Brain network analyses in clinical neuroscience

Network analyses are now considered fundamental for understanding brain function. Nonetheless neuroimaging characterisations of connectivity are just emerging in clinical neuroscience. Here, we briefly outline the concepts underlying structural, functional and effective connectivity, and discuss some cutting-edge approaches to the quantitative assessment of brain architecture and dynamics. As illustrated by recent evidence, comprehensive and integrative network analyses offer the potential for refining pathophysiological concepts and therapeutic strategies in neurological and psychiatric conditions across the lifespan

DNA end resection by Dna2–Sgs1–RPA and its stimulation by Top3–Rmi1 and Mre11–Rad50–Xrs2

The repair of DNA double-strand breaks (DSBs) by homologous recombination requires processing of broken ends. For repair to start, the DSB must first be resected to generate a 3′-single-stranded DNA (ssDNA) overhang, which becomes a substrate for the DNA strand exchange protein, Rad51 (ref. 1). Genetic studies have implicated a multitude of proteins in the process, including helicases, nucleases and topoisomerases. Here we biochemically reconstitute elements of the resection process and reveal that it requires the nuclease Dna2, the RecQ-family helicase Sgs1 and the ssDNA-binding protein replication protein-A (RPA). We establish that Dna2, Sgs1 and RPA constitute a minimal protein complex capable of DNA resection in vitro. Sgs1 helicase unwinds the DNA to produce an intermediate that is digested by Dna2, and RPA stimulates DNA unwinding by Sgs1 in a species-specific manner. Interestingly, RPA is also required both to direct Dna2 nucleolytic activity to the 5′-terminated strand of the DNA break and to inhibit 3′ to 5′ degradation by Dna2, actions that generate and protect the 3′-ssDNA overhang, respectively. In addition to this core machinery, we establish that both the topoisomerase 3 (Top3) and Rmi1 complex and the Mre11–Rad50–Xrs2 complex (MRX) have important roles as stimulatory components. Stimulation of end resection by the Top3–Rmi1 heterodimer and the MRX proteins is by complex formation with Sgs1 (refs 5, 6), which unexpectedly stimulates DNA unwinding. We suggest that Top3–Rmi1 and MRX are important for recruitment of the Sgs1–Dna2 complex to DSBs. Our experiments provide a mechanistic framework for understanding the initial steps of recombinational DNA repair in eukaryotes

Prevention of HIV infection among migrant population groups in Northeast Brazil O papel da migração na prevenção da infecção pelo HIV no Nordeste Brasileiro

HIV infection is spreading among the poor, women, and migrant communities in the interior of Northeast Brazil. The research focused on different configurations, beliefs, representations, and forms of social organization of behavior thought to be associated with the population's capacity to efficiently follow AIDS prevention measures. Participants located in neighborhoods known for having large migrant populations were identified by Family Health Program Workers in Fortaleza and Teresina. The study adopted a qualitative methodology. Several belief-system concepts and values, as well as the social organization of sexuality revealed in the study, represent obstacles both to AIDS prevention and condom use. Hunger, lack of prospects, and fear are associated with a social situation of poverty, exclusion, prejudice, and total absence of basic human rights When examined together, these elements define different configurations in the migrants' increased vulnerability to HIV/AIDS. The groups' increased vulnerability relates to the socioeconomic complexity that must be considered in HIV/AIDS control and prevention programs.<br>A infecção pelo HIV entre pobres, mulheres e populações migrantes do interior do Nordeste Brasileiro vem crescendo. As diferentes configurações, crenças e representações e formas de organização do comportamento, associadas à capacidade de seguir adequadamente medidas de prevenção, foram o foco desta investigação. Os participantes foram localizados em bairros com altas taxas de migração através do Programa Saúde da Família em Fortaleza e Teresina. Empregou-se a metodologia qualitativa nesta investigação. Vários sistemas de crenças, valores e organização social da sexualidade desta população representam obstáculos à prevenção da AIDS e inibem o uso do preservativo. Pobreza, falta de perspectiva e medo estão associados à situação de pobreza, exclusão social e preconceito e à total ausência de direitos humanos. Quando examinados conjuntamente, estes fatores definem diferentes configurações dos migrantes com uma elevada vulnerabilidade ao HIV/AIDS. A alta vulnerabilidade destes grupos, relacionada à complexidade sócio-econômica, deve ser considerada nos programas de prevenção e controle da AIDS

Persistence of minimal residual disease in bone marrow predicts outcome in follicular lymphomas treated with a rituximab-intensive program

We assessed the prognostic value of minimal residual disease (MRD) within the ML17638 phase 3 trial from the Fondazione Italiana Linfomi, investigating the role of rituximab maintenance in elderly follicular lymphoma (FL) patients after a brief first-line chemoimmunotherapy. MRD for the bcl-2/IgH translocation was determined on bonemarrowcells in a centralized laboratory belonging to the Euro-MRD consortium, using qualitative and quantitative polymerase chain reactions (PCRs). Of 234 enrolled patients, 227 (97%) were screened at diagnosis. A molecular marker (MM) was found in 51%. Patients with an MM were monitored at 8 subsequent times. Of the 675 expected follow-up samples, 83% were analyzed. Conversion to PCR negativity predicted better progression-free survival (PFS) at all post-treatment times (eg, end of therapy: 3-year PFS, 72% vs 39%; P < .007). MRD was predictive in both maintenance (83% vs 60%; P < .007) and observation (71% vs 50%; P < .001) groups. PCR positivity at the end of induction was an independent adverse predictor (hazard ratio, 3.1; 95% confidence interval, 1.36-7.07). MRD is a powerful independent outcome predictor in FL patients who receive rituximab-intensive programs, suggesting a need to investigate its value for decision-making. This trial was registered at www.clinicaltrial.gov as #NCT01144364. \uc2\ua9 2013 by The American Society of Hematology