Bench-to-bedside review: Developmental influences on the mechanisms, treatment and outcomes of cardiovascular dysfunction in neonatal versus adult sepsis

Sepsis is a significant cause of morbidity and mortality in neonates and adults, and the mortality rate doubles in patients who develop cardiovascular dysfunction and septic shock. Sepsis is especially devastating in the neonatal population, as it is one of the leading causes of death for hospitalized infants. In the neonate, there are multiple developmental alterations in both the response to pathogens and the response to treatment that distinguish this age group from adults. Differences in innate immunity and cytokine response may predispose neonates to the harmful effects of pro-inflammatory cytokines and oxidative stress, leading to severe organ dysfunction and sequelae during infection and inflammation. Underlying differences in cardiovascular anatomy, function and response to treatment may further alter the neonate's response to pathogen exposure. Unlike adults, little is known about the cardiovascular response to sepsis in the neonate. In addition, recent research has demonstrated that the mechanisms, inflammatory response, response to treatment and outcome of neonatal sepsis vary not only from that of adults, but vary among neonates based on gestational age. The goal of the present article is to review key pathophysiologic aspects of sepsis-related cardiovascular dysfunction, with an emphasis on defining known differences between adult and neonatal populations. Investigations of these relationships may ultimately lead to 'neonate-specific' therapeutic strategies for this devastating and costly medical problem

Agency Directors And Network Centrality: An Examination Of Resource Dependencies

A basic tenet of resource dependence theory is organizations must obtain resources from their environments in order to survive (Pfeffer and Salancik, 1978). Ac- cording to the theory, there are several strategic factors that affect how organizations manage inter- organizational resource exchanges. These strategic factors include (1) interlocking of board of director members, (2) joint programs or joint ventures, (3) organization size, and (4) top administrator contacts with other organizations (Pfeffer and Salancik 1978: 143-69). Organizations engage in these activities to reduce uncertainty and to develop favorable linkages in interorganizational network

Characterization of bulk hexagonal boron nitride single crystals grown by the metal flux technique

The optical and physical properties of hexagonal boron nitride single crystals grown from a molten metal solution are reported. The hBN crystals were grown by precipitation from a nickel-chromium flux with a boron nitride source, by slowly cooling from 1500 °C at 2-4°C/h under a nitrogen flow at atmospheric pressure. The hBN crystals formed on the surface of the flux with an apparent crystal size up to 1 to 2 mm in diameter. Individual grains were as large as 100-200 µm across. Typically, the flakes removed from the metal were 6 to 20 µm thick. Optical absorption measurements suggest a bandgap of 5.8 eV by neglecting the binding energy of excitons in hBN. The highest energy photoluminescence peak was at 5.75 eV at room temperature. The hBN crystals typically had a pit density of 5 x 10⁶ cm⁻² after etching in a molten eutectic mixture of potassium hydroxide and sodium hydroxide. The quality of these crystals suggests they are suitable as substrates for two dimensional materials such as graphene and gallium nitride based devices

Characterization and Structure of a Zn2+ and [2Fe-2S]-containing Copper Chaperone from Archaeoglobus Fulgidus

Bacterial CopZ proteins deliver copper to P1B-type Cu+-ATPases that are homologous to the human Wilson and Menkes disease proteins. The genome of the hyperthermophile Archaeoglobus fulgidus encodes a putative CopZ copper chaperone that contains an unusual cysteine rich N-terminal domain of 130 amino acids in addition to a C-terminal copper-binding domain with a conserved CXXC motif. The N-terminal domain (CopZ-NT) is homologous to proteins found only in extremophiles and is the only such protein that is fused to a copper chaperone. Surprisingly, optical, electron paramagnetic resonance, and X-ray absorption spectroscopic data indicate the presence of a [2Fe-2S] cluster in CopZ-NT. The intact CopZ protein binds two copper ions, one in each domain. The 1.8 Å resolution crystal structure of CopZ-NT reveals that the [2Fe-2S] cluster is housed within a novel fold and that the protein also binds a zinc ion at a four cysteine site. CopZ can deliver Cu+ to the A. fulgidus CopA N-terminal metal binding domain and is capable of reducing Cu2+ to Cu+. This unique fusion of a redox-active domain with a CXXC-containing copper chaperone domain is relevant to the evolution of copper homeostatic mechanisms and suggests new models for copper trafficking

Overexpression of the RNA-binding protein HuR impairs tumor growth in triple negative breast cancer associated with deficient angiogenesis [abstract]

Breast cancer is the second most common cancer in women and causes the death of 519,000 people worldwide. Many cancer genes are posttranscriptionally regulated by RNA-binding proteins (RBPs) and microRNAs. The RBP HuR binds to the AU-rich (ARE) regions of labile mRNAs, such as proto-oncogenes, stabilizing their mRNA and facilitating their translation into protein. HuR has been described to control genes in multiple areas of the acquired capabilities model of cancer and has been hypothesized to be a tumor maintenance gene, allowing for cancers to proliferate once they are established. We investigated the role of HuR in aggressive and difficult to treat triple-negative breast cancer

Shifts in Plant Functional Composition Following Long-term Drought in Grasslands

1. Plant traits can provide unique insights into plant performance at the community scale. Functional composition, defined by both functional diversity and community-weighted trait means (CWMs), can affect the stability of above-ground net primary production (ANPP) in response to climate extremes. Further complexity arises, however, when functional composition itself responds to environmental change. The duration of climate extremes, such as drought, is expected to increase with rising global temperatures; thus, understanding the impacts of long-term drought on functional composition and the corresponding effect that has on ecosystem function could improve predictions of ecosystem sensitivity to climate change. 2. We experimentally reduced growing season precipitation by 66% across six temperate grasslands for 4 years and measured changes in three indices of functional diversity (functional dispersion, richness and evenness), community-weighted trait means and phylogenetic diversity (PD). Specific leaf area (SLA), leaf nitrogen content (LNC) and (at most sites) leaf turgor loss point (pi(TLP)) were measured for species cumulatively representing similar to 90% plant cover at each site. 3. Long-term drought led to increased community functional dispersion in three sites, with negligible effects on the remaining sites. Species re-ordering following the mortality/senescence of dominant species was the main driver of increased functional dispersion. The response of functional diversity was not consistently matched by changes in phylogenetic diversity. Community-level drought strategies (assessed as CWMs) largely shifted from drought tolerance to drought avoidance and/or escape strategies, as evidenced by higher community-weighted pi(TLP), SLA and LNC. Lastly, ecosystem drought sensitivity (i.e. relative reduction in ANPP in drought plots) was positively correlated with community-weighted SLA and negatively correlated with functional diversity. 4. Synthesis. Increased functional diversity following long-term drought may stabilize ecosystem functioning in response to future drought. However, shifts in community-scale drought strategies may increase ecosystem drought sensitivity, depending on the nature and timing of drought. Thus, our results highlight the importance of considering both functional diversity and abundance-weighted traits means of plant communities as their collective effect may either stabilize or enhance ecosystem sensitivity to drought

Statistical Modeling of Extracellular Vesicle Cargo to Predict Clinical Trial Outcomes For Hypoplastic Left Heart Syndrome

Cardiac-derived c-kit+ progenitor cells (CPCs) are under investigation in the CHILD phase I clinical trial (NCT03406884) for the treatment of hypoplastic left heart syndrome (HLHS). The therapeutic efficacy of CPCs can be attributed to the release of extracellular vesicles (EVs). to understand sources of cell therapy variability we took a machine learning approach: combining bulk CPC-derived EV (CPC-EV) RNA sequencing and cardiac-relevan