangiogenesis following injury by regulating VEZF1-mediated transcription.
Epidemiological studies have associated pigment production with protection against certain human ... more Epidemiological studies have associated pigment production with protection against certain human diseases. In contrast to African Americans, European descendants are more likely to suffer from angiogenesis-dependent and inflammatory diseases, such as wet age-related macular degeneration (ARMD) and ulcerative colitis (UC), respectively. In this study, albino mice that produced high levels of fibromodulin (FMOD) developed less severe acute colitis compared with mice lacking in FMOD as assessed by clinical symptoms and histopathological changes. In a mouse model of dextran sodium sulfate (DSS)-induced acute colitis, FMOD depletion affected the expression and localization of tight junction proteins, contributing to the destruction of the epithelial barrier. Furthermore, this study revealed a stronger inflammatory response after DSS treatment in the absence of FMOD, where FMOD depletion led to an increase in activated T cells, plasmacytoid dendritic cells (pDCs), and type I IFN productio...
Cardiomyopathy often leads to dilated cardiomyopathy (DCM) when caused by viral myocarditis. Apop... more Cardiomyopathy often leads to dilated cardiomyopathy (DCM) when caused by viral myocarditis. Apoptosis is long considered as the principal process of cell death in cardiomyocytes, but programmed necrosis or necroptosis is recently believed to play an important role in cardiomyocyte cell death. We investigated the role of necroptosis and its interdependency with other processes of cell death, autophagy, and apoptosis in a rat system of experimental autoimmune myocarditis (EAM). We successfully created a rat model system of EAM by injecting porcine cardiac myosin (PCM) and showed that in EAM, all three forms of cell death increase considerably, resulting in the deterioration of cardiac conditions with an increase in inflammatory infiltration in cardiomyocytes. To explore whether necroptosis occurs in EAM rats independent of autophagy, we treated EAM rats with a RIP1/RIP3/MLKL kinase-mediated necroptosis inhibitor, Necrostatin-1 (Nec-1). In Nec-1 treated rats, cell death proceeds throu...
Human visceral leishmaniasis (HVL), caused by the Leishmania donovani complex, is lethal if not p... more Human visceral leishmaniasis (HVL), caused by the Leishmania donovani complex, is lethal if not promptly diagnosed and treated (1). Yet in the Mediterranean and Middle East, only a small percentage of infections progress to clinical disease (2,3). HVL in this region is primarily a disease of young children; however, its epidemiology is changing. In southern Europe, 50% of new cases are in adults coinfected with HIV (4). HVL is endemic in northern Israel; 68 cases, mostly from Arab villages, were documented from 1960 to 1989 (5). Since 1993, a drastic reduction in the disease was observed, despite the identification of nine active sites of canine visceral leishmaniasis (VL) in this region (G. Baneth and C. L. Jaffe, unpub. data). Recent studies have identified an emerging focus of human and canine disease near major population centers in central Israel and the Palestinian Authority (6,7). In this study, HVL seroprevalence in northern Israel was compared with that in a region free of ...
SummaryDoes fibrotic gut stiffening caused by inflammatory bowel diseases (IBD) direct the fate o... more SummaryDoes fibrotic gut stiffening caused by inflammatory bowel diseases (IBD) direct the fate of intestinal stem cells (ISCs)? To address this question we first developed a novel long-term culture of quasi-3D gut organoids plated on hydrogel matrix of varying stiffness. Stiffening from 0.6kPa to 9.6kPa significantly reduces Lgr5high ISCs and Ki67+ progenitor cells while promoting their differentiation towards goblet cells. These stiffness-driven events are attributable to YAP nuclear translocation. Matrix stiffening also extends the expression of the stemness marker Olfactomedin 4 (Olfm4) into villus-like regions, mediated by cytoplasmic YAP. We next used single-cell RNA sequencing to generate for the first time the stiffness-regulated transcriptional signatures of ISCs and their differentiated counterparts. These signatures confirm the impact of stiffening on ISC fate and additionally suggest a stiffening-induced switch in metabolic phenotype, from oxidative phosphorylation to gl...
Several angiogenesis-dependent diseases, including age-related macular degeneration and infantile... more Several angiogenesis-dependent diseases, including age-related macular degeneration and infantile hemangioma, display differential prevalence among Black, as compared to White individuals. Although socioeconomic status and genetic architecture have been suggested as explaining these differences, we have recently shown that pigment production per se might be involved. For example, we have shown that the extracellular protein fibromodulin is a pro-angiogenic factor highly secreted by melanocytes in White but not Black individuals. Still, additional pigment-dependent angiogenic factors and their molecular mechanisms remain to be identified. Understanding the contribution of pigmentation to angiogenesis in health and disease is essential for precision medicine of angiogenesis-dependent diseases with racial disparity. Toward that goal, we compared the transcriptomes of Black and White individuals in three tissues with angiogenic activity, namely artery, whole blood, and skin. We identifi...
Myocardial infarction (MI) remains the leading cause of death in the western world. Despite advan... more Myocardial infarction (MI) remains the leading cause of death in the western world. Despite advancements in interventional revascularization technologies, many patients are not candidates for them due to comorbidities or lack of local resources. Non-invasive approaches to accelerate revascularization within ischemic tissues through angiogenesis by providing Vascular Endothelial Growth Factor (VEGF) in protein or gene form has been effective in animal models but not in humans likely due to its short half-life and systemic toxicity. Here, we tested the hypothesis that PR1P, a small VEGF binding peptide that we developed, which stabilizes and upregulates endogenous VEGF, could be used to improve outcome from MI in rodents. To test this hypothesis, we induced MI in mice and rats via left coronary artery ligation and then treated animals with every other day intraperitoneal PR1P or scrambled peptide for 14 days. Hemodynamic monitoring and echocardiography in mice and echocardiography in ...
Abstract. In 1994–1995, a child and five dogs from villages located between Jerusalem and Tel-Avi... more Abstract. In 1994–1995, a child and five dogs from villages located between Jerusalem and Tel-Aviv, Israel were diagnosed with visceral leishmaniasis (VL). Based on these findings, the distribution of VL in domestic and wild canids in central Israel was examined. In the two villages where canine index cases were identified, a substantial proportion (11.5%, 14 of 122) of the dogs examined were seropositive. However, the rate of infection in five neigh-boring villages was only 1 % (1 of 99). Parasites were cultured from 92 % (12 of 13) of the seropositive dogs biopsied and the strains were characterized as Leishmania infantum by a clamped polymorphic–polymerase chain reaction, monoclonal antibodies, and/or excreted factor serology. The discovery of VL close to major urban centers is an important public health issue. The disease appears to have emerged recently in this area, and it is unclear whether the parasite was re-introduced or was continuously present at low levels in this regio...
Asymptomatic human visceral leishmaniasis was identified in Israel by using an enzyme-linked immu... more Asymptomatic human visceral leishmaniasis was identified in Israel by using an enzyme-linked immunosorbent assay. Positive serum samples were more prevalent in visceral leishmaniasis–endemic (2.97%) compared to nonendemic (1.01%) regions (p=0.021). Parasite exposure was higher than expected, despite the small number of clinical cases, suggesting factors other than infection per se influence clinical outcome. Human visceral leishmaniasis (HVL), caused by the Leishmania donovani complex, is lethal if not promptly diagnosed and treated (1). Yet in the Mediterranean and Middle East, only a small percentage of infections progress to clinical disease (2,3). HVL in this region is primarily a disease of young children; however, its epidemiology is changing. In southern Europe, 50 % of new cases are in adults coinfected with HIV (4).
RhoB controls coordination of adult angiogenesis and lymphangiogenesis following injury by regula... more RhoB controls coordination of adult angiogenesis and lymphangiogenesis following injury by regulating VEZF1-mediated transcription.
Epidemiological studies have associated pigment production with protection against certain human ... more Epidemiological studies have associated pigment production with protection against certain human diseases. In contrast to African Americans, European descendants are more likely to suffer from angiogenesis-dependent and inflammatory diseases, such as wet age-related macular degeneration (ARMD) and ulcerative colitis (UC), respectively. In this study, albino mice that produced high levels of fibromodulin (FMOD) developed less severe acute colitis compared with mice lacking in FMOD as assessed by clinical symptoms and histopathological changes. In a mouse model of dextran sodium sulfate (DSS)-induced acute colitis, FMOD depletion affected the expression and localization of tight junction proteins, contributing to the destruction of the epithelial barrier. Furthermore, this study revealed a stronger inflammatory response after DSS treatment in the absence of FMOD, where FMOD depletion led to an increase in activated T cells, plasmacytoid dendritic cells (pDCs), and type I IFN productio...
Cardiomyopathy often leads to dilated cardiomyopathy (DCM) when caused by viral myocarditis. Apop... more Cardiomyopathy often leads to dilated cardiomyopathy (DCM) when caused by viral myocarditis. Apoptosis is long considered as the principal process of cell death in cardiomyocytes, but programmed necrosis or necroptosis is recently believed to play an important role in cardiomyocyte cell death. We investigated the role of necroptosis and its interdependency with other processes of cell death, autophagy, and apoptosis in a rat system of experimental autoimmune myocarditis (EAM). We successfully created a rat model system of EAM by injecting porcine cardiac myosin (PCM) and showed that in EAM, all three forms of cell death increase considerably, resulting in the deterioration of cardiac conditions with an increase in inflammatory infiltration in cardiomyocytes. To explore whether necroptosis occurs in EAM rats independent of autophagy, we treated EAM rats with a RIP1/RIP3/MLKL kinase-mediated necroptosis inhibitor, Necrostatin-1 (Nec-1). In Nec-1 treated rats, cell death proceeds throu...
Human visceral leishmaniasis (HVL), caused by the Leishmania donovani complex, is lethal if not p... more Human visceral leishmaniasis (HVL), caused by the Leishmania donovani complex, is lethal if not promptly diagnosed and treated (1). Yet in the Mediterranean and Middle East, only a small percentage of infections progress to clinical disease (2,3). HVL in this region is primarily a disease of young children; however, its epidemiology is changing. In southern Europe, 50% of new cases are in adults coinfected with HIV (4). HVL is endemic in northern Israel; 68 cases, mostly from Arab villages, were documented from 1960 to 1989 (5). Since 1993, a drastic reduction in the disease was observed, despite the identification of nine active sites of canine visceral leishmaniasis (VL) in this region (G. Baneth and C. L. Jaffe, unpub. data). Recent studies have identified an emerging focus of human and canine disease near major population centers in central Israel and the Palestinian Authority (6,7). In this study, HVL seroprevalence in northern Israel was compared with that in a region free of ...
SummaryDoes fibrotic gut stiffening caused by inflammatory bowel diseases (IBD) direct the fate o... more SummaryDoes fibrotic gut stiffening caused by inflammatory bowel diseases (IBD) direct the fate of intestinal stem cells (ISCs)? To address this question we first developed a novel long-term culture of quasi-3D gut organoids plated on hydrogel matrix of varying stiffness. Stiffening from 0.6kPa to 9.6kPa significantly reduces Lgr5high ISCs and Ki67+ progenitor cells while promoting their differentiation towards goblet cells. These stiffness-driven events are attributable to YAP nuclear translocation. Matrix stiffening also extends the expression of the stemness marker Olfactomedin 4 (Olfm4) into villus-like regions, mediated by cytoplasmic YAP. We next used single-cell RNA sequencing to generate for the first time the stiffness-regulated transcriptional signatures of ISCs and their differentiated counterparts. These signatures confirm the impact of stiffening on ISC fate and additionally suggest a stiffening-induced switch in metabolic phenotype, from oxidative phosphorylation to gl...
Several angiogenesis-dependent diseases, including age-related macular degeneration and infantile... more Several angiogenesis-dependent diseases, including age-related macular degeneration and infantile hemangioma, display differential prevalence among Black, as compared to White individuals. Although socioeconomic status and genetic architecture have been suggested as explaining these differences, we have recently shown that pigment production per se might be involved. For example, we have shown that the extracellular protein fibromodulin is a pro-angiogenic factor highly secreted by melanocytes in White but not Black individuals. Still, additional pigment-dependent angiogenic factors and their molecular mechanisms remain to be identified. Understanding the contribution of pigmentation to angiogenesis in health and disease is essential for precision medicine of angiogenesis-dependent diseases with racial disparity. Toward that goal, we compared the transcriptomes of Black and White individuals in three tissues with angiogenic activity, namely artery, whole blood, and skin. We identifi...
Myocardial infarction (MI) remains the leading cause of death in the western world. Despite advan... more Myocardial infarction (MI) remains the leading cause of death in the western world. Despite advancements in interventional revascularization technologies, many patients are not candidates for them due to comorbidities or lack of local resources. Non-invasive approaches to accelerate revascularization within ischemic tissues through angiogenesis by providing Vascular Endothelial Growth Factor (VEGF) in protein or gene form has been effective in animal models but not in humans likely due to its short half-life and systemic toxicity. Here, we tested the hypothesis that PR1P, a small VEGF binding peptide that we developed, which stabilizes and upregulates endogenous VEGF, could be used to improve outcome from MI in rodents. To test this hypothesis, we induced MI in mice and rats via left coronary artery ligation and then treated animals with every other day intraperitoneal PR1P or scrambled peptide for 14 days. Hemodynamic monitoring and echocardiography in mice and echocardiography in ...
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