Ginger Stimulates Hematopoiesis via Bmp Pathway in Zebrafish

) has been widely used in traditional medicine; however, to date there is no scientific research documenting the potential of ginger to stimulate hematopoiesis. expression in the caudal hematopoietic tissue area. We further confirmed that Bmp/Smad pathway mediates this hematopoiesis promoting effect of ginger by using the Bmp-activated Bmp type I receptor kinase inhibitors dorsomorphin, LND193189 and DMH1.Our study provides a strong foundation to further evaluate the molecular mechanism of ginger and its bioactive components during hematopoiesis and to investigate their effects in adults. Our results will provide the basis for future research into the effect of ginger during mammalian hematopoiesis to develop novel erythropoiesis promoting agents

Defining the Conformational Features of Anchorless, Poorly Neuroinvasive Prions

Infectious prions cause diverse clinical signs and form an extraordinary range of structures, from amorphous aggregates to fibrils. How the conformation of a prion dictates the disease phenotype remains unclear. Mice expressing GPI-anchorless or GPI-anchored prion protein exposed to the same infectious prion develop fibrillar or nonfibrillar aggregates, respectively, and show a striking divergence in the disease pathogenesis. To better understand how a prion's physical properties govern the pathogenesis, infectious anchorless prions were passaged in mice expressing anchorless prion protein and the resulting prions were biochemically characterized. Serial passage of anchorless prions led to a significant decrease in the incubation period to terminal disease and altered the biochemical properties, consistent with a transmission barrier effect. After an intraperitoneal exposure, anchorless prions were only weakly neuroinvasive, as prion plaques rarely occurred in the brain yet were abundant in extracerebral sites such as heart and adipose tissue. Anchorless prions consistently showed very high stability in chaotropes or when heated in SDS, and were highly resistant to enzyme digestion. Consistent with the results in mice, anchorless prions from a human patient were also highly stable in chaotropes. These findings reveal that anchorless prions consist of fibrillar and highly stable conformers. The additional finding from our group and others that both anchorless and anchored prion fibrils are poorly neuroinvasive strengthens the hypothesis that a fibrillar prion structure impedes efficient CNS invasion

V3 Loop Sequence Space Analysis Suggests Different Evolutionary Patterns of CCR5- and CXCR4-Tropic HIV

The V3 loop of human immunodeficiency virus type 1 (HIV-1) is critical for coreceptor binding and is the main determinant of which of the cellular coreceptors, CCR5 or CXCR4, the virus uses for cell entry. The aim of this study is to provide a large-scale data driven analysis of HIV-1 coreceptor usage with respect to the V3 loop evolution and to characterize CCR5- and CXCR4-tropic viral phenotypes previously studied in small- and medium-scale settings. We use different sequence similarity measures, phylogenetic and clustering methods in order to analyze the distribution in sequence space of roughly 1000 V3 loop sequences and their tropism phenotypes. This analysis affords a means of characterizing those sequences that are misclassified by several sequence-based coreceptor prediction methods, as well as predicting the coreceptor using the location of the sequence in sequence space and of relating this location to the CD4+ T-cell count of the patient. We support previous findings that the usage of CCR5 is correlated with relatively high sequence conservation whereas CXCR4-tropic viruses spread over larger regions in sequence space. The incorrectly predicted sequences are mostly located in regions in which their phenotype represents the minority or in close vicinity of regions dominated by the opposite phenotype. Nevertheless, the location of the sequence in sequence space can be used to improve the accuracy of the prediction of the coreceptor usage. Sequences from patients with high CD4+ T-cell counts are relatively highly conserved as compared to those of immunosuppressed patients. Our study thus supports hypotheses of an association of immune system depletion with an increase in V3 loop sequence variability and with the escape of the viral sequence to distant parts of the sequence space

Cardiovascular magnetic resonance imaging of myocardial oedema following acute myocardial infarction: Is whole heart coverage necessary?

© 2016 Hamshere et al. Background: AAR measurement is useful when assessing the efficacy of reperfusion therapy and novel cardioprotective agents after myocardial infarction. Multi-slice (Typically 10-12) T2-STIR has been used widely for its measurement, typically with a short axis stack (SAX) covering the entire left ventricle, which can result in long acquisition times and multiple breath holds. This study sought to compare 3-slice T2-short-tau inversion recovery (T2- STIR) technique against conventional multi-slice T2-STIR technique for the assessment of area at risk (AAR). Methods: CMR imaging was performed on 167 patients after successful primary percutaneous coronary intervention. 82 patients underwent a novel 3-slice SAX protocol and 85 patients underwent standard 10-slice SAX protocol. AAR was obtained by manual endocardial and epicardial contour mapping followed by a semi- automated selection of normal myocardium; the volume was expressed as mass (%) by two independent observers. Results: 85 patients underwent both 10-slice and 3-slice imaging assessment showing a significant and strong correlation (intraclass correlation coefficient = 0.92;p < 0.0001) and a low Bland-Altman limit (mean difference -0.03 ± 3.21 %, 95 % limit of agreement,- 6.3 to 6.3) between the 2 analysis techniques. A further 82 patients underwent 3-slice imaging alone, both the 3-slice and the 10-slice techniques showed statistically significant correlations with angiographic risk scores (3-slice to BARI r = 0.36, 3-slice to APPROACH r = 0.42, 10-slice to BARI r = 0.27, 10-slice to APPROACH r = 0.46). There was low inter-observer variability demonstrated in the 3-slice technique, which was comparable to the 10-slice method (z = 1.035, p = 0.15). Acquisition and analysis times were quicker in the 3-slice compared to the 10-slice method (3-slice median time: 100 seconds (IQR: 65-171 s) vs (10-slice time: 355 seconds (IQR: 275-603 s); p < 0.0001. Conclusions: AAR measured using 3-slice T2-STIR technique correlates well with standard 10-slice techniques, with no significant bias demonstrated in assessing the AAR. The 3-slice technique requires less time to perform and analyse and is therefore advantageous for both patients and clinicians

The GPIIIA PlA2 polymorphism is associated with an increased risk of cardiovascular adverse events

<p>Abstract</p> <p>Background</p> <p>The clinical impact of PlA2 polymorphism has been investigated in several diseases, but the definition of its specific role on thrombotic cardiovascular complications has been challenging. We aimed to explore the effect of PlA2 polymorphism on outcome in patients with atherosclerosis.</p> <p>Methods</p> <p>We studied 400 consecutive patients with coronary artery disease (CAD) undergoing percutaneous coronary intervention. A replication study was conducted in 74 hypertensive patients with cerebrovascular events while a group of 100 healthy subjects was included as control population. PlA genotype was determined by PCR-RFLP on genomic DNA from peripheral blood cells. Major adverse cardiac events (MACE), were considered as end points, and recorded at a mean follow up of 24 ± 4.3 months.</p> <p>Results</p> <p>The frequencies of PlA2 polymorphism was similar between groups and genotype distribution was in Hardy-Weinberg equilibrium. In patients with CAD, the presence of PlA2 allele was associated with higher incidence of cardiac death (13.1% vs. 1.5%, p = 0.0001), myocardial infarction (10.7% vs. 2.6%, p = 0.004) and needs of new revascularization (34.8% vs. 17.7%, p = 0.010). Accordingly, the Kaplan-Meier analysis for event free survival in patients harboring the PlA2 allele showed worse long-term outcome for these patients (p = 0.015). Cox regression analysis identified the presence of PlA2 as an independent predictor of cardiac death (OR: 9.594, 95% CI: 2.6 to 35.3, p = 0.002) and overall MACE (OR: 1.829, 95% CI: 1.054 to 3.176, p = 0.032). In the replication study, the PlA2 polymorphism increased the risk of stroke (OR: 4.1, 95% CI: 1.63-12.4, p = 0.02) over TIA and was identified as an independent risk factor for stroke (B:-1.39; Wald: 7.15; p = 0.001).</p> <p>Conclusions</p> <p>Our study demonstrates that in patients with severe atherosclerosis the presence of PlA2 allele is associated with thrombotic cardiovascular complications.</p

Prion Seeding Activities of Mouse Scrapie Strains with Divergent PrPSc Protease Sensitivities and Amyloid Plaque Content Using RT-QuIC and eQuIC

Different transmissible spongiform encephalopathy (TSE)-associated forms of prion protein (e.g. PrPSc) can vary markedly in ultrastructure and biochemical characteristics, but each is propagated in the host. PrPSc propagation involves conversion from its normal isoform, PrPC, by a seeded or templated polymerization mechanism. Such a mechanism is also the basis of the RT-QuIC and eQuIC prion assays which use recombinant PrP (rPrPSen) as a substrate. These ultrasensitive detection assays have been developed for TSE prions of several host species and sample tissues, but not for murine models which are central to TSE pathogenesis research. Here we have adapted RT-QuIC and eQuIC to various murine prions and evaluated how seeding activity depends on glycophosphatidylinositol (GPI) anchoring and the abundance of amyloid plaques and protease-resistant PrPSc (PrPRes). Scrapie brain dilutions up to 10-8 and 10-13 were detected by RT-QuIC and eQuIC, respectively. Comparisons of scrapie-affected wild-type mice and transgenic mice expressing GPI anchorless PrP showed that, although similar concentrations of seeding activity accumulated in brain, the heavily amyloid-laden anchorless mouse tissue seeded more rapid reactions. Next we compared seeding activities in the brains of mice with similar infectivity titers, but widely divergent PrPRes levels. For this purpose we compared the 263K and 139A scrapie strains in transgenic mice expressing P101L PrPC. Although the brains of 263K-affected mice had no immunoblot-detectable PrPRes, RT-QuIC indicated that seeding activity was comparable to that associated with a high-PrPRes strain, 139A. Thus, in this comparison, RT-QuIC seeding activity correlated more closely with infectivity than with PrPRes levels. We also found that eQuIC, which incorporates a PrPSc immunoprecipitation step, detected seeding activity in plasma from wild-type and anchorless PrP transgenic mice inoculated with 22L, 79A and/or RML scrapie strains. Overall, we conclude that these new mouse-adapted prion seeding assays detect diverse types of PrPSc

On Dorsal Prothoracic Appendages in Treehoppers (Hemiptera: Membracidae) and the Nature of Morphological Evidence

A spectacular hypothesis was published recently, which suggested that the “helmet” (a dorsal thoracic sclerite that obscures most of the body) of treehoppers (Insecta: Hemiptera: Membracidae) is connected to the 1st thoracic segment (T1; prothorax) via a jointed articulation and therefore was a true appendage. Furthermore, the “helmet” was interpreted to share multiple characteristics with wings, which in extant pterygote insects are present only on the 2nd (T2) and 3rd (T3) thoracic segments. In this context, the “helmet” could be considered an evolutionary novelty. Although multiple lines of morphological evidence putatively supported the “helmet”-wing homology, the relationship of the “helmet” to other thoracic sclerites and muscles remained unclear. Our observations of exemplar thoraces of 10 hemipteran families reveal multiple misinterpretations relevant to the “helmet”-wing homology hypothesis as originally conceived: 1) the “helmet” actually represents T1 (excluding the fore legs); 2) the “T1 tergum” is actually the anterior dorsal area of T2; 3) the putative articulation between the “helmet” and T1 is actually the articulation between T1 and T2. We conclude that there is no dorsal, articulated appendage on the membracid T1. Although the posterior, flattened, cuticular evagination (PFE) of the membracid T1 does share structural and genetic attributes with wings, the PFE is actually widely distributed across Hemiptera. Hence, the presence of this structure in Membracidae is not an evolutionary novelty for this clade. We discuss this new interpretation of the membracid T1 and the challenges of interpreting and representing morphological data more broadly. We acknowledge that the lack of data standards for morphology is a contributing factor to misinterpreted results and offer an example for how one can reduce ambiguity in morphology by referencing anatomical concepts in published ontologies