Absence of truncating BRIP1 mutations in chromosome 17q-linked hereditary prostate cancer families

Background:In a genome-wide scan (GWS) of 175 multiplex prostate cancer (PCa) families from the University of Michigan Prostate Cancer Genetics Project (PCGP), linkage was observed to markers on chromosome 17q21–24, a region that includes two breast cancer susceptibility genes, BRCA1 and BRIP1. BRIP1 is a Fanconi anaemia gene (FANCJ) that interacts with the BRCT domain of BRCA1 and has a role in DNA damage repair. Protein truncating mutations in BRIP1 have been identified in hereditary breast and ovarian cancer families, and a recent report suggested that a recurrent truncating mutation (R798X) may have a role in PCa susceptibility.Methods:We examined the role of BRIP1 mutations in hereditary PCa through sequence analysis of 94 individuals from PCGP families showing linkage to 17q.Results:A total of 24 single-nucleotide polymorphisms, including 7 missense variants but no protein truncating mutations, were observed.Conclusion:The data presented here suggest that BRIP1 truncating mutations are uncommon in PCa cases and do not account for the linkage to chromosome 17q observed in our GWS. Additional investigation is needed to determine the significance, if any, of the observed BRIP1 missense variants in hereditary PCa

Discovery of blood transcriptomic markers for depression in animal models and pilot validation in subjects with early-onset major depression

Early-onset major depressive disorder (MDD) is a serious and prevalent psychiatric illness in adolescents and young adults. Current treatments are not optimally effective. Biological markers of early-onset MDD could increase diagnostic specificity, but no such biomarker exists. Our innovative approach to biomarker discovery for early-onset MDD combined results from genome-wide transcriptomic profiles in the blood of two animal models of depression, representing the genetic and the environmental, stress-related, etiology of MDD. We carried out unbiased analyses of this combined set of 26 candidate blood transcriptomic markers in a sample of 15–19-year-old subjects with MDD (N=14) and subjects with no disorder (ND, N=14). A panel of 11 blood markers differentiated participants with early-onset MDD from the ND group. Additionally, a separate but partially overlapping panel of 18 transcripts distinguished subjects with MDD with or without comorbid anxiety. Four transcripts, discovered from the chronic stress animal model, correlated with maltreatment scores in youths. These pilot data suggest that our approach can lead to clinically valid diagnostic panels of blood transcripts for early-onset MDD, which could reduce diagnostic heterogeneity in this population and has the potential to advance individualized treatment strategies

Injection of Pseudomonas aeruginosa Exo Toxins into Host Cells Can Be Modulated by Host Factors at the Level of Translocon Assembly and/or Activity

Pseudomonas aeruginosa type III secretion apparatus exports and translocates four exotoxins into the cytoplasm of the host cell. The translocation requires two hydrophobic bacterial proteins, PopB and PopD, that are found associated with host cell membranes following infection. In this work we examined the influence of host cell elements on exotoxin translocation efficiency. We developed a quantitative flow cytometry based assay of translocation that used protein fusions between either ExoS or ExoY and the ß-lactamase reporter enzyme. In parallel, association of translocon proteins with host plasma membranes was evaluated by immunodetection of PopB/D following sucrose gradient fractionation of membranes. A pro-myelocytic cell line (HL-60) and a pro-monocytic cell line (U937) were found resistant to toxin injection even though PopB/D associated with host cell plasma membranes. Differentiation of these cells to either macrophage- or neutrophil-like cell lines resulted in injection-sensitive phenotype without significantly changing the level of membrane-inserted translocon proteins. As previous in vitro studies have indicated that the lysis of liposomes by PopB and PopD requires both cholesterol and phosphatidyl-serine, we first examined the role of cholesterol in translocation efficiency. Treatment of sensitive HL-60 cells with methyl-ß-cyclodextrine, a cholesterol-depleting agent, resulted in a diminished injection of ExoS-Bla. Moreover, the PopB translocator was found in the membrane fraction, obtained from sucrose-gradient purifications, containing the lipid-raft marker flotillin. Examination of components of signalling pathways influencing the toxin injection was further assayed through a pharmacological approach. A systematic detection of translocon proteins within host membranes showed that, in addition to membrane composition, some general signalling pathways involved in actin polymerization may be critical for the formation of a functional pore. In conclusion, we provide new insights in regulation of translocation process and suggest possible cross-talks between eukaryotic cell and the pathogen at the level of exotoxin translocation

Are Hox Genes Ancestrally Involved in Axial Patterning? Evidence from the Hydrozoan Clytia hemisphaerica (Cnidaria)

Background: The early evolution and diversification of Hox-related genes in eumetazoans has been the subject of conflicting hypotheses concerning the evolutionary conservation of their role in axial patterning and the pre-bilaterian origin of the Hox and ParaHox clusters. The diversification of Hox/ParaHox genes clearly predates the origin of bilaterians. However, the existence of a "Hox code' predating the cnidarian-bilaterian ancestor and supporting the deep homology of axes is more controversial. This assumption was mainly based on the interpretation of Hox expression data from the sea anemone, but growing evidence from other cnidarian taxa puts into question this hypothesis. Methodology/Principal Findings: Hox, ParaHox and Hox-related genes have been investigated here by phylogenetic analysis and in situ hybridisation in Clytia hemisphaerica, an hydrozoan species with medusa and polyp stages alternating in the life cycle. Our phylogenetic analyses do not support an origin of ParaHox and Hox genes by duplication of an ancestral ProtoHox cluster, and reveal a diversification of the cnidarian HOX9-14 genes into three groups called A, B, C. Among the 7 examined genes, only those belonging to the HOX9-14 and the CDX groups exhibit a restricted expression along the oralaboral axis during development and in the planula larva, while the others are expressed in very specialised areas at the medusa stage. Conclusions/Significance: Cross species comparison reveals a strong variability of gene expression along the oral-aboral axis and during the life cycle among cnidarian lineages. The most parsimonious interpretation is that the Hox code, collinearity and conservative role along the antero-posterior axis are bilaterian innovations

A Reaction-Diffusion Model to Capture Disparity Selectivity in Primary Visual Cortex

Decades of experimental studies are available on disparity selective cells in visual cortex of macaque and cat. Recently, local disparity map for iso-orientation sites for near-vertical edge preference is reported in area 18 of cat visual cortex. No experiment is yet reported on complete disparity map in V1. Disparity map for layer IV in V1 can provide insight into how disparity selective complex cell receptive field is organized from simple cell subunits. Though substantial amounts of experimental data on disparity selective cells is available, no model on receptive field development of such cells or disparity map development exists in literature. We model disparity selectivity in layer IV of cat V1 using a reaction-diffusion two-eye paradigm. In this model, the wiring between LGN and cortical layer IV is determined by resource an LGN cell has for supporting connections to cortical cells and competition for target space in layer IV. While competing for target space, the same type of LGN cells, irrespective of whether it belongs to left-eye-specific or right-eye-specific LGN layer, cooperate with each other while trying to push off the other type. Our model captures realistic 2D disparity selective simple cell receptive fields, their response properties and disparity map along with orientation and ocular dominance maps. There is lack of correlation between ocular dominance and disparity selectivity at the cell population level. At the map level, disparity selectivity topography is not random but weakly clustered for similar preferred disparities. This is similar to the experimental result reported for macaque. The details of weakly clustered disparity selectivity map in V1 indicate two types of complex cell receptive field organization

Rescue of replication failure by Fanconi anaemia proteins

Chromosomal aberrations are often associated with incomplete genome duplication, for instance at common fragile sites, or as a consequence of chemical alterations in the DNA template that block replication forks. Studies of the cancer-prone disease Fanconi anaemia (FA) have provided important insights into the resolution of replication problems. The repair of interstrand DNA crosslinks induced by chemotherapy drugs is coupled with DNA replication and controlled by FA proteins. We discuss here the recent discovery of new FA-associated proteins and the development of new tractable repair systems that have dramatically improved our understanding of crosslink repair. We focus also on how FA proteins protect against replication failure in the context of fragile sites and on the identification of reactive metabolites that account for the development of Fanconi anaemia symptoms

Efeitos da aplicação do laser de baixa potência na regeneração do nervo isquiático de ratos

Os nervos periféricos sofrem constantes lesões de origem traumática, o que resulta em perdas funcionais. A terapia com laser de baixa potência vem sendo utilizada para minimizar os efeitos maléficos da inflamação e acelerar o processo de cicatrização dos tecidos lesados. Este estudo teve como objetivo verificar o efeito da irradiação do laser 830 nm no comportamento do nervo isquiático de ratos submetido a esmagamento. Foram utilizados 20 ratos, todos tendo tido o nervo isquiático esmagado, divididos em 4 grupos (n=5): P7 e P14, tratamento placebo por 7 e 14 dias; L7 e L14, tratamento por laser (dosagem de 4 J/cm²) por 7 e 14 dias. Os animais dos grupos P7 e P14 foram submetidos aos mesmos procedimentos, mas com o laser desligado. Os parâmetros analisados foram presença de infiltrado inflamatório e fibroblastos, destruição da bainha de mielina e degeneração axonal. Na análise estatística foi observada diferença estatística com relação a três parâmetros: os animais do grupo L14 apresentaram maior quantidade de fibroblastos (p=0,0001), menor degeneração da bainha de mielina (p=0,007) e menor quantidade de infiltrado inflamatório (p=0,001). A aplicação do laser de baixa potência contribuiu para a redução do processo inflamatório decorrente da lesão do nervo isquiático de ratos.Peripheral nerves are commonly subject to traumatic injuries, leading to functional loss. Low-power laser therapy has been used in order to minimize harmful effects of inflammation and to accelerate healing of injured tissues. The purpose of this study was to assess the effect of 830 nm-laser irradiation on rat sciatic nerves submitted to crush. Twenty male Wistar rats had their sciatic nerve crushed and were divided into 4 groups (n=5): Sham7 and Sham14, placebo-treated for 7 and 14 days; L7 and L14, laser-treated (at 4 J/cm²) for 7 and 14 days. Sham group animals were submitted to the same procedures, but with the laser turned off. Assessed parameters were inflammatory infiltrates, fibroblasts, myelin sheath destruction, and axonal degeneration. The statistical analysis showed significant differences in three parameters: L14 animals showed more fibroblasts (p=0.0001), lesser myelin sheath degeneration (p=0.007), and lesser inflammatory infiltrates (p=0.001). Low-power laser therapy hence contributed to reduce the inflammatory process due to rat sciatic nerve injury

A basal lithostrotian titanosaur (Dinosauria: Sauropoda) with a complete skull: Implications for the evolution and paleobiology of titanosauria

We describe Sarmientosaurus musacchioi gen. et sp. nov., a titanosaurian sauropod dinosaur from the Upper Cretaceous (Cenomanian - Turonian) Lower Member of the Bajo Barreal Formation of southern Chubut Province in central Patagonia, Argentina. The holotypic and only known specimen consists of an articulated, virtually complete skull and part of the cranial and middle cervical series. Sarmientosaurus exhibits the following distinctive features that we interpret as autapomorphies: (1) maximum diameter of orbit nearly 40% rostrocaudal length of cranium; (2) complex maxilla - lacrimal articulation, in which the lacrimal clasps the ascending ramus of the maxilla; (3) medial edge of caudal sector of maxillary ascending ramus bordering bony nasal aperture with low but distinct ridge; (4) ´tongue-like´ ventral process of quadratojugal that overlaps quadrate caudally; (5) separate foramina for all three branches of the trigeminal nerve; (6) absence of median venous canal connecting infundibular region to ventral part of brainstem; (7) subvertical premaxillary, procumbent maxillary, and recumbent dentary teeth; (8) cervical vertebrae with ´strut-like´ centroprezygapophyseal laminae; (9) extremely elongate and slender ossified tendon positioned ventrolateral to cervical vertebrae and ribs. The cranial endocast of Sarmientosaurus preserves some of the most complete information obtained to date regarding the brain and sensory systems of sauropods. Phylogenetic analysis recovers the new taxon as a basal member of Lithostrotia, as the most plesiomorphic titanosaurian to be preserved with a complete skull. Sarmientosaurus provides a wealth of new cranial evidence that reaffirms the close relationship of titanosaurs to Brachiosauridae. Moreover, the presence of the relatively derived lithostrotian Tapuiasaurus in Aptian deposits indicates that the new Patagonian genus represents a ´ghost lineage´ with a comparatively plesiomorphic craniodental form, the evolutionary history of which is missing for at least 13 million years of the Cretaceous. The skull anatomy of Sarmientosaurus suggests that multiple titanosaurian species with dissimilar cranial structures coexisted in the early Late Cretaceous of southern South America. Furthermore, the new taxon possesses a number of distinctive morphologies - such as the ossified cervical tendon, extremely pneumatized cervical vertebrae, and a habitually downward- facing snout - that have rarely, if ever, been documented in other titanosaurs, thus broadening our understanding of the anatomical diversity of this remarkable sauropod clade. The latter two features were convergently acquired by at least one penecontemporaneous diplodocoid, and may represent mutual specializations for consuming low-growing vegetation.Fil: Martínez, Rubén Darío. Universidad Nacional de la Patagonia; ArgentinaFil: Lamanna, Matthew C.. Carnegie Museum Of Natural History; Estados UnidosFil: Novas, Fernando Emilio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Museo Argentino de Ciencias Naturales "bernardino Rivadavia"; ArgentinaFil: Ridgely, Ryan C.. Ohio University College Of Osteopathic Medicine; Estados UnidosFil: Casal, Gabriel. Universidad Nacional de la Patagonia; ArgentinaFil: Martínez, Javier E.. Hospital Regional de Comodoro Rivadavia; ArgentinaFil: Vita, Javier R.. Resonancia Magnética Borelli; ArgentinaFil: Witmer, Lawrence M.. Ohio University College Of Osteopathic Medicine; Estados Unido