Ecological comparison of the risks of mother-to-child transmission and clinical manifestations of congenital toxoplasmosis according to prenatal treatment protocol

We compared the relative risks of mother-to-child transmission of Toxoplasma gondii and clinical manifestations due to congenital toxoplasmosis associated with intensive prenatal treatment in Lyon and Austria, short term treatment in 51% of Dutch women, and no treatment in Danish women. For each cohort, relative risks were standardized for gestation at seroconversion. In total, 856 mother–child pairs were studied: 549 in Lyon, 133 in Austria, 123 in Denmark and 51 in The Netherlands. The relative risk for mother-to-child transmission compared to Lyon was 1·24 (95% CI: 0·88, 1·59) in Austria; 0·59 (0·41, 0·81) in Denmark; and 0·65 (0·37, 1·01) in The Netherlands. Relative risks for clinical manifestations compared with Lyon (adjusted for follow-up to age 3 years) were: Austria 0·19 (0·04, 0·51); Denmark 0·60 (0·13, 1·08); and The Netherlands 1·46 (0·51, 2·72). There was no clear evidence that the risk of transmission or of clinical manifestations was lowest in centres with the most intensive prenatal treatment

Long term in vitro expansion of epithelial stem cells enabled by pharmacological inhibition of PAK1-ROCK-Myosin II and TGF-β signaling

Summary: Despite substantial self-renewal capability in vivo, epithelial stem and progenitor cells located in various tissues expand for a few passages in vitro in feeder-free condition before they succumb to growth arrest. Here, we describe the EpiX method, which utilizes small molecules that inhibit PAK1-ROCK-Myosin II and TGF-β signaling to achieve over one trillion-fold expansion of human epithelial stem and progenitor cells from skin, airway, mammary, and prostate glands in the absence of feeder cells. Transcriptomic and epigenomic studies show that this condition helps epithelial cells to overcome stresses for continuous proliferation. EpiX-expanded basal epithelial cells differentiate into mature epithelial cells consistent with their tissue origins. Whole-genome sequencing reveals that the cells retain remarkable genome integrity after extensive in vitro expansion without acquiring tumorigenicity. EpiX technology provides a solution to exploit the potential of tissue-resident epithelial stem and progenitor cells for regenerative medicine. : Zhang et al. screen a small-molecule collection and find that pharmacologic inhibition of TGF-β and PAK1-ROCK-Myosin II, in low calcium conditions, supports extended expansion of epithelial stem cells in 2D format. This approach enhances the potential of tissue-resident epithelial stem cells for cell therapy. Keywords: epithelial stem and progenitor cells, cell culture method, TGF-β, PAK1/ROCK/Myosin II, feeder-free, regenerative medicine, cell therap

GILZ-mimics as novel therapeutic agents for progressive multiple sclerosis

poster abstractMultiple sclerosis (MS), a leading cause of neurological disability is an inflammatory demyelinating disease of the central nervous system (CNS). The clinical course of MS is highly variable ranging from isolated neurologic episodes to frequently relapsing or progressive disease. Currently there are no effective treatments for progressive MS. The long-term goal of this project is to evaluate a novel therapeutic strategy for progressive MS. Under physiological conditions signaling via the transcription factor, nuclear factor-kappa B (NF-κB) and glucocorticoid (GC) stimulation pathways regulate the immuno-inflammatory responses of the CNS resident glial cells. While NF-κB induces transcriptional activation, signaling via GC receptor functions to suppress immune responses. Persistent activation of NF-κB in the glial cells precipitates neuronal degeneration and axonal loss characteristic of progressive MS. Interactome analysis between the GC and NF-κB pathways suggested a novel strategy to inhibit NF-κB. Glucocorticoid-induced leucine zipper (GILZ) is a GC inducible protein that binds p65, the functionally critical subunit of NF-κB, and prevent transactivation of pathological mediators. The sites of interaction are localized to the proline rich region of the GILZ protein and the p65 transactivation domain. A 23 residue GILZ peptide prevented nuclear translocation of p65 and suppressed disease in an animal model of MS. Structurally GILZ peptide adopted polyproline type II (PPII) helical conformation, a favorable feature for drug development. The objective of this study is to optimize the lead peptide and develop drug like analogs. Specific features of the GILZ-p65 interactions were adapted in the design of over 25 GILZ analogs such that each exhibit optimum PPII helix, bind p65 transactivation domain and potentially accommodate modified residues that enhance the binding specificity with the p65. The analogs were ranked after passing through the Lipinski filter to determine the drug like properties. The top ranked analogs will be evaluated for functional efficacy

Where is iron in erionite? A multidisciplinary study on fibrous erionite-Na from Jersey (Nevada, USA)

Fibrous erionite is a mineral fibre of great concern but to date mechanisms by which it induces cyto- and geno-toxic damage, and especially the role of iron associated to this zeolite species, remain poorly understood. One of the reasons is that we still don\u2019t know exactly where iron is in natural erionite. This work is focused on fibrous erionite-Na from Jersey (Nevada, USA) and attempts to draw a general model of occurrence of iron in erionite and relationship with toxicity mechanisms. It was found that iron is present as 6-fold coordinated Fe3+ not part of the zeolite structure. The heterogeneous nature of the sample was revealed as receptacle of different iron-bearing impurities (amorphous iron-rich nanoparticles, micro-particles of iron oxides/hydroxides, and flakes of nontronite). If iron is not part of the structure, its role should be considered irrelevant for erionite toxicity, and other factors like biopersistence should be invoked. An alternative perspective to the proposed model is that iron rich nano-particles and nontronite dissolve in the intracellular acidic environment, leaving a residue of iron atoms at specific surface sites anchored to the windows of the zeolite channels. These sites may be active later as low nuclearity groups

Разработка информационных систем управления рисками для предметных областей

This paper is about specifics of developing risk management information system in construction company and advertising business

Liver transplant outcomes after ex vivo machine perfusion: a meta-analysis

Background: The pressure on liver-transplant programmes has expanded the usage of extended-criteria allografts. Machine perfusion may be better than conventional static cold storage (SCS) in alleviating ischaemia-reperfusion injury in this setting. Recipient outcomes with hypothermic or normothermic machine perfusion were assessed against SCS here. Methods: A search in MEDLINE, EMBASE and Scopus was conducted in February 2021. Primary studies investigating ex vivo machine perfusion were assessed for the following outcomes: morbidity, ICU and hospital stay, graft and patient survival rates and relative costs. Meta-analysis was performed to obtain pooled summary measures. Results: Thirty-four articles involving 1742 patients were included, of which 20 were used for quantitative synthesis. Odds ratios favoured hypothermic machine perfusion (over SCS) with less early allograft dysfunction, ischaemic cholangiopathy, non-anastomotic strictures and graft loss. Hypothermic machine perfusion was associated with a shorter hospital stay and normothermic machine perfusion with reduced graft injury. Two randomized clinical trials found normothermic machine perfusion reduced major complication risks. Conclusion: Machine perfusion assists some outcomes with potential cost savings

Twinned calcite as an indicator of high differential stresses and low shock pressure conditions during impact cratering

Shock-related calcite twins are characterized in calcite-bearing metagranite cataclasites within crystalline megablocks of the Ries impact structure, Germany, as well as in cores from the FBN1973 research drilling. The calcite likely originates from pre-impact veins within the Variscan metagranites and gneisses, while the cataclasis is due to the Miocene impact. Quartz in the metagranite components does not contain planar deformation features, indicating low shock pressures (1/μm) of twins with widths <100 nm. Different types of twins (e-, f-, and r-twins) crosscutting each other can occur in one grain. Interaction of r- and f-twins results in a-type domains characterized by a misorientation relative to the host with a misorientation angle of 35°–40° and a misorientation axis parallel to an a-axis. Such a-type domains have not been recorded from deformed rocks in nature before. The high twin density and activation of different twin systems in one grain require high differential stresses (on the order of 1 GPa). Twinning of calcite at high differential stresses is consistent with deformation during impact cratering at relatively low shock pressure conditions. The twinned calcite microstructure can serve as a valuable low shock barometer

Defective antigen presentation by monocytes in ESRD patients not responding to hepatitis B vaccination: impaired HBsAg internalization and expression of ICAM-1 and HLA-DR/Ia molecules

This study was undertaken to evaluate the monocyte function of uraemic non-responders to hepatitis B vaccination. Therefore, some parameters concerning antigen processing by monocytes (Mo) as antigen presenting cells (APC) were analysed. It was found that in uraemic non-responders, (1) the internalization of HBsAg by monocytes was significantly decreasjed—HBsAg complexed with specific IgG or as immune complex isolated from patients is better internalized compared with free HBsAg; (2) during antigen presentation the expression of adhesion (ICAM-1) and accessory (HLA-DR/Ia) molecules was significantly decreased in uraemic patients, especially in non-responders; and (3) impaired internalization of HBsAg as well as a decrease in ICAM-1 and HLA-DR/Ia expression, correlated well with the blunted proliferation of CD4+ T cells stimulated by autologous monocytes induced by HBsAg