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Investigation of Roles of Cellular Prion Protein and Doppel Protein in Pathogenesis of Experimental Toxoplasma gondii Infection in Mice

Yıl 2013, Cilt: 2 Sayı: 1, 130 - 138, 01.01.2013

Öz

The aim of the present study was to investigate the roles of cellular prion protein PrPc and doppel Dpl protein in experimental infection caused by Toxoplasma gondii in mice. A total of 96 mice Balb/c , 40 of which were control and 56 was treatment group, were used for this purpose in the study. The mice in experiment group were divided into 8 groups, including 7 mice each, according to post inoculation time 6 and 12 hours, 1, 2, 3, 4, 5 and 6 days. These animals were injected with 1 ml inoculum of T. gondii RH strain including 500 tachyzoits/0.1 ml by intraperitoneal route. At the end those times, the mice were euthanased under deep anesthesia and systematically were necropsied. Macroscopically, first lesions were detected after 4 days post inoculation. Especially, multiple gray-whitish foci were detected on the liver and kidneys. In the lung section, the frothy fluid was leaked. At the 6th days post inoculation, three mice were found died; in this group other mice had a lightly cloudy exudate in peritoneal cavity as well as the lesions in the organs mentioned. Microscopically, many organs such as liver, kidneys, lungs and brains included mononuclear cells infiltrations with necrosis. The some brains revealed necrosis and focal gliosis. Immunohistochemical studies showed the presence of T. gondii antigen in many organs excepting with brain tissues. In the experiment groups, PrPc and Dpl expressions increased with postinoculation days, especially in spleen, kidneys, and lungs by immunohistochemistry. In conclusion, PrPc and Dpl showed an increase in the tissues in experimental T. gondii infection in mice, and this study indicated that both proteins would be important in such disease.

Kaynakça

  • Aguzzi A, Hardt W-D (2003). Dangerous liaisons between a microbe and the prion protein. Journal Experimental Medicine 198, 1-4.
  • Almeida CJG, Chiarini LB, da Silva JP, e Silva MR, Martins MA, Linden R (2004). The cellular prion protein modulates phagocytosis and inflammatory response. The Journal of Leukocyte Biology 77, 1-9.
  • Appleford PJ, Smith JE (2000). Strain and stage specific variation in Tox- oplasma gondii antigens. The International Journal for Parasitology 30, 1187-91.
  • Behrens A, Aguzzi A (2002). Small is not beautiful: antagonizing func- tions for the prion protein PrPc and its homologue Dpl. Trends in Neurosciences 25, 150-154.
  • Bogdan C, Röllinghoff M (1999). How do protozoan parasites survive inside macrophages? Parasitology Today, 15, 22-28.
  • Brown DR (2004). Role of the prion protein in copper turnover in astro- cytes. Neurobiology of Disease 15, 534-543.
  • Chiarini LB, Freitas AR, Zanata SM, Brentani RR, Martins VR, Linden R (2002). Cellular prion protein transduces neuroprotective signals. EMBO Journal 21, 3317-26.
  • Cui T, Holme A, Sassoon J, Brown DR (2003). Analyses of doppel protein toxicity. Cellular and Molecular Neurobiology 23, 144-155.
  • Deignan ME, Prior M, Stuart LE, Comerford EJ, McMahon HEM (2004). The structure function relatioship for the prion protein. The Journal of Alzheimer’s Disease 6, 283-289.
  • Dénes A, Humphreys N, Lane TE, Grencis R, Rothwell N (2010). Chronic systemic infection exacerbates ischaemic brain damage via a CCL5 (RANTES) mediated proinflammatory response in mice. Journal of Neuroscience 30, 10086–10095.
  • Denkers EY (1999). T lynphocyte-dependent effector mechanisma of immunity to toxoplasma gondii. Microbes and Infection 1, 699-708.
  • Derouin F, Garin YJ (1991) Toxoplasma gondii: blood and tissue kinet- ics during acute and chronic infections in mice. Exp Parasitol 73(4), 460-468.
  • Dubey JP, Beattie CP (1988). Toxoplasmosis of animals and man. CRC Pres, Inc., Florida.
  • Dubey JP, Shen SK, Kwok OC, Frenkel JK (1999). Infection and immunity with the RH strain of Toxoplasma gondii in rats and mice. Journal of Parasitology, 85, 657-662.
  • Eissa MH, Antonious SN, Salama MM, Fikry AA, Morsy TA (1990). Histo- pathological studies of acute, chronic and congenital infections of toxoplasmosis in mice. Journal of the Egyptian Society of Parasitol- ogy 20, 805-816.
  • Ford MJ, Burton LJ, Morris RJ, Hall MS (2002). Selective expression of prion protein in peripheral tissues of the adult mouse. Neurosci- ence 113, 177-192.
  • Harris DA (2003). Trafficking, turnover and membrane topology of PrP. British Medical Bulletin 66, 71-85.
  • Heussler VT, Küenzi P, Rottenberg S (2001). Inhibition of apoptosis by intracellular protozoan parasites. The International Journal of Para- sitology, 31, 1166-1176.
  • Kasper L, Courret N, Darche S, Luangsay S, Mennechet F, Minns L, Ra- chinel N, Ronet C, Buzoni-Gatel D (2004). Toxoplasma gondii and mucosal immunity. The International Journal for Parasitology 34, 401-409.
  • Kim B-H, Lee H-g, Choi J-K, Kim J-I, Choi E-K, Carp RI, Kim Y-S (2004). The cellular prion protein (PrPc) prevents apoptotic neuronal cell death and mitochondrial dysfuntion induced by serum deprivation. Molecular Brain Research 124, 40-50.
  • Klamt F, Dal-Pizzol F, Conte da Frota ML JR, Walz R, Andrades ME, da Silva EG, Brentani RR, Izquierdo I, Fonseca Moreira JC (2001). Imbal- ance of antioxidant defense in mice lacking cellular prion protein. Free Radical Biology and Medicine 30, 1137-1144.
  • Kubosaki A, Nishimura-Nasu Y, Nishimura T, Yusa S, Sakudo A, Saeki K, Matsumoto Y, Itohara S, Onodera T (2003). Expression of normal cellular prion protein (PrP(c)) on T lymphocytes and the effect of copper ion: Analysis by wild-type and prion protein gene-deficient mice. Biochemical and Biophysical Research Communications 307, 810-813.
  • Kubosaki A, Ueno A, Matsumoto Y, Doi K, Saeki K, Matsumoto Y, On- odera T (2000). Analysis of prion protein mRNA by in situ hybridi- zation in brain and placenta of sheep. Biochemical and Biophysical Research Communications 273, 890-893.
  • Kuwahara C, Takeuchi AM, Nishimura T, Haraguchi K, Kubosaki A, Mat- sumoto Y, Saeki K, Matsumoto Y, Yokoyama T, Itohara S, Onodera T (1999). Prions prevent neuronal cel-line death. Nature 400, 225- 226.
  • Lee YH, Kim KY, Kang MS, Shin DW (1995). Detection of Toxoplasma antigens and antibodies in mice infected with different strains of Toxoplasma gondii. Korean Journal of Parasitology 33, 201-210.
  • Lee YH, Channon JY, Matsuura T, Schwartzman JD, Shin DW, Kasper LH (1999). Functional and quantitative analysis of splenic T cell im- mune responses following oral Toxoplasma gondii infection in mice. Experimental Parasitology 91, 212-221.
  • Legname G, Nelken P, Guan Z, Kanyo ZF, DeArmond SJ, Prusiner SB (2002). Prion and doppel proteins bind to granule cells of the cere- bellum. Proceedings of the National Academy of Sciences USA, 99, 16285-16290.
  • Liang J, Kong Q (2012). α-Cleavage of cellular prion protein. Prion 6, 453-460.
  • Liu T, Zwingman T, Li R, Pan Tao, Wong B, Petersen RB, Gambetti P, Her- rup K, Sy M (2001). Differential expression of cellular prion protein in Mouse brain as detected with multiple anti-PrP monoclonal anti- bodies. Brain Research 896, 118-129.
  • Moore RC, Lee IY, Silverman GL, Harrison PM, Strome R, Heinrich C, Karunaratne A et al. (1999). Ataxia in prion protein (PrP-deficient mice is associated with upregulation of the novel PrP-like protein doppel. Journal of Molecular Biology 292, 797-817.
  • Özcel MA, İnci A, Turgay N, Köroğlu E (2007). Tıbbi ve Veteriner im- munoparazitoloji. Türkiye Parazitoloji Derneği Yayınları No:21, Meta Basım, İzmir.
  • Paltrinieri S, Comazzi S, Spagnolo V, Rondena M, Ponti W, Ceciliani F (2004). Bovine Doppel (Dpl) and Prion Protein (PrP) expression on lymphoid tissue and circulating leukocytes. Journal of Histochemis- try and Cytochemistry 52, 1639-1645.
  • Pimenta J, Dias FM, Marques CC, Baptista MC, Vasques MI, Horta AE, Barbas JP, Soares R, Mesquita P, Cabrita E, Fontes CM, Prates JA, Pereira RM (2012). The prion-like protein Doppel enhances ovine spermatozoa fertilizing ability. The Reproduction in Domestic Ani- mals 47, 196-202.
  • Riesner D (2003). Biochemistry and structure of PrPc and PrPsc. British Medical Bulletin 66, 21-33.
  • Rondena M, Ceciliani F, Comazzi S, Pocacqua V, Bazzocchi C, Luvoni C, Chigioni S, Paltrinieri S (2005). Identification of bovine doppel pro- tein in testis, ovary and ejeculated sprematozoa. Theriogenology 63, 1195-1206.
  • Sakaguchi S, Katamine S, Nishida N, Moriuchi R, Shigematsu K, Sugimo- to T, Nakatani A, Kataoka Y, Houtani T, Shirabe S, Okada H, Hasega- wa S, Miyamoto T, Noda T (1996). Loss of cerebellar Purkinje cells in aged mice homozygous for disrupted PrP gene. Nature 380, 528- 531.
  • Sinai AP, Payne TM, Carmen JC, Hardi L, Watson SJ, Molestina RE (2004). Mechanisms underlying the manipulation of host apoptotic pathways by Toxoplasma gondii. The International Journal for Par- asitology 34, 381-91
  • Sukthana Y, Waree P, Pongponratn E, Chaisri U, Riganti M (2003). Patho- logic study of acute toxoplasmosis in experimental animals. The Southeast Asian Journal of Tropical Medicine and Public Health 34, 16-21.
  • Suzuki Y, Yang Q, Remington JS (1995). Genetic resistance against acute toxoplasmosis depends on the strain of Toxoplasma gondii. Journal of Parasitology 81, 1032-1034.
  • Ringer TM, Axer H, Bernd F.M. Romeike BFM, Zinke J, Brunkhorst F, Witte OW, Günther A (2011). Neurological sequelae of sepsis: I) Septic encephalopathy. The Open Critical Care Medicine Journal 4, 2-7.
  • Tranulis MA, Espenes A, Comincini S, Skretting G, Harbitz I (2001). The PrP-like protein Doppel gene in sheep and cattle: cDNA sequence and expression. Mammalian Genome 12, 376-379.
  • Villard O, Candolfi E, Ferguson DJ, Marcellin L, Kien T (1997). Loss of oral infectivity of tissue cysts of Toxoplasma gondii RH strain to out- bred Swiss Webster mice. The International Journal for Parasitology 27, 1555-1559.
  • Waree P, Ferguson DJ, Pongponratn E, Chaisri U, Sukthana Y (2007). Immunohistochemical study of acute and chronic toxoplasmosis in experimentally infected mice The Southeast Asian Journal of Tropi- cal Medicine and Public Health 38, 223-231.
  • Watarai M, Makino S, Michikawa M, Yanagisawa K, Murakami S, Shira- hata T. (2002). Macrophage plasma membrane cholesterol contrib- utes to Brucella abortus infection of mice. Infection and Immunity 70, 4818-25.
  • Westeway D, Carlson GA. (2002). Mammalian prion proteins: enigma, variation and vaccination. Trends in Biochemical Sciences 27, 301- 307.
  • Zachary ve McGavin (2012). Pathologic Basis of Veterinary Disease, 5th Edition.

Farelerde Deneysel Toxoplasma gondii Enfeksiyonunun Patogenezisinde Hücresel Prion Protein ve Doppel Protein’in Rollerinin Araştırılması

Yıl 2013, Cilt: 2 Sayı: 1, 130 - 138, 01.01.2013

Öz

Bu çalışmada farelerde deneysel olarak oluşturulan Toxoplasma gondii enfeksiyonunda hücresel prion protein PrPc ve doppel proteinin Dpl rollerinin araştırılması amaçlanmıştır. Bu amaçla, 56 adet deneme ve 40 adet kontrol olmak üzere toplam 96 adet Balb/c fare kullanıldı. Çalışmada, her grupta 7 farenin bulunduğu 8 deneme grubu ile her deneme grubu için 5 farenin bulunduğu 8 kontrol grubu oluşturuldu. Deneme grubundaki hayvanlara T. gondii RH suşu takizoitleri 500 takizoit/0.1ml dozda, intraperitoneal yolla verildi. Farelerde enfeksiyondan sonraki 6. ve 12. saatlerde; daha sonra 1., 2., 3., 4., 5., 6. günlerde oluşan klinik bulgular kaydedilerek, sistematik nekropsileri yapıldı. Klinik olarak, ilk 3 günde her hangi bir bulgu gözlenmezken, 6. günde üç fare ölü bulundu. Makroskobik olarak, 4. günden itibaren karaciğer ve böbrek üzerinde boz beyaz renkte odaklar ile periton boşluğunda hafif bulanık bir eksudatın varlığı dikkati çekti. Mikroskobik olarak, böbrek, karaciğer, akciğer ve beyinde mononükleer hücre infiltrasyonu ile birlikte, ölenler başta olmak üzere, özellikle 5. ve 6. günlerde beyin ve karaciğerde fokal nekrotik değişiklikler ve mononüklear hücre infiltrasyonları saptandı. İmmunohistokimyasal olarak, T gondii antijeni beyin dışında böbrek, karaciğer, akciğer ve dalakta saptandı. Enfeksiyon dönemlerinde immunohistokimyasal incelemelerde PrPc, kontrollere göre merkezi sinir sistemi, dalak ve karaciğerde artan oranlarda saptanırken, Dpl artışı özellikle dalak, böbrek, karaciğerde daha belirgindi. Sonuç olarak, farelerde T. gondii enfeksiyonunda PrPc ve Dpl’nin dokularda ekspresyonlarının arttığı gözlendi ve böylece farelerde deneysel Toxoplasma gondii enfeksiyonunun patogenezisinde her iki proteinin de önemli olabileceği kanaatine varıldı.

Kaynakça

  • Aguzzi A, Hardt W-D (2003). Dangerous liaisons between a microbe and the prion protein. Journal Experimental Medicine 198, 1-4.
  • Almeida CJG, Chiarini LB, da Silva JP, e Silva MR, Martins MA, Linden R (2004). The cellular prion protein modulates phagocytosis and inflammatory response. The Journal of Leukocyte Biology 77, 1-9.
  • Appleford PJ, Smith JE (2000). Strain and stage specific variation in Tox- oplasma gondii antigens. The International Journal for Parasitology 30, 1187-91.
  • Behrens A, Aguzzi A (2002). Small is not beautiful: antagonizing func- tions for the prion protein PrPc and its homologue Dpl. Trends in Neurosciences 25, 150-154.
  • Bogdan C, Röllinghoff M (1999). How do protozoan parasites survive inside macrophages? Parasitology Today, 15, 22-28.
  • Brown DR (2004). Role of the prion protein in copper turnover in astro- cytes. Neurobiology of Disease 15, 534-543.
  • Chiarini LB, Freitas AR, Zanata SM, Brentani RR, Martins VR, Linden R (2002). Cellular prion protein transduces neuroprotective signals. EMBO Journal 21, 3317-26.
  • Cui T, Holme A, Sassoon J, Brown DR (2003). Analyses of doppel protein toxicity. Cellular and Molecular Neurobiology 23, 144-155.
  • Deignan ME, Prior M, Stuart LE, Comerford EJ, McMahon HEM (2004). The structure function relatioship for the prion protein. The Journal of Alzheimer’s Disease 6, 283-289.
  • Dénes A, Humphreys N, Lane TE, Grencis R, Rothwell N (2010). Chronic systemic infection exacerbates ischaemic brain damage via a CCL5 (RANTES) mediated proinflammatory response in mice. Journal of Neuroscience 30, 10086–10095.
  • Denkers EY (1999). T lynphocyte-dependent effector mechanisma of immunity to toxoplasma gondii. Microbes and Infection 1, 699-708.
  • Derouin F, Garin YJ (1991) Toxoplasma gondii: blood and tissue kinet- ics during acute and chronic infections in mice. Exp Parasitol 73(4), 460-468.
  • Dubey JP, Beattie CP (1988). Toxoplasmosis of animals and man. CRC Pres, Inc., Florida.
  • Dubey JP, Shen SK, Kwok OC, Frenkel JK (1999). Infection and immunity with the RH strain of Toxoplasma gondii in rats and mice. Journal of Parasitology, 85, 657-662.
  • Eissa MH, Antonious SN, Salama MM, Fikry AA, Morsy TA (1990). Histo- pathological studies of acute, chronic and congenital infections of toxoplasmosis in mice. Journal of the Egyptian Society of Parasitol- ogy 20, 805-816.
  • Ford MJ, Burton LJ, Morris RJ, Hall MS (2002). Selective expression of prion protein in peripheral tissues of the adult mouse. Neurosci- ence 113, 177-192.
  • Harris DA (2003). Trafficking, turnover and membrane topology of PrP. British Medical Bulletin 66, 71-85.
  • Heussler VT, Küenzi P, Rottenberg S (2001). Inhibition of apoptosis by intracellular protozoan parasites. The International Journal of Para- sitology, 31, 1166-1176.
  • Kasper L, Courret N, Darche S, Luangsay S, Mennechet F, Minns L, Ra- chinel N, Ronet C, Buzoni-Gatel D (2004). Toxoplasma gondii and mucosal immunity. The International Journal for Parasitology 34, 401-409.
  • Kim B-H, Lee H-g, Choi J-K, Kim J-I, Choi E-K, Carp RI, Kim Y-S (2004). The cellular prion protein (PrPc) prevents apoptotic neuronal cell death and mitochondrial dysfuntion induced by serum deprivation. Molecular Brain Research 124, 40-50.
  • Klamt F, Dal-Pizzol F, Conte da Frota ML JR, Walz R, Andrades ME, da Silva EG, Brentani RR, Izquierdo I, Fonseca Moreira JC (2001). Imbal- ance of antioxidant defense in mice lacking cellular prion protein. Free Radical Biology and Medicine 30, 1137-1144.
  • Kubosaki A, Nishimura-Nasu Y, Nishimura T, Yusa S, Sakudo A, Saeki K, Matsumoto Y, Itohara S, Onodera T (2003). Expression of normal cellular prion protein (PrP(c)) on T lymphocytes and the effect of copper ion: Analysis by wild-type and prion protein gene-deficient mice. Biochemical and Biophysical Research Communications 307, 810-813.
  • Kubosaki A, Ueno A, Matsumoto Y, Doi K, Saeki K, Matsumoto Y, On- odera T (2000). Analysis of prion protein mRNA by in situ hybridi- zation in brain and placenta of sheep. Biochemical and Biophysical Research Communications 273, 890-893.
  • Kuwahara C, Takeuchi AM, Nishimura T, Haraguchi K, Kubosaki A, Mat- sumoto Y, Saeki K, Matsumoto Y, Yokoyama T, Itohara S, Onodera T (1999). Prions prevent neuronal cel-line death. Nature 400, 225- 226.
  • Lee YH, Kim KY, Kang MS, Shin DW (1995). Detection of Toxoplasma antigens and antibodies in mice infected with different strains of Toxoplasma gondii. Korean Journal of Parasitology 33, 201-210.
  • Lee YH, Channon JY, Matsuura T, Schwartzman JD, Shin DW, Kasper LH (1999). Functional and quantitative analysis of splenic T cell im- mune responses following oral Toxoplasma gondii infection in mice. Experimental Parasitology 91, 212-221.
  • Legname G, Nelken P, Guan Z, Kanyo ZF, DeArmond SJ, Prusiner SB (2002). Prion and doppel proteins bind to granule cells of the cere- bellum. Proceedings of the National Academy of Sciences USA, 99, 16285-16290.
  • Liang J, Kong Q (2012). α-Cleavage of cellular prion protein. Prion 6, 453-460.
  • Liu T, Zwingman T, Li R, Pan Tao, Wong B, Petersen RB, Gambetti P, Her- rup K, Sy M (2001). Differential expression of cellular prion protein in Mouse brain as detected with multiple anti-PrP monoclonal anti- bodies. Brain Research 896, 118-129.
  • Moore RC, Lee IY, Silverman GL, Harrison PM, Strome R, Heinrich C, Karunaratne A et al. (1999). Ataxia in prion protein (PrP-deficient mice is associated with upregulation of the novel PrP-like protein doppel. Journal of Molecular Biology 292, 797-817.
  • Özcel MA, İnci A, Turgay N, Köroğlu E (2007). Tıbbi ve Veteriner im- munoparazitoloji. Türkiye Parazitoloji Derneği Yayınları No:21, Meta Basım, İzmir.
  • Paltrinieri S, Comazzi S, Spagnolo V, Rondena M, Ponti W, Ceciliani F (2004). Bovine Doppel (Dpl) and Prion Protein (PrP) expression on lymphoid tissue and circulating leukocytes. Journal of Histochemis- try and Cytochemistry 52, 1639-1645.
  • Pimenta J, Dias FM, Marques CC, Baptista MC, Vasques MI, Horta AE, Barbas JP, Soares R, Mesquita P, Cabrita E, Fontes CM, Prates JA, Pereira RM (2012). The prion-like protein Doppel enhances ovine spermatozoa fertilizing ability. The Reproduction in Domestic Ani- mals 47, 196-202.
  • Riesner D (2003). Biochemistry and structure of PrPc and PrPsc. British Medical Bulletin 66, 21-33.
  • Rondena M, Ceciliani F, Comazzi S, Pocacqua V, Bazzocchi C, Luvoni C, Chigioni S, Paltrinieri S (2005). Identification of bovine doppel pro- tein in testis, ovary and ejeculated sprematozoa. Theriogenology 63, 1195-1206.
  • Sakaguchi S, Katamine S, Nishida N, Moriuchi R, Shigematsu K, Sugimo- to T, Nakatani A, Kataoka Y, Houtani T, Shirabe S, Okada H, Hasega- wa S, Miyamoto T, Noda T (1996). Loss of cerebellar Purkinje cells in aged mice homozygous for disrupted PrP gene. Nature 380, 528- 531.
  • Sinai AP, Payne TM, Carmen JC, Hardi L, Watson SJ, Molestina RE (2004). Mechanisms underlying the manipulation of host apoptotic pathways by Toxoplasma gondii. The International Journal for Par- asitology 34, 381-91
  • Sukthana Y, Waree P, Pongponratn E, Chaisri U, Riganti M (2003). Patho- logic study of acute toxoplasmosis in experimental animals. The Southeast Asian Journal of Tropical Medicine and Public Health 34, 16-21.
  • Suzuki Y, Yang Q, Remington JS (1995). Genetic resistance against acute toxoplasmosis depends on the strain of Toxoplasma gondii. Journal of Parasitology 81, 1032-1034.
  • Ringer TM, Axer H, Bernd F.M. Romeike BFM, Zinke J, Brunkhorst F, Witte OW, Günther A (2011). Neurological sequelae of sepsis: I) Septic encephalopathy. The Open Critical Care Medicine Journal 4, 2-7.
  • Tranulis MA, Espenes A, Comincini S, Skretting G, Harbitz I (2001). The PrP-like protein Doppel gene in sheep and cattle: cDNA sequence and expression. Mammalian Genome 12, 376-379.
  • Villard O, Candolfi E, Ferguson DJ, Marcellin L, Kien T (1997). Loss of oral infectivity of tissue cysts of Toxoplasma gondii RH strain to out- bred Swiss Webster mice. The International Journal for Parasitology 27, 1555-1559.
  • Waree P, Ferguson DJ, Pongponratn E, Chaisri U, Sukthana Y (2007). Immunohistochemical study of acute and chronic toxoplasmosis in experimentally infected mice The Southeast Asian Journal of Tropi- cal Medicine and Public Health 38, 223-231.
  • Watarai M, Makino S, Michikawa M, Yanagisawa K, Murakami S, Shira- hata T. (2002). Macrophage plasma membrane cholesterol contrib- utes to Brucella abortus infection of mice. Infection and Immunity 70, 4818-25.
  • Westeway D, Carlson GA. (2002). Mammalian prion proteins: enigma, variation and vaccination. Trends in Biochemical Sciences 27, 301- 307.
  • Zachary ve McGavin (2012). Pathologic Basis of Veterinary Disease, 5th Edition.
Toplam 46 adet kaynakça vardır.

Ayrıntılar

Birincil Dil Türkçe
Bölüm Research Article
Yazarlar

M.yavuz Gülbahar Bu kişi benim

Tolga Güvenç Bu kişi benim

Murat Hökelek2 Bu kişi benim

Murat Yarım1 Bu kişi benim

Akçahan Gepdiremen Bu kişi benim

Gülay Çiftçi Bu kişi benim

Yonca B. Kabak Bu kişi benim

Yayımlanma Tarihi 1 Ocak 2013
Yayımlandığı Sayı Yıl 2013 Cilt: 2 Sayı: 1

Kaynak Göster

APA Gülbahar, M., Güvenç, T., Hökelek2, M., Yarım1, M., vd. (2013). Farelerde Deneysel Toxoplasma gondii Enfeksiyonunun Patogenezisinde Hücresel Prion Protein ve Doppel Protein’in Rollerinin Araştırılması. Animal Health Production and Hygiene, 2(1), 130-138.