Social Competitiveness and Plasticity of Neuroendocrine Function in Old Age: Influence of Neonatal Novelty Exposure and Maternal Care Reliability

Early experience is known to have a profound impact on brain and behavioral function later in life. Relatively few studies, however, have examined whether the effects of early experience remain detectable in the aging animal. Here, we examined the effects of neonatal novelty exposure, an early stimulation procedure, on late senescent rats' ability to win in social competition. During the first 3 weeks of life, half of each litter received daily 3-min exposures to a novel environment while the other half stayed in the home cage. At 24 months of age, pairs of rats competed against each other for exclusive access to chocolate rewards. We found that novelty-exposed rats won more rewards than home-staying rats, indicating that early experience exerts a life-long effect on this aspect of social dominance. Furthermore, novelty-exposed but not home-staying rats exhibited habituation of corticosterone release across repeated days of social competition testing, suggesting that early experience permanently enhances plasticity of the stress response system. Finally, we report a surprising finding that across individual rat families, greater effects of neonatal novelty exposure on stress response plasticity were found among families whose dams provided more reliable, instead of a greater total quantity of, maternal care

From bore-soliton-splash to a new wave-to-wire wave-energy model

We explore extreme nonlinear water-wave amplification in a contraction or, analogously, wave amplification in crossing seas. The latter case can lead to extreme or rogue-wave formation at sea. First, amplification of a solitary-water-wave compound running into a contraction is disseminated experimentally in a wave tank. Maximum amplification in our bore–soliton–splash observed is circa tenfold. Subsequently, we summarise some nonlinear and numerical modelling approaches, validated for amplifying, contracting waves. These amplification phenomena observed have led us to develop a novel wave-energy device with wave amplification in a contraction used to enhance wave-activated buoy motion and magnetically induced energy generation. An experimental proof-of-principle shows that our wave-energy device works. Most importantly, we develop a novel wave-to-wire mathematical model of the combined wave hydrodynamics, wave-activated buoy motion and electric power generation by magnetic induction, from first principles, satisfying one grand variational principle in its conservative limit. Wave and buoy dynamics are coupled via a Lagrange multiplier, which boundary value at the waterline is in a subtle way solved explicitly by imposing incompressibility in a weak sense. Dissipative features, such as electrical wire resistance and nonlinear LED loads, are added a posteriori. New is also the intricate and compatible finite-element space–time discretisation of the linearised dynamics, guaranteeing numerical stability and the correct energy transfer between the three subsystems. Preliminary simulations of our simplified and linearised wave-energy model are encouraging and involve a first study of the resonant behaviour and parameter dependence of the device

Determination of Therapeutic Equivalence of Generic Products of Gentamicin in the Neutropenic Mouse Thigh Infection Model

Background: Drug regulatory agencies (DRA) support prescription of generic products of intravenous antibiotics assuming therapeutic equivalence from pharmaceutical equivalence. Recent reports of deaths associated with generic heparin and metoprolol have raised concerns about the efficacy and safety of DRA-approved drugs. Methodology/Principal Findings: To challenge the assumption that pharmaceutical equivalence predicts therapeutic equivalence, we determined in vitro and in vivo the efficacy of the innovator product and 20 pharmaceutically equivalent generics of gentamicin. The data showed that, while only 1 generic product failed in vitro (MIC = 45.3 vs. 0.7 mg/L, P,0.05), 10 products (including gentamicin reference powder) failed in vivo against E. coli due to significantly inferior efficacy (E max = 4.81 to 5.32 vs. 5.99 log 10 CFU/g, P#0.043). Although the design lacked power to detect differences in survival after thigh infection with P. aeruginosa, dissemination to vital organs was significantly higher in animals treated with generic gentamicin despite 4 days of maximally effective treatment. Conclusion: Pharmaceutical equivalence does not predict therapeutic equivalence of generic gentamicin. Stricter criteri

Transcriptome Analysis of Epithelial and Stromal Contributions to Mammogenesis in Three Week Prepartum Cows

Transcriptome analysis of bovine mammary development has provided insight into regulation of mammogenesis. However, previous studies primarily examined expression of epithelial and stromal tissues combined, and consequently did not account for tissue specific contribution to mammary development. Our objective was to identify differences in gene expression in epithelial and intralobular stromal compartments. Tissue was biopsied from non-lactating dairy cows 3 weeks prepartum, cut into explants and incubated for 2 hr with insulin and hydrocortisone. Epithelial and intralobular stromal tissues were isolated with laser capture microdissection. Global gene expression was measured with Bovine Affymetrix GeneChips, and data were preprocessed using RMA method. Moderated t-tests from gene-specific linear model analysis with cell type as a fixed effect showed more than 3,000 genes were differentially expressed between tissues (P<0.05; FDR<0.17). Analysis of epithelial and stromal transcriptomes using Database for Annotation, Visualization and Integrated Discovery (DAVID) and Ingenuity Pathways Analysis (IPA) showed that epithelial and stromal cells contributed distinct molecular signatures. Epithelial signatures were enriched with gene sets for protein synthesis, metabolism and secretion. Stromal signatures were enriched with genes that encoded molecules important to signaling, extracellular matrix composition and remodeling. Transcriptome differences also showed evidence for paracrine interactions between tissues in stimulation of IGF1 signaling pathway, stromal reaction, angiogenesis, neurogenesis, and immune response. Molecular signatures point to the dynamic role the stroma plays in prepartum mammogenesis and highlight the importance of examining the roles of cell types within the mammary gland when targeting therapies and studying mechanisms that affect milk production

MAGE-C2/CT10 Protein Expression Is an Independent Predictor of Recurrence in Prostate Cancer

The cancer-testis (CT) family of antigens is expressed in a variety of malignant neoplasms. In most cases, no CT antigen is found in normal tissues, except in testis, making them ideal targets for cancer immunotherapy. A comprehensive analysis of CT antigen expression has not yet been reported in prostate cancer. MAGE-C2/CT-10 is a novel CT antigen. The objective of this study was to analyze extent and prognostic significance of MAGE-C2/CT10 protein expression in prostate cancer. 348 prostate carcinomas from consecutive radical prostatectomies, 29 castration-refractory prostate cancer, 46 metastases, and 45 benign hyperplasias were immunohistochemically analyzed for MAGE-C2/CT10 expression using tissue microarrays. Nuclear MAGE-C2/CT10 expression was identified in only 3.3% primary prostate carcinomas. MAGE-C2/CT10 protein expression was significantly more frequent in metastatic (16.3% positivity) and castration-resistant prostate cancer (17% positivity; p<0.001). Nuclear MAGE-C2/CT10 expression was identified as predictor of biochemical recurrence after radical prostatectomy (p = 0.015), which was independent of preoperative PSA, Gleason score, tumor stage, and surgical margin status in multivariate analysis (p<0.05). MAGE-C2/CT10 expression in prostate cancer correlates with the degree of malignancy and indicates a higher risk for biochemical recurrence after radical prostatectomy. Further, the results suggest MAGE-C2/CT10 as a potential target for adjuvant and palliative immunotherapy in patients with prostate cancer

Low potency toxins reveal dense interaction networks in metabolism

Background The chemicals of metabolism are constructed of a small set of atoms and bonds. This may be because chemical structures outside the chemical space in which life operates are incompatible with biochemistry, or because mechanisms to make or utilize such excluded structures has not evolved. In this paper I address the extent to which biochemistry is restricted to a small fraction of the chemical space of possible chemicals, a restricted subset that I call Biochemical Space. I explore evidence that this restriction is at least in part due to selection again specific structures, and suggest a mechanism by which this occurs. Results Chemicals that contain structures that our outside Biochemical Space (UnBiological groups) are more likely to be toxic to a wide range of organisms, even though they have no specifically toxic groups and no obvious mechanism of toxicity. This correlation of UnBiological with toxicity is stronger for low potency (millimolar) toxins. I relate this to the observation that most chemicals interact with many biological structures at low millimolar toxicity. I hypothesise that life has to select its components not only to have a specific set of functions but also to avoid interactions with all the other components of life that might degrade their function. Conclusions The chemistry of life has to form a dense, self-consistent network of chemical structures, and cannot easily be arbitrarily extended. The toxicity of arbitrary chemicals is a reflection of the disruption to that network occasioned by trying to insert a chemical into it without also selecting all the other components to tolerate that chemical. This suggests new ways to test for the toxicity of chemicals, and that engineering organisms to make high concentrations of materials such as chemical precursors or fuels may require more substantial engineering than just of the synthetic pathways involved

Revised Lithostratigraphy of the Sonsela Member (Chinle Formation, Upper Triassic) in the Southern Part of Petrified Forest National Park, Arizona

BACKGROUND: Recent revisions to the Sonsela Member of the Chinle Formation in Petrified Forest National Park have presented a three-part lithostratigraphic model based on unconventional correlations of sandstone beds. As a vertebrate faunal transition is recorded within this stratigraphic interval, these correlations, and the purported existence of a depositional hiatus (the Tr-4 unconformity) at about the same level, must be carefully re-examined. METHODOLOGY/PRINCIPAL FINDINGS: Our investigations demonstrate the neglected necessity of walking out contacts and mapping when constructing lithostratigraphic models, and providing UTM coordinates and labeled photographs for all measured sections. We correct correlation errors within the Sonsela Member, demonstrate that there are multiple Flattops One sandstones, all of which are higher than the traditional Sonsela sandstone bed, that the Sonsela sandstone bed and Rainbow Forest Bed are equivalent, that the Rainbow Forest Bed is higher than the sandstones at the base of Blue Mesa and Agate Mesa, that strata formerly assigned to the Jim Camp Wash beds occur at two stratigraphic levels, and that there are multiple persistent silcrete horizons within the Sonsela Member. CONCLUSIONS/SIGNIFICANCE: We present a revised five-part model for the Sonsela Member. The units from lowest to highest are: the Camp Butte beds, Lot's Wife beds, Jasper Forest bed (the Sonsela sandstone)/Rainbow Forest Bed, Jim Camp Wash beds, and Martha's Butte beds (including the Flattops One sandstones). Although there are numerous degradational/aggradational cycles within the Chinle Formation, a single unconformable horizon within or at the base of the Sonsela Member that can be traced across the entire western United States (the "Tr-4 unconformity") probably does not exist. The shift from relatively humid and poorly-drained to arid and well-drained climatic conditions began during deposition of the Sonsela Member (low in the Jim Camp Wash beds), well after the Carnian-Norian transition

Neutrophil Extracellular Traps in Breast Cancer and Beyond: Current Perspectives on NET Stimuli, Thrombosis and Metastasis, and Clinical Utility for Diagnosis and Treatment

Abstract The formation of neutrophil extracellular traps (NETs), known as NETosis, was first observed as a novel immune response to bacterial infection, but has since been found to occur abnormally in a variety of other inflammatory disease states including cancer. Breast cancer is the most commonly diagnosed malignancy in women. In breast cancer, NETosis has been linked to increased disease progression, metastasis, and complications such as venous thromboembolism. NET-targeted therapies have shown success in preclinical cancer models and may prove valuable clinical targets in slowing or halting tumor progression in breast cancer patients. We will briefly outline the mechanisms by which NETs may form in the tumor microenvironment and circulation, including the crosstalk between neutrophils, tumor cells, endothelial cells, and platelets as well as the role of cancer-associated extracellular vesicles in modulating neutrophil behavior and NET extrusion. The prognostic implications of cancer-associated NETosis will be explored in addition to development of novel therapeutics aimed at targeting NET interactions to improve outcomes in patients with breast cancer

RNA delivery by extracellular vesicles in mammalian cells and its applications.

The term 'extracellular vesicles' refers to a heterogeneous population of vesicular bodies of cellular origin that derive either from the endosomal compartment (exosomes) or as a result of shedding from the plasma membrane (microvesicles, oncosomes and apoptotic bodies). Extracellular vesicles carry a variety of cargo, including RNAs, proteins, lipids and DNA, which can be taken up by other cells, both in the direct vicinity of the source cell and at distant sites in the body via biofluids, and elicit a variety of phenotypic responses. Owing to their unique biology and roles in cell-cell communication, extracellular vesicles have attracted strong interest, which is further enhanced by their potential clinical utility. Because extracellular vesicles derive their cargo from the contents of the cells that produce them, they are attractive sources of biomarkers for a variety of diseases. Furthermore, studies demonstrating phenotypic effects of specific extracellular vesicle-associated cargo on target cells have stoked interest in extracellular vesicles as therapeutic vehicles. There is particularly strong evidence that the RNA cargo of extracellular vesicles can alter recipient cell gene expression and function. During the past decade, extracellular vesicles and their RNA cargo have become better defined, but many aspects of extracellular vesicle biology remain to be elucidated. These include selective cargo loading resulting in substantial differences between the composition of extracellular vesicles and source cells; heterogeneity in extracellular vesicle size and composition; and undefined mechanisms for the uptake of extracellular vesicles into recipient cells and the fates of their cargo. Further progress in unravelling the basic mechanisms of extracellular vesicle biogenesis, transport, and cargo delivery and function is needed for successful clinical implementation. This Review focuses on the current state of knowledge pertaining to packaging, transport and function of RNAs in extracellular vesicles and outlines the progress made thus far towards their clinical applications

Ubiquitous molecular substrates for associative learning and activity-dependent neuronal facilitation.

Recent evidence suggests that many of the molecular cascades and substrates that contribute to learning-related forms of neuronal plasticity may be conserved across ostensibly disparate model systems. Notably, the facilitation of neuronal excitability and synaptic transmission that contribute to associative learning in Aplysia and Hermissenda, as well as associative LTP in hippocampal CA1 cells, all require (or are enhanced by) the convergence of a transient elevation in intracellular Ca2+ with transmitter binding to metabotropic cell-surface receptors. This temporal convergence of Ca2+ and G-protein-stimulated second-messenger cascades synergistically stimulates several classes of serine/threonine protein kinases, which in turn modulate receptor function or cell excitability through the phosphorylation of ion channels. We present a summary of the biophysical and molecular constituents of neuronal and synaptic facilitation in each of these three model systems. Although specific components of the underlying molecular cascades differ across these three systems, fundamental aspects of these cascades are widely conserved, leading to the conclusion that the conceptual semblance of these superficially disparate systems is far greater than is generally acknowledged. We suggest that the elucidation of mechanistic similarities between different systems will ultimately fulfill the goal of the model systems approach, that is, the description of critical and ubiquitous features of neuronal and synaptic events that contribute to memory induction