The Soreq Applied Research Accelerator Facility (SARAF) - Overview, Research Programs and Future Plans

The Soreq Applied Research Accelerator Facility (SARAF) is under construction in the Soreq Nuclear Research Center at Yavne, Israel. When completed at the beginning of the next decade, SARAF will be a user facility for basic and applied nuclear physics, based on a 40 MeV, 5 mA CW proton/deuteron superconducting linear accelerator. Phase I of SARAF (SARAF-I, 4 MeV, 2 mA CW protons, 5 MeV 1 mA CW deuterons) is already in operation, generating scientific results in several fields of interest. The main ongoing program at SARAF-I is the production of 30 keV neutrons and measurement of Maxwellian Averaged Cross Sections (MACS), important for the astrophysical s-process. The world leading Maxwellian epithermal neutron yield at SARAF-I ($5\times 10^{10}$ epithermal neutrons/sec), generated by a novel Liquid-Lithium Target (LiLiT), enables improved precision of known MACSs, and new measurements of low-abundance and radioactive isotopes. Research plans for SARAF-II span several disciplines: Precision studies of beyond-Standard-Model effects by trapping light exotic radioisotopes, such as $^6$He, $^8$Li and $^{18,19,23}$Ne, in unprecedented amounts (including meaningful studies already at SARAF-I); extended nuclear astrophysics research with higher energy neutrons, including generation and studies of exotic neutron-rich isotopes relevant to the rapid (r-) process; nuclear structure of exotic isotopes; high energy neutron cross sections for basic nuclear physics and material science research, including neutron induced radiation damage; neutron based imaging and therapy; and novel radiopharmaceuticals development and production. In this paper we present a technical overview of SARAF-I and II, including a description of the accelerator and its irradiation targets; a survey of existing research programs at SARAF-I; and the research potential at the completed facility (SARAF-II).Comment: 32 pages, 31 figures, 10 tables, submitted as an invited review to European Physics Journal

aPKCζ affects directed cell migration through the regulation of myosin light chain phosphorylation

<p>Cell motility is an essential cellular process for a variety of biological events. It requires cross-talk between the signaling and the cytoskeletal systems. Despite the recognized importance of aPKCζ for cell motility, there is little understanding of the mechanism by which aPKCζ mediates extracellular signals to the cytoskeleton. In the present study, we report that aPKCζ is required for the cellular organization of acto-non-muscle myosin II (NMII) cytoskeleton, for proper cell adhesion and directed cell migration. We show that aPKCζ mediates EGF-dependent RhoA activation and recruitment to the cell membrane. We also show that aPKCζ mediates EGF-dependent myosin light chain (MRLC) phosphorylation that is carried out by Rho-associated protein kinase (ROCK), and that aPKCζ is required for EGF-dependent phosphorylation and inhibition of the myosin phosphatase targeting subunit (MYPT). Finally, we show that aPKCζ mediates the spatial organization of the acto-NMII cytoskeleton in response to EGF stimulation. Our data suggest that aPKCζ is an essential component regulator of acto-NMII cytoskeleton organization leading to directed cell migration, and is a mediator of the EGF signal to the cytoskeleton.</p

The Therapeutic Effect of Active Vitamin D Supplementation in Preventing the Progression of Diabetic Nephropathy in a Diabetic Mouse Model

Background. Diabetic nephropathy (DN) is one of the most common microvascular complications of diabetes and is the leading cause of end-stage renal disease (ESRD) and replacement therapy worldwide. Vitamin D levels in DN patients are very low due to the decrease in the synthesis and activity of 1-α hydroxylase in the proximal tubule cells and decrease in the vitamin D receptor abundance. To date, few studies have shown the antioxidant effects of 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3] on hyperglycemia-induced renal injury. The selective activator of the vitamin D receptor, paricalcitol, reduces proteinuria and slows the progression of kidney injury. The precise mechanism through which vitamin D affects diabetic status and provides kidney protection remains to be determined. Methods. Diabetes mellitus (DM) was induced in 94 8-week-old DBA/2J mice by intraperitoneal injection of streptozotocin (STZ). DM mice were randomly divided into receiving vehicle or treatment with paricalcitol, the active vitamin D analog, 1 week after DM induction or paricalcitol treatment 3 weeks after DM induction. An additional control group of healthy wild-type mice was not treated. Urine albumin, blood urea nitrogen, and creatinine levels were measured before and at the end of the paricalcitol treatment. Periodic acid-Schiff, immunohistochemistry staining, and western blot of the renal tissues of vitamin D receptor, villin, nephrin, and podocin expressions, were analyzed. Results. Paricalcitol treatment restored villin, nephrin, and podocin protein levels that were downregulated upon DM induction, and reduced fibronectin protein level. Vitamin D receptor activation by paricalcitol may reduce proteinuria of DN in mice and alleviate high-glucose-induced injury of kidney podocytes by regulating the key molecules such nephrin-podocin. Conclusions. Paricalcitol treatment was associated with improved structural changes in type 1 diabetic mice including upregulation of vitamin D receptor expression, and decreased fibrosis markers such as fibronectin. These effects may contribute to the consistent benefit of vitamin D analog to slow the deterioration in glomerular function and reduce the risk of ESRD in patients with type 1 and 2 diabetes mellitus. Our results suggest that additional use of paricalcitol may be beneficial in treating patients with diabetes under standard therapeutic strategies

The Iron-Klotho-VDR Axis Is a Major Determinant of Proximal Convoluted Tubule Injury in Haptoglobin 2-2 Genotype Diabetic Nephropathy Patients and Mice

The haptoglobin (Hp) genotype (1-1 and 2-2) is a major determinant of nephropathy progression in diabetes mellitus patients. Hp 2-2 diabetic mice have impaired Hb clearance and increased iron deposits and oxidative stress in the proximal tubules (PCT), leading to increased renal injury. However, the precise mechanism of the PCT injury in diabetic nephropathy (DN) remains elusive. In the kidney, 1,25(OH)2D3 suppresses the inflammatory response to renal tubular injury and requires normal renal expression of the α-klotho protein. In this study, we set out to test the hypothesis that the increased renal iron deposits in the PCT of Hp 2-2 DN affect the α-klotho-vitamin D receptor (VDR) axis and thereby exacerbates the PCT injury generated by the iron deposits. Immunohistochemical analysis of human and mouse kidney biopsies along with western blot analysis showed that the increased iron deposits in the PCT of the Hp 2-2 genotype were accompanied with significantly decreased α-klotho and VDR renal expression but significantly increased 1-α-hydroxylase renal expression. In conclusion, the iron-klotho-VDR axis is a major player in the mechanism contributing to iron-mediated PCT injury in diabetic Hp 2-2 mice and patients. Targeting this axis may open the way for new ideas regarding the pathogenesis and treatment of DN

Clinical Study Interaction between the Haptoglobin 2 Phenotype and Diabetes Mellitus on Systolic Pulmonary Arterial Pressure and Nitric Oxide Bioavailability in Hemodialysis Patients

Elevated systolic pulmonary artery pressure (s-PAP, ≥35 mmHg) serves as an independent predictor of mortality in hemodialysis (HD) and diabetic (DM) patients. A polymorphism in the antioxidant Haptoglobin (Hp) gene has been shown to regulate the bioavailability of nitric oxide (NO), a major mediator of pulmonary vascular tone. We therefore set out to test the hypothesis that the Hp polymorphism may be a determinant of developing elevated s-PAP specifically in the DM state due to a decreased bioavailability of NO. To test our hypothesis we Hp typed and performed transthoracic echocardiography on a series of HD patients and stratified them into elevated and normal s-PAP groups and then evaluated whether there was a significant association between the Hp type, elevated s-PAP, and decreased NO bioavailability as defined by low plasma nitrite. We found a statistically significant interaction between the Hp type and DM on the prevalence of elevated s-PAP and lower mean nitrite levels with the combination of elevated s-PAP and low nitrite levels being significantly more prevalent in Hp 2-2 DM individuals. We conclude that the Hp 2 type is associated with elevated s-PAP levels and low plasma nitrite levels in HD patients specifically in the DM state

Interaction between the Haptoglobin 2 Phenotype and Diabetes Mellitus on Systolic Pulmonary Arterial Pressure and Nitric Oxide Bioavailability in Hemodialysis Patients

Elevated systolic pulmonary artery pressure (s-PAP, ≥35 mmHg) serves as an independent predictor of mortality in hemodialysis (HD) and diabetic (DM) patients. A polymorphism in the antioxidant Haptoglobin (Hp) gene has been shown to regulate the bioavailability of nitric oxide (NO), a major mediator of pulmonary vascular tone. We therefore set out to test the hypothesis that the Hp polymorphism may be a determinant of developing elevated s-PAP specifically in the DM state due to a decreased bioavailability of NO. To test our hypothesis we Hp typed and performed transthoracic echocardiography on a series of HD patients and stratified them into elevated and normal s-PAP groups and then evaluated whether there was a significant association between the Hp type, elevated s-PAP, and decreased NO bioavailability as defined by low plasma nitrite. We found a statistically significant interaction between the Hp type and DM on the prevalence of elevated s-PAP and lower mean nitrite levels with the combination of elevated s-PAP and low nitrite levels being significantly more prevalent in Hp 2-2 DM individuals. We conclude that the Hp 2 type is associated with elevated s-PAP levels and low plasma nitrite levels in HD patients specifically in the DM state

The Soreq Applied Research Accelerator Facility (SARAF): Overview, research programs and future plans

The Soreq Applied Research Accelerator Facility (SARAF) is under construction in the Soreq Nuclear Research Center at Yavne, Israel. When completed at the beginning of the next decade, SARAF will be a user facility for basic and applied nuclear physics, based on a 40 MeV, 5 mA CW proton/deuteron superconducting linear accelerator. Phase I of SARAF (SARAF-I, 4 MeV, 2 mA CW protons, 5 MeV 1 mA CW deuterons) is already in operation, generating scientific results in several fields of interest. The main ongoing program at SARAF-I is the production of 30 keV neutrons and measurement of Maxwellian Averaged Cross Sections (MACS), important for the astrophysical s-process. The world leading Maxwellian epithermal neutron yield at SARAF-I ($5\times 10^{10}$ epithermal neutrons/sec), generated by a novel Liquid-Lithium Target (LiLiT), enables improved precision of known MACSs, and new measurements of low-abundance and radioactive isotopes. Research plans for SARAF-II span several disciplines: Precision studies of beyond-Standard-Model effects by trapping light exotic radioisotopes, such as $^6$He, $^8$Li and $^{18,19,23}$Ne, in unprecedented amounts (including meaningful studies already at SARAF-I); extended nuclear astrophysics research with higher energy neutrons, including generation and studies of exotic neutron-rich isotopes relevant to the rapid (r-) process; nuclear structure of exotic isotopes; high energy neutron cross sections for basic nuclear physics and material science research, including neutron induced radiation damage; neutron based imaging and therapy; and novel radiopharmaceuticals development and production. In this paper we present a technical overview of SARAF-I and II, including a description of the accelerator and its irradiation targets; a survey of existing research programs at SARAF-I; and the research potential at the completed facility (SARAF-II).Comment: 32 pages, 31 figures, 10 tables, submitted as an invited review to European Physics Journal

The tumor suppressor Lgl1 regulates NMII-A cellular distribution and focal adhesion morphology to optimize cell migration

ETOC: Lgl1 interacts directly with NMII-A, inhibiting its filament assembly. It excludes NMII-A from the cell leading edge. Depletion of Lgl1 affects the size and number of focal adhesions, cell polarity, and the rate of migrating cells. These results indicate that Lgl1 regulates the polarity of migrating cells by controlling NMII-A filament assembly