Lipid mediators in innate immunity against tuberculosis: opposing roles of PGE2 and LXA4 in the induction of macrophage death

Virulent Mycobacterium tuberculosis (Mtb) induces a maladaptive cytolytic death modality, necrosis, which is advantageous for the pathogen. We report that necrosis of macrophages infected with the virulent Mtb strains H37Rv and Erdmann depends on predominant LXA4 production that is part of the antiinflammatory and inflammation-resolving action induced by Mtb. Infection of macrophages with the avirulent H37Ra triggers production of high levels of the prostanoid PGE2, which promotes protection against mitochondrial inner membrane perturbation and necrosis. In contrast to H37Ra infection, PGE2 production is significantly reduced in H37Rv-infected macrophages. PGE2 acts by engaging the PGE2 receptor EP2, which induces cyclic AMP production and protein kinase A activation. To verify a role for PGE2 in control of bacterial growth, we show that infection of prostaglandin E synthase (PGES)−/− macrophages in vitro with H37Rv resulted in significantly higher bacterial burden compared with wild-type macrophages. More importantly, PGES−/− mice harbor significantly higher Mtb lung burden 5 wk after low-dose aerosol infection with virulent Mtb. These in vitro and in vivo data indicate that PGE2 plays a critical role in inhibition of Mtb replication

Novel genetic loci associated with hippocampal volume

The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (rg =-0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Female chromosome X mosaicism is age-related and preferentially affects the inactivated X chromosome

To investigate large structural clonal mosaicism of chromosome X, we analysed the SNP microarray intensity data of 38,303 women from cancer genome-wide association studies (20,878 cases and 17,425 controls) and detected 124 mosaic X events42Mb in 97 (0.25%) women. Here we show rates for X-chromosome mosaicism are four times higher than mean autosomal rates; X mosaic events more often include the entire chromosome and participants with X events more likely harbour autosomal mosaic events. X mosaicism frequency increases with age (0.11% in 50-year olds; 0.45% in 75-year olds), as reported for Y and autosomes. Methylation array analyses of 33 women with X mosaicism indicate events preferentially involve the inactive X chromosome. Our results provide further evidence that the sex chromosomes undergo mosaic events more frequently than autosomes, which could have implications for understanding the underlying mechanisms of mosaic events and their possible contribution to risk for chronic diseases

Schizophrenia-associated somatic copy-number variants from 12,834 cases reveal recurrent NRXN1 and ABCB11 disruptions

While germline copy-number variants (CNVs) contribute to schizophrenia (SCZ) risk, the contribution of somatic CNVs (sCNVs)—present in some but not all cells—remains unknown. We identified sCNVs using blood-derived genotype arrays from 12,834 SCZ cases and 11,648 controls, filtering sCNVs at loci recurrently mutated in clonal blood disorders. Likely early-developmental sCNVs were more common in cases (0.91%) than controls (0.51%, p = 2.68e−4), with recurrent somatic deletions of exons 1–5 of the NRXN1 gene in five SCZ cases. Hi-C maps revealed ectopic, allele-specific loops forming between a potential cryptic promoter and non-coding cis-regulatory elements upon 5′ deletions in NRXN1. We also observed recurrent intragenic deletions of ABCB11, encoding a transporter implicated in anti-psychotic response, in five treatment-resistant SCZ cases and showed that ABCB11 is specifically enriched in neurons forming mesocortical and mesolimbic dopaminergic projections. Our results indicate potential roles of sCNVs in SCZ risk

Chemistry and Properties of Medium-Mn Two-Stage TRIP Steels

Eight medium manganese steels ranging from 10 to 15 wt pct Mn have been produced with varying levels of aluminum, silicon, and carbon to create steels with varying TRIP (transformation-induced plasticity) character. Alloy chemistries were formulated to produce a range of intrinsic stacking fault energies (ISFE) from − 2.2 to 13.3 mJ/m2 when calculated at room temperature for an austenitic microstructure having the nominal alloy composition. Two-stage TRIP behavior was documented when the ISFE of the γ-austenite phase was 10.5 mJ/m2 or less, whereas an ISFE of 11.9 mJ/m2 or greater exhibited TWIP (twin-induced plasticity) with single-stage TRIP to form α-martensite. Properties were measured in both hot band (hot rolled) and batch annealed (hot rolled, cold rolled, and annealed) conditions. Hot band properties were influenced by the Si/Al ratio and this dependence was related to incomplete recovery during hot working for alloys with Si/Al ratios greater than one. Batch annealing was conducted at 873 K (600 °C) for 20 hours to produce ultrafine-grained microstructures with mean free slip distances less than 1 µm. Batch-annealed materials were found to exhibit a Hall—Petch dependence of the yield strength upon the mean free slip distance measured in the polyphase microstructure. Ultimate tensile strengths ranged from 1450 to 1060 MPa with total elongations of 27 to 43 pct. Tensile ductility was shown to be proportional to the sum of the products of volume fraction transformed times the volume change associated for each martensitic transformation. An empirical relationship based upon the nominal chemistry was derived for the ultimate tensile strength and elongation to failure for these batch-annealed steels. Two additional alloys were produced based upon the developed understanding of these two-stage TRIP steels and tensile strengths of 1150 MPa with 58 pct total elongation and 1400 MPa and 32 pct ductility were achieved

Immunocompromised patients with acute respiratory distress syndrome : Secondary analysis of the LUNG SAFE database

The aim of this study was to describe data on epidemiology, ventilatory management, and outcome of acute respiratory distress syndrome (ARDS) in immunocompromised patients. Methods: We performed a post hoc analysis on the cohort of immunocompromised patients enrolled in the Large Observational Study to Understand the Global Impact of Severe Acute Respiratory Failure (LUNG SAFE) study. The LUNG SAFE study was an international, prospective study including hypoxemic patients in 459 ICUs from 50 countries across 5 continents. Results: Of 2813 patients with ARDS, 584 (20.8%) were immunocompromised, 38.9% of whom had an unspecified cause. Pneumonia, nonpulmonary sepsis, and noncardiogenic shock were their most common risk factors for ARDS. Hospital mortality was higher in immunocompromised than in immunocompetent patients (52.4% vs 36.2%; p < 0.0001), despite similar severity of ARDS. Decisions regarding limiting life-sustaining measures were significantly more frequent in immunocompromised patients (27.1% vs 18.6%; p < 0.0001). Use of noninvasive ventilation (NIV) as first-line treatment was higher in immunocompromised patients (20.9% vs 15.9%; p = 0.0048), and immunodeficiency remained independently associated with the use of NIV after adjustment for confounders. Forty-eight percent of the patients treated with NIV were intubated, and their mortality was not different from that of the patients invasively ventilated ab initio. Conclusions: Immunosuppression is frequent in patients with ARDS, and infections are the main risk factors for ARDS in these immunocompromised patients. Their management differs from that of immunocompetent patients, particularly the greater use of NIV as first-line ventilation strategy. Compared with immunocompetent subjects, they have higher mortality regardless of ARDS severity as well as a higher frequency of limitation of life-sustaining measures. Nonetheless, nearly half of these patients survive to hospital discharge. Trial registration: ClinicalTrials.gov, NCT02010073. Registered on 12 December 2013

A review of morphing aircraft

Aircraft wings are a compromise that allows the aircraft to fly at a range of flight conditions, but the performance at each condition is sub-optimal. The ability of a wing surface to change its geometry during flight has interested researchers and designers over the years as this reduces the design compromises required. Morphing is short for metamorphose: however, there is neither an exact definition nor an agreement between the researchers about the type or the extent of the geometrical changes necessary to qualify an aircraft for the title “shape morphing”. Geometrical parameters that can be affected by morphing solutions can be categorized into: planform alteration (span, sweep and chord), out-of-plane transformation (twist, dihedral/gull, spanwise bending) and airfoil adjustment (camber and thickness).Changing the wing shape or geometry is not new. Historically, morphing solutions always led to penalties in terms of cost, complexity or weight, although in certain circumstances these were overcome by system level benefits. The current trend for highly efficient and “green” aircraft makes such compromises less acceptable, calling for innovative morphing designs able to provide more benefits and fewer drawbacks. Recent developments in “smart” materials may overcome the limitations and enhance the benefits from existing design solutions. The challenge is to design a structure that is capable of withstanding the prescribed loads, but is also able to change its shape: ideally there should be no distinction between the structure and the actuation system. The blending of morphing and smart structures in an integrated approach requires multi-disciplinary thinking from the early development, which significantly increases the overall complexity, even at the preliminary design stage. Morphing is a promising enabling technology for future, next generation aircraft. However, manufacturers and end users are still too skeptical of the benefits to adopt morphing in the near future. Many developed concepts have a technology readiness level that is still very low. The recent explosive growth of satellite services means that UAVs are the technology of choice for many investigations on wing morphing.This paper presents a review of the state of the art on morphing aircraft and focuses on structural, shape changing morphing concepts for both fixed and rotary wings, with particular reference to active systems. Inflatable solutions have been not considered, and skin issues and challenges are not discussed in detail. Although many interesting concepts have been synthesized, few have progressed to wing tunnel testing, and even fewer have flown. Furthermore, any successful wing morphing system must overcome the weight penalty due to the additional actuation systems.<br/