Ethical perspectives on advances in biogerontology

Worldwide populations are aging with economic development as a result of public health initiatives and advances in therapeutic discoveries. Since 1850, life expectancy has advanced by 1 year for every four. Accompanying this change is the rapid development of anti‐aging science. There are three schools of thought in the field of aging science. One perspective is the life course approach, which considers that aging is a good and natural process to be embraced as a necessary and positive aspect of life, where the aim is to improve the quality of existing lifespan and “compress” morbidity. Another view is that aging is undesirable, and that rejuvenation and indeed immortality are possible since the biological basis of aging is understood, and therefore, strategies are possible for engineering negligible senescence. Finally, a hybrid approach is that life span can be extended by anti‐aging medicines but with uncertain effects on health. While these advances offer much promise, the ethical perspectives are seldom discussed in cross‐disciplinary settings. This article discusses some of the key ethical issues arising from recent advances in biogerontology

Peptide dendrimer/lipid hybrid systems are efficient DNA transfection reagents: structure--activity relationships highlight the role of charge distribution across dendrimer generations.

Efficient DNA delivery into cells is the prerequisite of the genetic manipulation of organisms in molecular and cellular biology as well as, ultimately, in nonviral gene therapy. Current reagents, however, are relatively inefficient, and structure-activity relationships to guide their improvement are hard to come by. We now explore peptide dendrimers as a new type of transfection reagent and provide a quantitative framework for their evaluation. A collection of dendrimers with cationic and hydrophobic amino acid motifs (such as KK, KA, KH, KL, and LL) distributed across three dendrimer generations was synthesized by a solid-phase protocol that provides ready access to dendrimers in milligram quantities. In conjunction with a lipid component (DOTMA/DOPE), the best reagent, G1,2,3-KL ((LysLeu)8(LysLysLeu)4(LysLysLeu)2LysGlySerCys-NH2), improves transfection by 6-10-fold over commercial reagents under their respective optimal conditions. Emerging structure-activity relationships show that dendrimers with cationic and hydrophobic residues distributed in each generation are transfecting most efficiently. The trigenerational dendritic structure has an advantage over a linear analogue worth up to an order of magnitude. The success of placing the decisive cationic charge patterns in inner shells rather than previously on the surface of macromolecules suggests that this class of dendrimers significantly differs from existing transfection reagents. In the future, this platform may be tuned further and coupled to cell-targeting moieties to enhance transfection and cell specificity

Deepwater Horizon oil spill exposures and nonfatal myocardial infarction in the GuLF STUDY.

BACKGROUND: Workers involved in the response and clean-up of the 2010 Deepwater Horizon oil spill faced possible exposures to crude oil, burning oil, dispersants and other pollutants in addition to physical and emotional stress. These exposures may have increased risk of myocardial infarction (MI) among oil spill workers. METHODS: Gulf Long-term Follow-up (GuLF) STUDY participants comprise individuals who either participated in the Deepwater Horizon response efforts or registered for safety training but were not hired. Oil spill-related exposures were assessed during enrollment interviews conducted in 2011-2013. We estimated risk ratios (RR) and 95% confidence intervals for the associations of clean-up work characteristics with self-reported nonfatal MI up to three years post-spill. RESULTS: Among 31,109 participants without history of MI prior to the spill, 77% worked on the oil spill. There were 192 self-reported MI during the study period; 151 among workers. Among the full cohort, working on the oil spill clean-up (vs not working on the clean-up) and living in proximity to the oil spill (vs further away) were suggestively associated with a possible increased risk of nonfatal MI [RR: 1.22 (0.86, 1.73) and 1.15 (0.82, 1.60), respectively]. Among oil spill workers, working for > 180 days was associated with MI [RR for > 180 days (vs 1-30 days): 2.05 (1.05, 4.01)], as was stopping working due to heat [RR: 1.99 (1.43, 2.78)]. There were suggestive associations of maximum total hydrocarbon exposure ≥3.00 ppm (vs  180 days and stopping work due to heat increased risk of nonfatal MI. Future research should evaluate whether the observed associations are related to specific chemical exposures or other stressors associated with the spill

Toward scalable stochastic unit commitment. Part 2: Solver Configuration and Performance Assessment

In this second portion of a two-part analysis of a scalable computa- tional approach to stochastic unit commitment, we focus on solving stochastic mixed-integer programs in tractable run-times. Our solution technique is based on Rockafellar and Wets\u27 progressive hedging algorithm, a scenario-based decomposi- tion strategy for solving stochastic programs. To achieve high-quality solutions in tractable run-times, we describe critical, novel customizations of the progressive hedging algorithm for stochastic unit commitment. Using a variant of the WECC- 240 test case with 85 thermal generation units, we demonstrate the ability of our approach to solve realistic, moderate-scale stochastic unit commitment problems with reasonable numbers of scenarios in no more than 15 minutes of wall clock time on commodity compute platforms. Further, we demonstrate that the result- ing solutions are high-quality, with costs typically within 1-2.5% of optimal. For larger test cases with 170 and 340 thermal generators, we are able to obtain solu- tions of identical quality in no more than 25 minutes of wall clock time. A major component of our contribution is the public release of the optimization model, as- sociated test cases, and algorithm results, in order to establish a rigorous baseline for both solution quality and run times of stochastic unit commitment solvers

The impact of implementing an allergic rhinitis clinical management pathway (AR-CMaP) in the community pharmacy

Background The Allergic Rhinitis Clinical Management Pathway (AR-CMaP) was developed to overcome the challenge of implementing current AR guidelines in the Australian community pharmacy practice and support pharmacists in optimally managing patients' AR. Objective(s) To evaluate the impact of AR-CMaP on patients' behaviour and pharmacists' needs in managing AR in the pharmacy. Methods This study used a cross-sectional, pre-post study design in which the primary outcome was the appropriateness of medications purchased from community pharmacies in Australia. Patient data were collected before and after the implementation of AR-CMaP. Pharmacist needs were recorded before and after AR-CMaP training. Data were analysed descriptively. Results Six pharmacies, 19 pharmacists and a total of 416 patients were included in the study; 206 pre-AR-CMaP implementation and 210 post-AR-CMaP implementation. Pre-AR-CMaP, 22.4% of patients purchased appropriate AR medication compared with 29.0% post-AR-CMaP implementation. Over half the patient cohort (52%) consulted a pharmacist pre-AR-CMaP and 37% consulted a pharmacist post-AR-CMaP implementation. Post-AR-CMaP, pharmacists reported increased awareness of barriers such as patients' lack of time, patients' perceptions about the pharmacist's role and patient choice to self-manage. Pharmacists also rated an increased desire to interact with other health care providers (HCPs) in caring for patients with AR. Conclusions While there was a non-statistically significant increase in the proportion of patients purchasing optimal AR medication, AR-CMaP did empower patients to self-select their own medication without further detriment. Moreover, following the implementation of AR-CMaP, pharmacists developed a greater awareness of their role in AR management, exemplified by their increased desire to be actively involved in AR management and increased interaction with other HCPs. Future research needs to explore more effective tools to support pharmacists' clinical decision-making and target patients' self-selection of AR medications. This study highlights that there is an ingrained self-reliance of AR decision-making that has become a habit for people living with AR.This study is partly supported through an Investigator-Initiated Woolcock-Mylan Partnership Grant 001984.info:eu-repo/semantics/publishedVersio

An ionizing radiation acoustic imaging (iRAI) technique for real‐time dosimetric measurements for FLASH radiotherapy

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/163494/2/mp14358_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/163494/1/mp14358.pd

Heterosubtype Neutralizing Responses to Influenza A (H5N1) Viruses Are Mediated by Antibodies to Virus Haemagglutinin

Background: It is increasingly clear that influenza A infection induces cross-subtype neutralizing antibodies that may potentially confer protection against zoonotic infections. It is unclear whether this is mediated by antibodies to the neuraminidase (NA) or haemagglutinin (HA). We use pseudoviral particles (H5pp) coated with H5 haemagglutinin but not N1 neuraminidase to address this question. In this study, we investigate whether cross-neutralizing antibodies in persons unexposed to H5N1 is reactive to the H5 haemagglutinin. Methodology/Principal Findings: We measured H5-neutralization antibody titers pre- and post-vaccination using the H5N1 micro-neutralization test (MN) and H5pp tests in subjects given seasonal vaccines and in selected sera from European elderly volunteers in a H5N1 vaccine trial who had detectable pre-vaccination H5N1 MN antibody titers. We found detectable (titer ≥20) H5N1 neutralizing antibodies in a minority of pre-seasonal vaccine sera and evidence of a serological response to H5N1 in others after seasonal influenza vaccination. There was excellent correlation in the antibody titers between the H5N1 MN and H5pp tests. Similar correlations were found between MN and H5pp in the pre-vaccine sera from the cohort of H5N1 vaccine trial recipients. Conclusions/Significance: Heterosubtype neutralizing antibody to H5N1 in healthy volunteers unexposed to H5N1 is mediated by cross-reaction to the H5 haemagglutinin. Copyright: © 2009 Garcia et al.published_or_final_versio

Dominant-negative CREB inhibits heparanase functionality and melanoma cell invasion

Heparanase (HPSE-1) is an endo-β-D-glucuronidase involved in the degradation of cell-surface/extracellular matrix heparan sulfate (HS) in normal and neoplastic tissues. HPSE-1 represents the first example of purification and cloning of a mammalian HS-degradative enzyme. Elevated HPSE-1 levels are known to be associated with metastatic cancers, directly implicating HPSE-1 in metastatic events. The purpose of this study was to determine the role of cAMP response element-binding protein (CREB) in modulating HPSE-1-mediated effects on human melanoma cell invasion. Highly invasive, brain-metastatic melanoma cells (70W) were transfected with the dominant-negative CREB (KCREB) and subsequently analyzed for changes in their HPSE-1 content, functionality, and cell invasive properties. KCREB-transfected cells showed a decrease in HPSE-1 mRNA expression and activity. This correlated with a significantly decreased invasion of these cells through Matrigel™-coated filters. Furthermore, adenoviral vectors containing the full-length human HPSE-1 cDNA in sense orientation (Ad-S/hep) were constructed to investigate CREB effects on HPSE-1. Restoration of HPSE-1 expression and functionality following Ad-S/hep infection of KCREB-transfected 70W cells recovered melanoma cell invasiveness. These results demonstrate that KCREB inhibits HPSE-1 and suggest that one of the roles CREB plays in the acquisition of melanoma cells metastatic phenotype is affecting HPSE-1 activity. © 2004 Wiley-Liss, Inc

Competition-based model of pheromone component ratio detection in the moth

For some moth species, especially those closely interrelated and sympatric, recognizing a specific pheromone component concentration ratio is essential for males to successfully locate conspecific females. We propose and determine the properties of a minimalist competition-based feed-forward neuronal model capable of detecting a certain ratio of pheromone components independently of overall concentration. This model represents an elementary recognition unit for the ratio of binary mixtures which we propose is entirely contained in the macroglomerular complex (MGC) of the male moth. A set of such units, along with projection neurons (PNs), can provide the input to higher brain centres. We found that (1) accuracy is mainly achieved by maintaining a certain ratio of connection strengths between olfactory receptor neurons (ORN) and local neurons (LN), much less by properties of the interconnections between the competing LNs proper. An exception to this rule is that it is beneficial if connections between generalist LNs (i.e. excited by either pheromone component) and specialist LNs (i.e. excited by one component only) have the same strength as the reciprocal specialist to generalist connections. (2) successful ratio recognition is achieved using latency-to-first-spike in the LN populations which, in contrast to expectations with a population rate code, leads to a broadening of responses for higher overall concentrations consistent with experimental observations. (3) when longer durations of the competition between LNs were observed it did not lead to higher recognition accuracy