EPR and Structural Characterization of Water-Soluble Mn2+-Doped Si Nanoparticles.

Water-soluble poly(allylamine) Mn2+-doped Si (SiMn) nanoparticles (NPs) were prepared and show promise for biologically related applications. The nanoparticles show both strong photoluminescence and good magnetic resonance contrast imaging. The morphology and average diameter were obtained through transmission electron microscopy (TEM) and high-resolution transmission electron microscopy (HRTEM); spherical crystalline Si NPs with an average diameter of 4.2 ± 0.7 nm were observed. The doping maximum obtained through this process was an average concentration of 0.4 ± 0.3% Mn per mole of Si. The water-soluble SiMn NPs showed a strong photoluminescence with a quantum yield up to 13%. The SiMn NPs had significant T1 contrast with an r1 relaxivity of 11.1 ± 1.5 mM-1 s-1 and r2 relaxivity of 32.7 ± 4.7 mM-1 s-1 where the concentration is in mM of Mn2+. Dextran-coated poly(allylamine) SiMn NPs produced NPs with T1 and T2 contrast with a r1 relaxivity of 27.1 ± 2.8 mM-1 s-1 and r2 relaxivity of 1078.5 ± 1.9 mM-1 s-1. X-band electron paramagnetic resonance spectra are fit with a two-site model demonstrating that there are two types of Mn2+ in these NP's. The fits yield hyperfine splittings (A) of 265 and 238 MHz with significant zero field splitting (D and E terms). This is consistent with Mn in sites of symmetry lower than tetrahedral due to the small size of the NP's

Advances in cholera research: from molecular biology to public health initiatives

The aquatic bacterium Vibrio cholerae is the etiological agent of the diarrheal disease cholera, which has plagued the world for centuries. This pathogen has been the subject of studies in a vast array of fields, from molecular biology to animal models for virulence activity to epidemiological disease transmission modeling. V. cholerae genetics and the activity of virulence genes determine the pathogenic potential of different strains, as well as provide a model for genomic evolution in the natural environment. While animal models for V. cholerae infection have been used for decades, recent advances in this area provide a well-rounded picture of nearly all aspects of V. cholerae interaction with both mammalian and non-mammalian hosts, encompassing colonization dynamics, pathogenesis, immunological responses, and transmission to naïve populations. Microbiome studies have become increasingly common as access and affordability of sequencing has improved, and these studies have revealed key factors in V. cholerae communication and competition with members of the gut microbiota. Despite a wealth of knowledge surrounding V. cholerae, the pathogen remains endemic in numerous countries and causes sporadic outbreaks elsewhere. Public health initiatives aim to prevent cholera outbreaks and provide prompt, effective relief in cases where prevention is not feasible. In this review, we describe recent advancements in cholera research in these areas to provide a more complete illustration of V. cholerae evolution as a microbe and significant global health threat, as well as how researchers are working to improve understanding and minimize impact of this pathogen on vulnerable populations

Research priorities in the field of posttraumatic pain and disability: Results of a transdisciplinary consensus-generating workshop

© Copyright 2016 David M.Walton et al. Background. Chronic or persistent pain and disability following noncatastrophic \u27musculoskeletal\u27 (MSK) trauma is a pervasive public health problem. Recent intervention trials have provided little evidence of benefit from several specific treatments for preventing chronic problems. Such findings may appear to argue against formal targeted intervention for MSK traumas. However, these negative findings may reflect a lack of understanding of the causal mechanisms underlying the transition from acute to chronic pain, rendering informed and objective treatment decisions difficult. The Canadian Institutes of Health Research (CIHR) Institute ofMusculoskeletalHealth and Arthritis (IMHA) has recently identified better understanding of causalmechanisms as one of three priority foci of their most recent strategic plan. Objectives. A 2-day invitation-only active participation workshop was held inMarch 2015 that included 30 academics, clinicians, and consumers with the purpose of identifying consensus research priorities in the field of trauma-relatedMSK pain and disability, prediction, and prevention. Methods. Conversations were recorded, explored thematically, and member-checked for accuracy. Results. From the discussions, 13 themes were generated that ranged from a focus on identifying causal mechanisms and models to challenges with funding and patient engagement. Discussion. Novel priorities included the inclusion of consumer groups in research from the early conceptualization and design stages and interdisciplinary longitudinal studies that include evaluation of integrated phenotypes and mechanisms

Adult Neurogenesis Transiently Generates Oxidative Stress

An increasing body of evidence suggests that alterations in neurogenesis and oxidative stress are associated with a wide variety of CNS diseases, including Alzheimer’s disease, schizophrenia and Parkinson’s disease, as well as routine loss of function accompanying aging. Interestingly, the association between neurogenesis and the production of reactive oxidative species (ROS) remains largely unexamined. The adult CNS harbors two regions of persistent lifelong neurogenesis: the subventricular zone and the dentate gyrus (DG). These regions contain populations of quiescent neural stem cells (NSCs) that generate mature progeny via rapidly-dividing progenitor cells. We hypothesized that the energetic demands of highly proliferative progenitors generates localized oxidative stress that contributes to ROS-mediated damage within the neuropoietic microenvironment. In vivo examination of germinal niches in adult rodents revealed increases in oxidized DNA and lipid markers, particularly in the subgranular zone (SGZ) of the dentate gyrus. To further pinpoint the cell types responsible for oxidative stress, we employed an in vitro cell culture model allowing for the synchronous terminal differentiation of primary hippocampal NSCs. Inducing differentiation in primary NSCs resulted in an immediate increase in total mitochondria number and overall ROS production, suggesting oxidative stress is generated during a transient window of elevated neurogenesis accompanying normal neurogenesis. To confirm these findings in vivo, we identified a set of oxidation-responsive genes, which respond to antioxidant administration and are significantly elevated in genetic- and exercise-induced model of hyperactive hippocampal neurogenesis. While no direct evidence exists coupling neurogenesis-associated stress to CNS disease, our data suggest that oxidative stress is produced as a result of routine adult neurogenesis

Integrative genomic and proteomic analyses identify targets for Lkb1 deficient metastatic lung tumors

SummaryIn mice, Lkb1 deletion and activation of KrasG12D results in lung tumors with a high penetrance of lymph node and distant metastases. We analyzed these primary and metastatic de novo lung cancers with integrated genomic and proteomic profiles and have identified gene and phosphoprotein signatures associated with Lkb1 loss and progression to invasive and metastatic lung tumors. These studies revealed that SRC is activated in Lkb1 deficient primary and metastatic lung tumors and that the combined inhibition of SRC, PI3K and MEK1/2 resulted in synergistic tumor regression. These studies demonstrate that integrated genomic and proteomic analyses can be used to identify signaling pathways that may be targeted for treatment

Mechanical Strain Stabilizes Reconstituted Collagen Fibrils against Enzymatic Degradation by Mammalian Collagenase Matrix Metalloproteinase 8 (MMP-8)

Collagen, a triple-helical, self-organizing protein, is the predominant structural protein in mammals. It is found in bone, ligament, tendon, cartilage, intervertebral disc, skin, blood vessel, and cornea. We have recently postulated that fibrillar collagens (and their complementary enzymes) comprise the basis of a smart structural system which appears to support the retention of molecules in fibrils which are under tensile mechanical strain. The theory suggests that the mechanisms which drive the preferential accumulation of collagen in loaded tissue operate at the molecular level and are not solely cell-driven. The concept reduces control of matrix morphology to an interaction between molecules and the most relevant, physical, and persistent signal: mechanical strain.The investigation was carried out in an environmentally-controlled microbioreactor in which reconstituted type I collagen micronetworks were gently strained between micropipettes. The strained micronetworks were exposed to active matrix metalloproteinase 8 (MMP-8) and relative degradation rates for loaded and unloaded fibrils were tracked simultaneously using label-free differential interference contrast (DIC) imaging. It was found that applied tensile mechanical strain significantly increased degradation time of loaded fibrils compared to unloaded, paired controls. In many cases, strained fibrils were detectable long after unstrained fibrils were degraded.In this investigation we demonstrate for the first time that applied mechanical strain preferentially preserves collagen fibrils in the presence of a physiologically-important mammalian enzyme: MMP-8. These results have the potential to contribute to our understanding of many collagen matrix phenomena including development, adaptation, remodeling and disease. Additionally, tissue engineering could benefit from the ability to sculpt desired structures from physiologically compatible and mutable collagen

Efflux in Fungi: La Pièce de Résistance

Pathogens must be able to overcome both host defenses and antimicrobial treatment in order to successfully infect and maintain colonization of the host. One way fungi accomplish this feat and overcome intercellular toxin accumulation is efflux pumps, in particular ATP-binding cassette transporters and transporters of the major facilitator superfamily. Members of these two superfamilies remove many toxic compounds by coupling transport with ATP hydrolysis or a proton gradient, respectively. Fungal genomes encode a plethora of members of these families of transporters compared to other organisms. In this review we discuss the role these two fungal superfamilies of transporters play in virulence and resistance to antifungal agents. These efflux transporters are responsible not only for export of compounds involved in pathogenesis such as secondary metabolites, but also export of host-derived antimicrobial compounds. In addition, we examine the current knowledge of these transporters in resistance of pathogens to clinically relevant antifungal agents

Correlations of Gene Expression with Blood Lead Levels in Children with Autism Compared to Typically Developing Controls

The objective of this study was to examine the correlation between gene expression and lead (Pb) levels in blood in children with autism (AU, n = 37) compared to typically developing controls (TD, n = 15). We postulated that, though lead levels did not differ between the groups, AU children might metabolize lead differently compared to TD children. RNA was isolated from blood and processed on Affymetrix microarrays. Separate analyses of covariance (ANCOVA) corrected for age and gender were performed for TD, AU, and all subjects (AU + TD). To reduce false positives, only genes that overlapped these three ANCOVAs were considered. Thus, 48 probe sets correlated with lead levels in both AU and TD subjects and were significantly different between the groups (p(Diagnosis × log2 Pb) < 0.05). These genes were related mainly to immune and inflammatory processes, including MHC Class II family members and CD74. A large number (n = 791) of probe sets correlated (P ≤ 0.05) with lead levels in TD but not in AU subjects; and many probe sets (n = 162) correlated (P ≤ 0.05) with lead levels in AU but not in TD subjects. Only 30 probe sets correlated (P ≤ 0.05) with lead levels in a similar manner in the AU and TD groups. These data show that AU and TD children display different associations between transcript levels and low levels of lead. We postulate that this may relate to the underlying genetic differences between the two groups, though other explanations cannot be excluded