The science of early adversity: is there a role for large institutions in the care of vulnerable children?

It has been more than 80 years since researchers in child psychiatry first documented developmental delays among children separated from family environments and placed in orphanages or other institutions. Informed by such findings, global conventions, including the 1989 UN Convention on the Rights of the Child, assert a child's right to care within a family-like environment that offers individualised support. Nevertheless, an estimated 8 million children are presently growing up in congregate care institutions. Common reasons for institutionalisation include orphaning, abandonment due to poverty, abuse in families of origin, disability, and mental illness. Although the practice remains widespread, a robust body of scientific work suggests that institutionalisation in early childhood can incur developmental damage across diverse domains. Specific deficits have been documented in areas including physical growth, cognitive function, neurodevelopment, and social-psychological health. Effects seem most pronounced when children have least access to individualised caregiving, and when deprivation coincides with early developmental sensitive periods. Offering hope, early interventions that place institutionalised children into families have afforded substantial recovery. The strength of scientific evidence imparts urgency to efforts to achieve deinstitutionalisation in global child protection sectors, and to intervene early for individual children experiencing deprivation

Biological embedding of childhood adversity: from physiological mechanisms to clinical implications

Background: Adverse psychosocial exposures in early life, namely experiences such as child maltreatment, caregiver stress or depression, and domestic or community violence, have been associated in epidemiological studies with increased lifetime risk of adverse outcomes, including diabetes, heart disease, cancers, and psychiatric illnesses. Additional work has shed light on the potential molecular mechanisms by which early adversity becomes “biologically embedded” in altered physiology across body systems. This review surveys evidence on such mechanisms and calls on researchers, clinicians, policymakers, and other practitioners to act upon evidence. Observations Childhood psychosocial adversity has wide-ranging effects on neural, endocrine, immune, and metabolic physiology. Molecular mechanisms broadly implicate disruption of central neural networks, neuroendocrine stress dysregulation, and chronic inflammation, among other changes. Physiological disruption predisposes individuals to common diseases across the life course. Conclusions: Reviewed evidence has important implications for clinical practice, biomedical research, and work across other sectors relevant to public health and child wellbeing. Warranted changes include increased clinical screening for exposures among children and adults, scale-up of effective interventions, policy advocacy, and ongoing research to develop new evidence-based response strategies

The Somatic Genomic Landscape of Glioblastoma

We describe the landscape of somatic genomic alterations based on multi-dimensional and comprehensive characterization of more than 500 glioblastoma tumors (GBMs). We identify several novel mutated genes as well as complex rearrangements of signature receptors including EGFR and PDGFRA. TERT promoter mutations are shown to correlate with elevated mRNA expression, supporting a role in telomerase reactivation. Correlative analyses confirm that the survival advantage of the proneural subtype is conferred by the G-CIMP phenotype, and MGMT DNA methylation may be a predictive biomarker for treatment response only in classical subtype GBM. Integrative analysis of genomic and proteomic profiles challenges the notion of therapeutic inhibition of a pathway as an alternative to inhibition of the target itself. These data will facilitate the discovery of therapeutic and diagnostic target candidates, the validation of research and clinical observations and the generation of unanticipated hypotheses that can advance our molecular understanding of this lethal cancer

Highly Integrated Subsonic Air Intakes

Aerodynamic integration of air intakes with increasingly compact shaping and the optimization of their performance are challenging tasks for innovative design of advanced unmanned aerial vehicles (UAVs) featuring superior combat or reconnaissance abilities. In order to meet configurational requirements, diverterless intake designs with optimized entry shaping and sophisticated serpentine duct layout are primary goals in the overall development process. These design challenges, however, can generate intake flow characteristics, which can adversely impact the aerodynamic performance of the intake and the engine/intake compatibility. Unsteady flow physics like separation and reattachment as well as pre-entry and internal flow control imply an advanced degree of detailed understanding of the highly three-dimensional flow during the early design process. Installed thrust, range, and weight as additional key factors strongly relate to all these design requirements. Competitive aspects demand reduced development costs and short delivery times and thus are also main drivers within the UAV design process. Current diffuser flow management and control systems are largely empirically derived. Enhanced understanding of the flow physics involved in complex innovative intake design can lead to improved active and passive methodologies for controlling these internal flows. In order to reduce costly wind tunnel experiments during the development phase of aerial vehicles the ability to accurately predict the aerodynamic performance of highly integrated intakes is of great importance. The most promising simulation methods for time-accurate flow phenomena with high turbulence levels in an industrial environment are hybrid methods combining the inexpensive RANS (Reynolds- Averaged Navier-Stokes) and the accurate LES (Large Eddy Simulation) techniques

Numerical and Experimental Investigations on Highly Integrated Subsonic Air

Aerodynamic integration of air intakes and the optimization of their performance are challenging tasks for innovative design of advanced unmanned aerial vehicles (UAVs). The extension of Computational Fluid Dynamics (CFD) into application areas such as dynamic intake distortion prediction and thus engine/intake compatibility is made possible by modern hybrid methods and increasing computer resources. Within the Aerodynamics Action Group AD/AG-46 “Highly Integrated Subsonic Air Intakes” of the Group for Aeronautical Research and Technology in EURope (GARTEUR), CFD computations were carried out for the EIKON UAV configuration, which was designed and wind tunnel tested at FOI in Sweden. The major objectives of AD/AG-46 were to investigate the capability of Detached Eddy Simulation (DES) methods for the analysis of unsteady flow phenomena of serpentine air intakes and the accuracy levels of the computations. Numerical results for a variety of wind tunnel conditions were compared with Reynolds-Averaged Navier-Stokes (RANS) and unsteady RANS (URANS) data as well as with experimental results. The impact of not considering the wind tunnel walls in the CFD calculations on the computational results was investigated, revealing that the ventilated walls of the T1500 wind tunnel eliminate the blockage of the model within the closed test section and that free stream conditions can be applied for the computational boundary conditions. Since intake lip shaping is a vital design parameter impacting the intake internal flow and performance, the original geometry was compared with a modified cowl while maintaining low-observability features of the W-shaped cowl design. A trade-off study between boundary layer diversion versus ingestion was performed numerically by applying Euler boundary conditions to the walls of the numerical model of the UAV configuration, thus simulating the total removal or diversion of the boundary layer. The computed inviscid results were compared with the viscous data, quantifying the losses in total pressure recovery and the increase in distortion for the ingested test cases. Internal flow control in the intake duct of the UAV configuration was studied by numerically applying vortex generators, and the results were compared with experimental data. Numerical models were employed in order to simulate micro-jets as active flow control devices in the serpentine duct. Increasing of jet velocities resulted in smaller areas of flow separation and thus led to beneficial total pressure recoveries and distortion parameters. At DLR in Göttingen experiments with a generic high aspect ratio diverterless intake model were performed in the cryogenic blowdown wind tunnel DNW-KRG with the goal of contributing to a better understanding and correlation of installed performance predictions of highly integrated innovative intake designs. In a parametric study the combined effects of boundary layer ingestion and an S-shaped intake diffuser on total pressure recovery and distortion at the engine face were investigated as a function of Mach number, Reynolds number, boundary layer thickness, and intake mass flow ratio

Integrated Genomic and Epigenomic Analysis of Breast Cancer Brain Metastasis

<div><p>The brain is a common site of metastatic disease in patients with breast cancer, which has few therapeutic options and dismal outcomes. The purpose of our study was to identify common and rare events that underlie breast cancer brain metastasis. We performed deep genomic profiling, which integrated gene copy number, gene expression and DNA methylation datasets on a collection of breast brain metastases. We identified frequent large chromosomal gains in 1q, 5p, 8q, 11q, and 20q and frequent broad-level deletions involving 8p, 17p, 21p and Xq. Frequently amplified and overexpressed genes included ATAD2, BRAF, DERL1, DNMTRB and NEK2A. The ATM, CRYAB and HSPB2 genes were commonly deleted and underexpressed. Knowledge mining revealed enrichment in cell cycle and G2/M transition pathways, which contained AURKA, AURKB and FOXM1. Using the PAM50 breast cancer intrinsic classifier, Luminal B, Her2+/ER negative, and basal-like tumors were identified as the most commonly represented breast cancer subtypes in our brain metastasis cohort. While overall methylation levels were increased in breast cancer brain metastasis, basal-like brain metastases were associated with significantly lower levels of methylation. Integrating DNA methylation data with gene expression revealed defects in cell migration and adhesion due to hypermethylation and downregulation of PENK, EDN3, and ITGAM. Hypomethylation and upregulation of KRT8 likely affects adhesion and permeability. Genomic and epigenomic profiling of breast brain metastasis has provided insight into the somatic events underlying this disease, which have potential in forming the basis of future therapeutic strategies.</p></div

Vimentin protects cells against nuclear rupture and DNA damage during migration

Mammalian cells frequently migrate through tight spaces during normal embryogenesis, wound healing, diapedesis, or in pathological situations such as metastasis. Nuclear size and shape are important factors in regulating the mechanical properties of cells during their migration through such tight spaces. At the onset of migratory behavior, cells often initiate the expression of vimentin, an intermediate filament protein that polymerizes into networks extending from a juxtanuclear cage to the cell periphery. However, the role of vimentin intermediate filaments (VIFs) in regulating nuclear shape and mechanics remains unknown. Here, we use wild-type and vimentin-null mouse embryonic fibroblasts to show that VIFs regulate nuclear shape and perinuclear stiffness, cell motility in 3D, and the ability of cells to resist large deformations. These changes increase nuclear rupture and activation of DNA damage repair mechanisms, which are rescued by exogenous reexpression of vimentin. Our findings show that VIFs provide mechanical support to protect the nucleus and genome during migration

Receiver Operator Characteristic (ROC) Curve for BANK1 and CDKN1C for Determining Differential DNA Methylation Between BBM (n = 32) and Primary Breast Tumors (n = 48).

<p>The ROC curve is a graph of the true-positive rate versus the false-positive rate using different threshold values. Data plotted represent two BANK1 HumanMethylation27 array probes and 6/8 CDKN1C probes that demonstrate statistically significant differential methylation between BBM and primary tumors. The area under the curve (AUC) and <i>p</i>values are indicated on the graphs.</p