Abnormalities in a gene encoding a messenger RNA splicing enzyme were found in nearly two thirds of patients with myelodysplastic syndromes characterized by ring sideroblasts. Patients with mutations ...had improved survival as compared with those without mutations.
The myelodysplastic syndromes are a heterogeneous group of hematologic cancers characterized by low blood counts, most commonly anemia, and a risk of progression to acute myeloid leukemia.
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These disorders have increased in prevalence and are expected to continue to do so. Blood films and bone marrow–biopsy specimens from patients with myelodysplastic syndromes show dysplastic changes in myeloid cells, with abnormal proliferation and differentiation of one or more lineages. Target genes of recurrent chromosomal aberrations have been mapped,
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,
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and several genes have been identified as recurrently mutated in these disorders, including
NRAS
(encoding neuroblastoma RAS viral oncogene homologue),
TP53
(encoding . . .
The six week eruption of Eyjafjallajökull volcano in 2010 produced heavy ash fall in a sparsely populated area of southern and south eastern Iceland and disrupted European commercial flights for at ...least 6 days. We adopted a protocol for the rapid analysis of volcanic ash particles, for the purpose of informing respiratory health risk assessments. Ash collected from deposits underwent a multi-laboratory physicochemical and toxicological investigation of their mineralogical parameters associated with bio-reactivity, and selected in vitro toxicology assays related to pulmonary inflammatory responses. Ash from the eruption of Grímsvötn, Iceland, in 2011 was also studied. The results were benchmarked against ash from Soufrière Hills volcano, Montserrat, which has been extensively studied since the onset of eruptive activity in 1995.
For Eyjafjallajökull, the grain size distributions were variable: 2–13vol% of the bulk samples were <4µm, with the most explosive phases of the eruption generating abundant respirable particulate matter. In contrast, the Grímsvötn ash was almost uniformly coarse (<3.5vol%<4µm material). Surface area ranged from 0.3 to 7.7m2g−1 for Eyjafjallajökull but was very low for Grímsvötn (<0.6m2g−1). There were few fibre-like particles (which were unrelated to asbestos) and the crystalline silica content was negligible in both eruptions, whereas Soufrière Hills ash was cristobalite-rich with a known potential to cause silicosis. All samples displayed a low ability to deplete lung antioxidant defences, showed little haemolysis and low acute cytotoxicity in human alveolar type-1 like epithelial cells (TT1). However, cell-free tests showed substantial hydroxyl radical generation in the presence of hydrogen peroxide for Grímsvötn samples, as expected for basaltic, Fe-rich ash. Cellular mediators MCP-1, IL-6, and IL-8 showed chronic pro-inflammatory responses in Eyjafjallajökull, Grímsvötn and Soufrière Hills samples, despite substantial differences in the sample mineralogy and eruptive styles.
The value of the pro-inflammatory profiles in differentiating the potential respiratory health hazard of volcanic ashes remains uncertain in a protocol designed to inform public health risk assessment, and further research on their role in volcanic crises is warranted.
•Eyjafjallajökull and Grímsvötn volcanic ash fell on Iceland in 2010 and 2011.•The respiratory hazard was investigated in 2 rapid, multi-disciplinary lab. studies.•Up to 13vol% of the Eyjafjallajökull ash was respirable (<4µm diameter).•Crystalline silica in the samples was negligible and few fibrous particles were observed.•Both ash types showed positive chronic pro-inflammatory responses.
Defining HLA mismatch acceptability of organ transplant donors for sensitized recipients has traditionally been based on serologically defined HLA antigens. Now, however, it is well accepted that HLA ...antibodies specifically recognize a wide range of epitopes present on HLA antigens and that molecularly defined high resolution alleles corresponding to the same low resolution antigen can possess different epitope repertoires. Hence, determination of HLA compatibility at the allele level represents a more accurate approach to identify suitable donors for sensitized patients. This approach would offer opportunities for increased transplant rates and improved long term graft survivals.
Considering the convincing evidence that HLA antibodies specifically recognize epitopes shared between alleles, this group of investigators offers a scientific argument for the advantage of assessing HLA compatibility at the high‐resolution level. See editorial by Cecka et al on page 855.
Macrophages contribute to HIV-1 pathogenesis by forming a viral reservoir and mediating neurological disorders. Cell-free HIV-1 infection of macrophages is inefficient, in part due to low plasma ...membrane expression of viral entry receptors. We find that macrophages selectively capture and engulf HIV-1-infected CD4+ T cells leading to efficient macrophage infection. Infected T cells, both healthy and dead or dying, were taken up through viral envelope glycoprotein-receptor-independent interactions, implying a mechanism distinct from conventional virological synapse formation. Macrophages infected by this cell-to-cell route were highly permissive for both CCR5-using macrophage-tropic and otherwise weakly macrophage-tropic transmitted/founder viruses but restrictive for nonmacrophage-tropic CXCR4-using virus. These results have implications for establishment of the macrophage reservoir and HIV-1 dissemination in vivo.
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•Macrophages selectively capture and engulf HIV-1-infected T cells•Uptake of HIV-1-infected T cells drives efficient macrophage infection•T cell capture is viral Env independent; macrophage infection is Env-receptor dependent•This represents a route for macrophage infection by transmitted/founder viruses
Tissue macrophages play an important role in HIV-1 infection as viral reservoirs. Baxter et al find that engulfment of HIV-1-infected T cells represents an efficient route by which macrophages may become infected. This mode of spread enables weakly macrophage-tropic transmitted/founder viruses, implicated in viral transmission, to infect macrophages.
Numerical modelling of the residual stresses and strains within mechanical components is of great importance for improving the quality and reliability of design for structural integrity. A ...particularly versatile and powerful approach is offered by direct and inverse eigenstrain modelling. The nature of the eigenstrain modelling approach is that it not only generates an efficient parametric representation of the residual stress field, but also ensures consistency by enforcing stress equilibrium and strain compatibility. In the present study we propose a particular way of prescribing the eigenstrain field due to surface treatment such as shot peening. Eigenstrain variation is described by a continuous function of the distance from the boundary of the object in a two-dimensional model of its cross-section. The procedure is compatible with the use of commercial numerical simulation software, and allows correct assignment of all eigenstrain components. We apply the technique to the evaluation of residual strain within an additively manufactured nickel superalloy compressor blade that was subsequently subjected to shot peening treatment. Two experimental techniques are used to validate the model, namely, Focused Ion Beam ring core milling (FIB-DIC) and synchrotron X-ray Powder Diffraction (SXRPD). Consistency between model prediction and experimental measurements provides verification of the suitability of eigenstrain modelling as consistent basis for the incorporation of residual stress effects on the deformation behaviour of manufactured components.
•We propose a novel way of prescribing eigenstrain in 2D geometry of arbitrary shape.•The method can be implemented in any commercial structural FEM software.•We studied a compressor blade manufactured by ALM and subjected to shot peening.•Synchrotron XRD and FIB-DIC ring-core methods were used to measure residual strain.
The influence that neurons exert on astrocytic function is poorly understood. To investigate this, we first developed a system combining cortical neurons and astrocytes from closely related species, ...followed by RNA-seq and in silico species separation. This approach uncovers a wide programme of neuron-induced astrocytic gene expression, involving Notch signalling, which drives and maintains astrocytic maturity and neurotransmitter uptake function, is conserved in human development, and is disrupted by neurodegeneration. Separately, hundreds of astrocytic genes are acutely regulated by synaptic activity via mechanisms involving cAMP/PKA-dependent CREB activation. This includes the coordinated activity-dependent upregulation of major astrocytic components of the astrocyte-neuron lactate shuttle, leading to a CREB-dependent increase in astrocytic glucose metabolism and elevated lactate export. Moreover, the groups of astrocytic genes induced by neurons or neuronal activity both show age-dependent decline in humans. Thus, neurons and neuronal activity regulate the astrocytic transcriptome with the potential to shape astrocyte-neuron metabolic cooperation.
Children and adolescents make up almost a quarter of the world's population with 85% living in low- and middle-income countries (LMICs). Globally, mental (and substance use) disorders are the leading ...cause of disability in young people; however, the representativeness or 'coverage' of the prevalence data is unknown. Coverage refers to the proportion of the target population (ages 5-17 years) represented by the available data.
Prevalence data for conduct disorder (CD), attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorders (ASDs), eating disorders (EDs), depression, and anxiety disorders were sourced from systematic reviews conducted for the Global Burden of Disease Study 2010 (GBD 2010) and 2013 (GBD 2013). For each study, the location proportion was multiplied by the age proportion to give study coverage. Location proportion was calculated by dividing the total study location population by the total study location population. Age proportion was calculated by dividing the population of the country aged within the age range of the study sample by the population of the country aged within the age range of the study sample. If a study only sampled one sex, study coverage was halved. Coverage across studies was then summed for each country to give coverage by country. This method was repeated at the region and global level, and separately for GBD 2013 and GBD 2010.
Mean global coverage of prevalence data for mental disorders in ages 5-17 years was 6.7% (CD: 5.0%, ADHD: 5.5%, ASDs: 16.1%, EDs: 4.4%, depression: 6.2%, anxiety: 3.2%). Of 187 countries, 124 had no data for any disorder. Many LMICs were poorly represented in the available prevalence data, for example, no region in sub-Saharan Africa had more than 2% coverage for any disorder. While coverage increased between GBD 2010 and GBD 2013, this differed greatly between disorders and few new countries provided data.
The global coverage of prevalence data for mental disorders in children and adolescents is limited. Practical methodology must be developed and epidemiological surveys funded to provide representative prevalence estimates so as to inform appropriate resource allocation and support policies that address mental health needs of children and adolescents.
Among patients with occlusion of a large intracerebral vessel who had a clinical deficit that was disproportionately severe relative to the infarct volume, 90-day outcomes for disability were better ...with late thrombectomy plus standard care than with standard care alone.
We experimentally demonstrate dispersion compensation in a wavelength selective switch, and characterize the bandwidth-dispersion product. At a channel bit-rate of 80 Gbit/s, we compensate for ...various amounts of dispersion (up to ±60 ps/nm), tunable for each wavelength division multiplexed channel, solely by adjusting the phase front of the optical signal inside the wavelength selective switch. Error-free operation is obtained for all of the channels, and for each output port after propagation over various lengths of dispersive fiber.
Plazomicin is a next-generation aminoglycoside that is not affected by most clinically relevant aminoglycoside-modifying enzymes. The in vitro activities of plazomicin and comparator antimicrobials ...were evaluated against a collection of 5,015 bacterial isolates obtained from patients in Canadian hospitals between January 2011 and October 2012. Susceptibility testing was performed using the Clinical and Laboratory Standards Institute (CLSI) broth microdilution method, with MICs interpreted according to CLSI breakpoints, when available. Plazomicin demonstrated potent in vitro activity against members of the family Enterobacteriaceae, with all species except Proteus mirabilis having an MIC90 of ≤1 μg/ml. Plazomicin was active against aminoglycoside-nonsusceptible Escherichia coli, with MIC50 and MIC90 values identical to those for aminoglycoside-susceptible isolates. Furthermore, plazomicin demonstrated equivalent activities versus extended-spectrum β-lactamase (ESBL)-producing and non-ESBL-producing E. coli and Klebsiella pneumoniae, with 90% of the isolates inhibited by an MIC of ≤1 μg/ml. The MIC50 and MIC90 values for plazomicin against Pseudomonas aeruginosa were 4 μg/ml and 16 μg/ml, respectively, compared with 4 μg/ml and 8 μg/ml, respectively, for amikacin. Plazomicin had an MIC50 of 8 μg/ml and an MIC90 of 32 μg/ml versus 64 multidrug-resistant P. aeruginosa isolates. Plazomicin was active against methicillin-susceptible and methicillin-resistant Staphylococcus aureus, with both having MIC50 and MIC90 values of 0.5 μg/ml and 1 μg/ml, respectively. In summary, plazomicin demonstrated potent in vitro activity against a diverse collection of Gram-negative bacilli and Gram-positive cocci obtained over a large geographic area. These data support further evaluation of plazomicin in the clinical setting.
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