Mitochondrial protein import: precursor oxidation in a ternary complex with disulfide carrier and sulfhydryl oxidase

The biogenesis of mitochondrial intermembrane space proteins depends on specific machinery that transfers disulfide bonds to precursor proteins. The machinery shares features with protein relays for disulfide bond formation in the bacterial periplasm and endoplasmic reticulum. A disulfide-generating enzyme/sulfhydryl oxidase oxidizes a disulfide carrier protein, which in turn transfers a disulfide to the substrate protein. Current views suggest that the disulfide carrier alternates between binding to the oxidase and the substrate. We have analyzed the cooperation of the disulfide relay components during import of precursors into mitochondria and identified a ternary complex of all three components. The ternary complex represents a transient and intermediate step in the oxidation of intermembrane space precursors, where the oxidase Erv1 promotes disulfide transfer to the precursor while both oxidase and precursor are associated with the disulfide carrier Mia40

Model of surface instabilities induced by stress

We propose a model based on a Ginzburg-Landau approach to study a strain relief mechanism at a free interface of a non-hydrostatically stressed solid, commonly observed in thin-film growth. The evolving instability, known as the Grinfeld instability, is studied numerically in two and three dimensions. Inherent in the description is the proper treatment of nonlinearities. We find these nonlinearities can lead to competitive coarsening of interfacial structures, corresponding to different wavenumbers, as strain is relieved. We suggest ways to experimentally measure this coarsening.Comment: 4 pages (3 figures included

Grandes transacciones de tierras como mecanismo de apropiación y exportación de agua en la región del Chaco salteño

El fenómeno global de las grandes transacciones de tierras se potenció en los últimos años debido al aumento de la producción de alimentos. En Argentina, este fenómeno refleja también un proceso histórico de apropiación de tierra y de otros recursos naturales asociados, especialmente el acceso al agua. En la región del Chaco Salteño, el fenómeno se hace más notorio por la fuerte expansión de la frontera agropecuaria. En este trabajo se utilizó una base de datos global que se complementó con datos locales para identificar grandes transacciones de tierras, el tipo de producción en las mismas y otros datos que sirvieron para calcular la huella hídrica y el agua virtual asociadas a la producción agropecuaria en estas tierras. Estos dos indicadores permiten determinar la cantidad de agua utilizada para la producción de cultivos característicos de la región y también la cantidad de agua que es exportada a través de su comercialización en el mercado global de alimentos.The global phenomenon of large-scale land acquisitions intensified in recent years due to the increase in food production. In Argentina, this phenomenon reflects a historical process of appropriation of land and related natural resources, mainly water. In the Chaco region, land acquisitions have intensified together with the expansion of the so-called agricultural frontier. In this study, we estimated the water footprint and virtual water flows associated to large-scale land acquisitions in the Chaco region. Information on large-scale land acquisitions was obtained from the Land Matrix. Some information was verified during field trips to the study area. The water footprint and virtual water flows indicate the amount of water used for the production of specific crops and the water exported through their trade in the global food market.Asociación Argentina de Energías Renovables y Medio Ambiente (ASADES

Deficiency in the LIM-only protein Fhl2 impairs skin wound healing

After skin wounding, the repair process is initiated by the release of growth factors, cytokines, and bioactive lipids from injured vessels and coagulated platelets. These signal molecules induce synthesis and deposition of a provisional extracellular matrix, as well as fibroblast invasion into and contraction of the wounded area. We previously showed that sphingosine-1-phosphate (S1P) triggers a signal transduction cascade mediating nuclear translocation of the LIM-only protein Fhl2 in response to activation of the RhoA GTPase (Muller, J.M., U. Isele, E. Metzger, A. Rempel, M. Moser, A. Pscherer, T. Breyer, C. Holubarsch, R. Buettner, and R. Schule. 2000. EMBO J. 19:359–369; Muller, J.M., E. Metzger, H. Greschik, A.K. Bosserhoff, L. Mercep, R. Buettner, and R. Schule. 2002. EMBO J. 21:736–748.). We demonstrate impaired cutaneous wound healing in Fhl2-deficient mice rescued by transgenic expression of Fhl2. Furthermore, collagen contraction and cell migration are severely impaired in Fhl2-deficient cells. Consequently, we show that the expression of α-smooth muscle actin, which is regulated by Fhl2, is reduced and delayed in wounds of Fhl2-deficient mice and that the expression of p130Cas, which is essential for cell migration, is reduced in Fhl2-deficient cells. In summary, our data demonstrate a function of Fhl2 as a lipid-triggered signaling molecule in mesenchymal cells regulating their migration and contraction during cutaneous wound healing

HER2 and ESR1 mRNA expression levels and response to neoadjuvant trastuzumab plus chemotherapy in patients with primary breast cancer

Introduction: Recent data suggest that benefit from trastuzumab and chemotherapy might be related to expression of HER2 and estrogen receptor (ESR1). Therefore, we investigated HER2 and ESR1 mRNA levels in core biopsies of HER2-positive breast carcinomas from patients treated within the neoadjuvant GeparQuattro trial. Methods: HER2 levels were centrally analyzed by immunohistochemistry (IHC), silver in-situ hybridization (SISH) and qRT-PCR in 217 pretherapeutic formalin-fixed, paraffin-embedded (FFPE) core biopsies. All tumors had been HER2-positive by local pathology and had been treated with neoadjuvant trastuzumab/ chemotherapy in GeparQuattro. Results: Only 73% of the tumors (158 of 217) were centrally HER2-positive (cHER2-positive) by IHC/SISH, with cHER2-positive tumors showing a significantly higher pCR rate (46.8% vs. 20.3%, p<0.0005). HER2 status by qRT-PCR showed a concordance of 88.5% with the central IHC/SISH status, with a low pCR rate in those tumors that were HER2-negative by mRNA analysis (21.1% vs. 49.6%, p<0.0005). The level of HER2 mRNA expression was linked to response rate in ESR1-positive tumors, but not in ESR1-negative tumors. HER2 mRNA expression was significantly associated with pCR in the HER2-positive/ESR1-positive tumors (p=0.004), but not in HER2-positive/ESR1-negative tumors. Conclusions: Only patients with cHER2-positive tumors - irrespective of the method used - have an increased pCR rate with trastuzumab plus chemotherapy. In patients with cHER2-negative tumors the pCR rate is comparable to the pCR rate in the non-trastuzumab treated HER-negative population. Response to trastuzumab is correlated to HER2 mRNA levels only in ESR1-positive tumors. This study adds further evidence to the different biology of both subsets within the HER2-positive group

Lsd1 ablation triggers metabolic reprogramming of brown adipose tissue

Previous work indicated that lysine-specific demethylase 1 (Lsd1) can positively regulate the oxidative and thermogenic capacities of white and beige adipocytes. Here we investigate the role of Lsd1 in brown adipose tissue (BAT) and find that BAT- selective Lsd1 ablation induces a shift from oxidative to glycolytic metabolism. This shift is associated with downregulation of BAT-specific and upregulation of white adipose tissue (WAT)-selective gene expression. This results in the accumulation of di- and triacylglycerides and culminates in a profound whitening of BAT in aged Lsd1- deficient mice. Further studies show that Lsd1 maintains BAT properties via a dual role. It activates BAT-selective gene expression in concert with the transcription factor Nrf1 and represses WAT-selective genes through recruitment of the CoREST complex. In conclusion, our data uncover Lsd1 as a key regulator of gene expression and metabolic function in BAT

Nutrient Cycling in Tropical and Temperate Coastal Waters: Is Latitude Making a Difference?

Tropical coastal waters are highly dynamic and amongst the most biogeochemically active zones in the ocean. This review compares nitrogen (N) and phosphorus (P) cycles in temperate and tropical coastal waters. We review the literature to identify major similarities and differences between these two regions, specifically with regards to the impact of environmental factors (temperature, sunlight), riverine inputs, groundwater, lateral fluxes, atmospheric deposition, nitrogen fixation, organic nutrient cycling, primary production, respiration, sedimentary burial, denitrification and anammox. Overall, there are some similarities but also key differences in nutrient cycling, with differences relating mainly to temperature, sunlight, and precipitation amounts and patterns. We conclude that due to the differences in biogeochemical processes, we cannot directly apply cause and effect relationships and models from temperate systems in tropical coastal waters. Our review also highlights the considerable gaps in knowledge of the biogeochemical processes of tropical coastal waters compared with temperate systems. Given the ecological and societal importance of tropical coastal waters, we hope that highlighting the differences and similarities to temperate systems as well as the existing gaps, will inspire further studies on their biogeochemical processes. Such knowledge will be essential to better understand and forecast impacts on tropical coastal nutrient cycling at local, regional, and global scales

Медицинские и социальные аспекты коммерческого секса

Представлены демографические, медицинские, психологические и социальные характеристики женщин, оказывающих платные сексуальные услуги. Обсуждается проблема легализации и регламентации проституции в контексте профилактики инфекций, передающихся половым путем, и заражения ВИЧ.Demographic, medical, psychological and social characteristics of women rendering sexual services are described. The problem of legalization and regulation of prostitution in the context of prevention of sexually transmitted infections and HIV is discussed

ThX - a next-generation probe for the early detection of amyloid aggregates.

Neurodegenerative diseases such as Alzheimer's and Parkinson's are associated with protein misfolding and aggregation. Recent studies suggest that the small, rare and heterogeneous oligomeric species, formed early on in the aggregation process, may be a source of cytotoxicity. Thioflavin T (ThT) is currently the gold-standard fluorescent probe for the study of amyloid proteins and aggregation processes. However, the poor photophysical and binding properties of ThT impairs the study of oligomers. To overcome this challenge, we have designed Thioflavin X, (ThX), a next-generation fluorescent probe which displays superior properties; including a 5-fold increase in brightness and 7-fold increase in binding affinity to amyloidogenic proteins. As an extrinsic dye, this can be used to study unique structural amyloid features both in bulk and on a single-aggregate level. Furthermore, ThX can be used as a super-resolution imaging probe in single-molecule localisation microscopy. Finally, the improved optical properties (extinction coefficient, quantum yield and brightness) of ThX can be used to monitor structural differences in oligomeric species, not observed via traditional ThT imaging