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Sample records for c1 inhibitor deficiency

  1. C1 inhibitor deficiency: 2014 United Kingdom consensus document.

    PubMed

    Longhurst, H J; Tarzi, M D; Ashworth, F; Bethune, C; Cale, C; Dempster, J; Gompels, M; Jolles, S; Seneviratne, S; Symons, C; Price, A; Edgar, D

    2015-06-01

    C1 inhibitor deficiency is a rare disorder manifesting with recurrent attacks of disabling and potentially life-threatening angioedema. Here we present an updated 2014 United Kingdom consensus document for the management of C1 inhibitor-deficient patients, representing a joint venture between the United Kingdom Primary Immunodeficiency Network and Hereditary Angioedema UK. To develop the consensus, we assembled a multi-disciplinary steering group of clinicians, nurses and a patient representative. This steering group first met in 2012, developing a total of 48 recommendations across 11 themes. The statements were distributed to relevant clinicians and a representative group of patients to be scored for agreement on a Likert scale. All 48 statements achieved a high degree of consensus, indicating strong alignment of opinion. The recommendations have evolved significantly since the 2005 document, with particularly notable developments including an improved evidence base to guide dosing and indications for acute treatment, greater emphasis on home therapy for acute attacks and a strong focus on service organization.

  2. C1 inhibitor deficiency: 2014 United Kingdom consensus document

    PubMed Central

    Longhurst, H J; Tarzi, M D; Ashworth, F; Bethune, C; Cale, C; Dempster, J; Gompels, M; Jolles, S; Seneviratne, S; Symons, C; Price, A; Edgar, D

    2015-01-01

    C1 inhibitor deficiency is a rare disorder manifesting with recurrent attacks of disabling and potentially life-threatening angioedema. Here we present an updated 2014 United Kingdom consensus document for the management of C1 inhibitor-deficient patients, representing a joint venture between the United Kingdom Primary Immunodeficiency Network and Hereditary Angioedema UK. To develop the consensus, we assembled a multi-disciplinary steering group of clinicians, nurses and a patient representative. This steering group first met in 2012, developing a total of 48 recommendations across 11 themes. The statements were distributed to relevant clinicians and a representative group of patients to be scored for agreement on a Likert scale. All 48 statements achieved a high degree of consensus, indicating strong alignment of opinion. The recommendations have evolved significantly since the 2005 document, with particularly notable developments including an improved evidence base to guide dosing and indications for acute treatment, greater emphasis on home therapy for acute attacks and a strong focus on service organization. PMID:25605519

  3. C1 inhibitor functional deficiency in systemic lupus erythematosus (SLE).

    PubMed Central

    Jazwinska, E C; Gatenby, P A; Dunckley, H; Serjeantson, S W

    1993-01-01

    C1 inhibitor (C1-inh) was assayed in eight SLE patients presenting with consistently low levels of intact C4. C1-inh antigenic levels were normal in all patients; however, the function of the C1-inh tested against C1s and C1r was variable and outside the normal functional range in seven of the eight patients. The molecular weight of patients' C1-inh protein was 105 kD, corresponding to the size of the intact molecule. The C1-inh gene was analysed in all patients. Restriction fragments generated with TaqI, PstI and HgiAI gave no indication of a major C1-inh gene rearrangement. Direct genomic sequencing of exon VIII revealed three polymorphic point mutations, but there were no changes from the normal gene in or around the reactive-centre residue of C1-inh. Furthermore, we found no evidence for a C1-inh autoantibody in patients which could affect normal C1-inh function in vitro. These results indicate that the etiology of C1-inh dysfunction in SLE is heterogeneous and distinct from that reported in either hereditary or acquired angioedema. PMID:8485912

  4. Therapeutic management of hereditary angioedema due to C1 inhibitor deficiency.

    PubMed

    Zanichelli, Andrea; Mansi, Marta; Periti, Giulia; Cicardi, Marco

    2013-05-01

    Hereditary angioedema (HAE) due to C1 inhibitor (C1-INH) deficiency is a rare genetic disease characterized by recurrent swellings of the subcutaneous and submucosal tissues that can manifest as cutaneous edema, abdominal pain and laryngeal edema with airway obstruction. These symptoms have a significant impact on patients' quality of life. The reduction in C1-INH function leads to uncontrolled activation of the contact system and generation of bradykinin, the mediator of increased vascular permeability and edema formation. In the past, few treatment options were available; however, several new therapies with proven efficacy have recently become available to treat and prevent HAE attacks, such as plasma-derived and recombinant C1-INHs that replace the deficient protein, bradykinin receptor antagonist (icatibant) that blocks bradykinin activity and kallikrein inhibitor (ecallantide) that prevents bradykinin release. Such therapies can improve disease outcome. This article reviews the therapeutic management of HAE, which involves the treatment of acute attacks and prophylaxis.

  5. Overview of hereditary angioedema caused by C1-inhibitor deficiency: assessment and clinical management.

    PubMed

    Bork, K; Davis-Lorton, M

    2013-02-01

    Hereditary angioedema due to C1-inhibitor deficiency (HAE-C1-INH) is a rare, autosomal-dominant disease. HAE-C1-INH is characterized by recurrent attacks of marked, diffuse, nonpitting and nonpruritic skin swellings, painful abdominal attacks, and laryngeal edema. The extremities and the gastrointestinal tract are most commonly affected. Swelling of the upper respiratory mucosa poses the greatest risk because death from asphyxiation can result from laryngealedema. HAE-C1-INH attacks are variable, unpredictable, and may be induced by a variety of stimuli, including stress or physical trauma. Because the clinical presentation of HAE-C1-INH is similar to other types of angioedema, the condition may be a challenge to diagnose. Accurate identification of HAE-C1-INH is critical in order to avoid asphyxiation by laryngeal edema and to improve the burden of disease. Based on an understanding of the underlying pathophysiology of IHAE-C1-INH, drugs targeted specifically to the disease, such as C1-inhibitor therapy, bradykinin B2-receptor antagonists, and kallikrein-inhibitors, have become available for both treatment and prevention of angioedema attacks. This article reviews the clinical features, differential diagnosis, and current approaches to management of HAE-C1-INH.

  6. The Janus faces of acquired angioedema: C1-inhibitor deficiency, lymphoproliferation and autoimmunity.

    PubMed

    Wu, Maddalena Alessandra; Castelli, Roberto

    2016-02-01

    Several clinical and biological features of lymphoproliferative diseases have been associated with an increased risk of developing autoimmune manifestations. Acquired deficiency of C1-inhibitor (C1-INH) (AAE) is a rare syndrome clinically similar to hereditary angioedema (HAE) characterized by local increase in vascular permeability (angioedema) of the skin and the gastrointestinal and oro-pharyngo-laryngeal mucosa. Bradykinin, a potent vasoactive peptide, released from high molecular weight kininogen when it is cleaved by plasma kallikrein (a serine protease controlled by C1-INH), is the mediator of symptoms. In total 46% of AAE patients carry an underlying hematological disorder including monoclonal gammopathy of uncertain significance (MGUS) or B cell malignancies. However, 74% of AAE patients have anti-C1-INH autoantibodies without hematological, clinical or instrumental evidence of lymphoproliferative disease. Unlike HAE patients, AAE patients usually have late-onset symptoms, do not have a family history of angioedema and present variable response to treatment due to the hypercatabolism of C1-INH. Experiments show that C1-INH and/or the classical complement pathway were consumed by the neoplastic lymphatic tissues and/or anti-C1-INH neutralizing autoantibodies. Therapy of AAE follows two directions: 1) prevention/reversal of the symptoms of angioedema; and 2) treatment of the associated disease. Different forms of B cell disorders coexist and/or evolve into each other in AAE and seem to be dominated by an altered control of B cell proliferation, thus AAE represents an example of the strict link between autoimmunity and lymphoproliferation.

  7. Lack of increased prevalence of immunoregulatory disorders in hereditary angioedema due to C1-inhibitor deficiency.

    PubMed

    Farkas, Henriette; Csuka, Dorottya; Gács, Judit; Czaller, Ibolya; Zotter, Zsuzsanna; Füst, George; Varga, Lilian; Gergely, Péter

    2011-10-01

    Hereditary angioedema due to deficiency of C1-INH (HAE-C1-INH) is associated with enhanced consumption of the early complement components, which may predispose for autoimmune disease. We assessed the prevalence of such disorders among HAE- C1-INH patients and their impact on the natural course of HAE-C1-INH. Clinical data and immunoserological parameters of 130 HAE-C1-INH and 174 non-C1-INH-deficient patients with angioedema were analyzed. In our study, the incidence of immunoregulatory disorders was 11.5% in the population of HAE-C1-INH patients and 5.2% among non-C1-INH-deficient controls with angioedema. Immunoserology screening revealed a greater prevalence of anticardiolipin IgM (p=0.0118) among HAE-C1-INH patients, than in those with non-C1-INH-deficient angioedema. We did not find higher prevalence of immunoregulatory disorders among our HAE-C1-INH patients. However, in patients with confirmed immunoregulatory disorders, the latter influenced both the severity of HAE-C1-INH and the effectiveness of its long-term management. Appropriate management of the immunoregulatory disease thus identified improves the symptoms of HAE-C1-INH.

  8. A 'de novo' arisen case of angioedema C1-inhibitor deficiency dependent: possible mutagenic effect of azathioprine?

    PubMed

    Guastafierro, S; D'Apuzzo, A; Verrazzo, G; Lucivero, G; Coppola, L

    1999-06-01

    It is reported that a C1-inhibitor (CI-INH) deficiency dependent angiodema case arose 'de novo' in a child without a family history of this disease. His mother was undergoing immunosuppressive therapy (50 mg of azathioprine plus 8 mg of methyl-prednisolone daily) during pregnancy, uninterrupted for seven years because of a kidney transplant. All the other known causes of acquired C1-INH deficiency were excluded. An involvement of an azathioprine-induced C1-INH gene mutation is hypothised.

  9. Recombinant replacement therapy for hereditary angioedema due to C1 inhibitor deficiency.

    PubMed

    Moldovan, Dumitru; Bernstein, Jonathan A; Cicardi, Marco

    2015-01-01

    Hereditary angioedema is a rare genetic condition transmitted as an autosomal dominant trait and characterized most commonly by the production of either inadequate or nonfunctioning C1 esterase inhibitor (C1-INH), a blood protein that regulates proteases in the complement, fibrinolytic and contact systems. Patients with hereditary angioedema suffer from episodic, unpredictable manifestations of edema affecting multiple anatomical locations, including the GI tract, facial tissue, the upper airway, oropharynx, urogenital region and/or the arms and legs. A rational approach to treatment is replacement of C1-INH protein, to normalize the levels of C1-INH activity and halt the progression of the biochemical activation processes underlying the edema formation. Ruconest is a highly purified recombinant human C1-INH. This article will focus on the results of ten clinical studies demonstrating the efficacy and safety of Ruconest(®) (Pharming Group NV, Leiden, the Netherlands), which is now approved for use in Europe, Israel and the USA.

  10. A focused parameter update: hereditary angioedema, acquired C1 inhibitor deficiency, and angiotensin-converting enzyme inhibitor-associated angioedema.

    PubMed

    Zuraw, Bruce L; Bernstein, Jonathan A; Lang, David M; Craig, Timothy; Dreyfus, David; Hsieh, Fred; Khan, David; Sheikh, Javed; Weldon, David; Bernstein, David I; Blessing-Moore, Joann; Cox, Linda; Nicklas, Richard A; Oppenheimer, John; Portnoy, Jay M; Randolph, Christopher R; Schuller, Diane E; Spector, Sheldon L; Tilles, Stephen A; Wallace, Dana

    2013-06-01

    These parameters were developed by the Joint Task Force on Practice Parameters (JTFPP), representing the American Academy of Allergy, Asthma & Immunology (AAAAI); the American College of Allergy, Asthma & Immunology (ACAAI); and the Joint Council of Allergy, Asthma and Immunology. The AAAAI and the ACAAI have jointly accepted responsibility for establishing "A focused parameter update: Hereditary angioedema, acquired C1 inhibitor deficiency, and angiotensin-converting enzyme inhibitor-associated angioedema." This is a complete and comprehensive document at the current time. The medical environment is a changing environment, and not all recommendations will be appropriate for all patients. Because this document incorporated the efforts of many participants, no single individual, including those who served on the JTFPP, is authorized to provide an official AAAAI or ACAAI interpretation of these practice parameters. Any request for information about or an interpretation of these practice parameters by the AAAAI or ACAAI should be directed to the Executive Offices of the AAAAI, the ACAAI, and the Joint Council of Allergy, Asthma and Immunology. The Joint Task Force on Practice Parameters understands that the cost of diagnostic tests and therapeutic agents is an important concern that might appropriately influence the work-up and treatment chosen for a given patient. The JTFPP recognizes that the emphasis of our primary recommendations regarding a medication might vary, for example, depending on third-party payer issues and product patent expiration dates. However, because the cost of a given test or agent is so widely variable and there is a paucity of pharmacoeconomic data, the JTFPP generally does not consider cost when formulating practice parameter recommendations. In some instances the cost benefit of an intervention is considered relevant, and commentary might be provided. These parameters are not designed for use by pharmaceutical companies in drug promotion

  11. Hereditary Angioedema Due to C1 Inhibitor Deficiency in Serbia: Two Novel Mutations and Evidence of Genotype-Phenotype Association

    PubMed Central

    Andrejević, Slađana; Korošec, Peter; Šilar, Mira; Košnik, Mitja; Mijanović, Radovan; Bonači-Nikolić, Branka; Rijavec, Matija

    2015-01-01

    Hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE) is a rare autosomal dominant disease characterized by recurrent life-threatening oedemas and/or abdominal pain and caused by mutations affecting the C1 inhibitor gene, SERPING1. We sought to investigate the spectrum of SERPING1 mutations in Serbia and the possible genotype-phenotype association. C1-INH-HAE was diagnosed on the basis of clinical and laboratory criteria in 40 patients from 27 families; four were asymptomatic. Mutational analysis of the SERPING1 gene was performed by sequencing and multiplex ligation-dependent probe amplification. Disease-causing mutations in SERPING1 were identified in all patients. In C1-INH-HAE type I, we identified 19 different mutations, including 6 missense mutations, 6 nonsense mutations, 2 small deletions, 1 small insertion, 2 splicing defects and 2 large deletions. Two of the mutations (c.300C>T and c.1184_1185insTA) are reported here for the first time. All C1-INH-HAE type II patients from three families harboured the same substitution (c.1396C>T). Based on the type of mutation identified in the SERPING1 gene, patients were divided into two groups: group 1 (nonsense, frameshift, large deletions/insertions, splicing defect, and mutations at Arg444) or group 2 (missense, excluding mutations at Arg444). Significant differences were found in the clinical severity score (P = 0.005), prevalence of laryngeal (P = 0.040) and facial (P = 0.013) oedema, and long-term prophylaxis (P = 0.023) between the groups with different types of mutations. Because our population consisted of related subjects, differences in the severity score between mutation groups were further confirmed using the generalized estimating equation (P = 0.038). Our study identified 20 different disease-causing mutations, including two novel mutations, in all C1-INH-HAE patients, highlighting the heterogeneity of mutations in the SERPING1 gene. Furthermore, it appears that mutations with a clear effect

  12. Cleavage of the second component of complement by plasma proteases: implications in hereditary C1-inhibitor deficiency.

    PubMed Central

    Smith, M A; Kerr, M A

    1985-01-01

    EDTA plasma from patients with hereditary angioedema (HAE), the genetic deficiency of C1-inhibitor, when incubated at 37 degrees produces a kinin-like activity which can induce contraction of oestrus rat uterus. The second component of complement (C2) has previously been suggested to be the source of this kinin-like activity, with the implication that C2-kinin is a normal product of complement activation. Our results show that purified human C2 is cleaved rapidly to C2a and C2b when added to HAE plasma, but not normal plasma or plasma from a danazol-treated HAE patient. However, the addition to HAE plasma of C2 at 20 X normal plasma concentration had no effect on the kinin activity generated on incubation at 37 degrees. In the presence of soya bean trypsin inhibitor, the rate of C2 cleavage and products were unaltered but no kinin activity was generated. C2 was cleaved by purified C1s to C2a and C2b. Incubation of C2 with trypsin resulted in cleavage to C2a and C2b followed by more extensive cleavage of both C2a and C2b. Kallikrein cleaved C2 to C2a and C2b but plasmin had no effect on C2. In no case was kinin activity generated. When C2 was cleaved by C1s to C2a and C2b then incubated with trypsin, kallikrein, or plasmin, no kinin activity was generated: only trypsin cleaved the C2 fragments further. The results suggest that C2 is not the source of the kinin-like activity generated in hereditary angioedema plasma. Images Figure 4 Figure 5 Figure 6 Figure 7 PMID:2934317

  13. C1 inhibitor: quantification and purification.

    PubMed

    Varga, Lilian; Dobó, József

    2014-01-01

    C1 inhibitor is a multipotent serpin capable of inhibiting the classical and the lectin pathways of complement, the fibrinolytic system, and contact/kinin system of coagulation. Deficiency of C1 inhibitor manifest as hereditary angioedema (HAE), an autosomal dominant hereditary disease. Measuring the C1 inhibitor level is of vital importance for the diagnosis of HAE and also for monitoring patients receiving C1 inhibitor for therapy. Determination of the antigenic C1 inhibitor level by the radial immunodiffusion (RID) technique is described in detail in this chapter. The presented purification method of plasma C1 inhibitor is primarily based on its high carbohydrate content and its affinity to the lectin jacalin.

  14. Hereditary angioedema with normal C1 inhibitor.

    PubMed

    Bork, Konrad

    2013-11-01

    Until recently it was assumed that hereditary angioedema was a disease that results exclusively from a genetic deficiency of the C1 inhibitor. In 2000, families with hereditary angioedema, normal C1 inhibitor activity, and protein in plasma were described. Since then, numerous patients and families with that condition have been reported. Most of the patients were women. In many of the affected women, oral contraceptives, hormone replacement therapy containing estrogens, and pregnancies triggered the clinical symptoms. In some families mutations in the coagulation factor XII (Hageman factor) gene were detected.

  15. A Nationwide Study of Norwegian Patients with Hereditary Angioedema with C1 Inhibitor Deficiency Identified Six Novel Mutations in SERPING1

    PubMed Central

    Johnsrud, Irene; Kulseth, Mari Ann; Rødningen, Olaug Kristin; Landrø, Linn; Helsing, Per; Waage Nielsen, Erik; Heimdal, Ketil

    2015-01-01

    Hereditary angioedema with C1 inhibitor deficiency (C1-INH-HAE) is characterized by relapsing, non-pruritic swelling in skin and submucosal tissue. Symptoms can appear in early infancy when diagnosis is more difficult. In the absence of a correct diagnosis, treatment of abdominal attacks often lead to unnecessary surgery, and laryngeal edema can cause asphyxiation. A cohort study of 52 patients from 25 unrelated families in Norway was studied. Diagnosis of C1-INH-HAE was based on international consensus criteria including low functional and/or antigenic C1-INH values and antigenic C4. As SERPING1 mutations in Norwegian patients with C1-INH-HAE are largely undescribed and could help in diagnosis, we aimed to find and describe these mutations. Mutation analysis of the SERPING1 gene was performed by Sanger sequencing of all protein coding exons and exon-intron boundaries. Samples without detected mutation were further analyzed by multiplex ligation-dependent probe amplification to detect deletions and duplications. Novel mutations suspected to lead to splice defects were analyzed on the mRNA level. Fifty-two patients from 25 families were included. Forty-four (84,6%) suffered from C1-INH-HAE type I and eight (15,4%) suffered from C1-INH-HAE type II. Pathogenic or likely pathogenic mutations were found in 22/25 families (88%). Thirteen unique mutations were detected, including six previously undescribed. There were three missense mutations including one mutation affecting the reactive center loop at codon 466, three nonsense mutations, three small deletions/duplications, three gross deletions, and one splice mutation. PMID:26154504

  16. Hereditary C1q deficiency: a new family with C1qA deficiency.

    PubMed

    Sun-Tan, Cağman; Ozgür, Tuba Turul; Kilinç, Gamze; Topaloğlu, Rezan; Gököz, Ozay; Ersoy-Evans, Sibel; Sanal, Ozden

    2010-01-01

    Hereditary deficiency of complement component C1q is a rare genetic disorder with susceptibility to recurrent infections with polysaccharide-containing encapsulated microorganisms and a high prevalence of autoimmune diseases, most often systemic lupus erythematosus (SLE). Here, we report a 29-month-old boy who presented with facial rash and history of early death of a sibling with infections, who was found to have a selective deficiency of C1q. The facial rash was composed of patchy erythematous plaques and centrally hypopigmented macules and desquamation. Two siblings had died of severe bacterial infections and his uncle had died of meningitis. Molecular study disclosed a homozygous point mutation in the C1qA chain gene. Five members of the family, including the parents and three healthy siblings, were heterozygous for this mutation.

  17. Hereditary angioedema with normal C1 inhibitor: clinical characteristics and treatment response with plasma-derived human C1 inhibitor concentrate (Berinert(®)) in a French cohort.

    PubMed

    Bouillet, Laurence; Boccon-Gibod, Isabelle; Gompel, Anne; Floccard, Bernard; Martin, Ludovic; Blanchard-Delaunay, Claire; Launay, David; Fain, Olivier

    2017-03-01

    Hereditary angioedema (HAE) is a rare genetic disorder characterised by episodes of swelling without urticaria. Berinert® (CSL Behring) is a plasma-derived human C1 inhibitor (C1-INH) concentrate, approved for the treatment of HAE with C1-INH deficiency (C1-INH-HAE), however, it is often used off-label in Europe to treat HAE with normal C1-INH.

  18. C1q Deficiency and Neuropsychiatric Systemic Lupus Erythematosus

    PubMed Central

    van Schaarenburg, Rosanne A.; Magro-Checa, César; Bakker, Jaap A.; Teng, Y. K. Onno; Bajema, Ingeborg M.; Huizinga, Tom W.; Steup-Beekman, Gerda M.; Trouw, Leendert A.

    2016-01-01

    C1q deficiency is a rare immunodeficiency, which is strongly associated with the development of systemic lupus erythematosus (SLE). A mutation in one of the C1q genes can either lead to complete deficiency or to low C1q levels with C1q polypeptide in the form of low-molecular weight (LMW) C1q. Patients with C1q deficiency mainly present with cutaneous and renal involvement. Although less frequent, neuropsychiatric (NP) involvement has also been reported in 20% of the C1q-deficient patients. This involvement appears to be absent in other deficiencies of early components of the complement classical pathway (CP) (C1r/C1s, C2, or C4 deficiencies). We describe a new case with C1q deficiency with a homozygous G34R mutation in C1qC-producing LMW-C1q presenting with a severe SLE flare with NP involvement. The serum of this patient contained very low levels of a LMW variant of C1q polypeptides. Cell lysates contained the three chains of C1q, but no intact C1q was detected, consistent with the hypothesis of the existence of a LMW-C1q. Furthermore, we provide a literature overview of NP-SLE in C1q deficiency and hypothesize about the potential role of C1q in the pathogenesis of NP involvement in these patients. The onset of NP-SLE in C1q-deficient individuals is more severe when compared with complement competent NP-SLE patients. An important number of cases present with seizures and the most frequent findings in neuroimaging are changes in basal ganglia and cerebral vasculitis. A defective CP, because of non-functional C1q, does not protect against NP involvement in SLE. The absence of C1q and, subsequently, some of its biological functions may be associated with more severe NP-SLE. PMID:28082982

  19. Development of a disease-specific quality of life questionnaire for adult patients with hereditary angioedema due to C1 inhibitor deficiency (HAE-QoL): Spanish multi-centre research project

    PubMed Central

    2012-01-01

    Background There is a need for a disease-specific instrument for assessing health-related quality of life in adults with hereditary angioedema due to C1 inhibitor deficiency, a rare, disabling and life-threatening disease. In this paper we report the protocol for the development and validation of a specific questionnaire, with details on the results of the process of item generation, domain selection, and the expert and patient rating phase. Methods/Design Semi-structured interviews were completed by 45 patients with hereditary angioedema and 8 experts from 8 regions in Spain. A qualitative content analysis of the responses was carried out. Issues raised by respondents were grouped into categories. Content analysis identified 240 different responses, which were grouped into 10 conceptual domains. Sixty- four items were generated. A total of 8 experts and 16 patients assessed the items for clarity, relevance to the disease, and correct dimension assignment. The preliminary version of the specific health-related quality of life questionnaire for hereditary angioedema (HAE-QoL v 1.1) contained 44 items grouped into 9 domains. Discussion To the best of our knowledge, this is the first multi-centre research project that aims to develop a specific health-related quality of life questionnaire for adult patients with hereditary angioedema due to C1 inhibitor deficiency. A preliminary version of the specific HAE-QoL questionnaire was obtained. The qualitative analysis of interviews together with the expert and patient rating phase helped to ensure content validity. A pilot study will be performed to assess the psychometric properties of the questionnaire and to decide on the final version. PMID:22817696

  20. Hereditary and acquired C1-inhibitor-dependent angioedema: from pathophysiology to treatment.

    PubMed

    Zeerleder, Sacha; Levi, Marcel

    2016-01-01

    Uncontrolled generation of bradykinin (BK) due to insufficient levels of protease inhibitors controlling contact phase (CP) activation, increased activity of CP proteins, and/or inadequate degradation of BK into inactive peptides increases vascular permeability via BK-receptor 2 (BKR2) and results in subcutaneous and submucosal edema formation. Hereditary and acquired angioedema due to C1-inhibitor deficiency (C1-INH-HAE and -AAE) are diseases characterized by serious and potentially fatal attacks of subcutaneous and submucosal edemas of upper airways, facial structures, abdomen, and extremities, due to inadequate control of BK generation. A decreased activity of C1-inhibitor is the hallmark of C1-INH-HAE (types 1 and 2) due to a mutation in the C1-inhibitor gene, whereas the deficiency in C1-inhibitor in C1-INH-AAE is the result of autoimmune phenomena. In HAE with normal C1-inhibitor, a significant percentage of patients have an increased activity of factor XIIa due to a FXII mutation (FXII-HAE). Treatment of C1-inhibitor-dependent angioedema focuses on restoring control of BK generation by inhibition of CP proteases by correcting the balance between CP inhibitors and BK breakdown or by inhibition of BK-mediated effects at the BKR2 on endothelial cells. This review will address the pathophysiology, clinical picture, diagnosis and available treatment in C1-inhibitor-dependent angioedema focusing on BK-release and its regulation. Key Messages Inadequate control of bradykinin formation results in the formation of characteristic subcutaneous and submucosal edemas of the skin, upper airways, facial structures, abdomen and extremities as seen in hereditary and acquired C1-inhibitor-dependent angioedema. Diagnosis of hereditary and acquired C1-inhibitor-dependent angioedema may be troublesome as illustrated by the fact that there is a significant delay in diagnosis; a certain grade of suspicion is therefore crucial for quick diagnosis. Submucosal edema formation in

  1. Characterization of C1 inhibitor binding to neutrophils.

    PubMed Central

    Chang, N S; Boackle, R J; Leu, R W

    1991-01-01

    In a previous study we have isolated neutrophil membrane proteins that non-covalently bind to native C1-INH (105,000 MW) and a non-functional, degraded C1-INH (88,000 MW; C1-INH-88). To further characterize the binding nature, we have designed a novel kinetic C1 titration assay which enables not only a quantification of the removal of fluid-phase C1-INH by neutrophils, but also a concomitant measure of residual C1-INH function. Native C1-INH, when adsorbed to EDTA-pretreated neutrophils, lost its function in the inhibition of fluid-phase C1. The non-functional C1-INH-88, which is probably devoid of a reactive centre, was found to block the binding of native C1-INH to neutrophils. Pretreatment of neutrophils with serine esterase inhibitors did not abrogate binding capacity of the cells for C1-INH, whereas the binding affinity for C1-INH was lost when the cells were pretreated with trypsin. An array of human peripheral blood leucocytes and several lymphoid cell lines has surface binding sites for C1-INH, but not on human erythrocytes and U937 cells. Binding was further confirmed using (i) C1-INH-microsphere beads to neutrophils, in which the binding was blocked when pretreating neutrophils with excess C1-INH or with trypsin, and (ii) radiolabelled C1-INH to neutrophils, which was competitively blocked by unlabelled non-functional C1-INH-88. Desialylation of C1-INH significantly reduced its binding affinity for neutrophils, indicating that the membrane receptor sites on neutrophils could be specific for the binding of sialic acid residues on C1-INH. Overall, our studies indicate that neutrophils or other leucocytes possess specific surface binding sites for the sialic acid-containing portion of C1-INH. PMID:2045131

  2. Terminal complement complexes and C1/C1 inhibitor complexes in autoimmune thyroid disease.

    PubMed Central

    Weetman, A P; Cohen, S B; Oleesky, D A; Morgan, B P

    1989-01-01

    The potential role of complement activation and the membrane attack complex in the pathogenesis of Graves' disease and Hashimoto's thyroiditis has been investigated by measuring serum concentrations of the C1r-C1s-C1 inhibitor complex (C1/C1-inh) and the terminal complement complex (TCC), and by studying the binding to thyroid tissue of monoclonal and polyclonal antibodies against TCC neoantigens. Serum C1/C1-inh and TCC concentrations were significantly increased in 29 patients with untreated Graves' disease compared with 47 healthy subjects (P less than 0.001 for both), and decreased significantly after carbimazole treatment in 18 of these patients for whom post-treatment samples were available (P less than 0.01 and P less than 0.02, respectively). The serum TCC concentration, but not that of C1/C1-inh, was also significantly increased in 15 patients with Hashimoto's thyroiditis compared with the 47 healthy subjects (P less than 0.001). TCCs were identified by immunohistochemical staining around the thyroid follicles in thyroidectomy specimens from patients with Graves' disease (six out of six) and Hashimoto's thyroiditis (two out of two); normal thyroid tissue from two subjects showed no staining. These results suggest a role for complement, in particular the membrane attack complex in the pathogenesis of autoimmune thyroid disease. Images Fig. 3 PMID:2766576

  3. Complement, Kinins, and Hereditary Angioedema: Mechanisms of Plasma Instability when C1 Inhibitor is Absent.

    PubMed

    Kaplan, Allen P; Joseph, Kusumam

    2016-10-01

    Plasma of patients with types I and II hereditary angioedema is unstable if incubated in a plastic (i.e., inert) vessel at 37 °C manifested by progressively increasing formation of bradykinin. There is also a persistent low level of C4 in 95 % of patients even when they are symptomatic. These phenomena are due to the properties of the C1r subcomponent of C1, factor XII, and the bimolecular complex of prekallikrein with high molecular weight kininogen (HK). Purified C1r auto-activates in physiologic buffers, activates C1s, which in turn depletes C4. This occurs when C1 inhibitor is deficient. The complex of prekallikrein-HK acquires an inducible active site not present in prekallikrein which in Tris-type buffers cleaves HK stoichiometrically to release bradykinin, or in phosphate buffer auto-activates to generate kallikrein and bradykinin. Thus immunologic depletion of C1 inhibitor from factor XII-deficient plasma (phosphate is the natural buffer) auto-activates on incubation to release bradykinin. Normal C1 inhibitor prevents this from occurring. During attacks of angioedema, if factor XII auto-activates on surfaces, the initial factor XIIa formed converts prekallikrein to kallikrein, and kallikrein cleaves HK to release bradykinin. Kallikrein also rapidly activates most remaining factor XII to factor XIIa. Additional cleavages convert factor XIIa to factor XIIf and factor XIIf activates C1r enzymatically so that C4 levels approach zero, and C2 is depleted. There is also a possibility that kallikrein is generated first as a result of activation of the prekallikrein-HK complex by heat shock protein 90 released from endothelial cells, followed by kallikrein activation of factor XII.

  4. An update on the diagnosis and management of hereditary angioedema with abnormal C1 inhibitor.

    PubMed

    Davis-Lorton, Mark

    2015-02-01

    Hereditary angioedema (HAE) is a rare genetic disease caused by a deficiency in functional C1-esterase inhibitor characterized by recurrent episodes of angioedema in the absence of associated urticaria. Subcutaneous swellings are experienced by virtually all patients with HAE, and dermatologists are likely to encounter this manifestation, requiring that they be knowledgeable about diagnosis and treatment options. Diagnosis of HAE is often delayed because several of the symptoms can mimic other disease states. Delays in diagnosis can lead to increased inappropriate treatment and decreased patient quality of life. Once a proper diagnosis is made, treatment needs to be targeted to the individual patient and includes on-demand therapy and an option for short- and long-term prophylaxis. On-demand therapy is required for all patients who are diagnosed with HAE and effective options include plasma-derived and recombinant C1 inhibitors, kallikrein inhibitors, and bradykinin B2-receptor antagonists. Options available for prophylaxis include plasma-derived C1 inhibitors, attenuated androgens, and antifibrinolytic agents, although the latter 2 options are associated with significant adverse events. This article reviews the diagnosis and options for effective management of patients with HAE.

  5. Prevention of Hereditary Angioedema Attacks with a Subcutaneous C1 Inhibitor.

    PubMed

    Longhurst, Hilary; Cicardi, Marco; Craig, Timothy; Bork, Konrad; Grattan, Clive; Baker, James; Li, Huamin H; Reshef, Avner; Bonner, James; Bernstein, Jonathan A; Anderson, John; Lumry, William R; Farkas, Henriette; Katelaris, Constance H; Sussman, Gordon L; Jacobs, Joshua; Riedl, Marc; Manning, Michael E; Hebert, Jacques; Keith, Paul K; Kivity, Shmuel; Neri, Sergio; Levy, Donald S; Baeza, Maria L; Nathan, Robert; Schwartz, Lawrence B; Caballero, Teresa; Yang, William; Crisan, Ioana; Hernandez, María D; Hussain, Iftikhar; Tarzi, Michael; Ritchie, Bruce; Králíčková, Pavlina; Guilarte, Mar; Rehman, Syed M; Banerji, Aleena; Gower, Richard G; Bensen-Kennedy, Debra; Edelman, Jonathan; Feuersenger, Henrike; Lawo, John-Philip; Machnig, Thomas; Pawaskar, Dipti; Pragst, Ingo; Zuraw, Bruce L

    2017-03-23

    Background Hereditary angioedema is a disabling, potentially fatal condition caused by deficiency (type I) or dysfunction (type II) of the C1 inhibitor protein. In a phase 2 trial, the use of CSL830, a nanofiltered C1 inhibitor preparation that is suitable for subcutaneous injection, resulted in functional levels of C1 inhibitor activity that would be expected to provide effective prophylaxis of attacks. Methods We conducted an international, prospective, multicenter, randomized, double-blind, placebo-controlled, dose-ranging, phase 3 trial to evaluate the efficacy and safety of self-administered subcutaneous CSL830 in patients with type I or type II hereditary angioedema who had had four or more attacks in a consecutive 2-month period within 3 months before screening. We randomly assigned the patients to one of four treatment sequences in a crossover design, each involving two 16-week treatment periods: either 40 IU or 60 IU of CSL830 per kilogram of body weight twice weekly followed by placebo, or vice versa. The primary efficacy end point was the number of attacks of angioedema. Secondary efficacy end points were the proportion of patients who had a response (≥50% reduction in the number of attacks with CSL830 as compared with placebo) and the number of times that rescue medication was used. Results Of the 90 patients who underwent randomization, 79 completed the trial. Both doses of CSL830, as compared with placebo, reduced the rate of attacks of hereditary angioedema (mean difference with 40 IU, -2.42 attacks per month; 95% confidence interval [CI], -3.38 to -1.46; and mean difference with 60 IU, -3.51 attacks per month; 95% CI, -4.21 to -2.81; P<0.001 for both comparisons). Response rates were 76% (95% CI, 62 to 87) in the 40-IU group and 90% (95% CI, 77 to 96) in the 60-IU group. The need for rescue medication was reduced from 5.55 uses per month in the placebo group to 1.13 uses per month in the 40-IU group and from 3.89 uses in the placebo group to 0

  6. C1q deficiency: identification of a novel missense mutation and treatment with fresh frozen plasma.

    PubMed

    Topaloglu, Rezan; Taskiran, Ekim Z; Tan, Cagman; Erman, Baran; Ozaltin, Fatih; Sanal, Ozden

    2012-07-01

    A Turkish patient with C1q deficiency presented with a lupus-like disease, and a new missense mutation at A chain is presented. To characterize the genetic defect, all exons of the genes for the A, B, and C chains of C1q were sequenced in the patient. This revealed a missense mutation in the collagen-like domain of the A chain, p.Gly31 Arg. No other sequence variants, including the common silent mutations, were found in the three chains. Exon 1 of the C1q A chain was sequenced in 105 samples from healthy controls for this particular mutation. None of these carried the mutation. The C1q-deficient patient was treated with fresh frozen plasma infusions. Our findings showed that Turkish patients may have different mutations than the previously described common mutation, and once again, not only nonsense mutations but also missense mutations cause hereditary C1q deficiency. Regular fresh frozen plasma infusions to the patient have been clinically and therapeutically successful.

  7. Hereditary angioedema in a Jordanian family with a novel missense mutation in the C1-inhibitor N-terminal domain.

    PubMed

    Jaradat, Saied A; Caccia, Sonia; Rawashdeh, Rifaat; Melhem, Motasem; Al-Hawamdeh, Ali; Carzaniga, Thomas; Haddad, Hazem

    2016-03-01

    Hereditary angioedema due to C1-inhibitor deficiency (C1-INH-HAE) is an autosomal dominant disease caused by mutations in the SERPING1 gene. A Jordanian family, including 14 individuals with C1-INH-HAE clinical symptoms, was studied. In the propositus and his parents, SERPING1 had four mutations leading to amino acid substitutions. Two are known polymorphic variants (c.167T>C; p.Val34Ala and c.1438G>A; p.Val458Met), the others are newly described. One (c.203C>T; p.Thr46Ile) is located in the N-terminal domain of the C1-inhibitor protein and segregates with angioedema symptoms in the family. The other (c.800C>T; p.Ala245Val) belongs to the serpin domain, and derives from the unaffected father. DNA from additional 24 family members were screened for c.203C>T mutation in the target gene. All individuals heterozygous for the c.203C>T mutation had antigenic and functional plasma levels of C1-inhibitor below 50% of normal, confirming the diagnosis of type I C1-INH-HAE. Angioedema symptoms were present in 14 of 16 subjects carrier for the c.203T allele. Among these subjects, those carrying the c.800T variation had more severe and frequent symptoms than subjects without this mutation. This family-based study provides the first evidence that multiple amino acid substitutions in SERPING1 could influence C1-INH-HAE phenotype.

  8. Hereditary angioedema with normal C1 inhibitor in a French cohort: Clinical characteristics and response to treatment with icatibant

    PubMed Central

    Boccon‐Gibod, Isabelle; Launay, David; Gompel, Anne; Kanny, Gisele; Fabien, Vincent; Fain, Oliver

    2017-01-01

    Abstract Introduction The clinical characteristics and icatibant‐treatment outcomes of patients with hereditary angioedema with normal C1 inhibitor (HAE‐nC1 INH) are limited. Methods We retrospectively analyzed data from French HAE patients enrolled in the Icatibant Outcome Survey registry (from July 2009 to September 2013) to compare disease characteristics and the effectiveness and safety of acute icatibant‐treated angioedema attacks in patients with HAE‐nC1 INH, HAE with C1 INH deficiency (type I), or dysfunction (type II). Results One center in Grenoble contributed 22 patients with HAE‐nC1 INH and a family history of HAE while 15 centers across France contributed 153 patients with HAE type I and seven patients with HAE type II. Patients with HAE‐nC1 INH compared to HAE type I, respectively, were more likely to be female (88.1% vs. 63.4%), older at median age of disease onset (21 years vs. 15 years), and have a greater rate of abdominal (80% vs. 61%) and laryngeal (23% vs. 14%) attacks. Icatibant was effective in both groups though the median time to resolution of attack was significantly longer in the HAE‐nC1 INH group (20.0 h, 37 attacks) versus the HAE type I group (14.0 h, 67 attacks). Icatibant was self‐administered for 96.1% of attacks in patients with HAE‐nC1 INH and 75.8% in patients with HAE type I. No serious adverse side effects related to icatibant were reported. Conclusions These data help further define the disease characteristics of HAE‐nC1 INH in the French population and extend the limited data reporting the safe and effective use of icatibant in acute treatment of angioedema in French patients diagnosed with HAE‐nC1 INH. PMID:28250922

  9. [Acquired angioedema with C1-INH deficiency and accompanying chronic spontaneous urticaria in a patient with chronic lymphatic B cell leukemia].

    PubMed

    Klossowski, N; Braun, S A; von Gruben, V; Losem, C; Plewe, D; Homey, B; Meller, S

    2015-10-01

    Acquired angioedema due to C1 inhibitor deficiency (C1-INH-AAE) is characterized by recurrent edema of the subcutaneous and/or submucosal tissue without wheals and negative family history of angioedema. Here, we present the case of a patient with a chronic lymphatic B cell leukemia who suffered from both C1-INH-AAE and chronic spontaneous urticaria. Oral corticosteroids, antihistamines, and the anti-IgE antibody omalizumab were applied to treat the chronic urticaria in combination with the plasma-derived C1 esterase inhibitor concentrate Berinert® and the bradykinin B2 receptor antagonist icatibant, but the symptoms did not improved significantly. Thus, polychemotherapy targeting the slow-growing lymphoproliferative disease including rituximab was initiated, which resulted in remission of both the urticaria and the angioedema.

  10. Self-administered C1 esterase inhibitor concentrates for the management of hereditary angioedema: usability and patient acceptance

    PubMed Central

    Li, Huamin Henry

    2016-01-01

    Hereditary angioedema (HAE) is a rare genetic disease characterized by episodic subcutaneous or submucosal swelling. The primary cause for the most common form of HAE is a deficiency in functional C1 esterase inhibitor (C1-INH). The swelling caused by HAE can be painful, disfiguring, and life-threatening. It reduces daily function and compromises the quality of life of affected individuals and their caregivers. Among different treatment strategies, replacement with C1-INH concentrates is employed for on-demand treatment of acute attacks and long-term prophylaxis. Three human plasma-derived C1-INH preparations are approved for HAE treatment in the US, the European Union, or both regions: Cinryze®, Berinert®, and Cetor®; however, only Cinryze is approved for long-term prophylaxis. Postmarketing studies have shown that home therapy (self-administered or administered by a caregiver) is a convenient and safe option preferred by many HAE patients. In this review, we summarize the role of self-administered plasma-derived C1-INH concentrate therapy with Cinryze at home in the prophylaxis of HAE. PMID:27660422

  11. C1 inhibitor-mediated myocardial protection from chronic intermittent hypoxia-induced injury

    PubMed Central

    Fu, Jinrong; Guo, Furong; Chen, Cheng; Yu, Xiaoman; Hu, Ke; Li, Mingjiang

    2016-01-01

    The optimal treatment for chronic intermittent hypoxia (CIH)-induced cardiovascular injuries has yet to be determined. The aim of the current study was to explore the potential protective effect and mechanism of a C1 inhibitor in CIH in the myocardium. The present study used a rat model of CIH in which complement regulatory protein, known as C1 inhibitor (C1INH), was administered to the rats in the intervention groups. Cardiomyocyte apoptosis was detected by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling. The expression of proteins associated with the apoptotic pathway, such as B-cell lymphoma 2 (Bcl-2), Bax and caspase-3 were detected by western blot analysis. The expression of complement C3 protein and RNA were also analyzed. C1INH was observed to improve the cardiac function in rats with CIH. Myocardial myeloperoxidase activity, a marker of neutrophil infiltration, was significantly decreased in the C1INH intervention group compared with the CIH control group, and cardiomyocyte apoptosis was significantly attenuated (P<0.05). Western blotting and reverse transcription-polymerase chain reaction analysis indicated that the protein expression levels of Bcl-2 were decreased and those of Bax were increased in the CIH group compared with the normal control group, but the protein expression levels of Bcl-2 were increased and those of Bax were decreased in the C1INH intervention group, as compared with the CIH group. Furthermore, the CIH-induced expression and synthesis of complement C3 in the myocardium were also reduced in the C1INH intervention group. C1INH, in addition to inhibiting complement activation and inflammation, preserved cardiac function in CIH-mediated myocardial cell injury through an anti-apoptotic mechanism. PMID:27698713

  12. A novel mutation in exon 8 of C1 inhibitor (C1INH) gene leads to abolish its physiological stop codon in a large Chinese family with hereditary angioedema type I.

    PubMed

    Qu, Le; Wei, Bin; Liu, Mei; Zhang, Lili; Xiao, Ting; Chen, Hong-Duo; Zhou, Li; Mi, Qing-Sheng; He, Chundi

    2012-10-01

    C1 inhibitor (C1INH) plays an important role in the classical pathway of the complement system. Mutations in C1INH gene cause quantitative or qualitative deficiencies in C1INH, which can lead to hereditary angioedema (HAE) type I or II. Here, we identified a novel frame-shift mutation c.1391-1445del55 (p.v464fsx556) in exon 8 in a large Chinese family with HAE type I. This 55 base pairs deletion abolishes the original stop codon and introduces a new stop codon 220 bp downstream of the original one, and leads to mutated C1INH protein prolonged from 500 to 556 amino acids. The levels of C4 and C1INH as well as C1INH activity in serum were significantly reduced in affected individuals. This is the first report of a novel mutation abolishing the physiological stop codon of C1INH gene in a large Chinese family with HAE type I.

  13. Regulation of Complement and Contact System Activation via C1 Inhibitor Potentiation and Factor XIIa Activity Modulation by Sulfated Glycans – Structure-Activity Relationships

    PubMed Central

    Schoenfeld, Ann-Kathrin; Lahrsen, Eric; Alban, Susanne

    2016-01-01

    The serpin C1 inhibitor (C1-INH) is the only regulator of classical complement activation as well as the major regulator of the contact system. Its importance is demonstrated by hereditary angioedema (HAE), a severe disease with potentially life-threatening attacks due to deficiency or dysfunction of C1-INH. C1-INH replacement is the therapy of choice in HAE. In addition, C1-INH showed to have beneficial effects in other diseases characterized by inappropriate complement and contact system activation. Due to some limitations of its clinical application, there is a need for improving the efficacy of therapeutically applied C1-INH or to enhance the activity of endogenous C1-INH. Given the known potentiating effect of heparin on C1-INH, sulfated glycans (SG) may be such candidates. The aim of this study was to characterize suitable SG by evaluating structure-activity relationships. For this, more than 40 structurally distinct SG were examined for their effects on C1-INH, C1s and FXIIa. The SG turned out to potentiate the C1s inhibition by C1-INH without any direct influence on C1s. Their potentiating activity proved to depend on their degree of sulfation, molecular mass as well as glycan structure. In contrast, the SG had no effect on the FXIIa inhibition by C1-INH, but structure-dependently modulated the activity of FXIIa. Among the tested SG, β-1,3-glucan sulfates with a Mr ≤ 10 000 were identified as most promising lead candidates for the development of a glycan-based C1-INH amplifier. In conclusion, the obtained information on structural characteristics of SG favoring C1-INH potentiation represent an useful elementary basis for the development of compounds improving the potency of C1-INH in diseases and clinical situations characterized by inappropriate activation of complement and contact system. PMID:27783665

  14. Population pharmacokinetics of recombinant human C1 inhibitor in patients with hereditary angioedema

    PubMed Central

    Farrell, Colm; Hayes, Siobhan; Relan, Anurag; van Amersfoort, Edwin S; Pijpstra, Rienk; Hack, C Erik

    2013-01-01

    Aims To characterize the pharmacokinetics (PK) of recombinant human C1 inhibitor (rhC1INH) in healthy volunteers and hereditary angioedema (HAE) patients. Methods Plasma levels of C1INH following 294 administrations of rhC1INH in 133 subjects were fitted using nonlinear mixed-effects modelling. The model was used to simulate maximal C1INH levels for the proposed dosing scheme. Results A one-compartment model with Michaelis–Menten elimination kinetics described the data. Baseline C1INH levels were 0.901 [95% confidence interval (CI): 0.839–0.968] and 0.176 U ml−1 (95% CI: 0.154–0.200) in healthy volunteers and HAE patients, respectively. The volume of distribution of rhC1INH was 2.86 l (95% CI: 2.68–3.03). The maximal rate of elimination and the concentration corresponding to half this maximal rate were 1.63 U ml−1 h−1 (95% CI: 1.41–1.88) and 1.60 U ml−1 (95% CI: 1.14–2.24), respectively, for healthy volunteers and symptomatic HAE patients. The maximal elimination rate was 36% lower in asymptomatic HAE patients. Peak C1INH levels did not change upon repeated administration of rhC1INH. Bodyweight was found to be an important predictor of the volume of distribution. Simulations of the proposed dosing scheme predicted peak C1INH concentrations above the lower level of the normal range (0.7 U ml−1) for at least 94% of all patients. Conclusions The population PK model for C1INH supports a dosing scheme on a 50 U kg−1 basis up to 84 kg, with a fixed dose of 4200 U above 84 kg. The PK of rhC1INH following repeat administration are consistent with the PK following the first administration. PMID:23594263

  15. Effects of C1 inhibitor on tissue damage in a porcine model of controlled hemorrhage.

    PubMed

    Dalle Lucca, Jurandir J; Li, Yansong; Simovic, Milomir; Pusateri, Anthony E; Falabella, Michael; Dubick, Michael A; Tsokos, George C

    2012-07-01

    Activation of the complement system has been associated with tissue injury after hemorrhage and resuscitation in animals. We investigated whether administration of recombinant human C1-esterase inhibitor (rhC1-INH), a regulator of complement and contact activation systems, reduces tissue damage and cytokine release and improves metabolic acidosis in a porcine model of hemorrhagic shock. Male Yorkshire swine were assigned to experimental groups and subjected to controlled, isobaric hemorrhage to a target mean arterial pressure of 35 mmHg. Hypotension was maintained for 20 min followed by a bolus intravenous injection of rhC1-INH or vehicle; animals were then observed for 3 h. Blood chemistry and physiologic parameters were recorded. Lung and small intestine tissue samples were subjected to histopathologic evaluation and immunohistochemistry to determine the extent of injury and deposition of complement proteins. Cytokine levels and quantitative assessment of renal and hepatic function were measured via enzyme-linked immunosorbent assay and chemistry analyzer, respectively. Pharmacokinetics of rhC1-INH revealed dose proportionality for maximum concentration, half-life, and the time span in which the functional C1-INH level was greater than 1 IU/mL. Recombinant human C1-INH significantly reduced renal, intestinal, and lung tissue damage in a dose-dependent manner (100 and 250 IU/kg). In addition, rhC1-INH (250 IU/kg) markedly improved hemorrhage-induced metabolic acidosis and circulating tumor necrosis factor α. The tissue-protective effects of rhC1-INH appear to be related to its ability to reduce tissue complement activation and deposition. Recombinant human C1-INH decreased tissue complement activation and deposition in hemorrhaged animals, improved metabolic acidosis, reduced circulating tumor necrosis factor α, and attenuated tissue damage in this model. The observed beneficial effects of rhC1-INH treatment on tissue injury 20 min into severe hypotension

  16. C1-Inhibitor protects from focal brain trauma in a cortical cryolesion mice model by reducing thrombo-inflammation.

    PubMed

    Albert-Weissenberger, Christiane; Mencl, Stine; Schuhmann, Michael K; Salur, Irmak; Göb, Eva; Langhauser, Friederike; Hopp, Sarah; Hennig, Nelli; Meuth, Sven G; Nolte, Marc W; Sirén, Anna-Leena; Kleinschnitz, Christoph

    2014-01-01

    Traumatic brain injury (TBI) induces a strong inflammatory response which includes blood-brain barrier damage, edema formation and infiltration of different immune cell subsets. More recently, microvascular thrombosis has been identified as another pathophysiological feature of TBI. The contact-kinin system represents an interface between inflammatory and thrombotic circuits and is activated in different neurological diseases. C1-Inhibitor counteracts activation of the contact-kinin system at multiple levels. We investigated the therapeutic potential of C1-Inhibitor in a model of TBI. Male and female C57BL/6 mice were subjected to cortical cryolesion and treated with C1-Inhibitor after 1 h. Lesion volumes were assessed between day 1 and day 5 and blood-brain barrier damage, thrombus formation as well as the local inflammatory response were determined post TBI. Treatment of male mice with 15.0 IU C1-Inhibitor, but not 7.5 IU, 1 h after cryolesion reduced lesion volumes by ~75% on day 1. This protective effect was preserved in female mice and at later stages of trauma. Mechanistically, C1-Inhibitor stabilized the blood-brain barrier and decreased the invasion of immune cells into the brain parenchyma. Moreover, C1-Inhibitor had strong antithrombotic effects. C1-Inhibitor represents a multifaceted anti-inflammatory and antithrombotic compound that prevents traumatic neurodegeneration in clinically meaningful settings.

  17. C1q nephropathy and isolated CD59 deficiency manifesting as necrotizing crescentic glomerulonephritis: A rare association of two diseases.

    PubMed

    Gupta, Ruchika; Sharma, Alok; Agarwal, Sanjay K; Dinda, Amit K

    2015-11-01

    C1q nephropathy is a recently described clinico-pathologic entity with a variable clinical presentation and pathology. Crescentic glomerulonephritis (GN) has been reported in only two patients in the available literature. CD59 deficiency, along with lack of CD55, is responsible for paroxysmal nocturnal hemoglobinuria (PNH). Few cases of isolated CD59 deficiency have been described with PNH-like features. A middle-aged adult male presented with rapidly progressive renal failure. Serological investigations were negative. A renal biopsy revealed necrotizing crescentic GN with rupture of Bowman's capsule. Immunofluorescence on the frozen sections showed dominant mesangial deposits of C1q along with IgM. Hematological work-up of the patient revealed isolated CD59 deficiency. Hence, a final diagnosis of C1q nephropathy and CD59 deficiency manifesting as crescentic GN and hemolytic anemia was made. The co-existence of two rare disorders, C1q nephropathy and CD59 deficiency, in a patient with necrotizing crescentic GN is described for the first time to the best of our knowledge. The pathogenetic link of these two entities with the clinical manifestation requires further study.

  18. Recent developments in the treatment of acute abdominal and facial attacks of hereditary angioedema: focus on human C1 esterase inhibitor

    PubMed Central

    Cardona, Lourdes Pastó; Bellfill, Ramon Lleonart; Caus, Joaquim Marcoval

    2010-01-01

    Hereditary angioedema (HAE) is a potentially fatal genetic disorder typified by a deficiency (type I) or dysfunction (type II) of the C1-inhibitor (C1-INH) and characterized by swelling of the extremities, face, trunk, abdominal viscera, and upper airway. Type III is normal estrogen-sensitive C1-INH HAE. Bradykinin, the main mediator of HAE, binds to endothelial B2 receptors, increasing vascular permeability and resulting in edema. HAE management includes short- and long-term prophylaxis. For treating acute episodes, C1-INH concentrate is recommended with regression of symptoms achieved in 30–90 min. Infusions of 500–1000 U have been used in Europe for years. Two plasma-derived C1-INH concentrates have been licensed recently in the United States: Berinert® for treating acute attacks and Cinryze® for prophylaxis in adolescent/adult patients. A recombinant C1-INH that is being considered for approval (conestat alfa) exhibited significant superiority versus placebo. Ecallantide (Kalbitor®) is a selective kallikrein inhibitor recently licensed in the United States for treating acute attacks in patients aged >16 years. It is administered in three 10-mg subcutaneous injections with the risk of anaphylactic reactions. Icatibant (Firazyr®) is a bradykinin B2 receptor competitor. It is administered subcutaneously as a 30-mg injection and approved in Europe but not in the United States. PMID:23776358

  19. Impact of Oatp1c1 deficiency on thyroid hormone metabolism and action in the mouse brain.

    PubMed

    Mayerl, Steffen; Visser, Theo J; Darras, Veerle M; Horn, Sigrun; Heuer, Heike

    2012-03-01

    Organic anion-transporting polypeptide 1c1 (Oatp1c1) (also known as Slco1c1 and Oatp14) belongs to the family of Oatp and has been shown to facilitate the transport of T(4). In the rodent brain, Oatp1c1 is highly enriched in capillary endothelial cells and choroid plexus structures where it may mediate the entry of T(4) into the central nervous system. Here, we describe the generation and first analysis of Oatp1c1-deficient mice. Oatp1c1 knockout (KO) mice were born with the expected frequency, were not growth retarded, and developed without any overt neurological abnormalities. Serum T(3) and T(4) concentrations as well as renal and hepatic deiodinase type 1 expression levels were indistinguishable between Oatp1c1 KO mice and control animals. Hypothalamic TRH and pituitary TSH mRNA levels were not affected, but brain T(4) and T(3) content was decreased in Oatp1c1-deficient animals. Moreover, increased type 2 and decreased type 3 deiodinase activities indicate a mild hypothyroid situation in the brain of Oatp1c1 KO mice. Consequently, mRNA expression levels of gene products positively regulated by T(3) in the brain were down-regulated. This central nervous system-specific hypothyroidism is presumably caused by an impaired passage of T(4) across the blood-brain barrier and indicates a unique function of Oatp1c1 in facilitating T(4) transport despite the presence of other thyroid hormone transporters such as Mct8.

  20. Suppression of complement regulatory protein C1 inhibitor in vascular endothelial activation by inhibiting vascular cell adhesion molecule-1 action

    SciTech Connect

    Zhang, Haimou; Qin, Gangjian; Liang, Gang; Li, Jinan; Chiu, Isaac; Barrington, Robert A.; Liu, Dongxu . E-mail: dxliu001@yahoo.com

    2007-07-13

    Increased expression of adhesion molecules by activated endothelium is a critical feature of vascular inflammation associated with the several diseases such as endotoxin shock and sepsis/septic shock. Our data demonstrated complement regulatory protein C1 inhibitor (C1INH) prevents endothelial cell injury. We hypothesized that C1INH has the ability of an anti-endothelial activation associated with suppression of expression of adhesion molecule(s). C1INH blocked leukocyte adhesion to endothelial cell monolayer in both static assay and flow conditions. In inflammatory condition, C1INH reduced vascular cell adhesion molecule (VCAM-1) expression associated with its cytoplasmic mRNA destabilization and nuclear transcription level. Studies exploring the underlying mechanism of C1INH-mediated suppression in VCAM-1 expression were related to reduction of NF-{kappa}B activation and nuclear translocation in an I{kappa}B{alpha}-dependent manner. The inhibitory effects were associated with reduction of inhibitor I{kappa}B kinase activity and stabilization of the NF-{kappa}B inhibitor I{kappa}B. These findings indicate a novel role for C1INH in inhibition of vascular endothelial activation. These observations could provide the basis for new therapeutic application of C1INH to target inflammatory processes in different pathologic situations.

  1. Human inhibitor of the first component of complement, C1: characterization of cDNA clones and localization of the gene to chromosome 11.

    PubMed Central

    Davis, A E; Whitehead, A S; Harrison, R A; Dauphinais, A; Bruns, G A; Cicardi, M; Rosen, F S

    1986-01-01

    C1 inhibitor is a heavily glycosylated plasma protein that regulates the activity of the first component of complement (C1) by inactivation of the serine protease subcomponents, C1r and C1s. C1 inhibitor cDNA clones have been isolated, and one of these (pC1INH1, 950 base pairs) has been partially sequenced. Sequence analysis demonstrates that the C1 inhibitor is a member of the serpin "superfamily" of protease inhibitors. In the region sequenced, C1 inhibitor has 22% identity with antithrombin III, 26% with alpha 1-antitrypsin and alpha 1-antichymotrypsin, and 18% with human angiotensinogen. C1 inhibitor has a larger amino-terminal extension than do the other plasma protease inhibitors. In addition, inspection of residues that are invariant among the other protease inhibitors shows that C1 inhibitor differs at 14 of 41 of these positions. Thus, it appears that C1 inhibitor diverged from the group relatively early in evolution, although probably after the divergence of angiotensinogen. Southern blot analysis of BamHI-digested DNA from normal individuals and from rodent-human somatic cell hybrid cell lines (that contain a limited but varied human chromosome complement) was used to localize the human C1 inhibitor gene to chromosome 11. Images PMID:3458172

  2. Angiotensin-converting enzyme inhibitors-induced angioedema treated by C1 esterase inhibitor concentrate (Berinert®): about one case and review of the therapeutic arsenal.

    PubMed

    Lipski, Samuel Michael; Casimir, Georges; Vanlommel, Martine; Jeanmaire, Mathieu; Dolhen, Pierre

    2015-02-01

    C1 esterase inhibitor (Berinert®) is generally used to treat severe attack of hereditary angioedema. We describe here the case of a patient who presented with a severe angioedema induced by angiotensin-converting enzyme inhibitors (ACEIs) endangering her life. It could be successfully treated with that medicine.

  3. Small molecule inhibitors reveal Niemann-Pick C1 is essential for ebolavirus infection

    PubMed Central

    Côté, Marceline; Misasi, John; Ren, Tao; Bruchez, Anna; Lee, Kyungae; Filone, Claire Marie; Hensley, Lisa; Li, Qi; Ory, Daniel; Chandran, Kartik; Cunningham, James

    2011-01-01

    Summary Ebolavirus (EboV) is a highly pathogenic enveloped virus that causes outbreaks of zoonotic infection in Africa. The clinical symptoms are manifestations of the massive production of pro-inflammatory cytokines in response to infection1 and in many outbreaks, mortality exceeds 75%. The unpredictable onset, ease of transmission, rapid progression of disease, high mortality and lack of effective vaccine or therapy have created a high level of public concern about EboV2. Here we report the identification of a novel benzylpiperazine adamantane diamide-derived compound that inhibits EboV infection. Using mutant cell lines and informative derivatives of the lead compound, we show that the target of the inhibitor is the endosomal membrane protein Niemann-Pick C1 (NPC1). We find that NPC1 is essential for infection, that it binds to the virus glycoprotein (GP), and that the anti-viral compounds interfere with GP binding to NPC1. Combined with the results of previous studies of GP structure and function, our findings support a model of EboV infection in which cleavage of the GP1 subunit by endosomal cathepsin proteases removes heavily glycosylated domains to expose the N-terminal domain3–7, which is a ligand for NPC1 and regulates membrane fusion by the GP2 subunit8. Thus, NPC1 is essential for EboV entry and a target for anti-viral therapy. PMID:21866101

  4. Purification of human ceruloplasmin as a by-product of C1-inhibitor.

    PubMed

    Kouoh Elombo, F; Radosevich, M; Poulle, M; Descamps, J; Chtourou, S; Burnouf, T; Catteau, J P; Bernier, J L; Cotelle, N

    2000-12-01

    Human ceruloplasmin (Cp) has been purified from cryoprecipitate-poor plasma as a by-product of the C1-inhibitor production chain. Highly purified Cp was obtained by subsequent ion-exchange chromatography on sulfate-Fractogel EMD and TMAE-Fractogel EMD. Treatments for viral safety included application of the solvent-detergent method and two nanofiltration steps using 35- and 15-nm pore size filters at the end of the process. Overall antigen yield was 95 (+/-5) %. Purified human ceruloplasmin was studied by electron spin resonance (ESR) to characterize its different types of copper complexes and to check its antioxidant properties. We distinguished three types of complexes: one type-2 Cu(II) with g// = 2.25 and A// = 180 G and two type-I Cu(II) exhibiting different narrow hyperfine splitting (A// = 72 G and A// = 90 G) with close g// (2.20 and 2.21). Purified Cp has a specific activity of 24.5+/-0.2 mU/mg of proteins. This process provides a method for Cp purification that could be easily integrated into modern plasma fractionation.

  5. Hereditary angioedema with normal C1 inhibitor and factor XII mutation: a series of 57 patients from the French National Center of Reference for Angioedema.

    PubMed

    Deroux, A; Boccon-Gibod, I; Fain, O; Pralong, P; Ollivier, Y; Pagnier, A; Djenouhat, K; Du-Thanh, A; Gompel, A; Faisant, C; Launay, D; Bouillet, L

    2016-09-01

    Hereditary angioedema (HAE) is a rare disease associated with either a quantitative or qualitative deficiency in C1-inhibitor (C1-INH) or normal C1-INH. HAE with normal C1-INH is associated in 20% of cases with mutations in the gene for factor XII (FXII) or FXII-HAE. A recent review described 41 families, including 14 German and 15 Spanish families. We have constructed a register of French patients and their characteristics. A national survey was launched through the French National Center of Reference for Angioedema (CREAK) to study the clinical, biological and therapeutic characteristics of patients with HAE linked to a mutation of FXII gene. Fifty-seven patients were identified from 24 different families. In most cases they were young women (mean age at diagnosis: 31 years, mean age at first symptom: 21 years, female/male ratio: 76%). Twenty-one per cent of the patients experienced angioedema attacks only during pregnancy or when on oestrogen contraception. Sixty-three per cent had attacks at all times, but they were more severe during these same periods. Male carriers of the mutation were more frequently asymptomatic than females (P = 0·003). C1-INH concentrate and icatibant were both effective for treating attacks. The prophylactic use of tranexamic acid led to a 64% decrease in the number of attacks. This is one of the largest series reported of HAE patients with FXII mutation. The therapeutic management appeared to be identical to that of HAE with C1-INH deficiency.

  6. Deficiency in complement C1q improves histological and functional locomotor outcome after spinal cord injury

    PubMed Central

    Galvan, Manuel D.; Luchetti, Sabina; Burgos, Adrian M.; Nguyen, Hal X.; Hooshmand, Mitra J.; Anderson, Aileen J.; Hamers, Frank P.T.

    2009-01-01

    Although studies have suggested a role for the complement system in the pathophysiology of spinal cord injury (SCI), that role remains poorly defined. Additionally, the relative contribution of individual complement pathways in SCI is unknown. Our initial studies revealed that systemic complement activation was strongly influenced by genetic background and gender. Thus, to investigate the role of the classical complement pathway in contusion-induced SCI, male C1q knockout (KO) and wildtype (WT) mice on a complement sufficient background (BUB) received a mild-moderate T9 contusion injury with the Infinite Horizon (IH) impactor. BUB C1q KO mice exhibited greater locomotor recovery in comparison to BUB WT mice (p < 0.05). Improved recovery observed in BUB C1q KO mice was also associated with decreased threshold for withdrawal from a mild stimulus using von Frey filament testing. Surprisingly, quantification of microglia/macrophages (F4/80) by FACS analysis showed that BUB C1q KO mice exhibited a significantly greater percentage of macrophages in the spinal cord compared to BUB WT mice 3 days post injury (p < 0.05). However, this increased macrophage response appeared to be transient as stereological assessment of spinal cord tissue obtained 28 days post injury revealed no difference in F4/80 positive cells between groups. Stereological assessment of spinal cord tissue showed that BUB C1q KO mice had reduced lesion volume and an increase in tissue sparing in comparison to BUB WT mice (p < 0.05). Taken together, these data suggest that initiation of the classical complement pathway via C1q is detrimental to recovery after SCI. PMID:19091977

  7. Effects of C1 Inhibitor on Tissue Damage in a Porcine Model of Controlled Hemorrhage

    DTIC Science & Technology

    2012-07-01

    glucose, hematocrit (Hct), hemoglobin ( Hb ), sodium (Na+), potassium (K+), and ionized calcium (Ca2+) using i STAT cartridges (Abbott Laboratories, Abbott...Shock Society. Unauthorized reproduction of this article is prohibited. (Princeton, NJ). MicroVue C1 INH enzyme immunoassay (EIA) kit was purchased from...TABLE 3. Prehemorrhage and posthemorrhage metabolic data of hemorrhaged animals Group PSham H H + C1-100 H + C1-250 n 5 5 6 4 5 4 5 Prehemorrhage Hb , g

  8. High-affinity, noninhibitory pathogenic C1 domain antibodies are present in patients with hemophilia A and inhibitors

    PubMed Central

    Batsuli, Glaivy; Deng, Wei; Healey, John F.; Parker, Ernest T.; Baldwin, W. Hunter; Cox, Courtney; Nguyen, Brenda; Kahle, Joerg; Königs, Christoph; Li, Renhao; Lollar, Pete

    2016-01-01

    Inhibitor formation in hemophilia A is the most feared treatment-related complication of factor VIII (fVIII) therapy. Most inhibitor patients with hemophilia A develop antibodies against the fVIII A2 and C2 domains. Recent evidence demonstrates that the C1 domain contributes to the inhibitor response. Inhibitory anti-C1 monoclonal antibodies (mAbs) have been identified that bind to putative phospholipid and von Willebrand factor (VWF) binding epitopes and block endocytosis of fVIII by antigen presenting cells. We now demonstrate by competitive enzyme-linked immunosorbent assay and hydrogen-deuterium exchange mass spectrometry that 7 of 9 anti-human C1 mAbs tested recognize an epitope distinct from the C1 phospholipid binding site. These mAbs, designated group A, display high binding affinities for fVIII, weakly inhibit fVIII procoagulant activity, poorly inhibit fVIII binding to phospholipid, and exhibit heterogeneity with respect to blocking fVIII binding to VWF. Another mAb, designated group B, inhibits fVIII procoagulant activity, fVIII binding to VWF and phospholipid, fVIIIa incorporation into the intrinsic Xase complex, thrombin generation in plasma, and fVIII uptake by dendritic cells. Group A and B epitopes are distinct from the epitope recognized by the canonical, human-derived inhibitory anti-C1 mAb, KM33, whose epitope overlaps both groups A and B. Antibodies recognizing group A and B epitopes are present in inhibitor plasmas from patients with hemophilia A. Additionally, group A and B mAbs increase fVIII clearance and are pathogenic in a hemophilia A mouse tail snip bleeding model. Group A anti-C1 mAbs represent the first identification of pathogenic, weakly inhibitory antibodies that increase fVIII clearance. PMID:27381905

  9. C1q Deficiency Promotes Pulmonary Vascular Inflammation and Enhances the Susceptibility of the Lung Endothelium to Injury.

    PubMed

    Shah, Dilip; Romero, Freddy; Zhu, Ying; Duong, Michelle; Sun, Jianxin; Walsh, Kenneth; Summer, Ross

    2015-12-04

    The collectin proteins are innate immune molecules found in high concentrations on the epithelial and endothelial surfaces of the lung. While these proteins are known to have important anti-inflammatory actions in the airways of the lung little is known of their functional importance in the pulmonary circulation. We recently demonstrated that the circulating collectin protein adiponectin has potent anti-inflammatory effects on the lung endothelium, leading us to reason that other structurally related proteins might have similar effects. To test this hypothesis, we investigated the anti-inflammatory actions of C1q in lung endothelial homeostasis and the pulmonary vascular response to LPS or HCl injury. We show that lung endothelium from C1q-deficient (C1q(-/-)) mice expresses higher baseline levels of the vascular adhesion markers ICAM-1, VCAM-1, and E-selectin when compared with wild-type mice. Further, we demonstrate that these changes are associated with enhanced susceptibility of the lung to injury as evident by increased expression of adhesion markers, enhanced production of pro-inflammatory cytokines, and augmented neutrophil recruitment. Additionally, we found that C1q(-/-) mice also exhibited enhanced endothelial barrier dysfunction after injury as manifested by decreased expression of junctional adherens proteins and enhanced vascular leakage. Mechanistically, C1q appears to mediate its effects by inhibiting phosphorylation of p38 mitogen-activated protein kinase (MAPK) and blocking nuclear translocation of the P65 subunit of nuclear factor (NF)-κB. In summary, our findings indicate a previously unrecognized role for C1q in pulmonary vascular homeostasis and provide added support for the hypothesis that circulating collectin proteins have protective effects on the lung endothelium.

  10. Endothelial targeting with C1-inhibitor reduces complement activation in vitro and during ex vivo reperfusion of pig liver

    PubMed Central

    Bergamaschini, L; Gobbo, G; Gatti, S; Caccamo, L; Prato, P; Maggioni, M; Braidotti, P; Di Stefano, R; Fassati, L R

    2001-01-01

    Tissue damage during cold storage and reperfusion remains a major obstacle to wider use of transplantation. Vascular endothelial cells and complement activation are thought to be involved in the inflammatory reactions following reperfusion, so endothelial targeting of complement inhibitors is of great interest. Using an in vitro model of human umbilical vein endothelial cells (HUVEC) cold storage and an animal model of ex vivo liver reperfusion after cold ischaemia, we assessed the effect of C1-INH on cell functions and liver damage. We found that in vitro C1-INH bound to HUVEC in a manner depending on the duration of cold storage. Cell-bound C1-INH was functionally active since retained the ability to inhibit exogenous C1s. To assess the ability of cell-bound C1-INH to prevent complement activation during organ reperfusion, we added C1-INH to the preservation solution in an animal model of extracorporeal liver reperfusion. Ex vivo liver reperfusion after 8 h of cold ischaemia resulted in plasma C3 activation and reduction of total serum haemolytic activity, and at tissue level deposition of C3 associated with variable level of inflammatory cell infiltration and tissue damage. These findings were reduced when livers were stored in preservation solution containing C1-INH. Immunohistochemical analysis of C1-INH-treated livers showed immunoreactivity localized on the sinusoidal pole of the liver trabeculae, linked to sinusoidal endothelium, so it is likely that the protective effect was due to C1-INH retained by the livers. These results suggest that adding C1-INH to the preservation solution may be useful to reduce complement activation and tissue injury during the reperfusion of an ischaemic liver. PMID:11737055

  11. Endothelial targeting with C1-inhibitor reduces complement activation in vitro and during ex vivo reperfusion of pig liver.

    PubMed

    Bergamaschini, L; Gobbo, G; Gatti, S; Caccamo, L; Prato, P; Maggioni, M; Braidotti, P; Di Stefano, R; Fassati, L R

    2001-12-01

    Tissue damage during cold storage and reperfusion remains a major obstacle to wider use of transplantation. Vascular endothelial cells and complement activation are thought to be involved in the inflammatory reactions following reperfusion, so endothelial targeting of complement inhibitors is of great interest. Using an in vitro model of human umbilical vein endothelial cells (HUVEC) cold storage and an animal model of ex vivo liver reperfusion after cold ischaemia, we assessed the effect of C1-INH on cell functions and liver damage. We found that in vitro C1-INH bound to HUVEC in a manner depending on the duration of cold storage. Cell-bound C1-INH was functionally active since retained the ability to inhibit exogenous C1s. To assess the ability of cell-bound C1-INH to prevent complement activation during organ reperfusion, we added C1-INH to the preservation solution in an animal model of extracorporeal liver reperfusion. Ex vivo liver reperfusion after 8 h of cold ischaemia resulted in plasma C3 activation and reduction of total serum haemolytic activity, and at tissue level deposition of C3 associated with variable level of inflammatory cell infiltration and tissue damage. These findings were reduced when livers were stored in preservation solution containing C1-INH. Immunohistochemical analysis of C1-INH-treated livers showed immunoreactivity localized on the sinusoidal pole of the liver trabeculae, linked to sinusoidal endothelium, so it is likely that the protective effect was due to C1-INH retained by the livers. These results suggest that adding C1-INH to the preservation solution may be useful to reduce complement activation and tissue injury during the reperfusion of an ischaemic liver.

  12. Nebulized C1-Esterase Inhibitor does not Reduce Pulmonary Complement Activation in Rats with Severe Streptococcus Pneumoniae Pneumonia.

    PubMed

    de Beer, Friso; Lagrand, Wim; Glas, Gerie J; Beurskens, Charlotte J P; van Mierlo, Gerard; Wouters, Diana; Zeerleder, Sacha; Roelofs, Joris J T H; Juffermans, Nicole P; Horn, Janneke; Schultz, Marcus J

    2016-12-01

    Complement activation plays an important role in the pathogenesis of pneumonia. We hypothesized that inhibition of the complement system in the lungs by repeated treatment with nebulized plasma-derived human C1-esterase inhibitor reduces pulmonary complement activation and subsequently attenuates lung injury and lung inflammation. This was investigated in a rat model of severe Streptococcus pneumoniae pneumonia. Rats were intra-tracheally challenged with S. pneumoniae to induce pneumonia. Nebulized C1-esterase inhibitor or saline (control animals) was repeatedly administered to rats, 30 min before induction of pneumonia and every 6 h thereafter. Rats were sacrificed 20 or 40 h after inoculation with bacteria. Brochoalveolar lavage fluid and lung tissue were obtained for measuring levels of complement activation (C4b/c), lung injury and inflammation. Induction of pneumonia was associated with pulmonary complement activation (C4b/c at 20 h 1.24 % [0.56-2.59] and at 40 h 2.08 % [0.98-5.12], compared to 0.50 % [0.07-0.59] and 0.03 % [0.03-0.03] in the healthy control animals). The functional fraction of C1-INH was detectable in BALF, but no effect was found on pulmonary complement activation (C4b/c at 20 h 0.73 % [0.16-1.93] and at 40 h 2.38 % [0.54-4.19]). Twenty hours after inoculation, nebulized C1-esterase inhibitor treatment reduced total histology score, but this effect was no longer seen at 40 h. Nebulized C1-esterase inhibitor did not affect other markers of lung injury or lung inflammation. In this negative experimental animal study, severe S. pneumoniae pneumonia in rats is associated with pulmonary complement activation. Repeated treatment with nebulized C1-esterase inhibitor, although successfully delivered to the lungs, does not affect pulmonary complement activation, lung inflammation or lung injury.

  13. C1-transport in gastric micorsomes. An ATP-dependent influx sensitive to membrane potential and to protein kinase inhibitor.

    PubMed

    Soumarmon, A; Abastado, M; Bonfils, S; Lewin, M J

    1980-12-25

    Uptakes of radioactive C1- or 1- by gastric microsomal vesicles were stimulated 2- to 8-fold by AtP. The sensitivity of those uptakes to a C1- in equilibrium OH- ionophore and to osmotic swelling suggested they were due to transport rather than to binding. The ATP effect was labile, but dithiothreitol and methanol improved its stability. The stimulation of anion transport required magnesium; GTP and UTP were less potent than ATP whereas ADP and AMP had no effect. The apparent Km for ATP was estimated to be 2 X 10(-4) M at 22 degrees C. The rate of the ATP-dependent transport showed saturation-type kinetics, with half-maximal uptake at 10 mM for I- and 15 mM for C1-. Nonradioactive C1-, I-, and SCN- competed with 125I- uptake while SO42- did not. K+ valinomycin increased the ATP-dependent C1- uptake. The thermostable inhibitor of cAMP-dependent protein kinases inhibited the effect of ATP. These results suggest the existence of an anion conductance, permeant to C1-, I-, and SCN- and nonpermeant to SO42-, which could be linked to a cAMP-dependent protein kinase.

  14. 84 Immuno-Safety of Recombinant Human C1 Inhibitor in Patients With Hereditary Angioedema: An Integrated Analysis

    PubMed Central

    Hack, Erik; Relan, Anurag; Kaufman, Leonard; Pijpstra, Rienk

    2012-01-01

    Background Recombinant C1 inhibitor (rhC1INH) is a novel therapeutic option for the treatment of acute angioedema attacks in patients with hereditary angioedema (HAE). The amino acid sequence of rhC1INH is identical to that of endogenous C1INH. However, any recombinant protein may elicit antibodies against the protein and/or host related impurities (HRI). Clinical consequences of these antibodies can theoretically range from no clinical symptoms to allergic reactions and reduced C1INH activity due to neutralizing antibodies. Objective To analyze the immuno-safety of rhC1INH in symptomatic patients with HAE. Methods Plasma samples were collected pre-treatment and 22 and 90 days post-treatment of an acute angioedema attack. Plasma samples were tested for the presence of antibodies against plasma-derived C1INH and rhC1INH using 6 different, validated enzyme-linked immunosorbent assays (ELISAs), to detect IgM, IgG and IgA antibodies against plasma-derived C1INH or rhC1INH. Antibodies against HRI in plasma samples were measured in an ELISA testing for all antibody classes. Plasma samples from normal healthy controls and HAE patients, never exposed to rhC1INH, were used to estimate cut off levels of the assays. Plasma samples with antibody levels above the cut-off level in the screening assays were tested in confirmatory displacement assay in case of anti-HRI antibodies and in an assay for neutralizing antibodies in case of antibodies against C1INH. Results Data from 155 symptomatic HAE patients having received a total of 424 administrations of rhC1INH were analyzed. The frequency of anti-C1INH antibody levels above the assay cut-off was low and similar in pre- and post-exposure samples (1.7 and 1.8%, respectively). Results above the assay cut-off were sporadic and transient. Occurrence of anti-C1INH antibodies did not correlate with repeated treatment or time since last treatment. No neutralizing antibodies were detected. A total of 5/155 (3%) rhC1INH-treated patients

  15. Elucidating the Mechanism of Gain of Toxic Function From Mutant C1 Inhibitor Proteins in Hereditary Angioedema

    DTIC Science & Technology

    2015-10-01

    AD______________ AWARD NUMBER: W81XWH-14-1-0506 TITLE: Elucidating the Mechanism of Gain of Toxic Function From Mutant C1 Inhibitor Proteins...REPORT TYPE Annual 3. DATES COVERED 30 Sept 2014 – 29 Sept 2015 4. TITLE AND SUBTITLE Elucidating the Mechanism of Gain of Toxic Function From Mutant ...Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT HAE is autosomal dominant. Cells, heterozygous for the SERPING1 mutation, express both mutant and WT

  16. Efficacy and safety of an intravenous C1-inhibitor concentrate for long-term prophylaxis in hereditary angioedema

    PubMed Central

    Craig, Timothy; Shapiro, Ralph; Vegh, Arthur; Baker, James W.; Bernstein, Jonathan A.; Busse, Paula; Magerl, Markus; Martinez-Saguer, Inmaculada; Riedl, Marc A.; Lumry, William; Williams-Herman, Debora; Edelman, Jonathan; Feuersenger, Henrike; Machnig, Thomas

    2017-01-01

    Background: The plasma-derived, pasteurized, nanofiltered C1-inhibitor concentrate (pnfC1-INH) is approved in the United States as an intravenous (IV) on-demand treatment for hereditary angioedema (HAE) attacks, and, in Europe, as on demand and short-term prophylaxis. Objective: This analysis evaluated Berinert Patient Registry data regarding IV pnfC1-INH used as long-term prophylaxis (LTP). Methods: The international registry (2010–2014) collected prospective and retrospective usage, dosing, and safety data on individuals who used pnfC1-INH for any reason. Results: The registry included data on 47 subjects (80.9% female subjects; mean age, 44.8 years), which reflected 4082 infusions categorized as LTP and a total of 430.2 months of LTP administration. The median absolute dose of pnfC1-INH given for LTP was 1000 IU (range, 500–3000 IU), with a median time interval between infusion and a subsequent pnfC1-INH–treated attack of 72.0 hours (range, 0.0–166.4 hours). Fifteen subjects (31.9%) had no pnfC1-INH–treated HAE attacks within 7 days after pnfC1-INH infusion for LTP; 32 subjects (68.1%) experienced 246 attacks, with rates of 0.06 attacks per infusion and 0.57 attacks per month. A total of 81 adverse events were reported in 16 subjects (34.0%) (0.02 events per infusion; 0.19 events per month); only 3 adverse events were considered related to pnfC1-INH (noncardiac chest pain, postinfusion headache, deep vein thrombosis in a subject with an IV port). Conclusion: In this international registry, IV pnf-C1-INH given as LTP for HAE was safe and efficacious, with a low rate of attacks that required pnfC1-INH treatment, particularly within the first several days after LTP administration. PMID:28381322

  17. Molecular phylogeny of C1 inhibitor depicts two immunoglobulin-like domains fusion in fishes and ray-finned fishes specific intron insertion after separation from zebrafish

    SciTech Connect

    Kumar, Abhishek; Bhandari, Anita; Sarde, Sandeep J.; Goswami, Chandan

    2014-07-18

    Highlights: • C1 inhibitors of fishes have two Ig domains fused in the N-terminal end. • Spliceosomal introns gain in two Ig domains of selected ray-finned fishes. • C1 inhibitors gene is maintained from 450 MY on the same locus. • C1 inhibitors gene is missing in frog and lampreys. • C1 inhibitors of tetrapod and fishes differ in the RCL region. - Abstract: C1 inhibitor (C1IN) is a multi-facet serine protease inhibitor in the plasma cascades, inhibiting several proteases, notably, regulates both complement and contact system activation. Despite huge advancements in the understanding of C1IN based on biochemical properties and its roles in the plasma cascades, the phylogenetic history of C1IN remains uncharacterized. To date, there is no comprehensive study illustrating the phylogenetic history of C1IN. Herein, we explored phylogenetic history of C1IN gene in vertebrates. Fishes have C1IN with two immunoglobulin like domains attached in the N-terminal region. The RCL regions of CIIN from fishes and tetrapod genomes have variations at the positions P2 and P1′. Gene structures of C1IN gene from selected ray-finned fishes varied in the Ig domain region with creation of novel intron splitting exon Im2 into Im2a and Im2b. This intron is limited to ray-finned fishes with genome size reduced below 1 Gb. Hence, we suggest that genome compaction and associated double-strand break repairs are behind this intron gain. This study reveals the evolutionary history of C1IN and confirmed that this gene remains the same locus for ∼450 MY in 52 vertebrates analysed, but it is not found in frogs and lampreys.

  18. Inhibition of Myeloperoxidase Activity in Cystic Fibrosis Sputum by Peptide Inhibitor of Complement C1 (PIC1)

    PubMed Central

    Hair, Pamela S.; Sass, Laura A.; Krishna, Neel K.

    2017-01-01

    Myeloperoxidase is the major peroxidase enzyme in neutrophil granules and implicated in contributing to inflammatory lung damage in cystic fibrosis. Free myeloperoxidase is present in cystic fibrosis lung fluid and generates hypochlorous acid. Here we report a new inhibitor of myeloperoxidase activity, Peptide Inhibitor of Complement C1 (PIC1). Using TMB as the oxidizing substrate, PIC1 inhibited myeloperoxidase activity in cystic fibrosis sputum soluble fractions by an average of a 3.4-fold decrease (P = 0.02). PIC1 also dose-dependently inhibited myeloperoxidase activity in a neutrophil lysate or purified myeloperoxidase by up to 28-fold (P < 0.001). PIC1 inhibited myeloperoxidase activity similarly, on a molar basis, as the specific myeloperoxidase inhibitor 4-Aminobenzoic acid hydrazide (ABAH) for various oxidizing substrates. PIC1 was able to protect the heme ring of myeloperoxidase from destruction by NaOCl, assayed by spectral analysis. PIC1 incubated with oxidized TMB reversed the oxidation state of TMB, as measured by absorbance at 450 nm, with a 20-fold reduction in oxidized TMB (P = 0.02). This result was consistent with an antioxidant mechanism for PIC1. In summary, PIC1 inhibits the peroxidase activity of myeloperoxidase in CF sputum likely via an antioxidant mechanism. PMID:28135312

  19. Feasibility of home infusion and self-administration of nanofiltered C1 esterase inhibitor for routine prophylaxis in patients with hereditary angioedema and characterization of a training and support program.

    PubMed

    Gregory, Cherylann; Landmesser, Ladonna M; Corrigan, Larry; Mariano, David

    2014-01-01

    Hereditary angioedema (HAE) is a rare, chronic disease of C1 inhibitor deficiency. Study researchers evaluated the prevalence of home and self-administration of nanofiltered, human-derived C1 esterase inhibitor infusions and the implementation of a nursing training and support program. Home administration rate increased from 49.0% to 75.8%. The percentage who self-administered increased from 20.3% to 43.9%. Doses per week averaged 1.85 at home compared with 1.40 in infusion centers and physicians' offices. Patients required an average of 5 visits to be trained. Self-administration is a viable, feasible option in the management of HAE, which is facilitated by a nurse-managed training and support program.

  20. C1 esterase inhibitor

    MedlinePlus

    ... algorithm for the diagnosis, therapy and management of hereditary angioedema. Allergy Asthma Clin Immunol . 2010;6:24. PMID: ... chap 6. Read More Cirrhosis Complement Glomerulonephritis Hepatitis Hereditary angioedema Kidney transplant Lupus nephritis Systemic lupus erythematosus Ulcerative ...

  1. Plasma-Derived C1 Esterase Inhibitor for Acute Antibody-Mediated Rejection Following Kidney Transplantation: Results of a Randomized Double-Blind Placebo-Controlled Pilot Study.

    PubMed

    Montgomery, R A; Orandi, B J; Racusen, L; Jackson, A M; Garonzik-Wang, J M; Shah, T; Woodle, E S; Sommerer, C; Fitts, D; Rockich, K; Zhang, P; Uknis, M E

    2016-05-16

    Antibody-mediated rejection (AMR) is typically treated with plasmapheresis (PP) and intravenous immunoglobulin (standard of care; SOC); however, there is an unmet need for more effective therapy. We report a phase 2b, multicenter double-blind randomized placebo-controlled pilot study to evaluate the use of human plasma-derived C1 esterase inhibitor (C1 INH) as add-on therapy to SOC for AMR. Eighteen patients received 20 000 units of C1 INH or placebo (C1 INH n = 9, placebo n = 9) in divided doses every other day for 2 weeks. No discontinuations, graft losses, deaths, or study drug-related serious adverse events occurred. While the study's primary end point, a difference between groups in day 20 pathology or graft survival, was not achieved, the C1 INH group demonstrated a trend toward sustained improvement in renal function. Six-month biopsies performed in 14 subjects (C1 INH = 7, placebo = 7) showed no transplant glomerulopathy (TG) (PTC+cg≥1b) in the C1 INH group, whereas 3 of 7 placebo subjects had TG. Endogenous C1 INH measured before and after PP demonstrated decreased functional C1 INH serum concentration by 43.3% (p < 0.05) for both cohorts (C1 INH and placebo) associated with PP, although exogenous C1 INH-treated patients achieved supraphysiological levels throughout. This new finding suggests that C1 INH replacement may be useful in the treatment of AMR.

  2. Peptide Inhibitor of Complement C1 (PIC1) Rapidly Inhibits Complement Activation after Intravascular Injection in Rats

    PubMed Central

    Sharp, Julia A.; Hair, Pamela S.; Pallera, Haree K.; Kumar, Parvathi S.; Mauriello, Clifford T.; Nyalwidhe, Julius O.; Phelps, Cody A.; Park, Dalnam; Thielens, Nicole M.; Pascal, Stephen M.; Chen, Waldon; Duffy, Diane M.; Lattanzio, Frank A.; Cunnion, Kenji M.; Krishna, Neel K.

    2015-01-01

    The complement system has been increasingly recognized to play a pivotal role in a variety of inflammatory and autoimmune diseases. Consequently, therapeutic modulators of the classical, lectin and alternative pathways of the complement system are currently in pre-clinical and clinical development. Our laboratory has identified a peptide that specifically inhibits the classical and lectin pathways of complement and is referred to as Peptide Inhibitor of Complement C1 (PIC1). In this study, we determined that the lead PIC1 variant demonstrates a salt-dependent binding to C1q, the initiator molecule of the classical pathway. Additionally, this peptide bound to the lectin pathway initiator molecule MBL as well as the ficolins H, M and L, suggesting a common mechanism of PIC1 inhibitory activity occurs via binding to the collagen-like tails of these collectin molecules. We further analyzed the effect of arginine and glutamic acid residue substitution on the complement inhibitory activity of our lead derivative in a hemolytic assay and found that the original sequence demonstrated superior inhibitory activity. To improve upon the solubility of the lead derivative, a pegylated, water soluble variant was developed, structurally characterized and demonstrated to inhibit complement activation in mouse plasma, as well as rat, non-human primate and human serum in vitro. After intravenous injection in rats, the pegylated derivative inhibited complement activation in the blood by 90% after 30 seconds, demonstrating extremely rapid function. Additionally, no adverse toxicological effects were observed in limited testing. Together these results show that PIC1 rapidly inhibits classical complement activation in vitro and in vivo and is functional for a variety of animal species, suggesting its utility in animal models of classical complement-mediated diseases. PMID:26196285

  3. Molecular phylogeny of C1 inhibitor depicts two immunoglobulin-like domains fusion in fishes and ray-finned fishes specific intron insertion after separation from zebrafish.

    PubMed

    Kumar, Abhishek; Bhandari, Anita; Sarde, Sandeep J; Goswami, Chandan

    2014-07-18

    C1 inhibitor (C1IN) is a multi-facet serine protease inhibitor in the plasma cascades, inhibiting several proteases, notably, regulates both complement and contact system activation. Despite huge advancements in the understanding of C1IN based on biochemical properties and its roles in the plasma cascades, the phylogenetic history of C1IN remains uncharacterized. To date, there is no comprehensive study illustrating the phylogenetic history of C1IN. Herein, we explored phylogenetic history of C1IN gene in vertebrates. Fishes have C1IN with two immunoglobulin like domains attached in the N-terminal region. The RCL regions of CIIN from fishes and tetrapod genomes have variations at the positions P2 and P1'. Gene structures of C1IN gene from selected ray-finned fishes varied in the Ig domain region with creation of novel intron splitting exon Im2 into Im2a and Im2b. This intron is limited to ray-finned fishes with genome size reduced below 1 Gb. Hence, we suggest that genome compaction and associated double-strand break repairs are behind this intron gain. This study reveals the evolutionary history of C1IN and confirmed that this gene remains the same locus for ∼450 MY in 52 vertebrates analysed, but it is not found in frogs and lampreys.

  4. Mutation of a Salmonella serogroup-C1-specific gene abrogates O7-antigen biosynthesis and triggers NaCl-dependent motility deficiency.

    PubMed

    Zhou, Xiujuan; Liu, Bin; Shi, Chunlei; Shi, Xianming

    2014-01-01

    Several molecular detection marker genes specific for a number of individual Salmonella serogroups have been recently identified in our lab by comparative genomics for the genotyping of diverse serogroups. To further understand the correlation between serotype and genotype, the function of a Salmonella serogroup-C1-specific gene (SC_2092) was analyzed in this study. It was indicated from the topological prediction using the deduced amino acid sequence of SC_2092 that this putative protein was highly similar to the confirmed Wzx flippases. Furthermore, SDS-PAGE revealed that lipopolysaccharide (LPS) biosynthesis, specifically O-antigen synthesis, was incomplete in an SC_2092 in-frame deletion mutant, and no agglutination reaction with the O7 antibody was exhibited in this mutant. Therefore, it was revealed that this Salmonella serogroup-C1-specific gene SC_2092 encoded a putative flippase, which was required for O7-polysaccharide biosynthesis, and was designated here as wzxC1. Subsequently, the effects of the deletion of wzxC1 on bacterial motility and sodium chloride (NaCl) tolerance were evaluated. The wzxC1 mutant lacked swarming motility on solid surfaces and was impaired in swimming motility in soft agar. Moreover, microscopic examination and RT-qPCR exhibited that an increased auto-aggregation and a strong defect in flagella expression, respectively, were responsible for the reduced motility in this mutant. In addition, the wzxC1 mutant was more sensitive than the wild-type strain to NaCl, and auto-aggregation of mutant cells was observed immediately up on the addition of 1% NaCl to the medium. Interestingly, the motility deficiency of the mutant strain, as well as the cell agglomeration and the decrease in flagellar expression, were relieved in a NaCl-free medium. This is the first study to experimentally demonstrate a connection between a Salmonella serogroup specific gene identified by comparative genomics with the synthesis of a specific O

  5. COA7 (C1orf163/RESA1) mutations associated with mitochondrial leukoencephalopathy and cytochrome c oxidase deficiency

    PubMed Central

    Martinez Lyons, Anabel; Ardissone, Anna; Reyes, Aurelio; Robinson, Alan J; Moroni, Isabella; Fernandez-Vizarra, Erika; Zeviani, Massimo

    2016-01-01

    Background Assembly of cytochrome c oxidase (COX, complex IV, cIV), the terminal component of the mitochondrial respiratory chain, is assisted by several factors, most of which are conserved from yeast to humans. However, some of them, including COA7, are found in humans but not in yeast. COA7 is a 231aa-long mitochondrial protein present in animals, containing five Sel1-like tetratricopeptide repeat sequences, which are likely to interact with partner proteins. Methods Whole exome sequencing was carried out on a 19 year old woman, affected by early onset, progressive severe ataxia and peripheral neuropathy, mild cognitive impairment and a cavitating leukodystrophy of the brain with spinal cord hypotrophy. Biochemical analysis of the mitochondrial respiratory chain revealed the presence of isolated deficiency of cytochrome c oxidase (COX) activity in skin fibroblasts and skeletal muscle. Mitochondrial localization studies were carried out in isolated mitochondria and mitoplasts from immortalized control human fibroblasts. Results We found compound heterozygous mutations in COA7: a paternal c.410A>G, p.Y137C, and a maternal c.287+1G>T variants. Lentiviral-mediated expression of recombinant wild-type COA7 cDNA in the patient fibroblasts led to the recovery of the defect in COX activity and restoration of normal COX amount. In mitochondrial localization experiments, COA7 behaved as the soluble matrix protein Citrate Synthase. Conclusions We report here the first patient carrying pathogenic mutations of COA7, causative of isolated COX deficiency and progressive neurological impairment. We also show that COA7 is a soluble protein localized to the matrix, rather than in the intermembrane space as previously suggested. PMID:27683825

  6. Novel 11β-HSD1 inhibitors: C-1 versus C-2 substitution and effect of the introduction of an oxygen atom in the adamantane scaffold.

    PubMed

    Leiva, Rosana; Seira, Constantí; McBride, Andrew; Binnie, Margaret; Luque, F Javier; Bidon-Chanal, Axel; Webster, Scott P; Vázquez, Santiago

    2015-10-01

    The adamantane scaffold is found in several marketed drugs and in many investigational 11β-HSD1 inhibitors. Interestingly, all the clinically approved adamantane derivatives are C-1 substituted. We demonstrate that, in a series of paired adamantane isomers, substitution of the adamantane in C-2 is preferred over the substitution at C-1 and is necessary for potency at human 11β-HSD1. Furthermore, the introduction of an oxygen atom in the hydrocarbon scaffold of adamantane is deleterious to 11β-HSD1 inhibition. Molecular modeling studies provide a basis to rationalize these features.

  7. Molecular basis of multiple sulfatase deficiency, mucolipidosis II/III and Niemann-Pick C1 disease - Lysosomal storage disorders caused by defects of non-lysosomal proteins.

    PubMed

    Dierks, Thomas; Schlotawa, Lars; Frese, Marc-André; Radhakrishnan, Karthikeyan; von Figura, Kurt; Schmidt, Bernhard

    2009-04-01

    Multiple sulfatase deficiency (MSD), mucolipidosis (ML) II/III and Niemann-Pick type C1 (NPC1) disease are rare but fatal lysosomal storage disorders caused by the genetic defect of non-lysosomal proteins. The NPC1 protein mainly localizes to late endosomes and is essential for cholesterol redistribution from endocytosed LDL to cellular membranes. NPC1 deficiency leads to lysosomal accumulation of a broad range of lipids. The precise functional mechanism of this membrane protein, however, remains puzzling. ML II, also termed I cell disease, and the less severe ML III result from deficiencies of the Golgi enzyme N-acetylglucosamine 1-phosphotransferase leading to a global defect of lysosome biogenesis. In patient cells, newly synthesized lysosomal proteins are not equipped with the critical lysosomal trafficking marker mannose 6-phosphate, thus escaping from lysosomal sorting at the trans Golgi network. MSD affects the entire sulfatase family, at least seven members of which are lysosomal enzymes that are specifically involved in the degradation of sulfated glycosaminoglycans, sulfolipids or other sulfated molecules. The combined deficiencies of all sulfatases result from a defective post-translational modification by the ER-localized formylglycine-generating enzyme (FGE), which oxidizes a specific cysteine residue to formylglycine, the catalytic residue enabling a unique mechanism of sulfate ester hydrolysis. This review gives an update on the molecular bases of these enigmatic diseases, which have been challenging researchers since many decades and so far led to a number of surprising findings that give deeper insight into both the cell biology and the pathobiochemistry underlying these complex disorders. In case of MSD, considerable progress has been made in recent years towards an understanding of disease-causing FGE mutations. First approaches to link molecular parameters with clinical manifestation have been described and even therapeutical options have been

  8. Targeting MAGE-C1/CT7 Expression Increases Cell Sensitivity to the Proteasome Inhibitor Bortezomib in Multiple Myeloma Cell Lines

    PubMed Central

    de Carvalho, Fabricio; Costa, Erico T.; Camargo, Anamaria A.; Gregorio, Juliana C.; Masotti, Cibele; Andrade, Valeria C.C.; Strauss, Bryan E.; Caballero, Otavia L.; Atanackovic, Djordje; Colleoni, Gisele W.B.

    2011-01-01

    The MAGE-C1/CT7 encodes a cancer/testis antigen (CTA), is located on the chromosomal region Xq26–27 and is highly polymorphic in humans. MAGE-C1/CT7 is frequently expressed in multiple myeloma (MM) that may be a potential target for immunotherapy in this still incurable disease. MAGEC1/CT7 expression is restricted to malignant plasma cells and it has been suggested that MAGE-C1/CT7 might play a pathogenic role in MM; however, the exact function this protein in the pathophysiology of MM is not yet understood. Our objectives were (1) to clarify the role of MAGE-C1/CT7 in the control of cellular proliferation and cell cycle in myeloma and (2) to evaluate the impact of silencing MAGE-C1/CT7 on myeloma cells treated with bortezomib. Myeloma cell line SKO-007 was transduced for stable expression of shRNA-MAGE-C1/CT7. Downregulation of MAGE-C1/CT7 was confirmed by real time quantitative PCR and western blot. Functional assays included cell proliferation, cell invasion, cell cycle analysis and apoptosis. Western blot showed a 70–80% decrease in MAGE-C1/CT7 protein expression in inhibited cells (shRNA-MAGE-C1/CT7) when compared with controls. Functional assays did not indicate a difference in cell proliferation and DNA synthesis when inhibited cells were compared with controls. However, we found a decreased percentage of cells in the G2/M phase of the cell cycle among inhibited cells, but not in the controls (p<0.05). When myeloma cells were treated with bortezomib, we observed a 48% reduction of cells in the G2/M phase among inhibited cells while controls showed 13% (empty vector) and 9% (ineffective shRNA) reduction, respectively (p<0.01). Furthermore, inhibited cells treated with bortezomib showed an increased percentage of apoptotic cells (Annexin V+/PI-) in comparison with bortezomib-treated controls (p<0.001). We found that MAGE-C1/CT7 protects SKO-007 cells against bortezomib-induced apoptosis. Therefore, we could speculate that MAGE-C1/CT7 gene therapy could be

  9. Multi-Kinase Inhibitor C1 Triggers Mitotic Catastrophe of Glioma Stem Cells Mainly through MELK Kinase Inhibition

    PubMed Central

    Joshi, Kaushal; Nakano-Okuno, Mariko; Hong, Christopher; Nguyen, Chi-Hung; Kornblum, Harley I.; Molla, Annie; Nakano, Ichiro

    2014-01-01

    Glioblastoma multiforme (GBM) is a highly lethal brain tumor. Due to resistance to current therapies, patient prognosis remains poor and development of novel and effective GBM therapy is crucial. Glioma stem cells (GSCs) have gained attention as a therapeutic target in GBM due to their relative resistance to current therapies and potent tumor-initiating ability. Previously, we identified that the mitotic kinase maternal embryonic leucine-zipper kinase (MELK) is highly expressed in GBM tissues, specifically in GSCs, and its expression is inversely correlated with the post-surgical survival period of GBM patients. In addition, patient-derived GSCs depend on MELK for their survival and growth both in vitro and in vivo. Here, we demonstrate evidence that the role of MELK in the GSC survival is specifically dependent on its kinase activity. With in silico structure-based analysis for protein-compound interaction, we identified the small molecule Compound 1 (C1) is predicted to bind to the kinase-active site of MELK protein. Elimination of MELK kinase activity was confirmed by in vitro kinase assay in nano-molar concentrations. When patient-derived GSCs were treated with C1, they underwent mitotic arrest and subsequent cellular apoptosis in vitro, a phenotype identical to that observed with shRNA-mediated MELK knockdown. In addition, C1 treatment strongly induced tumor cell apoptosis in slice cultures of GBM surgical specimens and attenuated growth of mouse intracranial tumors derived from GSCs in a dose-dependent manner. Lastly, C1 treatment sensitizes GSCs to radiation treatment. Collectively, these data indicate that targeting MELK kinase activity is a promising approach to attenuate GBM growth by eliminating GSCs in tumors. PMID:24739874

  10. Inhibitors of the mitochondrial cytochrome b-c1 complex inhibit the cyanide-insensitive respiration of Trypanosoma brucei.

    PubMed

    Turrens, J F; Bickar, D; Lehninger, A L

    1986-06-01

    The cyanide-insensitive respiration of bloodstream trypomastigote forms of Trypanosoma brucei (75 +/- 8 nmol O2 min-1(mg protein)-1) is completely inhibited by the mitochondrial ubiquinone-like inhibitors 2-hydroxy-3-undecyl-1,4-naphthoquinone (UHNQ) and 5-n-undecyl-6-hydroxy-4,7-dioxobenzothiazole (UHDBT). The Ki values for UHDBT (30 nM) and UHNQ (2 microM) are much lower than the reported Ki for salicylhydroxamic acid (SHAM) (5 microM), a widely used inhibitor of the cyanide-insensitive oxidase. UHNQ also stimulated the glycerol-3-phosphate-dependent reduction of phenazine methosulfate, demonstrating that the site of UHNQ inhibition is on the terminal oxidase of the cyanide-insensitive respiration of T. brucei. These results suggest that a ubiquinone-like compound may act as an electron carrier between the two enzymatic components of the cyanide-insensitive glycerol-3-phosphate oxidase.

  11. Plasma-derived human C1-esterase inhibitor does not prevent mechanical ventilation-induced pulmonary complement activation in a rat model of Streptococcus pneumoniae pneumonia.

    PubMed

    de Beer, F M; Aslami, H; Hoeksma, J; van Mierlo, G; Wouters, D; Zeerleder, S; Roelofs, J J T H; Juffermans, N P; Schultz, M J; Lagrand, W K

    2014-11-01

    Mechanical ventilation has the potential to cause lung injury, and the role of complement activation herein is uncertain. We hypothesized that inhibition of the complement cascade by administration of plasma-derived human C1-esterase inhibitor (C1-INH) prevents ventilation-induced pulmonary complement activation, and as such attenuates lung inflammation and lung injury in a rat model of Streptococcus pneumoniae pneumonia. Forty hours after intratracheal challenge with S. pneumoniae causing pneumonia rats were subjected to ventilation with lower tidal volumes and positive end-expiratory pressure (PEEP) or high tidal volumes without PEEP, after an intravenous bolus of C1-INH (200 U/kg) or placebo (saline). After 4 h of ventilation blood, broncho-alveolar lavage fluid and lung tissue were collected. Non-ventilated rats with S. pneumoniae pneumonia served as controls. While ventilation with lower tidal volumes and PEEP slightly amplified pneumonia-induced complement activation in the lungs, ventilation with higher tidal volumes without PEEP augmented local complement activation more strongly. Systemic pre-treatment with C1-INH, however, failed to alter ventilation-induced complement activation with both ventilation strategies. In accordance, lung inflammation and lung injury were not affected by pre-treatment with C1-INH, neither in rats ventilated with lower tidal volumes and PEEP, nor rats ventilated with high tidal volumes without PEEP. Ventilation augments pulmonary complement activation in a rat model of S. pneumoniae pneumonia. Systemic administration of C1-INH, however, does not attenuate ventilation-induced complement activation, lung inflammation, and lung injury.

  12. Antithrombin III, but not C1 esterase inhibitor reduces inflammatory response in lipopolysaccharide-stimulated human monocytes in an ex-vivo whole blood setting.

    PubMed

    Kellner, Patrick; Nestler, Frank; Leimert, Anja; Bucher, Michael; Czeslick, Elke; Sablotzki, Armin; Raspè, Christoph

    2014-12-01

    In order to examine the immunomodulatory effects of antithrombin III (AT-III) and C1 esterase inhibitor (C1-INH) in human monocytes, we investigated the intracellular expression of interleukin (IL)-6, IL-8, and tumor necrosis factor (TNF)-α in an ex-vivo laboratory study in a whole blood setting. Heparinized whole blood samples from 23 healthy male and female volunteers (mean age: 27±7years) were pre-incubated with clinically relevant concentrations of AT-III (n=11) and C1-INH (n=12), then stimulated with 0.2 ng/mL lipopolysaccharide (LPS) for 3h. After phenotyping CD14⁺ monocytes, intracellular expression of IL-6, IL-8, and TNF-α was assessed using flow cytometry. In addition, 12 whole blood samples (AT-III and C1-INH, n=6 each) were examined using hirudin for anticoagulation; all samples were processed in the same way. To exclude cytotoxicity effects, 7-amino-actinomycin D and Nonidet P40 staining were used to investigate probes. This study is the first to demonstrate the influence of C1-INH and AT-III on the monocytic inflammatory response in a whole blood setting, which mimics the optimal physiological setting. Cells treated with AT-III exhibited significant downregulation of the proportion of gated CD14⁺ monocytes for IL-6 and IL-8, in a dose-dependent manner; downregulation for TNF-α did not reach statistical significance. There were no significant effects on mean fluorescence intensity (MFI). In contrast, C1-INH did not significantly reduce the proportion of gated CD14⁺ monocytes or the MFI regarding IL-6, TNF-α, and IL-8. When using hirudin for anticoagulation, no difference in the anti-inflammatory properties of AT-III and C1-INH in monocytes occurs. Taken together, in contrast to TNF-α, IL-6 and IL-8 were significantly downregulated in monocytes in an ex-vivo setting of human whole blood when treated with AT-III. This finding implicates monocytes as an important point of action regarding the anti-inflammatory properties of AT-III in sepsis. C1

  13. PARP1 inhibitor olaparib (Lynparza) exerts synthetic lethal effect against ligase 4-deficient melanomas

    PubMed Central

    Czyż, Małgorzata; Toma, Monika; Gajos-Michniewicz, Anna; Majchrzak, Kinga; Hoser, Grazyna; Szemraj, Janusz; Nieborowska-Skorska, Margaret; Cheng, Phil; Gritsyuk, Daniel; Levesque, Mitchell; Dummer, Reinhard; Sliwinski, Tomasz; Skorski, Tomasz

    2016-01-01

    Cancer including melanoma may be “addicted” to double strand break (DSB) repair and targeting this process could sensitize them to the lethal effect of DNA damage. PARP1 exerts an important impact on DSB repair as it binds to both single- and double- strand breaks. PARP1 inhibitors might be highly effective drugs triggering synthetic lethality in patients whose tumors have germline or somatic defects in DNA repair genes. We hypothesized that PARP1-dependent synthetic lethality could be induced in melanoma cells displaying downregulation of DSB repair genes. We observed that PARP1 inhibitor olaparib sensitized melanomas with reduced expression of DNA ligase 4 (LIG4) to an alkylatimg agent dacarbazine (DTIC) treatment in vitro, while normal melanocytes remained intact. PARP1 inhibition caused accumulation of DSBs, which was associated with apoptosis in LIG4 deficient melanoma cells. Our hypothesis that olaparib is synthetic lethal with LIG4 deficiency in melanoma cells was supported by selective anti-tumor effects of olaparib used either alone or in combination with dacarbazine (DTIC) in LIG4 deficient, but not LIG4 proficient cells. In addition, olaparib combined with DTIC inhibited the growth of LIG4 deficient human melanoma xenografts. This work for the first time demonstrates the effectiveness of a combination of PARP1 inhibitor olaparib and alkylating agent DTIC for treating LIG4 deficient melanomas. In addition, analysis of the TCGA and transcriptome microarray databases revealed numerous individual melanoma samples potentially displaying specific defects in DSB repair pathways, which may predispose them to synthetic lethality triggered by PARP1 inhibitor combined with a cytotoxic drug. PMID:27705909

  14. Ruthenium complexes as inhibitors of the aldo-keto reductases AKR1C1-1C3.

    PubMed

    Traven, Katja; Sinreih, Maša; Stojan, Jure; Seršen, Sara; Kljun, Jakob; Bezenšek, Jure; Stanovnik, Branko; Turel, Iztok; Rižner, Tea Lanišnik

    2015-06-05

    The human aldo-keto reductases (AKRs) from the 1C subfamily are important targets for the development of new drugs. In this study, we have investigated the possible interactions between the recombinant AKR1C enzymes AKR1C1-AKR1C3 and ruthenium(II) complexes; in particular, we were interested in the potential inhibitory actions. Five novel ruthenium complexes (1a, 1b, 2a, 2b, 2c), two precursor ruthenium compounds (P1, P2), and three ligands (a, b, c) were prepared and included in this study. Two different types of novel ruthenium(II) complexes were synthesized. First, bearing the sulphur macrocycle [9]aneS3, S-bonded dimethylsulphoxide (dmso-S), and an N,N-donor ligand, with the general formula of [Ru([9]aneS3)(dmso)(N,N-ligand)](PF6)2 (1a, 1b), and second, with the general formula of [(η(6)-p-cymene)RuCl(N,N-ligand)]Cl (2a, 2b, 2c). All of these synthesized compounds were characterized by high-resolution NMR spectroscopy, X-ray crystallography (compounds a, b, c, 1a, 1b) and other standard physicochemical methods. To evaluate the potential inhibitory actions of these compounds on the AKR1C enzymes, we followed enzymatically catalyzed oxidation of the substrate 1-acenaphthenol by NAD(+) in the absence and presence of various micromolar concentrations of the individual compounds. Among 10 compounds, one ruthenium complex (2b) and two precursor ruthenium compounds (P1, P2) inhibited all three AKR1C enzymes, and one ruthenium complex (2a) inhibited only AKR1C3. Ligands a, b and c revealed no inhibition of the AKR1C enzymes. All four of the active compounds showed multiple binding with the AKR1C enzymes that was characterized by an initial instantaneous inhibition followed by a slow quasi-irreversible step. To the best of our knowledge, this is the first study that has examined interactions between these AKR1C enzymes and ruthenium(II) complexes.

  15. Unmasking Heavily O-Glycosylated Serum Proteins Using Perchloric Acid: Identification of Serum Proteoglycan 4 and Protease C1 Inhibitor as Molecular Indicators for Screening of Breast Cancer

    PubMed Central

    Lee, Cheng-Siang; Taib, Nur Aishah Mohd; Ashrafzadeh, Ali; Fadzli, Farhana; Harun, Faizah; Rahmat, Kartini; Hoong, See Mee; Abdul-Rahman, Puteri Shafinaz; Hashim, Onn Haji

    2016-01-01

    Heavily glycosylated mucin glycopeptides such as CA 27.29 and CA 15–3 are currently being used as biomarkers for detection and monitoring of breast cancer. However, they are not well detected at the early stages of the cancer. In the present study, perchloric acid (PCA) was used to enhance detection of mucin-type O-glycosylated proteins in the serum in an attempt to identify new biomarkers for early stage breast cancer. Sensitivity and specificity of an earlier developed sandwich enzyme-linked lectin assay were significantly improved with the use of serum PCA isolates. When a pilot case-control study was performed using the serum PCA isolates of normal participants (n = 105) and patients with stage 0 (n = 31) and stage I (n = 48) breast cancer, higher levels of total O-glycosylated proteins in sera of both groups of early stage breast cancer patients compared to the normal control women were demonstrated. Further analysis by gel-based proteomics detected significant inverse altered abundance of proteoglycan 4 and plasma protease C1 inhibitor in both the early stages of breast cancer patients compared to the controls. Our data suggests that the ratio of serum proteoglycan 4 to protease C1 inhibitor may be used for screening of early breast cancer although this requires further validation in clinically representative populations. PMID:26890881

  16. Novel Mechanisms of PARP Inhibitor Resistance in BRCA1-Deficient Breast Cancers

    DTIC Science & Technology

    2015-12-01

    of single stranded DNA breaks especially through activation of base excision repair (BER) (Krishnakumar & Kraus, 2010). A synthetic lethal phenotype...1) Test candidate mechanisms of HR restoration: a) Determine HR activity in parental , rescue, and PARP inhibitor resistant lines: In my previous two...seen in the parental , BRCA1-deficient line using Rad51 and PALB2 as markers. b) Test BRCA1-restoration: In my previous annual reports, I showed that

  17. Synthetic lethal targeting of DNA double strand break repair deficient cells by human apurinic/apyrimidinic endonuclease (APE1) inhibitors

    PubMed Central

    Sultana, Rebeka; McNeill, Daniel R.; Abbotts, Rachel; Mohammed, Mohammed Z.; Zdzienicka, Małgorzata Z.; Qutob, Haitham; Seedhouse, Claire; Laughton, Charles A.; Fischer, Peter M.; Patel, Poulam M.; Wilson, David M.; Madhusudan, Srinivasan

    2013-01-01

    An apurinic/apyrimidinic (AP) site is an obligatory cytotoxic intermediate in DNA Base Excision Repair (BER) that is processed by human AP endonuclease 1 (APE1). APE1 is essential for BER and an emerging drug target in cancer. We have isolated novel small molecule inhibitors of APE1. In the current study we have investigated the ability of APE1 inhibitors to induce synthetic lethality in a panel of DNA double strand break (DSB) repair deficient and proficient cells; a) Chinese hamster (CH) cells: BRCA2 deficient (V-C8), ATM deficient (V-E5), wild type (V79) and BRCA2 revertant (V-C8(Rev1)). b) Human cancer cells: BRCA1 deficient (MDA-MB-436), BRCA1 proficient (MCF-7), BRCA2 deficient (CAPAN-1 and HeLa SilenciX cells), BRCA2 proficient (PANC1 and control SilenciX cells). We also tested synthetic lethality (SL) in CH ovary cells expressing a dominant–negative form of APE1 (E8 cells) using ATM inhibitors and DNA-PKcs inhibitors (DSB inhibitors). APE1 inhibitors are synthetically lethal in BRCA and ATM deficient cells. APE1 inhibition resulted in accumulation of DNA DSBs and G2/M cell cycle arrest. Synthetic lethality was also demonstrated in CH cells expressing a dominant–negative form of APE1 treated with ATM or DNA-PKcs inhibitors. We conclude that APE1 is a promising synthetic lethality target in cancer. PMID:22377908

  18. Is some better than none: are TEG and TGA profiles different in severe FVIII-deficient patients with inhibitors?

    PubMed

    Salinas, V; Carmona, R; Mohammed, B M; Martin, E J; Brophy, D F; Young, G

    2015-05-01

    Severe factor VIII (FVIII)-deficient patients with and without FVIII inhibitors cannot be distinguished using FVIII levels. The FVIII assay is sensitive to detect factor levels below 1%. While severe FVIII-deficient, non-inhibitor patients have FVIII < 1%, they may retain unmeasurable residual factor activity. In contrast, inhibitor patients have a FVIII antibody that presumably fully eliminates FVIII activity. It is unknown whether thromboelastography (TEG) and thrombin generation assay (TGA) can differentiate between patients with FVIII < 1% with and without the presence of FVIII inhibitors. The primary objective was to discern whether TEG and TGA could differentiate between severe FVIII-deficient patients with and without the presence of FVIII inhibitors. A secondary objective was to correlate TEG and TGA to annualized bleeding rates. This observational study performed TEG and TGA in healthy volunteers (N = 15), severe FVIII-deficient (N = 15) and severe FVIII-deficient patients with inhibitors (N = 15). Kaolin-activated TEG was better at differentiating reaction time (31.3 vs. 120 min respectively, P = 0.004) and kinetics time (6.1 vs. 23.1 min respectively, P = 0.028) between the non-inhibitor and inhibitor patients. TEG activated by tissue factor in plasma-containing corn trypsin inhibitor failed to differentiate groups. The TGA failed to differentiate peak thrombin, endogenous thrombin potential and lag time between groups. There was no correlation between TEG and TGA with annualized bleeding rates. Kaolin-activated TEG, but not TGA, differentiated between severe FVIII-deficient patients with and without inhibitors. These assays did not find a correlation to annualized bleeding rate.

  19. ATM-Deficient Colorectal Cancer Cells Are Sensitive to the PARP Inhibitor Olaparib.

    PubMed

    Wang, Chen; Jette, Nicholas; Moussienko, Daniel; Bebb, D Gwyn; Lees-Miller, Susan P

    2017-02-06

    The ataxia telangiectasia mutated (ATM) protein kinase plays a central role in the cellular response to DNA damage. Loss or inactivation of both copies of the ATM gene (ATM) leads to ataxia telangiectasia, a devastating childhood condition characterized by neurodegeneration, immune deficiencies, and cancer predisposition. ATM is also absent in approximately 40% of mantle cell lymphomas (MCLs), and we previously showed that MCL cell lines with loss of ATM are sensitive to poly-ADP ribose polymerase (PARP) inhibitors. Next-generation sequencing of patient tumors has revealed that ATM is altered in many human cancers including colorectal, lung, prostate, and breast. Here, we show that the colorectal cancer cell line SK-CO-1 lacks detectable ATM protein expression and is sensitive to the PARP inhibitor olaparib. Similarly, HCT116 colorectal cancer cells with shRNA depletion of ATM are sensitive to olaparib, and depletion of p53 enhances this sensitivity. Moreover, HCT116 cells are sensitive to olaparib in combination with the ATM inhibitor KU55933, and sensitivity is enhanced by deletion of p53. Together our studies suggest that PARP inhibitors may have potential for treating colorectal cancer with ATM dysfunction and/or colorectal cancer with mutation of p53 when combined with an ATM kinase inhibitor.

  20. Correction of Cystathionine β-synthase Deficiency in Mice by Treatment with Proteasome Inhibitors

    PubMed Central

    Gupta, Sapna; Wang, Liqun; Anderl, Janet; Slifker, Michael J.; Kirk, Christopher; Kruger, Warren D.

    2013-01-01

    Cystathionine beta-synthase (CBS) deficiency is an inborn error of metabolism characterized by extremely elevated levels of plasma total homocysteine. The vast majority of CBS-deficient patients have missense mutations located in the CBS gene that result in the production of either misfolded or unstable protein. Here, we examine the effect of proteasome inhibitors on mutant CBS function using two different mouse models of CBS deficiency. These mice lack mouse CBS and express a missense mutant human CBS enzyme (either p.I278T or p.S466L) that has less than 5% of normal liver CBS activity, resulting in a 10–30 fold elevation in plasma homocysteine levels. We show that treatment of these mice with two different proteasome inhibitors can induce liver Hsp70, Hsp40, and Hsp27, increase levels of active CBS, and lower plasma homocysteine levels to within the normal range. However, response rates varied, with 100% (8/8) of the p.S466L animals showing correction, but only 38% (10/26) of the p.I278T animals. In total, our data shows that treatment with proteostasis modulators can restore significant enzymatic activity to mutant misfolded CBS enzymes and suggests that they may be useful in treating certain types of genetic diseases caused by missense mutations. PMID:23592311

  1. Increased Activity and Altered Subcellular Distribution of Lysosomal Enzymes Determine Neuronal Vulnerability in Niemann-Pick Type C1-Deficient Mice

    PubMed Central

    Amritraj, Asha; Peake, Kyle; Kodam, Anitha; Salio, Chiara; Merighi, Adalberto; Vance, Jean E.; Kar, Satyabrata

    2009-01-01

    Niemann-Pick disease type C (NPC), caused by mutations in the Npc1 or Npc2 genes, is a progressive neurodegenerative disorder characterized by intracellular accumulation/redistribution of cholesterol in a number of tissues including the brain. This is accompanied by a severe loss of neurons in selected brain regions. In this study, we evaluated the role of lysosomal enzymes, cathepsins B and D, in determining neuronal vulnerability in NPC1-deficient (Npc1−/−) mouse brains. Our results showed that Npc1−/− mice exhibit an age-dependent degeneration of neurons in the cerebellum but not in the hippocampus. The cellular level/expression and activity of cathepsins B and D are increased more predominantly in the cerebellum than in the hippocampus of Npc1−/− mice. In addition, the cytosolic levels of cathepsins, cytochrome c, and Bax2 are higher in the cerebellum than in the hippocampus of Npc1−/− mice, suggesting a role for these enzymes in the degeneration of neurons. This suggestion is supported by our observation that degeneration of cultured cortical neurons treated with U18666A, which induces an NPC1-like phenotype at the cellular level, can be attenuated by inhibition of cathepsin B or D enzyme activity. These results suggest that the increased level/activity and altered subcellular distribution of cathepsins may be associated with the underlying cause of neuronal vulnerability in Npc1−/− brains. Therefore, their inhibitors may have therapeutic potential in attenuating NPC pathology. PMID:19893049

  2. ARID1A Deficiency Impairs the DNA Damage Checkpoint and Sensitizes Cells to PARP Inhibitors

    PubMed Central

    Shen, Jianfeng; Peng, Yang; Wei, Leizhen; Zhang, Wei; Yang, Lin; Lan, Li; Kapoor, Prabodh; Ju, Zhenlin; Mo, Qianxing; Shih, Ie-Ming; Uray, Ivan P.; Wu, Xiangwei; Brown, Powel H.; Shen, Xuetong; Mills, Gordon B.; Peng, Guang

    2015-01-01

    ARID1A, a chromatin remodeler of the SWI/SNF family, is a recently identified tumor suppressor that is mutated in a broad spectrum of human cancers. Thus, it is of fundamental clinical importance to understand its molecular functions and determine whether ARID1A deficiency can be exploited therapeutically. In this manuscript, we report a key function of ARID1A in regulating the DNA damage checkpoint. ARID1A is recruited to DNA double strand breaks (DSBs) via its interaction with the upstream DNA damage checkpoint kinase ATR. At the molecular level, ARID1A facilitates efficient processing of DSB to single strand ends, and sustains DNA damage signaling. Importantly, ARID1A deficiency sensitizes cancer cells to PARP inhibitors in vitro and in vivo providing a potential therapeutic strategy for patients with ARID1A-mutant tumors. PMID:26069190

  3. A second case of human C3b inhibitor (KAF) deficiency.

    PubMed Central

    Thompson, R A; Lachmann, P J

    1977-01-01

    The second case of C3b inhibitor deficiency is described in an 11-year-old girl who presented with recurrent attacks of meningitis, in between which she was well. Her serum showed all of the complement component changes noted in the first described case, although showing only a relatively slight defect in its ability to opsonize bacteria for phagocytosis and killing by polymorphonuclear leucocytes. This correlated with the patient's freedom from other infections. Images Fig. 2 Fig. 3 Fig. 4 Fig. 5 PMID:849647

  4. ATR inhibitors as a synthetic lethal therapy for tumours deficient in ARID1A

    PubMed Central

    Williamson, Chris T.; Miller, Rowan; Pemberton, Helen N.; Jones, Samuel E.; Campbell, James; Konde, Asha; Badham, Nicholas; Rafiq, Rumana; Brough, Rachel; Gulati, Aditi; Ryan, Colm J.; Francis, Jeff; Vermulen, Peter B.; Reynolds, Andrew R.; Reaper, Philip M.; Pollard, John R.; Ashworth, Alan; Lord, Christopher J.

    2016-01-01

    Identifying genetic biomarkers of synthetic lethal drug sensitivity effects provides one approach to the development of targeted cancer therapies. Mutations in ARID1A represent one of the most common molecular alterations in human cancer, but therapeutic approaches that target these defects are not yet clinically available. We demonstrate that defects in ARID1A sensitize tumour cells to clinical inhibitors of the DNA damage checkpoint kinase, ATR, both in vitro and in vivo. Mechanistically, ARID1A deficiency results in topoisomerase 2A and cell cycle defects, which cause an increased reliance on ATR checkpoint activity. In ARID1A mutant tumour cells, inhibition of ATR triggers premature mitotic entry, genomic instability and apoptosis. The data presented here provide the pre-clinical and mechanistic rationale for assessing ARID1A defects as a biomarker of single-agent ATR inhibitor response and represents a novel synthetic lethal approach to targeting tumour cells. PMID:27958275

  5. Unimpeded skin carcinogenesis in K14-HPV16 transgenic mice deficient for plasminogen activator inhibitor

    PubMed Central

    Masset, A.; Maillard, C.; Sounni, NE.; Jacobs, N.; Bruyère, F.; Delvenne, P.; Tacke, M.; Reinheckel, T.; Foidart, J-M.; Coussens, LM.; Noël, A.

    2011-01-01

    Angiogenesis, extracellular matrix remodeling and cell migration are associated with cancer progression and involve at least, the plasminogen activating system and its main physiological inhibitor, the plasminogen activator inhibitor-1 (PAI-1). Considering the recognized importance of PAI-1 in the regulation of tumor angiogenesis and invasion in murine models of skin tumor transplantation, we explored the functional significance of PAI-1 during early stages of neoplastic progression in the transgenic mouse model of multistage epithelial carcinogenesis (K14-HPV16 mice). We have studied the effect of genetic deletion of PAI-1 on inflammation, angiogenesis, lymphangiogenesis, as well as tumor progression. In this model, PAI-1 deficiency neither impaired keratinocyte hyperproliferation or tumor development, nor affected the infiltration of inflammatory cells and development of angiogenic or lymphangiogenic vasculature. We are reporting evidence for concomitant lymphangiogenic and angiogenic switches independent to PAI-1 status. Taken together, these data indicate that PAI-1 is not rate limiting for neoplastic progression and vascularization during premalignant progression, or that there is a functional redundancy between PAI-1 and other tumor regulators, masking the effect of PAI-1 deficiency in this long-term model of multi-stage epithelial carcinogenesis. PMID:20232379

  6. Hereditary angioedema with normal C1-INH (HAE type III).

    PubMed

    Riedl, Marc A

    2013-01-01

    Hereditary angioedema (HAE) with normal C1 inhibitor (C1-INH), also known as HAE type III, is a familial condition only clinically recognized within the past three decades. Similar to HAE from C1-INH deficiency (HAE types I and II), affected individuals experience unpredictable angioedema episodes of the skin, gastrointestinal tract, and airway. Unique clinical features of HAE with normal C1-INH include the predominance of affected women, frequent exacerbation by estrogen, and a prominence of angioedema that involves the face and oropharynx. The underlying pathophysiology of HAE with normal C1-INH is poorly understood, but indirect evidence points to contact pathway dysregulation with bradykinin-mediated angioedema. Currently, evaluation is complicated by a lack of confirmatory laboratory testing such that clinical criteria must often be used to make the diagnosis of HAE with normal C1-INH. Factor XII mutations have been identified in only a minority of persons affected by HAE with normal C1-INH, limiting the utility of such analysis. To date, no controlled clinical studies have examined the efficacy of therapeutic agents for HAE with normal C1-INH, although published evidence supports frequent clinical benefit with medications shown effective in HAE due to C1-INH deficiency.

  7. Model-based evaluation of similarity in pharmacokinetics of two formulations of the blood-derived plasma product c1 esterase inhibitor.

    PubMed

    Keizer, Ron J; Budde, Ilona Kleine; Sprengers, Paul F W; Levi, M; Beijnen, Jos H; Huitema, Alwin D R

    2012-02-01

    A novel formulation of C1 esterase inhibitor concentrate, a plasma product used in the treatment of hereditary angioedema (HAE), was studied in a clinical trial for similarity in pharmacokinetics (PK) compared with the reference product. Direct trial data were limited given the availability of patients, and therefore a modeling approach was used to study similarity. Type I error of the study was evaluated using simulations based on retrospective data. A population PK modeling analysis was performed on data from the trial. Analysis of variance was carried out on results of a noncompartmental PK analysis (NCA) of the clinical data. Simulations showed that type I error was inflated to 62% (P < .05) when bioequivalence criteria (confidence intervals within 80%-125%) were adhered to strictly. In the clinical trial, 13 HAE patients were evaluable. The population PK analysis showed no significant differences in PK parameters, whereas confidence intervals for all parameters were within 80% to 125%. The relative differences in area under the curve, incremental recovery, and mean residence time estimated using NCA were all close to 1. The novel formulation showed similar PK characteristics to the original formulation. The model-based approach showed that strict criteria for PK comparison could not be applied in this analysis.

  8. ATM-deficiency sensitizes Mantle Cell Lymphoma cells to PARP-1 inhibitors

    PubMed Central

    Williamson, Chris T.; Muzik, Huong; Turhan, Ali G.; Zamò, Alberto; O’Connor, Mark J.; Bebb, D. Gwyn; Lees-Miller, Susan P.

    2013-01-01

    Poly-ADP ribose polymerase-1 (PARP-1) inhibition is toxic to cells with mutations in the breast and ovarian cancer susceptibility genes BRCA1 or BRCA2, a concept, termed synthetic lethality. However, whether this approach is applicable to other human cancers with defects in other DNA repair genes has yet to be determined. The Ataxia-Telangiectasia Mutated (ATM) gene is altered in a number of human cancers including Mantle Cell Lymphoma (MCL). Here, we characterize a panel of MCL cell lines for ATM status and function and investigate the potential for synthetic lethality in MCL in the presence of small molecule inhibitors of PARP-1. We show that Granta-519 and UPN2 cells have low levels of ATM protein, are defective in DNA damage-induced ATM-dependent signaling, are radiation sensitive and have cell cycle checkpoint defects: all characteristics of defective ATM function. Significantly, Granta-519 and UPN2 cells were more sensitive to PARP-1 inhibition, than were the ATM-proficient MCL cell lines examined. Furthermore, the PARP-1 inhibitor olaparib (previously known as AZD2281/KU-0059436) significantly decreased tumour growth and increased overall survival in mice bearing subcutaneous xenografts of ATM-deficient Granta-519 cells, while producing only a modest effect on overall survival of mice bearing xenografts of the ATM-proficient cell line, Z138. Thus, PARP inhibitors have therapeutic potential in the treatment of MCL and the concept of synthetic lethality extends to human cancers with ATM alterations. PMID:20124459

  9. Magnesium Deficiency and Proton-Pump Inhibitor Use: A Clinical Review.

    PubMed

    William, Jeffrey H; Danziger, John

    2016-06-01

    The association of proton-pump inhibitor (PPI) use and hypomagnesemia has garnered much attention over the last 5 years. A large body of observational data has linked chronic PPI use with hypomagnesemia, presumably due to decreased intestinal absorption and consequent magnesium deficiency. However, despite the increasing prevalence of this highly popular class of medicine, and despite potential significant risks associated with magnesium depletion, including cardiac arrhythmias and seizures, there are no well-designed studies to delineate the nature of this observed association. Consequently, providers must use best judgment to inform clinical decision making. This review summarizes the current body of evidence linking PPI use with hypomagnesemia, acknowledges the possibility of significant residual confounding in the observational data, explains potential physiologic mechanisms, and offers clinical recommendations.

  10. Plasminogen activator inhibitor-1 gene-deficient mice. II. Effects on hemostasis, thrombosis, and thrombolysis.

    PubMed Central

    Carmeliet, P; Stassen, J M; Schoonjans, L; Ream, B; van den Oord, J J; De Mol, M; Mulligan, R C; Collen, D

    1993-01-01

    The effects of plasminogen activator inhibitor-1 (PAI-1) gene inactivation on hemostasis, thrombosis and thrombolysis were studied in homozygous PAI-1-deficient (PAI-1-/-) mice, generated by homologous recombination in D3 embryonic stem cells. Diluted (10-fold) whole blood clots from PAI-1-/- and from PAI-1 wild type (PAI-1+/+) mice underwent limited but significantly different (P < 0.001) spontaneous lysis within 3 h (6 +/- 1 vs 3 +/- 1%, respectively). A 25-microliters 125I-fibrin-labeled normal murine plasma clot, injected into a jugular vein, was lysed for 47 +/- 5, 66 +/- 3, and 87 +/- 7% within 8 h in PAI-1+/+, heterozygous PAI-1-deficient (PAI-1+/-), and PAI-1-/- mice, respectively (P = 0.002 for PAI-1+/+ vs PAI-1-/- mice). Corresponding values after pretreatment with 0.5 mg/kg endotoxin in PAI-1+/+ and PAI-1-/- mice, were 35 +/- 5 and 91 +/- 3% within 4 h, respectively (P < 0.001). 11 out of 26 PAI-1+/+ but only 1 out of 25 PAI-1-/- mice developed venous thrombosis (P = 0.004) within 6 d after injection of 10 or 50 micrograms endotoxin in the footpad. Spontaneous bleeding or delayed rebleeding could not be documented in PAI-1-/- mice after partial amputation of the tail or of the caecum. Thus, disruption of the PAI-1 gene in mice appears to induce a mild hyperfibrinolytic state and a greater resistance to venous thrombosis but not to impair hemostasis. Images PMID:8254029

  11. Targeting BRCA1- and BRCA2-deficient cells with RAD52 small molecule inhibitors

    PubMed Central

    Huang, Fei; Goyal, Nadish; Sullivan, Katherine; Hanamshet, Kritika; Patel, Mikir; Mazina, Olga M.; Wang, Charles X.; An, W. Frank; Spoonamore, James; Metkar, Shailesh; Emmitte, Kyle A.; Cocklin, Simon; Skorski, Tomasz; Mazin, Alexander V.

    2016-01-01

    RAD52 is a member of the homologous recombination (HR) pathway that is important for maintenance of genome integrity. While single RAD52 mutations show no significant phenotype in mammals, their combination with mutations in genes that cause hereditary breast cancer and ovarian cancer like BRCA1, BRCA2, PALB2 and RAD51C are lethal. Consequently, RAD52 may represent an important target for cancer therapy. In vitro, RAD52 has ssDNA annealing and DNA strand exchange activities. Here, to identify small molecule inhibitors of RAD52 we screened a 372,903-compound library using a fluorescence-quenching assay for ssDNA annealing activity of RAD52. The obtained 70 putative inhibitors were further characterized using biochemical and cell-based assays. As a result, we identified compounds that specifically inhibit the biochemical activities of RAD52, suppress growth of BRCA1- and BRCA2-deficient cells and inhibit RAD52-dependent single-strand annealing (SSA) in human cells. We will use these compounds for development of novel cancer therapy and as a probe to study mechanisms of DNA repair. PMID:26873923

  12. Ischemia-reperfusion injury is attenuated in VAP-1-deficient mice and by VAP-1 inhibitors.

    PubMed

    Kiss, Jan; Jalkanen, Sirpa; Fülöp, Ferenc; Savunen, Timo; Salmi, Marko

    2008-11-01

    Neutrophils mediate the damage caused by ischemia-reperfusion both at the site of primary injury and in remote organs. Vascular adhesion protein-1 (VAP-1) is an ectoenzyme expressed on endothelial cells and it has been shown to regulate leukocyte extravasation. Here we show for the first time using VAP-1-deficient mice that VAP-1 plays a significant role in the intestinal damage and acute lung injury after ischemia-reperfusion. Separate inhibition of VAP-1 by small molecule enzyme inhibitors and a function-blocking monoclonal antibody in WT mice revealed that the catalytic activity of VAP-1 is responsible for its pro-inflammatory action. The use of transgenic humanized VAP-1 mice also showed that the enzyme inhibitors alleviate both the ischemia-reperfusion injury in the gut and neutrophil accumulation in the lungs. These data thus indicate that VAP-1 regulates the inflammatory response in ischemia-reperfusion injury and suggest that blockade of VAP-1 may have therapeutic value.

  13. High-fat diet enhances and plasminogen activator inhibitor-1 deficiency attenuates bone loss in mice with Lewis Lung carcinoma

    Technology Transfer Automated Retrieval System (TEKTRAN)

    This study determined the effects of a high-fat diet and plasminogen activator inhibitor-1 deficiency (PAI-1-/-) on bone structure in mice bearing Lewis lung carcinoma (LLC) in lungs. Reduction in bone volume fraction (BV/TV) by 22% and 21%, trabecular number (Tb.N) by 8% and 4% and bone mineral de...

  14. RING domain–deficient BRCA1 promotes PARP inhibitor and platinum resistance

    PubMed Central

    Wang, Yifan; Krais, John J.; Bernhardy, Andrea J.; Nicolas, Emmanuelle; Cai, Kathy Q.; Harrell, Maria I.; Kim, Hyoung H.; George, Erin; Swisher, Elizabeth M.; Simpkins, Fiona

    2016-01-01

    Patients with cancers that harbor breast cancer 1 (BRCA1) mutations initially respond well to platinum and poly(ADP-ribose) polymerase inhibitor (PARPi) therapy; however, resistance invariably arises in these patients and is a major clinical problem. The BRCA1185delAG allele is a common inherited mutation located close to the protein translation start site that is thought to produce a shortened, nonfunctional peptide. In this study, we investigated the mechanisms that lead to PARPi and platinum resistance in the SUM1315MO2 breast cancer cell line, which harbors a hemizygous BRCA1185delAG mutation. SUM1315MO2 cells were initially sensitive to PARPi and cisplatin but readily acquired resistance. PARPi- and cisplatin-resistant clones did not harbor secondary reversion mutations; rather, PARPi and platinum resistance required increased expression of a really interesting gene (RING) domain–deficient BRCA1 protein (Rdd-BRCA1). Initiation of translation occurred downstream of the frameshift mutation, probably at the BRCA1-Met-297 codon. In contrast to full-length BRCA1, Rdd-BRCA1 did not require BRCA1-associated RING domain 1 (BARD1) interaction for stability. Functionally, Rdd-BRCA1 formed irradiation-induced foci and supported RAD51 foci formation. Ectopic overexpression of Rdd-BRCA1 promoted partial PARPi and cisplatin resistance. Furthermore, Rdd-BRCA1 protein expression was detected in recurrent carcinomas from patients who carried germline BRCA1185delAG mutations. Taken together, these results indicate that RING-deficient BRCA1 proteins are hypomorphic and capable of contributing to PARPi and platinum resistance when expressed at high levels. PMID:27454289

  15. Selective resistance to the PARP inhibitor olaparib in a mouse model for BRCA1-deficient metaplastic breast cancer

    PubMed Central

    Henneman, Linda; van Miltenburg, Martine H.; Michalak, Ewa M.; Braumuller, Tanya M.; Jaspers, Janneke E.; Drenth, Anne Paulien; de Korte-Grimmerink, Renske; Gogola, Ewa; Szuhai, Karoly; Schlicker, Andreas; Bin Ali, Rahmen; Pritchard, Colin; Huijbers, Ivo J.; Berns, Anton; Rottenberg, Sven; Jonkers, Jos

    2015-01-01

    Metaplastic breast carcinoma (MBC) is a rare histological breast cancer subtype characterized by mesenchymal elements and poor clinical outcome. A large fraction of MBCs harbor defects in breast cancer 1 (BRCA1). As BRCA1 deficiency sensitizes tumors to DNA cross-linking agents and poly(ADP-ribose) polymerase (PARP) inhibitors, we sought to investigate the response of BRCA1-deficient MBCs to the PARP inhibitor olaparib. To this end, we established a genetically engineered mouse model (GEMM) for BRCA1-deficient MBC by introducing the MET proto-oncogene into a BRCA1-associated breast cancer model, using our novel female GEMM ES cell (ESC) pipeline. In contrast to carcinomas, BRCA1-deficient mouse carcinosarcomas resembling MBC show intrinsic resistance to olaparib caused by increased P-glycoprotein (Pgp) drug efflux transporter expression. Indeed, resistance could be circumvented by using another PARP inhibitor, AZD2461, which is a poor Pgp substrate. These preclinical findings suggest that patients with BRCA1-associated MBC may show poor response to olaparib and illustrate the value of GEMM-ESC models of human cancer for evaluation of novel therapeutics. PMID:26100884

  16. Selective resistance to the PARP inhibitor olaparib in a mouse model for BRCA1-deficient metaplastic breast cancer.

    PubMed

    Henneman, Linda; van Miltenburg, Martine H; Michalak, Ewa M; Braumuller, Tanya M; Jaspers, Janneke E; Drenth, Anne Paulien; de Korte-Grimmerink, Renske; Gogola, Ewa; Szuhai, Karoly; Schlicker, Andreas; Bin Ali, Rahmen; Pritchard, Colin; Huijbers, Ivo J; Berns, Anton; Rottenberg, Sven; Jonkers, Jos

    2015-07-07

    Metaplastic breast carcinoma (MBC) is a rare histological breast cancer subtype characterized by mesenchymal elements and poor clinical outcome. A large fraction of MBCs harbor defects in breast cancer 1 (BRCA1). As BRCA1 deficiency sensitizes tumors to DNA cross-linking agents and poly(ADP-ribose) polymerase (PARP) inhibitors, we sought to investigate the response of BRCA1-deficient MBCs to the PARP inhibitor olaparib. To this end, we established a genetically engineered mouse model (GEMM) for BRCA1-deficient MBC by introducing the MET proto-oncogene into a BRCA1-associated breast cancer model, using our novel female GEMM ES cell (ESC) pipeline. In contrast to carcinomas, BRCA1-deficient mouse carcinosarcomas resembling MBC show intrinsic resistance to olaparib caused by increased P-glycoprotein (Pgp) drug efflux transporter expression. Indeed, resistance could be circumvented by using another PARP inhibitor, AZD2461, which is a poor Pgp substrate. These preclinical findings suggest that patients with BRCA1-associated MBC may show poor response to olaparib and illustrate the value of GEMM-ESC models of human cancer for evaluation of novel therapeutics.

  17. Histone deacetylase inhibitor (HDACi) suberoylanilide hydroxamic acid (SAHA)-mediated correction of α1-antitrypsin deficiency.

    PubMed

    Bouchecareilh, Marion; Hutt, Darren M; Szajner, Patricia; Flotte, Terence R; Balch, William E

    2012-11-02

    α1-Antitrypsin (α1AT) deficiency (α1ATD) is a consequence of defective folding, trafficking, and secretion of α1AT in response to a defect in its interaction with the endoplasmic reticulum proteostasis machineries. The most common and severe form of α1ATD is caused by the Z-variant and is characterized by the accumulation of α1AT polymers in the endoplasmic reticulum of the liver leading to a severe reduction (>85%) of α1AT in the serum and its anti-protease activity in the lung. In this organ α1AT is critical for ensuring tissue integrity by inhibiting neutrophil elastase, a protease that degrades elastin. Given the limited therapeutic options in α1ATD, a more detailed understanding of the folding and trafficking biology governing α1AT biogenesis and its response to small molecule regulators is required. Herein we report the correction of Z-α1AT secretion in response to treatment with the histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA), acting in part through HDAC7 silencing and involving a calnexin-sensitive mechanism. SAHA-mediated correction restores Z-α1AT secretion and serpin activity to a level 50% that observed for wild-type α1AT. These data suggest that HDAC activity can influence Z-α1AT protein traffic and that SAHA may represent a potential therapeutic approach for α1ATD and other protein misfolding diseases.

  18. Glutaminase and poly(ADP-ribose) polymerase inhibitors suppress pyrimidine synthesis and VHL-deficient renal cancers.

    PubMed

    Okazaki, Arimichi; Gameiro, Paulo A; Christodoulou, Danos; Laviollette, Laura; Schneider, Meike; Chaves, Frances; Stemmer-Rachamimov, Anat; Yazinski, Stephanie A; Lee, Richard; Stephanopoulos, Gregory; Zou, Lee; Iliopoulos, Othon

    2017-03-27

    Many cancer-associated mutations that deregulate cellular metabolic responses to hypoxia also reprogram carbon metabolism to promote utilization of glutamine. In renal cell carcinoma (RCC), cells deficient in the von Hippel-Lindau (VHL) tumor suppressor gene use glutamine to generate citrate and lipids through reductive carboxylation (RC) of α-ketoglutarate (αKG). Glutamine can also generate aspartate, the carbon source for pyrimidine biosynthesis, and glutathione for redox balance. Here we have shown that VHL-/- RCC cells rely on RC-derived aspartate to maintain de novo pyrimidine biosynthesis. Glutaminase 1 (GLS1) inhibitors depleted pyrimidines and increased ROS in VHL-/- cells but not in VHL+/+ cells, which utilized glucose oxidation for glutamate and aspartate production. GLS1 inhibitor-induced nucleoside depletion and ROS enhancement led to DNA replication stress and activation of an intra-S phase checkpoint, and suppressed the growth of VHL-/- RCC cells. These effects were rescued by administration of glutamate, αKG, or nucleobases with N-acetylcysteine. Further, we observed that the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib synergizes with GLS1 inhibitors to suppress the growth of VHL-/- cells in vitro and in vivo. This work describes a mechanism that explains the sensitivity of RCC tumor growth to GLS1 inhibitors and supports the development of therapeutic strategies for targeting VHL-deficient RCC.

  19. Successful use of daily intravenous infusion of C1 esterase inhibitor concentrate in the treatment of a hereditary angioedema patient with ascites, hypovolemic shock, sepsis, renal and respiratory failure.

    PubMed

    Pham, Hoang; Santucci, Stephanie; Yang, William H

    2014-01-01

    Hereditary angioedema (HAE) is a rare autosomal dominant disease most commonly associated with defects in C1 esterase inhibitor (C1-INH). HAE manifests as recurrent episodes of edema in various body locations. Atypical symptoms, such as ascites, acute respiratory distress syndrome, and hypovolemic shock, have also been reported. Management of HAE conventionally involves the treatment of acute attacks, as well as short- and long-term prophylaxis. Since attacks can be triggered by several factors, including stress and physical trauma, prophylactic therapy is recommended for patients undergoing surgery. Human plasma-derived C1-INH (pdC1-INH) concentrate is indicated for the treatment of both acute HAE attacks and pre-procedure prevention of HAE episodes in patients undergoing medical, dental, or surgical procedures. We report the first case of a patient with HAE who experienced an abdominal attack precipitated by a retroperitoneal bleed while being converted from warfarin to heparin in preparation for surgery. Subsequently, the patient had a protracted course in hospital with other complications, which included hypovolemic shock, ascites, severe sepsis from nosocomial pneumonia, renal and respiratory failure. Despite intensive interventions, the patient remained in a critical state for months; however, after a trial of daily intravenous infusion of pdC1-INH concentrate (Berinert®, CSL Behring GmbH, Marburg, Germany), clinical status improved, particularly renal function. Therefore, pdC1-INH concentrate may be an effective treatment option to consider for critically-ill patients with HAE.

  20. Mechanistic Rationale to Target PTEN-Deficient Tumor Cells with Inhibitors of the DNA Damage Response Kinase ATM.

    PubMed

    McCabe, Nuala; Hanna, Conor; Walker, Steven M; Gonda, David; Li, Jie; Wikstrom, Katarina; Savage, Kienan I; Butterworth, Karl T; Chen, Clark; Harkin, D Paul; Prise, Kevin M; Kennedy, Richard D

    2015-06-01

    Ataxia telangiectasia mutated (ATM) is an important signaling molecule in the DNA damage response (DDR). ATM loss of function can produce a synthetic lethal phenotype in combination with tumor-associated mutations in FA/BRCA pathway components. In this study, we took an siRNA screening strategy to identify other tumor suppressors that, when inhibited, similarly sensitized cells to ATM inhibition. In this manner, we determined that PTEN and ATM were synthetically lethal when jointly inhibited. PTEN-deficient cells exhibited elevated levels of reactive oxygen species, increased endogenous DNA damage, and constitutive ATM activation. ATM inhibition caused catastrophic DNA damage, mitotic cell cycle arrest, and apoptosis specifically in PTEN-deficient cells in comparison with wild-type cells. Antioxidants abrogated the increase in DNA damage and ATM activation in PTEN-deficient cells, suggesting a requirement for oxidative DNA damage in the mechanism of cell death. Lastly, the ATM inhibitor KU-60019 was specifically toxic to PTEN mutant cancer cells in tumor xenografts and reversible by reintroduction of wild-type PTEN. Together, our results offer a mechanistic rationale for clinical evaluation of ATM inhibitors in PTEN-deficient tumors.

  1. The Proton Pump Inhibitor Lansoprazole Improves the Skeletal Phenotype in Dystrophin Deficient mdx Mice

    PubMed Central

    Sali, Arpana; Many, Gina M.; Gordish-Dressman, Heather; van der Meulen, Jack H.; Phadke, Aditi; Spurney, Christopher F.; Cnaan, Avital; Hoffman, Eric P.; Nagaraju, Kanneboyina

    2013-01-01

    Background In Duchenne muscular dystrophy (DMD), loss of the membrane stabilizing protein dystrophin results in myofiber damage. Microinjury to dystrophic myofibers also causes secondary imbalances in sarcolemmic ion permeability and resting membrane potential, which modifies excitation-contraction coupling and increases proinflammatory/apoptotic signaling cascades. Although glucocorticoids remain the standard of care for the treatment of DMD, there is a need to investigate the efficacy of other pharmacological agents targeting the involvement of imbalances in ion flux on dystrophic pathology. Methodology/Principal Findings We designed a preclinical trial to investigate the effects of lansoprazole (LANZO) administration, a proton pump inhibitor, on the dystrophic muscle phenotype in dystrophin deficient (mdx) mice. Eight to ten week-old female mice were assigned to one of four treatment groups (n = 12 per group): (1) vehicle control; (2) 5 mg/kg/day LANZO; (3) 5 mg/kg/day prednisolone; and (4) combined treatment of 5 mg/kg/day prednisolone (PRED) and 5 mg/kg/day LANZO. Treatment was administered orally 5 d/wk for 3 months. At the end of the study, behavioral (Digiscan) and functional outcomes (grip strength and Rotarod) were assessed prior to sacrifice. After sacrifice, body, tissue and organ masses, muscle histology, in vitro muscle force, and creatine kinase levels were measured. Mice in the combined treatment groups displayed significant reductions in the number of degenerating muscle fibers and number of inflammatory foci per muscle field relative to vehicle control. Additionally, mice in the combined treatment group displayed less of a decline in normalized forelimb and hindlimb grip strength and declines in in vitro EDL force after repeated eccentric contractions. Conclusions/Significance Together our findings suggest that combined treatment of LANZO and prednisolone attenuates some components of dystrophic pathology in mdx mice. Our findings warrant

  2. Deficiency of cyclin-dependent kinase inhibitors p21{sup Cip1} and p27{sup Kip1} accelerates atherogenesis in apolipoprotein E-deficient mice

    SciTech Connect

    Akyuerek, Levent M.; Boehm, Manfred; Olive, Michelle; Zhou, Alex-Xianghua; San, Hong; Nabel, Elizabeth G.

    2010-05-28

    Cyclin-dependent kinase inhibitors, p21{sup Cip1} and p27{sup Kip1}, are upregulated during vascular cell proliferation and negatively regulate growth of vascular cells. We hypothesized that absence of either p21{sup Cip1} or p27{sup Kip1} in apolipoprotein E (apoE)-deficiency may increase atherosclerotic plaque formation. Compared to apoE{sup -/-} aortae, both apoE{sup -/-}/p21{sup -/-} and apoE{sup -/-}/p27{sup -/-} aortae exhibited significantly more atherosclerotic plaque following a high-cholesterol regimen. This increase was particularly observed in the abdominal aortic regions. Deficiency of p27{sup Kip1} accelerated plaque formation significantly more than p21{sup -/-} in apoE{sup -/-} mice. This increased plaque formation was in parallel with increased intima/media area ratios. Deficiency of p21{sup Cip1} and p27{sup Kip1} accelerates atherogenesis in apoE{sup -/-} mice. These findings have significant implications for our understanding of the molecular basis of atherosclerosis associated with excessive proliferation of vascular cells.

  3. Effects of a high-fat diet on spontaneous metastasis of Lewis lung carcinoma in plasminogen activator inhibitor-1 deficient and wild-type mice

    Technology Transfer Automated Retrieval System (TEKTRAN)

    We investigated the effects of plasminogen activator inhibitor-1 (PAI-1) deficiency on spontaneous metastasis of Lewis lung carcinoma (LLC) in PAI-1 deficient (PAI-1-/-) and wildtype mice (C57BL/6J background) fed the AIN93G diet or that diet modified with 45% calories from fat. The high-fat diet i...

  4. Alpha-1 proteinase inhibitors for the treatment of alpha-1 antitrypsin deficiency: safety, tolerability, and patient outcomes

    PubMed Central

    Chotirmall, Sanjay H; Al-Alawi, Mazen; McEnery, Thomas; McElvaney, Noel G

    2015-01-01

    Alpha-1 antitrypsin (AAT) deficiency remains an underrecognized genetic disease with predominantly pulmonary and hepatic manifestations. AAT is derived primarily from hepatocytes; however, macrophages and neutrophils are secondary sources. As the natural physiological inhibitor of several proteases, most importantly neutrophil elastase (NE), it plays a key role in maintaining pulmonary protease–antiprotease balance. In deficient states, unrestrained NE activity promotes damage to the lung matrix, causing structural defects and impairing host defenses. The commonest form of AAT deficiency results in a mutated Z AAT that is abnormally folded, polymerized, and aggregated in the liver. Consequently, systemic levels are lower, resulting in diminished pulmonary concentrations. Hepatic disease occurs due to liver aggregation of the protein, while lung destruction ensues from unopposed protease-mediated damage. In this review, we will discuss AAT deficiency, its clinical manifestations, and augmentation therapy. We will address the safety and tolerability profiles of AAT replacement in the context of patient outcomes and cost-effectiveness and outline future directions for work in this field. PMID:25673994

  5. Enhancement of radiation response in p53-deficient cancer cells by the Aurora-B kinase inhibitor AZD1152.

    PubMed

    Tao, Y; Zhang, P; Girdler, F; Frascogna, V; Castedo, M; Bourhis, J; Kroemer, G; Deutsch, E

    2008-05-22

    Overexpression of the Aurora-B kinase correlates with oncogenic transformation and poor prognosis. We evaluated the effects of the bona fide Aurora-B kinase inhibitor AZD1152 on tumor responses to ionizing radiation (IR). When p53(wt) HCT116 and A549 cells were pretreated with AZD1152-HQPA prior to IR, additive effects were observed. Interestingly, more pronounced tumoricidal effects were observed in p53-deficient HCT116 and HT29 cells, as well as A549 cells treated with the p53 inhibitor cyclic pifithrin-alpha. In vivo studies on xenografted mice confirmed enhanced tumor growth delay after the combination of IR plus AZD1152-IR as compared to IR alone. Again, this effect was more pronounced with p53-/- HCT116 and p53-mutant xenografts. The AZD1152-mediated radiosensitization was mimicked by knockdown of Aurora-B with a short interference RNA or by inhibition of Aurora-B by transfection with an inducible kinase-dead Aurora-B. The radiosensitizing effect of AZD1152 was lost in CHK2-/- and 14-3-3-/- HCT116 cells. Altogether, these data indicate that AZD1152 can radiosensitize tumor cell lines in vitro and in vivo, the fact that these effects are exacerbated in p53-deficient cancer cells is of potential interest for further clinical development.

  6. THE ENZYMATIC NATURE OF C'1r

    PubMed Central

    Naff, George B.; Ratnoff, Oscar D.

    1968-01-01

    Human C'1, a macromolecular complex composed of three subunits, is the zymogen for at least two distinct enzymes. Preparations of one subunit, C'1r, functioned as a protease which converted another subunit, C'1s, to C'1 esterase. The conversion of C'1s to C'1 esterase by C'1r was blocked by Liquoid, phenyl methylsulfonyl fluoride, and calcium ions, but not by soybean trypsin inhibitor, hirudin, or heparin. Preparations of C'1r also possessed two additional functions, i.e., the ability to hydrolyze certain synthetic amino acid esters and to participate in immune hemolysis. Evidence was presented which indicates that these three functions are properties of a single entity, C'1r, but not of the same portion of its molecular structure. These observations suggest that C'1r has at least two active sites, one for its reaction with C'1q, an additional subunit of C'1, and one for its reaction with C'1s; together, the three subcomponents, C'1q, C'1r, and C'1s, form a single functional unit, the first component of complement. PMID:5675434

  7. Polymorphisms in STAT4, PTPN2, PSORS1C1 and TRAF3IP2 Genes Are Associated with the Response to TNF Inhibitors in Patients with Rheumatoid Arthritis

    PubMed Central

    Politi, Cristina; Triggianese, Paola; Rufini, Sara; Kroegler, Barbara; Perricone, Carlo; Latini, Andrea; Novelli, Giuseppe; Borgiani, Paola; Perricone, Roberto

    2017-01-01

    Objective Rheumatoid Arthritis (RA) is a progressive autoimmune disease characterized by chronic joint inflammation and structural damage. Remission or at least low disease activity (LDA) represent potentially desirable goals of RA treatment. Single nucleotide polymorphisms (SNPs) in several genes might be useful for prediction of response to therapy. We aimed at exploring 4 SNPs in candidate genes (STAT4, PTPN2, PSORS1C1 and TRAF3IP2) in order to investigate their potential role in the response to therapy with tumor necrosis factor inhibitors (TNF-i) in RA patients. Methods In 171 RA patients we investigated the following SNPs: rs7574865 (STAT4), rs2233945 (PSORS1C1), rs7234029 (PTPN2) and rs33980500 (TRAF3IP2). Remission, LDA, and EULAR response were registered at 6 months and 2 years after initiation of first line TNF-i [Adalimumab (ADA) and Etanercept (ETN)]. Results STAT4 variant allele was associated with the absence of a good/moderate EULAR response at 2 years of treatment in the whole RA group and in ETN treated patients. The PTPN2 SNP was associated with no good/moderate EULAR response at 6 months in ADA treated patients. Patients carrying PSORS1C1 variant allele did not reach LDA at 6 months in both the whole RA group and ETN treated patients. TRAF3IP2 variant allele was associated with the lack of LDA and remission achievement at 6 months in all RA cohort while an association with no EULAR response at 2 years of treatment occurred only in ETN treated patients. Conclusions For the first time, we reported that SNPs in STAT4, PTPN2, PSORS1C1, and TRAF3IP2 are associated with response to TNF-i treatment in RA patients; however, these findings should be validated in a larger population. PMID:28107378

  8. Induction of an inhibitor antibody to factor XI in a patient with severe inherited factor XI deficiency by Rh immune globulin.

    PubMed

    Zucker, Michal; Zivelin, Ariella; Teitel, Jerome; Seligsohn, Uri

    2008-02-01

    In this paper, we report an inhibitor antibody to factor XI (FXI) in a woman with severe inherited FXI deficiency, induced by FXI present in an Rh immune globulin preparation. The patient is homozygous for the Glu117Stop mutation, associated with a FXI level of less than 1 U/dL. Unlike all previously described patients with severe FXI deficiency and an inhibitor, the patient had never been exposed to blood products. Following 3 injections of Rh immune globulin during pregnancy, she developed an inhibitor to FXI (8 Bethesda units) that was shown to bind specifically to FXI and inhibit factor IX cleavage by purified FXIa. The administered Rh immune globulin and 2 other similar products were shown to contain FXI. Clinicians should be aware of the potential for immunization of severely FXI-deficient patients by FXI present in Rh immune globulin preparations.

  9. Desensitization and immune tolerance induction in children with severe factor IX deficiency; inhibitors and adverse reactions to replacement therapy: a case-report and literature review.

    PubMed

    Bon, Andrea; Morfini, Massimo; Dini, Alessandro; Mori, Francesca; Barni, Simona; Gianluca, Sottilotta; de Martino, Maurizio; Novembre, Elio

    2015-02-19

    Hemophilia B is a rare X-linked recessive disorder with plasma factor IX (FIX) deficiency. 1-3% of patients treated with exogenous FIX-containing products develop inhibitors (i.e. polyclonal high affinity immunoglobulins) that neutralize the procoagulant activity of a specific coagulation factor. Although the incidence of inhibitors in hemophilia B patients is low, most are "high titer" and frequently associated with the development of severe allergic or anaphylactic reactions. Immune tolerance induction as a strategy for inhibitor eradication was first described in 1984. Unfortunately, the overall reported success of immune tolerance induction in FIX deficiency with inhibitors is approximately 25-40%.We report the case of a 2-year-old boy with hemophilia B severe FIX deficiency (<1%), inhibitor antibodies to FIX development, and a history of adverse reactions to FIX infusions, who underwent a successful desensitization and immune tolerance induction with a daily FIX infusion. With this regimen the inhibitor titer decreased with effective bleeding prevention.

  10. Nagashima-type palmoplantar keratosis: a common Asian type caused by SERPINB7 protease inhibitor deficiency.

    PubMed

    Kubo, Akiharu

    2014-08-01

    Nagashima-type palmoplantar keratosis (NPPK) is an autosomal recessive diffuse non-epidermolytic palmoplantar keratosis caused by mutations in SERPINB7, a member of the serine protease inhibitor superfamily. Genetic studies suggest that NPPK is the most common palmoplantar keratosis in Japan, and probably Asia, but one that is extremely rare in Western countries. In this issue, Yin et al. report a founder effect of a SERPINB7 mutation in Chinese populations.

  11. Novel Mechanisms of PARP Inhibitor Resistance in BRCA1-Deficient Breast Cancers

    DTIC Science & Technology

    2014-12-01

    Lorusso, n.d.; Tutt et al., 2010). BRCA1 is essential for error-free repair of DNA double strand breaks via homologous recombination (HR...for DNA damage and Rad51 as a marker of HR.   14   Figure 4: ATR inhibitor (ATRi) selectively inhibits homologous recombination ...Gudmundsdottir & Ashworth, 2006), while PARPs are thought to primarily function in repair of single stranded DNA breaks especially through activation of

  12. Effects of Pharmacological Inhibition and Genetic Deficiency of Plasminogen Activator Inhibitor-1 in Radiation-Induced Intestinal Injury

    SciTech Connect

    Abderrahmani, Rym; Francois, Agnes; Buard, Valerie; Benderitter, Marc; Sabourin, Jean-Christophe; Crandall, David L.; Milliat, Fabien

    2009-07-01

    Purpose: To investigate effects of plasminogen activator inhibitor 1 (PAI-1) genetic deficiency and pharmacological PAI-1 inhibition with PAI-039 in a mouse model of radiation-induced enteropathy. Methods and Materials: Wild-type (Wt) and PAI-1{sup -/-} knockout mice received a single dose of 19 Gy to an exteriorized localized intestinal segment. Sham and irradiated Wt mice were treated orally with 1 mg/g of PAI-039. Histological modifications were quantified using a radiation injury score. Moreover, intestinal gene expression was monitored by real-time PCR. Results: At 3 days after irradiation, PAI-039 abolished the radiation-induced increase in the plasma active form of PAI-1 and limited the radiation-induced gene expression of transforming growth factor {beta}1 (TGF-{beta}1), CTGF, PAI-1, and COL1A2. Moreover, PAI-039 conferred temporary protection against early lethality. PAI-039 treatment limited the radiation-induced increase of CTGF and PAI-1 at 2 weeks after irradiation but had no effect at 6 weeks. Radiation injuries were less severe in PAI-1{sup -/-} mice than in Wt mice, and despite the beneficial effect, 3 days after irradiation, PAI-039 had no effects on microscopic radiation injuries compared to untreated Wt mice. Conclusions: A genetic deficiency of PAI-1 is associated with amelioration of late radiation enteropathy. Pharmacological inhibition of PAI-1 by PAI-039 positively impacts the early, acute phase increase in plasma PAI-1 and the associated radiation-induced gene expression of inflammatory/extracellular matrix proteins. Since PAI-039 has been shown to inhibit the active form of PAI-1, as opposed to the complete loss of PAI-1 in the knockout animals, these data suggest that a PAI-1 inhibitor could be beneficial in treating radiation-induced tissue injury in acute settings where PAI-1 is elevated.

  13. AZD6738, a novel oral inhibitor of ATR, induces synthetic lethality with ATM-deficiency in gastric cancer cells.

    PubMed

    Min, Ahrum; Im, Seock-Ah; Jang, Hyemin; Kim, Seongyeong; Lee, Miso; Kim, Debora Keunyoung; Yang, Yaewon; Kim, Hee-Jun; Lee, Kyung-Hun; Kim, Jin Won; Kim, Tae-Yong; Oh, Do-Youn; Brown, Jeff; Lau, Alan; O Connor, Mark J; Bang, Yung-Jue

    2017-01-30

    Ataxia telangiectasia and Rad3-related (ATR) can be considered an attractive target for cancer treatment due to its deleterious effect on cancer cells harboring a homologous recombination defect (HRD). The aim of this study was to investigate the potential use of the ATR inhibitor, AZD6738, to treat gastric cancer. In SNU-601 cells with dysfunctional ATM, AZD6738 treatment led to an accumulation of DNA damage due to dysfunctional RAD51 foci formation, S phase arrest, and caspase 3-dependent apoptosis. In contrast, SNU-484 cells with functional ATM were not sensitive to AZD6738. Inhibition of ATM in SNU-484 cells enhanced AZD6738 sensitivity to a level comparable with that observed in SNU-601 cells, showing that activation of the ATM-Chk2 signaling pathway attenuates AZD6738 sensitivity. In addition, decreased HDAC1 expression was found to be associated with ATM inactivation in SNU-601 cells, demonstrating the interaction between HDAC1 and ATM can affect sensitivity to AZD6738. Furthermore, in an in vivo tumor xenograft mouse model, AZD6738 significantly suppressed tumor growth and increased apoptosis. These findings suggest synthetic lethality between ATR inhibition and ATM-deficiency in gastric cancer cells. Further clinical studies on the interaction between AZD 6738 and ATM-deficiency are warranted to develop novel treatment strategies for gastric cancer.

  14. Successful allogeneic hematopoietic stem cell transplantation in a boy with X-linked inhibitor of apoptosis deficiency presenting with hemophagocytic lymphohistiocytosis: A case report

    PubMed Central

    Jiang, Ming-Yan; Guo, Xia; Sun, Shu-Wen; Li, Qiang; Zhu, Yi-Ping

    2016-01-01

    X-linked inhibitor of apoptosis (XIAP) deficiency, also known as X-linked lymphoproliferative syndrome type 2 (XLP2), is a rare inherited primary immunodeficiency resulting from the XIAP (also known as BIRC4) mutation. XIAP deficiency is mainly associated with familial hemophagocytic lymphohistiocytosis (HLH) phenotypes, and genetic testing is crucial in diagnosing this syndrome. Allogeneic hematopoietic stem cell transplantation (HSCT) is currently the only successful strategy for the treatment of this disease; however, a limited number of studies has been published concerning the outcomes of allogeneic HSCT in patients with XIAP deficiency. The present study reported a successful allogeneic HSCT performed to treat XIAP deficiency in a Chinese boy presenting with HLH. Polymerase chain reaction and DNA sequencing were performed to confirm the diagnosis of XIAP deficiency, and allogeneic HSCT was performed. Genetic tests revealed a two-nucleotide deletion (c.1021_1022delAA) in the patient, which was inherited from his mother, and resulted in frameshift mutation and premature stop codon (p.N341fsX348); this is considered to be a disease-causing mutation. The XIAP deficiency patient underwent allogeneic HSCT, receiving busulfan-containing reduced intensity myeloablative conditioning regimen, with a good intermediate follow-up result obtained. Therefore, genetic testing is essential to confirm the diagnosis of XIAP deficiency and detect the carrier of mutation. The present case study may promote the investigation of allogeneic HSCT in patients with XIAP deficiency. PMID:27602064

  15. Calpain 1 inhibitor BDA-410 ameliorates α-klotho-deficiency phenotypes resembling human aging-related syndromes

    PubMed Central

    Nabeshima, Yoko; Washida, Miwa; Tamura, Masaru; Maeno, Akiteru; Ohnishi, Mutsuko; Shiroishi, Toshihiko; Imura, Akihiro; Razzaque, M. Shawkat; Nabeshima, Yo-ichi

    2014-01-01

    Taking good care of elderly is a major challenge of our society, and thus identification of potential drug targets to reduce age-associated disease burden is desirable. α-klotho-/- (α-kl) is a short-lived mouse model that displays multiple phenotypes resembling human aging-related syndromes. Such ageing phenotype of α-kl-/- mice is associated with activation of a proteolytic enzyme, Calpain-1. We hypothesized that uncontrolled activation of calpain-1 might be causing age-related phenotypes in α-kl-deficient mice. We found that daily administration of BDA-410, a calpain-1 inhibitor, strikingly ameliorated multiple aging-related phenotypes. Treated mice showed recovery of reproductive ability, increased body weight, reduced organ atrophy, and suppression of ectopic calcifications, bone mineral density reduction, pulmonary emphysema and senile atrophy of skin. We also observed ectopic expression of FGF23 in calcified arteries of α-kl-/- mice, which might account for the clinically observed association of increased FGF23 level with increased risk of cardiovascular mortality. These findings allow us to propose that modulation of calpain-1 activity is a potential therapeutic option for delaying age-associated organ pathology, particularly caused by the dysregulation of mineral ion homeostasis. PMID:25080854

  16. The farnesyltransferase inhibitors tipifarnib and lonafarnib inhibit cytokines secretion in a cellular model of mevalonate kinase deficiency.

    PubMed

    Marcuzzi, Annalisa; De Leo, Luigina; Decorti, Giuliana; Crovella, Sergio; Tommasini, Alberto; Pontillo, Alessandra

    2011-07-01

    The shortage of geranylgeranyl-pyrophosphate (GGPP) was associated to an increased IL-1β release in the autoinflammatory syndrome mevalonate kinase deficiency (MKD), a rare inherited disease that has no specific therapy. Farnesyltransferase inhibitors (FTIs) act at the end of mevalonate pathway. Two FTIs, tipifarnib (Tip) and lonafarnib (Lon), were therefore evaluated as possible therapeutical choices for the treatment of MKD. FTIs could lead to a redirection of the limited available number of mevalonate intermediates preferentially to GGPP synthesis, eventually preventing the uncontrolled inflammatory response. The effect of Tip and Lon on intracellular cholesterol level (ICL) and on proinflammatory cytokines secretion was evaluated in a cellular model of MKD, chemically obtained treating RAW 264.7 cells with lovastatin (Lova) and alendronate (Ald). The combination of FTIs with the isoprenoid geraniol (GOH) was also tested both in this model and in monocytes isolated from MKD patients. Tip and Lon proved to revert the ICL lowering and to significantly reduce the lipopolysaccharide-induced cytokines secretion in Ald-Lova -RAW 264.7 cells. This anti-inflammatory effect was amplified combining the use of GOH with FTIs. The effect of GOH and Tip was successfully replicated in MKD patients' monocytes. Tip and Lon showed a dramatic anti-inflammatory effect in monocytes where mevalonate pathway was chemically or genetically impaired.

  17. SLE and C1q: A quantitative ELISA for determining C1q levels in serum

    PubMed Central

    Dillon, Skyler P.; D’Souza, Anil; Kurien, Biji T.; Scofield, R. Hal

    2010-01-01

    C1q is of interest in SLE research due to deficiencies in its activity being associated with the disease. Current published protocols for measuring C1q vary greatly in their results and ease of reproducibility. Due to this, average C1q concentrations have been reported between 56 and 276 µg/ml in non-SLE serum. We present an improved method for quantifying C1q concentrations that employs a sandwich ELISA. This method has improved precision, cost efficiency, up-scaling, reproducibility, and uses significantly lesser volumes of serum sample when compared to RID and other methods for quantifying C1q. We report an average concentration of 113±40 µg/ml for C1q in non-SLE serum. The assay designed here will be useful in the high-throughput measurement of serum C1q in SLE cases. PMID:19370710

  18. Discovery of methyl 4'-methyl-5-(7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)-[1,1'-biphenyl]-3-carboxylate, an improved small-molecule inhibitor of c-Myc-max dimerization.

    PubMed

    Chauhan, Jay; Wang, Huabo; Yap, Jeremy L; Sabato, Philip E; Hu, Angela; Prochownik, Edward V; Fletcher, Steven

    2014-10-01

    c-Myc is a basic helix-loop-helix-leucine zipper (bHLH-ZIP) transcription factor that is responsible for the transcription of a wide range of target genes involved in many cancer-related cellular processes. Over-expression of c-Myc has been observed in, and directly contributes to, a variety of human cancers including those of the hematopoietic system, lung, prostate and colon. To become transcriptionally active, c-Myc must first dimerize with Myc-associated factor X (Max) via its own bHLH-ZIP domain. A proven strategy towards the inhibition of c-Myc oncogenic activity is to interfere with the structural integrity of the c-Myc-Max heterodimer. The small molecule 10074-G5 is an inhibitor of c-Myc-Max dimerization (IC50 =146 μM) that operates by binding and stabilizing c-Myc in its monomeric form. We have identified a congener of 10074-G5, termed 3jc48-3 (methyl 4'-methyl-5-(7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)-[1,1'-biphenyl]-3-carboxylate), that is about five times as potent (IC50 =34 μM) at inhibiting c-Myc-Max dimerization as the parent compound. 3jc48-3 exhibited an approximate twofold selectivity for c-Myc-Max heterodimers over Max-Max homodimers, suggesting that its mode of action is through binding c-Myc. 3jc48-3 inhibited the proliferation of c-Myc-over-expressing HL60 and Daudi cells with single-digit micromolar IC50 values by causing growth arrest at the G0 /G1 phase. Co-immunoprecipitation studies indicated that 3jc48-3 inhibits c-Myc-Max dimerization in cells, which was further substantiated by the specific silencing of a c-Myc-driven luciferase reporter gene. Finally, 3jc48-3's intracellular half-life was >17 h. Collectively, these data demonstrate 3jc48-3 to be one of the most potent, cellularly active and stable c-Myc inhibitors reported to date.

  19. E7449: A dual inhibitor of PARP1/2 and tankyrase1/2 inhibits growth of DNA repair deficient tumors and antagonizes Wnt signaling

    PubMed Central

    Wu, Jiayi; Chang, Paul; Kolber-Simonds, Donna; Ackermann, Karen; Twine, Natalie C.; Shie, Jue-Lon; Miu, Jingzang Tao; Huang, Kuan-Chun; Moniz, George A.; Nomoto, Kenichi

    2015-01-01

    Inhibition of Poly(ADP-ribose) Polymerase1 (PARP1) impairs DNA damage repair, and early generation PARP1/2 inhibitors (olaparib, niraparib, etc.) have demonstrated clinical proof of concept for cancer treatment. Here, we describe the development of the novel PARP inhibitor E7449, a potent PARP1/2 inhibitor that also inhibits PARP5a/5b, otherwise known as tankyrase1 and 2 (TNKS1 and 2), important regulators of canonical Wnt/β-catenin signaling. E7449 inhibits PARP enzymatic activity and additionally traps PARP1 onto damaged DNA; a mechanism previously shown to augment cytotoxicity. Cells deficient in DNA repair pathways beyond homologous recombination were sensitive to E7449 treatment. Chemotherapy was potentiated by E7449 and single agent had significant antitumor activity in BRCA-deficient xenografts. Additionally, E7449 inhibited Wnt/β-catenin signaling in colon cancer cell lines, likely through TNKS inhibition. Consistent with this possibility, E7449 stabilized axin and TNKS proteins resulting in β-catenin de-stabilization and significantly altered expression of Wnt target genes. Notably, hair growth mediated by Wnt signaling was inhibited by E7449. A pharmacodynamic effect of E7449 on Wnt target genes was observed in tumors, although E7449 lacked single agent antitumor activity in vivo, a finding typical for selective TNKS inhibitors. E7449 antitumor activity was increased through combination with MEK inhibition. Particularly noteworthy was the lack of toxicity, most significantly the lack of intestinal toxicity reported for other TNKS inhibitors. E7449 represents a novel dual PARP1/2 and TNKS1/2 inhibitor which has the advantage of targeting Wnt/β-catenin signaling addicted tumors. E7449 is currently in early clinical development. PMID:26513298

  20. Small-molecule inhibitors identify the RAD52-ssDNA interaction as critical for recovery from replication stress and for survival of BRCA2 deficient cells

    PubMed Central

    Hengel, Sarah R; Malacaria, Eva; Folly da Silva Constantino, Laura; Bain, Fletcher E; Diaz, Andrea; Koch, Brandon G; Yu, Liping; Wu, Meng; Pichierri, Pietro; Spies, M Ashley; Spies, Maria

    2016-01-01

    The DNA repair protein RAD52 is an emerging therapeutic target of high importance for BRCA-deficient tumors. Depletion of RAD52 is synthetically lethal with defects in tumor suppressors BRCA1, BRCA2 and PALB2. RAD52 also participates in the recovery of the stalled replication forks. Anticipating that ssDNA binding activity underlies the RAD52 cellular functions, we carried out a high throughput screening campaign to identify compounds that disrupt the RAD52-ssDNA interaction. Lead compounds were confirmed as RAD52 inhibitors in biochemical assays. Computational analysis predicted that these inhibitors bind within the ssDNA-binding groove of the RAD52 oligomeric ring. The nature of the inhibitor-RAD52 complex was validated through an in silico screening campaign, culminating in the discovery of an additional RAD52 inhibitor. Cellular studies with our inhibitors showed that the RAD52-ssDNA interaction enables its function at stalled replication forks, and that the inhibition of RAD52-ssDNA binding acts additively with BRCA2 or MUS81 depletion in cell killing. DOI: http://dx.doi.org/10.7554/eLife.14740.001 PMID:27434671

  1. A Nampt inhibitor FK866 mimics vitamin B3 deficiency by causing senescence of human fibroblastic Hs68 cells via attenuation of NAD(+)-SIRT1 signaling.

    PubMed

    Song, Tuzz-Ying; Yeh, Shu-Lan; Hu, Miao-Lin; Chen, Mei-Yau; Yang, Nae-Cherng

    2015-12-01

    Vitamin B3 (niacin) deficiency can cause pellagra with symptoms of dermatitis, diarrhea and dementia. However, it is unclear whether the vitamin B3 deficiency causes human aging. FK866 (a Nampt inhibitor) can reduce intracellular NAD(+) level and induce senescence of human Hs68 cells. However, the mechanisms underlying FK866-induced senescence of Hs68 cells are unclear. In this study, we used FK866 to mimic the effects of vitamin B3 deficiency to reduce the NAD(+) level and investigated the mechanisms of FK866-induced senescence of Hs68 cells. We hypothesized that FK866 induced the senescence of Hs68 cells via an attenuation of NAD(+)-silent information regulator T1 (SIRT1) signaling. We found that FK866 induced cell senescence and diminished cellular NAD(+) levels and SIRT1 activity (detected by acetylation of p53), and these effects were dramatically antagonized by co-treatment with nicotinic acid, nicotinamide, or NAD(+). In contrast, the protein expression of SIRT1, AMP-activated protein kinase, mammalian target of rapamycin, and nicotinamide phosphoribosyltransferase (Nampt) was not affected by FK866. In addition, the role of GSH in the FK866-induced cells senescence may be limited, as N-acetylcysteine did not antagonize FK866-induced cell senescence. These results suggest that FK866 induces cell senescence via attenuation of NAD(+)-SIRT1 signaling. The effects of vitamin B3 deficiency on human aging warrant further investigation.

  2. Proteasome inhibitor (MG132) rescues Nav1.5 protein content and the cardiac sodium current in dystrophin-deficient mdx (5cv) mice.

    PubMed

    Rougier, Jean-Sébastien; Gavillet, Bruno; Abriel, Hugues

    2013-01-01

    The cardiac voltage-gated sodium channel, Nav1.5, plays a central role in cardiac excitability and impulse propagation and associates with the dystrophin multiprotein complex at the lateral membrane of cardiomyocytes. It was previously shown that Nav1.5 protein content and the sodium current (l Na) were both decreased in cardiomyocytes of dystrophin-deficient mdx (5cv) mice. In this study, wild-type and mdx (5cv) mice were treated for 7 days with the proteasome inhibitor MG132 (10 μg/Kg/24 h) using implanted osmotic mini pumps. MG132 rescued both the total amount of Nav1.5 protein and l Na but, unlike in previous studies, de novo expression of dystrophin was not observed in skeletal or cardiac muscle. This study suggests that the reduced expression of Nav1.5 in dystrophin-deficient cells is dependent on proteasomal degradation.

  3. mTOR inhibitors radiosensitize PTEN-deficient non-small-cell lung cancer cells harboring an EGFR activating mutation by inducing autophagy.

    PubMed

    Kim, Eun Ju; Jeong, Jae-Hoon; Bae, Sangwoo; Kang, Seongman; Kim, Cheol Hyeon; Lim, Young-Bin

    2013-06-01

    Clinical resistance to gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), in patients with lung cancer has been linked to acquisition of the T790M resistance mutation in activated EGFR or amplification of MET. Phosphatase and tensin homolog (PTEN) loss has been recently reported as a gefitinib resistance mechanism in lung cancer. The aim of this study was to evaluate the efficacy of radiotherapy in non-small-cell lung cancer (NSCLC) with acquired gefitinib resistance caused by PTEN deficiency to suggest radiotherapy as an alternative to EGFR TKIs. PTEN deficient-mediated gefitinib resistance was generated in HCC827 cells, an EGFR TKI sensitive NSCLC cell line, by PTEN knockdown with a lentiviral vector expressing short hairpin RNA-targeting PTEN. The impact of PTEN knockdown on sensitivity to radiation in the presence or absence of PTEN downstream signaling inhibitors was investigated. PTEN knockdown conferred acquired resistance not only to gefitinib but also to radiation on HCC827 cells. mTOR inhibitors alone failed to reduce HCC827 cell viability, regardless of PTEN expression, but ameliorated PTEN knockdown-induced radioresistance. PTEN knockdown-mediated radioresistance was accompanied by repression of radiation-induced cytotoxic autophagy, and treatment with mTOR inhibitors released the repression of cytotoxic autophagy to overcome PTEN knockdown-induced radioresistance in HCC827 cells. These results suggest that inhibiting mTOR signaling could be an effective strategy to radiosensitize NSCLC harboring the EGFR activating mutation that acquires resistance to both TKIs and radiotherapy due to PTEN loss or inactivation mutations.

  4. Discovery and optimization of new benzimidazole- and benzoxazole-pyrimidone selective PI3Kβ inhibitors for the treatment of phosphatase and TENsin homologue (PTEN)-deficient cancers.

    PubMed

    Certal, Victor; Halley, Frank; Virone-Oddos, Angela; Delorme, Cécile; Karlsson, Andreas; Rak, Alexey; Thompson, Fabienne; Filoche-Rommé, Bruno; El-Ahmad, Youssef; Carry, Jean-Christophe; Abecassis, Pierre-Yves; Lejeune, Pascale; Vincent, Loic; Bonnevaux, Hélène; Nicolas, Jean-Paul; Bertrand, Thomas; Marquette, Jean-Pierre; Michot, Nadine; Benard, Tsiala; Below, Peter; Vade, Isabelle; Chatreaux, Fabienne; Lebourg, Gilles; Pilorge, Fabienne; Angouillant-Boniface, Odile; Louboutin, Audrey; Lengauer, Christoph; Schio, Laurent

    2012-05-24

    Most of the phosphoinositide-3 kinase (PI3K) kinase inhibitors currently in clinical trials for cancer treatment exhibit pan PI3K isoform profiles. Single PI3K isoforms differentially control tumorigenesis, and PI3Kβ has emerged as the isoform involved in the tumorigenicity of PTEN-deficient tumors. Herein we describe the discovery and optimization of a new series of benzimidazole- and benzoxazole-pyrimidones as small molecular mass PI3Kβ-selective inhibitors. Starting with compound 5 obtained from a one-pot reaction via a novel intermediate 1, medicinal chemistry optimization led to the discovery of compound 8, which showed a significant activity and selectivity for PI3Kβ and adequate in vitro pharmacokinetic properties. The X-ray costructure of compound 8 in PI3Kδ showed key interactions and structural features supporting the observed PI3Kβ isoform selectivity. Compound 8 achieved sustained target modulation and tumor growth delay at well tolerated doses when administered orally to SCID mice implanted with PTEN-deficient human tumor xenografts.

  5. Successful arthroscopic treatment of pigmented villonodular synovitis of the knee in a patient with congenital deficiency of plasminogen activator inhibitor-1 and recurrent haemarthrosis.

    PubMed

    Matsui, H; Takahashi, Y; Matsunaga, T; Tanaka-Horie, T; Minowa, H; Sugimoto, M; Tsukino, R; Mii, Y; Giddings, J; Yoshioka, A

    2001-01-01

    We report the arthroscopic treatment of pigmented villonodular synovitis (PVNS) in a 13-year-old Japanese boy with congenital partial deficiency of plasminogen activator inhibitor-1 (PAI-1). He was admitted to our hospital with recurrent haemarthrosis of his right knee. Characteristic abnormalities of fibrinolysis included shortened euglobulin lysis time, low PAI-1 activity and low PAI-1 antigen levels. In addition, levels of "active PAI" in the plasma, which is a measure of total PAI bound to exogenous plasminogen activator, were very low. These parameters remained low after venous occlusion. The diagnosis of PVNS was established by synovial membrane biopsy, and arthroscopic synovectomy was performed with adjuvant administration of intravenous tranexamic acid. Subsequent bleeding episodes have been well controlled by oral administration of tranexamic acid on demand.

  6. Association of Protein S Deficiency with Thrombosis in a Kindred with Increased Levels of Plasminogen Activator Inhibitor-1

    DTIC Science & Technology

    1993-10-15

    family with assay. Clin Chim Acts. 1983;127:279-88. hereditary thrombophilia . Blood. 1989;73:479-83. 22. Griffn JH, Gruber A, Fernandez JA. Reevaluation of...SMe E. Elevated plasminogen 25 Boiseol C, David H. Quantitative determination of serum triglycer- activator inhibitor (PAl), a cause of thrombophilia ...A study in 203 ides by the use of enzymes. Cliii Chem. 1973;19:476-82. patients with familial or sporadic venous thrombophilia . Thromb 26. Remnilgton

  7. In vivo anti-tumor activity of the PARP inhibitor niraparib in homologous recombination deficient and proficient ovarian carcinoma☆,☆☆

    PubMed Central

    AlHilli, Mariam M.; Becker, Marc A.; Weroha, S. John; Flatten, Karen S.; Hurley, Rachel M.; Harrell, Maria I.; Oberg, Ann L.; Maurer, Matt J.; Hawthorne, Kieran M.; Hou, Xiaonan; Harrington, Sean C.; McKinstry, Sarah; Meng, X. Wei; Wilcoxen, Keith M.; Kalli, Kimberly R.; Swisher, Elizabeth M.; Kaufmann, Scott H.; Haluska, Paul

    2017-01-01

    Objective Poly(ADP-ribose) polymerase (PARP) inhibitors have yielded encouraging responses in high-grade serous ovarian carcinomas (HGSOCs), but the optimal treatment setting remains unknown. We assessed the effect of niraparib on HGSOC patient-derived xenograft (PDX) models as well as the relationship between certain markers of homologous recombination (HR) status, including BRCA1/2 mutations and formation of RAD51 foci after DNA damage, and response of these PDXs to niraparib in vivo. Methods Massively parallel sequencing was performed on HGSOCs to identify mutations contributing to HR deficiency. HR pathway integrity was assessed using fluorescence microscopy-based RAD51 focus formation assays. Effects of niraparib (MK-4827) on treatment-naïve PDX tumor growth as monotherapy, in combination with carboplatin/paclitaxel, and as maintenance therapy were assessed by transabdominal ultrasound. Niraparib responses were correlated with changes in levels of poly(ADP-ribose), PARP1, and repair proteins by western blotting. Results Five PDX models were evaluated in vivo. Tumor regressions were induced by single-agent niraparib in one of two PDX models with deleterious BRCA2 mutations and in a PDX with RAD51C promoter methylation. Diminished formation of RAD51 foci failed to predict response, but Artemis loss was associated with resistance. Niraparib generally failed to enhance responses to carboplatin/paclitaxel chemotherapy, but maintenance niraparib therapy delayed progression in a BRCA2-deficient PDX. Conclusions Mutations in HR genes are neither necessary nor sufficient to predict response to niraparib. Assessment of repair status through multiple complementary assays is needed to guide PARP inhibitor therapy, design future clinical trials and identify ovarian cancer patients most likely to benefit from PARP inhibition. PMID:27614696

  8. High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs

    PubMed Central

    Rottenberg, Sven; Jaspers, Janneke E.; Kersbergen, Ariena; van der Burg, Eline; Nygren, Anders O. H.; Zander, Serge A. L.; Derksen, Patrick W. B.; de Bruin, Michiel; Zevenhoven, John; Lau, Alan; Boulter, Robert; Cranston, Aaron; O'Connor, Mark J.; Martin, Niall M. B.; Borst, Piet; Jonkers, Jos

    2008-01-01

    Whereas target-specific drugs are available for treating ERBB2-overexpressing and hormone receptor-positive breast cancers, no tailored therapy exists for hormone receptor- and ERBB2-negative (“triple-negative”) mammary carcinomas. Triple-negative tumors account for 15% of all breast cancers and frequently harbor defects in DNA double-strand break repair through homologous recombination (HR), such as BRCA1 dysfunction. The DNA-repair defects characteristic of BRCA1-deficient cells confer sensitivity to poly(ADP-ribose) polymerase 1 (PARP1) inhibition, which could be relevant to treatment of triple-negative tumors. To evaluate PARP1 inhibition in a realistic in vivo setting, we tested the PARP inhibitor AZD2281 in a genetically engineered mouse model (GEMM) for BRCA1-associated breast cancer. Treatment of tumor-bearing mice with AZD2281 inhibited tumor growth without signs of toxicity, resulting in strongly increased survival. Long-term treatment with AZD2281 in this model did result in the development of drug resistance, caused by up-regulation of Abcb1a/b genes encoding P-glycoprotein efflux pumps. This resistance to AZD2281 could be reversed by coadministration of the P-glycoprotein inhibitor tariquidar. Combination of AZD2281 with cisplatin or carboplatin increased the recurrence-free and overall survival, suggesting that AZD2281 potentiates the effect of these DNA-damaging agents. Our results demonstrate in vivo efficacy of AZD2281 against BRCA1-deficient breast cancer and illustrate how GEMMs of cancer can be used for preclinical evaluation of novel therapeutics and for testing ways to overcome or circumvent therapy resistance. PMID:18971340

  9. Selenium deficiency induced damages and altered expressions of metalloproteinases and their inhibitors (MMP1/3, TIMP1/3) in the kidneys of growing rats.

    PubMed

    Han, Jing; Liang, Hua; Yi, Jianhua; Tan, Wuhong; He, Shulan; Wu, Xiaofang; Shi, Xiaowei; Ma, Jing; Guo, Xiong

    2016-03-01

    Selenium is an essential trace element for the maintenance of structures and functions of kidney. To evaluate the effects of low selenium on the kidneys of growing rats, newborn rats were fed with selenium deficient and normal diets respectively for 109 days. As a result, rats fed with low selenium diets resulted in a decline in the body weight and the concentration of selenium in the kidney, especially the male rats from the low selenium groups. Moreover, the ultrastructure of glomerulus and tubules were damaged in low selenium group: the glomeruli were observed with hyperplasia of mesangial cells, fusion of podocyte foot processes and thickening of basement membrane; and the tubules were observed with vacuolar degenerated epithelial cells, increased edema fluid or protein solution between cells, microvilli edema, increased cell gaps and decreased cell links. Furthermore, the pathological changes in selenium deficient group included the increase of fibers around renal hilum aorta and in the renal collecting duct, and shed of cells in the proximal convoluted tubules. In addition, up-regulated expressions of matrix metalloproteinases (MMP1/3) and down-regulated expressions of their inhibitors (TIMP1/3) at the mRNA and protein levels were also appeared to be relevant to low selenium. The results suggested that low selenium in diet may cause low selenium concentration in the kidney of growing rat and lead to damages of the ultrastructure and extracellular matrix (ECM) of kidney.

  10. Quantitative MRI Establishes the Efficacy of PI3K Inhibitor (GDC-0941) Multi-Treatments in PTEN-deficient Mice Lymphoma

    PubMed Central

    WULLSCHLEGER, STEPHAN; GARCÍA-MARTÍNEZ, JUAN M.; DUCE, SUZANNE L.

    2012-01-01

    Aim To assess the efficacy of multiple treatment of phosphatidylinositol-3-kinase (PI3K) inhibitor on autochthonous tumours in phosphatase and tensin homologue (Pten)-deficient genetically engineered mouse cancer models using a longitudinal magnetic resonance imaging (MRI) protocol. Materials and Methods Using 3D MRI, B-cell follicular lymphoma growth was quantified in a Pten+/−Lkb1+/hypo mouse line, before, during and after repeated treatments with a PI3K inhibitor GDC-0941 (75 mg/kg). Results Mean pre-treatment linear tumour growth rate was 16.5±12.8 mm3/week. Repeated 28-day GDC-0941 administration, with 21 days “off-treatment”, induced average tumour regression of 41±7%. Upon cessation of the second treatment (which was not permanently cytocidal), tumours re-grew with an average linear growth rate of 40.1±15.5 mm3/week. There was no evidence of chemoresistance. Conclusion This protocol can accommodate complex dosing schedules, as well as combine different cancer therapies. It reduces biological variability problems and resulted in a 10-fold reduction in mouse numbers compared with terminal assessment methods. It is ideal for preclinical efficacy studies and for phenotyping molecularly characterized mouse models when investigating gene function. PMID:22287727

  11. BI-97C1, an Optically Pure Apogossypol Derivative as Pan-Active Inhibitor of Anti-apoptotic B-cell lymphoma/leukemia-2 (Bcl-2) Family Proteins

    PubMed Central

    Wei, Jun; Stebbins, John L.; Kitada, Shinichi; Dash, Rupesh; Placzek, William; Rega, Michele F.; Wu, Bainan; Cellitti, Jason; Zhai, Dayong; Yang, Li; Dahl, Russell; Fisher, Paul B.; Reed, John C.; Pellecchia, Maurizio

    2010-01-01

    In our continued attempts to identify novel and effective pan-Bcl-2 antagonists, we have recently reported a series of compound 2 (Apogossypol) derivatives, resulting in the chiral compound 4 (8r). We report here on synthesis and evaluation on its optically pure individual isomers. Compound 11 (BI-97C1), the most potent diastereoisomer of compound 4, inhibits the binding of BH3 peptides to Bcl-XL, Bcl-2, Mcl-1 and Bfl-1 with IC50 values of 0.31, 0.32, 0.20 and 0.62 μM, respectively. The compound also potently inhibits cell growth of human prostate cancer, lung cancer and lymphoma cell lines with EC50 values of 0.13, 0.56 and 0.049 μM, respectively and shows little cytotoxicity against bax−/−bak−/− cells. Compound 11 displays in vivo efficacy in transgenic mice models and also demonstrated superior single-agent antitumor efficacy in a prostate cancer mouse xenograft model. Therefore, compound 11 represents a potential drug lead for the development of novel apoptosis-based therapies against cancer. PMID:20443627

  12. Altered transition metal homeostasis in Niemann-Pick disease, Type C1

    PubMed Central

    Hung, Ya Hui; Faux, Noel G.; Killilea, David W.; Yanjanin, Nicole; Firnkes, Sally; Volitakis, Irene; Ganio, George; Walterfang, Mark; Hastings, Caroline; Porter, Forbes D.; Ory, Daniel S.; Bush, Ashley I.

    2014-01-01

    The loss of NPC1 protein function is the predominant cause of Niemann-Pick type C1 disease (NP-C1), a systemic and neurodegenerative disorder characterized by late-endosomal/lysosomal accumulation of cholesterol and other lipids. Limited evidence from post-mortem human tissues, an Npc1−/− mouse model, and cell culture studies also suggest failure of metal homeostasis in NP-C1. To investigate these findings, we performed a comprehensive transition metal analysis of cerebrospinal fluid (CSF), plasma and tissue samples from human NP-C1 patients and an Npc1−/− mouse model. NPC1 deficiency in the Npc1−/− mouse model resulted in a perturbation of transition metal homeostasis in the plasma and key organs (brain, liver, spleen, heart, lungs, and kidneys). Analysis of human patient CSF, plasma and post-mortem brain tissues also indicated disrupted metal homeostasis. There was a disparity in the direction of metal changes between the human and the Npc1−/− mouse samples, which may reflect species-specific metal metabolism. Nevertheless, common to both species is brain zinc accumulation. Furthermore, treatment with the glucosylceramide synthase inhibitor miglustat, the only drug shown in a controlled clinical trial to have some efficacy for NP-C1, did not correct the alterations in CSF and plasma transition metal and ceruloplasmin (CP) metabolism in NP-C1 patients. These findings highlight the importance of NPC1 function in metal homeostasis, and indicate that metal-targeting therapy may be of value as a treatment for NP-C. PMID:24343124

  13. Pathogenesis of peroxisomal deficiency disorders (Zellweger syndrome) may be mediated by misregulation of the GABAergic system via the diazepam binding inhibitor

    PubMed Central

    Breitling, Rainer

    2004-01-01

    Background Zellweger syndrome (ZS) is a fatal inherited disease caused by peroxisome biogenesis deficiency. Patients are characterized by multiple disturbances of lipid metabolism, profound hypotonia and neonatal seizures, and distinct craniofacial malformations. Median live expectancy of ZS patients is less than one year. While the molecular basis of peroxisome biogenesis and metabolism is known in considerable detail, it is unclear how peroxisome deficiency leads to the most severe neurological symptoms. Recent analysis of ZS mouse models has all but invalidated previous hypotheses. Hypothesis We suggest that a regulatory rather than a metabolic defect is responsible for the drastic impairment of brain function in ZS patients. Testing the hypothesis Using microarray analysis we identify diazepam binding inhibitor/acyl-CoA binding protein (DBI) as a candidate protein that might be involved in the pathogenic mechanism of ZS. DBI has a dual role as a neuropeptide antagonist of GABA(A) receptor signaling in the brain and as a regulator of lipid metabolism. Repression of DBI in ZS patients could result in an overactivation of GABAergic signaling, thus eventually leading to the characteristic hypotonia and seizures. The most important argument for a misregulation of GABA(A) in ZS is, however, provided by the striking similarity between ZS and "benzodiazepine embryofetopathy", a malformation syndrome observed after the abuse of GABA(A) agonists during pregnancy. Implications of the hypothesis We present a tentative mechanistic model of the effect of DBI misregulation on neuronal function that could explain some of the aspects of the pathology of Zellweger syndrome. PMID:15102341

  14. Disease-modifying effects of orally bioavailable NF-κB inhibitors in dystrophin-deficient muscle

    PubMed Central

    Hammers, David W.; Sleeper, Margaret M.; Forbes, Sean C.; Coker, Cora C.; Jirousek, Michael R.; Zimmer, Michael; Walter, Glenn A.; Sweeney, H. Lee

    2016-01-01

    Duchenne muscular dystrophy (DMD) is a devastating muscle disease characterized by progressive muscle deterioration and replacement with an aberrant fatty, fibrous matrix. Chronic upregulation of nuclear factor κB (NF-κB) is implicated as a driver of the dystrophic pathogenesis. Herein, 2 members of a novel class of NF-κB inhibitors, edasalonexent (formerly CAT-1004) and CAT-1041, were evaluated in both mdx mouse and golden retriever muscular dystrophy (GRMD) dog models of DMD. These orally bioavailable compounds consist of a polyunsaturated fatty acid conjugated to salicylic acid and potently suppress the pathogenic NF-κB subunit p65/RelA in vitro. In vivo, CAT-1041 effectively improved the phenotype of mdx mice undergoing voluntary wheel running, in terms of activity, muscle mass and function, damage, inflammation, fibrosis, and cardiac pathology. We identified significant increases in dysferlin as a possible contributor to the protective effect of CAT-1041 to sarcolemmal damage. Furthermore, CAT-1041 improved the more severe GRMD phenotype in a canine case study, where muscle mass and diaphragm function were maintained in a treated GRMD dog. These results demonstrate that NF-κB modulation by edasalonexent and CAT-1041 is effective in ameliorating the dystrophic process and these compounds are candidates for new treatments for DMD patients. PMID:28018975

  15. BRCA1-deficient breast cancer cell lines are resistant to MEK inhibitors and show distinct sensitivities to 6-thioguanine.

    PubMed

    Gu, Yuexi; Helenius, Mikko; Väänänen, Kristiina; Bulanova, Daria; Saarela, Jani; Sokolenko, Anna; Martens, John; Imyanitov, Evgeny; Kuznetsov, Sergey

    2016-06-17

    Germ-line or somatic inactivation of BRCA1 is a defining feature for a portion of human breast cancers. Here we evaluated the anti-proliferative activity of 198 FDA-approved and experimental drugs against four BRCA1-mutant (HCC1937, MDA-MB-436, SUM1315MO2, and SUM149PT) and four BRCA1-wild-type (MDA-MB-231, SUM229PE, MCF10A, and MCF7) breast cancer cell lines. We found that all BRCA1-mutant cell lines were insensitive to inhibitors of mitogen-activated protein kinase kinase 1 and 2 (MEK1/2) Selumetinib and Pimasertib in contrast to BRCA1-wildtype control cell lines. However, unexpectedly, only two BRCA1-mutant cell lines, HCC1937 and MDA-MB-436, were hypersensitive to a nucleotide analogue 6-thioguanine (6-TG). SUM149PT cells readily formed radiation-induced RAD51-positive nuclear foci indicating a functional homologous recombination, which may explain their resistance to 6-TG. However, the reason underlying 6-TG resistance of SUM1315MO2 cells remains unclear. Our data reveal a remarkable heterogeneity among BRCA1-mutant cell lines and provide a reference for future studies.

  16. BRCA1-deficient breast cancer cell lines are resistant to MEK inhibitors and show distinct sensitivities to 6-thioguanine

    PubMed Central

    Gu, Yuexi; Helenius, Mikko; Väänänen, Kristiina; Bulanova, Daria; Saarela, Jani; Sokolenko, Anna; Martens, John; Imyanitov, Evgeny; Kuznetsov, Sergey

    2016-01-01

    Germ-line or somatic inactivation of BRCA1 is a defining feature for a portion of human breast cancers. Here we evaluated the anti-proliferative activity of 198 FDA-approved and experimental drugs against four BRCA1-mutant (HCC1937, MDA-MB-436, SUM1315MO2, and SUM149PT) and four BRCA1-wild-type (MDA-MB-231, SUM229PE, MCF10A, and MCF7) breast cancer cell lines. We found that all BRCA1-mutant cell lines were insensitive to inhibitors of mitogen-activated protein kinase kinase 1 and 2 (MEK1/2) Selumetinib and Pimasertib in contrast to BRCA1-wildtype control cell lines. However, unexpectedly, only two BRCA1-mutant cell lines, HCC1937 and MDA-MB-436, were hypersensitive to a nucleotide analogue 6-thioguanine (6-TG). SUM149PT cells readily formed radiation-induced RAD51-positive nuclear foci indicating a functional homologous recombination, which may explain their resistance to 6-TG. However, the reason underlying 6-TG resistance of SUM1315MO2 cells remains unclear. Our data reveal a remarkable heterogeneity among BRCA1-mutant cell lines and provide a reference for future studies. PMID:27313062

  17. Evaluation of the therapeutic potential of carbonic anhydrase inhibitors in two animal models of dystrophin deficient muscular dystrophy.

    PubMed

    Giacomotto, Jean; Pertl, Cordula; Borrel, Caroline; Walter, Maggie C; Bulst, Stefanie; Johnsen, Bob; Baillie, David L; Lochmüller, Hanns; Thirion, Christian; Ségalat, Laurent

    2009-11-01

    Duchenne Muscular Dystrophy is an inherited muscle degeneration disease for which there is still no efficient treatment. However, compounds active on the disease may already exist among approved drugs but are difficult to identify in the absence of cellular models. We used the Caenorhabditis elegans animal model to screen a collection of 1000 already approved compounds. Two of the most active hits obtained were methazolamide and dichlorphenamide, carbonic anhydrase inhibitors widely used in human therapy. In C. elegans, these drugs were shown to interact with CAH-4, a putative carbonic anhydrase. The therapeutic efficacy of these compounds was further validated in long-term experiments on mdx mice, the mouse model of Duchenne Muscular Dystrophy. Mice were treated for 120 days with food containing methazolamide or dichlorphenamide at two doses each. Musculus tibialis anterior and diaphragm muscles were histologically analyzed and isometric muscle force was measured in M. extensor digitorum longus. Both substances increased the tetanic muscle force in the treated M. extensor digitorum longus muscle group, dichlorphenamide increased the force significantly by 30%, but both drugs failed to increase resistance of muscle fibres to eccentric contractions. Histological analysis revealed a reduction of centrally nucleated fibers in M. tibialis anterior and diaphragm in the treated groups. These studies further demonstrated that a C. elegans-based screen coupled with a mouse model validation strategy can lead to the identification of potential pharmacological agents for rare diseases.

  18. A novel BET bromodomain inhibitor, RVX-208, shows reduction of atherosclerosis in hyperlipidemic ApoE deficient mice.

    PubMed

    Jahagirdar, Ravi; Zhang, Haiyan; Azhar, Salman; Tobin, Jennifer; Attwell, Sarah; Yu, Raymond; Wu, Jin; McLure, Kevin G; Hansen, Henrik C; Wagner, Gregory S; Young, Peter R; Srivastava, Rai Ajit K; Wong, Norman C W; Johansson, Jan

    2014-09-01

    Despite the benefit of statins in reducing cardiovascular risk, a sizable proportion of patients still remain at risk. Since HDL reduces CVD risk through a process that involves formation of pre-beta particles that facilitates the removal of cholesterol from the lipid-laden macrophages in the arteries, inducing pre-beta particles, may reduce the risk of CVD. A novel BET bromodomain antagonist, RVX-208, was reported to raise apoA-I and increase preβ-HDL particles in non-human primates and humans. In the present study, we investigated the effect of RVX-208 on aortic lesion formation in hyperlipidemic apoE(-/-) mice. Oral treatments of apoE(-/-) mice with 150 mg/kg b.i.d RVX-208 for 12 weeks significantly reduced aortic lesion formation, accompanied by 2-fold increases in the levels of circulating HDL-C, and ∼50% decreases in LDL-C, although no significant changes in plasma apoA-I were observed. Circulating adhesion molecules as well as cytokines also showed significant reduction. Haptoglobin, a proinflammatory protein, known to bind with HDL/apoA-I, decreased >2.5-fold in the RVX-208 treated group. With a therapeutic dosing regimen in which mice were fed Western diet for 10 weeks to develop lesions followed by switching to a low fat diet and concurrent treatment with RVX-208 for 14 weeks, RVX-208 similarly reduced lesion formation by 39% in the whole aorta without significant changes in the plasma lipid parameters. RVX-208 significantly reduced the proinflammatory cytokines IP-10, MIP1(®) and MDC. These results show that the antiatherogenic activity of BET inhibitor, RVX-208, occurs via a combination of lipid changes and anti-inflammatory activities.

  19. Remodeling of the Vessel Wall after Copper-Induced Injury Is Highly Attenuated in Mice with a Total Deficiency of Plasminogen Activator Inhibitor-1

    PubMed Central

    Ploplis, Victoria A.; Cornelissen, Ivo; Sandoval-Cooper, Mayra J.; Weeks, Lisa; Noria, Francisco A.; Castellino, Francis J.

    2001-01-01

    Clinical studies have indicated that high plasma levels of fibrinogen, or decreased fibrinolytic potential, are conducive to an increased risk of cardiovascular disease. Other investigations have shown that insoluble fibrin promotes atherosclerotic lesion formation by affecting smooth muscle cell proliferation, collagen deposition, and cholesterol accumulation. To directly assess the physiological impact of an imbalanced fibrinolytic system on both early and late stages of this disease, mice deficient for plasminogen activator inhibitor-1 (PAI-1−/−) were used in a model of vascular injury/repair, and the resulting phenotype compared to that of wild-type (WT) mice. A copper-induced arterial injury was found to generate a lesion with characteristics similar to many of the clinical features of atherosclerosis. Fibrin deposition in the injured arterial wall at early (7 days) and late (21 days) times after copper cuff placement was prevalent in WT mice, but was greatly diminished in PAI-1−/− mice. A multilayered neointima with enhanced collagen deposition was evident at day 21 in WT mice. In contrast, only diffuse fibrin was identified in the adventitial compartments of arteries from PAI-1−/− mice, with no evidence of a neointima. Neovascularization was observed in the adventitia and was more extensive in WT arteries, relative to PAI-1−/− arteries. Additionally, enhanced PAI-1 expression and fat deposition were seen only in the arterial walls of WT mice. The results of this study emphasize the involvement of the fibrinolytic system in vascular repair processes after injury and indicate that alterations in the fibrinolytic balance in the vessel wall have a profound effect on the development and progression of vascular lesion formation. PMID:11141484

  20. Plasminogen Activator Inhibitor-1 Deficiency Augments Visceral Mesothelial Organization, Intrapleural Coagulation, and Lung Restriction in Mice with Carbon Black/Bleomycin–Induced Pleural Injury

    PubMed Central

    Jeffers, Ann; Alvarez, Alexia; Owens, Shuzi; Koenig, Kathleen; Quaid, Brandon; Komissarov, Andrey A.; Florova, Galina; Kothari, Hema; Pendurthi, Usha; Mohan Rao, L. Vijaya; Idell, Steven

    2014-01-01

    Local derangements of fibrin turnover and plasminogen activator inhibitor (PAI)-1 have been implicated in the pathogenesis of pleural injury. However, their role in the control of pleural organization has been unclear. We found that a C57Bl/6j mouse model of carbon black/bleomycin (CBB) injury demonstrates pleural organization resulting in pleural rind formation (14 d). In transgenic mice overexpressing human PAI-1, intrapleural fibrin deposition was increased, but visceral pleural thickness, lung volumes, and compliance were comparable to wild type. CBB injury in PAI-1−/− mice significantly increased visceral pleural thickness (P < 0.001), elastance (P < 0.05), and total lung resistance (P < 0.05), while decreasing lung compliance (P < 0.01) and lung volumes (P < 0.05). Collagen, α-smooth muscle actin, and tissue factor were increased in the thickened visceral pleura of PAI-1−/− mice. Colocalization of α-smooth muscle actin and calretinin within pleural mesothelial cells was increased in CBB-injured PAI-1−/− mice. Thrombin, factor Xa, plasmin, and urokinase induced mesothelial–mesenchymal transition, tissue factor expression, and activity in primary human pleural mesothelial cells. In PAI-1−/− mice, D-dimer and thrombin–antithrombin complex concentrations were increased in pleural lavage fluids. The results demonstrate that PAI-1 regulates CBB-induced pleural injury severity via unrestricted fibrinolysis and cross-talk with coagulation proteases. Whereas overexpression of PAI-1 augments intrapleural fibrin deposition, PAI-1 deficiency promotes profibrogenic alterations of the mesothelium that exacerbate pleural organization and lung restriction. PMID:24024554

  1. Uncoupling complement C1s activation from C1q binding in apoptotic cell phagocytosis and immunosuppressive capacity.

    PubMed

    Colonna, Lucrezia; Parry, Graham C; Panicker, Sandip; Elkon, Keith B

    2016-02-01

    Complement activation contributes to inflammation in many diseases, yet it also supports physiologic apoptotic cells (AC) clearance and its downstream immunosuppressive effects. The roles of individual complement components in AC phagocytosis have been difficult to dissect with artificially depleted sera. Using human in vitro systems and the novel antibody complement C1s inhibitor TNT003, we uncoupled the role of the enzymatic activation of the classical pathway from the opsonizing role of C1q in mediating a) the phagocytosis of early and late AC, and b) the immunosuppressive capacity of early AC. We found that C1s inhibition had a small impact on the physiologic clearance of early AC, leaving their immunosuppressive properties entirely unaffected, while mainly inhibiting the phagocytosis of late apoptotic/secondary necrotic cells. Our data suggest that C1s inhibition may represent a valuable therapeutic strategy to control classical pathway activation without causing significant AC accumulation in diseases without defects in AC phagocytosis.

  2. The orally active and bioavailable ATR kinase inhibitor AZD6738 potentiates the anti-tumor effects of cisplatin to resolve ATM-deficient non-small cell lung cancer in vivo.

    PubMed

    Vendetti, Frank P; Lau, Alan; Schamus, Sandra; Conrads, Thomas P; O'Connor, Mark J; Bakkenist, Christopher J

    2015-12-29

    ATR and ATM are DNA damage signaling kinases that phosphorylate several thousand substrates. ATR kinase activity is increased at damaged replication forks and resected DNA double-strand breaks (DSBs). ATM kinase activity is increased at DSBs. ATM has been widely studied since ataxia telangiectasia individuals who express no ATM protein are the most radiosensitive patients identified. Since ATM is not an essential protein, it is widely believed that ATM kinase inhibitors will be well-tolerated in the clinic. ATR has been widely studied, but advances have been complicated by the finding that ATR is an essential protein and it is widely believed that ATR kinase inhibitors will be toxic in the clinic. We describe AZD6738, an orally active and bioavailable ATR kinase inhibitor. AZD6738 induces cell death and senescence in non-small cell lung cancer (NSCLC) cell lines. AZD6738 potentiates the cytotoxicity of cisplatin and gemcitabine in NSCLC cell lines with intact ATM kinase signaling, and potently synergizes with cisplatin in ATM-deficient NSCLC cells. In contrast to expectations, daily administration of AZD6738 and ATR kinase inhibition for 14 consecutive days is tolerated in mice and enhances the therapeutic efficacy of cisplatin in xenograft models. Remarkably, the combination of cisplatin and AZD6738 resolves ATM-deficient lung cancer xenografts.

  3. Curtiss XSO3C-1 Seagull

    NASA Technical Reports Server (NTRS)

    1940-01-01

    Curtiss XSO3C-1 Seagull: Although drag reduction was very important to radial engined aircraft, it was no less important to aircraft such as this inline Ranger powered Curtiss XSO3C-1 Seagull. Here the Seagull is shown in the 30 x 60 Full Scale Tunnel in October of 1940. The XSO3C-1 was also undergoing study to improve engine cooling. Published in Aircraft; FST; Curtiss XSO3C-1 Seagull; Full Scale Tunnel; Nicklas

  4. Cell Surface Expression and Function of the Macromolecular C1 Complex on the Surface of Human Monocytes

    PubMed Central

    Hosszu, Kinga K.; Valentino, Alisa; Ji, Yan; Matkovic, Mara; Pednekar, Lina; Rehage, Nina; Tumma, Nithin; Peerschke, Ellinor I. B.; Ghebrehiwet, Berhane

    2011-01-01

    The synthesis of the subunits of the C1 complex (C1q, C1s, C1r), and its regulator C1 inhibitor (C1-Inh) by human monocytes has been previously established. However, surface expression of these molecules by monocytes has not been shown. Using flow cytometry and antigen-capture enzyme-linked immunosorbent assay, we show here for the first time that, in addition to C1q, peripheral blood monocytes, and the monocyte-derived U937 cells express C1s and C1r, as well as Factor B and C1-Inh on their surface. C1s and C1r immunoprecipitated with C1q, suggesting that at least some of the C1q on these cells is part of the C1 complex. Furthermore, the C1 complex on U937 cells was able to trigger complement activation via the classical pathway. The presence of C1-Inh may ensure that an unwarranted autoactivation of the C1 complex does not take place. Since C1-Inh closely monitors the activation of the C1 complex in a sterile or infectious inflammatory environment, further elucidation of the role of C1 complex is crucial to dissect its function in monocyte, dendritic cell, and T cell activities, and its implications in host defense and tolerance. PMID:22566921

  5. 29 CFR 2575.502c-1 - Adjusted civil penalty under section 502(c)(1).

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 29 Labor 9 2010-07-01 2010-07-01 false Adjusted civil penalty under section 502(c)(1). 2575.502c-1 Section 2575.502c-1 Labor Regulations Relating to Labor (Continued) EMPLOYEE BENEFITS SECURITY... ERISA Title I § 2575.502c-1 Adjusted civil penalty under section 502(c)(1). In accordance with...

  6. Clinical decision-making for vitamin K-1 and K-2 deficiency and coronary artery calcification with warfarin therapy: are diet, factor Xa inhibitors or both the answer?

    PubMed

    Wahlqvist, Mark L; Tanaka, Kiyoshi; Tzeng, Bing-Hsiean

    2013-01-01

    Coronary artery calcification is a recognised risk factor for ischaemic heart disease and mortality. Evidence is now strong that Mönckeberg's arteriosclerosis, a form of vascular calcification, can be attributable to vitamin K deficiency, but that vitamin K-2, especially the MK-4 form from foods like cheese can be protective. Warfarin blocks the recycling of hepatic and peripheral vitamin K leading to secondary vitamin K deficiency with adverse effects on vasculature, bone, kidneys, brain and other tissues and systems (inflammatory, immune function and neoplasia at least). There is individual susceptibility to vitamin K deficiency and warfarin sensitivity, partly explicable in terms of genetic polymorphisms, epigenetics, diet and pharmacotherapy. The emergence of extensive coronary calcification in a man with atrial fibrillation treated for a decade with warfarin is described by way of illustration and to raise the present clinical management conundrums. Finally, a putative set of recommendations is provided.

  7. Reduced difference of α₂-plasmin inhibitor levels between plasma and serum in patients with severe factor XIII deficiency, including autoimmune hemorrhaphilia due to anti-factor XIII antibodies.

    PubMed

    Ichinose, Akitada; Souri, Masayoshi

    2012-01-01

    Coagulation factor XIII/13 (FXIII/13) stabilizes fibrin molecules by creating crosslinks with other fibrin molecules as well as with α₂-plasmin inhibitor (α₂-PI). "Hemorrhagic acquired FXIII/13 deficiency" was formerly considered rare, but has been increasing recently in Japan. During the 10 months of our nationwide campaign, we diagnosed five new patients with "acquired hemorrhaphilia due to anti-FXIII/13 autoantibodies," after examining 20 newly suspected cases of "hemorrhagic acquired FXIII/13 deficiency." When FXIII/13 activity was reduced to less than 50% of normal, it was proportional to the difference in α₂-PI levels between plasma and serum (plasma-serum α₂-PI), likely due to its cross-linking to fibrin by activated FXIII/13. Accordingly, decreased amounts of the plasma-serum α₂-PI ex vivo may reflect reduced FXIII/13 activity in vivo. The plasma-serum α₂-PI may thus also be a useful diagnostic marker for severe FXIII/13 deficiency.

  8. A phase 1b dose expansion study of the pan-class I PI3K inhibitor buparlisib (BKM120) plus carboplatin and paclitaxel in PTEN deficient tumors and with dose intensified carboplatin and paclitaxel.

    PubMed

    Smyth, Lillian M; Monson, Kelsey R; Jhaveri, Komal; Drilon, Alexander; Li, Bob T; Abida, Wassim; Iyer, Gopa; Gerecitano, John F; Gounder, Mrinal; Harding, James J; Voss, Martin H; Makker, Vicky; Ho, Alan L; Razavi, Pedram; Iasonos, Alexia; Bialer, Philip; Lacouture, Mario E; Teitcher, Jerrold B; Erinjeri, Joseph P; Katabi, Nora; Fury, Matthew G; Hyman, David M

    2017-03-09

    Purpose We previously reported the phase I dose escalation study of buparlisib, a pan-class 1A PI3K inhibitor, combined with platinum/taxane-based chemotherapy in patients with advanced solid tumors. The combination was well tolerated and promising preliminary efficacy was observed in PTEN deficient tumors. This phase I dose expansion study now evaluates buparlisib plus high dose carboplatin and paclitaxel in unselected patients with advanced solid tumors and buparlisib plus standard dose carboplatin and paclitaxel in patients with PTEN deficient tumors (ClinicalTrials.gov, NCT01297452). Methods There were two expansion cohorts: Cohort A received continuous buparlisib (100 mg/daily) orally plus high dose carboplatin AUC 6 and paclitaxel 200 mg/m2; Cohort B treated patients with PTEN deficient tumors only and they received the recommended phase II dose (RP2D) of continuous buparlisib (100 mg/daily) orally plus standard dose carboplatin AUC 5 and paclitaxel 175 mg/m2. Both cohorts received chemotherapy intravenously on day 1 of the 21-day cycle with pegfilgrastim support. Primary endpoint in Cohort A was to evaluate the safety and tolerability of chemotherapy dose intensification with buparlisib and in Cohort B was to describe preliminary efficacy of the combination among patients with tumors harboring a PTEN mutation or homozygous deletion. Results 14 subjects were enrolled, 7 in Cohort A and 7 in Cohort B. Dose reductions were required in 5 (71%) and 3 (43%) patients, in cohort A and B respectively. Grade 3 adverse events in Cohort A included lymphopenia (n = 5 [71%]), hyperglycemia (n = 2, [29%]), diarrhea (n = 2, [29%]) and rash (n = 2, [29%]) and in cohort B included lymphopenia (n = 5 [71%]), hyperglycemia (n = 4 [57%]) and neutropenia (n = 2 [29%]. The mean number of cycles on protocol was 6. The overall objective response rate was 14% (2 /14). No objective responses were observed in the PTEN deficient cohort. Four out of 6 patients with

  9. Effects of Lewis lung carcinoma on trabecular microstructural changes in wild-type and plasminogen activator inhibitor-1 deficient mice fed a high-fat diet

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Bone is a major target organ of metastasis. The present study investigated the effects of Lewis lung carcinoma (LLC) on trabecular microstructural changes, using tomographic analysis, in distal femur and lumbar 4 vertebra from LLC-bearing wild-type and plasminogen activator inhibitor-1 (PAI-1) defi...

  10. Molecular characterization of a gene encoding extracellular serine protease isolated from a subtilisin inhibitor-deficient mutant of Streptomyces albogriseolus S-3253.

    PubMed Central

    Taguchi, S; Odaka, A; Watanabe, Y; Momose, H

    1995-01-01

    An extracellular serine protease produced by a mutant, M1, derived from Streptomyces albogriseolus S-3253 that no longer produces a protease inhibitor (Streptomyces subtilisin inhibitor [SSI]) was isolated. A 20-kDa protein was purified by its affinity for SSI and designated SAM-P20. The amino acid sequence of the amino-terminal region of SAM-P20 revealed high homology with the sequences of Streptomyces griseus proteases A and B, and the gene sequence confirmed the relationships. The sequence also revealed a putative amino acid signal sequence for SAM-P20 that apparently functioned to allow secretion of SAM-P20 from Escherichia coli carrying the recombinant gene. SAM-P20 produced by E. coli cells was shown to be sensitive to SSI inhibition. PMID:7887600

  11. Insulin-Like Growth Factor-Type 1 Receptor Inhibitor NVP-AEW541 Enhances Radiosensitivity of PTEN Wild-Type but Not PTEN-Deficient Human Prostate Cancer Cells

    SciTech Connect

    Isebaert, Sofie F.; Swinnen, Johannes V.; McBride, William H.; Haustermans, Karin M.

    2011-09-01

    Purpose: During the past decade, many clinical trials with both monoclonal antibodies and small molecules that target the insulin-like growth factor-type 1 receptor (IGF-1R) have been launched. Despite the important role of IGF-1R signaling in radioresistance, studies of such agents in combination with radiotherapy are lagging behind. Therefore, the aim of this study was to investigate the effect of the small molecule IGF-1R kinase inhibitor NVP-AEW541 on the intrinsic radioresistance of prostate cancer cells. Methods and Materials: The effect of NVP-AEW541 on cell proliferation, cell viability, IGF-1R signaling, radiosensitivity, cell cycle distribution, and double strand break repair was determined in three human prostate cancer cell lines (PC3, DU145, 22Rv1). Moreover, the importance of the PTEN pathway status was explored by means of transfection experiments with constitutively active Akt or inactive kinase-dead Akt. Results: NVP-AEW541 inhibited cell proliferation and decreased cell viability in a time-and dose-dependent manner in all three cell lines. Radiosensitization was observed in the PTEN wild-type cell lines DU145 and 22Rv1 but not in the PTEN-deficient PC3 cell line. NVP-AEW541-induced radiosensitization coincided with downregulation of phospho-Akt levels and high levels of residual double strand breaks. The importance of PTEN status in the radiosensitization effect was confirmed by transfection experiments with constitutively active Akt or inactive kinase-dead Akt. Conclusions: NVP-AEW541 enhances the effect of ionizing radiation in PTEN wild-type, but not in PTEN-deficient, prostate cancer cells. Proper patient selection based on the PTEN status of the tumor will be critical to the achievement of optimal results in clinical trials in which the combination of radiotherapy and this IGF-1R inhibitor is being explored.

  12. Alpha(2)-macroglobulin levels are high in adult patients with congenital antithrombin deficiency.

    PubMed

    Tripodi, A; Chantarangkul, V; De Stefano, V; Mannucci, P

    2000-04-15

    Antithrombin is responsible for about 80% of the progressive inhibitory activity of thrombin in human plasma. The role of other protease inhibitors known to inhibit thrombin is not completely clarified. However, their contribution may become relevant when antithrombin is low. We elected to investigate adult patients with congenital antithrombin deficiency to assess the concentration of other naturally occurring thrombin inhibitors such as alpha(2)-macroglobulin, alpha(1)-antitrypsin, heparin cofactor II, and C(1)-inhibitor. The study included 59 patients with congenital antithrombin deficiency with and without a previous history of thrombosis, together with an equal number of control subjects matched for age and sex. Statistically significant differences (patients vs. controls) were observed only for alpha(2)-macroglobulin (i.e., 120 vs. 102%, p<0.01). Further analysis of antithrombin-deficient carriers with and without a past history of thrombosis showed that alpha(2)-macroglobulin levels were higher than the 90th percentile of control distribution more often in asymptomatic than symptomatic men (odds ratio=0.04; confidence interval=0.003-0.60), but not in women (odds ratio=2.14; confidence interval=0.35-13.1). In conclusion, results from this cross sectional study showed that alpha(2)-macroglobulin levels were high in patients with congenital antithrombin deficiency. Furthermore, the high levels were found more often in asymptomatic than symptomatic men. Whether this increase provides protection against thrombosis should be evaluated in a prospective study.

  13. Nf1-deficient mouse Schwann cells are angiogenic and invasive and can be induced to hyperproliferate: reversion of some phenotypes by an inhibitor of farnesyl protein transferase.

    PubMed Central

    Kim, H A; Ling, B; Ratner, N

    1997-01-01

    We have developed a potential model of Schwann cell tumor formation in neurofibromatosis type 1 (NF1). We show that mouse Schwann cells heterozygous or null at Nf1 display angiogenic and invasive properties, mimicking the behavior of Schwann cells from human neurofibromas. Mutations at Nf1 are insufficient to promote Schwann cell hyperplasia. Here we show that Schwann cell hyperplasia can be induced by protein kinase A activation in mutant cells. Removal of serum from the culture medium also stimulates hyperplasia, but only in some mutant cells. After serum removal, clones of hyperproliferating Schwann cells lose contact with axons in vitro, develop growth factor-independent proliferation, and exhibit decreased expression of the cell differentiation marker P0 protein; hyperproliferating cells develop after a 1-week lag in Schwann cells heterozygous at Nf1. The experiments suggest that events subsequent to Nf1 mutations are required for development of Schwann cell hyperplasia. Finally, an anti-Ras farnesyl protein transferase inhibitor greatly diminished both clone formation and hyperproliferation of null mutant cells, but not invasion; farnesyl transferase inhibitors could be useful in treating benign manifestations of NF1. PMID:9001241

  14. 29 CFR 2575.502c-1 - Adjusted civil penalty under section 502(c)(1).

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... ACT OF 1974 ADJUSTMENT OF CIVIL PENALTIES UNDER ERISA TITLE I Adjustment of Civil Penalties Under ERISA Title I § 2575.502c-1 Adjusted civil penalty under section 502(c)(1). In accordance with the... section 502(c)(1) of the Employee Retirement Income Security Act of 1974, as amended (ERISA), is...

  15. 29 CFR 2575.502c-1 - Adjusted civil penalty under section 502(c)(1).

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... ACT OF 1974 ADJUSTMENT OF CIVIL PENALTIES UNDER ERISA TITLE I Adjustment of Civil Penalties Under ERISA Title I § 2575.502c-1 Adjusted civil penalty under section 502(c)(1). In accordance with the... section 502(c)(1) of the Employee Retirement Income Security Act of 1974, as amended (ERISA), is...

  16. 29 CFR 2575.502c-1 - Adjusted civil penalty under section 502(c)(1).

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... ACT OF 1974 ADJUSTMENT OF CIVIL PENALTIES UNDER ERISA TITLE I Adjustment of Civil Penalties Under ERISA Title I § 2575.502c-1 Adjusted civil penalty under section 502(c)(1). In accordance with the... section 502(c)(1) of the Employee Retirement Income Security Act of 1974, as amended (ERISA), is...

  17. 29 CFR 2575.502c-1 - Adjusted civil penalty under section 502(c)(1).

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... ACT OF 1974 ADJUSTMENT OF CIVIL PENALTIES UNDER ERISA TITLE I Adjustment of Civil Penalties Under ERISA Title I § 2575.502c-1 Adjusted civil penalty under section 502(c)(1). In accordance with the... section 502(c)(1) of the Employee Retirement Income Security Act of 1974, as amended (ERISA), is...

  18. The soluble recombinant form of a binding protein/receptor for the globular domain of C1q (gC1qR) enhances blood coagulation.

    PubMed

    Peerschke, E I; Jesty, J; Reid, K B; Ghebrehiwet, B

    1998-01-01

    The gC1qR is a ubiquitously expressed, 33 kDa cellular protein which recognizes the globular domains of C1q. Recent evidence suggests that the gC1qR also serves as the Zn(++)-dependent endothelial cell binding site for factor XII and high-molecular-weight kininogen, and activates intrinsic coagulation and kinin pathways in purified systems. In addition, activated lymphocytes have been reported to release soluble gC1qR. Thus, the present study investigated the procoagulant potential of soluble gC1qR in human plasma using the recombinant protein (rgC1qR). rgC1qR supported a dose-dependent shortening of extrinsic coagulation using the prothrombin time in the presence of diluted (1/50-1/500) thromboplastin. Maximum enhancement of the prothrombin time resulted in shortening of the clotting time from 78.8 +/- 0.4 s to 68.5 +/- 0.6 s (mean +/- SD, n = 8) in the presence of 50 micrograms/ml (1.5 mumol/l) rgC1qR. rgC1qR also enhanced the intrinsic pathway of coagulation evaluated in the absence of activators of the contact system, as demonstrated by a shortening of the plasma recalcification time from 348 +/- 66 s to 140 +/- 23 s (n = 4). rgC1qR, however, had no effect on intrinsic coagulation in the presence of undiluted kaolin or ellagic acid, and under these conditions failed to shorten the activated partial thromboplastin time of factor VIII or factor-IX-deficient plasma. rgC1qR further failed to affect thrombin and factor Xa generation assayed using chromogenic substrates, and did not enhance thrombin-induced conversion of fibrinogen to fibrin. Interestingly, the procoagulant activity of the rgC1qR was measurable in either factor-XII- or factor-XI-deficient plasma, suggesting that it was not exclusively focused on the contact system of coagulation. Although the mechanism of action of gC1qR on blood coagulation remains obscure, the data suggest a potential role for this protein in hemostatic and thrombotic events.

  19. Effect of an hdm-2 antagonist peptide inhibitor on cell cycle progression in p53-deficient H1299 human lung carcinoma cells.

    PubMed

    VanderBorght, A; Valckx, A; Van Dun, J; Grand-Perret, T; De Schepper, S; Vialard, J; Janicot, M; Arts, J

    2006-10-26

    The hdm-2 oncogene is overexpressed in several types of malignancies including osteosarcomas, soft tissue sarcomas and gliomas and hdm-2 has been associated with accelerated tumor formation in both hereditary and sporadic cancers. Among the other key binding partners, hdm-2 forms a complex with the tumor suppressor p53, resulting in a rapid proteasome-mediated degradation of the p53 protein. This positions the hdm-2-p53 complex as an attractive target for the development of anticancer therapy and recently the first small molecule hdm-2 antagonist has been reported. Development of hdm-2 antagonists is currently focused on malignancies containing a wild-type p53 genotype, which is the case in approximately half of human cancer indications. However, hdm-2 has also been implicated in oncogenesis in the absence of p53. We therefore studied the effect of hdm-2 antagonists in p53-deficient human H1299 lung carcinoma cells. The hdm-2 antagonistic peptide caused G1 cell cycle arrest, inhibited colony growth and induced expression of G1 checkpoint regulatory proteins, such as p21(waf1,cip1). These data demonstrate that hdm-2 regulates the G1 cell cycle checkpoint in a p53-independent manner, suggesting that hdm-2 antagonists represent a novel class of anticancer therapeutics with broad applicability towards tumors with different p53 genetic backgrounds.

  20. Protein Inhibitor of Activated STAT3 Suppresses Oxidized LDL-induced Cell Responses during Atherosclerosis in Apolipoprotein E-deficient Mice

    PubMed Central

    Wang, Rong; Zhang, Yanjin; Xu, Liran; Lin, Yan; Yang, Xiaofeng; Bai, Liang; Chen, Yulong; Zhao, Sihai; Fan, Jianglin; Cheng, Xianwu; Liu, Enqi

    2016-01-01

    Atherosclerosis is a serious public health concern. Excessive inflammatory responses of vascular cells are considered a pivotal pathogenesis mechanism underlying atherosclerosis development. It is known that Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) signalling plays an important role in atherosclerosis progression. Protein inhibitor of activated STAT3 (PIAS3) is the key negative regulator of JAK/STAT3 signalling. However, its effect on atherogenesis is unknown. Here, we observed that PIAS3 levels are reduced in atherosclerotic lesions and that PIAS3 expression decreases in conjunction with increases in interleukin-6 expression and atherosclerosis severity. Oxidized low-density lipoprotein (ox-LDL), an atherogenic stimulus, reduced PIAS3 expression, an effect that may be attributed to nitric oxide synthesis upregulation. In turn, PIAS3 overexpression effectively suppressed ox-LDL-induced inflammation, lipid accumulation and vascular smooth muscle cell proliferation. These results indicate that PIAS3 is a critical repressor of atherosclerosis progression. The findings of this study have contributed to our understanding on the pathogenesis of atherosclerosis and have provided us with a potential target through which we can inhibit atherosclerosis-related cellular responses. PMID:27845432

  1. Inhibition of the activation of Hageman factor (factor XII) by complement subcomponent C1q.

    PubMed

    Rehmus, E H; Greene, B M; Everson, B A; Ratnoff, O D

    1987-08-01

    Hageman factor (HF, Factor XII) is activated by glass, collagen, and ellagic acid, and initiates blood coagulation via the intrinsic pathway. C1q inhibits collagen-induced platelet aggregation and adherence of platelets to glass, effects attributable to the collagen-like region of C1q. We examined the actions of C1q on HF activation. Incubation of C1q with HF before addition of HF-deficient plasma extended the activated partial thromboplastin time. Similarly, when glass tubes were coated with C1q before testing, the partial thromboplastin time of normal plasma was increased. C1q reduced the activation of HF by ellagic acid, as measured by the release of p-nitroaniline from the synthetic substrate H-D-prolyl-L-phenylalanyl-L-arginine-p-nitroanilide dihydrochloride, an effect inhibited by monoclonal anti-human C1q murine IgG and by digestion of C1q by collagenase. Thus, C1q inhibits activation of HF in vitro in clot-promoting and amidolytic assays and suggests a regulatory mechanism for the inhibition of coagulation.

  2. Inhibition of the activation of Hageman factor (factor XII) by complement subcomponent C1q.

    PubMed Central

    Rehmus, E H; Greene, B M; Everson, B A; Ratnoff, O D

    1987-01-01

    Hageman factor (HF, Factor XII) is activated by glass, collagen, and ellagic acid, and initiates blood coagulation via the intrinsic pathway. C1q inhibits collagen-induced platelet aggregation and adherence of platelets to glass, effects attributable to the collagen-like region of C1q. We examined the actions of C1q on HF activation. Incubation of C1q with HF before addition of HF-deficient plasma extended the activated partial thromboplastin time. Similarly, when glass tubes were coated with C1q before testing, the partial thromboplastin time of normal plasma was increased. C1q reduced the activation of HF by ellagic acid, as measured by the release of p-nitroaniline from the synthetic substrate H-D-prolyl-L-phenylalanyl-L-arginine-p-nitroanilide dihydrochloride, an effect inhibited by monoclonal anti-human C1q murine IgG and by digestion of C1q by collagenase. Thus, C1q inhibits activation of HF in vitro in clot-promoting and amidolytic assays and suggests a regulatory mechanism for the inhibition of coagulation. PMID:3038961

  3. Disaccharidase deficiency.

    PubMed

    Bayless, T M; Christopher, N L

    1969-02-01

    This review of the literature and current knowledge concerning a nutritional disorder of disaccharidase deficiency discusses the following topics: 1) a description of disorders of disaccharide digestion; 2) some historical perspective on the laboratory and bedside advances in the past 10 years that have helped define a group of these digestive disorders; 3) a classification of conditions causing disaccharide intolerance; and 4) a discussion of some of the specific clinical syndromes emphasizing nutritional consequences of these syndromes. The syndromes described include congenital lactase deficiency, acquired lactase deficiency in teenagers and adults, acquired generalized disaccharidase deficiency secondary to diffuse mucosal damage, acquired lactose intolerance secondary to alterations in the intestinal transit, sucrase-isomaltase deficiencies, and other disease associations connected with lactase deficiency such as colitis.

  4. ACAT inhibitor pactimibe sulfate (CS-505) reduces and stabilizes atherosclerotic lesions by cholesterol-lowering and direct effects in apolipoprotein E-deficient mice.

    PubMed

    Terasaka, Naoki; Miyazaki, Atsuhiro; Kasanuki, Naomi; Ito, Kayoko; Ubukata, Naoko; Koieyama, Tadashi; Kitayama, Ken; Tanimoto, Tatsuo; Maeda, Naoyuki; Inaba, Toshimori

    2007-02-01

    The objective of the present study was to determine whether a novel acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, pactimibe sulfate (CS-505), could reduce atherosclerotic lesions beyond and independent of the reduction achieved by cholesterol lowering alone from two different types of lesions. (1) Early lesion model. Twelve-week-old apolipoprotein E (apoE)(-/-) mice were treated with 0.03 or 0.1% (w/w) CS-505, 0.1 or 0.3% avasimibe (CI-1011), or 3% cholestyramine for 12 weeks. Each treatment significantly reduced plasma cholesterol by a similar degree (43-48%). The antiatherosclerotic activity of 0.1% CS-505, however, was more efficacious than the effects of the other treatments (90% versus 40-50%). (2) Advanced lesion model. Twenty-four-week-old apoE(-/-) mice were treated with 0.03 or 0.1% CS-505 or 0.1% CI-1011 for 12 weeks. CS-505 at 0.1% revealed enhanced lesion reduction compared with 0.1% CI-1011 (77% versus 54%), whereas the plasma cholesterol-lowering effect of 0.1% CS-505 was almost the same as that of 0.1% CI-1011. Furthermore, immunohistochemical analysis demonstrated that CS-505 significantly reduced the number of macrophages and expression of matrix metalloproteinase (MMP)-2, MMP-9, and MMP-13. These data indicate that CS-505 can reduce and stabilize atherosclerotic lesions. This antiatherosclerotic activity is exerted via both cholesterol lowering and direct ACAT inhibition in plaque macrophages.

  5. Anxiety and depression with neurogenesis defects in exchange protein directly activated by cAMP 2-deficient mice are ameliorated by a selective serotonin reuptake inhibitor, Prozac

    PubMed Central

    Zhou, L; Ma, S L; Yeung, P K K; Wong, Y H; Tsim, K W K; So, K F; Lam, L C W; Chung, S K

    2016-01-01

    Intracellular cAMP and serotonin are important modulators of anxiety and depression. Fluoxetine, a selective serotonin reuptake inhibitor (SSRI) also known as Prozac, is widely used against depression, potentially by activating cAMP response element-binding protein (CREB) and increasing brain-derived neurotrophic factor (BDNF) through protein kinase A (PKA). However, the role of Epac1 and Epac2 (Rap guanine nucleotide exchange factors, RAPGEF3 and RAPGEF4, respectively) as potential downstream targets of SSRI/cAMP in mood regulations is not yet clear. Here, we investigated the phenotypes of Epac1 (Epac1−/−) or Epac2 (Epac2−/−) knockout mice by comparing them with their wild-type counterparts. Surprisingly, Epac2−/− mice exhibited a wide range of mood disorders, including anxiety and depression with learning and memory deficits in contextual and cued fear-conditioning tests without affecting Epac1 expression or PKA activity. Interestingly, rs17746510, one of the three single-nucleotide polymorphisms (SNPs) in RAPGEF4 associated with cognitive decline in Chinese Alzheimer's disease (AD) patients, was significantly correlated with apathy and mood disturbance, whereas no significant association was observed between RAPGEF3 SNPs and the risk of AD or neuropsychiatric inventory scores. To further determine the detailed role of Epac2 in SSRI/serotonin/cAMP-involved mood disorders, we treated Epac2−/− mice with a SSRI, Prozac. The alteration in open field behavior and impaired hippocampal cell proliferation in Epac2−/− mice were alleviated by Prozac. Taken together, Epac2 gene polymorphism is a putative risk factor for mood disorders in AD patients in part by affecting the hippocampal neurogenesis. PMID:27598965

  6. Anxiety and depression with neurogenesis defects in exchange protein directly activated by cAMP 2-deficient mice are ameliorated by a selective serotonin reuptake inhibitor, Prozac.

    PubMed

    Zhou, L; Ma, S L; Yeung, P K K; Wong, Y H; Tsim, K W K; So, K F; Lam, L C W; Chung, S K

    2016-09-06

    Intracellular cAMP and serotonin are important modulators of anxiety and depression. Fluoxetine, a selective serotonin reuptake inhibitor (SSRI) also known as Prozac, is widely used against depression, potentially by activating cAMP response element-binding protein (CREB) and increasing brain-derived neurotrophic factor (BDNF) through protein kinase A (PKA). However, the role of Epac1 and Epac2 (Rap guanine nucleotide exchange factors, RAPGEF3 and RAPGEF4, respectively) as potential downstream targets of SSRI/cAMP in mood regulations is not yet clear. Here, we investigated the phenotypes of Epac1 (Epac1(-/-)) or Epac2 (Epac2(-/-)) knockout mice by comparing them with their wild-type counterparts. Surprisingly, Epac2(-/-) mice exhibited a wide range of mood disorders, including anxiety and depression with learning and memory deficits in contextual and cued fear-conditioning tests without affecting Epac1 expression or PKA activity. Interestingly, rs17746510, one of the three single-nucleotide polymorphisms (SNPs) in RAPGEF4 associated with cognitive decline in Chinese Alzheimer's disease (AD) patients, was significantly correlated with apathy and mood disturbance, whereas no significant association was observed between RAPGEF3 SNPs and the risk of AD or neuropsychiatric inventory scores. To further determine the detailed role of Epac2 in SSRI/serotonin/cAMP-involved mood disorders, we treated Epac2(-/-) mice with a SSRI, Prozac. The alteration in open field behavior and impaired hippocampal cell proliferation in Epac2(-/-) mice were alleviated by Prozac. Taken together, Epac2 gene polymorphism is a putative risk factor for mood disorders in AD patients in part by affecting the hippocampal neurogenesis.

  7. MECHANISMS OF ACTIVATION OF C'1 ESTERASE IN HEREDITARY ANGIONEUROTIC EDEMA PLASMA IN VITRO

    PubMed Central

    Donaldson, Virginia H.

    1968-01-01

    The generation of C'1 esterase activity in siliconed plasma obtained from individuals with hereditary angioneurotic edema in remission tends to occur spontaneously, but can be hastened during its incubation with preparations of activated Hageman factor. This effect of activated Hageman factor could not be shown during its incubation with normal siliconed plasma, nor could consumption of normal serum inhibition of C'1 esterase be clearly shown. Soy bean trypsin inhibitor and heparin could impair this enhanced generation of C'1 esterase but neither inhibits the esterolytic function of C'1 esterase once formed. Trasylol was less effective in blocking this effect of activated Hageman factor. While the mechanism of the effect of activated Hageman factor upon C'1 activation remains obscure, it is apparent that some intermediate steps, possibly involving a kinin-forming system of plasma, may play a role. PMID:5299945

  8. Combined traumatic occiput-C1 and C1-C2 dissociation: 2 case reports.

    PubMed

    Gould, Stephen; Hishmeh, Shuriz; McKinney, Bart; Stephen, Mark

    2010-08-01

    Occiput-C1 and C1-C2 dissociations and dislocations have been well documented in the literature. However, after thorough review of the literature, we found very little in the literature regarding combined occiput-C1 and C1-C2 dissociations in adults who survived. We present 2 case reports describing the clinical presentation, initial management, operative treatment, and postoperative course of 2 patients who sustained traumatic combined occiput-C1 and C1-C2 dissociations. After initial stabilization, both patients underwent open reduction and posterior occipital-cervical fusion with segmental fixation. At recent follow-up, both patients maintain good sagittal alignment without loss of reduction, and they have radiographic progression to fusion, minimal pain, and improved neurologic function. Combined occiput-C1 and C1-C2 dissociations are rare but serious injuries. Incomplete dissociations may not be evident on initial radiographs. Computed tomography or magnetic resonance imaging is recommended for formal diagnosis. A traumatic dural tear may be present. We recommend open reduction and posterior occipital-cervical fusion with segmental fixation for these patients.

  9. Cooperative Research in C1 Chemistry

    SciTech Connect

    Gerald P. Huffman

    2000-10-27

    C1 chemistry refers to the conversion of simple carbon-containing materials that contain one carbon atom per molecule into valuable products. The feedstocks for C1 chemistry include natural gas, carbon dioxide, carbon monoxide, methanol and synthesis gas (a mixture of carbon monoxide and hydrogen). Synthesis gas, or syngas, is produced primarily by the reaction of natural gas, which is principally methane, with steam. It can also be produced by gasification of coal, petroleum coke, or biomass. The availability of syngas from coal gasification is expected to increase significantly in the future because of increasing development of integrated gasification combined cycle (IGCC) power generation. Because of the abundance of remote natural gas, the advent of IGCC, and environmental advantages, C1 chemistry is expected to become a major area of interest for the transportation fuel and chemical industries in the relatively near future. The CFFLS will therefore perform a valuable national service by providing science and engineering graduates that are trained in this important area. Syngas is the source of most hydrogen. Approximately 10 trillion standard cubic feet (SCF) of hydrogen are manufactured annually in the world. Most of this hydrogen is currently used for the production of ammonia and in a variety of refining and chemical operations. However, utilization of hydrogen in fuel cells is expected to grow significantly in the next century. Syngas is also the feedstock for all methanol and Fischer-Tropsch plants. Currently, world consumption of methanol is over 25 million tons per year. There are many methanol plants in the U.S. and throughout the world. Methanol and oxygenated transportation fuel products play a significant role in the CFFLS C1 program. Currently, the only commercial Fischer-Tropsch plants are overseas, principally in South Africa (SASOL). However, new plants are being built or planned for a number of locations. One possible location for future F

  10. Enhanced synaptic connectivity and epilepsy in C1q knockout mice.

    PubMed

    Chu, Yunxiang; Jin, Xiaoming; Parada, Isabel; Pesic, Alexei; Stevens, Beth; Barres, Ben; Prince, David A

    2010-04-27

    Excessive CNS synapses are eliminated during development to establish mature patterns of neuronal connectivity. A complement cascade protein, C1q, is involved in this process. Mice deficient in C1q fail to refine retinogeniculate connections resulting in excessive retinal innervation of lateral geniculate neurons. We hypothesized that C1q knockout (KO) mice would exhibit defects in neocortical synapse elimination resulting in enhanced excitatory synaptic connectivity and epileptiform activity. We recorded spontaneous and evoked field potential activity in neocortical slices and obtained video-EEG recordings from implanted C1q KO and wild-type (WT) mice. We also used laser scanning photostimulation of caged glutamate and whole cell recordings to map excitatory and inhibitory synaptic connectivity. Spontaneous and evoked epileptiform field potentials occurred at multiple sites in neocortical slices from C1q KO, but not WT mice. Laser mapping experiments in C1q KO slices showed that the proportion of glutamate uncaging sites from which excitatory postsynaptic currents (EPSCs) could be evoked ("hotspot ratio") increased significantly in layer IV and layer V, although EPSC amplitudes were unaltered. Density of axonal boutons was significantly increased in layer V pyramidal neurons of C1q KO mice. Implanted KO mice had frequent behavioral seizures consisting of behavioral arrest associated with bihemispheric spikes and slow wave activity lasting from 5 to 30 s. Results indicate that epileptogenesis in C1q KO mice is related to a genetically determined failure to prune excessive excitatory synapses during development.

  11. 21 CFR 866.5250 - Complement C2 inhibitor (inactivator) immunological test system.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... the reagents used to measure by immunochemical techniques the complement C1 inhibitor (a plasma protein) in serum. Complement C1 inhibitor occurs normally in plasma and blocks the action of the...

  12. 21 CFR 866.5250 - Complement C2 inhibitor (inactivator) immunological test system.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... the reagents used to measure by immunochemical techniques the complement C1 inhibitor (a plasma protein) in serum. Complement C1 inhibitor occurs normally in plasma and blocks the action of the...

  13. 21 CFR 866.5250 - Complement C2 inhibitor (inactivator) immunological test system.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... the reagents used to measure by immunochemical techniques the complement C1 inhibitor (a plasma protein) in serum. Complement C1 inhibitor occurs normally in plasma and blocks the action of the...

  14. 21 CFR 866.5250 - Complement C 2 inhibitor (inactivator) immunological test system.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... the reagents used to measure by immunochemical techniques the complement C1 inhibitor (a plasma protein) in serum. Complement C1 inhibitor occurs normally in plasma and blocks the action of the...

  15. 21 CFR 866.5250 - Complement C 2 inhibitor (inactivator) immunological test system.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... the reagents used to measure by immunochemical techniques the complement C1 inhibitor (a plasma protein) in serum. Complement C1 inhibitor occurs normally in plasma and blocks the action of the...

  16. COOPERATIVE RESEARCH IN C1 CHEMISTRY

    SciTech Connect

    Gerald P. Huffman

    2001-04-30

    Faculty and students from five universities (Kentucky, West Virginia, Utah, Pittsburgh and Auburn) are collaborating on a basic research program to develop novel C1 chemistry processes for the production of clean, high quality transportation fuel. An Industrial Advisory Board (IAB) with members from Chevron, Eastman Chemical, Energy International, Teir Associates, and the Department of Defense has been formed to provide practical guidance to the program. The program has two principal objectives. (1) Develop technology for conversion of C1 source materials (natural gas, synthesis gas, carbon dioxide and monoxide, and methanol) into clean, high efficiency transportation fuel. (2) Develop novel processes for producing hydrogen from natural gas and other hydrocarbons. Some of the principal accomplishments of the program in its first two years are: (1) The addition of acetylenic compounds in Fischer-Tropsch synthesis is found to produce significant amounts of oxygenated products in FT diesel fuels. Such oxygenated products should decrease particulate matter (PM) emissions. (2) Nanoscale, binary, Fe-based catalysts supported on alumina have been shown to have significant activity for the decomposition of methane into pure hydrogen and potentially valuable multi-walled carbon nanotubes. (3) Catalytic synthesis processes have been developed for synthesis of diethyl carbonate, higher ethers, and higher alcohols from C1 source materials. Testing of the effect of adding these oxygenates to diesel fuel on PM emissions has begun using a well-equipped small diesel engine test facility. (4) Supercritical fluid (SCF) FT synthesis has been conducted under SCF hexane using both Fe and Co catalysts. There is a marked effect on the hydrocarbon product distribution, with a shift to higher carbon number products. These and other results are summarized.

  17. Complement Component C1q Mediates Mitochondria-Driven Oxidative Stress in Neonatal Hypoxic–Ischemic Brain Injury

    PubMed Central

    Ten, Vadim S.; Yao, Jun; Ratner, Veniamin; Sosunov, Sergey; Fraser, Deborah A.; Botto, Marina; Baalasubramanian, Sivasankar; Morgan, B. Paul; Silverstein, Samuel; Stark, Raymond; Polin, Richard; Vannucci, Susan J.; Pinsky, David; Starkov, Anatoly A.

    2010-01-01

    Hypoxic–ischemic (HI) brain injury in infants is a leading cause of lifelong disability. We report a novel pathway mediating oxidative brain injury after hypoxia–ischemia in which C1q plays a central role. Neonatal mice incapable of classical or terminal complement activation because of C1q or C6 deficiency or pharmacologically inhibited assembly of membrane attack complex were subjected to hypoxia–ischemia. Only C1q−/− mice exhibited neuroprotection coupled with attenuated oxidative brain injury. This was associated with reduced production of reactive oxygen species (ROS) in C1q−/− brain mitochondria and preserved activity of the respiratory chain. Compared with C1q+/+ neurons, cortical C1q−/− neurons exhibited resistance to oxygen– glucose deprivation. However, postischemic exposure to exogenous C1q increased both mitochondrial ROS production and mortality of C1q−/− neurons. This C1q toxicity was abolished by coexposure to antioxidant Trolox (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid). Thus, the C1q component of complement, accelerating mitochondrial ROS emission, exacerbates oxidative injury in the developing HI brain. The terminal complement complex is activated in the HI neonatal brain but appeared to be nonpathogenic. These findings have important implications for design of the proper therapeutic interventions against HI neonatal brain injury by highlighting a pathogenic priority of C1q-mediated mitochondrial oxidative stress over the C1q deposition-triggered terminal complement activation. PMID:20147536

  18. Theoretical Insights into C1 Surface Chemistry

    NASA Astrophysics Data System (ADS)

    Neurock, Matthew

    2008-03-01

    Reforming and partial oxidation of methane as well as other C1 fuels are important processes in the production of hydrogen and synthesis gas and will likely play important roles future energy strategies. Herein we use theory and simulation to examine the reactivity of methane, methanol and dimethyl ether with CO2, H2O, or O2 over supported transition metals. We systematically probe the elementary C-H bond activation as well as the oxidation pathways involved in both reforming as the oxidation of methane and other C1 intermediates over well defined transition metal surfaces, metal alloys and metal nanoparticles. The calculations demonstrate well-established trends in C-H bond activation as the result of changes in the metal, the activating molecule (methane, methanol, and DME) as well as the reaction conditions. The reaction conditions ultimately dictate the surface coverage of carbon and oxygen which have important consequences on the surface reactivity. The theoretical and simulation results are compared with well defined experiments carried out at Berkeley over supported particles.

  19. Safety and pharmacokinetics of 120 mg/kg versus 60 mg/kg weekly intravenous infusions of alpha-1 proteinase inhibitor in alpha-1 antitrypsin deficiency: a multicenter, randomized, double-blind, crossover study (SPARK).

    PubMed

    Campos, Michael A; Kueppers, Friedrich; Stocks, James M; Strange, Charlie; Chen, Junliang; Griffin, Rhonda; Wang-Smith, Laurene; Brantly, Mark L

    2013-12-01

    Augmentation therapy with the approved dose of 60 mg/kg weekly intravenous (IV) alpha-1 proteinase inhibitor (alpha1-PI), achieves a trough serum level of 11 μM in individuals with alpha-1 antitrypsin deficiency (AATD), yet this is still below the level observed in healthy individuals. This study assessed the safety and pharmacokinetic profile of weekly infusions of a 120 mg/kg dose of alpha1-PI in 30 adults with AATD. Subjects with symptomatic, genetically determined (genotypes PI*ZZ, PI*Z(null), PI*(null)(null) or PI*(Z)Mmalton) AATD were randomly assigned to weekly infusions of 60 or 120 mg/kg alpha1-PI (Prolastin-C®) for 8 weeks before crossing over to the alternate dose for 8 weeks. Adverse events (AEs) (including exacerbations), vital signs, pulmonary function tests, and laboratory assessments were recorded. Pharmacokinetic measurements included AUC0-7days, Cmax, trough, tmax, and t1/2, based on serum alpha1-PI concentrations. In total for both treatments, 112 AEs were reported, with exacerbation of COPD being the most frequent, consistent with the subjects' diagnoses. Mean steady-state serum alpha1-PI concentrations following 120 mg/kg weekly IV alpha1-PI were higher than with the 60 mg/kg dose and mean trough concentrations were 27.7 versus 17.3 μM, respectively. Dose proportionality was demonstrated for AUC0-7days and Cmax, with low inter-subject variability. The 120 mg/kg alpha1-PI weekly dose was considered to be safe and well tolerated, and provided more favorable physiologic alpha1-PI serum levels than the currently recommended 60 mg/kg dose. The effect of this dosing regimen on slowing and/or preventing emphysema progression in subjects with AATD warrants further investigation.

  20. Loss of Cellular Sialidases Does Not Affect the Sialylation Status of the Prion Protein but Increases the Amounts of Its Proteolytic Fragment C1

    PubMed Central

    Katorcha, Elizaveta; Klimova, Nina; Makarava, Natallia; Savtchenko, Regina; Pan, Xuefang; Annunziata, Ida; Takahashi, Kohta; Miyagi, Taeko; Pshezhetsky, Alexey V.; d’Azzo, Alessandra; Baskakov, Ilia V.

    2015-01-01

    The central molecular event underlying prion diseases involves conformational change of the cellular form of the prion protein (PrPC), which is a sialoglycoprotein, into the disease-associated, transmissible form denoted PrPSc. Recent studies revealed a correlation between the sialylation status of PrPSc and incubation time to disease and introduced a new hypothesis that progression of prion diseases could be controlled or reversed by altering the sialylation level of PrPC. Of the four known mammalian sialidases, the enzymes that cleave off sialic acid residues, only NEU1, NEU3 and NEU4 are expressed in the brain. To test whether cellular sialidases control the steady-state sialylation level of PrPC and to identify the putative sialidase responsible for desialylating PrPC, we analyzed brain-derived PrPC from knockout mice deficient in Neu1, Neu3, Neu4, or from Neu3/Neu4 double knockouts. Surprisingly, no differences in the sialylation of PrPC or its proteolytic product C1 were noticed in any of the knockout mice tested as compared to the age-matched controls. However, significantly higher amounts of the C1 fragment relative to full-length PrPC were detected in the brains of Neu1 knockout mice as compared to WT mice or to the other knockout mice. Additional experiments revealed that in neuroblastoma cell line the sialylation pattern of C1 could be changed by an inhibitor of sialylatransferases. In summary, this study suggests that targeting cellular sialidases is apparently not the correct strategy for altering the sialylation levels of PrPC, whereas modulating the activity of sialylatransferases might offer a more promising approach. Our findings also suggest that catabolism of PrPC involves its α-cleavage followed by desialylation of the resulting C1 fragments by NEU1 and consequent fast degradation of the desialylated products. PMID:26569607

  1. Expression of recombinant human complement C1q allows identification of the C1r/C1s-binding sites

    PubMed Central

    Bally, Isabelle; Ancelet, Sarah; Moriscot, Christine; Gonnet, Florence; Mantovani, Alberto; Daniel, Régis; Schoehn, Guy; Arlaud, Gérard J.; Thielens, Nicole M.

    2013-01-01

    Complement C1q is a hexameric molecule assembled from 18 polypeptide chains of three different types encoded by three genes. This versatile recognition protein senses a wide variety of immune and nonimmune ligands, including pathogens and altered self components, and triggers the classical complement pathway through activation of its associated proteases C1r and C1s. We report a method for expression of recombinant full-length human C1q involving stable transfection of HEK 293-F mammalian cells and fusion of an affinity tag to the C-terminal end of the C chain. The resulting recombinant (r) C1q molecule is similar to serum C1q as judged from biochemical and structural analyses and exhibits the characteristic shape of a bunch of flowers. Analysis of its interaction properties by surface plasmon resonance shows that rC1q retains the ability of serum C1q to associate with the C1s-C1r-C1r-C1s tetramer, to recognize physiological C1q ligands such as IgG and pentraxin 3, and to trigger C1r and C1s activation. Functional analysis of rC1q variants carrying mutations of LysA59, LysB61, and/or LysC58, in the collagen-like stems, demonstrates that LysB61 and LysC58 each play a key role in the interaction with C1s-C1r-C1r-C1s, with LysA59 being involved to a lesser degree. We propose that LysB61 and LysC58 both form salt bridges with outer acidic Ca2+ ligands of the C1r and C1s CUB (complement C1r/C1s, Uegf, bone morphogenetic protein) domains. The expression method reported here opens the way for deciphering the molecular basis of the unusual binding versatility of C1q by mapping the residues involved in the sensing of its targets and the binding of its receptors. PMID:23650384

  2. Classical complement pathway component C1q: purification of human C1q, isolation of C1q collagen-like and globular head fragments and production of recombinant C1q-derivatives. Functional characterization.

    PubMed

    Kojouharova, Mihaela

    2014-01-01

    The classical complement pathway (CCP) activation is a multimolecular complex, composed of three subcomponents namely C1q, C1r, and C1s. C1q is the recognition subunit of this complex and its binding to the specific targets leads to the formation of active C1, which in turn activates the CCP in an immunoglobulin-dependent or -independent manner. C1q is a hexameric glycoprotein composed of 18 polypeptide chains of three different types (A, B, and C), organized in two fragments-collagen-like (CLR) and globular head (gC1q) possessing different functional activity. The contemporary knowledge of the C1q structure allows the isolation and purification of a C1q molecule from serum by combination of different chromatography procedures including ion-exchange, size-exclusion, and affinity chromatography, as well as the isolation of CLR and gC1q by limited enzymatic hydrolysis of the native C1q molecule. In this chapter, we described methods for purification of human C1q and its CLR and gC1q fragments, as well as methods for their biochemical and functional characterization. The production and purification of recombinant C1q derivatives ghA, ghB, and ghC (globular fragments of the individual C1q chains) are also presented.

  3. The non-inflammatory role of C1q during Her2/neu-driven mammary carcinogenesis.

    PubMed

    Bandini, Silvio; Macagno, Marco; Hysi, Albana; Lanzardo, Stefania; Conti, Laura; Bello, Amanda; Riccardo, Federica; Ruiu, Roberto; Merighi, Irene Fiore; Forni, Guido; Iezzi, Manuela; Quaglino, Elena; Cavallo, Federica

    2016-01-01

    There is an ever increasing amount of evidence to support the hypothesis that complement C1q, the first component of the classical complement pathway, is involved in the regulation of cancer growth, in addition to its role in fighting infections. It has been demonstrated that C1q is expressed in the microenvironment of various types of human tumors, including breast adenocarcinomas. This study compares carcinogenesis progression in C1q deficient (neuT-C1KO) and C1q competent neuT mice in order to investigate the role of C1q in mammary carcinogenesis. Significantly accelerated autochthonous neu(+) carcinoma progression was paralleled by accelerated spontaneous lung metastases occurrence in C1q deficient mice. Surprisingly, this effect was not caused by differences in the tumor-infiltrating cells or in the activation of the complement classical pathway, since neuT-C1KO mice did not display a reduction in C3 fragment deposition at the tumor site. By contrast, a significant higher number of intratumor blood vessels and a decrease in the activation of the tumor suppressor WW domain containing oxidoreductase (WWOX) were observed in tumors from neuT-C1KO as compare with neuT mice. In parallel, an increase in Her2/neu expression was observed on the membrane of tumor cells. Taken together, our findings suggest that C1q plays a direct role both on halting tumor angiogenesis and on inducing apoptosis in mammary cancer cells by coordinating the signal transduction pathways linked to WWOX and, furthermore, highlight the role of C1q in mammary tumor immune surveillance regardless of complement system activation.

  4. Glycosylation inhibition reduces cholesterol accumulation in NPC1 protein-deficient cells.

    PubMed

    Li, Jian; Deffieu, Maika S; Lee, Peter L; Saha, Piyali; Pfeffer, Suzanne R

    2015-12-01

    Lysosomes are lined with a glycocalyx that protects the limiting membrane from the action of degradative enzymes. We tested the hypothesis that Niemann-Pick type C 1 (NPC1) protein aids the transfer of low density lipoprotein-derived cholesterol across this glycocalyx. A prediction of this model is that cells will be less dependent upon NPC1 if their glycocalyx is decreased in density. Lysosome cholesterol content was significantly lower after treatment of NPC1-deficient human fibroblasts with benzyl-2-acetamido-2-deoxy-α-D-galactopyranoside, an inhibitor of O-linked glycosylation. Direct biochemical measurement of cholesterol showed that lysosomes purified from NPC1-deficient fibroblasts contained at least 30% less cholesterol when O-linked glycosylation was blocked. As an independent means to modify protein glycosylation, we used Chinese hamster ovary ldl-D cells defective in UDP-Gal/UDP-GalNAc 4-epimerase in which N- and O-linked glycosylation can be controlled. CRISPR generated, NPC1-deficient ldl-D cells supplemented with galactose accumulated more cholesterol than those in which sugar addition was blocked. In the absence of galactose supplementation, NPC1-deficient ldl-D cells also transported more cholesterol from lysosomes to the endoplasmic reticulum, as monitored by an increase in cholesteryl [(14)C]-oleate levels. These experiments support a model in which NPC1 protein functions to transfer cholesterol past a lysosomal glycocalyx.

  5. Mutation of the Conserved Calcium-Binding Motif in Neisseria gonorrhoeae PilC1 Impacts Adhesion but Not Piliation

    PubMed Central

    Cheng, Yuan; Johnson, Michael D. L.; Burillo-Kirch, Christine; Mocny, Jeffrey C.; Anderson, James E.; Garrett, Christopher K.; Redinbo, Matthew R.

    2013-01-01

    Neisseria gonorrhoeae PilC1 is a member of the PilC family of type IV pilus-associated adhesins found in Neisseria species and other type IV pilus-producing genera. Previously, a calcium-binding domain was described in the C-terminal domains of PilY1 of Pseudomonas aeruginosa and in PilC1 and PilC2 of Kingella kingae. Genetic analysis of N. gonorrhoeae revealed a similar calcium-binding motif in PilC1. To evaluate the potential significance of this calcium-binding region in N. gonorrhoeae, we produced recombinant full-length PilC1 and a PilC1 C-terminal domain fragment. We show that, while alterations of the calcium-binding motif disrupted the ability of PilC1 to bind calcium, they did not grossly affect the secondary structure of the protein. Furthermore, we demonstrate that both full-length wild-type PilC1 and full-length calcium-binding-deficient PilC1 inhibited gonococcal adherence to cultured human cervical epithelial cells, unlike the truncated PilC1 C-terminal domain. Similar to PilC1 in K. kingae, but in contrast to the calcium-binding mutant of P. aeruginosa PilY1, an equivalent mutation in N. gonorrhoeae PilC1 produced normal amounts of pili. However, the N. gonorrhoeae PilC1 calcium-binding mutant still had partial defects in gonococcal adhesion to ME180 cells and genetic transformation, which are both essential virulence factors in this human pathogen. Thus, we conclude that calcium binding to PilC1 plays a critical role in pilus function in N. gonorrhoeae. PMID:24002068

  6. Proteolytic inactivation of nuclear alarmin high-mobility group box 1 by complement protease C1s during apoptosis

    PubMed Central

    Yeo, J G; Leong, J; Arkachaisri, T; Cai, Y; Teo, B H D; Tan, J H T; Das, L; Lu, J

    2016-01-01

    Effective clearance of apoptotic cells by phagocytes prevents the release of intracellular alarmins and manifestation of autoimmunity. This prompt efferocytosis is complemented by intracellular proteolytic degradation that occurs within the apoptotic cells and in the efferosome of the phagocytes. Although the role of extracellular proteases in apoptotic cells clearance is unknown, the strong association of congenital C1s deficiency with Systemic Lupus Erythematosus highlights the protective nature that this extracellular protease has against autoimmunity. The archetypical role of serine protease C1s as the catalytic arm of C1 complex (C1qC1r2C1s2) involve in the propagation of the classical complement pathway could not provide the biological basis for this association. However, a recent observation of the ability of C1 complex to cleave a spectrum of intracellular cryptic targets exposed during apoptosis provides a valuable insight to the underlying protective mechanism. High-mobility group box 1 (HMGB1), an intracellular alarmin that is capable of inducing the formation of antinuclear autoantibodies and causes lupus-like conditions in mice, is identified as a novel potential target by bioinformatics analysis. This is verified experimentally with C1s, both in its purified and physiological form as C1 complex, cleaving HMGB1 into defined fragments of 19 and 12 kDa. This cleavage diminishes HMGB1 ability to enhance lipopolysaccharide mediated pro-inflammatory cytokines production from monocytes, macrophages and dendritic cells. Further mass spectrometric analysis of the C1 complex treated apoptotic cellular proteins demonstrated additional C1s substrates and revealed the complementary role of C1s in apoptotic cells clearance through the proteolytic cleavage of intracellular alarmins and autoantigens. C1 complex may have evolved as, besides the bacteriolytic arm of antibodies in which it activates the complement cascade, a tissue renewal mechanism that reduces the

  7. The neural guidance receptor Plexin C1 delays melanoma progression

    PubMed Central

    Chen, Y; Soong, J; Mohanty, S; Xu, L; Scott, G

    2013-01-01

    Plexin C1 is a type I transmembrane receptor with intrinsic R-Ras GTPase activity, which regulates cytoskeletal remodeling and adhesion in normal human melanocytes. Melanocytes are pigment-producing cells of the epidermis, precursors for melanoma, and express high levels of Plexin C1, which is lost in melanoma in vitro and in vivo. To determine if Plexin C1 is a tumor suppressor for melanoma, we introduced Plexin C1 into a primary human melanoma cell line, and phenotypes including migration, apoptosis, proliferation and tumor growth in mice were analyzed. Complimentary studies in which Plexin C1 was silenced in human melanocytes were performed. Plexin C1 significantly inhibited migration and proliferation in melanoma, whereas in melanocytes, loss of Plexin C1 increased migration and proliferation. In mouse xenografts, Plexin C1 delayed tumor growth of melanoma at early time points, but tumors eventually escaped the suppressive effects of Plexin C1, due to Plexin C1-dependent activation of the pro-survival protein Akt. R-Ras activation stimulates melanoma migration. Plexin C1 lowered R-Ras activity in melanoma and melanocytes, consistent with inhibitory effects of Plexin C1 on migration of melanocytes and melanoma. To determine if R-Ras is expressed in melanocytic lesions in vivo, staining of tissue microarrays of nevi and melanoma were performed. R-Ras expression was highly limited in melanocytic lesions, being essentially confined to primary melanoma, and almost completely absent in nevi and metastatic melanoma. These data suggest that loss of Plexin C1 in melanoma may promote early steps in melanoma progression through suppression of migration and proliferation, but pro-survival effects of Plexin C1 ultimately abrogate the tumor suppressive effects of Plexin C1. In primary melanoma, loss of Plexin C1 may function in early steps of melanoma progression by releasing inhibition of R-Ras activation, and stimulating migration. PMID:23160370

  8. The neural guidance receptor Plexin C1 delays melanoma progression.

    PubMed

    Chen, Y; Soong, J; Mohanty, S; Xu, L; Scott, G

    2013-10-10

    Plexin C1 is a type I transmembrane receptor with intrinsic R-Ras GTPase activity, which regulates cytoskeletal remodeling and adhesion in normal human melanocytes. Melanocytes are pigment-producing cells of the epidermis, precursors for melanoma, and express high levels of Plexin C1, which is lost in melanoma in vitro and in vivo. To determine if Plexin C1 is a tumor suppressor for melanoma, we introduced Plexin C1 into a primary human melanoma cell line, and phenotypes including migration, apoptosis, proliferation and tumor growth in mice were analyzed. Complimentary studies in which Plexin C1 was silenced in human melanocytes were performed. Plexin C1 significantly inhibited migration and proliferation in melanoma, whereas in melanocytes, loss of Plexin C1 increased migration and proliferation. In mouse xenografts, Plexin C1 delayed tumor growth of melanoma at early time points, but tumors eventually escaped the suppressive effects of Plexin C1, due to Plexin C1-dependent activation of the pro-survival protein Akt. R-Ras activation stimulates melanoma migration. Plexin C1 lowered R-Ras activity in melanoma and melanocytes, consistent with inhibitory effects of Plexin C1 on migration of melanocytes and melanoma. To determine if R-Ras is expressed in melanocytic lesions in vivo, staining of tissue microarrays of nevi and melanoma were performed. R-Ras expression was highly limited in melanocytic lesions, being essentially confined to primary melanoma, and almost completely absent in nevi and metastatic melanoma. These data suggest that loss of Plexin C1 in melanoma may promote early steps in melanoma progression through suppression of migration and proliferation, but pro-survival effects of Plexin C1 ultimately abrogate the tumor suppressive effects of Plexin C1. In primary melanoma, loss of Plexin C1 may function in early steps of melanoma progression by releasing inhibition of R-Ras activation, and stimulating migration.

  9. 26 CFR 1.682(c)-1 - Definitions.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 8 2010-04-01 2010-04-01 false Definitions. 1.682(c)-1 Section 1.682(c)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES Miscellaneous § 1.682(c)-1 Definitions. For definitions of the terms “husband” and “wife”...

  10. Plasminogen deficiency.

    PubMed

    Celkan, Tiraje

    2017-01-01

    Plasminogen plays an important role in fibrinolysis as well as wound healing, cell migration, tissue modeling and angiogenesis. Congenital plasminogen deficiency is a rare autosomal recessive disorder that leads to the development of thick, wood-like pseudomembranes on mucosal surfaces, mostly seen in conjunctivas named as ''ligneous conjunctivitis''. Local conjunctival use of fresh frozen plazma (FFP) in combination with other eye medications such as cyclosporin and artificial tear drops may relieve the symptoms. Topical treatment with plasminogen eye drops is the most promising treatment that is not yet available in Turkey.

  11. Transporters MCT8 and OATP1C1 maintain murine brain thyroid hormone homeostasis.

    PubMed

    Mayerl, Steffen; Müller, Julia; Bauer, Reinhard; Richert, Sarah; Kassmann, Celia M; Darras, Veerle M; Buder, Katrin; Boelen, Anita; Visser, Theo J; Heuer, Heike

    2014-05-01

    Allan-Herndon-Dudley syndrome (AHDS), a severe form of psychomotor retardation with abnormal thyroid hormone (TH) parameters, is linked to mutations in the TH-specific monocarboxylate transporter MCT8. In mice, deletion of Mct8 (Mct8 KO) faithfully replicates AHDS-associated endocrine abnormalities; however, unlike patients, these animals do not exhibit neurological impairments. While transport of the active form of TH (T3) across the blood-brain barrier is strongly diminished in Mct8 KO animals, prohormone (T4) can still enter the brain, possibly due to the presence of T4-selective organic anion transporting polypeptide (OATP1C1). Here, we characterized mice deficient for both TH transporters, MCT8 and OATP1C1 (Mct8/Oatp1c1 DKO). Mct8/Oatp1c1 DKO mice exhibited alterations in peripheral TH homeostasis that were similar to those in Mct8 KO mice; however, uptake of both T3 and T4 into the brains of Mct8/Oatp1c1 DKO mice was strongly reduced. Evidence of TH deprivation in the CNS of Mct8/Oatp1c1 DKO mice included highly decreased brain TH content as well as altered deiodinase activities and TH target gene expression. Consistent with delayed cerebellar development and reduced myelination, Mct8/Oatp1c1 DKO mice displayed pronounced locomotor abnormalities. Intriguingly, differentiation of GABAergic interneurons in the cerebral cortex was highly compromised. Our findings underscore the importance of TH transporters for proper brain development and provide a basis to study the pathogenic mechanisms underlying AHDS.

  12. Magnetism and the defect state in the magnetocaloric antiperovskite Mn3GaC1

    NASA Astrophysics Data System (ADS)

    Lewis, L. H.; Yoder, D.; Moodenbaugh, A. R.; Fischer, D. A.; Yu, M.-H.

    2006-02-01

    Magnetic and spectroscopic techniques were used to study the intermetallic antiperovskite Mn3GaC. An antiferromagnetic-ferromagnetic magnetostructural transition at 160 K underlies a remarkable magnetocaloric effect; these phenomena are suppressed in the substoichiometric composition Mn3GaC1-δ. X-ray absorption spectroscopy (XAS) data reported for three compositions Mn3GaC1-δ, δ = 0, 0.10, 0.22, are the basis for drawing inferences concerning the mechanism controlling magnetic order as a function of carbon stoichiometry. While the temperature dependence of the Mn3GaC carbon K edge reveals no observable change across the first-order magnetic transition, a clear splitting of the carbon absorption bands is observed that increases with increasing carbon deficiency. The room temperature Mn and Ga K edges indicate no significant variation with C content. FEFF 8.2 code calculations are in good qualitative agreement with data for the stoichiometric sample, but do not predict the changes in XAS observed in C-deficient samples. These results and the Goodenough-Anderson-Kanamori rules are the basis for a phenomenological model that attributes the carbon content dependence of the low temperature transition to the promotion of weak near-neighbour 90° Mn-Mn pairs in the carbon-deficient compound over the stronger 180° Mn-C-Mn interaction, locking in dominant ferromagnetism at low temperatures.

  13. Caspase cleavage of cytochrome c1 disrupts mitochondrial function and enhances cytochrome c release.

    PubMed

    Zhu, Yushan; Li, Min; Wang, Xiaohui; Jin, Haijing; Liu, Shusen; Xu, Jianxin; Chen, Quan

    2012-01-01

    Mitochondrial catastrophe can be the cause or consequence of apoptosis and is associated with a number of pathophysiological conditions. The exact relationship between mitochondrial catastrophe and caspase activation is not completely understood. Here we addressed the underlying mechanism, explaining how activated caspase could feedback to attack mitochondria to amplify further cytochrome c (cyto.c) release. We discovered that cytochrome c1 (cyto.c1) in the bc1 complex of the mitochondrial respiration chain was a novel substrate of caspase 3 (casp.3). We found that cyto.c1 was cleaved at the site of D106, which is critical for binding with cyto.c, following apoptotic stresses or targeted expression of casp.3 into the mitochondrial intermembrane space. We demonstrated that this cleavage was closely linked with further cyto.c release and mitochondrial catastrophe. These mitochondrial events could be effectively blocked by expressing non-cleavable cyto.c1 (D106A) or by caspase inhibitor z-VAD-fmk. Our results demonstrate that the cleavage of cyto.c1 represents a critical step for the feedback amplification of cyto.c release by caspases and subsequent mitochondrial catastrophe.

  14. A single-center study of C1q nephropathy in children.

    PubMed

    Roberti, Isabel; Baqi, Noosha; Vyas, Shefali; Kim, Dae Un

    2009-01-01

    C1q nephropathy (C1qN) is a rare idiopathic glomerulopathy typically seen in adolescents and young adults. All kidney biopsies done from 2002 to 2007 were analyzed (264). Thirteen cases of C1qN from 212 (6.6%) native biopsies and one case out of 52 (1.9%) transplant biopsies were reviewed regarding demographic features, clinical presentation, histopathology, treatment, and outcome. Age varied from 1 to 18 years; half were boys. Ten children (71.4%) presented with nephrotic syndrome (NS). The most common histopathology found was diffuse mesangial proliferative glomerulonephritis (DMP) by light microscopy (LM), with diffuse granular staining for C1q predominantly in the mesangium. Children with either NS or persistent gross hematuria received prednisone and angiotensin-converting enzyme inhibitors (ACEi) (11). Median follow-up was 36 months. Steroid response was complete in 6 patients (54.5%). Those with steroid resistance (5) or steroid dependence (2) received further immunosuppression with mycophenolate mofetil (MMF) or tacrolimus (Tac). Three children achieved complete remission and four partial remission. Frequent relapses were seen in 4/14 patients. Renal survival was 100%. Our report reveals a high incidence of C1qN in pediatric patients, with variable clinical presentation. Despite a high incidence of steroid resistance among those with NS, an excellent response was observed with the addition of further immunosuppression.

  15. [Acquired coagulant factor inhibitors].

    PubMed

    Nogami, Keiji

    2015-02-01

    Acquired coagulation factor inhibitors are an autoimmune disease causing bleeding symptoms due to decreases in the corresponding factor (s) which result from the appearance of autoantibodies against coagulation factors (inhibitor). This disease is quite different from congenital coagulation factor deficiencies based on genetic abnormalities. In recent years, cases with this disease have been increasing, and most have anti-factor VIII autoantibodies. The breakdown of the immune control mechanism is speculated to cause this disease since it is common in the elderly, but the pathology and pathogenesis are presently unclear. We herein describe the pathology and pathogenesis of factor VIII and factor V inhibitors. Characterization of these inhibitors leads to further analysis of the coagulation process and the activation mechanisms of clotting factors. In the future, with the development of new clotting examination method (s), we anticipate that further novel findings will be obtained in this field through inhibitor analysis. In addition, detailed elucidation of the coagulation inhibitory mechanism possibly leading to hemostatic treatment strategies for acquired coagulation factor disorders will be developed.

  16. Motion-preserving reduction and fixation of C1 Jefferson fracture using a C1 lateral mass screw construct.

    PubMed

    Jo, Kwang-Wook; Park, Ik-Seong; Hong, Jae Taek

    2011-05-01

    The treatment of C1 Jefferson fractures is controversial. Non-surgical treatment with halo fixation always bears the risk of insufficient healing with further instability and increasing neck pain. However, a C1-2 fusion can markedly decrease the rotatory motion of the neck. The aim of this report is to describe a new treatment for C1 Jefferson fractures. We used open reduction and C1 fixation using a bilateral C1 lateral mass screw construct. The screws were connected with a rod and nuts to reduce lateral spread of the lateral masses. This method is an alternative surgical option for C1 Jefferson fractures in select patients and can maintain important C1-2 joint motion.

  17. Vitamin Deficiency Anemia

    MedlinePlus

    Vitamin deficiency anemia Overview By Mayo Clinic Staff Vitamin deficiency anemia is a lack of healthy red blood ... normal amounts of certain vitamins. Vitamins linked to vitamin deficiency anemia include folate, vitamin B-12 and vitamin ...

  18. Alpha-1 Antitrypsin Deficiency

    MedlinePlus

    ... 1 antitrypsin (an-tee-TRIP-sin) deficiency, or AAT deficiency, is a condition that raises your risk ... and other diseases. Some people who have severe AAT deficiency develop emphysema (em-fi-SE-ma)—often ...

  19. HIV-associated thromboembolic phenomenon due to protein C deficiency.

    PubMed

    Goyal, Anmol; Shah, Ira

    2014-01-01

    HIV-infected individuals are at a high risk of developing arterial and venous thromboembolism. Opportunistic infections, protease inhibitors, low CD4 count, antiphospholipid antibodies, protein S, and protein C deficiencies are some important risk factors associated with it. However, thromboembolic phenomenon due to protein C deficiency has been rarely reported. We report a case of a 12-year-old girl with facial palsy due to middle cerebral artery infarct because of HIV infection and associated protein C deficiency.

  20. Thrombin inhibitor design.

    PubMed

    Sanderson, P E; Naylor-Olsen, A M

    1998-08-01

    Recently, iv formulated direct thrombin inhibitors have been shown to be safe and efficacious alternatives to heparin. These results have fueled the hopes for an orally active compound. Such a compound could be a significant advance over warfarin if it had predictable pharmacokinetics and a duration of action sufficient for once or twice a day dosing. In order to develop an orally active compound which meets these criteria, the deficiencies of the prototype inhibitor efegatran have had to be addressed. First, using a combination of structure based design and empirical structure optimization, more selective compounds have been identified by modifying the P1 group or by incorporating different peptidomimetic P2/P3 scaffolds. Secondly, this optimization has resulted in the development of potent and selective non-covalent inhibitors, thus bypassing the liabilities of the serine trap. Thirdly, oral bioavailability has been achieved while maintaining selectivity and efficacy through the incorporation of progressively less basic P1 groups. The duration of action of these compounds remains to be optimized. Other advances in thrombin inhibitor design have included the development of uncharged P1 groups and the discovery of two non-peptide templates.

  1. Missed C1 posterior arch fracture: a case report

    PubMed Central

    Munro, Donald S

    1990-01-01

    A case of a C1 posterior arch fracture following a fall is presented. The need to perform a thorough history and examination, regardless of previous examination findings, is emphasized. This is especially true when there is a history of recent trauma. A brief discussion of the characteristics and management of C1 fractures follows. ImagesFigure 1Figure 2Figure 3

  2. Anti-C1q in systemic lupus erythematosus.

    PubMed

    Stojan, G; Petri, M

    2016-07-01

    C1q is the first component of the classical complement pathway. Both clinically validated in-house ELISA assays as well as commercial ELISA kits are used for detection of anti-C1q antibodies. Anti-C1q autoantibodies can be detected in a wide range of autoimmune diseases and are highly sensitive for hypocomplementemic uticarial vasculitis. In SLE, anti-C1q are strongly associated with proliferative lupus nephritis, and their absence carries a negative predictive value for development of lupus nephritis of close to 100%. Anti-C1q in combination with anti-dsDNA and low complement has the strongest serological association with renal involvement. The anti-C1q titers correlate with global disease activity scores in patients with renal involvement, and higher titers seem to precede renal flares. After the successful treatment of a renal flare, anti-C1q has the tendency to decrease or even become undetectable. The main obstacle to the inclusion of anti-C1q in the classification criteria and clinical management of SLE is the lack of standardized laboratory assays.

  3. 26 CFR 1.661(c)-1 - Limitation on deduction.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 8 2010-04-01 2010-04-01 false Limitation on deduction. 1.661(c)-1 Section 1.661(c)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES Estates and Trusts Which May Accumulate Income Or Which Distribute Corpus §...

  4. 26 CFR 1.662(c)-1 - Different taxable years.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 8 2010-04-01 2010-04-01 false Different taxable years. 1.662(c)-1 Section 1.662(c)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES Estates and Trusts Which May Accumulate Income Or Which Distribute Corpus §...

  5. 26 CFR 1.678(c)-1 - Trusts for support.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 8 2010-04-01 2010-04-01 false Trusts for support. 1.678(c)-1 Section 1.678(c... (CONTINUED) INCOME TAXES Grantors and Others Treated As Substantial Owners § 1.678(c)-1 Trusts for support... cotrustee, to apply the income of the trust to the support or maintenance of a person whom the holder...

  6. 26 CFR 1.1092(c)-1 - Qualified covered calls.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 11 2010-04-01 2010-04-01 true Qualified covered calls. 1.1092(c)-1 Section 1... (CONTINUED) INCOME TAXES Wash Sales of Stock Or Securities § 1.1092(c)-1 Qualified covered calls. (a) In...), however, writing a qualified covered call option and owning the optioned stock is not treated as...

  7. Periodontal Ehlers-Danlos Syndrome Is Caused by Mutations in C1R and C1S, which Encode Subcomponents C1r and C1s of Complement.

    PubMed

    Kapferer-Seebacher, Ines; Pepin, Melanie; Werner, Roland; Aitman, Timothy J; Nordgren, Ann; Stoiber, Heribert; Thielens, Nicole; Gaboriaud, Christine; Amberger, Albert; Schossig, Anna; Gruber, Robert; Giunta, Cecilia; Bamshad, Michael; Björck, Erik; Chen, Christina; Chitayat, David; Dorschner, Michael; Schmitt-Egenolf, Marcus; Hale, Christopher J; Hanna, David; Hennies, Hans Christian; Heiss-Kisielewsky, Irene; Lindstrand, Anna; Lundberg, Pernilla; Mitchell, Anna L; Nickerson, Deborah A; Reinstein, Eyal; Rohrbach, Marianne; Romani, Nikolaus; Schmuth, Matthias; Silver, Rachel; Taylan, Fulya; Vandersteen, Anthony; Vandrovcova, Jana; Weerakkody, Ruwan; Yang, Margaret; Pope, F Michael; Byers, Peter H; Zschocke, Johannes

    2016-11-03

    Periodontal Ehlers-Danlos syndrome (pEDS) is an autosomal-dominant disorder characterized by early-onset periodontitis leading to premature loss of teeth, joint hypermobility, and mild skin findings. A locus was mapped to an approximately 5.8 Mb region at 12p13.1 but no candidate gene was identified. In an international consortium we recruited 19 independent families comprising 107 individuals with pEDS to identify the locus, characterize the clinical details in those with defined genetic causes, and try to understand the physiological basis of the condition. In 17 of these families, we identified heterozygous missense or in-frame insertion/deletion mutations in C1R (15 families) or C1S (2 families), contiguous genes in the mapped locus that encode subunits C1r and C1s of the first component of the classical complement pathway. These two proteins form a heterotetramer that then combines with six C1q subunits. Pathogenic variants involve the subunit interfaces or inter-domain hinges of C1r and C1s and are associated with intracellular retention and mild endoplasmic reticulum enlargement. Clinical features of affected individuals in these families include rapidly progressing periodontitis with onset in the teens or childhood, a previously unrecognized lack of attached gingiva, pretibial hyperpigmentation, skin and vascular fragility, easy bruising, and variable musculoskeletal symptoms. Our findings open a connection between the inflammatory classical complement pathway and connective tissue homeostasis.

  8. [Development of new antiatherosclerotic agents--ACAT inhibitors and CETP inhibitors].

    PubMed

    Miyazaki, A; Horiuchi, S

    1999-12-01

    Development of new antiatherosclerotic agents were reviewed focusing on ACAT inhibitors and CETP inhibitors. ACAT inhibitors enhance intracellular degradation of VLDL in hepatocytes. Cholesterol absorption in small intestine is inhibited by ACAT inhibitors. Thus, ACAT inhibitors reduce plasma cholesterol levels. In atherosclerotic lesions, ACAT inhibitors suppress foam cell formation (cholesteryl ester accumulation) in macrophages. Since ACAT inhibitors have multiple anti-atherogenic effects, they are considered future drugs controlling hypercholesterolemia and atherosclerosis. CETP inhibitors are expected to increase HDL and decrease LDL. Although the patients with CETP deficiency show high level of HDL, recent studies showed that they are not necessarily resistant to atherosclerosis. The strategy to inhibit CETP for suppressing atherosclerosis has not been established.

  9. Mice lacking C1q are protected from high fat diet-induced hepatic insulin resistance and impaired glucose homeostasis.

    PubMed

    Hillian, Antoinette D; McMullen, Megan R; Sebastian, Becky M; Roychowdhury, Sanjoy; Rowchowdhury, Sanjoy; Kashyap, Sangeeta R; Schauer, Philip R; Kirwan, John P; Feldstein, Ariel E; Nagy, Laura E

    2013-08-02

    Complement activation is implicated in the development of obesity and insulin resistance, and loss of signaling by the anaphylatoxin C3a prevents obesity-induced insulin resistance in mice. Here we have identified C1q in the classical pathway as required for activation of complement in response to high fat diets. After 8 weeks of high fat diet, wild-type mice became obese and developed glucose intolerance. This was associated with increased apoptotic cell death and accumulation of complement activation products (C3b/iC3b/C3c) in liver and adipose tissue. Previous studies have shown that high fat diet-induced apoptosis is dependent on Bid; here we report that Bid-mediated apoptosis was required for complement activation in adipose and liver. Although C1qa deficiency had no effect on high fat diet-induced apoptosis, accumulation of complement activation products and the metabolic complications of high fat diet-induced obesity were dependent on C1q. When wild-type mice were fed a high fat diet for only 3 days, hepatic insulin resistance was associated with the accumulation of C3b/iC3b/C3c in the liver. Mice deficient in C3a receptor were protected against this early high fat diet-induced hepatic insulin resistance, whereas mice deficient in the negative complement regulator CD55/DAF were more sensitive to the high fat diet. C1qa(-/-) mice were also protected from high fat diet-induced hepatic insulin resistance and complement activation. Evidence of complement activation was also detected in adipose tissue of obese women compared with lean women. Together, these studies reveal an important role for C1q in the classical pathway of complement activation in the development of high fat diet-induced insulin resistance.

  10. Cbln and C1q family proteins: new transneuronal cytokines.

    PubMed

    Yuzaki, M

    2008-06-01

    The C1q family is characterized by a C-terminal conserved global C1q domain, which is structurally very similar to the tumor necrosis factor homology domain. Although some C1q family members are expressed in the central nervous system, their functions have not been well characterized. Cbln1, a member of the Cbln subfamily of the C1q family, is predominantly expressed in cerebellar granule cells. Interestingly, Cbln1 was recently shown to play two unique roles at excitatory synapses formed between cerebellar granule cells and Purkinje cells: the formation and stabilization of synaptic contact, and the control of functional synaptic plasticity by regulating the postsynaptic endocytosis pathway. Since other Cbln subfamily members, Cbln2-Cbln4, are expressed in various regions of developing and mature brains, Cbln subfamily proteins may generally serve as a new class of transneuronal regulators of synapse development and synaptic plasticity in various brain regions.

  11. Expression of staphylococcal enterotoxin C1 in Escherichia coli.

    PubMed Central

    Bohach, G A; Schlievert, P M

    1987-01-01

    The structural gene encoding staphylococcal enterotoxin C1 was cloned into Escherichia coli and localized on a 1.5-kilobase HindIII-ClaI DNA fragment by subcloning. The toxin was partially purified from E. coli clones and shown to be immunologically identical to enterotoxin C1 from Staphylococcus aureus. The cloned toxin also had the same molecular weight (26,000) and charge heterogeneity as staphylococcus-derived enterotoxin. Toxins from both sources were equally biologically active. Images PMID:3542834

  12. 26 CFR 1.1402(c)-1 - Trade or business.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 12 2010-04-01 2010-04-01 false Trade or business. 1.1402(c)-1 Section 1.1402(c... (CONTINUED) INCOME TAXES Tax on Self-Employment Income § 1.1402(c)-1 Trade or business. In order for an individual to have net earnings from self-employment, he must carry on a trade or business, either as...

  13. 26 CFR 1.1402(c)-1 - Trade or business.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 12 2012-04-01 2012-04-01 false Trade or business. 1.1402(c)-1 Section 1.1402(c... (CONTINUED) INCOME TAXES (CONTINUED) Tax on Self-Employment Income § 1.1402(c)-1 Trade or business. In order for an individual to have net earnings from self-employment, he must carry on a trade or...

  14. 26 CFR 1.1402(c)-1 - Trade or business.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 12 2013-04-01 2013-04-01 false Trade or business. 1.1402(c)-1 Section 1.1402(c... (CONTINUED) INCOME TAXES (CONTINUED) Tax on Self-Employment Income § 1.1402(c)-1 Trade or business. In order for an individual to have net earnings from self-employment, he must carry on a trade or...

  15. The Crystal Structure Analysis of Group B Streptococcus Sortase C1: A Model for the ;Lid; Movement upon Substrate Binding

    SciTech Connect

    Khare, Baldeep; Fu, Zheng-Qing; Huang, I-Hsiu; Ton-That, Hung; Narayana, Sthanam V.L.

    2012-02-07

    A unique feature of the class-C-type sortases, enzymes essential for Gram-positive pilus biogenesis, is the presence of a flexible 'lid' anchored in the active site. However, the mechanistic details of the 'lid' displacement, suggested to be a critical prelude for enzyme catalysis, are not yet known. This is partly due to the absence of enzyme-substrate and enzyme-inhibitor complex crystal structures. We have recently described the crystal structures of the Streptococcus agalactiae SAG2603 V/R sortase SrtC1 in two space groups (type II and type III) and that of its 'lid' mutant and proposed a role of the 'lid' as a protector of the active-site hydrophobic environment. Here, we report the crystal structures of SAG2603 V/R sortase C1 in a different space group (type I) and that of its complex with a small-molecule cysteine protease inhibitor. We observe that the catalytic Cys residue is covalently linked to the small-molecule inhibitor without lid displacement. However, the type I structure provides a view of the sortase SrtC1 lid displacement while having structural elements similar to a substrate sorting motif suitably positioned in the active site. We propose that these major conformational changes seen in the presence of a substrate mimic in the active site may represent universal features of class C sortase substrate recognition and enzyme activation.

  16. The crystal structure analysis of group B Streptococcus sortase C1: a model for the "lid" movement upon substrate binding.

    PubMed

    Khare, Baldeep; Fu, Zheng-Qing; Huang, I-Hsiu; Ton-That, Hung; Narayana, Sthanam V L

    2011-12-09

    A unique feature of the class-C-type sortases, enzymes essential for Gram-positive pilus biogenesis, is the presence of a flexible "lid" anchored in the active site. However, the mechanistic details of the "lid" displacement, suggested to be a critical prelude for enzyme catalysis, are not yet known. This is partly due to the absence of enzyme-substrate and enzyme-inhibitor complex crystal structures. We have recently described the crystal structures of the Streptococcus agalactiae SAG2603 V/R sortase SrtC1 in two space groups (type II and type III) and that of its "lid" mutant and proposed a role of the "lid" as a protector of the active-site hydrophobic environment. Here, we report the crystal structures of SAG2603 V/R sortase C1 in a different space group (type I) and that of its complex with a small-molecule cysteine protease inhibitor. We observe that the catalytic Cys residue is covalently linked to the small-molecule inhibitor without lid displacement. However, the type I structure provides a view of the sortase SrtC1 lid displacement while having structural elements similar to a substrate sorting motif suitably positioned in the active site. We propose that these major conformational changes seen in the presence of a substrate mimic in the active site may represent universal features of class C sortase substrate recognition and enzyme activation.

  17. Pyruvate kinase deficiency

    MedlinePlus

    ... the second most common cause, after glucose-6-phosphate dehydrogenase (G6PD) deficiency . PKD is found in people ... Read More Anemia Autosomal recessive Enzyme Glucose-6-phosphate dehydrogenase deficiency Hemolytic anemia Review Date 10/27/ ...

  18. Vitamin D Deficiency

    MedlinePlus

    Vitamin D Deficiency A Patient’s Guide Vitamin D helps the body absorb calcium. Along with calcium, it is vital ... for physicians about testing for, treating, and preventing vitamin D deficiency. These guidelines do not apply to people who ...

  19. Folate-deficiency anemia

    MedlinePlus

    ... medlineplus.gov/ency/article/000551.htm Folate-deficiency anemia To use the sharing features on this page, please enable JavaScript. Folate-deficiency anemia is a decrease in red blood cells (anemia) ...

  20. Total synthesis of (-)-CP2-disorazole C1.

    PubMed

    Hopkins, Chad D; Schmitz, John C; Chu, Edward; Wipf, Peter

    2011-08-05

    The total synthesis of a bis-cyclopropane analog of the antimitotic natural product (-)-disorazole C(1) was accomplished in 23 steps and 1.1% overall yield. A vinyl cyclopropane cross-metathesis reaction generated a key (E)-alkene segment of the target molecule. IC(50) determinations of (-)-CP(2)-disorazole C(1) in human colon cancer cell lines indicated low nanomolar cytotoxic properties. Accordingly, this synthetic bioisostere represents the first biologically active disorazole analog not containing a conjugated diene or polyene substructure element.

  1. In silico structural characteristics and α-amylase inhibitory properties of Ric c 1 and Ric c 3, allergenic 2S albumins from Ricinus communis seeds.

    PubMed

    Do Nascimento, Viviane Veiga; Castro, Helena Carla; Abreu, Paula Alvarez; Oliveira, Antônia Elenir Amâncio; Fernandez, Jorge Hernandez; Araújo, Jucélia Da Silva; Machado, Olga Lima Tavares

    2011-05-11

    The major Ricinus communis allergens are the 2S albumins, Ric c 1 and Ric c 3. These proteins contain a trypsin/α-amylase inhibitor family domain, suggesting that they have a role in insect resistance. In this study, we verified that Ric c 1 and Ric c 3 inhibited the α-amylase activity of Callosobruchus maculatus, Zabrotes subfasciatus, and Tenebrio molitor (TMA) larvae as well as mammalian α-amylase. The toxicity of 2S albumin was determined through its incorporation in C. maculatus larvae as part of an artificial diet. Bioassays revealed that 2S albumin reduced larval growth by 20%. We also analyzed the tridimensional structures of Ric c 1 and Ric c 3 by (a) constructing a comparative model of Ric c 1 based on Ric c 3 NMR structure and (b) constructing the theoretical structure of the Ric c 1-TMA and Ric c 3-TMA complexes. Our biological and theoretical results revealed that Ric c 1 and Ric c 3 are a new class of α-amylase inhibitors. They could potentially be used to help design inhibitors that would be useful in diverse fields, ranging from diabetes treatment to crop protection.

  2. 26 CFR 1.1092(c)-1 - Qualified covered calls.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 11 2013-04-01 2013-04-01 false Qualified covered calls. 1.1092(c)-1 Section 1... stock price of $14.84. Using the bench marks for an equity option with standardized terms with an adjusted applicable stock price of $14.84, the highest available strike price less than the...

  3. 26 CFR 1.1092(c)-1 - Qualified covered calls.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 11 2014-04-01 2014-04-01 false Qualified covered calls. 1.1092(c)-1 Section 1... stock price of $14.84. Using the bench marks for an equity option with standardized terms with an adjusted applicable stock price of $14.84, the highest available strike price less than the...

  4. Angiogenesis Inhibitors

    MedlinePlus

    ... inhibitors: current strategies and future prospects. CA: A Cancer Journal for Clinicians 2010; 60(4):222–243. [PubMed Abstract] Chen HX, Cleck JN. Adverse effects of anticancer agents that target the VEGF pathway. Nature Reviews Clinical Oncology 2009; 6(8):465– ...

  5. Carboxylesterase inhibitors

    PubMed Central

    Hatfield, M. Jason; Potter, Philip M.

    2011-01-01

    Introduction Carboxylesterases play major roles in the hydrolysis of numerous therapeutically active compounds. This is, in part, due to the prevalence of the ester moiety in these small molecules. However, the impact these enzymes may play on drug stability and pharmacokinetics is rarely considered prior to molecule development. Therefore, the application of selective inhibitors of this class of proteins may have utility in modulating the metabolism, distribution and toxicity of agents that are subjected to enzyme hydrolysis. Areas covered This review details the development of all such compounds dating back to 1986, but principally focuses on the very recent identification of selective human carboxylesterases inhibitors. Expert opinion The implementation of carboxylesterase inhibitors may significantly revolutionize drug discovery. Such molecules may allow for improved efficacy of compounds inactivated by this class of enzymes and/or reduce the toxicity of agents that are activated by these proteins. Furthermore, since lack of carboxylesterase activity appears to have no obvious biological consequence, these compounds could be applied in combination with virtually any esterified drug. Therefore, inhibitors of these proteins may have utility in altering drug hydrolysis and distribution in vivo. The characteristics, chemical and biological properties, and potential uses of such agents, are discussed here. PMID:21609191

  6. Epidemiology of iodine deficiency.

    PubMed

    Vanderpump, Mark P

    2017-04-01

    Iodine is an essential component of the thyroid hormones thyroxine (T4) and triiodothyronine (T3) produced by the thyroid gland. Iodine deficiency impairs thyroid hormone production and has adverse effects throughout life, particularly early in life as it impairs cognition and growth. Iodine deficiency remains a significant problem despite major national and international efforts to increase iodine intake, primarily through the voluntary or mandatory iodization of salt. Recent epidemiological data suggest that iodine deficiency is an emerging issue in industrialized countries, previously thought of as iodine-sufficient. International efforts to control iodine deficiency are slowing, and reaching the third of the worldwide population that remains deficient poses major challenges.

  7. Caudally directed Inferior facetal and transfacetal screws for C1-C2 and C1-2-3 fixation.

    PubMed

    Goel, Atul

    2017-01-13

    An alternative caudally directed C2 inferior facetal screw is described. Such screw insertion can form the axial stabilization point in cases undergoing atlantoaxial lateral mass plate/rod and screw fixation and those undergoing C1-2and C1-2-3 spinal fixation. The C2 screw courses from the medial point of pedicle-laminar junction and travels caudally and laterally towards the C2-3 articulation. Deploying a longer screw that traverses in a transarticular fashion into the facetal mass of C3 vertebra one can perform C1-2-3 stabilization.Sixteen patients underwent C2 inferior facetal or C2-3 transarticular screw in combination with C1 screw for atlantoaxial fixation. Three of these patients with multilevel spinal instability underwent atlantoaxial and C2-3 fixation using the discussed technique. The technical issues, anatomical subtleties and indication for the use of the C2 inferior facetal screws are discussed. With an average follow-up of 9 months, all screws have successfully provided stability that resulted in arthrodesis of the treated spinal segments. Caudally directed C2 inferior facetal screw can enhance the armamentarium of the surgeon, provide an alternative to conventional techniques or a bailout option and add to safety of the procedure of atlantoaxial lateral mass fixation in anatomically challenged situations.

  8. PRD125, a potent and selective inhibitor of sterol O-acyltransferase 2 markedly reduces hepatic cholesteryl ester accumulation and improves liver function in lysosomal acid lipase-deficient mice.

    PubMed

    Lopez, Adam M; Chuang, Jen-Chieh; Posey, Kenneth S; Ohshiro, Taichi; Tomoda, Hiroshi; Rudel, Lawrence L; Turley, Stephen D

    2015-11-01

    In most organs, the bulk of cholesterol is unesterified, although nearly all possess a varying capability of esterifying cholesterol through the action of either sterol O-acyltransferase (SOAT) 1 or, in the case of hepatocytes and enterocytes, SOAT2. Esterified cholesterol (EC) carried in plasma lipoproteins is hydrolyzed by lysosomal acid lipase (LAL) when they are cleared from the circulation. Loss-of-function mutations in LIPA, the gene that encodes LAL, result in Wolman disease or cholesteryl ester storage disease (CESD). Hepatomegaly and a massive increase in tissue EC levels are hallmark features of both disorders. While these conditions can be corrected with enzyme replacement therapy, the question arose as to whether pharmacological inhibition of SOAT2 might reduce tissue EC accretion in CESD. When weaned at 21 days, Lal(-/-) mice, of either gender, had a whole liver cholesterol content that was 12- to 13-fold more than that of matching Lal(+/+) littermates (23 versus 1.8 mg, respectively). In Lal(-/-) males given the selective SOAT2 inhibitor PRD125 1,11-O-o-methylbenzylidene-7-O-p-cyanobenzoyl-1,7,11-trideacetylpyripyropene A in their diet (∼10 mg/day per kg body weight) from 21 to 53 days, whole liver cholesterol content was 48.6 versus 153.7 mg in untreated 53-day-old Lal(-/-) mice. This difference reflected a 59% reduction in hepatic EC concentration (mg/g), combined with a 28% fall in liver mass. The treated mice also showed a 63% reduction in plasma alanine aminotransferase activity, in parallel with decisive falls in hepatic mRNA expression levels for multiple proteins that reflect macrophage presence and inflammation. These data implicate SOAT2 as a potential target in CESD management.

  9. PRD125, a Potent and Selective Inhibitor of Sterol O-Acyltransferase 2 Markedly Reduces Hepatic Cholesteryl Ester Accumulation and Improves Liver Function in Lysosomal Acid Lipase-Deficient Mice

    PubMed Central

    Lopez, Adam M.; Chuang, Jen-Chieh; Posey, Kenneth S.; Ohshiro, Taichi; Tomoda, Hiroshi; Rudel, Lawrence L.

    2015-01-01

    In most organs, the bulk of cholesterol is unesterified, although nearly all possess a varying capability of esterifying cholesterol through the action of either sterol O-acyltransferase (SOAT) 1 or, in the case of hepatocytes and enterocytes, SOAT2. Esterified cholesterol (EC) carried in plasma lipoproteins is hydrolyzed by lysosomal acid lipase (LAL) when they are cleared from the circulation. Loss-of-function mutations in LIPA, the gene that encodes LAL, result in Wolman disease or cholesteryl ester storage disease (CESD). Hepatomegaly and a massive increase in tissue EC levels are hallmark features of both disorders. While these conditions can be corrected with enzyme replacement therapy, the question arose as to whether pharmacological inhibition of SOAT2 might reduce tissue EC accretion in CESD. When weaned at 21 days, Lal−/− mice, of either gender, had a whole liver cholesterol content that was 12- to 13-fold more than that of matching Lal+/+ littermates (23 versus 1.8 mg, respectively). In Lal−/− males given the selective SOAT2 inhibitor PRD125 1,11-O-o-methylbenzylidene-7-O-p-cyanobenzoyl-1,7,11-trideacetylpyripyropene A in their diet (∼10 mg/day per kg body weight) from 21 to 53 days, whole liver cholesterol content was 48.6 versus 153.7 mg in untreated 53-day-old Lal−/− mice. This difference reflected a 59% reduction in hepatic EC concentration (mg/g), combined with a 28% fall in liver mass. The treated mice also showed a 63% reduction in plasma alanine aminotransferase activity, in parallel with decisive falls in hepatic mRNA expression levels for multiple proteins that reflect macrophage presence and inflammation. These data implicate SOAT2 as a potential target in CESD management. PMID:26283692

  10. The effect of excision of the posterior arch of C1 on C1/C2 fusion using transarticular screws.

    PubMed

    Chang, K C; Samartzis, D; Fuego, S M; Dhatt, S S; Wong, Y W; Cheung, W Y; Luk, K D K; Cheung, K M C

    2013-07-01

    Transarticular screw fixation with autograft is an established procedure for the surgical treatment of atlantoaxial instability. Removal of the posterior arch of C1 may affect the rate of fusion. This study assessed the rate of atlantoaxial fusion using transarticular screws with or without removal of the posterior arch of C1. We reviewed 30 consecutive patients who underwent atlantoaxial fusion with a minimum follow-up of two years. In 25 patients (group A) the posterior arch of C1 was not excised (group A) and in five it was (group B). Fusion was assessed on static and dynamic radiographs. In selected patients CT imaging was also used to assess fusion and the position of the screws. There were 15 men and 15 women with a mean age of 51.2 years (23 to 77) and a mean follow-up of 7.7 years (2 to 11.6). Stable union with a solid fusion or a stable fibrous union was achieved in 29 patients (97%). In Group A, 20 patients (80%) achieved a solid fusion, four (16%) a stable fibrous union and one (4%) a nonunion. In Group B, stable union was achieved in all patients, three having a solid fusion and two a stable fibrous union. There was no statistically significant difference between the status of fusion in the two groups. Complications were noted in 12 patients (40%); these were mainly related to the screws, and included malpositioning and breakage. The presence of an intact or removed posterior arch of C1 did not affect the rate of fusion in patients with atlantoaxial instability undergoing C1/C2 fusion using transarticular screws and autograft.

  11. C1 Hermite shape preserving polynomial splines in R3

    NASA Astrophysics Data System (ADS)

    Gabrielides, Nikolaos C.

    2012-06-01

    The C 2 variable degree splines1-3 have been proven to be an efficient tool for solving the curve shape-preserving interpolation problem in two and three dimensions. Based on this representation, the current paper proposes a Hermite interpolation scheme, to construct C 1 shape-preserving splines of variable degree. After this, a slight modification of the method leads to a C 1 shape-preserving Hermite cubic spline. Both methods can easily be developed within a CAD system, since they compute directly (without iterations) the B-spline control polygon. They have been implemented and tested within the DNV Software CAD/CAE system GeniE. [Figure not available: see fulltext.

  12. Alzheimer's β-amyloid peptides can activate the early components of complement classical pathway in a C1q-independent manner

    PubMed Central

    Bergamaschini, L; Canziani, S; Bottasso, B; Cugno, M; Braidotti, P; Agostoni, A

    1999-01-01

    β-Amyloid (β-A) accumulates in the brain of patients with Alzheimer's disease (AD) and is presumably involved in the pathogenesis of this disease, on account of its neurotoxicity and complement-activating ability. Although assembly of β-A in particular aggregates seems to be crucial, soluble non-fibrillar β-A may also be involved. Non-fibrillar β-A does not bind C1q, so we investigated alternative mechanisms of β-A-dependent complement activation in vitro. On incubation with normal human plasma, non-fibrillar β-A 1-42, and truncated peptide 1–28, induced dose-dependent activation of C1s and C4, sparing C3, as assessed by densitometric analysis of immunostained membrane after SDS–PAGE and Western blotting. The mechanism of C4 activation was not dependent on C1q, because non-fibrillar β-A can still activate C1s and C4 in plasma genetically deficient in C1q (C1qd). In Factor XII-deficient plasma (F.XIId) the amount of cleaved C4 was about 5–10% less that in C1qd and in normal EDTA plasma; the reconstitution of F.XIId plasma with physiologic concentrations of F.XII resulted in an increased (8–15%) β-A-dependent cleavage of C4. Thus our results indicate that the C1q-independent activation of C1 and C4 can be partially mediated by the activation products of contact system. Since the activation of contact system and of C4 leads to generation of several humoral inflammatory peptides, non-fibrillar β-A might play a role in initiating the early inflammatory reactions leading to a multistep cascade contributing to neuronal and clinical dysfunction of AD brain. PMID:10193429

  13. Alzheimer's beta-amyloid peptides can activate the early components of complement classical pathway in a C1q-independent manner.

    PubMed

    Bergamaschini, L; Canziani, S; Bottasso, B; Cugno, M; Braidotti, P; Agostoni, A

    1999-03-01

    beta-Amyloid (beta-A) accumulates in the brain of patients with Alzheimer's disease (AD) and is presumably involved in the pathogenesis of this disease, on account of its neurotoxicity and complement-activating ability. Although assembly of beta-A in particular aggregates seems to be crucial, soluble non-fibrillar beta-A may also be involved. Non-fibrillar beta-A does not bind C1q, so we investigated alternative mechanisms of beta-A-dependent complement activation in vitro. On incubation with normal human plasma, non-fibrillar beta-A 1-42, and truncated peptide 1-28, induced dose-dependent activation of C1s and C4, sparing C3, as assessed by densitometric analysis of immunostained membrane after SDS-PAGE and Western blotting. The mechanism of C4 activation was not dependent on C1q, because non-fibrillar beta-A can still activate C1s and C4 in plasma genetically deficient in C1q (C1qd). In Factor XII-deficient plasma (F.XIId) the amount of cleaved C4 was about 5-10% less that in C1qd and in normal EDTA plasma; the reconstitution of F.XIId plasma with physiologic concentrations of F.XII resulted in an increased (8-15%) beta-A-dependent cleavage of C4. Thus our results indicate that the C1q-independent activation of C1 and C4 can be partially mediated by the activation products of contact system. Since the activation of contact system and of C4 leads to generation of several humoral inflammatory peptides, non-fibrillar beta-A might play a role in initiating the early inflammatory reactions leading to a multistep cascade contributing to neuronal and clinical dysfunction of AD brain.

  14. Colour vision deficiency.

    PubMed

    Simunovic, M P

    2010-05-01

    Colour vision deficiency is one of the commonest disorders of vision and can be divided into congenital and acquired forms. Congenital colour vision deficiency affects as many as 8% of males and 0.5% of females--the difference in prevalence reflects the fact that the commonest forms of congenital colour vision deficiency are inherited in an X-linked recessive manner. Until relatively recently, our understanding of the pathophysiological basis of colour vision deficiency largely rested on behavioural data; however, modern molecular genetic techniques have helped to elucidate its mechanisms. The current management of congenital colour vision deficiency lies chiefly in appropriate counselling (including career counselling). Although visual aids may be of benefit to those with colour vision deficiency when performing certain tasks, the evidence suggests that they do not enable wearers to obtain normal colour discrimination. In the future, gene therapy remains a possibility, with animal models demonstrating amelioration following treatment.

  15. Acquired color vision deficiency.

    PubMed

    Simunovic, Matthew P

    2016-01-01

    Acquired color vision deficiency occurs as the result of ocular, neurologic, or systemic disease. A wide array of conditions may affect color vision, ranging from diseases of the ocular media through to pathology of the visual cortex. Traditionally, acquired color vision deficiency is considered a separate entity from congenital color vision deficiency, although emerging clinical and molecular genetic data would suggest a degree of overlap. We review the pathophysiology of acquired color vision deficiency, the data on its prevalence, theories for the preponderance of acquired S-mechanism (or tritan) deficiency, and discuss tests of color vision. We also briefly review the types of color vision deficiencies encountered in ocular disease, with an emphasis placed on larger or more detailed clinical investigations.

  16. Complement C1r and C1s genes are duplicated in the mouse: differential expression generates alternative isomorphs in the liver and in the male reproductive system.

    PubMed Central

    Garnier, Gérard; Circolo, Antonella; Xu, Yuanyuan; Volanakis, John E

    2003-01-01

    C1r and C1s are the serine proteases that form the catalytic unit of the C1 complex, the first component of complement. In the present study, we found that the genes encoding murine C1r and C1s are duplicated. One set of these genes, referred to as c1rA and c1sA, are primarily expressed in the liver and are therefore the homologues of the human C1r and C1s genes. The other two genes, termed c1rB and c1sB, are expressed exclusively in male reproductive tissues, specifically the coagulating gland and the prostate. The predicted C1rB and C1sB proteins share 96 and 93% amino acid identity with C1rA and C1sA respectively. Most of the substitutions are clustered in the serine protease domains, suggesting differences in catalytic efficiencies and/or substrate specificities or alternatively adaptation to different physiological environments. The high homology of C1rB and C1sB with C1rA and C1sA in the non-catalytic regions indicates that they are probably capable of assembling the C1 complex. The expression of alternative genes encoding isomorphs of activating components of complement in male reproductive tissues raises the possibility of new mechanisms of complement activation in the male genital tract or of novel functions for complement proteases in reproduction. PMID:12513694

  17. Autism and Folate Deficiency

    DTIC Science & Technology

    2010-05-01

    W81XWH-09-1-0246 TITLE: Autism and Folate Deficiency PRINCIPAL INVESTIGATOR: Richard H. Finnell, Ph.D...5a. CONTRACT NUMBER W81XWH-09-1-0246 Autism and Folate Deficiency 5b. GRANT NUMBER AR080064-Concept Award 5c. PROGRAM ELEMENT NUMBER...risk factor for autism : alterations in m ethionine metabolism in autistic patients may be due to a functional folate deficiency, and folate receptor

  18. Reduction of CO2 to C1 products and fuel

    USGS Publications Warehouse

    Mill, T.; Ross, D.

    2002-01-01

    Photochemical semiconductor processes readily reduced CO2 to a broad range of C1 products. However the intrinsic and solar efficiencies for the processes were low. Improved quantum efficiencies could be realized utilizing quantum-sized particles, but at the expense of using less of the visible solar spectrum. Conversely, semiconductors with small bandgaps used more of the visible solar spectrum at the expense of quantum efficiency. Thermal reduction of CO2 with Fe(II) was thermodynamically favored for forming many kinds of organic compounds and occurred readily with olivine and other Fe(II) minerals above 200??C to form higher alkanes and alkenes. No added hydrogen was required.

  19. C1-Cx revisited: intramolecular synergism in a cellulase.

    PubMed Central

    Din, N; Damude, H G; Gilkes, N R; Miller, R C; Warren, R A; Kilburn, D G

    1994-01-01

    Endoglucanase A (CenA) from the bacterium Cellulomonas fimi is composed of a catalytic domain and a nonhydrolytic cellulose-binding domain that can function independently. The individual domains interact synergistically in the disruption and hydrolysis of cellulose fibers. This intramolecular synergism is distinct from the well-known intermolecular synergism between individual cellulases. The catalytic domain corresponds to the hydrolytic Cx system and the cellulose-binding domain corresponds to the nonhydrolytic C1 system postulated by Reese et al. [Reese, E. T., Sui, R. G. H. & Levinson, H. S. (1950) J. Bacteriol. 59, 485-497] to be required for the hydrolysis of cellulose. PMID:7972069

  20. Refinable C(1) spline elements for irregular quad layout.

    PubMed

    Nguyen, Thien; Peters, Jörg

    2016-03-01

    Building on a result of U. Reif on removable singularities, we construct C(1) bi-3 splines that may include irregular points where less or more than four tensor-product patches meet. The resulting space complements PHT splines, is refinable and the refined spaces are nested, preserving for example surfaces constructed from the splines. As in the regular case, each quadrilateral has four degrees of freedom, each associated with one spline and the splines are linearly independent. Examples of use for surface construction and isogeometric analysis are provided.

  1. Posterior arch C-1 screw technique: a cadaveric comparison study.

    PubMed

    Moisi, Marc; Fisahn, Christian; Tkachenko, Lara; Jeyamohan, Shiveindra; Reintjes, Stephen; Grunert, Peter; Norvell, Daniel C; Tubbs, R Shane; Page, Jeni; Newell, David W; Nora, Peter; Oskouian, Rod J; Chapman, Jens

    2017-03-17

    OBJECTIVE Posterior atlantoaxial stabilization and fusion using C-1 lateral mass screw fixation has become commonly used in the treatment of instability and for reconstructive indications since its introduction by Goel and Laheri in 1994 and modification by Harms in 2001. Placement of such lateral mass screws can be challenging because of the proximity to the spinal cord, vertebral artery, an extensive venous plexus, and the C-2 nerve root, which overlies the designated starting point on the posterior center of the lateral mass. An alternative posterior access point starting on the posterior arch of C-1 could provide a C-2 nerve root-sparing starting point for screw placement, with the potential benefit of greater directional control and simpler trajectory. The authors present a cadaveric study comparing an alternative strategy (i.e., a C-1 screw with a posterior arch starting point) to the conventional strategy (i.e., using the lower lateral mass entry site), specifically assessing the safety of screw placement to preserve the C-2 nerve root. METHODS Five US-trained spine fellows instrumented 17 fresh human cadaveric heads using the Goel/Harms C-1 lateral mass (GHLM) technique on the left and the posterior arch lateral mass (PALM) technique on the right, under fluoroscopic guidance. After screw placement, a CT scan was obtained on each specimen to assess for radiographic screw placement accuracy. Four faculty spine surgeons, blinded to the surgeon who instrumented the cadaver, independently graded the quality of screw placement using a modified Upendra classification. RESULTS Of the 17 specimens, the C-2 nerve root was anatomically impinged in 13 (76.5%) of the specimens. The GHLM technique was graded Type 1 or 2, which is considered "acceptable," in 12 specimens (70.6%), and graded Type 3 or 4 ("unacceptable") in 5 specimens (29.4%). In contrast, the PALM technique had 17 (100%) of 17 graded Type 1 or 2 (p = 0.015). There were no vertebral artery injuries found

  2. Centrosomal localisation of the cancer/testis (CT) antigens NY-ESO-1 and MAGE-C1 is regulated by proteasome activity in tumour cells.

    PubMed

    Pagotto, Anna; Caballero, Otavia L; Volkmar, Norbert; Devalle, Sylvie; Simpson, Andrew J G; Lu, Xin; Christianson, John C

    2013-01-01

    The Cancer/Testis (CT) antigen family of genes are transcriptionally repressed in most human tissues but are atypically re-expressed in many malignant tumour types. Their restricted expression profile makes CT antigens ideal targets for cancer immunotherapy. As little is known about whether CT antigens may be regulated by post-translational processing, we investigated the mechanisms governing degradation of NY-ESO-1 and MAGE-C1 in selected cancer cell lines. Inhibitors of proteasome-mediated degradation induced the partitioning of NY-ESO-1 and MAGE-C1 into a detergent insoluble fraction. Moreover, this treatment also resulted in increased localisation of NY-ESO-1 and MAGE-C1 at the centrosome. Despite their interaction, relocation of either NY-ESO-1 or MAGE-C1 to the centrosome could occur independently of each other. Using a series of truncated fragments, the regions corresponding to NY-ESO-1(91-150) and MAGE-C1(900-1116) were established as important for controlling both stability and localisation of these CT antigens. Our findings demonstrate that the steady state levels of NY-ESO-1 and MAGE-C1 are regulated by proteasomal degradation and that both behave as aggregation-prone proteins upon accumulation. With proteasome inhibitors being increasingly used as front-line treatment in cancer, these data raise issues about CT antigen processing for antigenic presentation and therefore immunogenicity in cancer patients.

  3. Suppression of Fe deficiency gene expression by jasmonate.

    PubMed

    Maurer, Felix; Müller, Sabine; Bauer, Petra

    2011-05-01

    Fe deficiency genes are regulated in response to external supply of Fe as well as internal plant signals. Internal plant signals include plant hormones and systemic signals which coordinate shoot physiological requirements for Fe with local availability of Fe in roots. Induction of IRT1 and FRO2 gene expression can be used to monitor the Fe deficiency status of plant roots. Here, we investigated the role of jasmonate in the regulation of Fe deficiency responses and in the split root system. We found that jasmonate suppressed expression levels of IRT1 and FRO2 but not their inducibility in response to Fe deficiency. Analysis of the jasmonate-resistant mutant jar1-1 and pharmacological application of the lipoxygenase inhibitor ibuprofene supported an inhibitory effect of this plant hormone. Inhibition of IRT1 and FRO2 gene expression by jasmonate did not require the functional regulator FIT. By performing split root analyses we found that systemic down-regulation of Fe deficiency responses by Fe sufficiency of the shoot was not compromised by ibuprofene and in the jasmonate-insensitive mutant coi1-1. Therefore, we conclude that jasmonate acts as an inhibitor in fine-tuning Fe deficiency responses but that it is not involved in the systemic down-regulation of Fe deficiency responses in the root.

  4. Iron induced nickel deficiency

    Technology Transfer Automated Retrieval System (TEKTRAN)

    It is increasingly apparent that economic loss due to nickel (Ni) deficiency likely occurs in horticultural and agronomic crops. While most soils contain sufficient Ni to meet crop requirements, situations of Ni deficiency can arise due to antagonistic interactions with other metals. This study asse...

  5. Cerebral Folate Deficiency

    ERIC Educational Resources Information Center

    Gordon, Neil

    2009-01-01

    Cerebral folate deficiency (CFD) is associated with low levels of 5-methyltetrahydrofolate in the cerebrospinal fluid (CSF) with normal folate levels in the plasma and red blood cells. The onset of symptoms caused by the deficiency of folates in the brain is at around 4 to 6 months of age. This is followed by delayed development, with deceleration…

  6. MENTAL DEFICIENCY. SECOND EDITION.

    ERIC Educational Resources Information Center

    HILLIARD, L.T.; KIRMAN, BRIAN H.

    REVISED TO INCLUDE LEGISLATIVE AND ADMINISTRATIVE PROCEDURES NEW IN BRITAIN SINCE THE 1957 EDITION, THE TEXT INCLUDES RECENT ADVANCES IN ETIOLOGY, PATHOLOGY, AND TREATMENT OF MENTAL DEFICIENCY. CONSIDERATION OF THE BACKGROUND OF MENTAL DEFICIENCY INCLUDES HISTORICAL AND LEGAL ASPECTS, THE SOCIAL BACKGROUND OF MENTAL DEFECT, PRENATAL CAUSES OF…

  7. Small-molecule arginase inhibitors.

    PubMed

    Ivanenkov, Yan A; Chufarova, Nina V

    2014-01-01

    Arginase is an enzyme that metabolizes L-arginine to L-ornithine and urea. In addition to its fundamental role in the hepatic ornithine cycle, it also influences the immune systems in humans and mice. Arginase participates in many inflammatory disorders by decreasing the synthesis of nitric oxide and inducing fibrosis and tissue regeneration. L-arginine deficiency, which is modulated by myeloid cell arginase, suppresses T-cell immune response. This mechanism plays a fundamental role in inflammation-associated immunosuppression. Pathogens can synthesize their own arginase to elude immune reaction. Small-molecule arginase inhibitors are currently described as promising therapeutics for the treatment of several diseases, including allergic asthma, inflammatory bowel disease, ulcerative colitis, cardiovascular diseases (atherosclerosis and hypertension), diseases associated with pathogens (e.g., Helicobacter pylori, Trypanosoma cruzi, Leishmania, Mycobacterium tuberculosis and Salmonella), cancer and induced or spontaneous immune disorders. This article summarizes recent patents in the area of arginase inhibitors and discusses their properties.

  8. Analysis of the Interaction between Globular Head Modules of Human C1q and Its Candidate Receptor gC1qR

    PubMed Central

    Pednekar, Lina; Pathan, Ansar A.; Paudyal, Basudev; Tsolaki, Anthony G.; Kaur, Anuvinder; Abozaid, Suhair M.; Kouser, Lubna; Khan, Haseeb A.; Peerschke, Ellinor I.; Shamji, Mohamed H.; Stenbeck, Gudrun; Ghebrehiwet, Berhane; Kishore, Uday

    2016-01-01

    The heterotrimeric globular head (gC1q) domain of human C1q is made up of the C-terminal ends of the three individual chains, ghA, ghB, and ghC. A candidate receptor for the gC1q domain is a multi-functional pattern recognition protein, gC1qR. Since understanding of gC1qR and gC1q interaction could provide an insight into the pleiotropic functions of gC1qR, this study was undertaken to identify the gC1qR-binding site on the gC1q domain, using the recombinant ghA, ghB, and ghC modules and their substitution mutants. Our results show that ghA, ghB, and ghC modules can interact with gC1qR independently, thus reinforcing the notion of modularity within the gC1q domain of human C1q. Mutational analysis revealed that while Arg162 in the ghA module is central to interaction between gC1qR and C1q, a single amino acid substitution (arginine to glutamate) in residue 114 of the ghB module resulted in enhanced binding. Expression of gC1qR and C1q in adherent monocytes with or without pro-inflammatory stimuli was also analyzed by qPCR; it showed an autocrine/paracrine basis of C1q and gC1qR interaction. Microscopic studies revealed that C1q and gC1qR are colocalized on PBMCs. Cell proliferation assays indicated that ghA, ghB, and ghC modules were able to attenuate phytohemagglutinin-stimulated proliferation of PBMCs. Addition of gC1qR had an additive effect on the anti-proliferative effect of globular head modules. In summary, our results identify residues involved in C1q-gC1qR interaction and explain, to a certain level, their involvement on the immune cell surface, which is relevant for C1q-induced functions including inflammation, infection, and immunity. PMID:28018340

  9. Analysis of the Interaction between Globular Head Modules of Human C1q and Its Candidate Receptor gC1qR.

    PubMed

    Pednekar, Lina; Pathan, Ansar A; Paudyal, Basudev; Tsolaki, Anthony G; Kaur, Anuvinder; Abozaid, Suhair M; Kouser, Lubna; Khan, Haseeb A; Peerschke, Ellinor I; Shamji, Mohamed H; Stenbeck, Gudrun; Ghebrehiwet, Berhane; Kishore, Uday

    2016-01-01

    The heterotrimeric globular head (gC1q) domain of human C1q is made up of the C-terminal ends of the three individual chains, ghA, ghB, and ghC. A candidate receptor for the gC1q domain is a multi-functional pattern recognition protein, gC1qR. Since understanding of gC1qR and gC1q interaction could provide an insight into the pleiotropic functions of gC1qR, this study was undertaken to identify the gC1qR-binding site on the gC1q domain, using the recombinant ghA, ghB, and ghC modules and their substitution mutants. Our results show that ghA, ghB, and ghC modules can interact with gC1qR independently, thus reinforcing the notion of modularity within the gC1q domain of human C1q. Mutational analysis revealed that while Arg162 in the ghA module is central to interaction between gC1qR and C1q, a single amino acid substitution (arginine to glutamate) in residue 114 of the ghB module resulted in enhanced binding. Expression of gC1qR and C1q in adherent monocytes with or without pro-inflammatory stimuli was also analyzed by qPCR; it showed an autocrine/paracrine basis of C1q and gC1qR interaction. Microscopic studies revealed that C1q and gC1qR are colocalized on PBMCs. Cell proliferation assays indicated that ghA, ghB, and ghC modules were able to attenuate phytohemagglutinin-stimulated proliferation of PBMCs. Addition of gC1qR had an additive effect on the anti-proliferative effect of globular head modules. In summary, our results identify residues involved in C1q-gC1qR interaction and explain, to a certain level, their involvement on the immune cell surface, which is relevant for C1q-induced functions including inflammation, infection, and immunity.

  10. Resolution of C1q deposition but not of the clinical nephrotic syndrome after immunomodulating therapy in focal sclerosis

    PubMed Central

    Tibor Fülöp, Tibor; Csongrádi, Éva; Lerant, Anna A.; Lewin, Matthew; Lewin, Jack R.

    2015-01-01

    Background: The natural evolution of C1q nephropathy (C1qNP) during immunosuppressive treatment is relatively little studied or understood. Case Presentation: A 30 year-old Caucasian female was referred to us for further management of biopsy-proven C1qNP and severe nephrotic syndrome. Serologic work-up remained negative, including complement C3 and C4 levels and repeated testing for antinuclear antibodies. A renal biopsy revealed minimal change nephropathy vs. focal sclerosis on light microscopy and C1qNP on immunopathology. She has failed trials of high-dose oral prednisone, mycophenolate mofetil 1,500 mg twice a day and a subsequent regimen of monthly IV cyclophosphamide 750 mg × 9 cycles. She also received the maximum tolerated angiotensin-converting enzyme inhibitor and spironolactone therapy. Random urine protein-to-creatinine (UPC) ratio predicted proteinuria in the range between 5-35 gm/day, while serum creatinine rose progressively from 1.0 mg/dL to 1.4 mg/dL (to convert to μmol/L, multiply by 88.4). A decision was made to repeat renal biopsy to reassess the underlying histology. The biopsy revealed focal sclerosis but no C1q deposition. Conclusions: Our case illustrates at least two points: first, an established pathologic diagnosis does not obviate the need for repeated renal biopsy later on, should diagnostic uncertainty persist. Second, histological diagnoses may evolve over time, especially in a patient receiving active and powerful immune-modulating treatment. In our case, the clinical nephrosis did not change with immunosuppressive therapy while C1q deposition ceased, making this latter entity likely the immunologically mediated process. PMID:25964890

  11. Interaction of HmC1q with leech microglial cells: involvement of C1qBP-related molecule in the induction of cell chemotaxis

    PubMed Central

    2012-01-01

    Background In invertebrates, the medicinal leech is considered to be an interesting and appropriate model to study neuroimmune mechanisms. Indeed, this non-vertebrate animal can restore normal function of its central nervous system (CNS) after injury. Microglia accumulation at the damage site has been shown to be required for axon sprouting and for efficient regeneration. We characterized HmC1q as a novel chemotactic factor for leech microglial cell recruitment. In mammals, a C1q-binding protein (C1qBP alias gC1qR), which interacts with the globular head of C1q, has been reported to participate in C1q-mediated chemotaxis of blood immune cells. In this study, we evaluated the chemotactic activities of a recombinant form of HmC1q and its interaction with a newly characterized leech C1qBP that acts as its potential ligand. Methods Recombinant HmC1q (rHmC1q) was produced in the yeast Pichia pastoris. Chemotaxis assays were performed to investigate rHmC1q-dependent microglia migration. The involvement of a C1qBP-related molecule in this chemotaxis mechanism was assessed by flow cytometry and with affinity purification experiments. The cellular localization of C1qBP mRNA and protein in leech was investigated using immunohistochemistry and in situ hybridization techniques. Results rHmC1q-stimulated microglia migrate in a dose-dependent manner. This rHmC1q-induced chemotaxis was reduced when cells were preincubated with either anti-HmC1q or anti-human C1qBP antibodies. A C1qBP-related molecule was characterized in leech microglia. Conclusions A previous study showed that recruitment of microglia is observed after HmC1q release at the cut end of axons. Here, we demonstrate that rHmC1q-dependent chemotaxis might be driven via a HmC1q-binding protein located on the microglial cell surface. Taken together, these results highlight the importance of the interaction between C1q and C1qBP in microglial activation leading to nerve repair in the medicinal leech. PMID:22356764

  12. High-Resolution Mapping of the Drosophila Fourth Chromosome Using Site-Directed Terminal Deficiencies

    PubMed Central

    Sousa-Neves, Rui; Lukacsovich, Tamas; Mizutani, Claudia Mieko; Locke, John; Podemski, Lynn; Marsh, J. Lawrence

    2005-01-01

    For more than 80 years, the euchromatic right arm of the Drosophila fourth chromosome (101F-102F) has been one of the least genetically accessible regions of the fly genome despite the fact that many important genes reside there. To improve the mapping of genes on the fourth chromosome, we describe a strategy to generate targeted deficiencies and we describe 13 deficiencies that subdivide the 300 kb between the cytological coordinates 102A6 and 102C1 into five discrete regions plus a 200-kb region from 102C1 to 102D6. Together these deficiencies substantially improve the mapping capabilities for mutant loci on the fourth chromosome. PMID:15466427

  13. Autophagy inhibitors.

    PubMed

    Pasquier, Benoit

    2016-03-01

    Autophagy is a lysosome-dependent mechanism of intracellular degradation. The cellular and molecular mechanisms underlying this process are highly complex and involve multiple proteins, including the kinases ULK1 and Vps34. The main function of autophagy is the maintenance of cell survival when modifications occur in the cellular environment. During the past decade, extensive studies have greatly improved our knowledge and autophagy has exploded as a research field. This process is now widely implicated in pathophysiological processes such as cancer, metabolic, and neurodegenerative disorders, making it an attractive target for drug discovery. In this review, we will summarize the different types of inhibitors that affect the autophagy machinery and provide some potential therapeutic perspectives.

  14. Overview of GCOM-C1/SGLI science

    NASA Astrophysics Data System (ADS)

    Honda, Yoshiaki; Kajiwara, Koji; Sharma, Ram; Ono, Akiko; Imaoka, Kenji; Murakami, Hiroshi; Hori, Masahiro; Ono, Yusaku; Rostand, Dim

    2012-11-01

    For monitoring of global environmental change, the Japan Aerospace Exploration Agency (JAXA) has made a new plan of Global Change Observation Mission (GCOM). SGLI (Second Generation GLI) onboard GCOM-C (Climate) satellite, which is one of this mission, provides an optical sensor from Near-UV to TIR. Characteristic specifications of SGLI are as follows; 1) 250m resolutions over land and area along the shore, 2) Three directional polarization observation (red and NIR), and 3) 500m resolutions temperature over land and area along shore. These characteristics are useful in many fields of social benefits. In addition, 51 products will be made by mainly 35 principal investigators. We introduce the overview of GCOM-C1/SGLI science.

  15. Plasma enhanced C1 chemistry for green technology

    NASA Astrophysics Data System (ADS)

    Nozaki, Tomohiro

    2013-09-01

    Plasma catalysis is one of the innovative next generation green technologies that meet the needs for energy and materials conservation as well as environmental protection. Non-thermal plasma uniquely generates reactive species independently of reaction temperature, and these species are used to initiate chemical reactions at unexpectedly lower temperatures than normal thermochemical reactions. Non-thermal plasma thus broadens the operation window of existing chemical conversion processes, and ultimately allows modification of the process parameters to minimize energy and material consumption. We have been specifically focusing on dielectric barrier discharge (DBD) as one of the viable non-thermal plasma sources for practical fuel reforming. In the presentation, room temperature one-step conversion of methane to methanol and hydrogen using a miniaturized DBD reactor (microplasma reactor) is highlighted. The practical impact of plasma technology on existing C1-chemistry is introduced, and then unique characteristics of plasma fuel reforming such as non-equilibrium product distribution is discussed.

  16. C1,1 regularity for degenerate elliptic obstacle problems

    NASA Astrophysics Data System (ADS)

    Daskalopoulos, Panagiota; Feehan, Paul M. N.

    2016-03-01

    The Heston stochastic volatility process is a degenerate diffusion process where the degeneracy in the diffusion coefficient is proportional to the square root of the distance to the boundary of the half-plane. The generator of this process with killing, called the elliptic Heston operator, is a second-order, degenerate-elliptic partial differential operator, where the degeneracy in the operator symbol is proportional to the distance to the boundary of the half-plane. In mathematical finance, solutions to the obstacle problem for the elliptic Heston operator correspond to value functions for perpetual American-style options on the underlying asset. With the aid of weighted Sobolev spaces and weighted Hölder spaces, we establish the optimal C 1 , 1 regularity (up to the boundary of the half-plane) for solutions to obstacle problems for the elliptic Heston operator when the obstacle functions are sufficiently smooth.

  17. A Selection of Recent Advances in C1 Chemistry.

    PubMed

    Mesters, Carl

    2016-06-07

    This review presents a selection of recent publications related to the chemistry and catalysis of C1 molecules, including methane, methanol, carbon monoxide, and carbon dioxide. These molecules play an important role in the current supply of energy and chemicals and will likely become even more relevant because of the need to decarbonize fuels (shift from coal to natural gas) in line with CO2 capture and use to mitigate global warming, as well as a gradual shift on the supply side from crude oil to natural gas. This review includes both recent industrial developments, such as the huge increase in methanol-to-olefins-capacity build in China and the demonstration of oxidative coupling of methane, and scientific developments in these chemistries facilitated by improved capabilities in, for example, analytical tools and computational modeling.

  18. 21 CFR 864.7290 - Factor deficiency test.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... defects, to monitor certain types of therapy, to detect coagulation inhibitors, and to detect a carrier state (a person carrying both a recessive gene for a coagulation factor deficiency such as hemophilia and the corresponding normal gene). (b) Classification. Class II (performance standards)....

  19. 21 CFR 864.7290 - Factor deficiency test.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... defects, to monitor certain types of therapy, to detect coagulation inhibitors, and to detect a carrier state (a person carrying both a recessive gene for a coagulation factor deficiency such as hemophilia and the corresponding normal gene). (b) Classification. Class II (performance standards)....

  20. 21 CFR 864.7290 - Factor deficiency test.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... defects, to monitor certain types of therapy, to detect coagulation inhibitors, and to detect a carrier state (a person carrying both a recessive gene for a coagulation factor deficiency such as hemophilia and the corresponding normal gene). (b) Classification. Class II (performance standards)....

  1. 21 CFR 864.7290 - Factor deficiency test.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... defects, to monitor certain types of therapy, to detect coagulation inhibitors, and to detect a carrier state (a person carrying both a recessive gene for a coagulation factor deficiency such as hemophilia and the corresponding normal gene). (b) Classification. Class II (performance standards)....

  2. 21 CFR 864.7290 - Factor deficiency test.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... defects, to monitor certain types of therapy, to detect coagulation inhibitors, and to detect a carrier state (a person carrying both a recessive gene for a coagulation factor deficiency such as hemophilia and the corresponding normal gene). (b) Classification. Class II (performance standards)....

  3. Hereditary fructose intolerance and alpha(1) antitrypsin deficiency.

    PubMed

    Hillebrand, G; Schneppenheim, R; Oldigs, H D; Santer, R

    2000-07-01

    A patient with coexisting hereditary fructose intolerance (HFI) and alpha(1) antitrypsin deficiency (alpha(1)ATD) is described. Protease inhibitor typing was not conclusive, presumably because of impaired N-glycosylation secondary to HFI. The case underlines the diagnostic role of molecular genetic techniques in inborn errors of metabolism.

  4. Betaine deficiency in maize

    SciTech Connect

    Lerma, C. ); Rich, P.J.; Ju, G.C.; Yang, Wenju; Rhodes, D. ); Hanson, A.D. )

    1991-04-01

    Maize (Zea mays L.) is a betaine-accumulating species, but certain maize genotypes lack betaine almost completely; a single recessive gene has been implicated as the cause of this deficiency. This study was undertaken to determine whether betaine deficiency in diverse maize germplasm is conditioned by the same genetic locus, and to define the biochemical lesion(s) involved. Complementation tests indicated that all 13 deficient genotypes tested shared a common locus. One maize population (P77) was found to be segregating for betaine deficiency, and true breeding individuals were used to produce related lines with and without betaine. Leaf tissue of both betaine-positive and betaine-deficient lines readily converted supplied betaine aldehyde to betaine, but only the betaine-containing line was able to oxidize supplied choline to betaine. This locates the lesion in betaine-deficient plants at the choline {r arrow} betaine aldehyde step of betaine synthesis. Consistent with this location, betaine-deficient plants were shown to have no detectable endogenous pool of betaine aldehyde.

  5. 75 FR 53861 - Airworthiness Directives; Robert E. Rust, Jr. Model DeHavilland DH.C1 Chipmunk 21, DH.C1 Chipmunk...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-09-02

    ...-025-AD; Amendment 39-16426; AD 2010-18-01] RIN 2120-AA64 Airworthiness Directives; Robert E. Rust, Jr... adopting a new airworthiness directive (AD) for all Robert E. Rust, Jr. Models DeHavilland DH.C1 Chipmunk... Robert E. Rust, Jr. Models DeHavilland DH.C1 Chipmunk 21, DH.C1 Chipmunk 22, and DH.C1 Chipmunk...

  6. Iodine deficiency: Clinical implications.

    PubMed

    Niwattisaiwong, Soamsiri; Burman, Kenneth D; Li-Ng, Melissa

    2017-03-01

    Iodine is crucial for thyroid hormone synthesis and fetal neurodevelopment. Major dietary sources of iodine in the United States are dairy products and iodized salt. Potential consequences of iodine deficiency are goiter, hypothyroidism, cretinism, and impaired cognitive development. Although iodine status in the United States is considered sufficient at the population level, intake varies widely across the population, and the percentage of women of childbearing age with iodine deficiency is increasing. Physicians should be aware of the risks of iodine deficiency and the indications for iodine supplementation, especially in women who are pregnant or lactating.

  7. NO synthase-generated NO acts downstream of auxin in regulating Fe-deficiency-induced root branching that enhances Fe-deficiency tolerance in tomato plants

    PubMed Central

    Jin, Chong Wei; Shamsi, Imran Haider; Luo, Bing Fang; Lin, Xian Yong

    2011-01-01

    In response to Fe-deficiency, various dicots increase their root branching which contributes to the enhancement of ferric-chelate reductase activity. Whether this Fe-deficiency-induced response eventually enhances the ability of the plant to tolerate Fe-deficiency or not is still unclear and evidence is also scarce about the signals triggering it. In this study, it was found that the SPAD-chlorophyll meter values of newly developed leaves of four tomato (Solanum lycocarpum) lines, namely line227/1 and Roza and their two reciprocal F1 hybrid lines, were positively correlated with their root branching under Fe-deficient conditions. It indicates that Fe-deficiency-induced root branching is critical for plant tolerance to Fe-deficiency. In another tomato line, Micro-Tom, the increased root branching in Fe-deficient plants was accompanied by the elevation of endogenous auxin and nitric oxide (NO) levels, and was suppressed either by the auxin transport inhibitors NPA and TIBA or the NO scavenger cPTIO. On the other hand, root branching in Fe-sufficient plants was induced either by the auxin analogues NAA and 2,4-D or the NO donors NONOate or SNP. Further, in Fe-deficient plants, NONOate restored the NPA-terminated root branching, but NAA did not affect the cPTIO-terminated root branching. Fe-deficiency-induced root branching was inhibited by the NO-synthase (NOS) inhibitor L-NAME, but was not affected by the nitrate reductase (NR) inhibitor NH4+, tungstate or glycine. Taking all of these findings together, a novel function and signalling pathway of Fe-deficiency-induced root branching is presented where NOS-generated rather than NR-generated NO acts downstream of auxin in regulating this Fe-deficiency-induced response, which enhances the plant tolerance to Fe-deficiency. PMID:21511908

  8. Expression of Organic Anion Transporting Polypeptide 1c1 and Monocarboxylate Transporter 8 in the Rat Placental Barrier and the Compensatory Response to Thyroid Dysfunction

    PubMed Central

    Sun, Yi-na; Liu, Yuan-jun; Zhang, Lu; Ye, Yan; Lin, Lai-xiang; Li, Yong-mei; Yan, Yu-qin; Chen, Zu-pei

    2014-01-01

    Thyroid hormones (THs) must pass from mother to fetus for normal fetal development and require the expression of placental TH transporters. We investigate the compensatory effect of placental organic anion transporting polypeptide 1c1 (Oatp1c1) and monocarboxylate transporter 8 (Mct8) on maternal thyroid dysfunction. We describe the expressions of these two transporters in placental barriers and trophoblastic cell populations in euthyroidism and thyroid dysfunction resulting from differential iodine nutrition at gestation day (GD) 16 and 20, that is, before and after the onset of fetal thyroid function. Immunohistochemistry revealed that in the blood-placenta barrier, these two TH transporters were strongly expressed in the villous interstitial substance and were weakly expressed in trophoblast cells. Levels of Oatp1c1 protein obviously increased in the placental fetal portion during maternal thyroid deficiency at GD16. Under maternal thyroid deficiency after the production of endogenous fetal TH, quantitative PCR analysis revealed down-regulation of Oatp1c1 occurred along with up-regulation of Mct8 in trophoblast cell populations isolated by laser capture microdissection (LCM); this was consistent with the protein levels in the fetal portion of the placenta. In addition, decreased D3 mRNA at GD16 and increased D2 mRNA on two gestational days were observed in trophoblast cells with thyroid dysfunction. However, levels of Oatp1c1 mRNA at GD16 and D3 mRNA at GD20 were too low to be detectable in trophoblast cells. In conclusion, placental Oatp1c1 plays an essential compensatory role when the transplacental passage of maternal THs is insufficient at the stage before the fetal TH production. In addition, the coordinated effects of Oatp1c1, Mct8, D2 and D3 in the placental barrier may regulate both transplacental TH passage and the development of trophoblast cells during thyroid dysfunction throughout the pregnancy. PMID:24763672

  9. Expression of organic anion transporting polypeptide 1c1 and monocarboxylate transporter 8 in the rat placental barrier and the compensatory response to thyroid dysfunction.

    PubMed

    Sun, Yi-na; Liu, Yuan-jun; Zhang, Lu; Ye, Yan; Lin, Lai-xiang; Li, Yong-mei; Yan, Yu-qin; Chen, Zu-pei

    2014-01-01

    Thyroid hormones (THs) must pass from mother to fetus for normal fetal development and require the expression of placental TH transporters. We investigate the compensatory effect of placental organic anion transporting polypeptide 1c1 (Oatp1c1) and monocarboxylate transporter 8 (Mct8) on maternal thyroid dysfunction. We describe the expressions of these two transporters in placental barriers and trophoblastic cell populations in euthyroidism and thyroid dysfunction resulting from differential iodine nutrition at gestation day (GD) 16 and 20, that is, before and after the onset of fetal thyroid function. Immunohistochemistry revealed that in the blood-placenta barrier, these two TH transporters were strongly expressed in the villous interstitial substance and were weakly expressed in trophoblast cells. Levels of Oatp1c1 protein obviously increased in the placental fetal portion during maternal thyroid deficiency at GD16. Under maternal thyroid deficiency after the production of endogenous fetal TH, quantitative PCR analysis revealed down-regulation of Oatp1c1 occurred along with up-regulation of Mct8 in trophoblast cell populations isolated by laser capture microdissection (LCM); this was consistent with the protein levels in the fetal portion of the placenta. In addition, decreased D3 mRNA at GD16 and increased D2 mRNA on two gestational days were observed in trophoblast cells with thyroid dysfunction. However, levels of Oatp1c1 mRNA at GD16 and D3 mRNA at GD20 were too low to be detectable in trophoblast cells. In conclusion, placental Oatp1c1 plays an essential compensatory role when the transplacental passage of maternal THs is insufficient at the stage before the fetal TH production. In addition, the coordinated effects of Oatp1c1, Mct8, D2 and D3 in the placental barrier may regulate both transplacental TH passage and the development of trophoblast cells during thyroid dysfunction throughout the pregnancy.

  10. Targeting Atp6v1c1 Prevents Inflammation and Bone Erosion Caused by Periodontitis and Reveals Its Critical Function in Osteoimmunology.

    PubMed

    Li, Sheng; Hao, Liang; Wang, Lin; Lu, Yun; Li, Qian; Zhu, Zheng; Shao, Jian-Zhong; Chen, Wei

    2015-01-01

    Periodontal disease (Periodontitis) is a serious disease that affects a majority of adult Americans and is associated with other systemic diseases, including diabetes, rheumatoid arthritis, and other inflammatory diseases. While great efforts have been devoted toward understanding the pathogenesis of periodontitis, there remains a pressing need for developing potent therapeutic strategies for targeting this pervasive and destructive disease. In this study, we utilized novel adeno-associated virus (AAV)-mediated Atp6v1c1 knockdown gene therapy to treat bone erosion and inflammatory caused by periodontitis in mouse model. Atp6v1c1 is a subunit of the V-ATPase complex and regulator of the assembly of the V0 and V1 domains of the V-ATPase complex. We demonstrated previously that Atp6v1c1 has an essential function in osteoclast mediated bone resorption. We hypothesized that Atp6v1c1 may be an ideal target to prevent the bone erosion and inflammation caused by periodontitis. To test the hypothesis, we employed AAV RNAi knockdown of Atp6v1c1 gene expression to prevent bone erosion and gingival inflammation simultaneously. We found that lesion-specific injection of AAV-shRNA-Atp6v1c1 into the periodontal disease lesions protected against bone erosion (>85%) and gingival inflammation caused by P. gingivalis W50 infection. AAV-mediated Atp6v1c1 knockdown dramatically reduced osteoclast numbers and inhibited the infiltration of dendritic cells and macrophages in the bacteria-induced inflammatory lesions in periodontitis. Silencing of Atp6v1c1 expression also prevented the expressions of osteoclast-related genes and pro-inflammatory cytokine genes. Our data suggests that AAV-shRNA-Atp6v1c1 treatment can significantly attenuate the bone erosion and inflammation caused by periodontitis, indicating the dual function of AAV-shRNA-Atp6v1c1 as an inhibitor of bone erosion mediated by osteoclasts, and as an inhibitor of inflammation through down-regulation of pro

  11. Galactosylation of IgA1 Is Associated with Common Variation in C1GALT1.

    PubMed

    Gale, Daniel P; Molyneux, Karen; Wimbury, David; Higgins, Patricia; Levine, Adam P; Caplin, Ben; Ferlin, Anna; Yin, Peiran; Nelson, Christopher P; Stanescu, Horia; Samani, Nilesh J; Kleta, Robert; Yu, Xueqing; Barratt, Jonathan

    2017-02-16

    IgA nephropathy (IgAN), an important cause of kidney failure, is characterized by glomerular IgA deposition and is associated with changes in O-glycosylation of the IgA1 molecule. Here, we sought to identify genetic factors contributing to levels of galactose-deficient IgA1 (Gd-IgA1) in white and Chinese populations. Gd-IgA1 levels were elevated in IgAN patients compared with ethnically matched healthy subjects and correlated with evidence of disease progression. White patients with IgAN exhibited significantly higher Gd-IgA1 levels than did Chinese patients. Among individuals without IgAN, Gd-IgA1 levels did not correlate with kidney function. Gd-IgA1 level heritability (h(2)), estimated by comparing midparental and offspring Gd-IgA1 levels, was 0.39. Genome-wide association analysis by linear regression identified alleles at a single locus spanning the C1GALT1 gene that strongly associated with Gd-IgA1 level (β=0.26; P=2.35×10(-9)). This association was replicated in a genome-wide association study of separate cohorts comprising 308 patients with membranous GN from the UK (P<1.00×10(-6)) and 622 controls with normal kidney function from the UK (P<1.00×10(-10)), and in a candidate gene study of 704 Chinese patients with IgAN (P<1.00×10(-5)). The same extended haplotype associated with elevated Gd-IgA1 levels in all cohorts studied. C1GALT1 encodes a galactosyltransferase enzyme that is important in O-galactosylation of glycoproteins. These findings demonstrate that common variation at C1GALT1 influences Gd-IgA1 level in the population, which independently associates with risk of progressive IgAN, and that the pathogenic importance of changes in IgA1 O-glycosylation may vary between white and Chinese patients with IgAN.

  12. Catalytic routes to fuels from C1 and oxygenate molecules.

    PubMed

    Wang, Shuai; Agirrezabal-Telleria, Iker; Bhan, Aditya; Simonetti, Dante; Takanabe, Kazuhiro; Iglesia, Enrique

    2017-03-16

    This account illustrates concepts in chemical kinetics underpinned by the formalism of transition state theory using catalytic processes that enable the synthesis of molecules suitable as fuels from C1 and oxygenate reactants. Such feedstocks provide an essential bridge towards a carbon-free energy future, but their volatility and low energy density require the formation of new C-C bonds and the removal of oxygen. These transformations are described here through recent advances in our understanding of the mechanisms and site requirements in catalysis by surfaces, with emphasis on enabling concepts that tackle ubiquitous reactivity and selectivity challenges. The hurdles in forming the first C-C bond from C1 molecules are illustrated by the oxidative coupling of methane, in which surface O-atoms form OH radicals from O2 and H2O molecules. These gaseous OH species act as strong H-abstractors and activate C-H bonds with earlier transition states than oxide surfaces, thus rendering activation rates less sensitive to the weaker C-H bonds in larger alkane products than in CH4 reactants. Anhydrous carbonylation of dimethyl ether forms a single C-C bond on protons residing within inorganic voids that preferentially stabilize the kinetically-relevant transition state through van der Waals interactions that compensate for the weak CO nucleophile. Similar solvation effects, but by intrapore liquids instead of inorganic hosts, also become evident as alkenes condense within MCM-41 channels containing isolated Ni(2+) active sites during dimerization reactions. Intrapore liquids preferentially stabilize transition states for C-C bond formation and product desorption, leading to unprecedented reactivity and site stability at sub-ambient temperatures and to 1-alkene dimer selectivities previously achieved only on organometallic systems with co-catalysts or activators. C1 homologation selectively forms C4 and C7 chains with a specific backbone (isobutane, triptane) on solid acids

  13. Iron deficiency anemia

    MedlinePlus

    ... GM. Disorders of iron homeostasis: iron deficiency and overload. In: Hoffman R, Benz EJ Jr, Silberstein LE, ... to achieve this important distinction for online health information and services. Learn more about A.D.A. ...

  14. [Selenium deficiency in pregnancy?].

    PubMed

    Lechner, W; Jenewein, I; Ritzberger, G; Sölder, E; Waitz-Penz, A; Schirmer, M; Abfalter, E

    1990-07-15

    Selenium content was investigated by atomic absorbtion spectroscopy in 32 normal pregnant women in the 38th-42, week of pregnancy. In congruence with other investigations from middle and northern Europe, selenium deficiency was stated in all of the patients.

  15. Adenine phosphoribosyltransferase deficiency.

    PubMed

    Bollée, Guillaume; Harambat, Jérôme; Bensman, Albert; Knebelmann, Bertrand; Daudon, Michel; Ceballos-Picot, Irène

    2012-09-01

    Complete adenine phosphoribosyltransferase (APRT) deficiency is a rare inherited metabolic disorder that leads to the formation and hyperexcretion of 2,8-dihydroxyadenine (DHA) into urine. The low solubility of DHA results in precipitation of this compound and the formation of urinary crystals and stones. The disease can present as recurrent urolithiasis or nephropathy secondary to crystal precipitation into renal parenchyma (DHA nephropathy). The diagnostic tools available-including stone analysis, crystalluria, and APRT activity measurement-make the diagnosis easy to confirm when APRT deficiency is suspected. However, the disease can present at any age, and the variability of symptoms can present a diagnostic challenge to many physicians. The early recognition and treatment of APRT deficiency are of crucial importance for preventing irreversible loss of renal function, which still occurs in a non-negligible proportion of cases. This review summarizes the genetic and metabolic mechanisms underlying stone formation and renal disease, along with the diagnosis and management of APRT deficiency.

  16. Factor V deficiency

    MedlinePlus

    ... as many as 20 different proteins in blood plasma. These proteins are called blood coagulation factors. Factor ... You will be given fresh blood plasma or fresh frozen plasma infusions ... These treatments will correct the deficiency temporarily.

  17. Factor VII deficiency

    MedlinePlus

    ... if one or more of these factors are missing or are not functioning like they should. Factor VII is one such coagulation factor. Factor VII deficiency runs in families (inherited) and is very rare. Both parents must ...

  18. Factor II deficiency

    MedlinePlus

    ... if one or more of these factors are missing or are not functioning like they should. Factor II is one such coagulation factor. Factor II deficiency runs in families (inherited) and is very rare. Both parents must ...

  19. Vitamin D deficiency

    PubMed Central

    Gani, Linsey Utami; How, Choon How

    2015-01-01

    Vitamin D deficiency is common and may contribute to osteopenia, osteoporosis and falls risk in the elderly. Screening for vitamin D deficiency is important in high-risk patients, especially for patients who suffered minimal trauma fractures. Vitamin D deficiency should be treated according to the severity of the deficiency. In high-risk adults, follow-up serum 25-hydroxyvitamin D concentration should be measured 3–4 months after initiating maintenance therapy to confirm that the target level has been achieved. All patients should maintain a calcium intake of at least 1,000 mg for women aged ≤ 50 years and men ≤ 70 years, and 1,300 mg for women > 50 years and men > 70 years. PMID:26311908

  20. The C1 and C2 domains of blood coagulation factor VIII mediate its endocytosis by dendritic cells

    PubMed Central

    Gangadharan, Bagirath; Ing, Mathieu; Delignat, Sandrine; Peyron, Ivan; Teyssandier, Maud; Kaveri, Srinivas V.; Lacroix-Desmazes, Sébastien

    2017-01-01

    The development of inhibitory antibodies to therapeutic factor VIII is the major complication of replacement therapy in patients with hemophilia A. The first step in the initiation of the anti-factor VIII immune response is factor VIII interaction with receptor(s) on antigen-presenting cells, followed by endocytosis and presentation to naïve CD4+ T cells. Recent studies indicate a role for the C1 domain in factor VIII uptake. We investigated whether charged residues in the C2 domain participate in immunogenic factor VIII uptake. Co-incubation of factor VIII with BO2C11, a monoclonal C2-specific immunoglobulin G, reduced factor VIII endocytosis by dendritic cells and presentation to CD4+ T cells, and diminished factor VIII immunogenicity in factor VIII-deficient mice. The mutation of basic residues within the BO2C11 epitope of C2 replicated reduced in vitro immunogenic uptake, but failed to prevent factor VIII immunogenicity in mice. BO2C11 prevents factor VIII binding to von Willebrand factor, thus potentially biasing factor VIII immunogenicity by perturbing its half-life. Interestingly, a factor VIIIY1680C mutant, that does not bind von Willebrand factor, demonstrated unaltered endocytosis by dendritic cells as well as immunogenicity in factor VIII-deficient mice. Co-incubation of factor VIIIY1680C with BO2C11, however, resulted in decreased factor VIII immunogenicity in vivo. In addition, a previously described triple C1 mutant showed decreased uptake in vitro, and reduced immunogenicity in vivo, but only in the absence of endogenous von Willebrand factor. Taken together, the results indicate that residues in the C1 and/or C2 domains of factor VIII are implicated in immunogenic factor VIII uptake, at least in vitro. Conversely, in vivo, the binding to endogenous von Willebrand factor masks the reducing effect of mutations in the C domains on factor VIII immunogenicity. PMID:27758819

  1. Forkhead Box C1 Regulates Human Primary Keratinocyte Terminal Differentiation

    PubMed Central

    Deng, Liehua; Yang, Hengwen; Zhu, Leqing; Wang, Xiao; Edwards, Michael G.; Richers, Brittany; Leung, Donald Y. M.

    2016-01-01

    The epidermis serves as a critical protective barrier between the internal and external environment of the human body. Its remarkable barrier function is established through the keratinocyte (KC) terminal differentiation program. The transcription factors specifically regulating terminal differentiation remain largely unknown. Using a RNA-sequencing (RNA-seq) profiling approach, we found that forkhead box c 1 (FOXC1) was significantly up-regulated in human normal primary KC during the course of differentiation. This observation was validated in human normal primary KC from several different donors and human skin biopsies. Silencing FOXC1 in human normal primary KC undergoing differentiation led to significant down-regulation of late terminal differentiation genes markers including epidermal differentiation complex genes, keratinization genes, sphingolipid/ceramide metabolic process genes and epidermal specific cell-cell adhesion genes. We further demonstrated that FOXC1 works down-stream of ZNF750 and KLF4, and upstream of GRHL3. Thus, this study defines FOXC1 as a regulator specific for KC terminal differentiation and establishes its potential position in the genetic regulatory network. PMID:27907090

  2. Near-ultraviolet spectroscopy of Comet Austin (1989c1)

    NASA Technical Reports Server (NTRS)

    Valk, Jacobus H.; O'Dell, C. R.; Cochran, Anita L.; Cochran, William D.; Opal, Chet B. S.; Barker, Edwin S.

    1992-01-01

    Comet Austin (1989c1) was observed post-perihelion at a heliocentric distance near 1.25 AU. The wavelength range was from the atmospheric cutoff at 3000 to 4000 A. The coma spectra were calibrated into flux units and the contaminating sky spectrum and solar scattered light continuum were subtracted, leaving an ultraviolet spectrum of about 1.5-A resolution and excellent signal-to-noise ratio. The spectrum is dominated by emissions from OH, NH, CH, C3, and CN, some of the weaker emissions of which are seen here for the first time. More bands of CO(2+) were found than in any previous investigation and several intensity anomalies were noted; H2CO, OH(+), NCN, N(2+), and CN(+) may be present. Several emission features well above the noise level remain unidentified. The relative intensities of the OH and CN bands agree with the predictions of resonance fluorescence when one considers the potential effects of contamination by other molecules. The effects of the ozone absorption spectrum are not fully removed by the data-reduction process, although this does not affect these results.

  3. [Prevention of iron deficiency and iron deficiency anemia in tropical areas].

    PubMed

    Dillon, J C

    2000-01-01

    Iron deficiency is the most widespread nutritional disease in the World. It is prevalent in tropical areas especially in pregnant women and children. The main cause in these areas is consumption of foods containing inhibitors of iron absorption resulting in insufficient bioavailability. In advanced stages of iron deficiency, low hemoglobin levels lead to anemia. Functional consequences of anemia depend on age including mental and physical retardation in children and work disability in adults. Although other disorders including parasitic, infectious, genetic, and nutritional diseases may be involved in anemia in tropical areas, iron deficiency is always a factor because of nutritional conditions. The WHO has proposed laboratory criteria for use in establishing the incidence of iron deficiency and related anemia in a given population. Based on several surveys, four preventive strategies have been developed, i.e., dietary diversification, iron supplementation, general public health measures, and food fortification. Each of these strategies has advantages and disadvantages. The prevailing consensus is that coordinated use of these approaches holds forth the only hope of impacting the incidence of iron-deficiency anemia in tropical regions.

  4. Fluorescence induction characteristics of iron deficient cyanobacteria

    SciTech Connect

    Henry, R.; Guikema, J.A.

    1986-04-01

    The fluorescence induction characteristics of Anacystis nidulans were examined after cultures were stressed with iron deficiency. When these cells were illuminated with 620 nm light to excite phycocyanin, a fluorescence induction transient was observed which was not present in normal cells. The transient had a rise time of approximately 3-4 sec, and was abolished when cells were preilluminated with 620 nm light. One goal of this work was to ascertain the role of electron transfer between PSII and either PSI or the respiratory system in causing the fluorescence transient. The effects of electron transport inhibitors and uncouplers on fluorescence induction were examined. Respiratory inhibitors, such as KCN, had little or no effect on the fluorescence transient. p-Chloromercuribenzoic acid, at concentrations below 0.5 mM, delayed the transient rise time without causing a decrease in the extent. Uncouplers, such as gramicidin and CCCP, caused a decrease in the extent of the transient.

  5. Alpha 1-antitrypsin deficiency: memorandum from a WHO meeting.

    PubMed Central

    1997-01-01

    alpha 1-Antitrypsin (AAT) deficiency, also known as alpha 1-antiprotease inhibitor deficiency, is a disease caused by genetically determined AAT deficiency. It occurs as a result of inheritance of two protease inhibitor (PI) deficiency alleles from the AAT gene locus (designated PI) on chromosomal segment 14q32.1. The most common deficiency allele is PI*Z and a large majority of individuals with severe AAT deficiency are PI type ZZ. The disease occurs predominantly in white persons of European origin and its frequency in Europe and North America is comparable to that of cystic fibrosis (1 in 2000 to 1 in 7000.) Persons with AAT deficiency may have no clinical manifestations. Chronic obstructive pulmonary disease (COPD) with a high frequency of panacinar emphysema is the most prevalent clinical disorder associated with AAT deficiency and the most frequent cause of disability and death. Tobacco smoking is the major risk factor for developing COPD, which generally begins by the third decade of life, much earlier than "usual" COPD that occurs in AAT-replete individuals. Liver disease, the second most frequent clinical manifestation of AAT deficiency, typically presents as cholestasis in infancy but is usually not severe and generally remits by adolescence. Chronic liver disease develops infrequently, although AAT deficiency is the commonest cause of chronic liver disease in childhood. Cirrhosis and carcinoma of the liver affect at least 25% of AAT-deficient adults over the age of 50 years. AAT deficiency appears to be widely underdiagnosed and based on predicted gene frequencies even in the most intensely studied populations, only a small proportion of those predicted to have AAT deficiency have been diagnosed. Human AAT is available in limited quantity for augmentation therapy. This Memorandum summarizes the discussions and recommendations made by participants at a WHO meeting held in Geneva on 18-20 March 1996 to review existing knowledge about this highly prevalent

  6. Human C1qRp is identical with CD93 and the mNI-11 antigen but does not bind C1q.

    PubMed

    McGreal, Eamon P; Ikewaki, Nobunao; Akatsu, Hiroyasu; Morgan, B Paul; Gasque, Philippe

    2002-05-15

    It has been suggested that the human C1qRp is a receptor for the complement component C1q; however, there is no direct evidence for an interaction between C1q and C1qRp. In this study, we demonstrate that C1q does not show enhanced binding to C1qRp-transfected cells compared with control cells. Furthermore, a soluble recombinant C1qRp-Fc chimera failed to interact with immobilized C1q. The proposed role of C1qRp in the phagocytic response in vivo is also unsupported in that we demonstrate that this molecule is not expressed by macrophages in a variety of human tissues and the predominant site of expression is on endothelial cells. Studies on the rodent homolog of C1qRp, known as AA4, have suggested that this molecule may function as an intercellular adhesion molecule. Here we show that C1qRp is the Ag recognized by several previously described mAbs, mNI-11 and two anti-CD93 Abs (clones X2 and VIMD2b). Interestingly, mNI-11 (Fab') has been shown to promote monocyte-monocyte and monocyte-endothelial cell adhesive interactions. We produced a recombinant C1qRp-Fc chimera containing the C-type lectin-like domain of C1qRp and found specific binding to vascular endothelial cells in sections of inflamed human tonsil, indicating the presence of a C1qRp ligand at this site. This interaction was Ca(2+) independent and was not blocked by our anti-C1qRp mAb BIIG-4, but was blocked by the proadhesive mAb mNI-11. Collectively, these data indicate that C1qRp is not a receptor for C1q, and they support the emerging role of C1qRp (here renamed CD93) in functions relevant to intercellular adhesion.

  7. Necroptosis in Niemann–Pick disease, type C1: a potential therapeutic target

    PubMed Central

    Cougnoux, A; Cluzeau, C; Mitra, S; Li, R; Williams, I; Burkert, K; Xu, X; Wassif, C A; Zheng, W; Porter, F D

    2016-01-01

    Niemann–Pick disease, type C1 (NPC1) is a neurodegenerative, lysosomal storage disorder due to mutation of the NPC1 gene. The NPC1 phenotype is characterized by progressive neuronal dysfunction, including cerebellar ataxia and dementia. There is histological evidence of neuroinflammation and progressive neuronal loss, with cerebellar Purkinje cells particularly vulnerable to loss of NPC1 function. Necroptosis was evaluated as a mechanism of neuronal loss. Receptor-interacting protein kinase 1 (RIP1) and RIP3 are key components of the necrosomal complex that regulates necroptotic cell death. We report increased expression of RIP1 and RIP3 in NPC1 fibroblasts, NPC1 iPS cell-derived neuronal precursors, and in cerebellar tissue from both NPC1 mice and patients. Our data suggest a positive correlation between NPC1 neurological disease severity and assembly of the necrosome complex. Furthermore, we demonstrate that pharmacological inhibition of RIP1 decreases cell death both in vitro and in vivo. Treatment of Npc1-mutant mice with necrostatin-1, an allosteric inhibitor of RIP1, significantly delayed cerebellar Purkinje cell loss, progression of neurological symptoms, and death. Collectively, our data identified necroptosis as a key component of the molecular network that contributes to neuronal loss in NPC1 and establish that inhibition of necroptosis is a potential therapeutic intervention. PMID:26986514

  8. Congenital prothrombin deficiency.

    PubMed

    Lancellotti, Stefano; De Cristofaro, Raimondo

    2009-06-01

    Prothrombin deficiency is among the rarest inherited coagulation disorders, with a prevalence of approximately 1:2,000,000. Two main phenotypes can be distinguished: (1) hypoprothrombinemia (type I deficiency), characterized by concomitantly low levels of activity and antigen; and (2) dysprothrombinemia (type II deficiency), characterized by the normal or near-normal synthesis of a dysfunctional protein. In some cases, hypoprothrombinemia associated with dysprothrombinemia was also described in compound heterozygous defects. No living patient with undetectable plasma prothrombin has been reported to date. Prothrombin is encoded by a gene of approximately 21 kb located on chromosome 11 and containing 14 exons. Forty different mutations have been identified and characterized in prothrombin deficiency. Many of them surround the catalytic site, whereas another "hot spot" is localized in the recognition domain called anion binding exosite I, also called fibrinogen recognition site. Recently, mutations were identified also in the Na (+)-binding loop and in the light A-chain of thrombin. Most hypoprothrombinemia-associated mutations are missense, but there are also nonsense mutations leading to stop codons and one single nucleotide deletion. Finally, the main aspects of clinical manifestations and therapy of congenital prothrombin deficiency are presented and discussed.

  9. Iron deficiency anaemia.

    PubMed

    Lopez, Anthony; Cacoub, Patrice; Macdougall, Iain C; Peyrin-Biroulet, Laurent

    2016-02-27

    Anaemia affects roughly a third of the world's population; half the cases are due to iron deficiency. It is a major and global public health problem that affects maternal and child mortality, physical performance, and referral to health-care professionals. Children aged 0-5 years, women of childbearing age, and pregnant women are particularly at risk. Several chronic diseases are frequently associated with iron deficiency anaemia--notably chronic kidney disease, chronic heart failure, cancer, and inflammatory bowel disease. Measurement of serum ferritin, transferrin saturation, serum soluble transferrin receptors, and the serum soluble transferrin receptors-ferritin index are more accurate than classic red cell indices in the diagnosis of iron deficiency anaemia. In addition to the search for and treatment of the cause of iron deficiency, treatment strategies encompass prevention, including food fortification and iron supplementation. Oral iron is usually recommended as first-line therapy, but the most recent intravenous iron formulations, which have been available for nearly a decade, seem to replenish iron stores safely and effectively. Hepcidin has a key role in iron homoeostasis and could be a future diagnostic and therapeutic target. In this Seminar, we discuss the clinical presentation, epidemiology, pathophysiology, diagnosis, and acute management of iron deficiency anaemia, and outstanding research questions for treatment.

  10. Fabrication of dye-sensitized solar cells using chlorophylls c1 and c2 and their oxidized forms c1' and c2' from Undaria pinnatifida (Wakame)

    NASA Astrophysics Data System (ADS)

    Wang, Xiao-Feng; Zhan, Cong-Hong; Maoka, Takashi; Wada, Yuji; Koyama, Yasushi

    2007-10-01

    Two different types of chlorophyll c ( c1 and c2) and their oxidized forms ( c1' and c2') were isolated from a brown seaweed, Undaria pinnatifida, and their structures were determined by mass spectrometry and 1H NMR spectroscopy. The order of conversion efficiencies in titania-based solar cells using these chlorophyll sensitizers, i.e., c2(4.6%)>c1(3.4%)>c2'(2.6%)≧c1'(2.5%), were explained in terms of a more extended conjugated system and the resultant higher electron densities in Chl c2 than Chl c1 as well as the different configurations and electron densities of the vinyl carboxyl group in Chls c2' and c1'.

  11. Facial Nerve Recovery in KbDb and C1q Knockout Mice: A Role for Histocompatibility Complex 1

    PubMed Central

    Akdagli, Seden; Williams, Ryan A.; Kim, Hyun J.; Yan, Yuling; Mustapha, Mirna

    2016-01-01

    Background: Understanding the mechanisms in nerve damage can lead to better outcomes for neuronal rehabilitation. The purpose of our study was to assess the effect of major histocompatibility complex I deficiency and inhibition of the classical complement pathway (C1q) on functional recovery and cell survival in the facial motor nucleus (FMN) after crush injury in adult and juvenile mice. Methods: A prospective blinded analysis of functional recovery and cell survival in the FMN after a unilateral facial nerve crush injury in juvenile and adult mice was undertaken between wild-type, C1q knockout (C1q−/−), and KbDb knockout (KbDb−/−) groups. Whisker function was quantified to assess functional recovery. Neuron counts were performed to determine neuron survival in the FMN after recovery. Results: After facial nerve injury, all adult wild-type mice fully recovered. Juvenile mice recovered incompletely corresponding to a greater neuron loss in the FMN of juveniles compared with adults. The C1q−/− juvenile and adult groups did not differ from wild type. The KbDb−/− adults demonstrated 50% recovery of whisker movement and decreased cell survival in FMN. The KbDb−/− juvenile group did not demonstrate any difference from control group. Conclusion: Histocompatibility complex I plays a role for neuroprotection and enhanced facial nerve recovery in adult mice. Inhibition of the classical complement pathway alone does not affect functional recovery or neuronal survival. The alternative and mannose binding pathways pose alternative means for activating the final components of the pathway that may lead to acute nerve damage. PMID:28293529

  12. The production and secretion of complement component C1q by human mast cells.

    PubMed

    van Schaarenburg, Rosanne A; Suurmond, Jolien; Habets, Kim L L; Brouwer, Mieke C; Wouters, Diana; Kurreeman, Fina A S; Huizinga, Tom W J; Toes, René E M; Trouw, Leendert A

    2016-10-01

    C1q is the initiation molecule of the classical pathway of the complement system and is produced by macrophages and immature dendritic cells. As mast cells share the same myeloid progenitor cells, we have studied whether also mast cells can produce and secrete C1q. Mast cells were generated in vitro from CD34+ progenitor cells from buffy coats or cord blood. Fully differentiated mast cells were shown by both RNA sequencing and qPCR to express C1QA, C1QB and C1QC. C1q produced by mast cells has a similar molecular make-up as serum C1q. Reconstituting C1q depleted serum with mast cell supernatant in haemolytic assays, indicated that C1q secreted by mast cells is functionally active. The level of C1q in supernatants produced under basal conditions was considerably enhanced upon stimulation with LPS, dexamethasone in combination with IFN- γ or via FcεRI triggering. Mast cells in human tissues stained positive for C1q in both healthy and in inflamed tissue. Moreover, mast cells in healthy and diseased skin appear to be the predominant C1q positive cells. Together, our data reveal that mast cells are able to produce and secrete functional active C1q and indicate mast cells as a local source of C1q in human tissue.

  13. Thiamine Deficiency and Delirium

    PubMed Central

    Ali, Shahid; Freeman, C.; Barker, Narviar C.; Jabeen, Shagufta; Maitra, Sarbani; Olagbemiro, Yetunde; Richie, William; Bailey, Rahn K.

    2013-01-01

    Thiamine is an essential vitamin that plays an important role in cellular production of energy from ingested food and enhances normal neuronal actives. Deficiency of this vitamin leads to a very serious clinical condition known as delirium. Studies performed in the United States and other parts of the world have established the link between thiamine deficiency and delirium. This literature review examines the physiology, pathophysiology, predisposing factors, clinical manifestations (e.g., Wernicke’s encephalopathy, Wernicke-Korsakoff syndrome, structural and functional brain injuries) and diagnosis of thiamine deficiency and delirium. Current treatment practices are also discussed that may improve patient outcome, which ultimately may result in a reduction in healthcare costs. PMID:23696956

  14. [Vitamin deficiencies and hypervitaminosis].

    PubMed

    Mino, M

    1999-10-01

    There have recently been very few deficiencies with respect to fat soluble and water soluble vitamins in Japan All-trans-retinoic acid as induction or maintenance treatment improves disease free and overall survival against acute promyelocytic leukemia. In the isolated vitamin E deficiencies gene mutation has been cleared for alpha-tocopherol transferprotein. Recently, a relation of nutritional vitamin K intake and senile osteoporosis in women was epidemiologically demonstrated on a prospective study. Thiamin was yet noticed as development of deficiency in alcoholism, while the importance of supplemental folic acid during pregnancy has become especially clear in light of studies showing that folic acid supplements reduce the risk of neural tube defects in the fetus. With respect to hypervitaminosis, the Council for Responsible Nutrition (CRN), USA, has established safe intakes by identifying the NOAEL (No Observed Adverse Effect Level) and LOAEL (Lowest Observed Adverse Effect Level). Summaries of NOAEL and LOAEL for individual vitamins were shown.

  15. Antepartum ornithine transcarbamylase deficiency.

    PubMed

    Nakajima, Hitoshi; Sasaki, Yosuke; Maeda, Tadashi; Takeda, Masako; Hara, Noriko; Nakanishi, Kazushige; Urita, Yoshihisa; Hattori, Risa; Miura, Ken; Taniguchi, Tomoko

    2014-01-01

    Ornithine transcarbamylase deficiency (OTCD) is the most common type urea cycle enzyme deficiencies. This syndrome results from a deficiency of the mitochondrial enzyme ornithine transcarbamylase, which catalyzes the conversion of ornithine and carbamoyl phosphate to citrullin. Our case was a 28-year-old female diagnosed with OTCD following neurocognitive deficit during her first pregnancy. Although hyperammonemia was suspected as the cause of the patient's mental changes, there was no evidence of chronic liver disease. Plasma amino acid and urine organic acid analysis revealed OTCD. After combined modality treatment with arginine, sodium benzoate and hemodialysis, the patient's plasma ammonia level stabilized and her mental status returned to normal. At last she recovered without any damage left.

  16. Natural killer cell deficiency.

    PubMed

    Orange, Jordan S

    2013-09-01

    Natural killer (NK) cells are part of the innate immune defense against infection and cancer and are especially useful in combating certain viral pathogens. The utility of NK cells in human health has been underscored by a growing number of persons who are deficient in NK cells and/or their functions. This can be in the context of a broader genetically defined congenital immunodeficiency, of which there are more than 40 presently known to impair NK cells. However, the abnormality of NK cells in certain cases represents the majority immunologic defect. In aggregate, these conditions are termed NK cell deficiency. Recent advances have added clarity to this diagnosis and identified defects in 3 genes that can cause NK cell deficiency, as well as some of the underlying biology. Appropriate consideration of these diagnoses and patients raises the potential for rational therapeutic options and further innovation.

  17. Inhibitors of Kallikrein in Human Plasma

    PubMed Central

    McConnell, David J.

    1972-01-01

    Human plasma was fractionated by ammonium sulfate precipitation, DEAE-cellulose chromatography, and Sephadex G-200 gel filtration to determine which method would give the greatest number of clearly separable kallikrein inhibitory peaks. With G-200 gel filtration three peaks could be separated which were demonstrated to contain α2-macroglobulin, C1̄ inactivator, and α1-antitrypsin. No other kallikrein inhibitors could be identified. The fractions containing C1̄ inactivator and α2-macroglobulin appeared to be more effective against kallikrein than that containing α1-antitrypsin. A patient with hereditary angioneurotic edema was shown to have an abnormal C1̄ inactivator protein capable of interfering with kallikrein's biologic, but not its esterolytic activity. Heat-treated human plasma, a commonly used source of kininogen for experiments with kallikrein, was shown to have kallikrein inhibitory activity. PMID:4113391

  18. Multiple sulfatase deficiency.

    PubMed

    Soong, B W; Casamassima, A C; Fink, J K; Constantopoulos, G; Horwitz, A L

    1988-08-01

    Multiple sulfatase deficiency is an inherited disorder characterized by a deficiency of several sulfatases and the accumulation of sulfatides, glycosaminoglycans, sphingolipids, and steroid sulfates in tissues and body fluids. The clinical manifestations represent the summation of two diseases: late infantile metachromatic leukodystrophy and mucopolysaccharidosis. We present a 9-year-old girl with a phenotype similar to a mucopolysaccharidosis: short stature, microcephaly, and mild facial dysmorphism, along with dysphagia, retinal degeneration, developmental arrest, and ataxia. We discuss the importance of measuring the sulfatase activities in the leukocytes, and the instability of sulfatases in the cultured skin fibroblasts.

  19. Molecular characterization of the complement C1q, C2 and C4 genes in Brazilian patients with juvenile systemic lupus erythematosus

    PubMed Central

    Liphaus, Bernadete L; Umetsu, Natalia; Jesus, Adriana A; Bando, Silvia Y; Silva, Clovis A; Carneiro-Sampaio, Magda

    2015-01-01

    OBJECTIVE: To perform a molecular characterization of the C1q, C2 and C4 genes in patients with juvenile systemic lupus erythematosus. METHODS: Patient 1 (P1) had undetectable C1q, patient 2 (P2) and patient 3 (P3) had decreased C2 and patient 4 (P4) had decreased C4 levels. All exons and non-coding regions of the C1q and C2 genes were sequenced. Mononuclear cells were cultured and stimulated with interferon gamma to evaluate C1q, C2 and C4 mRNA expression by quantitative real-time polymerase chain reaction. RESULTS: C1q sequencing revealed heterozygous silent mutations in the A (c.276 A>G Gly) and C (c.126 C>T Pro) chains, as well as a homozygous single-base change in the 3′ non-coding region of the B chain (c*78 A>G). C1qA mRNA expression without interferon was decreased compared with that of healthy controls (p<0.05) and was decreased after stimulation compared with that of non-treated cells. C1qB mRNA expression was decreased compared with that of controls and did not change with stimulation. C1qC mRNA expression was increased compared with that of controls and was even higher after stimulation. P2 and P3 had Type I C2 deficiency (heterozygous 28 bp deletion at exon 6). The C2 mRNA expression in P3 was 23 times lower compared with that of controls and did not change after stimulation. The C4B mRNA expression of P4 was decreased compared with that of controls and increased after stimulation. CONCLUSIONS: Silent mutations and single-base changes in the 3′ non-coding regions may modify mRNA transcription and C1q production. Type I C2 deficiency should be evaluated in JSLE patients with decreased C2 serum levels. Further studies are needed to clarify the role of decreased C4B mRNA expression in JSLE pathogenesis. PMID:26017655

  20. Human diploid fibroblasts have receptors for the globular domain of C1Q

    SciTech Connect

    Bordin, S.; Page, R.C.

    1986-03-01

    The authors showed that mass cultures of fibroblasts grown from gingival explants in DB medium with 10% human serum are enriched in a phenotype that binds C1q with an affinity much higher than the rest of the population. Because of potential biologic importance of C1q receptors, the authors studied whether the interaction between C1q and this phenotype was mediated by the globular or collagenous domains of the molecule. Globular fragments were prepared by digesting C1q with collagenase, and collagenous fragments obtained after pepsin treatment. C1q binding on cells in suspension was determined by reaction with /sup 125/I-C1q as reported. Competition experiments were performed under conditions in which intact /sup 125/I-C1q binding saturated all available receptors. The results showed that collagenous fragments inhibited 20% of the /sup 125/I-C1q binding to high affinity receptors, whereas inhibition by globular fragments was 70%. Unlabeled intact C1q and collagen type 1 were used as controls, and inhibited 92% and 17% of C1q binding, respectively. These studies show that C1q interacts with the fibroblast phenotype expressing high affinity receptors through its globular domain. The authors suggest that at sites of trauma, native C1 may bind to the surface of these cells via the globular domain of C1q, and that this unique phenotype may play an important role in tissue repair.

  1. Diagnosing oceanic nutrient deficiency

    NASA Astrophysics Data System (ADS)

    Moore, C. Mark

    2016-11-01

    The supply of a range of nutrient elements to surface waters is an important driver of oceanic production and the subsequent linked cycling of the nutrients and carbon. Relative deficiencies of different nutrients with respect to biological requirements, within both surface and internal water masses, can be both a key indicator and driver of the potential for these nutrients to become limiting for the production of new organic material in the upper ocean. The availability of high-quality, full-depth and global-scale datasets on the concentrations of a wide range of both macro- and micro-nutrients produced through the international GEOTRACES programme provides the potential for estimation of multi-element deficiencies at unprecedented scales. Resultant coherent large-scale patterns in diagnosed deficiency can be linked to the interacting physical-chemical-biological processes which drive upper ocean nutrient biogeochemistry. Calculations of ranked deficiencies across multiple elements further highlight important remaining uncertainties in the stoichiometric plasticity of nutrient ratios within oceanic microbial systems and caveats with regards to linkages to upper ocean nutrient limitation. This article is part of the themed issue 'Biological and climatic impacts of ocean trace element chemistry'.

  2. Color vision deficiencies

    NASA Astrophysics Data System (ADS)

    Vannorren, D.

    1982-04-01

    Congenital and acquired color vision defects are described in the context of physiological data. Light sources, photometry, color systems and test methods are described. A list of medicines is also presented. The practical social consequences of color vision deficiencies are discussed.

  3. C1q/TNF-related Protein 4 (CTRP4) Is a Unique Secreted Protein with Two Tandem C1q Domains That Functions in the Hypothalamus to Modulate Food Intake and Body Weight*

    PubMed Central

    Byerly, Mardi S.; Petersen, Pia S.; Ramamurthy, Santosh; Seldin, Marcus M.; Lei, Xia; Provost, Elayne; Wei, Zhikui; Ronnett, Gabriele V.; Wong, G. William

    2014-01-01

    CTRP4 is a unique member of the C1q family, possessing two tandem globular C1q domains. Its physiological function is poorly defined. Here, we show that CTRP4 is an evolutionarily conserved, ∼34-kDa secretory protein expressed in the brain. In human, mouse, and zebrafish brain, CTRP4 expression begins early in development and is widespread in the central nervous system. Neurons, but not astrocytes, express and secrete CTRP4, and secreted proteins form higher-order oligomeric complexes. CTRP4 is also produced by peripheral tissues and circulates in blood. Its serum levels are increased in leptin-deficient obese (ob/ob) mice. Functional studies suggest that CTRP4 acts centrally to modulate energy metabolism. Refeeding following an overnight fast induced the expression of CTRP4 in the hypothalamus. Central administration of recombinant protein suppressed food intake and altered the whole-body energy balance in both chow-fed and high-fat diet-fed mice. Suppression of food intake by CTRP4 is correlated with a decreased expression of orexigenic neuropeptide (Npy and Agrp) genes in the hypothalamus. These results establish CTRP4 as a novel nutrient-responsive central regulator of food intake and energy balance. PMID:24366864

  4. 26 CFR 1.860C-1 - Taxation of holders of residual interests.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 9 2010-04-01 2010-04-01 false Taxation of holders of residual interests. 1.860C-1 Section 1.860C-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES Real Estate Investment Trusts § 1.860C-1 Taxation of...

  5. 26 CFR 301.6230(c)-1 - Claim arising out of erroneous computation, etc.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 18 2010-04-01 2010-04-01 false Claim arising out of erroneous computation, etc. 301.6230(c)-1 Section 301.6230(c)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE....6230(c)-1 Claim arising out of erroneous computation, etc. (a) In general. A claim for refund...

  6. 26 CFR 1.673(c)-1 - Reversionary interest after income beneficiary's death.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 8 2012-04-01 2012-04-01 false Reversionary interest after income beneficiary's death. 1.673(c)-1 Section 1.673(c)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE... Substantial Owners § 1.673(c)-1 Reversionary interest after income beneficiary's death. The subject matter...

  7. 26 CFR 1.673(c)-1 - Reversionary interest after income beneficiary's death.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 8 2014-04-01 2014-04-01 false Reversionary interest after income beneficiary's death. 1.673(c)-1 Section 1.673(c)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE... Substantial Owners § 1.673(c)-1 Reversionary interest after income beneficiary's death. The subject matter...

  8. 26 CFR 1.673(c)-1 - Reversionary interest after income beneficiary's death.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 8 2011-04-01 2011-04-01 false Reversionary interest after income beneficiary's death. 1.673(c)-1 Section 1.673(c)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE... Substantial Owners § 1.673(c)-1 Reversionary interest after income beneficiary's death. The subject matter...

  9. 26 CFR 1.673(c)-1 - Reversionary interest after income beneficiary's death.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... § 1.673(c)-1 Reversionary interest after income beneficiary's death. The subject matter of section 673... 26 Internal Revenue 8 2010-04-01 2010-04-01 false Reversionary interest after income beneficiary's death. 1.673(c)-1 Section 1.673(c)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF...

  10. 26 CFR 1.673(c)-1 - Reversionary interest after income beneficiary's death.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... Substantial Owners § 1.673(c)-1 Reversionary interest after income beneficiary's death. The subject matter of... 26 Internal Revenue 8 2013-04-01 2013-04-01 false Reversionary interest after income beneficiary's death. 1.673(c)-1 Section 1.673(c)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF...

  11. 17 CFR 270.23c-1 - Repurchase of securities by closed-end companies.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... closed-end companies. 270.23c-1 Section 270.23c-1 Commodity and Securities Exchanges SECURITIES AND EXCHANGE COMMISSION (CONTINUED) RULES AND REGULATIONS, INVESTMENT COMPANY ACT OF 1940 § 270.23c-1 Repurchase of securities by closed-end companies. (a) A registered closed-end company may purchase for cash...

  12. 26 CFR 1.674(c)-1 - Excepted powers exercisable only by independent trustees.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... trustees. 1.674(c)-1 Section 1.674(c)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE... § 1.674(c)-1 Excepted powers exercisable only by independent trustees. Section 674(c) provides an exception to the general rule of section 674(a) for certain powers that are exercisable by...

  13. 26 CFR 1.674(c)-1 - Excepted powers exercisable only by independent trustees.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... trustees. 1.674(c)-1 Section 1.674(c)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE... Substantial Owners § 1.674(c)-1 Excepted powers exercisable only by independent trustees. Section 674(c) provides an exception to the general rule of section 674(a) for certain powers that are exercisable...

  14. Genetics Home Reference: isolated growth hormone deficiency

    MedlinePlus

    ... Isolated growth hormone deficiency Educational Resources (10 links) Boston Children's Hospital CLIMB: Growth Hormone Deficiency Information Sheet (PDF) Disease InfoSearch: Isolated growth hormone deficiency ...

  15. Alteration of drug metabolizing enzymes in sulphite oxidase deficiency

    PubMed Central

    Tutuncu, Begum; Kuçukatay, Vural; Arslan, Sevki; Sahin, Barbaros; Semiz, Asli; Sen, Alaattin

    2012-01-01

    The aim of this study was to investigate the possible effects of sulphite oxidase (SOX, E.C. 1.8.3.1) deficiency on xenobiotic metabolism. For this purpose, SOX deficiency was produced in rats by the administration of a low molybdenum diet with concurrent addition of 200 ppm tungsten to their drinking water. First, hepatic SOX activity in deficient groups was measured to confirm SOX deficiency. Then, aminopyrine N-demethylase, aniline 4-hydroxylase, aromatase, caffeine N-demethylase, cytochrome b5 reductase, erythromycin N-demethylase, ethoxyresorufin O-deethylase, glutathione S-transferase, N-nitrosodimethylamine N-demethylase and penthoxyresorufin O-deethylase activities were determined to follow changes in the activity of drug metabolizing enzymes in SOX-deficient rats. Our results clearly demonstrated that SOX deficiency significantly elevated A4H, caffeine N-demethylase, erythromycin N-demethylase and N-nitrosodimethylamine N-demethylase activities while decreasing ethoxyresorufin O-deethylase and aromatase activities. These alterations in drug metabolizing enzymes can contribute to the varying susceptibility and response of sulphite-sensitive individuals to different drugs and/or therapeutics used for treatments. PMID:22798713

  16. Genetics Home Reference: proopiomelanocortin deficiency

    MedlinePlus

    ... Open All Close All Description Proopiomelanocortin (POMC) deficiency causes severe obesity that begins at an early age. In addition ... and severe obesity. POMC deficiency is a rare cause of obesity; POMC gene mutations are not frequently associated with ...

  17. Sanitary Surveys & Significant Deficiencies Presentation

    EPA Pesticide Factsheets

    The Sanitary Surveys & Significant Deficiencies Presentation highlights some of the things EPA looks for during drinking water system site visits, how to avoid significant deficiencies and what to do if you receive one.

  18. Genetics Home Reference: biotinidase deficiency

    MedlinePlus

    ... links) Children Living With Inherited Metabolic Diseases (CLIMB) (UK): Biotinidase Deficiency (PDF) Disease InfoSearch: Biotinidase Deficiency Illinois ... Group Children Living with Inherited Metabolic Diseases (CLIMB) (UK) National Organization for Rare Disorders (NORD) GeneReviews (1 ...

  19. Suppression of Methylation-Mediated Transcriptional Gene Silencing by βC1-SAHH Protein Interaction during Geminivirus-Betasatellite Infection

    PubMed Central

    Raja, Priya; Li, Sizhun; Wolf, Jamie N.; Shen, Qingtang; Bisaro, David M.; Zhou, Xueping

    2011-01-01

    DNA methylation is a fundamental epigenetic modification that regulates gene expression and represses endogenous transposons and invading DNA viruses. As a counter-defense, the geminiviruses encode proteins that inhibit methylation and transcriptional gene silencing (TGS). Some geminiviruses have acquired a betasatellite called DNA β. This study presents evidence that suppression of methylation-mediated TGS by the sole betasatellite-encoded protein, βC1, is crucial to the association of Tomato yellow leaf curl China virus (TYLCCNV) with its betasatellite (TYLCCNB). We show that TYLCCNB complements Beet curly top virus (BCTV) L2- mutants deficient for methylation inhibition and TGS suppression, and that cytosine methylation levels in BCTV and TYLCCNV genomes, as well as the host genome, are substantially reduced by TYLCCNB or βC1 expression. We also demonstrate that while TYLCCNB or βC1 expression can reverse TGS, TYLCCNV by itself is ineffective. Thus its AC2/AL2 protein, known to have suppression activity in other geminiviruses, is likely a natural mutant in this respect. A yeast two-hybrid screen of candidate proteins, followed by bimolecular fluorescence complementation analysis, revealed that βC1 interacts with S-adenosyl homocysteine hydrolase (SAHH), a methyl cycle enzyme required for TGS. We further demonstrate that βC1 protein inhibits SAHH activity in vitro. That βC1 and other geminivirus proteins target the methyl cycle suggests that limiting its product, S-adenosyl methionine, may be a common viral strategy for methylation interference. We propose that inhibition of methylation and TGS by βC1 stabilizes geminivirus/betasatellite complexes. PMID:22028660

  20. Suppression of methylation-mediated transcriptional gene silencing by βC1-SAHH protein interaction during geminivirus-betasatellite infection.

    PubMed

    Yang, Xiuling; Xie, Yan; Raja, Priya; Li, Sizhun; Wolf, Jamie N; Shen, Qingtang; Bisaro, David M; Zhou, Xueping

    2011-10-01

    DNA methylation is a fundamental epigenetic modification that regulates gene expression and represses endogenous transposons and invading DNA viruses. As a counter-defense, the geminiviruses encode proteins that inhibit methylation and transcriptional gene silencing (TGS). Some geminiviruses have acquired a betasatellite called DNA β. This study presents evidence that suppression of methylation-mediated TGS by the sole betasatellite-encoded protein, βC1, is crucial to the association of Tomato yellow leaf curl China virus (TYLCCNV) with its betasatellite (TYLCCNB). We show that TYLCCNB complements Beet curly top virus (BCTV) L2⁻ mutants deficient for methylation inhibition and TGS suppression, and that cytosine methylation levels in BCTV and TYLCCNV genomes, as well as the host genome, are substantially reduced by TYLCCNB or βC1 expression. We also demonstrate that while TYLCCNB or βC1 expression can reverse TGS, TYLCCNV by itself is ineffective. Thus its AC2/AL2 protein, known to have suppression activity in other geminiviruses, is likely a natural mutant in this respect. A yeast two-hybrid screen of candidate proteins, followed by bimolecular fluorescence complementation analysis, revealed that βC1 interacts with S-adenosyl homocysteine hydrolase (SAHH), a methyl cycle enzyme required for TGS. We further demonstrate that βC1 protein inhibits SAHH activity in vitro. That βC1 and other geminivirus proteins target the methyl cycle suggests that limiting its product, S-adenosyl methionine, may be a common viral strategy for methylation interference. We propose that inhibition of methylation and TGS by βC1 stabilizes geminivirus/betasatellite complexes.

  1. Glucose-6-phosphate dehydrogenase deficiency

    MedlinePlus

    G6PD deficiency; Hemolytic anemia due to G6PD deficiency; Anemia - hemolytic due to G6PD deficiency ... Gallagher PG. Hemolytic anemias. In: Goldman L, Schafer AI, eds. Goldman's Cecil Medicine . 25th ed. Philadelphia, PA: Elsevier Saunders; 2016:chap 161. Janz ...

  2. Proton pump inhibitors

    MedlinePlus

    Proton pump inhibitors (PPIs) are medicines that work by reducing the amount of stomach acid made by ... Proton pump inhibitors are used to: Relieve symptoms of acid reflux, or gastroesophageal reflux disease (GERD). This ...

  3. Language deficiency in children.

    PubMed

    Morehead, D M; Morehead, K E; Morehead, W A

    1980-01-01

    Research in cognition and language has provided useful constructs which suggests that specific deficits underlie language deficiencies in children. In addition, this research has provided procedures that the determine what a child knows about language at a particular level of development and has established a sequence of linguistic development that maps the specific content and structure of training programs. Two new areas of research offer additional approaches to assessment and remediation. One approach focuses on the actual principles and strategies that normal children use to learn language, making it possible to determine which methods are most efficient. The second research approach looks at the contextual conditions adults and children provide the first language learner. Preliminary work suggests that the natural conditions found universally in first language learning may be the best indicators of how to proceed with language-deficient children.

  4. Decorin deficiency promotes hepatic carcinogenesis

    PubMed Central

    Horváth, Zsolt; Kovalszky, Ilona; Fullár, Alexandra; Kiss, Katalin; Schaff, Zsuzsa; Iozzo, Renato V.; Baghy, Kornélia

    2014-01-01

    Hepatocellular carcinoma represents one of the most-rapidly spreading cancers in the world. In the majority of cases, an inflammation-driven fibrosis or cirrhosis precedes the development of the tumor. During malignant transformation, the tumor microenvironment undergoes qualitative and quantitative changes that modulate the behavior of the malignant cells. A key constituent for the hepatic microenvironment is the small leucine-rich proteoglycan decorin, known to interfere with cellular events of tumorigenesis mainly by blocking various receptor tyrosine kinases (RTK) such as EGFR, Met, IGF-IR, PDGFR and VEGFR2. In this study, we characterized cell signaling events evoked by decorin deficiency in two experimental models of hepatocarcinogenesis using thioacetamide or diethyl nitrosamine as carcinogens. Genetic ablation of decorin led to enhanced tumor occurrence as compared to wild-type animals. These findings correlated with decreased levels of the cyclin-dependent kinase inhibitor p21WAF1/CIP1 and a concurrent elevation in retinoblastoma protein phosphorylation via cyclin dependent kinase 4. Decreased steady state p21Waf1/Cip1 levels correlated with enhanced expression of transcription factor AP4, a known transcriptional repressor of p21Waf1/Cip1, and enhanced c-Myc protein levels. In addition, translocation of β-catenin was a typical event in diethyl nitrosamine-evoked tumors. In parallel, decreased phosphorylation of both c-Myc and β-catenin was observed in Dcn−/− livers likely due to the hindered GSK3β-mediated targeting of these proteins to proteasomal degradation. We discovered that in a genetic background lacking decorin, four RTKs were constitutively activated (phosphorylated), including three known targets of decorin such as PDGFRα, EGFR, IGF-IR, and a novel RTK MSPR/RON. Our findings provide powerful genetic evidence for a crucial in vivo role of decorin during hepatocarcinogenesis as lack of decorin in the liver and hepatic stroma facilitates

  5. Silencing of atp6v1c1 prevents breast cancer growth and bone metastasis.

    PubMed

    Feng, Shengmei; Zhu, Guochun; McConnell, Matthew; Deng, Lianfu; Zhao, Qiang; Wu, Mengrui; Zhou, Qi; Wang, Jinshen; Qi, Jin; Li, Yi-Ping; Chen, Wei

    2013-01-01

    Previous studies have shown that Atp6v1c1, a regulator of the assembly of the V0 and V1 domains of the V-ATPase complex, is up-regulated in metastatic oral tumors. Despite these studies, the function of Atp6v1c1 in tumor growth and metastasis is still unknown. Atp6v1c1's expression in metastatic oral squamous cell carcinoma indicates that Atp6v1c1 has an important function in cancer growth and metastasis. We hypothesized that elevated expression of Atp6v1c1 is essential to cancer growth and metastasis and that Atp6v1c1 promotes cancer growth and metastasis through activation of V-ATPase activity. To test this hypothesis, a Lentivirus-mediated RNAi knockdown approach was used to study the function of Atp6v1c1 in mouse 4T1 mammary tumor cell proliferation and migration in vitro and cancer growth and metastasis in vivo. Our data revealed that silencing of Atp6v1c1 in 4T1 cancer cells inhibited lysosomal acidification and severely impaired 4T1 cell growth, migration, and invasion through Matrigel in vitro. We also show that Atp6v1c1 knockdown with Lenti-c1s3, a lentivirus targeting Atp6v1c1 for shRNA mediated knockdown, can significantly inhibit 4T1 xenograft tumor growth, metastasis, and osteolytic lesions in vivo. Our study demonstrates that Atp6v1c1 may promote breast cancer growth and bone metastasis through regulation of lysosomal V-ATPase activity, indicating that Atp6v1c1 may be a viable target for breast cancer therapy and silencing of Atp6v1c1 may be an innovative therapeutic approach for the treatment and prevention of breast cancer growth and metastasis.

  6. Iron-Deficiency Anemia (For Parents)

    MedlinePlus

    ... Your 1- to 2-Year-Old Iron-Deficiency Anemia KidsHealth > For Parents > Iron-Deficiency Anemia Print A ... common nutritional deficiency in children. About Iron-Deficiency Anemia Every red blood cell in the body contains ...

  7. How Is Iron-Deficiency Anemia Treated?

    MedlinePlus

    ... the NHLBI on Twitter. How Is Iron-Deficiency Anemia Treated? Treatment for iron-deficiency anemia will depend ... may be advised. Treatments for Severe Iron-Deficiency Anemia Blood Transfusion If your iron-deficiency anemia is ...

  8. Monoamine Reuptake Inhibitors in Parkinson's Disease

    PubMed Central

    Huot, Philippe; Fox, Susan H.; Brotchie, Jonathan M.

    2015-01-01

    The motor manifestations of Parkinson's disease (PD) are secondary to a dopamine deficiency in the striatum. However, the degenerative process in PD is not limited to the dopaminergic system and also affects serotonergic and noradrenergic neurons. Because they can increase monoamine levels throughout the brain, monoamine reuptake inhibitors (MAUIs) represent potential therapeutic agents in PD. However, they are seldom used in clinical practice other than as antidepressants and wake-promoting agents. This review article summarises all of the available literature on use of 50 MAUIs in PD. The compounds are divided according to their relative potency for each of the monoamine transporters. Despite wide discrepancy in the methodology of the studies reviewed, the following conclusions can be drawn: (1) selective serotonin transporter (SERT), selective noradrenaline transporter (NET), and dual SERT/NET inhibitors are effective against PD depression; (2) selective dopamine transporter (DAT) and dual DAT/NET inhibitors exert an anti-Parkinsonian effect when administered as monotherapy but do not enhance the anti-Parkinsonian actions of L-3,4-dihydroxyphenylalanine (L-DOPA); (3) dual DAT/SERT inhibitors might enhance the anti-Parkinsonian actions of L-DOPA without worsening dyskinesia; (4) triple DAT/NET/SERT inhibitors might exert an anti-Parkinsonian action as monotherapy and might enhance the anti-Parkinsonian effects of L-DOPA, though at the expense of worsening dyskinesia. PMID:25810948

  9. Phenylalanine hydroxylase deficiency.

    PubMed

    Mitchell, John J; Trakadis, Yannis J; Scriver, Charles R

    2011-08-01

    Phenylalanine hydroxylase deficiency is an autosomal recessive disorder that results in intolerance to the dietary intake of the essential amino acid phenylalanine. It occurs in approximately 1:15,000 individuals. Deficiency of this enzyme produces a spectrum of disorders including classic phenylketonuria, mild phenylketonuria, and mild hyperphenylalaninemia. Classic phenylketonuria is caused by a complete or near-complete deficiency of phenylalanine hydroxylase activity and without dietary restriction of phenylalanine most children will develop profound and irreversible intellectual disability. Mild phenylketonuria and mild hyperphenylalaninemia are associated with lower risk of impaired cognitive development in the absence of treatment. Phenylalanine hydroxylase deficiency can be diagnosed by newborn screening based on detection of the presence of hyperphenylalaninemia using the Guthrie microbial inhibition assay or other assays on a blood spot obtained from a heel prick. Since the introduction of newborn screening, the major neurologic consequences of hyperphenylalaninemia have been largely eradicated. Affected individuals can lead normal lives. However, recent data suggest that homeostasis is not fully restored with current therapy. Treated individuals have a higher incidence of neuropsychological problems. The mainstay of treatment for hyperphenylalaninemia involves a low-protein diet and use of a phenylalanine-free medical formula. This treatment must commence as soon as possible after birth and should continue for life. Regular monitoring of plasma phenylalanine and tyrosine concentrations is necessary. Targets of plasma phenylalanine of 120-360 μmol/L (2-6 mg/dL) in the first decade of life are essential for optimal outcome. Phenylalanine targets in adolescence and adulthood are less clear. A significant proportion of patients with phenylketonuria may benefit from adjuvant therapy with 6R-tetrahydrobiopterin stereoisomer. Special consideration must be

  10. Identification of the srtC1 Transcription Start Site and Catalytically Essential Residues Required for Actinomyces oris T14V SrtC1 Activity

    DTIC Science & Technology

    2011-07-27

    al., 1999, 2002; Frankel et al., 2007), Cys 193 in SrtC1 from Streptococcus pneumoniae (Manzano et al., 2008) and Cys 219 in SrtC1 from Group B...Sortase mediated pilus fiber biogenesis in Streptococcus pneumoniae . Structure 16: 1838 1848. Manzano C, Izore T, Job V, Di Guilmi AM & Dessen A... Streptococcus (Cozzi et al., 2011) are critical for each of their corresponding sortase activities. When two other residues (Leu263 and Thr265) in this

  11. Application of polymethacrylate resin as stationary phase in liquid chromatography with UV detection for C1-C7 aliphatic monocarboxylic acids and C1-C7 aliphatic monoamines.

    PubMed

    Ohta, Kazutoku; Towata, Atsuya; Ohashi, Masayoshi; Takeuchi, Toyohide

    2004-06-11

    The application of unfunctionized polymethacrylate resin (TSKgel G3000PWXL) as a stationary phase in liquid chromatography with UV detection for C1-C7 aliphatic monocarboxylic acids (formic acid, acetic acid, propionic acid, butyric acid, isovaleric acid, valeric acid, 3,3-dimethylbutyric acid, 4-methylvaleric acid, hexanoic acid, 2-methylhexanoic acid, 5-methylhexanoic acid and heptanoic acid) and C1-C7 aliphatic monoamines (methylamine, ethylamine, propylamine, isobutylamine, butylamine, isoamylamine, amylamine, 1,3-dimethylbutylamine, hexylamine, 2-heptylamine and heptylamine) was carried out. Using dilute sulfuric acid as the eluent, the TSKgel G3000PWXL, resin acted as an advanced stationary phase for these C1-C7 carboxylic acids. Excellent simultaneous separation and symmetrical peaks for these C1-C7 carboxylic acids were achieved on a TSKgel G3000PWXL column (150 mm x 6 mm i.d.) in 60 min with 0.25 mM sulfuric acid containing 1 mM 2-methylheptanoic acid at pH 3.3 as the eluent. Using dilute sodium hydroxide as the eluent, the TSKgel G3000PWXL resin also behaved as an advanced stationary phase for these C1-C7 amines. Excellent simultaneous separation and good peaks for these C1-C7 amines were achieved on the TSKgel G3000PWXL column in 60 min with 10 mM sodium hydroxide containing 0.5 mM 1-methylheptylamine at pH 11.9 as the eluent.

  12. Biodegradation and adsorption of C1- and C2-phenanthrenes and C1- and C2-dibenzothiophenes in the presence of clay minerals: effect on forensic diagnostic ratios.

    PubMed

    Ugochukwu, Uzochukwu C; Head, Ian M; Manning, David A C

    2014-07-01

    The impact of modified montmorillonites on adsorption and biodegradation of crude oil C1-phenanthrenes, C1-dibenzothiophenes, C2-phenanthrenes and C2-dibenzothiophenes was investigated in aqueous clay/oil microcosm experiments with a hydrocarbon degrading microorganism community. Consequently, the effect on C1-dibenzothiophenes/C1-phenanthrenes, C2-dibenzothiophenes/C2-phenanthrenes, 2+3-methyldibenzothiophene/4-methyldibenzothiophene and 1-methyldibenzothiophene/4-methyldibenzothiophene ratios commonly used as diagnostic ratios for oil forensic studies was evaluated. The clay mineral samples were treated to produce acid activated montmorillonite, organomontmorillonite and homoionic montmorillonite which were used in this study. The different clay minerals (modified and unmodified) showed varied degrees of biodegradation and adsorption of the C1-phenanthrenes, C1-dibenzothiophenes, C2-phenanthrenes and C2-dibenzothiophenes. The study indicated that as opposed to biodegradation, adsorption has no effect on the diagnostic ratios. Among the diagnostic ratios reviewed, only C2-dibenzothiophenes/C2-phenanthrenes ratio was neither affected by adsorption nor biodegradation making this ratio very useful in forensic studies of oil spills and oil-oil correlation.

  13. Serum C1q as a novel biomarker of sarcopenia in older adults.

    PubMed

    Watanabe, Shinya; Sato, Koji; Hasegawa, Natsuki; Kurihara, Toshiyuki; Matsutani, Kenji; Sanada, Kiyoshi; Hamaoka, Takafumi; Fujita, Satoshi; Iemitsu, Motoyuki

    2015-03-01

    Aging-induced elevation in C1q secretion activates the Wnt signaling pathway in muscles, leading to the development of muscle fibrosis. However, the association between serum C1q level and muscle mass and strength remains unclear in humans. The aim of the study was to elucidate whether serum C1q level is associated with aging- and resistance training-induced changes in muscle mass and strength. First, in a cross-sectional study, we investigated the association between serum C1q level and muscle mass and strength in 131 healthy subjects, aged 20-81 yr. Second, in an intervention study, we examined the association between the effects of serum C1q level and muscle mass and strength on 12 wk resistance training in 11 healthy older adults (60-81 yr). In the cross-sectional study, serum C1q level increased with aging and was negatively correlated with muscle mass and strength. Furthermore, 12 wk resistance training in older adults reduced the age-associated elevation in serum C1q levels. The training effect of serum C1q level significantly correlated with the change in the cross-sectional area of the thigh (r = -0.703; P < 0.01). Serum C1q level may reflect loss of muscle mass; therefore, C1q may be a novel biomarker of sarcopenia.

  14. Charge density influences C1 domain ligand affinity and membrane interactions

    PubMed Central

    Lewin, Nancy E.; Kedei, Noemi; Hill, Colin S.; Selezneva, Julia S.; Valle, Christopher J.; Woo, Wonhee; Gorshkova, Inna; Blumberg, Peter M.

    2014-01-01

    The C1 domain, which represents the recognition motif on protein kinase C for the lipophilic second messenger diacylglycerol and its ultrapotent analog the phorbol esters, has emerged as a promising therapeutic target for cancer and other indications. Potential target selectivity is markedly enhanced both because binding reflects ternary complex formation between ligand, the C1 domain, and phospholipid, and because binding drives membrane insertion of the C1 domain, permitting aspects of the C1 domain surface outside the binding site per se to influence binding energetics. Here, focusing on charged residues identified in atypical C1 domains which contribute to their loss of ligand binding activity, we show that increasing charge along the rim of the binding cleft of the protein kinase C δ C1b domain raises the requirement for anionic phospholipids. Correspondingly, it shifts the selectivity of C1 domain translocation to the plasma membrane, which is more negatively charged than internal membranes. This change in localization is most pronounced in the case of more hydrophilic ligands, which provide weaker membrane stabilization than do the more hydrophobic ligands, and thus contributes an element to the structure activity relations for C1 domain ligands. Co-expressing pairs of C1 containing constructs with differing charges each expressing a distinct fluorescent tag provided a powerful tool to demonstrate the effect of increasing charge in the C1 domain. PMID:24777910

  15. Functional characterization of βC1 gene of Cotton leaf curl Multan betasatellite.

    PubMed

    Tiwari, Neha; Sharma, P K; Malathi, V G

    2013-02-01

    Whitefly-transmitted Begomoviruses having circular single stranded DNA genome cause severe leaf curl diseases in the tropical and subtropical region. The majority of Old World monopartite begomoviruses with DNA A component is associated with a satellite DNA of 1.3 kb length referred to as betasatellites. The presence of betasatellite is required to express typical symptoms in the primary hosts. Increased symptom expression in betasatellite's presence is attributed to a 13-15 kDa βC1 protein encoded by the βC1 gene on complementary sense strand. The exact mechanism by which the βC1 protein contributes to the symptoms' severity and helper viral DNA's accumulation is not yet understood. Here, we studied the βC1 protein of Cotton leaf curl Multan betasatellite, associated with mono and bipartite begomoviruses. The βC1 protein was expressed in prokaryotic system as 6XHis-βC1 fusion protein and recombinant protein showed size- and sequence-specific DNA binding activity. The host proteins which may interact with βC1 were identified by binding βC1 recombinant protein with heptapeptide in phage display library. The βC1-interacting host proteins predicted belong to metabolic and defense pathways, indicating that βC1 protein has a pivotal role in viral pathogenicity.

  16. XPB Induces C1D Expression to Counteract UV-Induced Apoptosis

    PubMed Central

    Li, Guang; Liu, Juhong; Abu-Asab, Mones; Masabumi, Shibuya; Maru, Yoshiro

    2010-01-01

    Although C1D has been shown to be involved in DNA double-strand breaks repair, how C1D expression was induced and the mechanism(s) by which C1D facilitates DNA repair in mammalian cells remain poorly understood. We and others have previously shown that expression of XPB protein efficiently compensated the UV-irradiation sensitive phenotype of 27-1 cells which lacks functional XPB. To further explore XPB-regulated genes that could be involved in UV-induced DNA repair, Differential Display analysis of mRNA level from CHO-9, 27-1 and 27-1 complemented with wild-type XPB were performed and C1D gene was identified as one of the major genes whose expression was significantly up-regulated by restoring XPB function. We found that XPB is essential to induce C1D transcription after UV-irradiation. The increase of C1D expression effectively compensates the UV-induced proteolysis of C1D and thus maintains cellular C1D level to cope with DNA damage inflicted by UV-irradiation. We further showed that although insufficient to rescue 27-1 cells from UV-induced apoptosis by itself, C1D facilitates XPB DNA repair through direct interaction with XPB. Our findings provided direct evidence that C1D is associated with DNA repair complex and may promote repair of UV-induced DNA damage. PMID:20530579

  17. The effects of fluoride on cell migration, cell proliferation, and cell metabolism in GH4C1 pituitary tumour cells.

    PubMed

    Mendoza-Schulz, A; Solano-Agama, C; Arreola-Mendoza, L; Reyes-Márquez, B; Barbier, O; Del Razo, L M; Mendoza-Garrido, M E

    2009-10-28

    The consumption of drinking water rich in fluoride has toxic effects on the central nervous system. In cell biology research, fluoride is currently used as a phosphatase inhibitor. The aim of the present study was to evaluate the effect of fluoride on different physiological processes in GH4C1 pituitary tumour cells. We used a range of different fluoride concentrations, from levels below normal human serum concentrations (0.23 and 1.2 micromol/L) to those observed in chronically exposed persons (10.7 micromol/L) and above (107 and 1072 micromol/L). Treatment of 10.7 micromol/L fluoride resulted in a discrete induction of DNA synthesis, without a change in cell number. Cell migration, a behaviour stimulated by growth factors, was increased in cells treated with 2.4 micromol/L. At this fluoride concentration, changes in phosphorylation status of both cytoskeletal and cytosolic protein fractions, as well as in actin cytoskeletal arrangements were observed. The GH4C1 fluoride treated cells had significantly less cellular protein than control cells, suggesting an effect of fluoride on hormone secretion and protein synthesis in this endocrine cell. The bioreduction of MTT was significantly increased with a wide range of fluoride concentrations. With the highest fluoride concentration, 1072 micromol/L, all of the analysed parameters were significantly reduced, suggesting that this dose is highly toxic in GH4C1 cells. Our results show that biologically relevant concentrations of fluoride are capable of increasing cell migration in tumour cells, suggesting that exposure to fluoride could stimulate tumour invasion.

  18. Carnitine palmitoyltransferase II deficiency

    PubMed Central

    Roe, C R.; Yang, B-Z; Brunengraber, H; Roe, D S.; Wallace, M; Garritson, B K.

    2008-01-01

    Background: Carnitine palmitoyltransferase II (CPT II) deficiency is an important cause of recurrent rhabdomyolysis in children and adults. Current treatment includes dietary fat restriction, with increased carbohydrate intake and exercise restriction to avoid muscle pain and rhabdomyolysis. Methods: CPT II enzyme assay, DNA mutation analysis, quantitative analysis of acylcarnitines in blood and cultured fibroblasts, urinary organic acids, the standardized 36-item Short-Form Health Status survey (SF-36) version 2, and bioelectric impedance for body fat composition. Diet treatment with triheptanoin at 30% to 35% of total daily caloric intake was used for all patients. Results: Seven patients with CPT II deficiency were studied from 7 to 61 months on the triheptanoin (anaplerotic) diet. Five had previous episodes of rhabdomyolysis requiring hospitalizations and muscle pain on exertion prior to the diet (two younger patients had not had rhabdomyolysis). While on the diet, only two patients experienced mild muscle pain with exercise. During short periods of noncompliance, two patients experienced rhabdomyolysis with exercise. None experienced rhabdomyolysis or hospitalizations while on the diet. All patients returned to normal physical activities including strenuous sports. Exercise restriction was eliminated. Previously abnormal SF-36 physical composite scores returned to normal levels that persisted for the duration of the therapy in all five symptomatic patients. Conclusions: The triheptanoin diet seems to be an effective therapy for adult-onset carnitine palmitoyltransferase II deficiency. GLOSSARY ALT = alanine aminotransferase; AST = aspartate aminotransferase; ATP = adenosine triphosphate; BHP = β-hydroxypentanoate; BKP = β-ketopentanoate; BKP-CoA = β-ketopentanoyl–coenzyme A; BUN = blood urea nitrogen; CAC = citric acid cycle; CoA = coenzyme A; CPK = creatine phosphokinase; CPT II = carnitine palmitoyltransferase II; LDL = low-density lipoprotein; MCT

  19. Iatrogenic nutritional deficiencies.

    PubMed

    Young, R C; Blass, J P

    1982-01-01

    This article catalogs the nutritional deficiencies inadvertently introduced by certain treatment regimens. Specifically, the iatrogenic effects on nutrition of surgery, hemodialysis, irradiation, and drugs are reviewed. Nutritional problems are particularly frequent consequences of surgery on the gastrointestinal tract. Gastric surgery can lead to deficiencies of vitamin B12, folate, iron, and thiamine, as well as to metabolic bone disease. The benefits of small bowel bypass are limited by the potentially severe nutritional consequences of this procedure. Following bypass surgery, patients should be monitored for signs of possible nutritional probems such as weight loss, neuropathy, cardiac arrhythmias, loss of stamina, or changes in mental status. Minimal laboratory tests should include hematologic evaluation, B12, folate, iron, albumin, calcium, phosphorus, alkaline phosphatase, transaminases, sodium, potassium, chloride, and carbon dioxide levels. Roentgenologic examination of the bone should also be obtained. Loss of bone substance is a major consequence of many forms of treatment, and dietary supplementation with calcium is warranted. Patients undergoing hemodialysis have shown carnitine and choline deficiencies, potassium depletion, and hypovitaminosis, as well as osteomalacia. Chronic drug use may alter intake, synthesis, absorption, transport, storage, metabolism, or excretion of nutrients. Patients vary markedly in the metabolic effects of drugs, and recommendations for nutrition must be related to age, sex, reproductive status, and genetic endowment. Moreover, the illness being treated can itself alter nutritional requirements and the effect of the treatment on nutrient status. The changes in nutritional levels induced by use of estrogen-containing oral contraceptives (OCs) are obscure; however, the effects on folate matabolism appear to be of less clinical import than previously suggested. Reduction in pyridoxine and serum vitamin B12 levels has been

  20. Occurrence and Antioxidant Activity of C1 Degradation Products in Cocoa

    PubMed Central

    De Taeye, Cédric; Kankolongo Cibaka, Marie-Lucie; Collin, Sonia

    2017-01-01

    Procyanidin C1 is by far the main flavan-3-ol trimer in cocoa. Like other flavan-3-ols, however, it suffers a lot during heat treatments such as roasting. RP-HPLC-HRMS/MS(ESI(−))analysis applied to an aqueous model medium containing commercial procyanidin C1 proved that epimerization is the main reaction involved in its degradation (accounting for 62% of degradation products). In addition to depolymerization, cocoa procyanidin C1 also proved sensitive to oxidation, yielding once- and twice-oxidized dimers. No chemical oligomer involving the native trimer was found in either model medium or cocoa, while two C1 isomers were retrieved. C1 degradation products exhibited antioxidant activity (monitored by RP-HPLC-Online TEAC) close to that of C1 (when expressed in µM TE/mg·kg−1). PMID:28264525

  1. The C1q complement family of synaptic organizers: not just complementary.

    PubMed

    Yuzaki, Michisuke

    2017-02-17

    Molecules that regulate formation, differentiation, and maintenance of synapses are called synaptic organizers. Recently, various 'C1q family' proteins have been shown to be released from neurons, and serve as a new class of synaptic organizers. Cbln1 and C1ql1 proteins regulate the formation and maintenance of parallel fiber-Purkinje cell and climbing fiber-Purkinje cell synapses, respectively, in the cerebellum. Cbln1 also modulates the function of postsynaptic delta2 glutamate receptors to regulate synaptic plasticity. C1ql2 and C1ql3, released from mossy fibers, determine the synaptic localization of postsynaptic kainate receptors in the hippocampus. C1ql3 also regulates the formation of synapses between the basolateral amygdala and the prefrontal cortex. These findings indicate the diverse functions of C1q family proteins in various brain regions.

  2. Regulation of ClC-1 and KATP channels in action potential-firing fast-twitch muscle fibers.

    PubMed

    Pedersen, Thomas Holm; de Paoli, Frank Vincenzo; de Paoli, Frank Vinzenco; Flatman, John A; Nielsen, Ole Baekgaard

    2009-10-01

    Action potential (AP) excitation requires a transient dominance of depolarizing membrane currents over the repolarizing membrane currents that stabilize the resting membrane potential. Such stabilizing currents, in turn, depend on passive membrane conductance (G(m)), which in skeletal muscle fibers covers membrane conductances for K(+) (G(K)) and Cl(-) (G(Cl)). Myotonic disorders and studies with metabolically poisoned muscle have revealed capacities of G(K) and G(Cl) to inversely interfere with muscle excitability. However, whether regulation of G(K) and G(Cl) occur in AP-firing muscle under normal physiological conditions is unknown. This study establishes a technique that allows the determination of G(Cl) and G(K) with a temporal resolution of seconds in AP-firing muscle fibers. With this approach, we have identified and quantified a biphasic regulation of G(m) in active fast-twitch extensor digitorum longus fibers of the rat. Thus, at the onset of AP firing, a reduction in G(Cl) of approximately 70% caused G(m) to decline by approximately 55% in a manner that is well described by a single exponential function characterized by a time constant of approximately 200 APs (phase 1). When stimulation was continued beyond approximately 1,800 APs, synchronized elevations in G(K) ( approximately 14-fold) and G(Cl) ( approximately 3-fold) caused G(m) to rise sigmoidally to approximately 400% of its level before AP firing (phase 2). Phase 2 was often associated with a failure to excite APs. When AP firing was ceased during phase 2, G(m) recovered to its level before AP firing in approximately 1 min. Experiments with glibenclamide (K(ATP) channel inhibitor) and 9-anthracene carboxylic acid (ClC-1 Cl(-) channel inhibitor) revealed that the decreased G(m) during phase 1 reflected ClC-1 channel inhibition, whereas the massively elevated G(m) during phase 2 reflected synchronized openings of ClC-1 and K(ATP) channels. In conclusion, G(Cl) and G(K) are acutely regulated in AP

  3. Placental steroid deficiency: association with arylsulfatase A deficiency.

    PubMed Central

    Vidgoff, J; Buxman, M M; Shapiro, L J; Dimond, R L; Wilson, T G; Hepburn, C A; Tabei, T; Heinrichs, W R

    1982-01-01

    A family with an obstetric history consistent with placental sulfatase deficiency has X-linked ichthyosis. Steroid sulfatase deficiency was confirmed in placenta, leukocytes, and cultured skin fibroblasts of affected males; arylsulfatase A diminution was also observed in these tissues of both affected males and 2 generations of related females. No symptoms of metachromatic leukodystrophy are present in any family members. In this family, placental sulfatase deficiency, and arylsulfatase A pseudodeficiency are nonallelic. PMID:6123259

  4. 29 CFR 2550.404c-1 - ERISA section 404(c) plans.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 29 Labor 9 2014-07-01 2014-07-01 false ERISA section 404(c) plans. 2550.404c-1 Section 2550.404c-1... REGULATIONS FOR FIDUCIARY RESPONSIBILITY § 2550.404c-1 ERISA section 404(c) plans. (a) In general. (1) Section 404(c) of the Employee Retirement Income Security Act of 1974 (ERISA or the Act) provides that if...

  5. 29 CFR 2550.404c-1 - ERISA section 404(c) plans.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 29 Labor 9 2011-07-01 2011-07-01 false ERISA section 404(c) plans. 2550.404c-1 Section 2550.404c-1... REGULATIONS FOR FIDUCIARY RESPONSIBILITY § 2550.404c-1 ERISA section 404(c) plans. (a) In general. (1) Section 404(c) of the Employee Retirement Income Security Act of 1974 (ERISA or the Act) provides that if...

  6. Engineering Botulinum Neurotoxin C1 as a Molecular Vehicle for Intra-Neuronal Drug Delivery.

    PubMed

    Vazquez-Cintron, Edwin J; Beske, Phillip H; Tenezaca, Luis; Tran, Bao Q; Oyler, Jonathan M; Glotfelty, Elliot J; Angeles, Christopher A; Syngkon, Aurelia; Mukherjee, Jean; Kalb, Suzanne R; Band, Philip A; McNutt, Patrick M; Shoemaker, Charles B; Ichtchenko, Konstantin

    2017-02-21

    Botulinum neurotoxin (BoNT) binds to and internalizes its light chain into presynaptic compartments with exquisite specificity. While the native toxin is extremely lethal, bioengineering of BoNT has the potential to eliminate toxicity without disrupting neuron-specific targeting, thereby creating a molecular vehicle capable of delivering therapeutic cargo into the neuronal cytosol. Building upon previous work, we have developed an atoxic derivative (ad) of BoNT/C1 through rationally designed amino acid substitutions in the metalloprotease domain of wild type (wt) BoNT/C1. To test if BoNT/C1 ad retains neuron-specific targeting without concomitant toxic host responses, we evaluated the localization, activity, and toxicity of BoNT/C1 ad in vitro and in vivo. In neuronal cultures, BoNT/C1 ad light chain is rapidly internalized into presynaptic compartments, but does not cleave SNARE proteins nor impair spontaneous neurotransmitter release. In mice, systemic administration resulted in the specific co-localization of BoNT/C1 ad with diaphragmatic motor nerve terminals. The mouse LD50 of BoNT/C1 ad is 5 mg/kg, with transient neurological symptoms emerging at sub-lethal doses. Given the low toxicity and highly specific neuron-targeting properties of BoNT/C1 ad, these data suggest that BoNT/C1 ad can be useful as a molecular vehicle for drug delivery to the neuronal cytoplasm.

  7. Engineering Botulinum Neurotoxin C1 as a Molecular Vehicle for Intra-Neuronal Drug Delivery

    PubMed Central

    Vazquez-Cintron, Edwin J.; Beske, Phillip H.; Tenezaca, Luis; Tran, Bao Q.; Oyler, Jonathan M.; Glotfelty, Elliot J.; Angeles, Christopher A.; Syngkon, Aurelia; Mukherjee, Jean; Kalb, Suzanne R.; Band, Philip A.; McNutt, Patrick M.; Shoemaker, Charles B.; Ichtchenko, Konstantin

    2017-01-01

    Botulinum neurotoxin (BoNT) binds to and internalizes its light chain into presynaptic compartments with exquisite specificity. While the native toxin is extremely lethal, bioengineering of BoNT has the potential to eliminate toxicity without disrupting neuron-specific targeting, thereby creating a molecular vehicle capable of delivering therapeutic cargo into the neuronal cytosol. Building upon previous work, we have developed an atoxic derivative (ad) of BoNT/C1 through rationally designed amino acid substitutions in the metalloprotease domain of wild type (wt) BoNT/C1. To test if BoNT/C1 ad retains neuron-specific targeting without concomitant toxic host responses, we evaluated the localization, activity, and toxicity of BoNT/C1 ad in vitro and in vivo. In neuronal cultures, BoNT/C1 ad light chain is rapidly internalized into presynaptic compartments, but does not cleave SNARE proteins nor impair spontaneous neurotransmitter release. In mice, systemic administration resulted in the specific co-localization of BoNT/C1 ad with diaphragmatic motor nerve terminals. The mouse LD50 of BoNT/C1 ad is 5 mg/kg, with transient neurological symptoms emerging at sub-lethal doses. Given the low toxicity and highly specific neuron-targeting properties of BoNT/C1 ad, these data suggest that BoNT/C1 ad can be useful as a molecular vehicle for drug delivery to the neuronal cytoplasm. PMID:28220863

  8. Anti-C1q Autoantibodies, Novel Tests, and Clinical Consequences

    PubMed Central

    Mahler, Michael; van Schaarenburg, Rosanne A.; Trouw, Leendert A.

    2013-01-01

    Although anti-C1q autoantibodies have been described more than four decades ago a constant stream of papers describing clinical associations or functional consequences highlights that anti-C1q antibodies are still hot and happening. By far the largest set of studies focus on anti-C1q antibodies is systemic lupus erythematosus (SLE). In SLE anti-C1q antibodies associate with involvement of lupus nephritis in such a way that in the absence of anti-C1q antibodies it is unlikely that a flare in nephritis will occur. Anti-C1q antibodies occur in several autoimmune conditions but also in healthy individuals. Although considerable progress has been made in the understanding of how anti-C1q antibodies may contribute to tissue injury there is still a lot to learn about the processes involved in the breaking of tolerance to this protein. There has been considerable improvement in the assays employed to test for the presence of anti-C1q antibodies. Hopefully with these new and standardized assays at hand larger clinical association studies will be conducted with independent replication. Such large-scale studies will reveal the true value of clinical testing for anti-C1q autoantibodies in several clinical conditions. PMID:23717311

  9. Prostaglandin E2 is critical for the development of niacin-deficiency-induced photosensitivity via ROS production

    NASA Astrophysics Data System (ADS)

    Sugita, Kazunari; Ikenouchi-Sugita, Atsuko; Nakayama, Yasuko; Yoshioka, Haruna; Nomura, Takashi; Sakabe, Jun-Ichi; Nakahigashi, Kyoko; Kuroda, Etsushi; Uematsu, Satoshi; Nakamura, Jun; Akira, Shizuo; Nakamura, Motonobu; Narumiya, Shuh; Miyachi, Yoshiki; Tokura, Yoshiki; Kabashima, Kenji

    2013-10-01

    Pellagra is a photosensitivity syndrome characterized by three ``D's'': diarrhea, dermatitis, and dementia as a result of niacin deficiency. However, the molecular mechanisms of photosensitivity dermatitis, the hallmark abnormality of this syndrome, remain unclear. We prepared niacin deficient mice in order to develop a murine model of pellagra. Niacin deficiency induced photosensitivity and severe diarrhea with weight loss. In addition, niacin deficient mice exhibited elevated expressions of COX-2 and PGE syntheses (Ptges) mRNA. Consistently, photosensitivity was alleviated by a COX inhibitor, deficiency of Ptges, or blockade of EP4 receptor signaling. Moreover, enhanced PGE2 production in niacin deficiency was mediated via ROS production in keratinocytes. In line with the above murine findings, human skin lesions of pellagra patients confirmed the enhanced expression of Ptges. Niacin deficiency-induced photosensitivity was mediated through EP4 signaling in response to increased PGE2 production via induction of ROS formation.

  10. Pharmacologic targeting of S6K1 in PTEN-deficient neoplasia

    PubMed Central

    Liu, Hongqi; Feng, Xizhi; Ennis, Kelli N.; Behrmann, Catherine A.; Sarma, Pranjal; Jiang, Tony T.; Kofuji, Satoshi; Niu, Liang; Stratton, Yiwen; Thomas, Hala Elnakat; Yoon, Sang-Oh; Sasaki, Atsuo T.; Plas, David R.

    2017-01-01

    SUMMARY Genetic S6K1 inactivation can induce apoptosis in PTEN-deficient cells. We analyzed the therapeutic potential of S6K1 inhibitors in PTEN-deficient T cell leukemia and glioblastoma. Results revealed that the S6K1 inhibitor LY-2779964 was relatively ineffective as a single agent, while S6K1-targeting AD80 induced cytotoxicity selectively in PTEN-deficient cells. In vivo, AD80 rescued 50% of mice transplanted with PTEN-deficient leukemia cells. Cells surviving LY-2779964 treatment exhibited inhibitor-induced S6K1 phosphorylation due to increased mTOR-S6K1 co-association, which primed rapid recovery of S6K1 signaling. In contrast, AD80 avoided S6K1 phosphorylation and mTOR co-association, resulting in durable suppression of S6K1-induced signaling and protein synthesis. Kinome analysis revealed that AD80 coordinately inhibits S6K1 together with the TAM family tyrosine kinase AXL. TAM suppression by BMS-777607 or genetic knockdown potentiated cytotoxic responses to LY-2779964 in PTEN-deficient glioblastoma cells. These results reveal that combination targeting of S6K1 and TAMs is a potential strategy for treatment of PTEN-deficient malignancy. PMID:28249155

  11. by Cu Deficiencies

    NASA Astrophysics Data System (ADS)

    Wei, Tian-Ran; Li, Fu; Li, Jing-Feng

    2014-06-01

    This work revealed that the Cu-deficient ternary compounds Cu3- x SbSe4 free of Te and Pb exhibit enhanced thermoelectric performance. Cu3- x SbSe4 ( x = 0, 0.025, 0.050, 0.075) polycrystalline materials with high phase purity were fabricated by a facile method combining mechanical alloying and spark plasma sintering. Effects of Cu deficiencies on crystal structures, microstructures, element chemical states, and thermoelectric properties were systematically studied. High carrier concentration was obtained for the compositions Cu2.95SbSe4 and Cu2.925SbSe4 due to additional Cu vacancies, contributing to a remarkable increase in electrical conductivity. Together with a satisfactorily large Seebeck coefficient above 300 μV/K, a high power factor of about 890 μW/m-K2 at 523 K was achieved for Cu2.95SbSe4 and Cu2.925SbSe4, almost 60% larger than that of the stoichiometric sample with x = 0. The maximum ZT value was increased to 0.50 at 673 K in the Cu2.925SbSe4 sample sintered at a high temperature (703 K); this is the highest value reported so far for the undoped Cu3SbSe4 system.

  12. Familial apolipoprotein E deficiency.

    PubMed Central

    Schaefer, E J; Gregg, R E; Ghiselli, G; Forte, T M; Ordovas, J M; Zech, L A; Brewer, H B

    1986-01-01

    A unique kindred with premature cardiovascular disease, tubo-eruptive xanthomas, and type III hyperlipoproteinemia (HLP) associated with familial apolipoprotein (apo) E deficiency was examined. Homozygotes (n = 4) had marked increases in cholesterol-rich very low density lipoproteins (VLDL) and intermediate density lipoproteins (IDL), which could be effectively lowered with diet and medication (niacin, clofibrate). Homozygotes had only trace amounts of plasma apoE, and accumulations of apoB-48 and apoA-IV in VLDL, IDL, and low density lipoproteins. Radioiodinated VLDL apoB and apoE kinetic studies revealed that the homozygous proband had markedly retarded fractional catabolism of VLDL apoB-100, apoB-48 and plasma apoE, as well as an extremely low apoE synthesis rate as compared to normals. Obligate heterozygotes (n = 10) generally had normal plasma lipids and mean plasma apoE concentrations that were 42% of normal. The data indicate that homozygous familial apoE deficiency is a cause of type III HLP, is associated with markedly decreased apoE production, and that apoE is essential for the normal catabolism of triglyceride-rich lipoprotein constituents. Images PMID:3771793

  13. Vitamin D Deficiency

    PubMed Central

    Alshishtawy, Moeness Moustafa

    2012-01-01

    Recently, scientists have generated a strong body of evidence providing new information about the preventive effect of vitamin D on a broad range of disorders. This evidence suggests that vitamin D is much more than a nutrient needed for bone health; it is an essential hormone required for regulation of a large number of physiological functions. Sufficient concentration of serum 25-hydroxyvitamin D is essential for optimising human health. This article reviews the present state-of-the-art knowledge about vitamin D’s status worldwide and refers to recent articles discussing some of the general background of vitamin D, including sources, benefits, deficiencies, and dietary requirements, especially in pregnancy. They offer evidence that vitamin D deficiency could be a major public health burden in many parts of the world, mostly because of sun deprivation. The article also discusses the debate about optimal concentration of circulating serum 25-hydroxyvitamin D, and explores different views on the amount of vitamin D supplementation required to achieve and maintain this concentration. PMID:22548132

  14. PARP inhibitors for BRCA1/2-mutated and sporadic ovarian cancer: current practice and future directions

    PubMed Central

    Konecny, G E; Kristeleit, R S

    2016-01-01

    Poly(ADP-ribose) polymerase (PARP) inhibitors cause targeted tumour cell death in homologous recombination (HR)-deficient cancers, including BRCA-mutated tumours, by exploiting synthetic lethality. PARP inhibitors are being evaluated in late-stage clinical trials of ovarian cancer (OC). Recently, olaparib was the first PARP inhibitor approved in the European Union and United States for the treatment of advanced BRCA-mutated OC. This paper reviews the role of BRCA mutations for tumorigenesis and PARP inhibitor sensitivity, and summarises the clinical development of PARP inhibitors for the treatment of patients diagnosed with OC. Among the five key PARP inhibitors currently in clinical development, olaparib has undergone the most extensive clinical investigation. PARP inhibitors have demonstrated durable antitumour activity in BRCA-mutated advanced OC as a single agent in the treatment and maintenance setting, particularly in platinum-sensitive disease. PARP inhibitors are well tolerated; however, further careful assessment of moderate and late-onset toxicity is mandatory in the maintenance and adjuvant setting, respectively. PARP inhibitors are also being evaluated in combination with chemotherapeutic and novel targeted agents to potentiate antitumour activities. Current research is extending the use of PARP inhibitors beyond BRCA mutations to other sensitising molecular defects that result in HR-deficient cancer, and is defining an HR-deficiency signature. Trials are underway to determine whether such a signature will predict sensitivity to PARP inhibitors in women with sporadic OC. PMID:27736844

  15. [Iron deficiency and digestive disorders].

    PubMed

    Cozon, G J N

    2014-11-01

    Iron deficiency anemia still remains problematic worldwide. Iron deficiency without anemia is often undiagnosed. We reviewed, in this study, symptoms and syndromes associated with iron deficiency with or without anemia: fatigue, cognitive functions, restless legs syndrome, hair loss, and chronic heart failure. Iron is absorbed through the digestive tract. Hepcidin and ferroportin are the main proteins of iron regulation. Pathogenic micro-organisms or intestinal dysbiosis are suspected to influence iron absorption.

  16. Vitamin D deficiency in HIV: a shadow on long-term management?

    PubMed

    Orkin, Chloe; Wohl, David A; Williams, Andrew; Deckx, Henri

    2014-01-01

    Vitamin D deficiency in HIV infection has attracted much interest. The best known clinical outcomes of vitamin D deficiency are rickets (children) and osteomalacia (adults). Several non-skeletal disorders have also been linked to suboptimal vitamin D levels in the general population. The prevalence of vitamin D deficiency varies widely (6-100%) across diverse patient populations, with no evidence that it is higher in HIV-positive versus noninfected adults. Vitamin D deficiency may blunt immune restoration and exacerbate HIV complications (e.g. opportunistic infections, poor perinatal outcomes, wasting, HIV disease progression, AIDS events, and death). The nonnucleoside reverse transcriptase inhibitor efavirenz was associated with a relatively high risk of vitamin D deficiency; nevirapine, etravirine, and rilpivirine were noted to have less or no impact on vitamin D versus efavirenz in the limited data available. Protease inhibitors have either no or a low association with vitamin D deficiency. Nucleoside/nucleotide reverse transcriptase inhibitors (with the possible exception of zidovudine) also did not appear to be associated with vitamin D deficiency. Management of vitamin D deficiency in HIV-positive adults has not been rigorously evaluated; some guidelines recommend more vitamin D supplementation for HIV-positive adults on antiretrovirals versus the general population (e.g. 2-3 times higher vitamin D daily intake for the age group; loading dose up to 10,000 IU/day for 8-10 weeks and a maintenance dose of 800-2,000 IU/day). In conclusion, although vitamin D deficiency in HIV-positive adults can be prevalent, current evidence for its causes and impact is relatively weak. More data, particularly from large, controlled, long-term trials, regarding the benefits of correcting vitamin D levels in HIV-positive adults are needed.

  17. Functional C1q is present in the skin mucus of Siberian sturgeon (Acipenser baerii).

    PubMed

    Fan, Chunxin; Wang, Jian; Zhang, Xuguang; Song, Jiakun

    2015-01-01

    The skin mucus of fish acts as the first line of self-protection against pathogens in the aquatic environment and comprises a number of innate immune components. However, the presence of the critical classical complement component C1q, which links the innate and adaptive immune systems of mammalians, has not been explored in a primitive actinopterygian fish. In this study, we report that C1q is present in the skin mucus of the Siberian sturgeon (Acipenser baerii). The skin mucus was able to inhibit the growth of Escherichia coli. The bacteriostatic activity of the skin mucus was reduced by heating and by pre-incubation with EDTA or mouse anti-human C1q antibody. We also detected C1q protein in skin mucus using the western blot procedure and isolated a cDNA that encodes the Siberian sturgeon C1qC, which had 44.7-51.4% identity with C1qCs in teleosts and tetrapods. A phylogenetic analysis revealed that Siberian sturgeon C1qC lies at the root of the actinopterygian branch and is separate from the tetrapod branch. The C1qC transcript was expressed in many tissues as well as in skin. Our data indicate that C1q is present in the skin mucus of the Siberian sturgeon to protect against water-borne bacteria, and the C1qC found in the sturgeon may represent the primitive form of teleost and tetrapod C1qCs.

  18. Spinolaminar Line Test as a Screening Tool for C1 Stenosis

    PubMed Central

    Oshima, Yasushi; Kelly, Michael P.; Song, Kwang-Sup; Park, Moon Soo; Chuntarapas, Tapanut; Vo, Katie D.; Yeom, Jin S.; Takeshita, Katsushi; Riew, K. Daniel

    2015-01-01

    Study Design Retrospective cohort. Objective To clarify the sensitivity of C3–C2 spinolaminar line test as a screening tool for the stenosis of C1 space available for the cord (SAC). Methods Spine clinic records from April 2005 to August 2011 were reviewed. The C1 SAC was measured on lateral radiographs, and the relative positions between a C1 posterior arch and the C3–C2 spinolaminar line were examined and considered “positive” when the C1 ring lay ventral to the line. Computed tomography (CT) scans and magnetic resonance imaging (MRI) were utilized to measure precise diameters of C1 and C2 SAC and to check the existence of spinal cord compression. Results Four hundred eighty-seven patients were included in this study. There were 246 men and 241 women, with an average age of 53 years (range: 18 to 86). The mean SAC at C1 on radiographs was 21.2 mm (range: 13.5 to 28.2). Twenty-one patients (4.3%) were positive for the spinolaminar line test; all of these patients had C1 SAC of 19.4 mm or less. Eight patients (1.6%) had C1 SAC smaller than C2 on CT examination; all of these patients had a positive spinolaminar test, with high sensitivity (100%) and specificity (97%). MRI analysis revealed that two of the eight patients with a smaller C1 SAC had spinal cord compression at the C1 level. Conclusion Although spinal cord compression at the level of atlas without instability is a rare condition, the spinolaminar line can be used as a screening of C1 stenosis. PMID:27190740

  19. Inhibitors of Pyruvate Carboxylase

    PubMed Central

    Zeczycki, Tonya N.; Maurice, Martin St.; Attwood, Paul V.

    2010-01-01

    This review aims to discuss the varied types of inhibitors of biotin-dependent carboxylases, with an emphasis on the inhibitors of pyruvate carboxylase. Some of these inhibitors are physiologically relevant, in that they provide ways of regulating the cellular activities of the enzymes e.g. aspartate and prohibitin inhibition of pyruvate carboxylase. Most of the inhibitors that will be discussed have been used to probe various aspects of the structure and function of these enzymes. They target particular parts of the structure e.g. avidin – biotin, FTP – ATP binding site, oxamate – pyruvate binding site, phosphonoacetate – binding site of the putative carboxyphosphate intermediate. PMID:22180764

  20. Acquired Factor V Inhibitor

    PubMed Central

    Hirai, Daisuke; Yamashita, Yugo; Masunaga, Nobutoyo; Katsura, Toshiaki; Akao, Masaharu; Okuno, Yoshiaki; Koyama, Hiroshi

    2016-01-01

    Inhibitors directed against factor V rarely occur, and the clinical symptoms vary. We herein report the case of a patient who presented with a decreased factor V activity that had decreased to <3 %. We administered vitamin K and 6 units of fresh frozen plasma, but she thereafter developed an intracerebral hemorrhage. It is unclear whether surgery >10 years earlier might have caused the development of a factor V inhibitor. The treatment of acquired factor V inhibitors is mainly the transfusion of platelet concentrates and corticosteroids. Both early detection and the early initiation of the treatment of factor V inhibitor are thus considered to be important. PMID:27746446

  1. Replication Fork Stability Confers Chemoresistance in BRCA-deficient Cells

    PubMed Central

    Chaudhuri, Arnab Ray; Callen, Elsa; Ding, Xia; Gogola, Ewa; Duarte, Alexandra A.; Lee, Ji-Eun; Wong, Nancy; Lafarga, Vanessa; Calvo, Jennifer A.; Panzarino, Nicholas J.; John, Sam; Day, Amanda; Crespo, Anna Vidal; Shen, Binghui; Starnes, Linda M.; de Ruiter, Julian R.; Daniel, Jeremy A.; Konstantinopoulos, Panagiotis A.; Cortez, David; Cantor, Sharon B.; Fernandez-Capetillo, Oscar; Ge, Kai; Jonkers, Jos; Rottenberg, Sven; Sharan, Shyam K.; Nussenzweig, André

    2016-01-01

    Brca1- and Brca2-deficient cells have reduced capacity to repair DNA double-strand breaks (DSBs) by homologous recombination (HR) and consequently are hypersensitive to DNA damaging agents, including cisplatin and poly(ADP-ribose) polymerase (PARP) inhibitors. Here we show that loss of the MLL3/4 complex protein, PTIP, protects Brca1/2-deficient cells from DNA damage and rescues the lethality of Brca2-deficient embryonic stem cells. However, PTIP deficiency does not restore HR activity at DSBs. Instead, its absence inhibits the recruitment of the MRE11 nuclease to stalled replication forks, which in turn protects nascent DNA strands from extensive degradation. More generally, acquisition of PARPi and cisplatin resistance is associated with replication fork (RF) protection in Brca2-deficient tumor cells that do not develop Brca2 reversion mutations. Disruption of multiple proteins, including PARP1 and CHD4, leads to the same end point of RF protection, highlighting the complexities by which tumor cells evade chemotherapeutic interventions and acquire drug resistance. PMID:27443740

  2. Treatment of rare factor deficiencies in 2016.

    PubMed

    Peyvandi, Flora; Menegatti, Marzia

    2016-12-02

    Rare bleeding disorders (RBDs) are a heterogeneous group of coagulation disorders characterized by fibrinogen, prothrombin, factors V, VII, X, XI, or XIII (FV, FVII, FX, FXI, or FXIII, respectively), and the combined factor V + VIII and vitamin K-dependent proteins deficiencies, representing roughly 5% of all bleeding disorders. They are usually transmitted as autosomal, recessive disorders, and the prevalence of the severe forms could range from 1 case in 500 000 for FVII up to 1 in 2-3 million for FXIII in the general population. Patients affected with RBDs may present a wide range of clinical symptoms, varying from mucocutaneous bleeding, common to all types of RBDs to the most life-threatening symptoms such as central nervous system and gastrointestinal bleeding. Treatment of these disorders is mainly based on the replacement of the deficient factor, using specific plasma-derived or recombinant products. In countries where these facilities are not available, bleedings could be managed using cryoprecipitate, fresh frozen plasma (FFP), or virus-inactivated plasma. Minor bleedings could be managed using antifibrinolytic agents. Recently, 2 novel drugs, recombinant FXIIIA and a plasma-derived FX, have been added to the list of available specific hemostatic factors; only prothrombin and FV deficiencies still remain without a specific product. Novel no-replacement therapies, such as monoclonal antibody anti-tissue factor pathway inhibitor, RNA interference, and a bispecific antibody that is an FVIIIa mimetic, enhancing thrombin generation through different mechanisms, were developed for patients with hemophilia and may in the future be a good therapeutic option also in RBDs.

  3. Systemic Lupus Erythematosus and Deficiencies of Early Components of the Complement Classical Pathway

    PubMed Central

    Macedo, Ana Catarina Lunz; Isaac, Lourdes

    2016-01-01

    The complement system plays an important role in the innate and acquired immune response against pathogens. It consists of more than 30 proteins found in soluble form or attached to cell membranes. Most complement proteins circulate in inactive forms and can be sequentially activated by the classical, alternative, or lectin pathways. Biological functions, such as opsonization, removal of apoptotic cells, adjuvant function, activation of B lymphocytes, degranulation of mast cells and basophils, and solubilization and clearance of immune complex and cell lysis, are dependent on complement activation. Although the activation of the complement system is important to avoid infections, it also can contribute to the inflammatory response triggered by immune complex deposition in tissues in autoimmune diseases. Paradoxically, the deficiency of early complement proteins from the classical pathway (CP) is strongly associated with development of systemic lupus erythematous (SLE) – mainly C1q deficiency (93%) and C4 deficiency (75%). The aim of this review is to focus on the deficiencies of early components of the CP (C1q, C1r, C1s, C4, and C2) proteins in SLE patients. PMID:26941740

  4. 26 CFR 1.641(c)-1 - Electing small business trust.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 8 2010-04-01 2010-04-01 false Electing small business trust. 1.641(c)-1...) INCOME TAX (CONTINUED) INCOME TAXES Estates, Trusts, and Beneficiaries § 1.641(c)-1 Electing small business trust. (a) In general. An electing small business trust (ESBT) within the meaning of section...

  5. Relevance of anti-C1q autoantibodies to lupus nephritis.

    PubMed

    Tsirogianni, Alexandra; Pipi, Elena; Soufleros, Kostantinos

    2009-09-01

    The first component of the classical pathway of the complement system (C1q) is considered to have a crucial role in the clearance of immune complexes (ICs) as well as in the removal of waste material originating from apoptotic cells. A prolonged exposure of C1q epitopes to the immune system could eventually lead to an autoimmune response against itself. Although autoantibodies against C1q are found in several diseases, their clinical interest originates from their strong association to active lupus nephritis (LN). Several studies indicate that anti-C1q autoantibodies could serve as a reliable serologic marker in the assessment of LN activity compared to other immunological tests. Additionally, it was suggested that anti-C1q autoantibodies could play a role in LN pathogenesis. Their potential pathogenic actions likely depend on genetic background, titers, Ig classes and subclasses, and specific epitopes of anti-C1q autoantibodies as well as C1q availability and allocation. It is still unclear which different types of anti-C1q autoantibodies dominate in each case and if their upregulation is pathogenic, an epiphenomenon of aberrant tissue damage, or compensatory to an uncontrolled immune response.

  6. 17 CFR 240.15c1-9 - Use of pro forma balance sheets.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 17 Commodity and Securities Exchanges 3 2013-04-01 2013-04-01 false Use of pro forma balance sheets. 240.15c1-9 Section 240.15c1-9 Commodity and Securities Exchanges SECURITIES AND EXCHANGE... pro forma balance sheets. The term manipulative, deceptive, or other fraudulent device or...

  7. 17 CFR 240.15c1-9 - Use of pro forma balance sheets.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 17 Commodity and Securities Exchanges 4 2014-04-01 2014-04-01 false Use of pro forma balance sheets. 240.15c1-9 Section 240.15c1-9 Commodity and Securities Exchanges SECURITIES AND EXCHANGE... pro forma balance sheets. The term manipulative, deceptive, or other fraudulent device or...

  8. 17 CFR 240.15c1-9 - Use of pro forma balance sheets.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 17 Commodity and Securities Exchanges 3 2012-04-01 2012-04-01 false Use of pro forma balance sheets. 240.15c1-9 Section 240.15c1-9 Commodity and Securities Exchanges SECURITIES AND EXCHANGE... pro forma balance sheets. The term manipulative, deceptive, or other fraudulent device or...

  9. 17 CFR 240.15c1-9 - Use of pro forma balance sheets.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 17 Commodity and Securities Exchanges 3 2010-04-01 2010-04-01 false Use of pro forma balance sheets. 240.15c1-9 Section 240.15c1-9 Commodity and Securities Exchanges SECURITIES AND EXCHANGE... pro forma balance sheets. The term manipulative, deceptive, or other fraudulent device or...

  10. 17 CFR 240.15c1-9 - Use of pro forma balance sheets.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 17 Commodity and Securities Exchanges 3 2011-04-01 2011-04-01 false Use of pro forma balance sheets. 240.15c1-9 Section 240.15c1-9 Commodity and Securities Exchanges SECURITIES AND EXCHANGE... pro forma balance sheets. The term manipulative, deceptive, or other fraudulent device or...

  11. 26 CFR 1.280C-1 - Disallowance of certain deductions for wage or salary expenses.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... salary expenses. 1.280C-1 Section 1.280C-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE... Disallowance of certain deductions for wage or salary expenses. If an employer elects to claim the targeted... reduce its deduction for wage or salary expenses paid or incurred in the year the credit is earned by...

  12. 26 CFR 1.280C-1 - Disallowance of certain deductions for wage or salary expenses.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... salary expenses. 1.280C-1 Section 1.280C-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE... certain deductions for wage or salary expenses. If an employer elects to claim the targeted jobs credit... deduction for wage or salary expenses paid or incurred in the year the credit is earned by the...

  13. 26 CFR 1.280C-1 - Disallowance of certain deductions for wage or salary expenses.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... salary expenses. 1.280C-1 Section 1.280C-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE... Disallowance of certain deductions for wage or salary expenses. If an employer elects to claim the targeted... reduce its deduction for wage or salary expenses paid or incurred in the year the credit is earned by...

  14. 26 CFR 1.280C-1 - Disallowance of certain deductions for wage or salary expenses.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... salary expenses. 1.280C-1 Section 1.280C-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE... Disallowance of certain deductions for wage or salary expenses. If an employer elects to claim the targeted... reduce its deduction for wage or salary expenses paid or incurred in the year the credit is earned by...

  15. 26 CFR 1.280C-1 - Disallowance of certain deductions for wage or salary expenses.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... salary expenses. 1.280C-1 Section 1.280C-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE... Disallowance of certain deductions for wage or salary expenses. If an employer elects to claim the targeted... reduce its deduction for wage or salary expenses paid or incurred in the year the credit is earned by...

  16. 26 CFR 301.6104(c)-1 - Disclosure of certain information to State officers.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 18 2010-04-01 2010-04-01 false Disclosure of certain information to State officers. 301.6104(c)-1 Section 301.6104(c)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE...) of this section, the Internal Revenue Service will notify the Attorney General and the principal...

  17. Generalized van der Waals Hamiltonian: periodic orbits and C1 nonintegrability.

    PubMed

    Guirao, Juan L G; Llibre, Jaume; Vera, Juan A

    2012-03-01

    The aim of this paper is to study the periodic orbits of the generalized van der Waals Hamiltonian system. The tool for studying such periodic orbits is the averaging theory. Moreover, for this Hamiltonian system we provide information on its C(1) nonintegrability, i.e., on the existence of a second first integral of class C(1).

  18. 26 CFR 1.512(c)-1 - Special rules applicable to partnerships; in general.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 7 2010-04-01 2010-04-01 true Special rules applicable to partnerships; in general. 1.512(c)-1 Section 1.512(c)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Taxation of Business Income of...

  19. 26 CFR 31.3406(c)-1 - Notified payee underreporting of reportable interest or dividend payments.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 15 2010-04-01 2010-04-01 false Notified payee underreporting of reportable interest or dividend payments. 31.3406(c)-1 Section 31.3406(c)-1 Internal Revenue INTERNAL REVENUE SERVICE...)(2)) made with respect to an account of a payee if the Internal Revenue Service or a broker...

  20. 26 CFR 1.641(c)-1 - Electing small business trust.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 8 2011-04-01 2011-04-01 false Electing small business trust. 1.641(c)-1... small business trust. (a) In general. An electing small business trust (ESBT) within the meaning of... meaning of section 642(c)(1). The limitations of section 681, regarding unrelated business income,...

  1. 26 CFR 1.641(c)-1 - Electing small business trust.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 8 2014-04-01 2014-04-01 false Electing small business trust. 1.641(c)-1... small business trust. (a) In general. An electing small business trust (ESBT) within the meaning of... meaning of section 642(c)(1). The limitations of section 681, regarding unrelated business income,...

  2. [Vitamin deficiencies in breastfed children due to maternal dietary deficiency].

    PubMed

    Kollée, L A A

    2006-03-04

    Dietary deficiencies of vitamin B12 and vitamin D during pregnancy and lactation may result in health problems in exclusively breastfed infants. Vitamin-B12 deficiency in these infants results in irritability, anorexia and failure to thrive during the first 4-8 months of life. Severe and permanent neurodevelopmental disturbances may occur. The most at risk for vitamin-B12 deficiency are breast-fed infants ofveganist and vegetarian mothers. Mothers who cover their skin prevent exposure to the sun and may consequently be at risk for vitamin-D deficiency, as well as putting their offspring at risk. In prenatal and perinatal care, it is important to take the maternal dietary history in order to be able to prevent or treat these disorders. Guidelines for obstetrical and neonatal care should include the topic of vitamin deficiency.

  3. Hereditary galactokinase deficiency

    PubMed Central

    Cook, J. G. H.; Don, N. A.; Mann, Trevor P.

    1971-01-01

    A baby with galactokinase deficiency, a recessive inborn error of galactose metabolism, is described. The case is exceptional in that there was no evidence of gypsy blood in the family concerned. The investigation of neonatal hyperbilirubinaemia led to the discovery of galactosuria. As noted by others, the paucity of presenting features makes early diagnosis difficult, and detection by biochemical screening seems desirable. Cataract formation, of early onset, appears to be the only severe persisting complication and may be due to the biosynthesis and accumulation of galactitol in the lens. Ophthalmic surgeons need to be aware of this enzyme defect, because with early diagnosis and dietary treatment these lens changes should be reversible. PMID:5109408

  4. Presence of arylsulfatase A (ARS A) in multiple sulfatase deficiency disorder fibroblasts.

    PubMed

    Fluharty, A L; Stevens, R L; Davis, L L; Shapiro, L J; Kihara, H

    1978-05-01

    Multiple deficiency disorder fibroblasts cultured in MEM-CO2 showed deficiencies of arylsulfatase A(ARS A) comparable to the deficiency in metachromatic leukodystrophy fibroblasts. However, the MSDD fibroblasts cultured in MEM-HEPES contained near normal levels of ARS A. Moreover, the enzyme from the latter fibroblasts was indistinguishable from ARS A of control fibroblasts on DEAE-cellulose chromatography, ratio of activity with several substrates, thermal inactivation, sensitivity to inhibitors, and precipitation by antiserum to human ARS A. These data support the conclusion that the ARS A genome is intact in MSDD fibroblasts and, by extension, in MSDD patients. Other sulfatases were present at levels ranging from mildly deficient to near normal but never as low as seen in the corresponding specific sulfatase deficient disorders.

  5. Peroxisomal bifunctional enzyme deficiency.

    PubMed Central

    Watkins, P A; Chen, W W; Harris, C J; Hoefler, G; Hoefler, S; Blake, D C; Balfe, A; Kelley, R I; Moser, A B; Beard, M E

    1989-01-01

    Peroxisomal function was evaluated in a male infant with clinical features of neonatal adrenoleukodystrophy. Very long chain fatty acid levels were elevated in both plasma and fibroblasts, and beta-oxidation of very long chain fatty acids in cultured fibroblasts was significantly impaired. Although the level of the bile acid intermediate trihydroxycoprostanoic acid was slightly elevated in plasma, phytanic acid and L-pipecolic acid levels were normal, as was plasmalogen synthesis in cultured fibroblasts. The latter three parameters distinguish this case from classical neonatal adrenoleukodystrophy. In addition, electron microscopy and catalase subcellular distribution studies revealed that, in contrast to neonatal adrenoleukodystrophy, peroxisomes were present in the patient's tissues. Immunoblot studies of peroxisomal beta-oxidation enzymes revealed that the bifunctional enzyme (enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase) was deficient in postmortem liver samples, whereas acyl-CoA oxidase and the mature form of beta-ketothiolase were present. Density gradient centrifugation of fibroblast homogenates confirmed that intact peroxisomes were present. Immunoblots of fibroblasts peroxisomal fractions showed that they contained acyl-CoA oxidase and beta-ketothiolase, but bifunctional enzyme was not detected. Northern analysis, however, revealed that mRNA coding for the bifunctional enzyme was present in the patient's fibroblasts. These results indicate that the primary biochemical defect in this patient is a deficiency of peroxisomal bifunctional enzyme. It is of interest that the phenotype of this patient resembled neonatal adrenoleukodystrophy and would not have been distinguished from this disorder by clinical study alone. Images PMID:2921319

  6. Iodine deficiency in Europe.

    PubMed

    Delange, F

    1995-01-18

    Iodine is a trace element present in the human body in minute amounts (15-20 mg in adults, i.e. 0.0285 x 10(-3)% of body weight). The only confirmed function of iodine is to constitute an essential substrate for the synthesis of thyroid hormones, tetraiodothyronine, thyroxine or T4 and triiodothyronine, T3 (1). In thyroxine, iodine is 60% by weight. Thyroid hormones, in turn, play a decisive role in the metabolism of all cells of the organism (2) and in the process of early growth and development of most organs, especially of the brain (3). Brain development in humans occurs from fetal life up to the third postnatal year (4). Consequently, a deficit in iodine and/or in thyroid hormones occurring during this critical period of life will result not only in the slowing down of the metabolic activities of all the cells of the organism but also in irreversible alterations in the development of the brain. The clinical consequence will be mental retardation (5). When the physiological requirements of iodine are not met in a given population, a series of functional and developmental abnormalities occur (Table 1), including thyroid function abnormalities and, when iodine deficiency is severe, endemic goiter and cretinism, endemic mental retardation, decreased fertility rate, increased perinatal death, and infant mortality. These complications, which constitute an hindrance to the development of the affected population, are grouped under the general heading of Iodine Deficiency Disorders, IDD (6). Broad geographic areas exist in which the population is affected by IDD.(ABSTRACT TRUNCATED AT 250 WORDS)

  7. ROS Production and ERK Activity Are Involved in the Effects of d-β-Hydroxybutyrate and Metformin in a Glucose Deficient Condition

    PubMed Central

    Lamichhane, Santosh; Bastola, Tonking; Pariyar, Ramesh; Lee, Eun-Sol; Lee, Ho-Sub; Lee, Dae Ho; Seo, Jungwon

    2017-01-01

    Hypoglycemia, a complication of insulin or sulfonylurea therapy in diabetic patients, leads to brain damage. Furthermore, glucose replenishment following hypoglycemic coma induces neuronal cell death. In this study, we investigated the molecular mechanism underlying glucose deficiency-induced cytotoxicity and the protective effect of d-β-hydroxybutyrate (D-BHB) using SH-SY5Y cells. The cytotoxic mechanism of metformin under glucose deficiency was also examined. Cell viability under 1 mM glucose (glucose deficiency) was significantly decreased which was accompanied by increased production of reactive oxygen species (ROS) and decreased phosphorylation of extracellular signal-regulated kinase (ERK) and glycogen synthase 3 (GSK3β). ROS inhibitor reversed the glucose deficiency-induced cytotoxicity and restored the reduced phosphorylation of ERK and GSK3β. While metformin did not alter cell viability in normal glucose media, it further increased cell death and ROS production under glucose deficiency. However, D-BHB reversed cytotoxicity, ROS production, and the decrease in phosphorylation of ERK and GSK3β induced by the glucose deficiency. ERK inhibitor reversed the D-BHB-induced increase in cell viability under glucose deficiency, whereas GSK3β inhibitor did not restore glucose deficiency-induced cytotoxicity. Finally, the protective effect of D-BHB against glucose deficiency was confirmed in primary neuronal cells. We demonstrate that glucose deficiency-induced cytotoxicity is mediated by ERK inhibition through ROS production, which is attenuated by D-BHB and intensified by metformin. PMID:28335557

  8. C2 laminar screw and C1-2 transarticular screw combined with C1 laminar hooks for atlantoaxial instability with unilateral vertebral artery injury.

    PubMed

    Guo, Qunfeng; Liu, Jun; Ni, Bin; Lu, Xuhua; Zhou, Fengjin

    2011-09-01

    Transarticular screw fixation (TASF) is technically demanding, with high risk of vertebral artery (VA) injury. How to manage intraoperative VA injury and choose optimal alternative fixation becomes a concern of spinal surgeons. In this study, the management strategy for a patient with suspected intraoperative VA injury was analyzed. A 53-year-old woman developed type II odontoid fracture and brain stem injury due to a motor vehicle accident 3 months earlier. After conservative treatments, the brain stem injury improved, but with residual ocular motility defect in the right eye. The odontoid fracture did not achieve fusion with displacement and absorption of fracture fragments. After admission, atlantoaxial fixation using bilateral C1-2 transarticular screws (TASs) combined with C1 laminar hooks was planed. The first TAS was inserted successfully. Unfortunately, suspected VA injury developed during tapping the tract for the second TAS. Considering the previous brain stem injury and that directly inserting the screw to tamponade the hemorrhage might cause VA stenosis or occlusion, we blocked the screw trajectory with bone wax. C2 laminar screw was implanted instead of intended TAS on the injured side. The management strategy for suspected VA injury should depend on intraoperative circumstances and be tailored to patients. Blocking screw trajectory with bone wax is a useful method to stop bleeding. Atlantoaxial fixation using C2 laminar screw and C1-2 TAS combined with C1 laminar hooks is an ideal alternative procedure.

  9. Separation and conductimetric detection of C1-C7 aliphatic monocarboxylic acids and C1-C7 aliphatic monoamines on unfunctionized polymethacrylate resin columns.

    PubMed

    Ohta, Kazutoku; Towata, Atsuya; Ohashi, Masayoshi; Takeuchi, Toyohide

    2004-06-11

    The application of unfunctionized polymethacrylate resin (TSKgel G3000PWXL) as a stationary phase in liquid chromatography with conductimetric detection for C1-C7 aliphatic monocarboxylic acids (formic acid, acetic acid, propionic acid, butyric acid, isovaleric acid, valeric acid, 3,3-dimethylbutyric acid, 4-methylvaleric acid, hexanoic acid, 2-methylhexanoic acid, 5-methylhexanoic acid and heptanoic acid) and C1-C7 aliphatic monoamines (methylamine, ethylamine, propylamine, isobutylamine, butylamine, isoamylamine, amylamine, 1,3-dimethylbutylamine, hexylamine, 2-heptylamine and heptylamine) was attempted with C8 aliphatic monocarboxylic acids (2-propylvaleric acid, 2-ethylhexanoic acid, 2-methylheptanoic acid and octanoic acid) and C8 aliphatic monoamines (1,5-dimethylhexylamine, 2-ethylhexylamine, 1-methylheptylamine and octylamine) as eluents, respectively. Using 1 mM 2-methylheptanoic acid at pH 4.0 as the eluent, excellent separation and relatively high sensitive detection for these C1-C7 carboxylic acids were achieved on a TSKgel G3000PWXL column (150 mm x 6 mm i.d.) in 60 min. Using 2 mM octylamine at pH 11.0 as the eluent, excellent separation and relatively high sensitive detection for these C1-C7 amines were also achieved on the TSKgel G3000PWXL column in 60 min.

  10. Urease Inhibitor Drug Treatment for Urea Cycle Disorders

    ClinicalTrials.gov

    2016-08-23

    Ornithine Transcarbamylase Deficiency; Argininosuccinate Synthetase Deficiency (Citrullinemia); Argininosuccinic Acid Lyase Deficiency (Argininosuccinic Aciduria); Carbamyl-Phosphate Synthase I Deficiency

  11. Congenital deficiency of meibomian glands.

    PubMed Central

    Bron, A J; Mengher, L S

    1987-01-01

    A 16-year-old girl presented with contact lens intolerance. She was found to have a marked deficiency of meibomian glands in the upper lids and almost total absence in the lower lids. Evidence of tear film instability was found and attributed to deficient lid oil production. A daily wear soft contact lens was later fitted and tolerated. PMID:3580344

  12. Vitamin B12 deficiency anemia

    MedlinePlus

    ... body tissues. There are many types of anemia. Vitamin B12 deficiency anemia is a low red blood cell count ... anemia often do well with treatment. Long-term vitamin B12 deficiency can cause nerve damage. This may be permanent ...

  13. Basic Skills: Dealing with Deficiencies.

    ERIC Educational Resources Information Center

    New Mexico State Univ., Las Cruces.

    Research findings on college instruction and basic skills deficiencies are discussed in 12 papers from the first Regional Conference on University Teaching. Titles and authors are as follows: "Basic Skills: Dealing with Deficiencies" (Susanne D. Roueche, with responses by Gary B. Donart, Betty Harris, and James Nordyke); "Is Higher Education an…

  14. Iron deficiency: definition and diagnosis.

    PubMed

    Cook, J D; Skikne, B S

    1989-11-01

    There has been a continuous refinement over the past several decades of methods to detect iron deficiency and assess its magnitude. The optimal combination of measurements differs for clinical and epidemiological assessment. Clinically, the major problem is to distinguish true iron deficiency from other causes of iron-deficient erythropoiesis, such as the anaemia of chronic disease. Epidemiologically, techniques that provide quantified estimates of body iron are preferable. For both purposes, the serum ferritin is the focal point of the laboratory detection of iron deficiency. Serum ferritin measurements provide a reliable index of body iron stores in healthy individuals, a cost-effective method of screening for iron deficiency, and a useful alternative to bone marrow examinations in the evaluation of anaemic patients. Preliminary studies indicate that measurement of the serum transferrin receptor may be the most reliable way to assess deficits in tissue iron supply.

  15. Novel corrosion inhibitor technology

    SciTech Connect

    Van de Ven, P.; Fritz, P.; Pellet, R.

    1999-11-01

    A novel, patented corrosion inhibitor technology has been identified for use in heat transfer applications such as automotive and heavy-duty coolant. The new technology is based on a low-toxic, virtually depletion-free carboxylic acid corrosion inhibitor package that performs equally well in mono ethylene glycol and in less toxic propylene glycol coolants. An aqueous inhibitor concentrate is available to provide corrosion protection where freezing protection is not an issue. In the present paper, this inhibitor package is evaluated in the different base fluids: mono ethylene glycol, mono propylene glycol and water. Results are obtained in both standardized and specific corrosion tests as well as in selected field trials. These results indicate that the inhibitor package remains effective and retains the benefits previously identified in automotive engine coolant applications: excellent corrosion protection under localized conditions, general corrosion conditions as well as at high temperature.

  16. Assessment of the relative contribution of different protease inhibitors to the inhibition of plasmin in vivo.

    PubMed

    Levi, M; Roem, D; Kamp, A M; de Boer, J P; Hack, C E; ten Cate, J W

    1993-02-01

    It has been shown that the most important inhibitor of plasmin is alpha 2-antiplasmin, however, other protease inhibitors are able to inhibit this proteolytic enzyme as well. The contribution of the various protease inhibitors to the inhibition of plasmin in vivo has never been quantitatively assessed. To assess the relative contribution of the different protease inhibitors on the inhibition of plasmin we developed a series of sensitive immunoassays for the detection of complexes between plasmin and the protease inhibitors alpha 2-antiplasmin, alpha 2-macroglobulin, antithrombin III, alpha 1-antitrypsin and C1-inhibitor, utilizing monoclonal antibodies that are specifically directed against complexed protease inhibitors and a monoclonal antibody against plasmin. It was confirmed that alpha 2-antiplasmin is the most important inhibitor of plasmin in vivo, however, complexes of plasmin with alpha 2-macroglobulin, antithrombin III, alpha 1-antitrypsin- and C1-inhibitor were also detected. Particularly during activation of fibrinolysis complexes between plasmin and inhibitors other than alpha 2-antiplasmin were detected. It was observed that during different situations the inhibition profile of plasmin was not constant e.g. in patients with diffuse intravascular coagulation plasma levels of plasmin-alpha 1-antitrypsin and plasmin-C1-inhibitor were increased whereas in plasma from patients who were treated with thrombolytic agents complexes of plasmin with alpha 2-macroglobulin and with antithrombin III were significantly elevated. In conclusion, we confirmed the important role of alpha 2-antiplasmin in the inhibition of plasmin, however, in situations in which fibrinolysis is activated other protease inhibitors also account for the inhibition of plasmin in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)

  17. A PP2C-1 Allele Underlying a Quantitative Trait Locus Enhances Soybean 100-Seed Weight.

    PubMed

    Lu, Xiang; Xiong, Qing; Cheng, Tong; Li, Qing-Tian; Liu, Xin-Lei; Bi, Ying-Dong; Li, Wei; Zhang, Wan-Ke; Ma, Biao; Lai, Yong-Cai; Du, Wei-Guang; Man, Wei-Qun; Chen, Shou-Yi; Zhang, Jin-Song

    2017-03-28

    Cultivated soybeans may lose some useful genetic locus during domestication. Introgression of genes from wild soybeans may broaden the genetic background and improve soybean agronomic traits. Here, through whole-genome sequencing of an RIL population derived from a cross between a wild soybean ZYD7 and a cultivated soybean HN44, and mapping of QTLs for seed weight, we discover that a phosphatase 2C-1 (PP2C-1) allele from wild soybean ZYD7 contributes to the increase of seed weight/size in transgenic plants. The PP2C-1 may achieve this function by enhancing cell size of integument and activating a subset of seed trait-related genes. The PP2C-1 was further found to associate with a transcription factor GmBZR1 and facilitate accumulation of dephosphorylated GmBZR1. In contrast, a PP2C-2 allele with variations of a few amino acids at N-terminus does not exhibit this function. Moreover, the GmBZR1 can promote seed weight/size in transgenic plants. Through analysis of cultivated soybean accessions, we find that 40% of the examined accessions do not have the PP2C-1 allele, suggesting that these accessions can be improved through introduction of the PP2C-1 allele. Our study identifies an elite allele PP2C-1, which can enhance seed weight/size. Manipulation of the allele by molecule-assisted breeding may increase production in soybean and other legumes/crops.

  18. Amplitude analysis of the χc 1→η π+π- decays

    NASA Astrophysics Data System (ADS)

    Ablikim, M.; Achasov, M. N.; Ahmed, S.; Ai, X. C.; Albayrak, O.; Albrecht, M.; Ambrose, D. J.; Amoroso, A.; An, F. F.; An, Q.; Bai, J. Z.; Bakina, O.; Baldini Ferroli, R.; Ban, Y.; Bennett, D. W.; Bennett, J. V.; Berger, N.; Bertani, M.; Bettoni, D.; Bian, J. M.; Bianchi, F.; Boger, E.; Boyko, I.; Briere, R. A.; Cai, H.; Cai, X.; Cakir, O.; Calcaterra, A.; Cao, G. F.; Cetin, S. A.; Chai, J.; Chang, J. F.; Chelkov, G.; Chen, G.; Chen, H. S.; Chen, J. C.; Chen, M. L.; Chen, S.; Chen, S. J.; Chen, X.; Chen, X. R.; Chen, Y. B.; Cheng, H. P.; Chu, X. K.; Cibinetto, G.; Dai, H. L.; Dai, J. P.; Dbeyssi, A.; Dedovich, D.; Deng, Z. Y.; Denig, A.; Denysenko, I.; Destefanis, M.; de Mori, F.; Ding, Y.; Dong, C.; Dong, J.; Dong, L. Y.; Dong, M. Y.; Dou, Z. L.; Du, S. X.; Duan, P. F.; Fan, J. Z.; Fang, J.; Fang, S. S.; Fang, X.; Fang, Y.; Farinelli, R.; Fava, L.; Feldbauer, F.; Felici, G.; Feng, C. Q.; Fioravanti, E.; Fritsch, M.; Fu, C. D.; Gao, Q.; Gao, X. L.; Gao, Y.; Gao, Z.; Garzia, I.; Goetzen, K.; Gong, L.; Gong, W. X.; Gradl, W.; Greco, M.; Gu, M. H.; Gu, Y. T.; Guan, Y. H.; Guo, A. Q.; Guo, L. B.; Guo, R. P.; Guo, Y.; Guo, Y. P.; Haddadi, Z.; Hafner, A.; Han, S.; Hao, X. Q.; Harris, F. A.; He, K. L.; Heinsius, F. H.; Held, T.; Heng, Y. K.; Holtmann, T.; Hou, Z. L.; Hu, C.; Hu, H. M.; Hu, J. F.; Hu, T.; Hu, Y.; Huang, G. S.; Huang, J. S.; Huang, X. T.; Huang, X. Z.; Huang, Y.; Huang, Z. L.; Hussain, T.; Ikegami Andersson, W.; Ji, Q.; Ji, Q. P.; Ji, X. B.; Ji, X. L.; Jiang, L. W.; Jiang, X. S.; Jiang, X. Y.; Jiao, J. B.; Jiao, Z.; Jin, D. P.; Jin, S.; Johansson, T.; Julin, A.; Kalantar-Nayestanaki, N.; Kang, X. L.; Kang, X. S.; Kavatsyuk, M.; Ke, B. C.; Kiese, P.; Kliemt, R.; Kloss, B.; Kolcu, O. B.; Kopf, B.; Kornicer, M.; Kupsc, A.; Kühn, W.; Lange, J. S.; Lara, M.; Larin, P.; Leithoff, H.; Leng, C.; Li, C.; Li, Cheng; Li, D. M.; Li, F.; Li, F. Y.; Li, G.; Li, H. B.; Li, H. J.; Li, J. C.; Li, Jin; Li, K.; Li, K.; Li, Lei; Li, P. R.; Li, Q. Y.; Li, T.; Li, W. D.; Li, W. G.; Li, X. L.; Li, X. N.; Li, X. Q.; Li, Y. B.; Li, Z. B.; Liang, H.; Liang, Y. F.; Liang, Y. T.; Liao, G. R.; Lin, D. X.; Liu, B.; Liu, B. J.; Liu, C. X.; Liu, D.; Liu, F. H.; Liu, Fang; Liu, Feng; Liu, H. B.; Liu, H. H.; Liu, H. H.; Liu, H. M.; Liu, J.; Liu, J. B.; Liu, J. P.; Liu, J. Y.; Liu, K.; Liu, K. Y.; Liu, L. D.; Liu, P. L.; Liu, Q.; Liu, S. B.; Liu, X.; Liu, Y. B.; Liu, Y. Y.; Liu, Z. A.; Liu, Zhiqing; Loehner, H.; Long, Y. F.; Lou, X. C.; Lu, H. J.; Lu, J. G.; Lu, Y.; Lu, Y. P.; Luo, C. L.; Luo, M. X.; Luo, T.; Luo, X. L.; Lyu, X. R.; Ma, F. C.; Ma, H. L.; Ma, L. L.; Ma, M. M.; Ma, Q. M.; Ma, T.; Ma, X. N.; Ma, X. Y.; Ma, Y. M.; Maas, F. E.; Maggiora, M.; Malik, Q. A.; Mao, Y. J.; Mao, Z. P.; Marcello, S.; Messchendorp, J. G.; Mezzadri, G.; Min, J.; Min, T. J.; Mitchell, R. E.; Mo, X. H.; Mo, Y. J.; Morales Morales, C.; Muchnoi, N. Yu.; Muramatsu, H.; Musiol, P.; Nefedov, Y.; Nerling, F.; Nikolaev, I. B.; Ning, Z.; Nisar, S.; Niu, S. L.; Niu, X. Y.; Olsen, S. L.; Ouyang, Q.; Pacetti, S.; Pan, Y.; Patteri, P.; Pelizaeus, M.; Peng, H. P.; Peters, K.; Pettersson, J.; Ping, J. L.; Ping, R. G.; Poling, R.; Prasad, V.; Qi, H. R.; Qi, M.; Qian, S.; Qiao, C. F.; Qin, L. Q.; Qin, N.; Qin, X. S.; Qin, Z. H.; Qiu, J. F.; Rashid, K. H.; Redmer, C. F.; Ripka, M.; Rong, G.; Rosner, Ch.; Ruan, X. D.; Sarantsev, A.; Savrié, M.; Schnier, C.; Schoenning, K.; Schumann, S.; Shan, W.; Shao, M.; Shen, C. P.; Shen, P. X.; Shen, X. Y.; Sheng, H. Y.; Shi, M.; Song, W. M.; Song, X. Y.; Sosio, S.; Spataro, S.; Sun, G. X.; Sun, J. F.; Sun, S. S.; Sun, X. H.; Sun, Y. J.; Sun, Y. Z.; Sun, Z. J.; Sun, Z. T.; Tang, C. J.; Tang, X.; Tapan, I.; Thorndike, E. H.; Tiemens, M.; Uman, I.; Varner, G. S.; Wang, B.; Wang, B. L.; Wang, D.; Wang, D. Y.; Wang, K.; Wang, L. L.; Wang, L. S.; Wang, M.; Wang, P.; Wang, P. L.; Wang, W.; Wang, W. P.; Wang, X. F.; Wang, Y.; Wang, Y. D.; Wang, Y. F.; Wang, Y. Q.; Wang, Z.; Wang, Z. G.; Wang, Z. H.; Wang, Z. Y.; Wang, Z. Y.; Weber, T.; Wei, D. H.; Weidenkaff, P.; Wen, S. P.; Wiedner, U.; Wolke, M.; Wu, L. H.; Wu, L. J.; Wu, Z.; Xia, L.; Xia, L. G.; Xia, Y.; Xiao, D.; Xiao, H.; Xiao, Z. J.; Xie, Y. G.; Xiu, Q. L.; Xu, G. F.; Xu, J. J.; Xu, L.; Xu, Q. J.; Xu, Q. N.; Xu, X. P.; Yan, L.; Yan, W. B.; Yan, W. C.; Yan, Y. H.; Yang, H. J.; Yang, H. X.; Yang, L.; Yang, Y. X.; Ye, M.; Ye, M. H.; Yin, J. H.; You, Z. Y.; Yu, B. X.; Yu, C. X.; Yu, J. S.; Yuan, C. Z.; Yuan, W. L.; Yuan, Y.; Yuncu, A.; Zafar, A. A.; Zallo, A.; Zeng, Y.; Zeng, Z.; Zhang, B. X.; Zhang, B. Y.; Zhang, C.; Zhang, C. C.; Zhang, D. H.; Zhang, H. H.; Zhang, H. Y.; Zhang, J.; Zhang, J. J.; Zhang, J. L.; Zhang, J. Q.; Zhang, J. W.; Zhang, J. Y.; Zhang, J. Z.; Zhang, K.; Zhang, L.; Zhang, S. Q.; Zhang, X. Y.; Zhang, Y.; Zhang, Y.; Zhang, Y. H.; Zhang, Y. N.; Zhang, Y. T.; Zhang, Yu; Zhang, Z. H.; Zhang, Z. P.; Zhang, Z. Y.; Zhao, G.; Zhao, J. W.; Zhao, J. Y.; Zhao, J. Z.; Zhao, Lei; Zhao, Ling; Zhao, M. G.; Zhao, Q.; Zhao, Q. W.; Zhao, S. J.; Zhao, T. C.; Zhao, Y. B.; Zhao, Z. G.; Zhemchugov, A.; Zheng, B.; Zheng, J. P.; Zheng, W. J.; Zheng, Y. H.; Zhong, B.; Zhou, L.; Zhou, X.; Zhou, X. K.; Zhou, X. R.; Zhou, X. Y.; Zhu, K.; Zhu, K. J.; Zhu, S.; Zhu, S. H.; Zhu, X. L.; Zhu, Y. C.; Zhu, Y. S.; Zhu, Z. A.; Zhuang, J.; Zotti, L.; Zou, B. S.; Zou, J. H.; Besiii Collaboration

    2017-02-01

    Using 448.0 ×1 06 ψ (3686 ) events collected with the BESIII detector, an amplitude analysis is performed for ψ (3686 )→γ χc 1 , χc 1→η π+π- decays. The most dominant two-body structure observed is a0(980 )±π∓ ; a0(980 )±→η π± . The a0(980 ) line shape is modeled using a dispersion relation, and a significant nonzero a0(980 ) coupling to the η'π channel is measured. We observe χc 1→a2(1700 )π production for the first time, with a significance larger than 17 σ . The production of mesons with exotic quantum numbers, JP C=1-+ , is investigated, and upper limits for the branching fractions χc 1→π1(1400 )±π∓ , χc 1→π1(1600 )±π∓ , and χc 1→π1(2015 )±π∓ , with subsequent π1(X )±→η π± decay, are determined.

  19. Atomic resolution model of the antibody Fc interaction with the complement C1q component.

    PubMed

    Schneider, Sebastian; Zacharias, Martin

    2012-05-01

    The globular C1q heterotrimer is a subunit of the C1 complement factor. Binding of the C1q subunit to the constant (Fc) part of antibody molecules is a first step and key event of complement activation. Although three-dimensional structures of C1q and antibody Fc subunits have been determined experimentally no atomic resolution structure of the C1q-Fc complex is known so far. Based on systematic protein-protein docking searches and Molecular Dynamics simulations a structural model of the C1q-IgG1-Fc-binding geometry has been obtained. The structural model is compatible with available experimental data on the interaction between the two partner proteins. It predicts a binding geometry that involves mainly the B-subunit of the C1q-trimer and both subunits of the IgG1-Fc-dimer with small conformational adjustments with respect to the unbound partners to achieve high surface complementarity. In addition to several charge-charge and polar contacts in the rim region of the interface it also involves nonpolar contacts between the two proteins and is compatible with the carbohydrate moiety of the Fc subunit. The model for the complex structure provides a working model for rationalizing available biochemical data on this important interaction and can form the basis for the design of Fc variants with a greater capacity to activate the complement system for example on binding to cancer cells or other target structures.

  20. Interactions between copper deficiency, selenium deficiency and adriamycin toxicity

    SciTech Connect

    Fischer, J.; Tackett, R.; Johnson, M.A. )

    1991-03-15

    The objective of this study was to test the hypothesis that there are interactions between copper (Cu) and selenium (Se) status, and adriamycin (ADR) toxicity. Male Sprague Dawley rats were fed Cu,Se adequate; Cu deficient, Se adequate ({minus}Cu); Cu adequate, Se deficient; or Cu,Se deficient diets for 38-41 days. ADR or saline (SAL) were administered weekly for the last 4 weeks of the study. Cu deficiency was confirmed by a 3-fold decrease in liver Cu,Zn-superoxide dismutase and liver Cu, and a 5-fold decrease in RBC Cu,Zn-SOD. Se deficiency was confirmed by a 10-fold decrease in liver glutathione peroxidase (GSH-Px). ADR, Cu deficiency and Se deficiency all caused EKG abnormalities. However, Cu and Se deficiencies did not enhance ADR's influence on EKGs. ADR increased lipid peroxidation in liver by 15% and in heart by 18% (NS). Cu deficiency decreased ADR-induced lipid peroxidation in heart tissue by 25%. ADR influenced Se status by significantly increasing heart GSH-Px, and Cu status by increasing liver Cu, plasma ceruloplasmin and liver Cu, Zn-SOD. These elevations in Cu,Zn-SOD and GSH-Px may be a consequence of the increased lipid peroxidation initiated by ADR. In {minus}Cu rats, ADR caused severe hemolytic anemia characterized by a 19% decrease in hematocrit and a 17-fold increase in splenic Fe. These data suggest that there are numerous interactions between ADR toxicity and Cu and Se status.

  1. ATM protein is deficient in over 40% of lung adenocarcinomas.

    PubMed

    Villaruz, Liza C; Jones, Helen; Dacic, Sanja; Abberbock, Shira; Kurland, Brenda F; Stabile, Laura P; Siegfried, Jill M; Conrads, Thomas P; Smith, Neil R; O'Connor, Mark J; Pierce, Andrew J; Bakkenist, Christopher J

    2016-09-06

    Lung cancer is the leading cause of cancer-related mortality in the USA and worldwide, and of the estimated 1.2 million new cases of lung cancer diagnosed every year, over 30% are lung adenocarcinomas. The backbone of 1st-line systemic therapy in the metastatic setting, in the absence of an actionable oncogenic driver, is platinum-based chemotherapy. ATM and ATR are DNA damage signaling kinases activated at DNA double-strand breaks (DSBs) and stalled and collapsed replication forks, respectively. ATM protein is lost in a number of cancer cell lines and ATR kinase inhibitors synergize with cisplatin to resolve xenograft models of ATM-deficient lung cancer. We therefore sought to determine the frequency of ATM loss in a tissue microarray (TMA) of lung adenocarcinoma. Here we report the validation of a commercial antibody (ab32420) for the identification of ATM by immunohistochemistry and estimate that 61 of 147 (41%, 95% CI 34%-50%) cases of lung adenocarcinoma are negative for ATM protein expression. As a positive control for ATM staining, nuclear ATM protein was identified in stroma and immune infiltrate in all evaluable cases. ATM loss in lung adenocarcinoma was not associated with overall survival. However, our preclinical findings in ATM-deficient cell lines suggest that ATM could be a predictive biomarker for synergy of an ATR kinase inhibitor with standard-of-care cisplatin. This could improve clinical outcome in 100,000's of patients with ATM-deficient lung adenocarcinoma every year.

  2. Dimension spectrum of asymptotically additive potentials for C1 average conformal repellers

    NASA Astrophysics Data System (ADS)

    Cao, Yongluo

    2013-09-01

    In this paper, the dimension spectrum of asymptotically additive potentials for C1 average conformal repellers is considered. First, we give dimension estimates of arbitrary subsets for C1 average conformal repellers and we also consider the pointwise dimension of invariant measures. Furthermore, we consider the dimension spectrum of asymptotically additive potentials and its properties. As applications, we give an affirmative answer to the problem posed by Olsen (2003 J. Math. Pures Appl. 82 1591-649) for general types of level sets and obtain the dimension spectrum of weak Gibbs measures for continuous potentials on C1 average conformal repellers.

  3. Kidney Disease in Adenine Phosphoribosyltransferase Deficiency

    PubMed Central

    Runolfsdottir, Hrafnhildur Linnet; Palsson, Runolfur; Sch. Agustsdottir, Inger M.; Indridason, Olafur S.; Edvardsson, Vidar O.

    2015-01-01

    Background Adenine phosphoribosyltransferase (APRT) deficiency is a purine metabolism disorder causing kidney stones and chronic kidney disease (CKD). The course of nephrolithiasis and CKD has not been well characterized. The objective of this study was to examine long-term kidney outcomes in patients with APRT deficiency. Study Design An observational cohort study. Setting & Participants All patients enrolled in the APRT Deficiency Registry of the Rare Kidney Stone Consortium. Outcomes Kidney stones, acute kidney injury (AKI), stage of CKD and kidney failure, estimated glomerular filtration rate (eGFR) and changes in eGFR. Measurements Serum creatinine and eGFR calculated using creatinine-based equations. Results Of 53 patients, 30 (57%) were female and median age at diagnosis was 37.0 (range, 0.6–67.9) years. The median duration of follow-up was 10.3 (range, 0.0–31.5) years. At diagnosis, kidney stones had developed in 29 patients (55%) and 20 (38%) had CKD stages 3–5, including 11 patients (21%) with stage 5. At latest follow-up, 33 patients (62%) had had kidney stones; 18 (34%), AKI; and 22 (42%), CKD stage 3–5. Of the 14 (26%) patients with CKD stage 5, 12 had initiated renal replacement therapy. Kidney stones recurred in 18 of 33 patients (55%). The median eGFR slope was −0.38 (range, −21.99 to 1.42) mL/min/1.73 m2 per year in patients receiving treatment with xanthine dehydrogenase inhibitor and −5.74 (range, −75.8 to −0.10) mL/min/1.73 m2 per year in those not treated prior to the development of stage 5 CKD (p=0.001). Limitations Use of observational registry data. Conclusions Progressive CKD and AKI episodes are major features of APRT deficiency, while nephrolithiasis is the most common presentation. Advanced CKD without history of kidney stones is more prevalent than previously reported. Our data suggest that timely therapy may retard CKD progression. PMID:26724837

  4. Genetics Home Reference: protein C deficiency

    MedlinePlus

    ... Management Genetic Testing (1 link) Genetic Testing Registry: Thrombophilia, hereditary, due to protein C deficiency, autosomal dominant ... my area? Other Names for This Condition hereditary thrombophilia due to protein C deficiency PROC deficiency Related ...

  5. Genetics Home Reference: glucose phosphate isomerase deficiency

    MedlinePlus

    ... Understand Genetics Home Health Conditions GPI deficiency glucose phosphate isomerase deficiency Enable Javascript to view the expand/ ... Download PDF Open All Close All Description Glucose phosphate isomerase (GPI) deficiency is an inherited disorder that ...

  6. Genetics Home Reference: dopamine transporter deficiency syndrome

    MedlinePlus

    ... Genetics Home Health Conditions dopamine transporter deficiency syndrome dopamine transporter deficiency syndrome Enable Javascript to view the ... boxes. Download PDF Open All Close All Description Dopamine transporter deficiency syndrome is a rare movement disorder. ...

  7. Facts about Vitamin K Deficiency Bleeding

    MedlinePlus

    ... Button Information For... Media Policy Makers Facts about Vitamin K Deficiency Bleeding Recommend on Facebook Tweet Share Compartir Vitamins ... serious bleeding problems if not supplemented. What is Vitamin K Deficiency Bleeding or VKDB? Vitamin K deficiency bleeding or ...

  8. What Causes Alpha-1 Antitrypsin Deficiency?

    MedlinePlus

    ... Causes Alpha-1 Antitrypsin Deficiency? Alpha-1 antitrypsin (AAT) deficiency is an inherited disease. "Inherited" means it's ... parents to children through genes. Children who have AAT deficiency inherit two faulty AAT genes, one from ...

  9. How Is Alpha-1 Antitrypsin Deficiency Treated?

    MedlinePlus

    ... Alpha-1 Antitrypsin Deficiency Treated? Alpha-1 antitrypsin (AAT) deficiency has no cure, but its related lung ... pulmonary disease). If you have symptoms related to AAT deficiency, your doctor may recommend: Medicines called inhaled ...

  10. Primary Immune Deficiency Disease Genetics & Inheritance

    MedlinePlus

    ... twitter share with linkedin Primary Immune Deficiency Disease Genetics & Inheritance Primary Immune Deficiency Diseases (PIDDs) Primary Immune Deficiency Diseases (PIDDs) Types of PIDDs Genetics & Inheritance Talking to Your Doctor Featured Research Credit: ...

  11. Genetics Home Reference: lysosomal acid lipase deficiency

    MedlinePlus

    ... Home Health Conditions lysosomal acid lipase deficiency lysosomal acid lipase deficiency Enable Javascript to view the expand/ ... Download PDF Open All Close All Description Lysosomal acid lipase deficiency is an inherited condition characterized by ...

  12. Improvement in Lipid and Protein Trafficking in Niemann-Pick C1 Cells by Correction of a Secondary Enzyme Defect

    PubMed Central

    Devlin, Cecilia; Pipalia, Nina H.; Liao, Xianghai; Schuchman, Edward H.; Maxfield, Frederick R.; Tabas, Ira

    2010-01-01

    Different primary lysosomal trafficking defects lead to common alterations in lipid trafficking, suggesting cooperative interactions among lysosomal lipids. However, cellular analysis of the functional consequences of this phenomenon is lacking. As a test case, we studied cells with defective Niemann-Pick C1 (NPC1) protein, a cholesterol trafficking protein whose defect gives rise to lysosomal accumulation of cholesterol and other lipids, leading to NPC disease. NPC1 cells also develop a secondary defect in acid sphingomyelinase (SMase) activity despite a normal acid SMase gene (SMPD1). When acid SMase activity was restored to normal levels in NPC1-deficient CHO cells through SMPD1 transfection, there was a dramatic reduction in lysosomal cholesterol. Two other defects, excess lysosomal bis-(monoacylglycerol) phosphate (BMP) and defective transferrin receptor (TfR) recycling, were also markedly improved. To test its relevance in human cells, the acid SMase activity defect in fibroblasts from NPC1 patients was corrected by SMPD1 transfection or acid SMase enzyme replacement. Both treatments resulted in a dramatic reduction in lysosomal cholesterol. These data show that correcting one aspect of a complex lysosomal lipid storage disease can reduce the cellular consequences even if the primary genetic defect is not corrected. PMID:20412078

  13. CRYSTALLINE SOYBEAN TRYPSIN INHIBITOR

    PubMed Central

    Kunitz, M.

    1947-01-01

    A study has been made of the general properties of crystalline soybean trypsin inhibitor. The soy inhibitor is a stable protein of the globulin type of a molecular weight of about 24,000. Its isoelectric point is at pH 4.5. It inhibits the proteolytic action approximately of an equal weight of crystalline trypsin by combining with trypsin to form a stable compound. Chymotrypsin is only slightly inhibited by soy inhibitor. The reaction between chymotrypsin and the soy inhibitor consists in the formation of a reversibly dissociable compound. The inhibitor has no effect on pepsin. The inhibiting action of the soybean inhibitor is associated with the native state of the protein molecule. Denaturation of the soy protein by heat or acid or alkali brings about a proportional decrease in its inhibiting action on trypsin. Reversal of denaturation results in a proportional gain in the inhibiting activity. Crystalline soy protein when denatured is readily digestible by pepsin, and less readily by chymotrypsin and by trypsin. Methods are given for measuring trypsin and inhibitor activity and also protein concentration with the aid of spectrophotometric density measurements at 280 mµ. PMID:19873496

  14. Iron deficiency and thrombocytosis.

    PubMed

    Holbro, A; Volken, T; Buser, A; Sigle, J P; Halter, J P; Passweg, J R; Tichelli, A; Infanti, L

    2017-01-01

    According to many textbooks, iron deficiency (ID) is associated with reactive thrombocytosis. In this study, we aimed to investigate the correlation between serum ferritin levels and platelet counts in a large cohort of healthy blood donors. We included all whole blood and apheresis donors aged 18 years or older with at least one ferritin measurement and one platelet count performed at the same visit between 1996 and 2014. A total of 130 345 blood counts and ferritin measurements obtained from 22 046 healthy donors were analysed. Overall, no correlation between serum ferritin and platelet count was observed (r = -0.03, ρ = 0.04 for males, and r = 0.01, ρ = -0.02 for females, respectively). Associations remained clinically negligible after adjusting for age, time since previous blood donation, number of donations and restricting the analysis to ferritin deciles. In this large, retrospective single-centre study, correlations between low ferritin and platelet count in a large and homogeneous cohort of healthy donors were negligible. Further studies in patients with more severe anaemia and patients with inflammation are warranted.

  15. Betaine Deficiency in Maize 1

    PubMed Central

    Lerma, Claudia; Rich, Patrick J.; Ju, Grace C.; Yang, Wen-Ju; Hanson, Andrew D.; Rhodes, David

    1991-01-01

    Maize (Zea mays L.) is a betaine-accumulating species, but certain maize genotypes lack betaine almost completely; a single recessive gene has been implicated as the cause of this deficiency (D Rhodes, PJ Rich [1988] Plant Physiol 88: 102-108). This study was undertaken to determine whether betaine deficiency in diverse maize germplasm is conditioned by the same genetic locus, and to define the biochemical lesion(s) involved. Complementation tests indicated that all 13 deficient genotypes tested shared a common locus. One maize population (P77) was found to be segregating for betaine deficiency, and true breeding individuals were used to produce related lines with and without betaine. Leaf tissue of both betaine-positive and betaine-deficient lines readily converted supplied betaine aldehyde to betaine, but only the betaine-containing line was able to oxidize supplied choline to betaine. This locates the lesion in betaine-deficient plants at the choline → betaine aldehyde step of betaine synthesis. Consistent with this location, betaine-deficient plants were shown to have no detectable endogenous pool of betaine aldehyde. PMID:16668098

  16. Iron Deficiency Anemia in Pregnancy.

    PubMed

    Breymann, Christian

    2015-10-01

    Anemia is a common problem in obstetrics and perinatal care. Any hemoglobin below 10.5 g/dL can be regarded as true anemia regardless of gestational age. Reasons for anemia in pregnancy are mainly nutritional deficiencies, parasitic and bacterial diseases, and inborn red blood cell disorders such as thalassemias. The main cause of anemia in obstetrics is iron deficiency, which has a worldwide prevalence between estimated 20%-80% and consists of a primarily female population. Stages of iron deficiency are depletion of iron stores, iron-deficient erythropoiesis without anemia, and iron deficiency anemia, the most pronounced form of iron deficiency. Pregnancy anemia can be aggravated by various conditions such as uterine or placental bleedings, gastrointestinal bleedings, and peripartum blood loss. In addition to the general consequences of anemia, there are specific risks during pregnancy for the mother and the fetus such as intrauterine growth retardation, prematurity, feto-placental miss ratio, and higher risk for peripartum blood transfusion. Besides the importance of prophylaxis of iron deficiency, the main therapy options for the treatment of pregnancy anemia are oral iron and intravenous iron preparations.

  17. Iatrogenic limbal stem cell deficiency.

    PubMed Central

    Holland, E J; Schwartz, G S

    1997-01-01

    PURPOSE: To describe a group of patients with limbal stem cell (SC) deficiency without prior diagnosis of a specific disease entity known to be causative of SC deficiency. METHODS: We performed a retrospective review of the records of all patients with ocular surface disease presenting to the University of Minnesota between 1987 and 1996. Patients were categorized according to etiology of limbal deficiency. Patients who did not have a specific diagnosis previously described as being causative for limbal deficiency were analyzed. Risk factors, clinical findings and sequelae were evaluated. RESULTS: Eight eyes of six patients with stem cell deficiency not secondary to a known diagnosis were described. All eyes had prior ocular surgery involving the corneoscleral limbus. Six eyes had been on chronic topical medications and all eyes had concurrent external disease such as pterygium, keratoconjunctivitis sicca, rosacea or herpes simplex virus keratitis. All eyes had superior quadrants affected corresponding to areas of prior limbal surgery. Sequelae of disease included corneal scarring and neo-vascularization, and five eyes had with visual acuity of 20/200 or worse. CONCLUSIONS: Because the epitheliopathy started peripherally and extended centrally in all patients, we feel it represents a stem cell deficiency. The fact that all patients were affected superiorly, at sites of a prior limbal surgical incision, points to surgical trauma to the SC as the likely major etiologic factor for the deficiency. The surgical trauma to the limbal SC probably made these cells more susceptible to damage from other external disease influences and toxicity from chronic topical medications. Because the stem cell deficiency is secondary to prior ocular surgery and chronic topical medications, we propose the term "iatrogenic limbal stem cell deficiency". Images FIGURE 1 FIGURE 2A FIGURE 2B FIGURE 3A FIGURE 3B PMID:9440165

  18. (+)-Rimocidin Synthetic Studies: Construction of the C(1-27) Aglycone Skeleton

    PubMed Central

    Smith, Amos B.; Foley, Megan A.; Dong, Shuzhi; Orbin, Alia

    2010-01-01

    Assembly of the C(1-27) macrocyclic skeleton of rimocidinolide, the aglycone of (+)-rimocidin (1), has been achieved in convergent fashion. Key features of the synthetic strategy entail application of multicomponent Type 1 Anion Relay Chemistry (ARC), in conjunction with the SN2/SN2' reaction manifolds of vinyl epoxides, both employing 2-susbtituted-1,3-dithianes to construct the C(1-19) carbon backbone. Yamaguchi union of a C(20-27) vinyl borate ester, possessing the all trans triene, with an advanced C(1-19) vinyl iodide followed by macrocyclization via Suzuki-Miyaura cross-coupling completed construction of the C(1-27) rimocidinolide skeleton. PMID:19621880

  19. Observation of the h(c)(1P) Using e+ e- collisions above the DD threshold.

    PubMed

    Pedlar, T K; Cronin-Hennessy, D; Hietala, J; Dobbs, S; Metreveli, Z; Seth, K K; Tomaradze, A; Xiao, T; Martin, L; Powell, A; Wilkinson, G; Mendez, H; Ge, J Y; Miller, D H; Shipsey, I P J; Xin, B; Adams, G S; Hu, D; Moziak, B; Napolitano, J; Ecklund, K M; Insler, J; Muramatsu, H; Park, C S; Pearson, L J; Thorndike, E H; Ricciardi, S; Thomas, C; Artuso, M; Blusk, S; Mountain, R; Skwarnicki, T; Stone, S; Zhang, L M; Bonvicini, G; Cinabro, D; Lincoln, A; Smith, M J; Zhou, P; Zhu, J; Naik, P; Rademacker, J; Asner, D M; Edwards, K W; Randrianarivony, K; Tatishvili, G; Briere, R A; Vogel, H; Onyisi, P U E; Rosner, J L; Alexander, J P; Cassel, D G; Das, S; Ehrlich, R; Gibbons, L; Gray, S W; Hartill, D L; Heltsley, B K; Kreinick, D L; Kuznetsov, V E; Patterson, J R; Peterson, D; Riley, D; Ryd, A; Sadoff, A J; Shi, X; Sun, W M; Yelton, J; Rubin, P; Lowrey, N; Mehrabyan, S; Selen, M; Wiss, J; Libby, J; Kornicer, M; Mitchell, R E; Shepherd, M R; Tarbert, C M; Besson, D

    2011-07-22

    Using 586  pb(-1) of e+ e- collision data at E(c.m.) = 4170  MeV, produced at the Cornell Electron Storage Ring collider and collected with the CLEO-c detector, we observe the process e+ e- → π+ π- h(c)(1P). We measure its cross section to be 15.6±2.3±1.9±3.0  pb, where the third error is due to the external uncertainty on the branching fraction of ψ(2S) → π0 h(c)(1P), which we use for normalization. We also find evidence for e+ e- → ηh(c)(1P) at 4170 MeV at the 3σ level and see hints of a rise in the e+ e- → π+ π- h(c)(1P) cross section at 4260 MeV.

  20. Retro-odontoid cystic mass treated by laminectomy and C1-C2 fixation.

    PubMed

    Lin, Dasheng; Ding, Zhenqi; Guo, Yanjie; Lian, Kejian

    2014-11-01

    Retro-odontoid cysts associated with chronic atlantoaxial subluxation are extremely rare. This article describes a case of retro-odontoid cystic mass associated with chronic atlantoaxial subluxation and its management with posterior C1 and partial C2 laminectomy and C1-C2 pedicle screw fixation without resection of the retro-odontoid cyst. A 64-year-old woman experienced a sudden onset of neck pain, hand and foot paresthesia. Atlantoaxial instability associated with a retro-odontoid cystic mass was found in the imaging. The patient underwent posterior C1 and partial C2 laminectomy and C1-C2 pedicle screws fixation without resection of the retro-odontoid cyst. During the 24 months followup period, the cyst disappeared completely and the patient remained symptom free and returned to independent daily living. These findings suggest that posterior laminectomy and fixation without resection of the retro-odontoid cyst is relatively simple and safe and the results are satisfactory.

  1. Development of the Advanced Technology Microwave Sounder (ATMS) for NPOESS C1

    NASA Astrophysics Data System (ADS)

    Brann, C.; Kunkee, D.

    2008-12-01

    The National Polar-orbiting Operational Environmental Satellite System's Advanced Technology Microwave Sounder (ATMS) is planned for flight on the first NPOESS mission (C1) in 2013. The C1 ATMS will be the second instrument of the ATMS series and will provide along with the companion Cross-track Infrared Sounder (CrIS), atmospheric temperature and moisture profiles for NPOESS. The first flight of the ATMS is scheduled in 2010 on the NPOESS Preparatory Project (NPP) satellite, which is an early instrument risk reduction component of the NPOESS mission. This poster will focus on the development of the ATMS for C1 including aspects of the sensor calibration, antenna beam and RF characteristics and scanning. New design aspects of the C1 ATMS, required primarily by parts obsolescence, will also be addressed in this poster.

  2. 26 CFR 1.1244(c)-1 - Section 1244 stock defined.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... under section 1244(c)(1)(C). Payments for the parking of automobiles ordinarily do not constitute rents... means the entire amount received as an annuity under an annuity, endowment, or life insurance...

  3. 26 CFR 1.412(c)(1)-1 - Determinations to be made under funding method-terms defined.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ...-terms defined. 1.412(c)(1)-1 Section 1.412(c)(1)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT... Plans, Etc. § 1.412(c)(1)-1 Determinations to be made under funding method—terms defined. (a) Actuarial... bargained plans, see § 1.412(c)(1)-2; for principles applicable to funding methods in general,...

  4. Organophosphates and monocyte esterase deficiency.

    PubMed Central

    McClean, E; Mackey, H; Markey, G M; Morris, T C

    1995-01-01

    AIMS--To examine the possibility that monocyte esterase deficiency (MED) could be caused by exposure to organophosphates. METHODS--Pseudocholinesterase, paraoxonase and arylesterase activities were measured in the serum and acetylcholinesterase activity was measured in the red cells of a group of monocyte esterase deficient subjects and compared with the enzyme activities of a control group of monocyte esterase positive subjects. RESULTS--No significant difference was found between the enzyme activities of the monocyte esterase deficient group and the control group for any of the esterases investigated. CONCLUSION--Current or recent exposure to organophosphorus is not the cause of MED. PMID:7560207

  5. Genetics Home Reference: hereditary antithrombin deficiency

    MedlinePlus

    ... Merck Manual Home Edition for Patients and Caregivers: Thrombophilia National Blood Clot Alliance: Antithrombin Deficiency Orphanet: Hereditary thrombophilia due to congenital antithrombin deficiency Patient Support and ...

  6. 17 CFR 240.15c1-8 - Sales at the market.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 17 Commodity and Securities Exchanges 3 2011-04-01 2011-04-01 false Sales at the market. 240.15c1... Securities Exchange Act of 1934 Rules Relating to Over-The-Counter Markets § 240.15c1-8 Sales at the market... securities exchange that such security is being offered to such customer “at the market” or at a...

  7. 17 CFR 240.15c1-8 - Sales at the market.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 17 Commodity and Securities Exchanges 3 2010-04-01 2010-04-01 false Sales at the market. 240.15c1... Securities Exchange Act of 1934 Rules Relating to Over-The-Counter Markets § 240.15c1-8 Sales at the market... securities exchange that such security is being offered to such customer “at the market” or at a...

  8. 26 CFR 1.1244(c)-1 - Section 1244 stock defined.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 11 2012-04-01 2012-04-01 false Section 1244 stock defined. 1.1244(c)-1 Section....1244(c)-1 Section 1244 stock defined. (a) In general. For purposes of §§ 1.1244(a)-1 to 1.1244(e)-1, inclusive: (1) The term pre-November 1978 stock means stock issued after June 30, 1958, and on or...

  9. Minimum variance and variance of outgoing quality limit MDS-1(c1, c2) plans

    NASA Astrophysics Data System (ADS)

    Raju, C.; Vidya, R.

    2016-06-01

    In this article, the outgoing quality (OQ) and total inspection (TI) of multiple deferred state sampling plans MDS-1(c1,c2) are studied. It is assumed that the inspection is rejection rectification. Procedures for designing MDS-1(c1,c2) sampling plans with minimum variance of OQ and TI are developed. A procedure for obtaining a plan for a designated upper limit for the variance of the OQ (VOQL) is outlined.

  10. Characterization of the membrane-targeting C1 domain in Pasteurella multocida toxin.

    PubMed

    Kamitani, Shigeki; Kitadokoro, Kengo; Miyazawa, Masayuki; Toshima, Hirono; Fukui, Aya; Abe, Hiroyuki; Miyake, Masami; Horiguchi, Yasuhiko

    2010-08-13

    Pasteurella multocida toxin (PMT) is a virulence factor responsible for the pathogenesis of some forms of pasteurellosis. The toxin activates G(q)- and G(12/13)-dependent pathways through the deamidation of a glutamine residue in the alpha-subunit of heterotrimeric GTPases. We recently reported the crystal structure of the C terminus (residues 575-1285) of PMT (C-PMT), which is composed of three domains (C1, C2, and C3), and that the C1 domain is involved in the localization of C-PMT to the plasma membrane, and the C3 domain possesses a cysteine protease-like catalytic triad. In this study, we analyzed the membrane-targeting function of the C1 domain in detail. The C1 domain consists of seven helices of which the first four (residues 590-670), showing structural similarity to the N terminus of Clostridium difficile toxin B, were found to be involved in the recruitment of C-PMT to the plasma membrane. C-PMT lacking these helices (C-PMT DeltaC1(4H)) neither localized to the plasma membrane nor stimulated the G(q/12/13)-dependent signaling pathways. When the membrane-targeting property was complemented by a peptide tag with an N-myristoylation motif, C-PMT DeltaC1(4H) recovered the PMT activity. Direct binding between the C1 domain and liposomes containing phospholipids was evidenced by surface plasmon resonance analyses. These results indicate that the C1 domain of C-PMT functions as a targeting signal for the plasma membrane.

  11. 17 CFR 240.15c1-8 - Sales at the market.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 17 Commodity and Securities Exchanges 4 2014-04-01 2014-04-01 false Sales at the market. 240.15c1... Securities Exchange Act of 1934 Rules Relating to Over-The-Counter Markets § 240.15c1-8 Sales at the market... securities exchange that such security is being offered to such customer “at the market” or at a...

  12. 17 CFR 240.15c1-8 - Sales at the market.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 17 Commodity and Securities Exchanges 3 2012-04-01 2012-04-01 false Sales at the market. 240.15c1... Securities Exchange Act of 1934 Rules Relating to Over-The-Counter Markets § 240.15c1-8 Sales at the market... securities exchange that such security is being offered to such customer “at the market” or at a...

  13. 17 CFR 240.15c1-8 - Sales at the market.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 17 Commodity and Securities Exchanges 3 2013-04-01 2013-04-01 false Sales at the market. 240.15c1... Securities Exchange Act of 1934 Rules Relating to Over-The-Counter Markets § 240.15c1-8 Sales at the market... securities exchange that such security is being offered to such customer “at the market” or at a...

  14. Two human homeobox genes, c1 and c8: structure analysis and expression in embryonic development

    SciTech Connect

    Simeone, A.; Mavilio, F.; Acampora, D.; Giampaolo, A.; Faiella, A.; Zappavigna, V.; D'Esposito, M.; Pannese, M.; Russo, G.; Boncinelli, E.; Peschle, C.

    1987-07-01

    Two human cDNA clones (HHO.c1.95 and HHO.c8.5111) containing a homeobox region have been characterized, and the respective genomic regions have been partially analyzed. Expression of the corresponding genes, termed c1 and c8, was evaluated in different organs and body parts during human embryonic/fetal development. HHO.c1.95 apparently encodes a 217-amino acid protein containing a class I homeodomain that shares 60 out of 61 amino acid residues with the Antennapedia homeodomain of Drosophila melanogaster. HHO.c8.5111 encodes a 153-amino acid protein containing a homeodomains identical to that of the frog AC1 gene. Clones HHO.c1 and HHO.c8 detect by blot-hybridization one and two specific polyadenylylated transcripts, respectively. These are differentially expressed in spinal cord, backbone rudiments, limb buds (or limbs), heart, and skin of human embryos and early fetuses in the 5- to 9-week postfertilization period, thus suggesting that the c1 and c8 genes play a key role in a variety of developmental processes. Together, the results of the embryonic/fetal expression of c1 and c8 and those of two previously analyzed genes (c10 and c13) indicate a coherent pattern of expression of these genes in early human ontogeny.

  15. The Cyclic Peptide Ecumicin Targeting ClpC1 Is Active against Mycobacterium tuberculosis In Vivo

    PubMed Central

    Gao, Wei; Kim, Jin-Yong; Anderson, Jeffrey R.; Akopian, Tatos; Hong, Seungpyo; Jin, Ying-Yu; Kandror, Olga; Kim, Jong-Woo; Lee, In-Ae; Lee, Sun-Young; McAlpine, James B.; Mulugeta, Surafel; Sunoqrot, Suhair; Wang, Yuehong; Yang, Seung-Hwan; Yoon, Tae-Mi; Goldberg, Alfred L.; Pauli, Guido F.; Cho, Sanghyun

    2014-01-01

    Drug-resistant tuberculosis (TB) has lent urgency to finding new drug leads with novel modes of action. A high-throughput screening campaign of >65,000 actinomycete extracts for inhibition of Mycobacterium tuberculosis viability identified ecumicin, a macrocyclic tridecapeptide that exerts potent, selective bactericidal activity against M. tuberculosis in vitro, including nonreplicating cells. Ecumicin retains activity against isolated multiple-drug-resistant (MDR) and extensively drug-resistant (XDR) strains of M. tuberculosis. The subcutaneous administration to mice of ecumicin in a micellar formulation at 20 mg/kg body weight resulted in plasma and lung exposures exceeding the MIC. Complete inhibition of M. tuberculosis growth in the lungs of mice was achieved following 12 doses at 20 or 32 mg/kg. Genome mining of lab-generated, spontaneous ecumicin-resistant M. tuberculosis strains identified the ClpC1 ATPase complex as the putative target, and this was confirmed by a drug affinity response test. ClpC1 functions in protein breakdown with the ClpP1P2 protease complex. Ecumicin markedly enhanced the ATPase activity of wild-type (WT) ClpC1 but prevented activation of proteolysis by ClpC1. Less stimulation was observed with ClpC1 from ecumicin-resistant mutants. Thus, ClpC1 is a valid drug target against M. tuberculosis, and ecumicin may serve as a lead compound for anti-TB drug development. PMID:25421483

  16. Complement Protein C1q Forms a Complex with Cytotoxic Prion Protein Oligomers

    PubMed Central

    Erlich, Paul; Dumestre-Pérard, Chantal; Ling, Wai Li; Lemaire-Vieille, Catherine; Schoehn, Guy; Arlaud, Gérard J.; Thielens, Nicole M.; Gagnon, Jean; Cesbron, Jean-Yves

    2010-01-01

    A growing number of studies have investigated the interaction between C1q and PrP, but the oligomeric form of PrP involved in this interaction remains to be determined. Aggregation of recombinant full-length murine PrP in the presence of 100 mm NaCl allowed us to isolate three different types of oligomers by size-exclusion chromatography. In contrast to PrP monomers and fibrils, these oligomers activate the classical complement pathway, the smallest species containing 8–15 PrP protomers being the most efficient. We used Thioflavine T fluorescence to monitor PrP aggregation and showed that, when added to the reaction, C1q has a cooperative effect on PrP aggregation and leads to the formation of C1q-PrP complexes. In these complexes, C1q interacts through its globular domains preferentially with the smallest oligomers, as shown by electron microscopy, and retains the ability to activate the classical complement pathway. Using two cell lines, we also provide evidence that C1q inhibits the cytotoxicity induced by the smallest PrP oligomers. The cooperative interaction between C1q and PrP could represent an early step in the disease, where it prevents elimination of the prion seed, leading to further aggregation. PMID:20410306

  17. Post-transplant development of C1q-positive HLA antibodies and kidney graft survival.

    PubMed

    Piazza, Antonina; Poggi, Elvira; Ozzella, Giuseppina; Adorno, Domenico

    2013-01-01

    The development of de novo human leukocyte antigen (HLA) donor specific antibodies (DSA), detected by both cytotoxic or solid phase assays, was considered the major risk factor for allograft failure in kidney transplantation. However, it was shown that not all patients with persistent production of DSA suffered loss of their grafts. Modified Luminex-Single Antigen assays, able to identify C1q-fixing antibodies, represent a new strategy in assessing the clinical relevance of detected DSA. This study demonstrated that C1q-fixing capability of de novo DSA is a clinically relevant marker of worse outcome and inferior graft survival in kidney transplantation. In fact, our findings evidenced a very low graft survival only in the patients who developed DSA able to fix C1q during post-transplant course, while patients producing C1q-negative DSA had good graft survival, which was comparable to that found in our previous study for DSA-negative patients. Moreover, anti-HLA class II antibodies had a higher incidence than anti-HLA class I, and the ability to fix C1q was significantly more frequent among anti-DQ DSA than anti-DR DSA. Monitoring of de novo C1q-DSA production represents a useful, non-invasive tool for risk stratification and prediction of graft outcome in kidney transplantation.

  18. [Niacin deficiency and cutaneous immunity].

    PubMed

    Ikenouchi-Sugita, Atsuko; Sugita, Kazunari

    2015-01-01

    Niacin, also known as vitamin B3, is required for the synthesis of coenzymes, nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). Niacin binds with G protein-coupled receptor (GPR) 109A on cutaneous Langerhans cells and causes vasodilation with flushing in head and neck area. Niacin deficiency due to excessive alcohol consumption, certain drugs or inadequate uptake in diet causes pellagra, a photosensitivity dermatitis. Recently several studies have revealed the mechanism of photosensitivity in niacin deficiency, which may pave a way for new therapeutic approaches. The expression level of prostaglandin E synthase (PTGES) is up-regulated in the skin of both pellagra patients and niacin deficient pellagra mouse models. In addition, pellagra is mediated through prostaglandin E₂-EP4 (PGE₂-EP4) signaling via reactive oxygen species (ROS) production in keratinocytes. In this article, we have reviewed the role of niacin in immunity and the mechanism of niacin deficiency-induced photosensitivity.

  19. Genetics Home Reference: transcobalamin deficiency

    MedlinePlus

    ... Version: Failure to Thrive Merck Manual Consumer Version: Vitamin Deficiency Anemia Merck Manual Professional Version: Vitamin B12 Orphanet: ... Neutropenia Washington University, St. Louis: Neuromuscular Disease Center: Vitamin B12 (Cobalamin) ... Patient Support and Advocacy Resources (3 links) American ...

  20. Genetics Home Reference: tetrahydrobiopterin deficiency

    MedlinePlus

    ... named? Additional Information & Resources MedlinePlus (3 links) Encyclopedia: Serum Phenylalanine Screening Health Topic: Newborn Screening Health Topic: Phenylketonuria Genetic and Rare Diseases Information Center (1 link) Tetrahydrobiopterin deficiency Educational Resources ( ...

  1. Multiple sulfatase deficiency: degradation of arylsulfatase A and B after endocytosis in fibroblasts.

    PubMed

    Steckel, F; Hasilik, A; von Figura, K

    1985-08-15

    Multiple sulfatase deficiency can be classified into group I with severe and group II with moderate deficiencies in sulfatases. In fibroblasts in both groups the stability of arylsulfatase A and of the 47000-Mr form of arylsulfatase B is decreased [F. Steckel, A. Hasilik & K. von Figura (1985) Eur. J. Biochem. 151, 141-145]. After endocytosis in control fibroblasts or those from multiple sulfatase deficiency, arylsulfatase A and B derived from the latter were subjected to enhanced degradation in both types of recipient cells. The degradation was closely linked in time to endocytosis. Whereas instability of arylsulfatase A derived from different cell lines from multiple sulfatase deficiency was comparable, a marked heterogeneity was observed for the instability of the 47000-Mr polypeptide of arylsulfatase B. Each of the cell lines from multiple sulfatase deficiency synthesized arylsulfatase A and B polypeptides with normal and with decreased stability. Treatment with benzyloxycarbonyl-Phe-Ala-CHN2, an inhibitor of cysteine proteinases, stabilized arylsulfatase A polypeptides and partially restored arylsulfatase A activity in group II fibroblasts. The inhibitor had no protective effect on the 47000-Mr polypeptide or the activity of arylsulfatase B. The bearing of these findings on the yet unknown primary defect in multiple sulfatase deficiency is discussed.

  2. The dipeptidyl peptidase inhibitor linagliptin and the angiotensin II receptor blocker telmisartan show renal benefit by different pathways in rats with 5/6 nephrectomy.

    PubMed

    Tsuprykov, Oleg; Ando, Ryotaro; Reichetzeder, Christoph; von Websky, Karoline; Antonenko, Viktoriia; Sharkovska, Yuliya; Chaykovska, Lyubov; Rahnenführer, Jan; Hasan, Ahmed A; Tammen, Harald; Alter, Markus; Klein, Thomas; Ueda, Seiji; Yamagishi, Sho-Ichi; Okuda, Seiya; Hocher, Berthold

    2016-05-01

    Dipeptidyl peptidase (DPP)-4 inhibitors delay chronic kidney disease (CKD) progression in experimental diabetic nephropathy in a glucose-independent manner. Here we compared the effects of the DPP-4 inhibitor linagliptin versus telmisartan in preventing CKD progression in non-diabetic rats with 5/6 nephrectomy. Animals were allocated to 1 of 4 groups: sham operated plus placebo; 5/6 nephrectomy plus placebo; 5/6 nephrectomy plus linagliptin; and 5/6 nephrectomy plus telmisartan. Interstitial fibrosis was significantly decreased by 48% with linagliptin but a non-significant 24% with telmisartan versus placebo. The urine albumin-to-creatinine ratio was significantly decreased by 66% with linagliptin and 92% with telmisartan versus placebo. Blood pressure was significantly lowered by telmisartan, but it was not affected by linagliptin. As shown by mass spectrometry, the number of altered peptide signals for linagliptin in plasma was 552 and 320 in the kidney. For telmisartan, there were 108 peptide changes in plasma and 363 in the kidney versus placebo. Linagliptin up-regulated peptides derived from collagen type I, apolipoprotein C1, and heterogeneous nuclear ribonucleoproteins A2/B1, a potential downstream target of atrial natriuretic peptide, whereas telmisartan up-regulated angiotensin II. A second study was conducted to confirm these findings in 5/6 nephrectomy wild-type and genetically deficient DPP-4 rats treated with linagliptin or placebo. Linagliptin therapy in wild-type rats was as effective as DPP-4 genetic deficiency in terms of albuminuria reduction. Thus, linagliptin showed comparable efficacy to telmisartan in preventing CKD progression in non-diabetic rats with 5/6 nephrectomy. However, the underlying pathways seem to be different.

  3. Gene Therapy for Alpha-1 Antitrypsin Deficiency Lung Disease.

    PubMed

    Chiuchiolo, Maria J; Crystal, Ronald G

    2016-08-01

    Alpha-1 antitrypsin (AAT) deficiency, characterized by low plasma levels of the serine protease inhibitor AAT, is associated with emphysema secondary to insufficient protection of the lung from neutrophil proteases. Although AAT augmentation therapy with purified AAT protein is efficacious, it requires weekly to monthly intravenous infusion of AAT purified from pooled human plasma, has the risk of viral contamination and allergic reactions, and is costly. As an alternative, gene therapy offers the advantage of single administration, eliminating the burden of protein infusion, and reduced risks and costs. The focus of this review is to describe the various strategies for AAT gene therapy for the pulmonary manifestations of AAT deficiency and the state of the art in bringing AAT gene therapy to the bedside.

  4. Dilated Cardiomyopathy Induced by Chronic Starvation and Selenium Deficiency

    PubMed Central

    2016-01-01

    Protein energy malnutrition (PEM) has been rarely documented as a cause of cardiovascular abnormalities, including dilated cardiomyopathy. Selenium is responsible for antioxidant defense mechanisms in cardiomyocytes, and its deficiency in the setting of PEM and disease related malnutrition (DRM) may lead to exacerbation of the dilated cardiomyopathy. We report a rare case of a fourteen-year-old boy who presented with symptoms of congestive heart failure due to DRM and PEM (secondary to chronic starvation) along with severe selenium deficiency. An initial echocardiogram showed severely depressed systolic function consistent with dilated cardiomyopathy. Aggressive nutritional support and replacement of selenium and congestive heart failure medications that included diuretics and ACE inhibitors with the addition of carvedilol led to normalization of the cardiac function within four weeks. He continues to have significant weight gain and is currently completely asymptomatic from a cardiovascular standpoint. PMID:27994905

  5. Numb-deficient satellite cells have regeneration and proliferation defects

    PubMed Central

    George, Rajani M.; Biressi, Stefano; Beres, Brian J.; Rogers, Erik; Mulia, Amanda K.; Allen, Ronald E.; Rawls, Alan; Rando, Thomas A.; Wilson-Rawls, Jeanne

    2013-01-01

    The adaptor protein Numb has been implicated in the switch between cell proliferation and differentiation made by satellite cells during muscle repair. Using two genetic approaches to ablate Numb, we determined that, in its absence, muscle regeneration in response to injury was impaired. Single myofiber cultures demonstrated a lack of satellite cell proliferation in the absence of Numb, and the proliferation defect was confirmed in satellite cell cultures. Quantitative RT-PCR from Numb-deficient satellite cells demonstrated highly up-regulated expression of p21 and Myostatin, both inhibitors of myoblast proliferation. Transfection with Myostatin-specific siRNA rescued the proliferation defect of Numb-deficient satellite cells. Furthermore, overexpression of Numb in satellite cells inhibited Myostatin expression. These data indicate a unique function for Numb during the initial activation and proliferation of satellite cells in response to muscle injury. PMID:24170859

  6. 1-Nitropyrene (1-NP) induces apoptosis and apparently a non-apoptotic programmed cell death (paraptosis) in Hepa1c1c7 cells

    SciTech Connect

    Asare, Nana Landvik, Nina E.; Lagadic-Gossmann, Dominique; Rissel, Mary; Tekpli, Xavier; Ask, Kjetil; Lag, Marit; Holme, Jorn A.

    2008-07-15

    Mechanistic studies of nitro-PAHs (polycyclic aromatic hydrocarbons) of interest might help elucidate which chemical characteristics are most important in eliciting toxic effects. 1-Nitropyrene (1-NP) is the predominant nitrated PAH emitted in diesel exhaust. 1-NP-exposed Hepa1c1c7 cells exhibited marked changes in cellular morphology, decreased proliferation and different forms of cell death. A dramatic increase in cytoplasmic vacuolization was observed already after 6 h of exposure and the cells started to round up at 12 h. The rate of cell proliferation was markedly reduced at 24 h and apoptotic as well as propidium iodide (PI)-positive cells appeared. Electron microscopic examination revealed that the vacuolization was partly due to mitochondria swelling. The caspase inhibitor Z-VAD-FMK inhibited only the apoptotic cell death and Nec-1 (an inhibitor of necroptosis) exhibited no inhibitory effects on either cell death or vacuolization. In contrast, cycloheximide markedly reduced both the number of apoptotic and PI-positive cells as well as the cytoplasmic vacuolization, suggesting that 1-NP induced paraptotic cell death. All the MAPKs; ERK1/2, p38 and JNK, appear to be involved in the death process since marked activation was observed upon 1-NP exposure, and their inhibitors partly reduced the induced cell death. The ERK1/2 inhibitor PD 98057 completely blocked the induced vacuolization, whereas the other MAPKs inhibitors only had minor effects on this process. These findings suggest that 1-NP may cause apoptosis and paraptosis. In contrast, the corresponding amine (1-aminopyrene) elicited only minor apoptotic and necrotic cell death, and cells with characteristics typical of paraptosis were absent.

  7. C1-c2 pedicle screw fixation for treatment of old odontoid fractures.

    PubMed

    Qi, Lei; Li, Mu; Zhang, Shuai; Si, Haipeng; Xue, Jingsong

    2015-02-01

    Nonunion and C1-C2 instability of odontoid fractures usually result from delayed diagnosis and inappropriate treatment. However, the available treatment options for odontoid fractures remain controversial. The authors evaluated the effectiveness of internal screw fixation via the C1 and C2 pedicle in cases of old odontoid fractures. This retrospective study included 21 patients with old odontoid fractures (13 men and 8 women; mean age, 46.5 years; range, 24-69 years). Internal screw fixation via the C1 and C2 pedicle was performed in all patients. Fracture reduction and C1-C2 fusion were assessed with imaging. The neck pain visual analog scale score and cervical spinal cord functional Japanese Orthopaedic Association score (for those who had cervical spinal cord injury) were used to evaluate the effectiveness of treatment. Postoperative complications were recorded. Postoperative imaging showed that the C1-C2 dislocation was satisfactorily repositioned in all patients. Bone fusion was observed 1 year after surgery in all patients. No loosening or breaking of internal fixation occurred. The preoperative neck pain visual analog scale score was 5.9±1.5 and improved significantly to 1.8±0.8 after surgery (P<.001). The Japanese Orthopaedic Association score in patients with cervical spinal injury (n=14) was 9.2±1.9 and also significantly improved to 13.8±1.9 at the last follow-up examination (P<.001), with an average improvement rate of 61.0%. No iatrogenic vertebral artery injury or severe spinal cord injury occurred. Screw fixation via the C1 and C2 pedicle was found to be an effective and safe surgical approach for the treatment of old odontoid fractures with C1-C2 dislocation or instability.

  8. ClC-1 chloride channels: state-of-the-art research and future challenges

    PubMed Central

    Imbrici, Paola; Altamura, Concetta; Pessia, Mauro; Mantegazza, Renato; Desaphy, Jean-François; Camerino, Diana Conte

    2015-01-01

    The voltage-dependent ClC-1 chloride channel belongs to the CLC channel/transporter family. It is a homodimer comprising two individual pores which can operate independently or simultaneously according to two gating modes, the fast and the slow gate of the channel. ClC-1 is preferentially expressed in the skeletal muscle fibers where the presence of an efficient Cl- homeostasis is crucial for the correct membrane repolarization and propagation of action potential. As a consequence, mutations in the CLCN1 gene cause dominant and recessive forms of myotonia congenita (MC), a rare skeletal muscle channelopathy caused by abnormal membrane excitation, and clinically characterized by muscle stiffness and various degrees of transitory weakness. Elucidation of the mechanistic link between the genetic defects and the disease pathogenesis is still incomplete and, at this time, there is no specific treatment for MC. Still controversial is the subcellular localization pattern of ClC-1 channels in skeletal muscle as well as its modulation by some intracellular factors. The expression of ClC-1 in other tissues such as in brain and heart and the possible assembly of ClC-1/ClC-2 heterodimers further expand the physiological properties of ClC-1 and its involvement in diseases. A recent de novo CLCN1 truncation mutation in a patient with generalized epilepsy indeed postulates an unexpected role of this channel in the control of neuronal network excitability. This review summarizes the most relevant and state-of-the-art research on ClC-1 chloride channels physiology and associated diseases. PMID:25964741

  9. The orexinergic neurons receive synaptic input from C1 cells in rats

    PubMed Central

    Bochorishvili, Genrieta; Nguyen, Thanh; Coates, Melissa B.; Viar, Kenneth E.; Stornetta, Ruth L.; Guyenet, Patrice G.

    2014-01-01

    The C1 cells, located in the rostral ventrolateral medulla (RVLM), are activated by pain, hypoxia, hypoglycemia, infection and hypotension and elicit cardiorespiratory stimulation, adrenaline and ACTH release, and arousal. The orexin neurons contribute to the autonomic responses to acute psychological stress. Here, using an anatomical approach, we consider whether the orexin neurons could also be contributing to the autonomic effects elicited by C1 neuron activation. Phenylethanolamine N-methyl transferase-immunoreactive (PNMT-ir) axons were detected amongst orexin-ir somata and close appositions between PNMT-ir axonal varicosities and orexin-ir profiles were observed. The existence of synapses between PNMT-ir boutons labeled with diaminobenzidine and orexinergic neurons labeled with immunogold was confirmed by electron microscopy. We labeled RVLM neurons with a lentiviral vector that expresses the fusion protein ChR2-mCherry under the control of the catecholaminergic neuron-selective promoter PRSx8 and obtained light and ultrastructural evidence that these neurons innervate the orexin cells. Using a Cre-dependent adeno-associated vector and TH-Cre rats we confirmed that the projection from RVLM catecholaminergic neurons to the orexinergic neurons originates predominantly from PNMT-ir catecholaminergic (i.e. C1 cells). The C1 neurons were found to establish predominantly asymmetric synapses with orexin-ir cell bodies or dendrites. These synapses were packed with small clear vesicles and also contained dense core vesicles. In summary, the orexin neurons are among the hypothalamic neurons contacted and presumably excited by the C1 cells. The C1-orexin neuronal connection is probably one of several suprabulbar pathways through which the C1 neurons activate breathing and the circulation, raise blood glucose and facilitate arousal from sleep. PMID:24984694

  10. Alanine mutagenesis of the primary antigenic escape residue cluster, c1, of apical membrane antigen 1.

    PubMed

    Dutta, Sheetij; Dlugosz, Lisa S; Clayton, Joshua W; Pool, Christopher D; Haynes, J David; Gasser, Robert A; Batchelor, Adrian H

    2010-02-01

    Antibodies against apical membrane antigen 1 (AMA1) inhibit invasion of Plasmodium merozoites into red cells, and a large number of single nucleotide polymorphisms on AMA1 allow the parasite to escape inhibitory antibodies. The availability of a crystal structure makes it possible to test protein engineering strategies to develop a monovalent broadly reactive vaccine. Previously, we showed that a linear stretch of polymorphic residues (amino acids 187 to 207), localized within the C1 cluster on domain 1, conferred the highest level of escape from inhibitory antibodies, and these were termed antigenic escape residues (AER). Here we test the hypothesis that immunodampening the C1 AER will divert the immune system toward more conserved regions. We substituted seven C1 AER of the FVO strain Plasmodium falciparum AMA1 with alanine residues (ALA). The resulting ALA protein was less immunogenic than the native protein in rabbits. Anti-ALA antibodies contained a higher proportion of cross-reactive domain 2 and domain 3 antibodies and had higher avidity than anti-FVO. No overall enhancement of cross-reactive inhibitory activity was observed when anti-FVO and anti-ALA sera were compared for their ability to inhibit invasion. Alanine mutations at the C1 AER had shifted the immune response toward cross-strain-reactive epitopes that were noninhibitory, refuting the hypothesis but confirming the importance of the C1 cluster as an inhibitory epitope. We further demonstrate that naturally occurring polymorphisms that fall within the C1 cluster can predict escape from cross-strain invasion inhibition, reinforcing the importance of the C1 cluster genotype for antigenic categorization and allelic shift analyses in future phase 2b trials.

  11. ClC-1 chloride channels: state-of-the-art research and future challenges.

    PubMed

    Imbrici, Paola; Altamura, Concetta; Pessia, Mauro; Mantegazza, Renato; Desaphy, Jean-François; Camerino, Diana Conte

    2015-01-01

    The voltage-dependent ClC-1 chloride channel belongs to the CLC channel/transporter family. It is a homodimer comprising two individual pores which can operate independently or simultaneously according to two gating modes, the fast and the slow gate of the channel. ClC-1 is preferentially expressed in the skeletal muscle fibers where the presence of an efficient Cl(-) homeostasis is crucial for the correct membrane repolarization and propagation of action potential. As a consequence, mutations in the CLCN1 gene cause dominant and recessive forms of myotonia congenita (MC), a rare skeletal muscle channelopathy caused by abnormal membrane excitation, and clinically characterized by muscle stiffness and various degrees of transitory weakness. Elucidation of the mechanistic link between the genetic defects and the disease pathogenesis is still incomplete and, at this time, there is no specific treatment for MC. Still controversial is the subcellular localization pattern of ClC-1 channels in skeletal muscle as well as its modulation by some intracellular factors. The expression of ClC-1 in other tissues such as in brain and heart and the possible assembly of ClC-1/ClC-2 heterodimers further expand the physiological properties of ClC-1 and its involvement in diseases. A recent de novo CLCN1 truncation mutation in a patient with generalized epilepsy indeed postulates an unexpected role of this channel in the control of neuronal network excitability. This review summarizes the most relevant and state-of-the-art research on ClC-1 chloride channels physiology and associated diseases.

  12. Rare deficiency types of alpha 1-antitrypsin: electrophoretic variation and DNA haplotypes.

    PubMed Central

    Cox, D W; Billingsley, G D

    1989-01-01

    A deficiency of the plasma protease inhibitor alpha 1-antitrypsin (alpha 1AT), is usually associated with the deficiency allele PI*Z. However, other alleles can also produce a deficiency. Some of these rare deficiency alleles produce a low concentration (3%-15% of normal) of alpha 1AT and include Mmalton, Mduarte, Mheerlen, and Mprocida. Null, or nonproducing, alleles are associated with trace amounts (less than 1%) of plasma alpha 1AT. We have identified, using isoelectric focusing, the deficiency alleles in 222 patients (68 children and 154 adults) with alpha 1AT deficiency. In addition to PI*Z, we found low-producing alleles PI*Mmalton and PI*Mcobalt and four null (PI*QO) alleles. On the basis of a population frequency of .0122 for PI*Z, frequencies for other deficiency alleles are 1.1 x 10(-4) for PI*Mmalton, 2.5 x 10(-5) for PI*Mcobalt (which may be the same as that for PI*Mduarte, and 1.4 x 10(-4) for all null alleles combined. Using 12 polymorphic restriction sites with seven different restriction enzymes, we have obtained DNA haplotypes for each of the rare deficiency types. All of the rare deficiency alleles can be distinguished from PI*Z by their DNA haplotype, and most can be distinguished from each other. DNA haplotypes are useful to indicate the presence of new types of null alleles, to identify genetic compounds for rare deficiency alleles, and to identify the original normal allele from which each deficiency allele is derived. Images Figure 1 Figure 2 Figure 3 Figure 4 PMID:2786333

  13. Cortistatin vaccination--a solution to growth hormone deficiency.

    PubMed

    Moaeen-ud-Din, M; Malik, Nosheen; Guo, Yang Li; Ali, Ahmad; Babar, Masroor Ellahi

    2009-12-01

    Cortistatin and somatostatin are neuropeptides which have inhibitory effects on growth hormone through common five receptors. Although, both have inhibitory effects but, only cortistatin has direct inhibitory effects on growth hormone secretagogue and is more potent inhibitor of growth hormone than somatostatin. This control of growth hormone can be manipulated through immunoneutralization of cortistatin through cortistatin DNA vaccine rather than antibodies application. A DNA vaccine of cortistatin can be produced using recombinant DNA technology in a eukaryotic expression system and will serve as a tool not to only alleviate the growth hormone deficiency problems in human but, can also be used to improve growth rate in farm animals.

  14. Protein C deficiency: summary of the 1995 database update.

    PubMed Central

    Reitsma, P H

    1996-01-01

    The coagulation cascade is controlled by several anticoagulant safeguards that avoid excessive clot formation. Disorders of these anticoagulant mechanisms are an important health problem, as they lead to increased risk of thromboembolism. Protein C deficiency is probably the most extensively studied abnormality in natural anticoagulants. Under the auspices of the Subcommittee on Plasma Coagulation Inhibitors of the Scientific and Standardization Committee of the International Society of Thrombosis and Haemostasis a working party of researchers maintains a database of mutations that have been characterized in the protein C gene. The 1995 update of this database comprises 331 entries that describe 160 unique mutational events. Here essential features of the database are reviewed. PMID:8594568

  15. The Skeletal Phenotype of Chondroadherin Deficient Mice

    PubMed Central

    Wenglén, Christina; Petzold, Christiane; Tanner, Elizabeth K.; Brorson, Sverre-Henning; Baekkevold, Espen S.; Önnerfjord, Patrik; Reinholt, Finn P.; Heinegård, Dick

    2013-01-01

    Chondroadherin, a leucine rich repeat extracellular matrix protein with functions in cell to matrix interactions, binds cells via their α2β1 integrin as well as via cell surface proteoglycans, providing for different sets of signals to the cell. Additionally, the protein acts as an anchor to the matrix by binding tightly to collagens type I and II as well as type VI. We generated mice with inactivated chondroadherin gene to provide integrated studies of the role of the protein. The null mice presented distinct phenotypes with affected cartilage as well as bone. At 3–6 weeks of age the epiphyseal growth plate was widened most pronounced in the proliferative zone. The proteome of the femoral head articular cartilage at 4 months of age showed some distinct differences, with increased deposition of cartilage intermediate layer protein 1 and fibronectin in the chondroadherin deficient mice, more pronounced in the female. Other proteins show decreased levels in the deficient mice, particularly pronounced for matrilin-1, thrombospondin-1 and notably the members of the α1-antitrypsin family of proteinase inhibitors as well as for a member of the bone morphogenetic protein growth factor family. Thus, cartilage homeostasis is distinctly altered. The bone phenotype was expressed in several ways. The number of bone sialoprotein mRNA expressing cells in the proximal tibial metaphysic was decreased and the osteoid surface was increased possibly indicating a change in mineral metabolism. Micro-CT revealed lower cortical thickness and increased structure model index, i.e. the amount of plates and rods composing the bone trabeculas. The structural changes were paralleled by loss of function, where the null mice showed lower femoral neck failure load and tibial strength during mechanical testing at 4 months of age. The skeletal phenotype points at a role for chondroadherin in both bone and cartilage homeostasis, however, without leading to altered longitudinal growth. PMID

  16. [Clinical cases of acquired coagulation inhibitors].

    PubMed

    Yamane, T; Hino, M; Ota, K; Akahori, M; Hirai, M; Inoue, T; Mugitani, A; Tatsumi, N

    2000-12-01

    The acquired coagulation factor inhibitors are classified into alloantibodies, which appear in association with supplementary treatment for congenital coagulation factor deficiency, and autoantibodies, which are spontaneously produced. We report here 2 cases of acquired factor VIII inhibitor and 1 case of factor V inhibitor. Case 1: A 52-year-old woman noted swelling of the right parotid region in March 1988. Though contrast examination was scheduled, she was admitted for detailed examination due to a markedly prolonged coagulation time. An APTT correction test suggested that decreased factor VIII activity was due to the presence of an inhibitor. Since antinuclear antibody and SS-A antibody were positive and infiltration by lymphocytes in the salivary gland acini in a lip biopsy specimen was detected, Sjögren's syndrome was diagnosed. Case 2: A 33-year-old woman had normal delivery of her second child in February 1998. In June 1998, she suffered slight contusion in the left lower limb. The affected site became swollen and painful, making walking difficult. Since both upper limbs became markedly swollen after 1 week, she visited our hospital. Prolonged APTT and a marked decrease in factor VIII activity were observed. Factor VIII inhibitor titer was high at 19 Bethesda units. Case 3: A 64-year-old man had had asymptomatic macroscopic hematuria since the beginning of August 1998 but was placed under observation since no abnormal findings were observed on various imaging tests. However, he was admitted to Osaka City General Medical Center because of vesicular tamponade. Factor V activity was markedly decreased to 1.0%. PT correction test suggested that decreased factor V activity was due to the presence of an inhibitor. The underlying disease could not be determined in this case. In patients with acquired coagulation inhibitors, bleeding symptoms are reported to be mild in many cases, and severe bleeding is rare. However, cases of death without severe bleeding or

  17. Identification of factor inhibitors by diagnostic haemostasis laboratories: a large multi-centre evaluation.

    PubMed

    Favaloro, Emmanuel J; Bonar, Roslyn; Duncan, Elizabeth; Earl, Gail; Low, Joyce; Aboud, Margaret; Just, Sarah; Sioufi, John; Street, Alison; Marsden, Katherine

    2006-07-01

    We have assessed the proficiency of diagnostic haemostasis facilities to correctly identify coagulation factor abnormalities and inhibitors. Forty-two laboratories participating in the external Quality Assurance Program (QAP) conducted by the RCPA agreed to participate and were each sent a set of eight samples (each 3 x 1 ml) for evaluation. They were asked to blind test these samples for the presence or absence of inhibitors, and where identified, to perform further analysis (including specific inhibitor analysis). In order to make the exercise more challenging, in addition to true factor inhibitors, samples were provided that reflected potential pre-analytical variables that might arise and complicate inhibitor detection or lead to false inhibitor identification. In brief, the sample set comprised a true high level factor (F) V inhibitor, a true moderate level FVIII inhibitor (but sample was defibrinogenated), a true lupus anticoagulant (LA), a normal (but slightly aged) plasma sample, a normal serum sample, a normal EDTA sample, an oral anticoagulant/vitamin K deficiency sample, and a gross heparin ( approximately 10 U/ml) contaminated sample. Sixty-three percent of participants correctly identified the true FV inhibitor as such, although the reported range varied greatly [10 to >250 Bethesda units (BU/ml)] and 46% correctly identified the true FVIII inhibitor, despite the complication of the sample presentation, although the reported range also varied (7 to 64 BU/ml). Some laboratories either failed to identify the inhibitor present, or misidentified the inhibitor type. The LA, the oral anticoagulant/vitamin K deficiency, the normal serum sample, and the normal (aged) sample were also correctly identified by most laboratories, as was the absence of specific factor inhibitors in these samples. However, a small subset of laboratories incorrectly identified the presence of specific factor inhibitors in some of these samples. The heparin sample was also correctly

  18. C1q complement component and -antibodies reflect SLE activity and kidney involvement.

    PubMed

    Horák, P; Hermanová, Z; Zadrazil, J; Ciferská, H; Ordeltová, M; Kusá, L; Zurek, M; Tichý, T

    2006-07-01

    The role of the complement system in the pathogenesis of systemic diseases is very ambivalent. In systemic lupus erythematosus (SLE), many abnormalities in the activation of the complement system have been reported. The most important antibodies formed against the complement system in SLE are the ones associated with the C1q component. The aim of this study was to assess separately the anti-C1q antibodies and C1q component in the serum from 65 patients with SLE, then in individuals with (n=33) and without (n=32) lupus nephritis and with active (n=36) and nonactive (n=29) form of the disease (European Consensus Lupus Activity Measurement, ECLAM>3, ECLAMC1q antibodies were measured by the Enzyme-Linked Immunosorbent Assay (ELISA) test, while radial immunodiffusion according to Mancini was used to measure the C1q complement component. The mean serum levels were 90.89+/-13 IU/ml for anti-C1q antibodies and 145+/-52 mg/l for C1q. The significant difference in C1q antibodies levels was found between individuals with and without lupus nephritis (117.5+/-52 IU/ml vs. 28.2+/-12.2 IU/ml, p=0.0001) and between those with active and nonactive SLE (154.6+/-115 IU/ml vs. 50.6+/-73, p=0.001). C1q complement component was statistically lower in patients with lupus nephritis (144+/-30 mg/l vs. 175+/-50 mg/ml, p=0.002) and in active patients (138+/-40 mg/l vs. 202+/-20 mg/l, p=0.001). If the two parameters are measured together, they seem to have a mirror-like pattern of serum concentration, and they are potential markers of SLE activity and of the presence of lupus nephritis.

  19. Variation in complement protein C1q is not a major contributor to cognitive impairment in Parkinson’s disease

    PubMed Central

    Carbutt, Sophia; Duff, Jennifer; Yarnall, Alison; Burn, David J.; Hudson, Gavin

    2015-01-01

    Traditional dogma regarding the brain as an immune exempt organ has changed in recent years. New research has highlighted the role of the classical complement cascade in both synaptic elimination and function, driven largely by the role of the pathway initiating protein C1q. Given the links between C1q and cognitive function we assessed the genetic variability of the C1q encoding genes: C1QA, C1QB and C1QC between PD patients and matched controls. Despite a strong link between C1Q/cognitive decline and PD/cognitive decline we were unable to find a link between common C1Q variation and PD. We conclude that common C1Q-A/B/C genetic variation is unlikely to contribute to cognitive decline or the missing heritability in PD. PMID:25817358

  20. Simulation of XPS C1s spectra of organic monolayers by quantum chemical methods.

    PubMed

    Giesbers, Marcel; Marcelis, Antonius T M; Zuilhof, Han

    2013-04-16

    Several simple methods are presented and evaluated to simulate the X-ray photoelectron spectra (XPS) of organic monolayers and polymeric layers by density functional theory (DFT) and second-order Møller-Plesset theory (MP2) in combination with a series of basis sets. The simulated carbon (C1s) XPS spectra as obtained via B3LYP/6-311G(d,p) or M11/6-311G(d,p) calculations are in good agreement (average mean error <0.3 eV) with the experimental spectra, and good estimates of C1s spectra can be obtained via E(C1s)(exp) = 0.9698EC1s(theory) + 20.34 (in eV) (B3LYP/6-311G(d,p)). As a result, the simulated C1s XPS spectra can elucidate the binding energies of the different carbon species within an organic layer and, in this way, greatly aid the assignment of complicated C1s XPS spectra. The paper gives a wide range of examples, including haloalkanes, esters, (thio-)ethers, leaving groups, clickable functionalities, and bioactive moieties.

  1. The semaphorin 7A receptor Plexin C1 is lost during melanoma metastasis.

    PubMed

    Lazova, Rossitza; Gould Rothberg, Bonnie E; Rimm, David; Scott, Glynis

    2009-04-01

    The transformation of normal melanocytes, or melanocyte stem cells, to melanoma, is a complex process involving multiple mechanisms. Loss of tumor suppressor proteins, which function as brakes on cell growth, migration, or cell survival, was recognized early on as an important mechanism for initiation and progression of melanoma. Semaphorins and their cognate receptors, Plexins and neuropilins, are involved in neuronal pathfinding, immune function, and tumor progression through effects on blood vessel growth and cell migration. Semaphorin 7A (Sema7A) is a membrane-linked semaphorin that is expressed by human keratinocytes, and we have shown that Sema7A binds to human melanocytes through beta1-integrins and the Plexin C1 receptor. Functional studies showed that Sema7A stimulates cytoskeletal reorganization in human melanocytes, resulting in adhesion and dendrite formation. Downstream targets of Plexin C1 signaling in human melanocytes include cofilin and LIM kinase II, both of which are critical mediators of cell adhesion and migration. In this report, we analyzed the expression of Plexin C1 using immunohistochemistry on sections of primary and matched metastatic lesions from 19 subjects and in a large melanoma tumor microarray. Our data show a significant loss of Plexin C1 in metastatic melanoma compared with primary melanoma, suggesting the possibility that the Plexin C1 receptor is a tumor suppressor protein for melanoma.

  2. Protein phosphatase AP2C1 negatively regulates basal resistance and defense responses to Pseudomonas syringae.

    PubMed

    Shubchynskyy, Volodymyr; Boniecka, Justyna; Schweighofer, Alois; Simulis, Justinas; Kvederaviciute, Kotryna; Stumpe, Michael; Mauch, Felix; Balazadeh, Salma; Mueller-Roeber, Bernd; Boutrot, Freddy; Zipfel, Cyril; Meskiene, Irute

    2017-01-06

    Mitogen-activated protein kinases (MAPKs) mediate plant immune responses to pathogenic bacteria. However, less is known about the cell autonomous negative regulatory mechanism controlling basal plant immunity. We report the biological role of Arabidopsis thaliana MAPK phosphatase AP2C1 as a negative regulator of plant basal resistance and defense responses to Pseudomonas syringae AP2C2, a closely related MAPK phosphatase, also negatively controls plant resistance. Loss of AP2C1 leads to enhanced pathogen-induced MAPK activities, increased callose deposition in response to pathogen-associated molecular patterns or to P. syringae pv. tomato (Pto) DC3000, and enhanced resistance to bacterial infection with Pto. We also reveal the impact of AP2C1 on the global transcriptional reprogramming of transcription factors during Pto infection. Importantly, ap2c1 plants show salicylic acid-independent transcriptional reprogramming of several defense genes and enhanced ethylene production in response to Pto This study pinpoints the specificity of MAPK regulation by the different MAPK phosphatases AP2C1 and MKP1, which control the same MAPK substrates, nevertheless leading to different downstream events. We suggest that precise and specific control of defined MAPKs by MAPK phosphatases during plant challenge with pathogenic bacteria can strongly influence plant resistance.

  3. The C1 area of rostral ventrolateral medulla: a central site integrating autonomic responses to hemorrhage.

    PubMed

    Reis, D J; Ruggiero, D A; Morrison, S F

    1989-12-01

    Activation of the sympathetic neurons and release of adrenomedullary catecholamines are the principal early reflex responses to hemorrhage. These are initiated by arterial baro- and chemoreceptors, from other cardiopulmonary receptors, and by intracerebral receptors responding to ischemia. A principal gateway for integrating the autonomic responses are a small collection of neurons in a region of the rostral ventrolateral medulla (RVL), containing a cluster of neurons of the C1 adrenergic cell group, the C1 area. Neurons in the C1 area of RVL project exclusively to autonomic nuclei of the spinal cord, are tonically active, and fire with a rhythm linked to the cardiac cycle. They are essential for maintaining resting discharge of sympathetic nerves and, consequently, arterial pressure (AP) and heart rate. They also are critical for reflex changes in AP in the baro- and chemoreceptor, somato-sympathetic (pain), and cerebral ischemic reflexes. Neurons of the C1 area are under tonic excitatory and inhibitory control by pathways from other autonomic centers. They are controlled by a range of neurotransmitters including, gamma aminobutyric acid (GABA), acetylcholine, catecholamines, enkephalin, and several neuropeptides. They also serve as a site of action for the hypotensive actions of several clinically important neurotransmitters. The C1-area of RVL may play a critical role in the autonomic responses to hemorrhage and may be an important target for drugs seeking to treat hemorrhagic shock.

  4. Evidence of Real-Space Transfer in Buried-Channel GexC1-x Devices

    NASA Astrophysics Data System (ADS)

    Liu, En-Shao; Kelly, David; Donnelly, Joseph; Tutuc, Emanuel; Banerjee, Sanjay

    2008-03-01

    We present experimental evidence of real-space transfer (RST) in buried-channel GexC1-x p-type metal-oxide-semiconductor field effect transistors (MOSFET) containing a Si cap layer. The output characteristics of these devices reveal a negative differential resistance (NDR) below 150K, at the onset of the saturation regime. This observation indicates a charge transfer from GexC1-x layer into the Si cap at sufficiently large drain bias values. The lower hole mobility of the Si cap with respect to the GexC1-x, translates into a drain current reduction, hence the observed NDR. Our low-field, temperature-dependent mobility measurements indeed reveal a higher effective carrier mobility in the buried-channel GexC1-x layer with respect to a Si-reference sample, which suggests that the observed NDR is caused by RST of holes from the GexC1-x into the Si layer.

  5. Opportunistic Screening of Vitamin B12 Deficiency in IT Professionals Presenting for Routine Health Check-up

    PubMed Central

    Patel, Rishi Devilal; Ingole, Sonali Jitendra; Pandave, Harshal Tukaram

    2015-01-01

    Introduction Vitamin B12 deficiency is mainly diagnosed in symptomatic patients. However, the deficiency may also be prevalent in asymptomatic patients. Our aim was to study the prevalence of Vit B12 deficiency in IT professionals (Information Technology Professionals from Software industry) who presented for routine health screening and to correlate the deficiency to various parameters. Materials and Methods This was single centre, observational study comprising of 84 IT professionals. The data was collected in structured format. The study was designed to identify prevalence of Vit B12 deficiency and correlate to other factors such as type of diet, income level & regular use of medication (such as Antacid & Metformin). Results Total 28 individuals were found to be deficient (33.34%). Prevalence of Vit B12 deficiency amongst Vegetarian and non vegetarian diet adhering subjects was 47.5% and 20.45% respectively. B12 deficiency was also prevalent in high income age group. Further chronic intake of PPI (Proton pump inhibitor) and Metformin was associated with prevalence of 37.5% and 33.34% in the present study. Conclusion During health screening of IT Professionals, significant prevalence of Vit B12 deficiency was noted across all income groups & non vegetarian diet consuming subjects also. There is significant correlation between Vit B12 deficiency with chronic use of PPI and Metformin. PMID:26816929

  6. Congenital combined deficiency of coagulation factors VII and II in a young adult.

    PubMed

    Dasanu, Constantin A; Natale, Frances O; DeSilva, Hema N

    2010-01-01

    We present herein a case of a young female with congenital combined coagulation factor VII (FVII) and factor II (FII) deficiencies. She was completely asymptomatic and found to have a prolonged prothrombin time during a routine preoperative evaluation. Low levels of plasma FVII and FII in the absence of an inhibitor confirmed the diagnosis in our patient. Congenital combined FVII and FIX deficiency as well as combined FVII and FX deficiency have been previously reported. The congenital combined deficiency of FVII and FII in our patient is exceptional and represents the first such instance in the English literature. Furthermore, we hypothesize that she had not shown any bleeding manifestations because of possible compensation for the missing factors II and VII by enhanced activity of some intrinsic coagulation pathway components or depression of fibrinolysis.

  7. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency

    PubMed Central

    Le, D.T.; Uram, J.N.; Wang, H.; Bartlett, B.R.; Kemberling, H.; Eyring, A.D.; Skora, A.D.; Luber, B.S.; Azad, N.S.; Laheru, D.; Biedrzycki, B.; Donehower, R.C.; Zaheer, A.; Fisher, G.A.; Crocenzi, T.S.; Lee, J.J.; Duffy, S.M.; Goldberg, R.M.; de la Chapelle, A.; Koshiji, M.; Bhaijee, F.; Huebner, T.; Hruban, R.H.; Wood, L.D.; Cuka, N.; Pardoll, D.M.; Papadopoulos, N.; Kinzler, K.W.; Zhou, S.; Cornish, T.C.; Taube, J.M.; Anders, R.A.; Eshleman, J.R.; Vogelstein, B.; Diaz, L.A.

    2015-01-01

    BACKGROUND Somatic mutations have the potential to encode “non-self” immunogenic antigens. We hypothesized that tumors with a large number of somatic mutations due to mismatch-repair defects may be susceptible to immune checkpoint blockade. METHODS We conducted a phase 2 study to evaluate the clinical activity of pembrolizumab, an anti–programmed death 1 immune checkpoint inhibitor, in 41 patients with progressive metastatic carcinoma with or without mismatch-repair deficiency. Pembrolizumab was administered intravenously at a dose of 10 mg per kilogram of body weight every 14 days in patients with mismatch repair–deficient colorectal cancers, patients with mismatch repair–proficient colorectal cancers, and patients with mismatch repair–deficient cancers that were not colorectal. The coprimary end points were the immune-related objective response rate and the 20-week immune-related progression-free survival rate. RESULTS The immune-related objective response rate and immune-related progression-free survival rate were 40% (4 of 10 patients) and 78% (7 of 9 patients), respectively, for mismatch repair–deficient colorectal cancers and 0% (0 of 18 patients) and 11% (2 of 18 patients) for mismatch repair–proficient colorectal cancers. The median progression-free survival and overall survival were not reached in the cohort with mismatch repair–deficient colorectal cancer but were 2.2 and 5.0 months, respectively, in the cohort with mismatch repair–proficient colorectal cancer (hazard ratio for disease progression or death, 0.10 [P<0.001], and hazard ratio for death, 0.22 [P = 0.05]). Patients with mismatch repair–deficient noncolorectal cancer had responses similar to those of patients with mismatch repair–deficient colorectal cancer (immune-related objective response rate, 71% [5 of 7 patients]; immune-related progression-free survival rate, 67% [4 of 6 patients]). Whole-exome sequencing revealed a mean of 1782 somatic mutations per tumor in

  8. Unnatural C-1 homologues of pancratistatin — Synthesis and promising biological activities

    PubMed Central

    Vshyvenko, Sergey; Scattolon, Jon; Hudlicky, Tomas; Romero, Anntherese E.; Kornienko, Alexander; Ma, Dennis; Tuffley, Ian; Pandey, Siyaram

    2016-01-01

    Several C-1 homologues of pancratistatin and 7-deoxypancratistatin were synthesized by a phenanthrene–phenathridone oxidative recyclization strategy. The key steps involved the enzymatic dihydroxylation of bromobenzene, addition of an aryl alane to an epoxyaziridine, an intramolecular aziridine opening on silica gel in solid phase, and the above-mentioned recylization strategy. Experimental and spectral data are reported for all new compounds. All synthesized C-1 homologues of pancratistatin and 7-deoxypancratistatin were evaluated for antiproliferative activity in a panel of human cancer cell lines. As expected, the 7-hydroxy compounds were found to be more potent and the activity of the C-1 benzoxymethyl analogue exceeded that of narciclasine, which was used as a positive control. PMID:28017970

  9. SGLT2 inhibitors.

    PubMed

    Dardi, I; Kouvatsos, T; Jabbour, S A

    2016-02-01

    Diabetes mellitus is a serious health issue and an economic burden, rising in epidemic proportions over the last few decades worldwide. Although several treatment options are available, only half of the global diabetic population achieves the recommended or individualized glycemic targets. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a new class of antidiabetic agents with a novel insulin-independent action. SGLT2 is a transporter found in the proximal renal tubules, responsible for the reabsorption of most of the glucose filtered by the kidney. Inhibition of SGLT2 lowers the blood glucose level by promoting the urinary excretion of excess glucose. Due to their insulin-independent action, SGLT2 inhibitors can be used with any degree of beta-cell dysfunction or insulin resistance, related to a very low risk of hypoglycemia. In addition to improving glycemic control, SGLT2 inhibitors have been associated with a reduction in weight and blood pressure when used as monotherapy or in combination with other antidiabetic agents in patients with type 2 diabetes mellitus (T2DM). Treatment with SGLT2 inhibitors is usually well tolerated; however, they have been associated with an increased incidence of urinary tract and genital infections, although these infections are usually mild and easy to treat. SGLT2 inhibitors are a promising new option in the armamentarium of drugs for patients with T2DM.

  10. Changes in thyroid status during perinatal development of MCT8-deficient male mice.

    PubMed

    Ferrara, Alfonso Massimiliano; Liao, Xiao-Hui; Gil-Ibáñez, Pilar; Marcinkowski, Teresa; Bernal, Juan; Weiss, Roy E; Dumitrescu, Alexandra M; Refetoff, Samuel

    2013-07-01

    Patients with the monocarboxylate transporter 8 (MCT8) deficiency syndrome present with a severe psychomotor retardation and abnormal serum thyroid hormone (TH) levels, consisting of high T(3) and low T(4) and rT(3). Mice deficient in Mct8 replicate the thyroid phenotype of patients with the MCT8 gene mutations. We analyzed the serum TH levels and action in the cerebral cortex and in the liver during the perinatal period of mice deficient in Mct8 to assess how the thyroid abnormalities of Mct8 deficiency develop and to study the thyroidal status of specific tissues. During perinatal life, the thyroid phenotype of Mct8-deficient mice is different from that of adult mice. They manifest hyperthyroxinemia at embryonic day 18 and postnatal day 0. This perinatal hyperthyroxinemia is accompanied by manifestations of TH excess as evidenced by a relative increase in the expression of genes positively regulated by T3 in both the cerebral cortex and liver. An increased tissue accumulation of T(4) and T(3) and the expression of TH alternative transporters, including Lat1, Lat2, Oatp1c1, and Oatp3a1 in the cortex and Lat2 and Oatp1b2 in the liver, suggested that Mct8 deficiency either directly interferes with tissue efflux of TH or indirectly activates other transporters to increase TH uptake. This report is the first to identify that the ontogenesis of TH abnormalities in Mct8-deficient mice manifests with TH excess in the perinatal period.

  11. Antithrombin III/SerpinC1 insufficiency exacerbates renal ischemia/reperfusion injury

    PubMed Central

    Wang, Feng; Zhang, Guangyuan; Lu, Zeyuan; Geurts, Aron M; Usa, Kristie; Jacob, Howard J; Cowley, Allen W; Wang, Niansong; Liang, Mingyu

    2015-01-01

    Antithrombin III, encoded by SerpinC1, is a major anti-coagulation molecule in vivo and has anti-inflammatory effects. We found that patients with low antithrombin III activities presented a higher risk of developing acute kidney injury after cardiac surgery. To study this further, we generated SerpinC1 heterozygous knockout rats and followed the development of acute kidney injury in a model of modest renal ischemia/reperfusion injury. Renal injury, assessed by serum creatinine and renal tubular injury scores after 24 h of reperfusion, was significantly exacerbated in SerpinC1+/− rats compared to wild-type littermates. Concomitantly, renal oxidative stress, tubular apoptosis, and macrophage infiltration following this injury were significantly aggravated in SerpinC1+/− rats. However, significant thrombosis was not found in the kidneys of any group of rats. Antithrombin III is reported to stimulate the production of prostaglandin I2, a known regulator of renal cortical blood flow, in addition to having anti-inflammatory effects and to protect against renal failure. Prostaglandin F1α, an assayable metabolite of prostaglandin I2, was increased in the kidneys of the wild-type rats at 3 h after reperfusion. The increase of prostaglandin F1α was significantly blunted in SerpinC1+/− rats, which preceded increased tubular injury and oxidative stress. Thus, our study found a novel role of SerpinC1 insufficiency in increasing the severity of renal ischemia/reperfusion injury. PMID:26108065

  12. Endovascular Treatment of a Vertebral Artery Pseudoaneurysm Following Posterior C1-C2 Transarticular Screw Fixation

    SciTech Connect

    Mendez, Jose C. Gonzalez-Llanos, Francisco

    2005-01-15

    We present a case of vertebral artery pseudoaneurysm after a posterior C1-C2 transarticular screw fixation procedure that was effectively treated with endovascular coil occlusion. Vertebral artery pseudoaneurysm complicating posterior C1-C2 transarticular fixation is extremely rare, with only one previous case having been reported previously. Endovascular occlusion is better achieved in the subacute phase of the pseudoaneurysm, when the wall of the pseudoaneurysm has matured and stabilized. Further follow-up angiographies are mandatory in order to confirm that there is no recurrence of the lesion.

  13. Solar gases in meteorites - The origin of chondrites and C1 carbonaceous chondrites

    NASA Technical Reports Server (NTRS)

    Heymann, D.

    1978-01-01

    Evidence suggesting that chondritic meteorites broke off from parent bodies in earth-crossing orbits is considered. It is suggested that ordinary chondrites have an asteroidal origin, and the possibility that C1 chondrites have a cometary origin is examined. Indications of heavy shock and reheating among L and H chondrites provides support for an asteroidal origin, while the Apollo and Amor objects are too small to be unfragmented asteroids, as proposed in the Anders theory of the origin of gas-rich meteorites. Events associated with the megaregolith are discussed in the framework of the proposed cometary origin of C1 chondrites.

  14. C1q binding to Dengue Virus inhibits infection of THP-1 and cellular inflammatory responses

    PubMed Central

    Douradinha, Bruno; McBurney, Sean P.; de Melo, Klecia M. Soares; Smith, Amanda P.; Krishna, Neel K.; Barratt-Boyes, Simon M.; Evans, Jared D.; Nascimento, Eduardo J. M.; Marques, Ernesto T. A

    2014-01-01

    Summary Dengue virus infection elicits a spectrum of clinical presentations ranging from asymptomatic to severe disease. The mechanisms leading to severe dengue are not known, however it has been reported that the complement system is hyper-activated in severe dengue. Screening of complement proteins demonstrated that C1q, a pattern recognition molecule, can bind directly to Dengue Virus Envelope protein and to whole Dengue Virus serotype 2. Incubation of Dengue Virus serotype 2 with C1q prior to infection of THP-1 cells led to decreased virus infectivity and modulation of mRNA expression of immunoregulatory molecules suggesting reduced inflammatory responses. PMID:24246304

  15. Iron Deficiency and Bariatric Surgery

    PubMed Central

    Jáuregui-Lobera, Ignacio

    2013-01-01

    It is estimated that the prevalence of anaemia in patients scheduled for bariatric surgery is higher than in the general population and the prevalence of iron deficiencies (with or without anaemia) may be higher as well. After surgery, iron deficiencies and anaemia may occur in a higher percentage of patients, mainly as a consequence of nutrient deficiencies. In addition, perioperative anaemia has been related with increased postoperative morbidity and mortality and poorer quality of life after bariatric surgery. The treatment of perioperative anaemia and nutrient deficiencies has been shown to improve patients’ outcomes and quality of life. All patients should undergo an appropriate nutritional evaluation, including selective micronutrient measurements (e.g., iron), before any bariatric surgical procedure. In comparison with purely restrictive procedures, more extensive perioperative nutritional evaluations are required for malabsorptive procedures due to their nutritional consequences. The aim of this study was to review the current knowledge of nutritional deficits in obese patients and those that commonly appear after bariatric surgery, specifically iron deficiencies and their consequences. As a result, some recommendations for screening and supplementation are presented. PMID:23676549

  16. Leaf Senescence by Magnesium Deficiency

    PubMed Central

    Tanoi, Keitaro; Kobayashi, Natsuko I.

    2015-01-01

    Magnesium ions (Mg2+) are the second most abundant cations in living plant cells, and they are involved in various functions, including photosynthesis, enzyme catalysis, and nucleic acid synthesis. Low availability of Mg2+ in an agricultural field leads to a decrease in yield, which follows the appearance of Mg-deficient symptoms such as chlorosis, necrotic spots on the leaves, and droop. During the last decade, a variety of physiological and molecular responses to Mg2+ deficiency that potentially link to leaf senescence have been recognized, allowing us to reconsider the mechanisms of Mg2+ deficiency. This review focuses on the current knowledge about the physiological responses to Mg2+ deficiency including a decline in transpiration, accumulation of sugars and starch in source leaves, change in redox states, increased oxidative stress, metabolite alterations, and a decline in photosynthetic activity. In addition, we refer to the molecular responses that are thought to be related to leaf senescence. With these current data, we give an overview of leaf senescence induced by Mg deficiency. PMID:27135350

  17. Cholinesterase inhibitors from botanicals

    PubMed Central

    Ahmed, Faiyaz; Ghalib, Raza Murad; Sasikala, P.; Ahmed, K. K. Mueen

    2013-01-01

    Alzheimer's disease (AD) is a progressive neurodegenerative disease, wherein a progressive loss of cholinergic synapses occurs in hippocampus and neocortex. Decreased concentration of the neurotransmitter, acetylcholine (ACh), appears to be critical element in the development of dementia, and the most appropriate therapeutic approach to treat AD and other form of dementia is to restore acetylcholine levels by inhibiting both major form of cholinesterase: Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Consequently, researches have focused their attention towards finding cholinesterase inhibitors from natural products. A large number of such inhibitors have been isolated from medicinal plants. This review presents a comprehensive account of the advances in field of cholinesterase inhibitor phytoconstituents. The structures of some important phytoconstituents (collected through www.Chemspider.com) are also presented and the scope for future research is discussed. PMID:24347920

  18. 20 CFR 664.205 - How is the “deficient in basic literacy skills” criterion in § 664.200(c)(1) defined and documented?

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ...) Computes or solves problems, reads, writes, or speaks English at or below the 8th grade level on a... to compute or solve problems, read, write, or speak English at a level necessary to function on...

  19. 20 CFR 664.205 - How is the “deficient in basic literacy skills” criterion in § 664.200(c)(1) defined and documented?

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... problems, reads, writes, or speaks English at or below the 8th grade level on a generally accepted... problems, read, write, or speak English at a level necessary to function on the job, in the...

  20. 20 CFR 664.205 - How is the “deficient in basic literacy skills” criterion in § 664.200(c)(1) defined and documented?

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ...) Computes or solves problems, reads, writes, or speaks English at or below the 8th grade level on a... to compute or solve problems, read, write, or speak English at a level necessary to function on...

  1. 20 CFR 664.205 - How is the “deficient in basic literacy skills” criterion in § 664.200(c)(1) defined and documented?

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... problems, reads, writes, or speaks English at or below the 8th grade level on a generally accepted... problems, read, write, or speak English at a level necessary to function on the job, in the...

  2. 20 CFR 664.205 - How is the “deficient in basic literacy skills” criterion in § 664.200(c)(1) defined and documented?

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ...) Computes or solves problems, reads, writes, or speaks English at or below the 8th grade level on a... to compute or solve problems, read, write, or speak English at a level necessary to function on...

  3. An amphioxus gC1q protein binds human IgG and initiates the classical pathway: Implications for a C1q-mediated complement system in the basal chordate.

    PubMed

    Gao, Zhan; Li, Mengyang; Ma, Jie; Zhang, Shicui

    2014-12-01

    The origin of the classical complement pathway remains open during chordate evolution. A C1q-like member, BjC1q, was identified in the basal chordate amphioxus. It is predominantly expressed in the hepatic caecum, hindgut, and notochord, and is significantly upregulated following challenge with bacteria or lipoteichoic acid and LPS. Recombinant BjC1q and its globular head domain specifically interact with lipoteichoic acid and LPS, but BjC1q displays little lectin activity. Moreover, rBjC1q can assemble to form the high molecular weight oligomers necessary for binding to proteases C1r/C1s and for complement activation, and binds human C1r/C1s/mannan-binding lectin-associated serine protease-2 as well as amphioxus serine proteases involved in the cleavage of C4/C2, and C3 activation. Importantly, rBjC1q binds with human IgG as well as an amphioxus Ig domain containing protein, resulting in the activation of the classical complement pathway. This is the first report showing that a C1q-like protein in invertebrates is able to initiate classical pathway, raising the possibility that amphioxus possesses a C1q-mediated complement system. It also suggests a new scenario for the emergence of the classical complement pathway, in contrast to the proposal that the lectin pathway evolved into the classical pathway.

  4. Glucose-6-Phosphate Dehydrogenase Deficiency.

    PubMed

    Luzzatto, Lucio; Nannelli, Caterina; Notaro, Rosario

    2016-04-01

    G6PD is a housekeeping gene expressed in all cells. Glucose-6-phosphate dehydrogenase (G6PD) is part of the pentose phosphate pathway, and its main physiologic role is to provide NADPH. G6PD deficiency, one of the commonest inherited enzyme abnormalities in humans, arises through one of many possible mutations, most of which reduce the stability of the enzyme and its level as red cells age. G6PD-deficient persons are mostly asymptomatic, but they can develop severe jaundice during the neonatal period and acute hemolytic anemia when they ingest fava beans or when they are exposed to certain infections or drugs. G6PD deficiency is a global health issue.

  5. Orthogonal polynomial Schauder bases in C[-1,1] with optimal growth of degrees

    SciTech Connect

    Skopina, M A

    2001-04-30

    For each {epsilon}>0 an orthogonal Schauder basis of algebraic polynomials P{sub n} in C[-1,1] is constructed such that the degrees of the polynomials have the estimate n(1+{epsilon}). This growth rate is the lowest possible.

  6. Compartment C1, engine room. View down compionway of top of ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    Compartment C-1, engine room. View down compionway of top of engine cylinder heads; note slots in frame at left of photograph, slots hold steel bars which form a protective grating above the engines during battle. (081) - USS Olympia, Penn's Landing, 211 South Columbus Boulevard, Philadelphia, Philadelphia County, PA

  7. 29 CFR Appendix B to Subpart C of... - Figures C-1 through C-16

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 29 Labor 9 2010-07-01 2010-07-01 false Figures C-1 through C-16 B Appendix B to Subpart C of Part 1928 Labor Regulations Relating to Labor (Continued) OCCUPATIONAL SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR (CONTINUED) OCCUPATIONAL SAFETY AND HEALTH STANDARDS FOR AGRICULTURE Roll-Over Protective Structures Pt. 1928, Subpt. C, App....

  8. C1 anterior arch preservation in transnasal odontoidectomy using three-dimensional endoscope: A case report

    PubMed Central

    Zenga, Francesco; Marengo, Nicola; Pacca, Paolo; Pecorari, Giancarlo; Ducati, Alessandro

    2015-01-01

    Background: The transoral ventral corridor is the most common approach used to reach the craniovertebral junction (CVJ). Over the last decade, many case reports have demonstrated the transnasal corridor to the odontoid peg represents a practicable route to remove the tip of the odontoid process. The biomechanical consequences of the traditional odontoidectomy led to the necessity of a cervical spine stabilization. Preserving the inferior portion of the C1 anterior arch should prevent instability. Case Description: This is the first report in which the technique to remove the tip of the odontoid while preserving the C1 anterior arch is described by means of a three-dimensional (3D) endoscope. A 53-year-old man underwent a transnasal 3D endoscopic approach because of a complex CVJ malformation. The upper-medial portion of the C1 anterior arch was removed preserving its continuity, and the odontoidectomy was performed. After surgery, a dynamic X-ray scan showed no difference in CVJ motility in comparison with the preoperative one. Conclusions: The stereoscopic perception augmented the precision of the surgical gesture in the deep field. The importance of a 3D view relates to the depth of field, which a two-dimensional endoscopy cannot provide. This affects the preservation of the C1 anterior arch because of the presence of critical structures that are exposed to potential damage if not displayed. PMID:26759737

  9. Cleanup Verification Package for the 118-C-1, 105-C Solid Waste Burial Ground

    SciTech Connect

    M. J. Appel and J. M. Capron

    2007-07-25

    This cleanup verification package documents completion of remedial action for the 118-C-1, 105-C Solid Waste Burial Ground. This waste site was the primary burial ground for general wastes from the operation of the 105-C Reactor and received process tubes, aluminum fuel spacers, control rods, reactor hardware, spent nuclear fuel and soft wastes.

  10. 40 CFR Appendix C-1 to Subpart E... - Required Provisions-Consulting Engineering Agreements

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... Engineering Agreements C Appendix C-1 to Subpart E of Part 35 Protection of Environment ENVIRONMENTAL... Provisions—Consulting Engineering Agreements 1. General 2. Responsibility of the Engineer 3. Scope of Work 4... drawings, designs, specifications, reports, and incidental engineering work or materials...

  11. 40 CFR Appendix C-1 to Subpart E... - Required Provisions-Consulting Engineering Agreements

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... Engineering Agreements C Appendix C-1 to Subpart E of Part 35 Protection of Environment ENVIRONMENTAL... Provisions—Consulting Engineering Agreements 1. General 2. Responsibility of the Engineer 3. Scope of Work 4... drawings, designs, specifications, reports, and incidental engineering work or materials...

  12. A South American Prehistoric Mitogenome: Context, Continuity, and the Origin of Haplogroup C1d

    PubMed Central

    Sans, Mónica; Figueiro, Gonzalo; Hughes, Cris E.; Lindo, John; Hidalgo, Pedro C.; Malhi, Ripan S.

    2015-01-01

    Based on mitochondrial DNA (mtDNA), it has been estimated that at least 15 founder haplogroups peopled the Americas. Subhaplogroup C1d3 was defined based on the mitogenome of a living individual from Uruguay that carried a lineage previously identified in hypervariable region I sequences from ancient and modern Uruguayan individuals. When complete mitogenomes were studied, additional substitutions were found in the coding region of the mitochondrial genome. Using a complete ancient mitogenome and three modern mitogenomes, we aim to clarify the ancestral state of subhaplogroup C1d3 and to better understand the peopling of the region of the Río de la Plata basin, as well as of the builders of the mounds from which the ancient individuals were recovered. The ancient mitogenome, belonging to a female dated to 1,610±46 years before present, was identical to the mitogenome of one of the modern individuals. All individuals share the mutations defining subhaplogroup C1d3. We estimated an age of 8,974 (5,748–12,261) years for the most rece