Paroxysmal kinesigenic dyskinesias is a paroxysmal movement disorder characterized by recurrent, brief attacks of abnormal involuntary movements induced by sudden voluntary movements. Although ...several loci, including the pericentromeric region of chromosome 16, have been linked to paroxysmal kinesigenic dyskinesias, the causative gene has not yet been identified. Here, we identified proline-rich transmembrane protein 2 (PRRT2) as a causative gene of paroxysmal kinesigenic dyskinesias by using a combination of exome sequencing and linkage analysis. Genetic linkage mapping with 11 markers that encompassed the pericentromeric of chromosome 16 was performed in 27 members of two families with autosomal dominant paroxysmal kinesigenic dyskinesias. Then, the whole-exome sequencing was performed in three patients from these two families. By combining the defined linkage region (16p12.1-q12.1) and the results of exome sequencing, we identified an insertion mutation c.649_650InsC (p.P217fsX7) in one family and a nonsense mutation c.487C>T (p.Q163X) in another family. To confirm our findings, we sequenced the exons and flanking introns of PRRT2 in another three families with paroxysmal kinesigenic dyskinesias. The c.649_650InsC (p.P217fsX7) mutation was identified in two of these families, whereas a missense mutation, c.796C>T (R266W), was identified in another family with paroxysmal kinesigenic dyskinesias. All of these mutations completely co-segregated with the phenotype in each family. None of these mutations was identified in 500 normal unaffected individuals of matched geographical ancestry. Thus, we have identified PRRT2 as the first causative gene of paroxysmal kinesigenic dyskinesias, warranting further investigations to understand the pathogenesis of this disorder.
Anemia is characteristic of myelodysplastic syndromes (MDS). The mechanisms of anemia in MDS are unclear. Using a mouse genetic approach, here we show that dual deficiency of mDia1 and miR-146a, ...encoded on chromosome 5q and commonly deleted in MDS (del(5q) MDS), causes an age-related anemia and ineffective erythropoiesis mimicking human MDS. We demonstrate that the ageing bone marrow microenvironment is important for the development of ineffective erythropoiesis in these mice. Damage-associated molecular pattern molecules (DAMPs), whose levels increase in ageing bone marrow, induced TNFα and IL-6 upregulation in myeloid-derived suppressor cells (MDSCs) in mDia1/miR-146a double knockout mice. Mechanistically, we reveal that pathologic levels of TNFα and IL-6 inhibit erythroid colony formation and differentially affect terminal erythropoiesis through reactive oxygen species-induced caspase-3 activation and apoptosis. Treatment of the mDia1/miR-146a double knockout mice with all-trans retinoic acid, which promoted the differentiation of MDSCs and ameliorated the inflammatory bone marrow microenvironment, significantly rescued anemia and ineffective erythropoiesis. Our study underscores the dual roles of the ageing microenvironment and genetic abnormalities in the pathogenesis of ineffective erythropoiesis in del(5q) MDS.
A recent study has suggested that yeast cell wall product (YP) enhanced serum hemagglutination inhibition (HI) titers and intestinal sIgA responses in chickens immunized with Newcastle disease virus ...(NDV) vaccine. In the present study, the cell-mediated immune responses elicited by NDV and YP were investigated in commercial broilers. Broilers were fed 0 or 0.1% YP and immunized with a live NDV vaccine via an intraocular-and-intranasal route at 14 and 28 days old. After that, blood samples were collected for determination of HI titer, cytokine content, and blood analysis. Eight chickens were randomly selected from each group and sacrificed. Lymphocytes were harvested from the spleens for lymphocyte proliferation and flow cytometry analysis. Total RNA was extracted from spleen and jejunum for RT-qPCR analysis. The results showed that YP significantly increased serum concentration of IL-4, IL-6, IFN-γ, TNF-β, as well as promoted lymphocytes proliferation in broilers immunized with NDV vaccine. The enhanced cell-mediated immunity is correlated with the upregulated mRNA expression of TGF-β, IL-6, TLR5, GATA-3, and T-bet in the spleen and upregulated mRNA expression of CCR-9, J-chain, pIgR, and TLR3 in the jejunum of chickens. It is noteworthy that no significant side effect was observed after the administration of YP. Therefore, YP could be safely used as potential immunopotentiator assisting NDV vaccine for chickens.
The relatively low strength of aluminum (Al) alloys and Al matrix composites at high temperatures has greatly limited their applications in aerospace and automobile areas. In this study, ...high-performance carbon nanotubes (CNTs)/Al composites with high room-temperature tensile strength over 500 MPa were tested at elevated temperatures up to 400 °C. Results showed that the strength of CNTs/Al composites increased with increasing CNT content up to 5 vol%. CNTs/Al composites showed improved reinforcing effects at elevated temperatures compared with those at room temperature. Consequently, the 5 vol%CNTs/Al composite achieved high tensile strength of 205 MPa when tested at 400 °C, which was superior to those values (less than 100 MPa) of most available Al matrix composites. The underlying mechanism was thoroughly discussed from the grain sizes, phase compositions, interface reaction and strengthening mechanisms at different testing temperatures. The results have revealed the excellent high-temperature properties of CNTs/Al composites and their potential use at elevated temperatures.
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•CNTs could mitigate the strength deterioration in composites at high temperatures.•The thermal stability of CNTs/Al composite was higher than Raw Al and BM Al.•The ultimate tensile strength of CNTs/Al composite achieved 205 MPa at temperature 400 °C.•CNTs reinforcing effect at high temperatures was superior to other reinforcement.
Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) is associated with an increased risk of graft failure and severe graft-versus-host disease (GVHD). Recent studies have shown that ...mesenchymal stromal cells (MSCs) display potent immunosuppressive effects and can support normal hematopoiesis. In a multi-center trial, we co-transplanted culture-expanded donor-derived bone marrow MSCs (BM-MSCs) into 35 children with severe aplastic anemia (SAA) undergoing haplo-HSCT. All 35 patients (100%) achieved hematopoietic reconstitution and showed sustained full donor chimerism. The median time for myeloid engraftment was 14 days (range 10–22 days), while that for platelet engraftment was 18 days (range 9–36 days). The incidence of grade II–IV acute GVHD and chronic GVHD was 25.71 and 22.86%, respectively. The overall survival rate was 85.71% with a median of 22 months (range 3.5–37 months). The combined transplantation of haploidentical HSCs and BM-MSCs into children with SAA without an HLA-identical sibling donor is relatively safe and may represent an effective new therapy to improve survival rates and reduce the risk of graft failure.
Aims/hypothesis We sought to establish the extent and basis for adaptive changes in beta cell numbers in human pregnancy. Methods Pancreas was obtained at autopsy from women who had died while ...pregnant (n = 18), post-partum (n = 6) or were not pregnant at or shortly before death (controls; n = 20). Pancreases were evaluated for fractional pancreatic beta cell area, islet size and islet fraction of beta cells, beta cell replication (Ki67) and apoptosis (TUNEL), and indirect markers of beta cell neogenesis (insulin-positive cells in ducts and scattered beta cells in pancreas). Results The pancreatic fractional beta cell area was increased by ∼1.4-fold in human pregnancy, with no change in mean beta cell size. In pregnancy there were more small islets rather than an increase in islet size or beta cells per islet. No increase in beta cell replication or change in beta cell apoptosis was detected, but duct cells positive for insulin and scattered beta cells were increased with pregnancy. Conclusions/interpretation The adaptive increase in beta cell numbers in human pregnancy is not as great as in most reports in rodents. This increase in humans is achieved by increased numbers of beta cells in apparently new small islets, rather than duplication of beta cells in existing islets, which is characteristic of pregnancy in rodents.
Nanoparticles strung on nanotubes, like a beaded necklace (see Figure), have been synthesized by a simple low temperature supercritical solution method. That the crystalline spherical Co3O4 ...nanoparticles on multiwalled carbon nanotubes are a step towards high‐density integrated nanometer‐scale functional devices is demonstrated by the fabrication of Schottky junction diodes from individual “beaded” nanotubes.
•A new method enables high-throughput fabrication of micro-and nanomechanical samples.•A new tool combing femtosecond laser and focused ion beam (FIB) for efficient and precise machining.•In-situ ...mechanical testing sample can be fabricated site-specific in all dimensions.•The processable sample size ranges from nanometer to millimeter; size effect study.
There is an increasing interest in understanding materials’ mechanical properties at small length scales. Mechanical testing from nano- to meso-scale has seen a rapid development over the last decade, leading to a high demand of sample fabrication. In the present work, a novel method of micro-and nanomechanical sample preparation is introduced based on a new technique combining femtosecond laser and focused ion beam (FIB), namely LaserFIB. The new method greatly simplifies the sample preparation workflow by taking advantage of the fast milling-rate of femtosecond laser and the high precision of FIB. It significantly improves the processing efficiency and success rate, allowing for the high-throughput preparation of reproducible micro- and nanomechanical specimens. The novel method has far more advantages: (1) it allows for site-specific sample preparation based on scanning electron microscope (SEM) characterization (lateral and depth direction of bulk material) (2) following the new workflow, mechanical specimens are still connected to the bulk by its natural bonding, yielding more reliable mechanical testing results; (3) it extends the processable sample size to meso-scale while still remaining high precision and high efficiency; (4) the seamless transfer between laser and FIB/SEM chamber greatly reduces the risk of sample damage and is very friendly for environmental sensitive materials. The new method solves critical problems for high-throughput multiscale mechanical sample preparation, greatly contributing to the development of nano to meso-scale mechanical testing by making sample preparation efficient and convenient.
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