HCV Tumor Promoting Effect Is Dependent on Host Genetic Background

BACKGROUND: The hepatitis C virus (HCV) is one of the major risk factors for the development of hepatocellular carcinoma (HCC). Nevertheless, transgenic mice which express the whole HCV polyprotein (HCV-Tg) do not develop HCC. Whereas chronic HCV infection causes inflammation in patients, in HCV-Tg mice, the host immune reaction against viral proteins is lacking. We aimed to test the role of HCV proteins in HCC development on the background of chronic inflammation in vivo. METHODOLOGY/PRINCIPAL FINDINGS: We crossed HCV-Tg mice that do not develop HCC with the Mdr2-knockout (Mdr2-KO) mice which develop inflammation-associated HCC, to generate Mdr2-KO/HCV-Tg mice. We studied the effect of the HCV transgene on tumor incidence, hepatocyte mitosis and apoptosis, and investigated the potential contributing factors for the generated phenotype by gene expression and protein analyses. The Mdr2-KO/HCV-Tg females from the N2 generation of this breeding (having 75% of the FVB/N genome and 25% of the C57BL/6 genome) produced significantly larger tumors in comparison with Mdr2-KO mice. In parallel, the Mdr2-KO/HCV-Tg females had an enhanced inflammatory gene expression signature. However, in the N7 generation (having 99.2% of the FVB/N genome and 0.8% of the C57BL/6 genome) there was no difference in tumor development between Mdr2-KO/HCV-Tg and Mdr2-KO animals of both sexes. The HCV transgene was similarly expressed in the livers of Mdr2-KO/HCV-Tg females of both generations, as revealed by detection of the HCV transcript and the core protein. CONCLUSION: These findings suggest that the HCV transgene accelerated inflammation-associated hepatocarcinogenesis in a host genetic background-dependent manner

X-linked primary ciliary dyskinesia due to mutations in the cytoplasmic axonemal dynein assembly factor PIH1D3

By moving essential body fluids and molecules, motile cilia and flagella govern respiratory mucociliary clearance, laterality determination and the transport of gametes and cerebrospinal fluid. Primary ciliary dyskinesia (PCD) is an autosomal recessive disorder frequently caused by non-assembly of dynein arm motors into cilia and flagella axonemes. Before their import into cilia and flagella, multi-subunit axonemal dynein arms are thought to be stabilized and pre-assembled in the cytoplasm through a DNAAF2–DNAAF4–HSP90 complex akin to the HSP90 co-chaperone R2TP complex. Here, we demonstrate that large genomic deletions as well as point mutations involving PIH1D3 are responsible for an X-linked form of PCD causing disruption of early axonemal dynein assembly. We propose that PIH1D3, a protein that emerges as a new player of the cytoplasmic pre-assembly pathway, is part of a complementary conserved R2TP-like HSP90 co-chaperone complex, the loss of which affects assembly of a subset of inner arm dyneins

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

Corpo e envelhecimento na cultura brasileira

This article intends to ponder about how meaningful the woman ageing is within the Brazilian society by reviewing some interviews with Brazilian and German women. Considering a culture where the body itself means a significant asset in marriage, sexual, and professional markets, how are the women growing old? What are the key fears that the Brazilian women experiment when they are ageing? What does ageing mean in certain social segments? These are the main issues discussed here.Este artigo pretende refletir sobre o significado do envelhecimento feminino na sociedade brasileira, a partir da análise de entrevistas realizadas com mulheres brasileiras e alemãs.Em uma cultura em que o corpo é um importante capital, no mercado de casamento, no mercado sexual e no profissional, como as mulheres vivenciam o envelhecimento? Quais os principais medos das brasileiras ao envelhecerem? Qual o significado do envelhecimento em determinados segmentos sociais? São estas as principais questões discutidas aqui

Antropologia e novas corporalidades

Já na década de 1980, o antropólogo Gilberto Freyre, como sempre de forma pioneira e polêmica, buscou pensar o corpo da mulher brasileira e suas transformações. No livro Modos de homem, modas de mulher (1987), Freyre afirmava que: Pode-se dizer da mulher que tende a ser, quanto a modas para seus vestidos, seus sapatos, seus penteados, um tanto maria-vai-com-asoutras. Portanto, a corresponder ao que a moda tem de uniformizante. Mas é da argúcia feminina a iniciativa de reagir contra essa uniformização absoluta, de acordo com características pessoais que não se ajustem a imposições de uma moda disto ou daquilo. Neste particular, é preciso reconhecer-se, na brasileira morena, o direito de repudiar modas s norteeuropéias destinadas a mulheres louras e alvas (ibidem:33)

Unpacking Mobility, Sex Trafficking, and HIV Vulnerability in Two Mexico-U.S. Border Cities

Background: Sex trafficking is a human rights abuse that carries particularly negative health and social consequences, including HIV and sexually transmitted infections (STIs). While HIV/STI infection and sex trafficking have been linked in Asia, the context of these associations and their applicability in Mexico is poorly understood.Aims: Aims of this dissertation were to (1) Critically review evidence linking mobility, trafficking, and HIV vulnerability in Mexico and Central America; (2) Explore associations between features of the risk environment, sex work and drug use history, and underage sex work among female sex workers (FSWs) in Tijuana and Cd. Juarez, Mexico; and (3) Describe and "unpack" sex trafficking and its relationship to HIV/STI vulnerability among formerly trafficked FSWs in Tijuana.Methods: This study employed qualitative and quantitative methods to investigate sex trafficking, mobility and HIV vulnerability. In Chapter 2, a critical review of the epidemiology and context of HIV vulnerability among mobile populations in Central America and Mexico was conducted. Chapter 3 draws upon questionnaires and HIV/STI testing among FSWs (n=624) in Tijuana and Cd. Juarez. In Chapter 4, in-depth interviews were conducted with formerly trafficked FSWs in Tijuana (n=31). Results: Chapter 2 found that among mobile groups in Central America and Mexico, social isolation, socio-economic impacts of displacement, gender inequalities, and stigma/discrimination strongly shape HIV/STI risk. In Chapter 3, underage sex work entry was positively associated with inhalants as the first drug used, forced first injection, number of drug treatment attempts, and recent receptive syringe-sharing. Number of recent condom negotiation attempts with steady partners and depression as a reason for first injecting were negatively associated with underage entry into sex work. In Chapter 4, sex trafficking was linked to elevated HIV/STI vulnerability through gender-based violence, economic vulnerability, migration, and stigma.Conclusions: These findings contribute to a foundation of knowledge to advocate for strategies to reduce sex trafficking and HIV. Multi-level, intersectoral interventions to prevent sex trafficking and HIV infection are needed for vulnerable youths, migrants, and FSWs in Mexico-U.S. border cities; recommended components include strengthening the response to gender-based violence, peer-delivered prevention, and the provision of shelter, food, job placements, and psychological support