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Publications (74)345.29 Total impact
Article: Gα13 Switch Region 2 Binds to the Talin Head Domain and Activates αIIbβ3 Integrin in Human Platelets[Show abstract] [Hide abstract]
ABSTRACT: Even though GPCR signaling in human platelets is directly involved in hemostasis and thrombus formation, the sequence of events by which G protein activation leads to αIIbβ3 integrin activation (inside-out signaling) is not clearly defined. We previously demonstrated that a conformationally sensitive domain of one G protein, i.e., Gα13 switch region 1 (Gα13SR1), can directly participate in the platelet inside-out signaling process. Interestingly however, the dependence on Gα13SR1 signaling was limited to PAR1 receptors, and did not involve signaling through other important platelet GPCRs. Based on the limited scope of this involvement, and the known importance of G13 in hemostasis and thrombosis, the present study examined whether signaling through another switch region of G13, i.e., Gα13 switch region 2 (Gα13SR2) may represent a more global mechanism of platelet activation. Using multiple experimental approaches, our results demonstrate that Gα13SR2 forms a bi-molecular complex with the head domain of talin and thereby promotes β3 integrin activation. Moreover, additional studies provided evidence that Gα13SR2 is not constitutively associated with talin in unactivated platelets, but becomes bound to talin in response to elevated intraplatelet calcium levels. Collectively, these findings provide evidence for a novel paradigm of inside-out signaling in platelets, whereby β3 integrin activation involves the direct binding of the talin head domain to the switch region 2 sequence of the Gα13 subunit. Copyright © 2015, The American Society for Biochemistry and Molecular Biology.
Article: Merozoite surface protein 1 recognition of host glycophorin A mediates malaria parasite invasion of red blood cells[Show abstract] [Hide abstract]
ABSTRACT: Plasmodium falciparum invasion of human red blood cells (RBCs) is an intricate process requiring a number of distinct ligand-receptor interactions at the merozoite-erythrocyte interface. Merozoite surface protein 1 (MSP1), a highly abundant ligand coating the merozoite surface in all species of malaria, is essential for RBC invasion and considered a leading candidate for inclusion in a multi-subunit vaccine against malaria. Our previous studies identified an interaction between the carboxyl-terminus of MSP1 and RBC band 3. Here, by employing phage display technology, we report a novel interaction between the amino-terminus of MSP1 and RBC glycophorin A (GPA). Mapping of the binding domains established a direct interaction between malaria MSP1 and human GPA within a region of MSP1 known to potently inhibit P. falciparum invasion of human RBCs. Furthermore, a genetically modified mouse model lacking the Band 3-GPA complex in RBCs is completely resistant to malaria infection in vivo. These findings suggest an essential role of the MSP1-GPA-Band 3 complex during the initial adhesion phase of malaria parasite invasion of red blood cells. Copyright © 2015 American Society of Hematology.
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ABSTRACT: In this issue of Blood, Rieger et al show that malaria parasite infiltration in the human placenta requires a specific geometry and affinity of host receptors to facilitate strong adhesion.
Article: Human erythrocyte Band 3 functions as a receptor for the sialic acid-independent invasion of Plasmodium falciparum. Role of the RhopH3-MSP1 complex.[Show abstract] [Hide abstract]
ABSTRACT: Plasmodium falciparum takes advantage of two broadly defined alternate invasion pathways when infecting human erythrocytes: one that depends on and the other that is independent of host sialic acid residues on the erythrocyte surface. Within the sialic acid-dependent (SAD) and sialic acid-independent (SAID) invasion pathways, several alternate host receptors are used by Plasmodium falciparum based on its particular invasion phenotype. Earlier, we reported that two putative extracellular regions of human erythrocyte band 3 termed 5C and 6A function as host invasion receptor segments binding parasite proteins MSP1 and MSP9 via a SAID mechanism. In this study, we developed two mono-specific anti-peptide chicken IgY antibodies to demonstrate that the 5C and 6A regions of band 3 are exposed on the surface of human erythrocytes. These antibodies inhibited erythrocyte invasion by the Plasmodium falciparum 3D7 and 7G8 strains (SAID invasion phenotype), and the blocking effect was enhanced in sialic acid-depleted erythrocytes. In contrast, the IgY antibodies had only a marginal inhibitory effect on FCR3 and Dd2 strains (SAD invasion phenotype). A direct biochemical interaction between erythrocyte band 3 epitopes and parasite RhopH3, identified by the yeast two-hybrid screen, was established. RhopH3 formed a complex with MSP119 and 5ABC region of band 3, and a recombinant segment of RhopH3 inhibited parasite invasion in human erythrocytes. Together, these findings provide evidence that erythrocyte band 3 functions as a major host invasion receptor in the SAID invasion pathway by assembling a multi-protein complex composed of parasite ligands RhopH3 and MSP1.
Article: Plasmodium falciparum signal peptide peptidase cleaves malaria heat shock protein 101 (HSP101). Implications for gametocytogenesis[Show abstract] [Hide abstract]
ABSTRACT: Previously we described the identification of a Plasmodium falciparum signal peptide peptidase (PfSPP) functioning at the blood stage of malaria infection. Our studies also demonstrated that mammalian SPP inhibitors prevent malaria parasite growth at the late-ring/early trophozoite stage of intra-erythrocytic development. Consistent with its role in development, we tested the hypothesis that PfSPP functions at the endoplasmic reticulum of Plasmodium falciparum where it cleaves membrane-bound signal peptides generated following the enzyme activity of signal peptidase. The localization of PfSPP to the endoplasmic reticulum was confirmed by immunofluorescence microscopy and immunogold electron microscopy. Biochemical analysis indicated the existence of monomer and dimer forms of PfSPP in the parasite lysate. A comprehensive bioinformatics screen identified several candidate PfSPP substrates in the parasite genome. Using an established transfection based in vivo luminescence assay, malaria heat shock protein 101 (HSP101) was identified as a substrate of PfSPP, and partial inhibition of PfSPP correlated with the emergence of gametocytes. This finding unveils the first known substrate of PfSPP, and provides new perspectives for the function of intra-membrane proteolysis at the erythrocyte stage of malaria parasite life cycle.
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ABSTRACT: Mast cells play a central role in allergy through secretion of both preformed and newly synthesized mediators. Mast cell mediator secretion is controlled by a complex network of signaling events. Despite intensive studies, signaling pathways in the regulation of mast cell mediator secretion remain incompletely defined. In this study, we examined the role of calpain in IgE-dependent mast cell activation. IgE-mediated activation of mouse bone marrow-derived mast cells enhanced calpain activity. Inhibition of calpain activity by a number of calpain inhibitors reduced IgE-mediated mast cell degranulation both in vitro and in vivo. Calpain inhibitors blocked IgE-mediated TNF and IL-6 production in vitro and reduced late-phase allergic response in vivo. Importantly, mouse calpain-1 null bone marrow-derived mast cells showed reduced IgE-mediated mast cell degranulation in vitro and in vivo, diminished cytokine and chemokine production in vitro, and impaired late-phase allergic response in vivo. Further studies revealed that calpain-1 deficiency led to specific attenuation of IκB-NF-κB pathway and IKK-SNAP23 pathway, whereas calcium flux, MAPK, Akt, and NFAT pathway proceed normally in IgE-activated calpain-1 null mast cells. Thus, calpain-1 is identified as a novel regulator in IgE-mediated mast cell activation and could serve as a potential therapeutic target for the management of allergic inflammation.
Article: Distinct Roles for -Calpain and m-Calpain in Synaptic NMDAR-Mediated Neuroprotection and Extrasynaptic NMDAR-Mediated Neurodegeneration[Show abstract] [Hide abstract]
ABSTRACT: Prolonged calpain activation is widely recognized as a key component of neurodegeneration in a variety of pathological conditions. Numerous reports have also indicated that synaptic activation of NMDA receptors (NMDARs) provides neuroprotection against a variety of insults. Here, we report the paradoxical finding that such neuroprotection involves calpain activation. NMDAR activation in cultured rat cortical neurons was neuroprotective against starvation and oxidative stress-induced damage. It also resulted in the degradation of two splice variants of PH domain and Leucine-rich repeat Protein Phosphatase 1 (PHLPP1), PHLPP1α and PHLPP1β, which inhibit the Akt and ERK1/2 pathways. Synaptic NMDAR-induced neuroprotection and PHLPP1 degradation were blocked by calpain inhibition. Lentiviral knockdown of PHLPP1 mimicked the neuroprotective effects of synaptic NMDAR activation and occluded the effects of calpain inhibition on neuroprotection. In contrast to synaptic NMDAR activation, extrasynaptic NMDAR activation had no effect on PHLPP1 and the Akt and ERK1/2 pathways, but resulted in calpain-mediated degradation of striatal-enriched protein tyrosine phosphatase (STEP) and neuronal death. Using μ-calpain- and m-calpain-selective inhibitors and μ-calpain and m-calpain siRNAs, we found that μ-calpain-dependent PHLPP1 cleavage was involved in synaptic NMDAR-mediated neuroprotection, while m-calpain-mediated STEP degradation was associated with extrasynaptic NMDAR-induced neurotoxicity. Furthermore, m-calpain inhibition reduced while μ-calpain knockout exacerbated NMDA-induced neurotoxicity in acute mouse hippocampal slices. Thus, synaptic NMDAR-coupled μ-calpain activation is neuroprotective, while extrasynaptic NMDAR-coupled m-calpain activation is neurodegenerative. These results help to reconcile a number of contradictory results in the literature and have critical implications for the understanding and potential treatment of neurodegenerative diseases.
Article: Calpain-2 Compensation Promotes Angiotensin II-Induced Ascending and Abdominal Aortic Aneurysms in Calpain-1 Deficient Mice[Show abstract] [Hide abstract]
ABSTRACT: Recently, we demonstrated that angiotensin II (AngII)-infusion profoundly increased both aortic protein and activity of calpains, calcium-activated cysteine proteases, in mice. In addition, pharmacological inhibition of calpain attenuated AngII-induced abdominal aortic aneurysm (AA) in mice. Recent studies have shown that AngII infusion into mice leads to aneurysmal formation localized to the ascending aorta. However, the precise functional contribution of calpain isoforms (-1 or -2) in AngII-induced abdominal AA formation is not known. Similarly, a functional role of calpain in AngII-induced ascending AA remains to be defined. Using BDA-410, an inhibitor of calpains, and calpain-1 genetic deficient mice, we examined the relative contribution of calpain isoforms in AngII-induced ascending and abdominal AA development.
Article: The effects of Capn1 gene inactivation on skeletal muscle growth, development, and atrophy, and the compensatory role of other proteolytic systems[Show abstract] [Hide abstract]
ABSTRACT: Myofibrillar protein turnover is a key component of muscle growth and degeneration, requiring proteolytic enzymes to degrade the skeletal muscle proteins. The objective of this study was to investigate the role of the calpain proteolytic system in muscle growth development using μ-calpain knockout (KO) mice in comparison with control wild-type (WT) mice, and evaluate the subsequent effects of silencing this gene on other proteolytic systems. No differences in muscle development between genotypes were observed during the early stages of growth due to the up regulation of other proteolytic systems. The KO mice showed significantly greater m-calpain protein abundance (P < 0.01) and activity (P < 0.001), and greater caspase 3/7 activity (P < 0.05). At 30 wk of age, KO mice showed increased protein:DNA (P < 0.05) and RNA:DNA ratios (P < 0.01), greater protein content (P < 0.01) at the expense of lipid deposition (P < 0.05), and an increase in size and number of fast-twitch glycolytic muscle fibers (P < 0.05), suggesting that KO mice exhibit an increased capacity to accumulate and maintain protein in their skeletal muscle. Also, expression of proteins associated with muscle regeneration (neural cell adhesion molecule and myoD) were both reduced in the mature KO mice (P < 0.05 and P < 0.01, respectively), indicating less muscle regeneration and, therefore, less muscle damage. These findings indicate the concerted action of proteolytic systems to ensure muscle protein homeostasis in vivo. Furthermore, these data contribute to the existing evidence of the importance of the calpain system's involvement in muscle growth, development, and atrophy. Collectively, these data suggest that there are opportunities to target the calpain system to promote the growth and/or restoration of skeletal muscle mass.
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ABSTRACT: Background: Inactivation of integrin αIIbβ3 reverses platelet aggregate formation upon coagulation. Results and conclusion: Platelets from patient (Scott) and mouse (Capn1(-/-) and Ppif(-/-)) blood reveal a dual mechanism of αIIbβ3 inactivation: by calpain-2 cleavage of integrin-associated proteins and by cyclophilin D/TMEM16F-dependent phospholipid scrambling. Significance: These data provide novel insight into the switch mechanisms from aggregating to procoagulant platelets. Aggregation of platelets via activated integrin αIIbβ3 is a prerequisite for thrombus formation. Phosphatidylserine-exposing platelets with a key role in the coagulation process disconnect from a thrombus by integrin inactivation via an unknown mechanism. Here we show that αIIbβ3 inactivation in procoagulant platelets relies on a sustained high intracellular Ca(2+), stimulating intracellular cleavage of the β3 chain, talin, and Src kinase. Inhibition of calpain activity abolished protein cleavage, but only partly suppressed αIIbβ3 inactivation. Integrin αIIbβ3 inactivation was unchanged in platelets from Capn1(-/-) mice, suggesting a role of the calpain-2 isoform. Scott syndrome platelets, lacking the transmembrane protein TMEM16F and having low phosphatidylserine exposure, displayed reduced αIIbβ3 inactivation with the remaining activity fully dependent on calpain. In platelets from Ppif(-/-) mice, lacking mitochondrial permeability transition pore (mPTP) formation, agonist-induced phosphatidylserine exposure and αIIbβ3 inactivation were reduced. Treatment of human platelets with cyclosporin A gave a similar phenotype. Together, these data point to a dual mechanism of αIIbβ3 inactivation via calpain(-2) cleavage of integrin-associated proteins and via TMEM16F-dependent phospholipid scrambling with an assistant role of mPTP formation.
Article: Pharmacological inhibition of calpain-1 prevents red cell dehydration and reduces Gardos channel activity in a mouse model of sickle cell disease[Show abstract] [Hide abstract]
ABSTRACT: Sickle cell disease (SCD) is a globally distributed hereditary red blood cell (RBC) disorder. One of the hallmarks of SCD is the presence of circulating dense RBCs, which are important in SCD-related clinical manifestations. In human dense sickle cells, we found reduced calpastatin activity and protein expression compared to either healthy RBCs or unfractionated sickle cells, suggesting an imbalance between activator and inhibitor of calpain-1 in favor of activator in dense sickle cells. Calpain-1 is a nonlysosomal cysteine proteinase that modulates multiple cell functions through the selective cleavage of proteins. To investigate the relevance of this observation in vivo, we evaluated the effects of the orally active inhibitor of calpain-1, BDA-410 (30 mg/kg/d), on RBCs from SAD mice, a mouse model for SCD. In SAD mice, BDA-410 improved RBC morphology, reduced RBC density (D(20); from 1106±0.001 to 1100±0.001 g/ml; P<0.05) and increased RBC-K(+) content (from 364±10 to 429±12.3 mmol/kg Hb; P<0.05), markedly reduced the activity of the Ca(2+)-activated K(+)channel (Gardos channel), and decreased membrane association of peroxiredoxin-2. The inhibitory effect of calphostin C, a specific inhibitor of protein kinase C (PKC), on the Gardos channel was eliminated after BDA-410 treatment, which suggests that calpain-1 inhibition affects the PKC-dependent fraction of the Gardos channel. BDA-410 prevented hypoxia-induced RBC dehydration and K(+) loss in SAD mice. These data suggest a potential role of BDA-410 as a novel therapeutic agent for treatment of SCD.-De Franceschi, L., Franco, R. S., Bertoldi, M., Brugnara, C., Matté, A., Siciliano, A., Wieschhaus, A. J., Chishti, A. H., Joiner, C. H. Pharmacological inhibition of calpain-1 prevents red cell dehydration and reduces Gardos channel activity in a mouse model of sickle cell disease.
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ABSTRACT: Dematin is a broadly expressed membrane-cytoskeletal protein that has been well characterized in erythrocytes and to a lesser extent in non-erythroid cells. However, dematins function in platelets is not known. Here, we show that dematin is abundantly expressed in both human and mouse platelets. Platelets harvested from the dematin headpiece knockout (HPKO) mouse model exhibit a striking defect in the mobilization of calcium in response to multiple agonists of platelet activation. The reduced calcium mobilization in HPKO platelets is associated with concomitant inhibition of platelet aggregation and granule secretion. Integrin αIIbβ3 activation in response to agonists is attenuated in the HPKO platelets. The mutant platelets show nearly normal spreading on fibrinogen and an unaltered basal cAMP level; however, the clot retraction was compromised in the mutant mice. Immunofluorescence analysis indicated that dematin is present both at the dense tubular system (DTS) and plasma membrane fractions of platelets. Proteomic analysis of dematin-associated proteins in human platelets identified inositol 1,4,5-trisphosphate 3-kinase isoform B (IP3KB) as a binding partner, which was confirmed by immunoprecipitation analysis. IP3KB, a DTS protein, is a major regulator of calcium homeostasis. Loss of the dematin headpiece resulted in a decrease of IP3KB at the membrane and increased levels of IP3KB in the cytosol. Collectively, these findings unveil dematin as a novel regulator of internal calcium mobilization in platelets affecting multiple signaling and cytoskeletal functions. Implications of a conserved role of dematin in the regulation of calcium homeostasis in other cell types will be discussed.
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ABSTRACT: Pharmacological inhibitors of cysteine proteases have provided useful insights into the regulation of calpain activity in erythrocytes. However, the precise biological function of calpain activity in erythrocytes remains poorly understood. Erythrocytes express calpain-1, an isoform regulated by calpastatin, the endogenous inhibitor of calpains. In the present study, we investigated the function of calpain-1 in mature erythrocytes using our calpain-1-null [KO (knockout)] mouse model. The calpain-1 gene deletion results in improved erythrocyte deformability without any measurable effect on erythrocyte lifespan in vivo. The calcium-induced sphero-echinocyte shape transition is compromised in the KO erythrocytes. Erythrocyte membrane proteins ankyrin, band 3, protein 4.1R, adducin and dematin are degraded in the calcium-loaded normal erythrocytes but not in the KO erythrocytes. In contrast, the integrity of spectrin and its state of phosphorylation are not affected in the calcium-loaded erythrocytes of either genotype. To assess the functional consequences of attenuated cytoskeletal remodelling in the KO erythrocytes, the activity of major membrane transporters was measured. The activity of the K+-Cl- co-transporter and the Gardos channel was significantly reduced in the KO erythrocytes. Similarly, the basal activity of the calcium pump was reduced in the absence of calmodulin in the KO erythrocyte membrane. Interestingly, the calmodulin-stimulated calcium pump activity was significantly elevated in the KO erythrocytes, implying a wider range of pump regulation by calcium and calmodulin. Taken together, and with the atomic force microscopy of the skeletal network, the results of the present study provide the first evidence for the physiological function of calpain-1 in erythrocytes with therapeutic implications for calcium imbalance pathologies such as sickle cell disease.
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ABSTRACT: Calpains are implicated in a wide range of cellular functions including the maintenance of hemostasis via the regulation of cytoskeletal modifications in platelets. Determine the functional role of calpain isoforms in platelet spreading. Platelets from calpain-1(-/-) mice show enhanced spreading on collagen- and fibrinogen-coated surfaces as revealed by immunofluorescence, differential interference contrast (DIC) and scanning electron microscopy. The treatment of mouse platelets with MDL, a cell permeable inhibitor of calpains 1/2, resulted in increased spreading. The PTP1B-mediated enhanced tyrosine dephosphorylation in calpain-1(-/-) platelets did not fully account for the enhanced spreading as platelets from the double knockout mice lacking calpain-1 and PTP1B showed only a partial rescue of the spreading phenotype. In non-adherent platelets, proteolysis and GTPase activity of RhoA and Rac1 were indistinguishable between the wild-type (WT) and calpain-1(-/-) platelets. In contrast, the ECM-adherent calpain-1(-/-) platelets showed higher Rac1 activity at the beginning of spreading, whereas RhoA was more active at later time points. The ECM-adherent calpain-1(-/-) platelets showed an elevated level of RhoA protein but not Rac1 and Cdc42. Proteolysis of recombinant RhoA, but not Rac1 and Cdc42, indicates that RhoA is a calpain-1 substrate in vitro. Potentiation of the platelet spreading phenotype in calpain-1(-/-) mice suggests a novel role of calpain-1 in hemostasis, and may explain the normal bleeding time observed in the calpain-1(-/-) mice.
Article: Targeted Gene Inactivation of Calpain-1 Suppresses Cortical Degeneration Due to Traumatic Brain Injury and Neuronal Apoptosis Induced by Oxidative Stress[Show abstract] [Hide abstract]
ABSTRACT: Calpains are calcium-regulated cysteine proteases that have been implicated in the regulation of cell death pathways. Here, we used our calpain-1 null mouse model to evaluate the function of calpain-1 in neural degeneration following a rodent model of traumatic brain injury. In vivo, calpain-1 null mice show significantly less neural degeneration and apoptosis and a smaller contusion 3 days post-injury than wild type littermates. Protection from traumatic brain injury corroborated with the resistance of calpain-1 neurons to apoptosis induced by oxidative stress. Biochemical analysis revealed that caspase-3 activation, extracellular calcium entry, mitochondrial membrane permeability, and release of apoptosis-inducing factor from mitochondria are partially blocked in the calpain-1 null neurons. These findings suggest that the calpain-1 knock-out mice may serve as a useful model system for neuronal protection and apoptosis in traumatic brain injury and other neurodegenerative disorders in which oxidative stress plays a role.
Article: Identification of a specific region of Plasmodium falciparum EBL-1 that binds to host receptor glycophorin B and inhibits merozoite invasion in human red blood cells[Show abstract] [Hide abstract]
ABSTRACT: The malaria parasite Plasmodium falciparum invades human erythrocytes through multiple pathways utilizing several ligand-receptor interactions. These interactions are broadly classified in two groups according to their dependency on sialic acid residues. Here, we focus on the sialic acid-dependent pathway by using purified glycophorins and red blood cells (RBCs) to screen a cDNA phage display library derived from P. falciparum FCR3 strain, a sialic acid-dependent strain. This screen identified several parasite proteins including the erythrocyte-binding ligand-1, EBL-1. The phage cDNA insert encoded the 69-amino acid peptide, termed F2i, which is located within the F2 region of the DBL domain, designated here as D2, of EBL-1. Recombinant D2 and F2i polypeptides bound to purified glycophorins and RBCs, and the F2i peptide was found to interfere with binding of D2 domain to its receptor. Both D2 and F2i polypeptides bound to trypsin-treated but not neuraminidase or chymotrypsin-treated erythrocytes, consistent with known glycophorin B resistance to trypsin, and neither the D2 nor F2i polypeptide bound to glycophorin B-deficient erythrocytes. Importantly, purified D2 and F2i polypeptides partially inhibited merozoite reinvasion in human erythrocytes. Our results show that the host erythrocyte receptor glycophorin B directly interacts with the DBL domain of parasite EBL-1, and the core binding site is contained within the 69 amino acid F2i region (residues 601-669) of the DBL domain. Together, these findings suggest that a recombinant F2i peptide with stabilized structure could provide a protective function at blood stage infection and represents a valuable addition to a multi-subunit vaccine against malaria.
Article: Atomic force microscopy demonstration of cytoskeleton instability in mouse erythrocytes with dematin-headpiece and β-adducin deficiency[Show abstract] [Hide abstract]
ABSTRACT: The pattern of disassembly of the cytoskeletal network of murine erythrocytes with deficiency of either dematin-headpiece or β-adducin or both proteins were investigated using atomic force microscopy. A heterogeneous complex structure with fine filament features and coarse features was observed in the cytoskeleton of wild type mouse erythrocytes, whereas a significant amount of rearrangement and aggregation occurred in the mutants, particularly in the cells carrying double gene mutations. These results are consistent with the cellular and biochemical phenotype of the mutant cell membranes as being more fragile due to weakened vertical connections with the plasma membrane.
Article: Vital Role of the Calpain-Calpastatin System for Placental-Integrity-Dependent Embryonic Survival[Show abstract] [Hide abstract]
ABSTRACT: Although the calpain-calpastatin system has been implicated in a number of pathological conditions, its normal physiological role remains largely unknown. To investigate the functions of this system, we generated conventional and conditional calpain-2 knockout mice. The conventional calpain-2 knockout embryos died around embryonic day 15, preceded by cell death associated with caspase activation and DNA fragmentation in placental trophoblasts. In contrast, conditional knockout mice in which calpain-2 is expressed in the placenta but not in the fetus were spared. These results suggest that calpain-2 contributes to trophoblast survival via suppression of caspase activation. Double-knockout mice also deficient in calpain-1 and calpastatin resulted in accelerated and rescued embryonic lethality, respectively, suggesting that calpain-1 and -2 at least in part share similar in vivo functions under the control of calpastatin. Triple-knockout mice exhibited early embryonic lethality, a finding consistent with the notion that this protease system is vital for embryonic survival.
Article: Transglutaminase-mediated remodeling of the human erythrocyte membrane skeleton: Relevance for erythrocyte diseases with shortened cell lifespan
Article: The Drosophila miR-310 Cluster Negatively Regulates Synaptic Strength at the Neuromuscular Junction[Show abstract] [Hide abstract]
ABSTRACT: Emerging data implicate microRNAs (miRNAs) in the regulation of synaptic structure and function, but we know little about their role in the regulation of neurotransmission in presynaptic neurons. Here, we demonstrate that the miR-310-313 cluster is required for normal synaptic transmission at the Drosophila larval neuromuscular junction. Loss of miR-310-313 cluster leads to a significant enhancement of neurotransmitter release, which can be rescued with temporally restricted expression of mir-310-313 in larval presynaptic neurons. Kinesin family member, Khc-73 is a functional target for miR-310-313 as its expression is increased in mir-310-313 mutants and reducing it restores normal synaptic function. Cluster mutants show an increase in the active zone protein Bruchpilot accompanied by an increase in electron dense T bars. Finally, we show that repression of Khc-73 by miR-310-313 cluster influences the establishment of normal synaptic homeostasis. Our findings establish a role for miRNAs in the regulation of neurotransmitter release.
Top Journals
Tufts University
Бостон, Georgia, United States
- • Department of Molecular Physiology and Pharmacology
- • Department of Anatomy and Cellular Biology
University of Illinois at Chicago
Chicago, Illinois, United States
- Department of Pharmacology (Chicago)
Drexel University
Filadelfia, Pennsylvania, United States
- Department of Microbiology & Immunology
University of Illinois, Urbana-ChampaignUrbana, Illinois, United States
St. Elizabeth's Medical CenterBoston, Massachusetts, United States
Baylor College of Medicine
Houston, TX, United States
- Department of Molecular & Human Genetics
University of Bristol
Bristol, ENG, United Kingdom
- School of Physiology and Pharmacology
American Society of HematologyOrlando, Florida, United States


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Toms River, NJ 08753
"Honest, friendly, trustworthy and accommodating."— Michael, a Verified CustomerView all reviews
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- Steven Wuesthoff, Owner
- Established 1989
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I really enjoyed my evaluation of Pro-Cat Automotive. Steven Wuesthoff, the owner, is a very qualified and experienced professional who works hard to demonstrate the best practices in owning and operating a highly qualified repair facility. The commitment of this family owned and operated facility really shined through in several ways during our review. This RepairPal Certified shop employs experienced professionals and invests in keeping them up to date on the latest customer service and automotive training available. This training, coupled with some of the best automotive tools and computer diagnostic equipment help them to make accurate professional diagnosis and repairs to your modern vehicle. Their most recent customers described this team as pleasant, courteous, reasonably priced, and trustworthy during our unbiased review. The repairs performed at this shop are backed by a 24-month / 24,000-mile warranty for your peace of mind. Local shuttle service, early bird drop off, and a clean comfortable waiting area with wireless Internet are all available for your convenience.ReviewsMap
Auto Repair Experience
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- Established 1989
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- 111 Years of Car Repair Experience
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•PRO-CAT is PROFESSIONAL ASE AUTO REPAIR and SERVICE CENTER,
•Family Owned and Operated 27 years. serving Toms River and Ocean County. Opened in 1989 as small family owned auto repair shop with 2 service bays 1 lift,
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Overall Rating27 Verified Reviews
Customer ReviewsMichael – Verified CustomerMarch 08, 2014
Honest, friendly, trustworthy and accommodating.Robert – Verified CustomerMarch 08, 2014
Good service. Honest people.Mickey – Verified CustomerMarch 07, 2014
They do a good job, they tell you what has to be done and they don't beat around the bush like the rest.Maureen – Verified CustomerMarch 06, 2014
Good service, polite staff.Show more reviewsMichael – Verified CustomerMarch 06, 2014
The service was great just felt communication could of been a little better. However, they could of been busy.Susan – Verified CustomerFebruary 28, 2014
I have been going there for a long time. They have good service, work, and are friendly.Jean – Verified CustomerFebruary 27, 2014
Friendly, Professional, and left feeling as if i got more then I payed for. For a repair, the experience excellent i would recommend this shop to a friend.Molly – Verified CustomerFebruary 22, 2014
Service is always great, everything is always thoroughly explained.John – Verified CustomerFebruary 19, 2014
They did the work I wanted done, and they are very reliable.Show more reviewsBob – Verified CustomerFebruary 18, 2014
Service is reasonably priced and good quality.Robert – Verified CustomerFebruary 14, 2014
I have a long history with them. They are reliable trustworthy and have earned my trust. I have no reason to go anywhere else.John – Verified CustomerFebruary 11, 2014
Excellent professional service. They explain what needs to be done and why. They do not push you into anything. Fair prices.Rachel – Verified CustomerFebruary 10, 2014
They were cheaper than the other places, I think they were honest but I'm not sure.David – Verified CustomerJanuary 31, 2014
I trust them.Show more reviewsVerified CustomerJanuary 31, 2014
They missed a repair that was needed. I had to spend more money and find that out by going to a different shop.Nancy – Verified CustomerJanuary 27, 2014
As a customer I was able to speak with mechanic, and/or owner of facility. Concerned front desk staff.Verified CustomerJanuary 16, 2014
They seem to do the job properly.Edward – Verified CustomerJanuary 13, 2014
Good customer service, good service, good repairs. All good.Daniel – Verified CustomerJanuary 10, 2014
Good friendly service. Trustable service. They provide a full explanation on what needs to be done and then give you the option of what you want done.Show more reviewsJim – Verified CustomerJanuary 09, 2014
I have used them in the past and they do good quality work.Thomas – Verified CustomerJanuary 07, 2014
Sukee and Steve are always a pleasure to speak to. Their honesty and integrity go a long distance in my book.John – Verified CustomerJanuary 07, 2014
THE SERVICE I ASK FOR IS PROVIDED AND I HAVE NO PROBLEM.jreid2138August 16, 2014
Approx. two years ago I took my '01 Ford Winstar to ProCat for a trans fluid change and oil change... when I got the car back in my driveway there was trans fluid spilling all over the ground had a tow truck bring it back to Procat and they said there was a rod sticking through the side of my trans? They don't know what it was or where it came from (came from inside the trans) Then they said they couldn't do anything about it. Thank you Steve and Sunni for basically ruining the last two years for me and my family, We had to hurry and find another car so we could resume working ($5000 for a used car plus Procat made me pay for the shotty repair another $900.00) My wife didn't want me to file a lawsuit and I didn't nor did I summit a complaint to the BBB (they're useless) The only recourse I had was to suck it up. NEVER AGAIN PROCAT p.s. they use to be a friend of our familyJayCee10March 17, 2013
I brought in my vehicle 3 months ago for an oil change and wheel alignment. From the moment I got into my car after repair, I noticed the alignment was still off. The oil change I requested was 4 quarts of Synthetic oil. However as the weeks went by, I started to wonder if they had really used synthetic. I decided to do my own oil change today, and only TWO QUARTS OF OIL CAME OUT! I don't know if they used synthetic or not, BUT THEY ONLY USED TWO QUARTS OF OIL WHEN MY CAR CALLED FOR FOUR. Steve Westhuoff is a smooth talking scam artist, that will say anything to divert your attention away from any complaints you may have. DO NOT TRUST THIS PLACE. I urge anyone who gets an oil change here, to check the level of your oil after letting the car sit. Also, the oil filter used was Proline. Google it, and you will see how horrible a filter it is.5 verified customers did not leave comments but provided these ratings:by 2 verified reviewersby 1 verified reviewerby 1 verified reviewerby Cathy
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Audio + Music Tutorials
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Covers organizing, sharing, and enjoying digital audio and video files with iTunes.
Explores all aspects of Apple's popular music and media management application, from basic audio management and playback to advanced syncing.
Quickly get up to speed with the new version of Apple's music player, from the revamped interface to multiple-library support.
Explore how to best utilize iTunes and your iPod.
"I'm loving your audio courses. But the gold medal goes to Brian Lee White's Mixing a Rock Song in Pro Tools. This course is like watching over Brian's shoulder as he mixes a song start to finish, and I am getting so much out of each video. Thrilling." —Daniel
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text:
10 Terrifying Non-Horror Films From The Criterion Collection
- By Landon Palmer
- @landonspeak
- October 31, 2012
Warning: some spoilers ahead. For a company known for its arthouse fare, The Criterion Collection is not short on great horror films. From early oddities like Haxan to silent classics like Vampyr to classic B-movies like Corridors of Blood to cult classics like House to newer visions like Antichrist to...
This Week in Blu-ray: Wolfman's Got Nards
- By Neil Miller
- @rejects
- November 24, 2009
Another week, another round of dollars to be spent here on This Week in Blu-ray. And just like last week, there are a few movies worth buying....
DVD's I Bought This Week: August 4th
- By Rob Hunter
- @FakeRobHunter
- August 6, 2009
Rob Hunter loves movies. He also loves working as Jack Burton's favorite mechanic helping to keep the Pork Chop Express tuned to a 6.9 on the Richter scale. These two joys come together in the form of cash money payments that he receives every week and immediately uses...
The 14 Must See Movies of Awards Season 2008
- By Neil Miller
- @rejects
- December 14, 2008
Are you an awards season junkie? Do you love to be able to sit there and look smart in front of your friends and family, most of whom only make it out to the movies once a year to see the latest Jim Carrey comedy, by being able to talk...


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February 25th Show
Health Care Bill
President Obama is pushing his case for a health care bill to a small group of Republicans and Democrats today, on live television. Despite the high-profile bipartisan meeting, expectations among the public remain low. Today's meeting comes the same week the president unveiled his own draft of a health care bill, the third attempt at crafting legislation. NPR's senior Washington editor Ron Elving and health policy correspondent Julie Rovner explain what happened at today's summit and what's the likely next step for a health care overhaul.
"Which Way Home"
Five films have been nominated for an Academy Award for best feature documentary. Rebecca Camissa got the nod for her most-recent film, Which Way Home?, which follows Central American migrants on a long, dangerous journey on the top of a freight train through Mexico to the U.S. border. As part of the TOTN series of conversations with each of the documentary nominees, Camissa talks about making the film, and what it would mean to win the Oscar.
Olympics Wrap-Up
As the 2010 Winter Games enters its final days, the U.S. women's hockey team vies for gold as the men's team advances to the semifinals. And at Whistler, Lindsey Vonn's hopes for a third medal are dashed, and Julia Mancuso's along with her. NPR's Tom Goldman and Howard Berkes share the latest big wins and upsets, highlight some of the Games' unsung athletes, and tell us what to watch for before the competition wraps up on Sunday. Plus, no athletes have tested positive for performance enhancing drugs. We'll ask if doping at the Olympics is a thing of the past.
What's the Answer to 9-across?
On Tuesday, we posted on our web site the crossword used as the final puzzle last weekend at the American Crossword Puzzle Tournament (ACPT). The host of the ACPT, Will Shortz, called it "extremely difficult." Neal Conan talks with the author of this puzzle, Mike Shenk, who constructs puzzles for the Wall Street Journal, about how to create tough puzzles, and what it's like to watch people try to solve them.
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text:
Motorcycle Awareness: Obstacles
The Motor Accident Commission of South Australia has embarked on a fresh new approach in the battle to encourage motorcyclists to ride safely. The new campaign, created by Clemenger BBDO Adelaide, utilises Moto GP racing footage and demonstrates the real dangers riders face on the road due to roadside obstacles.
Advertising Agency: Clemenger BBDO Adelaide, Australia
Creative Director: Greg Knagge
Art Directors: Geoff Robertson, Paul Stratton
Copywriter: Matt O'Grady
Agency Producer: Jules Callen
Account Managers: John McLaren, Bryce Coombe, Tim Pearce, Courtney Stables
Director: Phil Meatcham
Aired: October 2009
25 comments
Micky Doohan!! Woot, I love this commercial! I'm a big fan of MotoGP and motorrider safety on the circuit AND road.
Absolutely great! This social commercial goes straight to the point. I loveeeee it
very very very simple, but good idea.
maybe, less colorful could have been a better look
(i love fast motorcycles and watch every race.)
very very very simple, but good idea.
maybe, less colorful could have been a better look
(i love fast motorcycles and watch every race.)
ingenious campaigns are simple.
this one used stockphotage and some editing to get the message communicated.
the idea is straight forward, the execution didnt cost much and the rating is 9/10.
great job folks!
Simple but very confronting. Does exactly what it should do!
Hate advertising? Make better ads.
I think it's a great ad - and gets the point across.
One small point - I notice they don't show hazards like road signs or 'cheese-cutter' barrier wires that could be made safer for motorcyclists!
It actually hurts in my guts to watch the guy slide towards the concrete bench.
Swami Jivan Utsav
Very well done! I hope I will see this again sooner or later. Or maybe often as you still do it for everyone.


text:
Vision: A Healthy Texas
As temperatures push past 100 degrees across much of the state, the Texas
Department of State Health Services reminds people to be aware of the signs of
heat illness and take precautions to protect themselves. The elderly, young
children, people with chronic diseases and those without access to air
conditioning are most at risk.
Staying in an air conditioned area, either at home or at public places like
malls, libraries or community centers, is the best way to combat heat. If air
conditioning is not available, open windows, pull down shades to keep out direct
sunlight and use fans and cross-ventilation to cool rooms.
Other precautions:
Drink plenty of water. Drink liquids 30 minutes before going
outside and continue even if you don't feel thirsty. Avoid alcohol, caffeine and
sugary drinks.
(News Media Contact: Chris Van Deusen, DSHS
Assistant Press Officer, 512-458-7753)
DSHS Press Office on Twitter
Internet Policy | HHS Agencies | Homeland Security | Statewide Search | Texas.gov | Privacy Practices


text:
Now Foods, Pau D' Arco Tea, Caffeine Free, 30 Tea Bags, 2 oz (60 g) (Discontinued Item)
By Now Foods20 Reviews
Shipping Weight:?0.6 lbs (0.27 kg)
Shipping Weight
The Shipping Weight includes the product, protective packaging material and the actual shipping box. In addition, the Shipping Weight may be adjusted for the Dimensional Weight (e.g. length, width & height) of a package. It is important to note that certain types of products (e.g. glass containers, liquids, fragile, refrigerated or ice packed) will often require protective packaging material. As such, these products will reflect a higher Shipping Weight compared to the unprotected product.
- Product Code: NOW-04301
- UPC Code: 733739043016
- Package Quantity: 30 Tea Bags, 2 oz (60 g)
- Dimensions: 2.9 x 3.8 x 5.5 in, 0.25 lbs (0.11 kg)
Product Overview
- Botanicals
From the steamy tropical jungles of the Amazon in Brazil comes Pau D'Arco. Derived from the inner bark of this tree, it is considered the "life" of the tree by the Calaway tribe of the Amazon, direct descendents of the Incas. Enjoy the wildly exotic flavor of the Amazonian rain forests with Pau D'Arco Tea from NOW.
Other Ingredients
100% inner bark pau d' arco (tabebuia impetiginosa) (inner bark).
Contains no caffeine, artificial colors, flavors, preservatives or sugars.
|Supplement Facts
|Serving Size: 1 Tea Bag (2g)
|Servings Per Container 30
|Amount Per Serving
|% Daily Value*
|Total Fat
|Total Carbohydrates
|Not a significant source of calories from fat, saturated fat, cholesterol, dietary fiber, sugars, vitamin A, vitamin C, calcium and iron.
|* Percent Daily Values are based on a 2,000 calorie diet.
iHerb Customer Reviews
The taste of this tea came as a wonderful surprise. I'd read is was great at keeping yeast at bay and, therefore, good for women to drink on a regular basis, but had no idea I would enjoy it as much as I do. It has a light "earthy" taste, with a subtle hint of fruit. Very yummy.
Better than green tea...this tea prevents cancer and fungus. I have Candida overgrowth so it made me sick at first and then after a week, I felt better. (That's part of the process). I add a little Stevia and it taste great. Comes with string and each bag is individually wrapped.


text:
Contents tagged with DataControls
Invalid postback or callback argument
I'm sure many of you have seen this error message when developing your web application:
A new way to DataBind()
The Problem
I've been thinking alot recently about the problems with data binding (and they're alot). There are some patterns that play well with ASP.NET (and are repeated everywhere) and some that don't quite fit the model. One of those patterns that don't mesh well is, setting the DataSource property of any of the DataControls. Before ASP.NET 2.0 and DataSource controls we'd have to set the DataSource property and manually call DataBind.
In 3.5 SP1 we added new properties to GridView and DetailsView which allows the page developer to change the way AutoGenerateColumns creates its columns. This feature is well know in Dynamic Data, but it is not tied to this technology. Dynamic Data takes advantage of this by looking at the meta data that users set on properties to generate columns.
You too can roll your own IAutoFieldGenerator. Lets look at the interface:
How <%# Bind %> Works
In my last post I spoke about 2-way databinding and how it can be used to extract values from control properties. How does this all work? Lets take a look at a page with 2-way databinding:
Getting your data out of the data controls
After you've created a layout with a data control of your choice and eventually bound them to some datasource, you almost always want to get that data back out of them(and why wouldn't you, its your data). One thing you'll learn about developing asp.net webpages is that its like petting a porcupine (yikes). If you go with the flow, you probably won't get stuck, but the moment you try to go against the grain you end up with a hand full of thorns.
Most of the data controls have events ending in ing and ed e.g. RowUpdating, RowUpdated etc. In most of the event handlers of the ing events it is easy to get the values from the event args.


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IT leaders at healthcare providers are under siege. ROI, legacy systems, cloud software, and the EHR wars are a few of their current concerns. >>>
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While provider organizations continue the spending frenzy on their health information technology capabilities, not all are pleased with their purchases. >>>
Spending on electronic health records systems by hospitals and health systems continues to rise, as enthusiasm for them wanes among senior healthcare executives, survey results show. >>>
Pursuing expensive inpatient volume in the traditional sense is a strategic dead end. Any new construction undertaken by hospitals and health systems should be based on adaptability, patient flow, and efficiency gains—not bed count. >>>
Hospital and health system leaders know the reimbursement transformation is coming—even if it hasn't reached them yet—and they are beginning to form alliances with regional providers to find strength in numbers. >>>
The process is going forward despite the protestations of the American Medical Association, which has complained that CMS "has missed nearly every deadline laid out in the law and regulations to implement it." >>>
Emergency departments play a unique and critical role in maintaining the health and well-being of a community. Emerging best practices in care team composition and patient flow can improve ED throughput and patient satisfaction. >>>
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Renting is easy, fast, and cheap! Renting from eCampus.com can save you hundreds of dollars compared to the cost of new or used books each semester. At the end of the semester, simply ship the book back to us with a free UPS shipping label! No need to worry about selling it back.
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Capricorn Cap Anderson has been homeschooled by his hippie grandmother, Rain. When Rain is injured in a fall, Cap is forced to attend the local middle school. Although he knows a lot about Zen Buddhism, nothing has prepared him for the politics of public school.


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text: I am given the following: A spherically propogating shell contains N neutrons, which are all in the sate [tex]\psi[/tex](r,0)=4[tex]\pi[/tex]i[tex]j_{1}[/tex](kr)(3/[tex]\sqrt{34}[/tex][tex]Y^{0}_{1}[/tex]+5/[tex]\sqrt{34}[/tex][tex]Y^{-1}_{1}[/tex]) at t = 0. How do we find [tex]\psi[/tex](r,t)? My attempt: I have a few thoughts; could you apply the time-independent schrodinger equation to find the energy of the state? If that is the case then you would simply tack on the factor of [tex]e^{-i\omega*t}[/tex]. Then you would know that [tex]\hbar*\omega[/tex]=E. . . . right?


text:
Reapplicant vs. New Applicant
The number of reapplicants accepted to the bachelor's program at the Tacoma and Spokane, WA as well as the Anchorage, AK training sites accounts for 20% of the 2014 BCHS accepted class.
Gender Statistics
The number of male and female students in the bachelor's program is nearly equal, with the percentage of men somewhat higher. The number of male students selected is almost 55%, a figure that is significantly different than the national average.
Average Age
The mean age of BCHS students accepted is 34 years, which is slightly older than the mean age of the MCHS accepted class but in-line with the overall 2014 entering class.
Academic Backgrounds
The degree status of students accepted into the BCHS class ranges from having some college-level courses and certificate training to those with a bachelor's or master's degree in another discipline. A small group of students with doctorate-level professional training and international medical graduates was also accepted in this degree program.
Regional Statistics
The majority of the BCHS class accepted in 2014 is from the WWAMI region, with students from Washington making up the high percentage at just over 41%. Alaska residents accounted for nearly 42%, the majority of these students enter the Anchorage class with plans to stay in Alaska after graduating. Outreach efforts in Wyoming, Montana and Idaho continue as we focus on increasing access to PA education for those in rural communities with unmet need. Students selected from outside the WWAMI region typically have ties to the region through military service, family in the area, or were originally from this region.
Military Statistics
Military members are strongly represented in the undergraduate degree option, with over 30% of the 2014 BCHS class being veteran or current military members. The undergraduate degree option offered by MEDEX Northwest continues to draw a large number of military applicants with a high number of training credits that can be applied toward meeting MEDEX prerequisites. We value this historical component of the MEDEX applicant pool and continue to actively recruit, mentor and, train current and former military members.


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If this passes, I know who will NOT be getting my vote come next election…ANYONE that votes for this. This is not what North Dakota is all about. We are ones that love each other and embrace our differences. Be aware legislators or beware.
Senate Dem-NPL Leadership Urges Rejection of Amendments which would make SB 2252 a "Pro-Discrimination" Bill
(BISMARCK, N.D.) – North Dakota Senate Dem-NPL leadership today urged a no vote on recent amendments to SB 2252, legislation which seeks to prevent discrimination based on sexual orientation. The "hog house" amendments to the bill, passed by the Senate Judiciary Committee late Tuesday, not only completely eliminate protections for those who suffer discrimination based on sexual orientation, but also widen discrimination on the basis of age and limit remedies to those who have proved they were terminated from employment because of their race, gender, religion or for other discriminatory reasons.
"We introduced this bill on a bipartisan basis to prevent discrimination," Senate Dem-NPL Leader Mac Schneider said. "Somewhat stunningly, the amendment would permit discrimination against more people on the basis of age. If these amendments pass, it actually becomes a pro-discrimination bill."
Under the amendments to SB 2252, the legislation would no longer amend the North Dakota Fair Housing Act and the North Dakota Human Rights Act to protect against discrimination based on sexual orientation.
Instead, the amended bill would state that North Dakota does not "condone discrimination on the basis of sexual orientation[,]" while making clear that those discriminated against on that basis have no legal protection or recourse under state law. Specifically, the amendments state that there is no "right to a cause of action for damages for a claim of discrimination on the basis of sexual orientation" and that the bill would not "create any rights or protections with respect to discrimination on the basis of sexual orientation[.]"
"That is literally the definition of 'condoning' discrimination," Schneider added.
Furthermore, the bill changes two key provisions of the Human Rights Act, both of which are wholly unrelated to the issue of discrimination based on sexual orientation. First, the amendment changes the legal definition of "Age" for purposes of determining age discrimination from "at least forty years of age" to at least "fifty-five years of age." Should the statute become law, in other words, an employer could legally terminate a 54 year old employee purely because of his or her age.
Second, the bill seeks to limit remedies provided under existing law to those who prove discrimination at an administrative hearing or in court. In cases of employment discrimination, individuals would be limited to one year of back pay instead of the two years available under current law.
"The North Dakota Human Rights Act has been on the books in North Dakota since 1983," Schneider said. "To use this bill to weaken the Act is wrong. It is devious. The Senate should reject these amendments."
The amendment is expected to be debated on the Senate floor Thursday, February 14th.
9 thoughts on "Senate Dem-NPL Leadership Urges Rejection of Amendments which would make SB 2252 a "Pro-Discrimination" Bill"
As a former ND Democratic legislator who served seven sessions, two in dismal minorities, I can only say "SS-DD."
As a person who stood in front of this committee to give my testimony in favor of the bill the way it was originally written, these amendments are a slap in the face. I am a North Dakotan, born and raised. I deserve to live and work in my home state without fear of discrimination based on my real or perceived sexual orientation with regard to my housing and my career.
Not that I don't trust politicians, but I would much prefer people link to the actual wording rather than their oft times biased interpretation. Your constituents really are intelligent enough to read and understand.
As a citizen of what long ago started out as a free country, nowadays we seem to find ourselves amidst more and more government rules and regulations. That said, I truly believe the amendments to SB 2252 should be passed. Now before getting up in arms about the former statement, here are my reasons. I believe that if you are an employer or a homeowner you deserve the right to choose who works at your company or lives in your house. This is simply a freedom that one deservers when living in a so called free country. Therefore, although I know this bill isn't about permitting or not permitting discrimination, one must look at the bigger picture. That is, any amendments that could potentially, at least, loosen the reigns upon these unnecessary regulatory policies should be passed. The proposed amendments to SB 2252 are just that: loosening the reigns on what we as citizens can and cannot do in regards to normal rights we deserve. Now that I have stated my reasoning, I would like to emphasize that I am not proposing citizens should be allowed to do anything simply because they live in a so called 'free' country. I am in no way saying that living in a free country should allow citizens to engage in illegal activities of all and any sorts, I am merely stating that the line between illegal and legal activity has been set in a position that works, decades ago. But year after year that line is moving and moving and it is making its way into unnecessary territory which is exactly where the SB 2252 amendments reside. Lastly, if an employer or house owner wants to discriminate, that is the right they deserve, but eventually there sins of discrimination will catch up to them and they will get what they always had coming. I hope that although employers should have the right to discriminate that they choose not to simply because it is wrong. Hopefully their businesses and houses run amuck. But to implement laws stating that any and every bad thing is against the law simply because it is immoral, is not the solution. If discrimination is against the law, shouldn't things like wasting water and electricity, contributing to global warming, or even teasing other individuals be unlawful as well?
Isn't being employed in a "Right to Work" state already rotten enough?
Here's the link to the amendments. Pretty much exactly what was said in the press release: http://www.legis.nd.gov/assembly/63-2013/documents/13-0758-01003m.pdf?20130213230037
It's interesting to note that Sen. O'Connell voted against every other member of his party on SB2252.
I also find it interesting that Mr O'Connell has been a director of both Farmers Union and Farm Bureau.
Comments are closed.


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Yes, Lily...lovely and who could ever forget this and the story behind it: www.youtube.com/watch?v=JxPj3GAYYZ0
A fine bird, but tethered to a post doesn't appeal.
1Runnybeak1 wrote (see)
STAR G L . I'm 3yrs old here. Can't find my 'dancing pic' at he mo. its very quiet on here today. Are you exhausted from all the dancing yesterday.
STAR G L . I'm 3yrs old here. Can't find my 'dancing pic' at he mo.
its very quiet on here today. Are you exhausted from all the dancing yesterday.
Altogether...on the good ship lollipop.
star gaze lily wrote (see)
Both lovely David, also love this one...... www.youtube.com/watch?v=roqqACI1ABY
Both lovely David, also love this one......
I hadn't heard that one, Lily....thank you. It was written by Lionel Richie, so bound to be good.
www.youtube.com/watch?v=RaFJcJO3RH4 - Ah bliss!
We have sweet pea germination after 18 days, I left them outside under a bench/seat rather than in a coldframe or cold greenhouse.
Morning, KEF....I agree, I very much dislike Halloween, along with a lot of other American imports.
High five?
Hi, Dordogne Damsel. As always a well reasoned post......but that final paragraph, oh dear (shock horror smiley)...... now if we men were so sexist!
Who's a pretty boy?
Is it fixed, or is it viewers voting for talentless dancers? ....Either way, tonight's show & results were a complete farce.
For what it's worth, I read in this week's press, that Judy Murray & Anton are receiving more or less double the viewers votes than any other contestant.
Even Frank will like this: www.youtube.com/watch?v=HQW7I62TNOw - wrote by the Bee Gees
Another unforgettable classic from my yoof: www.youtube.com/watch?v=RgwpHYzcwUA


text:
With Instructables you can share what you make with the world, and tap into an ever-growing community of creative experts.
Tim and Declan take apart a Chinese food take-out container to see how it keeps food from leaking out.
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WREXLabs Episode #3 - Mini-Massagerby gigocorp
Practical Origami: instant handles for paper bagsby Berkana
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My Sweet Baby Boy *trigger*
Amy married to my best friend since 2003
Courtney 6/06 & our angel ^Drew^ 6/11-9/11
TTC #3--Looking for our rainbow after the rain.
Oh my gosh I am soooooo sorry for your loss. I can not imagine the pain you must be feeling right now :( Sending tons of thoughts and prayers your way.
Megan (32) married to Dave (38) on November 15, 2008.
Rowan Cain born June 18, 2011!
Tatum Reese born November 29, 2013!
I am so very sorry!!! You will be in my thoughts and prayers!!!
Mom to Shelby and Jackson
There is no foot so small that it cannot leave an imprint on this world- For the precious June bugs who didn't make it.
I'm so sorry.
Monica (33) married Vincent (34) 9/1/01
proud parents of Vincent (1/20/02) Alina (2/4/07) and Mateo (6/20/11)
:(I just kissed her a million times. I can't imagine. Im so sorry. Praying for you and your family. <3
Tristian- mommy to Gianna Lynn (06-06-11)
So sorry. thoughts and prayers for you and your family.
A & A together since 11/30/06.
My full moon, due date, bruin's winning the stanley cup Baby Girl born 6/15/11 ( . Y . )
Blessed beyond measure!!
Audra, DH Jason, DS Mason 3/08, DD Finley 6/11, Fur Babies Knuckles, Madison, & Ranger
Im so sorry. Words cannot express my feelings for your loss. God bless you .
Nicole -Wife to my hottie,Drew
Loving mama to my Monkey ,Ethan 3/7/09 & Johnny Banans -6/22/2011
Im so sorry, I cant even imagine.
T&Ps for you and your family.
DS Cohen James 2008
DD Nova Lynn 2011 VBAC!


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The world's best Champagne stopper? It just might be. From Le Creuset, this was specifically requested by our Champagne buyer. With a single motion, the Champagne Crown Sealer locks carbonation inside champagne and sparkling wine bottles, preserving contents for days with its airtight rubber seal. Airtight seal retains carbonation in a partly-used bottle. Slides easily onto the neck of the bottle. Beautiful design makes for an eye-catching stopper!
The item you have chosen is not in stock in our retail stores or within our main warehouse.
Gift Bag - Hadmade Red/Gold - 17688
Gift Bag - Handmade Paper Gold 17322 or 17435
Wine Mummy 2-Pack
Gift Bag - Handmade Paper - Blue 17436 or 17761
Gift Bag - Red and Gold - 17178


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Special Issue: Current Developments in Food-Addiction Research
Guest Editor: Dr. Caroline Davis


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Barre driver hospitalized after late-night mishapApril 21,2013
Barre man hurt
in NH car crash
BRADFORD A Barre man who was hospitalized in New Hampshire following a late-night accident on Route 25 will face at least one criminal charge when he returns to Vermont.
Vermont State Police said Mark Ekins, 47, was driving with a criminally suspended license when he swerved off the road and into a ditch shortly after 11 p.m. Thursday. Ekins was injured in the accident and taken to Dartmouth-Hitchcock Medical Center in Hanover, N.H.
The extent of Ekins injuries was not disclosed, but police said alcohol may have been a factor and the results of a blood test are pending.
At a minimum, police said, Ekins will be cited to appear in court on a charge of driving with a criminally suspended license.MORE IN This Just In
NEWPORT — An unidentified caller made a threat to the Department of Children and... Full Story
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STARmeterSEE RANK
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Tolga Çevik
Actor | Writer | Soundtrack
Tolga Çevik was born on May 12, 1974 in Istanbul, Turkey. He is an actor and writer, known for Magic Carpet Ride (2005), Patron Mutlu Son Istiyor (2014) and Away from Home (2001). He has been married to Özge Yilmaz since September 9, 2004. They have two children. See full bio »
Born:in Istanbul, Turkey
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Asia's Dragon Baby Boom Coming to an End
The Lunar New Year is about three weeks away. While in Hawaii that will mean celebrations and cultural events, in Asia it will mean the end to a very busy year at the region's maternity wards. HPR's Bill Dorman has more in today's Asia Minute.
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Orange Blossom Lodge No. 80, Free and Accepted Masons of Florida, was chartered by the Most Worshipful Grand Lodge of Free and Accepted Masons of Florida on the 22nd day of January 1885.
We have our meetings on every 1st and 3rd Monday at 7:30 PM.
Supporting Masonic Activities in Central Florida of the PROUD! 17th Masonic District for over 130 years!! We are also the closest Lodge to the Greatest Family Place on Earth, Walt Disney World, and many other Family Vacation Attractions.
Our Lodge begins with a Gourmet Meal open to everyone, starting at 6:00PM and preceding the meeting. As always, all traveling Brothers, and their families, are invited to join us for fellowship and a meal, and make OBL80 your "Home away from Home!" Join us in our festivities!
If you are a Brother Mason, and would like to join our conversations, send us a request on FaceBook.
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I have a header that defines a large number of macros, some of whom depend on other macros -- however, the dependencies are all resolved within this header.
I need a one-liner for printing out the value of a macro defined in that header.
As an example:
#define MACRO_A 0x60000000
#define MACRO_B MACRO_A + 0x00010000
As a first blush:
echo MACRO_B | ${CPREPROCESSOR} --include /path/to/header
... which nearly gives me what I want:
# A number of lines that are not important
# ...
0x60000000 + 0x00010000
... however, I'm trying to keep this from ballooning into a huge sequence of "pipe it to this, then pipe it to that ...".
I've also tried this:
echo 'main(){ printf( "0x%X", MACRO_B ); }' \
| ${CPREPROCESSOR} --include /path/to/header --include /usr/include/stdio.h
... but it (the gcc compiler) complains that -E is required when processing code on standard input, so I end up having to write out to a temporary file to compile/run this.
Is there a better way?


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Recent Articles by Wests Tigers
Benji Marshall to leave Wests Tigers
BENJI Marshall has requested as release from the final two years of his contract with Wests Tigers.
Tigers release Pettyborne to Wigan
WESTS Tigers have today granted hard working forward Eddy Pettybourne a release to join English Super League Club Wigan.
Wests Tigers statement on Nathan Brown
WESTS Tigers Under 20s forward Nathan Brown will accept a two-week suspension from the NRL match review committee after being charged with grade-three contrary conduct.
Wests Tigers re-sign Keith Galloway
WESTS Tigers are pleased to announce the re-signing of Keith Galloway on a three-year deal.
Martin Taupau signs with Wests Tigers
WESTS Tigers have today taken a step in bolstering their forward pack for next season with the signing of tough Canterbury-Bankstown Bulldogs prop Martin Taupau on a three-year deal.
Jacob Miller released to join Hull FC
WESTS Tigers have today released half-back Jacob Miller.
Final decision yet to be made on Marshall
WESTS Tigers Coach Mick Potter is still considering whether Benji Marshall will line up against the Bulldogs at ANZ Stadium tomorrow night.
Wests Tigers injury update ahead of Round 8
 WESTS Tigers centres Blake Ayshford and Chris Lawrence are expected to be out for up to six weeks each.
Pat Richards returns to Wests Tigers
WESTS Tigers is pleased to announce the signing of former premiership winning winger Pat Richards to a two-year contract from 2014.
Judiciary news: Adam Blair cleared to play
WESTS Tigers forward Adam Blair has tonight been cleared by the NRL judiciary to play St. George-Illawarra Dragons at the Sydney Cricket Ground this Sunday.


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County and tribal aging offices can answer questions about needs, services and opportunities for older persons in their communities.
Tribal Aging Offices:
For contact information, click on your county in the list below. Following these links will open up a new window and take you to the Aging and Long Term Care Resources website.
County Aging Offices:
Last Revised: May 8, 2015


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What's New
- Fixed several crashes
- Added support for iOS 7
App Description
Easily generate your own memes and share them with your friends!
Yo dawg, we heard you like memes, so we put a meme generator in your iThing so you can meme while you iThing!
Meme Generator is the easiest way to generate memes in your iOS device. Download it now and start creating your own memes and sharing them with your friends. The fun never stops! Furthermore, this app is completely free and doesn't add any watermarks to your memes. And you can't explain that!
- Easy to use and clean interface
- Lots of images to create your memes
- Use your own images to create new memes
- Share your memes with your friends, directly from the application
- Synchronize your memes and custom images between all your devices using iCloud
App Changes
- June 14, 2014 Initial release