New combined CFH/MCP mutations and a rare clinical course in atypical haemolytic uraemic syndrome

Atypical haemolytic uraemic syndrome (aHUS) is a rare, life-threatening, chronic, genetic disease due to uncontrolled alternative pathway complement activation. In this report, we discuss the case of a heterozygous carrier of a mutation on both factor H and membrane cofactor protein, who persistently presents haemolytic anaemia without need for blood transfusions, normal platelet count, normal renal function and no signs or symptoms of organ injury due to thrombotic microangiopathy 4 years after the diagnosis of aHUS.info:eu-repo/semantics/publishedVersio

A less expensive NiMnGa based Heusler alloy for magnetic refrigeration

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)We present a study of the substitution of Mn by Cu on the compound Ni2Mn1-xCuxGa0.9Al0.1, showing that the substitution of a small amount of Al on the Ga site does not affect the magnetic and magnetocaloric potential compared to Ni-2(Mn,Cu)Ga alloy. The samples were prepared with 10% substitution of Al and with Cu concentrations of x = 0.0, 0.2, and 0.3. Magnetization measurements as a function of temperature performed from 10 to 400 K, with an applied field of 0.02 T showed a ferromagnetic state, with critical temperature T-c = 295 and 300 K for the samples with Cu, x = 0.2 and 0.3, respectively. For the sample without Cu, a complex behavior is observed at T-c = 370 K, with martensitic transition at 220 K and a premartensitic at 250 K. Analysis of x-rays diffractograms at room temperature show a L2(1) structure for x = 0.0, while for x = 0.2 a mixture of L2(1) and martensitic is present, and the sample with x = 0.3 it is in a fully martensitic phase. Heat capacity measurements were performed in order to calculate magnetocaloric effect in the samples. The results indicate that in Ni(Mn,Cu)Ga alloys, a partial substitution of Ga by Al still produce a high refrigerant capacity while reducing the costs of fabrication. (C) 2012 American Institute of Physics. [doi:10.1063/1.3675064]1117Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP

Limited genomic divergence between intraspecific forms of Culex pipiens under different ecological pressures

Abstract Background: Divergent selection can be a major driver of ecological speciation. In insects of medical importance, understanding the speciation process is both of academic interest and public health importance. In the West Nile virus vector Culex pipiens, intraspecific pipiens and molestus forms vary in ecological and physiological traits. Populations of each form appear to share recent common ancestry but patterns of genetic differentiation across the genome remain unknown. Here, we undertook an AFLP genome scan on samples collected from both sympatric and allopatric populations from Europe and the USA to quantify the extent of genomic differentiation between the two forms. Results: The forms were clearly differentiated but each exhibited major population sub-structuring between continents. Divergence between pipiens and molestus forms from USA was higher than in both inter- and intra-continental comparisons with European samples. The proportion of outlier loci between pipiens and molestus (≈3 %) was low but consistent in both continents, and similar to those observed between sibling species of other mosquito species which exhibit contemporary gene flow. Only two of the outlier loci were shared between inter-form comparisons made within Europe and USA. Conclusion: This study supports the molestus and pipiens status as distinct evolutionary entities with low genomic divergence. The low number of shared divergent loci between continents suggests a relatively limited number of genomic regions determining key typological traits likely to be driving incipient speciation and/or adaptation of molestus to anthropogenic habitats

Highly Dynamic Host Actin Reorganization around Developing Plasmodium Inside Hepatocytes

Plasmodium sporozoites are transmitted by Anopheles mosquitoes and infect hepatocytes, where a single sporozoite replicates into thousands of merozoites inside a parasitophorous vacuole. The nature of the Plasmodium-host cell interface, as well as the interactions occurring between these two organisms, remains largely unknown. Here we show that highly dynamic hepatocyte actin reorganization events occur around developing Plasmodium berghei parasites inside human hepatoma cells. Actin reorganization is most prominent between 10 to 16 hours post infection and depends on the actin severing and capping protein, gelsolin. Live cell imaging studies also suggest that the hepatocyte cytoskeleton may contribute to parasite elimination during Plasmodium development in the liver

Enzymatic degradation of starch thermoplastic blends using samples of different thickness

The material studied was a thermoplastic blend of corn starch with a poly(ethylene-vinyl alcohol) copolymer, SEVA-C. The influence of both the material’s exposed surface and enzyme concentration on degradation kinetics was studied. As α-amylase is present in the blood plasma, experiments were performed, varying the material thickness and the α-amylase between 50 and 100 units/l, at 37°C, lasting up to 90 days. Four different batches using SEVA-C and starch samples of different thickness were performed. The positive correlation between degradation rate and the exposed material surface was confirmed, since thin films with larger exposed surfaces were degraded faster than thick square plates having the same total mass. The degradation extent depends on the total amount of amorphous starch present in the formulation rather than on the amount of enzyme used and the minimum thickness to ensure maximum degradation was estimated to be close to 0.25 mm

The actin-myosin regulatory MRCK kinases: regulation, biological functions and associations with human cancer

The contractile actin-myosin cytoskeleton provides much of the force required for numerous cellular activities such as motility, adhesion, cytokinesis and changes in morphology. Key elements that respond to various signal pathways are the myosin II regulatory light chains (MLC), which participate in actin-myosin contraction by modulating the ATPase activity and consequent contractile force generation mediated by myosin heavy chain heads. Considerable effort has focussed on the role of MLC kinases, and yet the contributions of the myotonic dystrophy-related Cdc42-binding kinases (MRCK) proteins in MLC phosphorylation and cytoskeleton regulation have not been well characterized. In contrast to the closely related ROCK1 and ROCK2 kinases that are regulated by the RhoA and RhoC GTPases, there is relatively little information about the CDC42-regulated MRCKα, MRCKβ and MRCKγ members of the AGC (PKA, PKG and PKC) kinase family. As well as differences in upstream activation pathways, MRCK and ROCK kinases apparently differ in the way that they spatially regulate MLC phosphorylation, which ultimately affects their influence on the organization and dynamics of the actin-myosin cytoskeleton. In this review, we will summarize the MRCK protein structures, expression patterns, small molecule inhibitors, biological functions and associations with human diseases such as cancer

Comparative Expression Profiling of the Chlamydia trachomatis pmp Gene Family for Clinical and Reference Strains

Chlamydia trachomatis, an obligate intracellular pathogen, is a leading worldwide cause of ocular and urogenital diseases. Advances have been made in our understanding of the nine-member polymorphic membrane protein (Pmp) gene (pmp) family of C. trachomatis. However, there is only limited information on their biologic role, especially for biological variants (biovar) and clinical strains.We evaluated expression for pmps throughout development for reference strains E/Bour and L2/434, representing different biovars, and for clinical E and L2 strains. Immunoreactivity of patient sera to recombinant (r)Pmps was also determined. All pmps were expressed at two hours. pmpA had the lowest expression but was up-regulated at 12 h for all strains, indicating involvement in reticulate body development. For pmpD, expression peaked at 36 h. Additionally, 57.7% of sera from infected and 0% from uninfected adolescents were reactive to rPmpD (p = 0.001), suggesting a role in immunogenicity. pmpF had the highest expression levels for all clinical strains and L2/434 with differential expression of the pmpFE operon for the same strains. Sera were nonreactive to rPmpF despite immunoreactivity to rMOMP and rPmpD, suggesting that PmpF is not associated with humoral immune responses. pmpFE sequences for clinical strains were identical to those of the respective reference strains. We identified the putative pmpFE promoter, which was, surprisingly, 100% conserved for all strains. Analyses of ribosomal binding sites, RNase E, and hairpin structures suggested complex regulatory mechanism(s) for this >6 Kb operon.The dissimilar expression of the same pmp for different C. trachomatis strains may explain different strain-specific needs and phenotypic distinctions. This is further supported by the differential immunoreactivity to rPmpD and rPmpF of sera from patients infected with different strains. Furthermore, clinical E strains did not correlate with the E reference strain at the gene expression level, reinforcing the need for expansive studies of clinical strains

A unique serum IgG glycosylation signature predicts development of Crohn’s disease and is associated with pathogenic antibodies to mannose glycan

Inflammatory bowel disease (IBD) is characterized by chronic inflammation in the gut. There is growing evidence in Crohn’s disease (CD) of the existence of a preclinical period characterized by immunological changes preceding symptom onset that starts years before diagnosis. Gaining insight into this preclinical phase will allow disease prediction and prevention. Analysis of preclinical serum samples, up to 6 years before IBD diagnosis (from the PREDICTS cohort), revealed the identification of a unique glycosylation signature on circulating antibodies (IgGs) characterized by lower galactosylation levels of the IgG fragment crystallizable (Fc) domain that remained stable until disease diagnosis. This specific IgG2 Fc glycan trait correlated with increased levels of antimicrobial antibodies, specifically anti-Saccharomyces cerevisiae (ASCA), pinpointing a glycome–ASCA hub detected in serum that predates by years the development of CD. Mechanistically, we demonstrated that this agalactosylated glycoform of ASCA IgG, detected in the preclinical phase, elicits a proinflammatory immune pathway through the activation and reprogramming of innate immune cells, such as dendritic cells and natural killer cells, via an FcγR-dependent mechanism, triggering NF-κB and CARD9 signaling and leading to inflammasome activation. This proinflammatory role of ASCA was demonstrated to be dependent on mannose glycan recognition and galactosylation levels in the IgG Fc domain. The pathogenic properties of (anti-mannose) ASCA IgG were validated in vivo. Adoptive transfer of antibodies to mannan (ASCA) to recipient wild-type mice resulted in increased susceptibility to intestinal inflammation that was recovered in recipient FcγR-deficient mice. Here we identify a glycosylation signature in circulating IgGs that precedes CD onset and pinpoint a specific glycome–ASCA pathway as a central player in the initiation of inflammation many years before CD diagnosis. This pathogenic glyco-hub may constitute a promising new serum biomarker for CD prediction and a potential target for disease prevention.We wish to acknowledge the Gastroenterology Department of Centro Hospitalar Universitário de Santo António, in particular P. Lago, for providing samples from individuals with established CD. We kindly thank J. Rojo from the Instituto de Investigaciones Químicas (Universidad de Sevilla) for providing us with the di-GlcNAc glycodendrimer. We would also like to acknowledge J. V. Ravetch (Rockefeller University) and M. S. Cragg (University of Southampton) for kindly providing us with the FcγR-deficient mice used in the in vivo studies. S.S.P. acknowledges funding from the US Department of Defense, US Army Medical Research Acquisition Activity and FY18Peer-Reviewed Medical Research Program Investigator-Initiated Research Award (award number W81XWH1920053). S.S.P. also acknowledges funding from the European Crohn’s and Colitis Organisation (ECCO) Pioneer Award 2021, the International Organization for the study of Inflammatory Bowel Disease (IOIBD) and the Portuguese Foundation for Science and Technology (FCT; EXPL/MED-ONC/0496/2021). J.G. acknowledges funding from European Society of Clinical Microbiology and Infectious Diseases (ESCMID ResearchGrant 2022), European Crohn’s and Colitis Organisation (ECCO Grant 2023) and FCT (2020.00088.CEECIND). C.S.R. thanks FCT forfunding (2020.08422.BD). I.A. acknowledges funding from FCT (2022.00337.CEECIND) and the BIAL Foundation and PortugueseMedical Association (Maria de Sousa Award 2023). E.L.-G. thanks FCT for funding (UI/BD/152866/2022). F.P. and Z.H.G. were partially supported by the Kenneth-Rainin Foundation (20210021). B.C. acknowledges funding from FCT(CEECINST/00123/2021/CP1772/CT0001). J.T. acknowledges funding from the Portuguese Society of Gastroenterology and from Luz Saúde (Grupo dE iNvestIgação em Patologia Digestiva LUz Saúde LH.INV.F2019015). This study was also cofunded by the EuropeanUnion (GlycanTrigger, grant agreement number 101093997). The views and opinions expressed are, however, those of the author(s) only and do not necessarily reflect those of the European Union or the European Research Council Executive Agency. Neither the European Union nor the granting authority can be held responsible for them. This study was conducted under support of Peer-Reviewed Medical Research Program (PR180831P1). The views expressed in this article reflect the results of the research conducted by the authors and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, the Henry M. Jackson Foundation for the Advancement of Military Medicine or the US Government. There are no restrictions on its use. This article was prepared while R.M.L. was employed at Henry M. Jackson Foundation for the Advancement of Military Medicine. The opinions expressed in this article are those of the authors and do not reflect the view of the National Institutes of Health, the Department of Health and Human Services or the US Government. C.K.P. is an employee of the US Government. This work was prepared as part of official duties. Title 17 U.S.C. §105provides that ‘Copyright protection under this title is not available for any work of the United States Government.’ Title 17 U.S.C. §101 defines a US Government work as a work prepared by a military service member or employee of the US Government as part of that person’s official duties