Utilisation des infrastructures de la Grille EGI pour les simulations de CTA

Utilisation des infrastructures de la Grille EGI pour les simulations de CT

Localization of MMR proteins on meiotic chromosomes in mice indicates distinct functions during prophase I

Mammalian MutL homologues function in DNA mismatch repair (MMR) after replication errors and in meiotic recombination. Both functions are initiated by a heterodimer of MutS homologues specific to either MMR (MSH2–MSH3 or MSH2–MSH6) or crossing over (MSH4–MSH5). Mutations of three of the four MutL homologues (Mlh1, Mlh3, and Pms2) result in meiotic defects. We show herein that two distinct complexes involving MLH3 are formed during murine meiosis. The first is a stable association between MLH3 and MLH1 and is involved in promoting crossing over in conjunction with MSH4–MSH5. The second complex involves MLH3 together with MSH2–MSH3 and localizes to repetitive sequences at centromeres and the Y chromosome. This complex is up-regulated in Pms2−/− males, but not females, providing an explanation for the sexual dimorphism seen in Pms2−/− mice. The association of MLH3 with repetitive DNA sequences is coincident with MSH2–MSH3 and is decreased in Msh2−/− and Msh3−/− mice, suggesting a novel role for the MMR family in the maintenance of repeat unit integrity during mammalian meiosis

UJI AKTIVITAS PROTEASE DAN KARAKTERISASI PH ACTINOMYCETES ISOLAT ATH-03 ASAL TAHURA POCUT MEURAH INTAN KABUPATEN ACEH BESAR

ABSTRAKKata kunci: Aktivitas Protease, Karakterisasi pH, Actinomycetes.Penelitian Uji Aktivitas Protease dan Karakterisasi pH Actinomycetes Isolat ATH-03 Asal Tahura Pocut Meurah Intan Kabupaten Aceh Besar telah dilaksanakan sejak tanggal 3 September sampai dengan 27 Desember 2012. Penelitian ini bertujuan untuk mengukur aktivitas protease dan mengetahui pH optimum aktivitas protease dari isolat Actinomycetes ATH-03. Metode penelitian yang digunakan adalah metode Eksperimen dengan Rancangan Acak Lengkap Non Faktorial dengan 6 kali perlakuan, 2 kali ulangan. Data yang diperoleh dianalisis secara deskriptif yang terkait dengan nilai indeks proteolitik sebagai dasar seleksi isolat Actinomycetes. Isolat Actinomycetes berasal dari koleksi Laboratorium Mikrobiologi Jurusan Biologi FMIPA Universitas Syiah Kuala. Delapan belas isolat Actinomycetes menunjukkan aktivitas pada Media NA yang mengandung susu skim 1%. Isolat ATH-03 dipilih dalam penelitian ini karena memiliki zona bening yang lebar dengan indeks proteolitik (IP) tertinggi 8,537 setelah inkubasi selama 48 jam pada Media NAS. Protease ekstraseluler dikarakterisasi menggunakan media NB yang mengandung susu skim 1% sebagai media produksi. Waktu optimum pemanenan ekstrak kasar protease isolat ATH-03 pada hari ke-7 dengan aktivitas sebesar 0,083 U/ml, kadar protein 0,003 mg/ml dan aktivitas spesifik mencapai 23,72 U/mg. Hasil karakterisasi pH ekstrak kasar enzim isolat ATH-03 menunjukkan aktivitas optimum pada pH 8 yaitu 0,067 U/ml, protease yang dihasilkan oleh isolat ini aktif pada kisaran pH netral.Banda Ace

8-Aryl-6-chloro-3-nitro-2-(phenylsulfonylmethyl)imidazo[1,2-a]pyridines as potent antitrypanosomatid molecules bioactivated by type 1 nitroreductases

Based on a previously identified antileishmanial 6,8-dibromo-3-nitroimidazo[1,2-a]pyridine derivative, a Suzuki-Miyaura coupling reaction at position 8 of the scaffold was studied and optimized from a 8-bromo-6-chloro-3-nitroimidazo[1,2-a]pyridine substrate. Twenty-one original derivatives were prepared, screened in vitro for activity against L infantum axenic amastigotes and T. brucei brucei trypomastigotes and evaluated for their cytotoxicity on the HepG2 human cell line. Thus, 7 antileishmanial hit compounds were identified, displaying IC50 values in the 1.1-3 mu M range. Compounds 13 and 23, the 2 most selective molecules (SI = >18 or >17) were additionally tested on both the promastigote and intramacrophage amastigote stages of L donovani. The two molecules presented a good activity (IC50 = 1.2-1.3 mu M) on the promastigote stage but only molecule 23, bearing a 4-pyridinyl substituent at position 8, was active on the intracellular amastigote stage, with a good IC50 value (2.3 mu M), slightly lower than the one of miltefosine (IC50 = 4.3 mu M). The antiparasitic screening also revealed 8 antitrypanosomal hit compounds, including 14 and 20, 2 very active (IC50 = 0.04-0.16 mu M) and selective (SI = >313 to 550) molecules toward T brucei brucei, in comparison with drug-candidate fexinidazole (IC50 = 0.6 & SI > 333) or reference drugs suramin and eflornithine (respective IC50 = 0.03 and 13.3 mu M). Introducing an aryl moiety at position 8 of the scaffold quite significantly increased the antitrypanosomal activity of the pharmacophore. Antikinetoplastid molecules 13, 14, 20 and 23 were assessed for bioactivation by parasitic nitroreductases (either in L donovani or in T. brucei brucei), using genetically modified parasite strains that over-express NTRs: all these molecules are substrates of type 1 nitroreductases (NTRI), such as those that are responsible for the bioactivation of fexinidazole. Reduction potentials measured for these 4 hit compounds were higher than that of fexinidazole (-0.83 V), ranging from -0.70 to -0.64 V

Nongenotoxic 3-Nitroimidazo[1,2-a]pyridines Are NTR1 Substrates That Display Potent in Vitro Antileishmanial Activity

Twenty nine original 3-nitroimidazo[1,2-a]pyridine derivatives, bearing a phenylthio (or benzylthio) moiety at position 8 of the scaffold, were synthesized. In vitro evaluation highlighted compound 5 as an antiparasitic hit molecule displaying low cytotoxicity for the human HepG2 cell line (CC50 > 100 mu M) alongside good antileishmanial activities (IC50 = 1-2.1 mu M) against L. donovani, L. infantum, and L. major; and good antitrypanosomal activities (IC50 = 1.3-2.2 mu M) against T. brucei brucei and T. cruzi, in comparison to several reference drugs such as miltefosine, fexinidazole, eflornithine, and benznidazole (IC50 = 0.6 to 13.3 mu M). Molecule 5, presenting a low reduction potential (E degrees = -0.63 V), was shown to be selectively bioactivated by the L. donovani type 1 nitroreductase (NTR1). Importantly, molecule 5 was neither mutagenic (negative Ames test), nor genotoxic (negative comet assay), in contrast to many other nitroaromatics. Molecule 5 showed poor microsomal stability; however, its main metabolite (sulfoxide) remained both active and nonmutagenic, making 5 a good candidate for further in vivo studies

Brain structure across the lifespan : the influence of stress and mood

Normal brain aging is an inevitable and heterogeneous process characterized by a selective pattern of structural changes. Such heterogeneity arises as a consequence of cumulative effects over the lifespan, including stress and mood effects, which drive different micro- and macro-structural alterations in the brain. Investigating these differences in healthy age-related changes is a major challenge for the comprehension of the cognitive status. Herein we addressed the impact of normal aging, stress, mood, and their interplay in the brain gray and white matter (WM) structure. We showed the critical impact of age in the WM volume and how stress and mood influence brain volumetry across the lifespan. Moreover, we found a more profound effect of the interaction of aging/stress/mood on structures located in the left hemisphere. These findings help to clarify some divergent results associated with the aging decline and to enlighten the association between abnormal volumetric alterations and several states that may lead to psychiatric disorders.We are thankful to all study participants. This work was funded by the European Commission (FP7): "SwitchBox" (Contract HEALTH-F2-2010-259772) and co-financed by the Portuguese North Regional Operational Program (ON.2 - O Novo Norte) under the National Strategic Reference Framework (QREN), through the European Regional Development Fund (FEDER). Jose M. Soares, Paulo Marques, and Nadine C. Santos are supported by fellowships of the project "SwitchBox"; Ricardo Magalhaes is supported by a fellowship from the project FCTANR/NEU-OSD/0258/2012 funded by FCT/MEC (www.fct.pt) and by ON.2 - ONOVONORTE - North - Portugal Regional Operational Programme 2007/2013, of the National Strategic Reference Framework (NSRF) 2007/2013, through FEDER