Neutrophils in cancer: neutral no more

Neutrophils are indispensable antagonists of microbial infection and facilitators of wound healing. In the cancer setting, a newfound appreciation for neutrophils has come into view. The traditionally held belief that neutrophils are inert bystanders is being challenged by the recent literature. Emerging evidence indicates that tumours manipulate neutrophils, sometimes early in their differentiation process, to create diverse phenotypic and functional polarization states able to alter tumour behaviour. In this Review, we discuss the involvement of neutrophils in cancer initiation and progression, and their potential as clinical biomarkers and therapeutic targets

Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders

Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyper-activity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.Peer reviewe

Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects

Copy number variants (CNVs) have been strongly implicated in the genetic etiology of schizophrenia (SCZ). However, genome-wide investigation of the contribution of CNV to risk has been hampered by limited sample sizes. We sought to address this obstacle by applying a centralized analysis pipeline to a SCZ cohort of 21,094 cases and 20,227 controls. A global enrichment of CNV burden was observed in cases (OR=1.11, P=5.7×10−15), which persisted after excluding loci implicated in previous studies (OR=1.07, P=1.7 ×10−6). CNV burden was enriched for genes associated with synaptic function (OR = 1.68, P = 2.8 ×10−11) and neurobehavioral phenotypes in mouse (OR = 1.18, P= 7.3 ×10−5). Genome-wide significant evidence was obtained for eight loci, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.2, 15q13.3, distal 16p11.2, proximal 16p11.2 and 22q11.2. Suggestive support was found for eight additional candidate susceptibility and protective loci, which consisted predominantly of CNVs mediated by non-allelic homologous recombination

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe

Hyperoxemia and excess oxygen use in early acute respiratory distress syndrome : Insights from the LUNG SAFE study

Publisher Copyright: © 2020 The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.Background: Concerns exist regarding the prevalence and impact of unnecessary oxygen use in patients with acute respiratory distress syndrome (ARDS). We examined this issue in patients with ARDS enrolled in the Large observational study to UNderstand the Global impact of Severe Acute respiratory FailurE (LUNG SAFE) study. Methods: In this secondary analysis of the LUNG SAFE study, we wished to determine the prevalence and the outcomes associated with hyperoxemia on day 1, sustained hyperoxemia, and excessive oxygen use in patients with early ARDS. Patients who fulfilled criteria of ARDS on day 1 and day 2 of acute hypoxemic respiratory failure were categorized based on the presence of hyperoxemia (PaO2 > 100 mmHg) on day 1, sustained (i.e., present on day 1 and day 2) hyperoxemia, or excessive oxygen use (FIO2 ≥ 0.60 during hyperoxemia). Results: Of 2005 patients that met the inclusion criteria, 131 (6.5%) were hypoxemic (PaO2 < 55 mmHg), 607 (30%) had hyperoxemia on day 1, and 250 (12%) had sustained hyperoxemia. Excess FIO2 use occurred in 400 (66%) out of 607 patients with hyperoxemia. Excess FIO2 use decreased from day 1 to day 2 of ARDS, with most hyperoxemic patients on day 2 receiving relatively low FIO2. Multivariate analyses found no independent relationship between day 1 hyperoxemia, sustained hyperoxemia, or excess FIO2 use and adverse clinical outcomes. Mortality was 42% in patients with excess FIO2 use, compared to 39% in a propensity-matched sample of normoxemic (PaO2 55-100 mmHg) patients (P = 0.47). Conclusions: Hyperoxemia and excess oxygen use are both prevalent in early ARDS but are most often non-sustained. No relationship was found between hyperoxemia or excessive oxygen use and patient outcome in this cohort. Trial registration: LUNG-SAFE is registered with ClinicalTrials.gov, NCT02010073publishersversionPeer reviewe

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

In Vivo Versus In Vitro Degradation of a 3D Printed Resorbable Device for Ligation of Vascular Tissue in Horses

A resorbable 3D printed polydioxanone (PDO) device is manufactured to facilitate ligation of vascular tissue during surgery. The device must provide sufficient mechanical performance throughout the healing period. Therefore, degradation and mechanical performance of the device are investigated as a function of in vivo and in vitro aging. During aging the PDO device released cyclic and linear water-soluble products. In vivo aging resulted in higher relative number of linear oligomers in comparison to in vitro aging. A major loss of mechanical performance is observed after only 10 days in vivo and the Young's modulus (E) and tensile strength at break (sigma(b)) decreased by 28% and 54%, respectively. This is in contrast to in vitro aging, where no loss of mechanical properties is observed during the same period. The in vivo aged devices exhibit clear holes in the matrices after 28 days, while apparent cracks are observed first after 140 days in vitro. These results highlight the sensitivity of the degradation process of resorbable devices with regards to the interactions of the device with the surrounding environment (tissues) and demonstrate the importance of in vivo testing as compliment to in vitro testing before clinical use of devices

Fungal textiles : Wet spinning of fungal microfibers to produce monofilament yarns

The cell wall of a zygomycetes fungus was successfully wet spun into monofilament yarns and demonstrated as a novel resource for production of sustainable textiles. Furthermore, the fungus could be cultivated on bread waste, an abundant food waste with large negative environmental impact if not further utilized. Rhizopus delemar was first cultivated in bread waste in a bubble column bioreactor. The fungal cell wall collected through alkali treatment of fungal biomass contained 36 and 23% glucosamine and N-acetyl glucosamine representing chitosan and chitin in the cell wall, respectively. The amino groups of chitosan were protonated by utilizing acetic or lactic acid. This resulted in the formation of a uniform hydrogel of fungal microfibers. The obtained hydrogel was wet spun into an ethanol coagulation bath to form an aggregated monofilament, which was finally dried. SEM images confirmed the alignment of fungal microfibers along the monofilament axis. The wet spun monofilaments had tensile strengths up to 69.5 MPa and Young's modulus of 4.97 GPa. This work demonstrates an environmentally benign procedure to fabricate renewable fibers from fungal cell wall cultivated on abundant food waste, which opens a window to creation of sustainable fungal textiles

Microwave Assisted Hydrothermal Carbonization and Solid State Postmodification of Carbonized Polypropylene

Functional carbon materials produced through a hydrothermal treatment of waste products have gained interest. Particularly, the method is considered more facile and green compared to conventional decomposition methods. Here, we demonstrated an upcycling of polypropylene (PP) waste to carbon materials by a microwave assisted hydrothermal treatment. The solid product obtained from the hydrothermal treatment was analyzed by multiple techniques to reveal the structure and the influence of processing conditions on PP degradation and hydrothermal carbonization. Chemical analyses showed the presence of carbonaceous material independent of acid amount (20 and 30 mL), temperature (210 and 250 °C), and time (20–80 min). A complete transformation of PP content to amorphous carbon required 60 min at 250 °C. The mass yield of the solid product decreased as a function of harsher processing conditions. At the same time, thermogravimetric analysis illustrated products with increasing thermal stability and a larger amount of remaining residue at 600 °C. The solid products consisted of irregular fragments and sheet-like structures. A solid state microwave process in air atmosphere was performed on a product with incomplete carbonization. The modification resulted in a decreased C/O ratio, and TGA analysis in nitrogen showed high thermal stability and degree of carbonization as indicated by the remaining residue of 86.4% at 600 °C. The new insights provided on the hydrothermal carbonization, and postmodification in air atmosphere, can catalyze effective handling of plastic waste by enabling transformation of low quality waste into functional carbon materials