Mucociliary dysfunction in HIV and smoked substance abuse

Impaired mucociliary clearance (MCC) is a hallmark of acquired chronic airway diseases like chronic bronchitis associated with chronic obstructive pulmonary disease (COPD) and asthma. This manifests as microbial colonization of the lung consequently leading to recurrent respiratory infections. People living with HIV demonstrate increased incidence of these chronic airway diseases. Bacterial pneumonia continues to be an important comorbidity in people living with HIV even though anti-retroviral therapy has succeeded in restoring CD4+ cell counts. People living with HIV demonstrate increased microbial colonization of the lower airways. The microbial flora is similar to that observed in diseases like cystic fibrosis and COPD suggesting that mucociliary dysfunction could be a contributing factor to the increased incidence of chronic airway diseases in people living with HIV. The three principal components of the MCC apparatus are, a mucus layer, ciliary beating, and a periciliary airway surface liquid (ASL) layer that facilitates ciliary beating. Cystic fibrosis transmembrane conductance regulator (CFTR) plays a pivotal role in regulating the periciliary ASL. HIV proteins can suppress all the components of the MCC apparatus by increasing mucus secretion and suppressing CFTR function. This can decrease ASL height leading to suppressed ciliary beating. The effects of HIV on MCC are exacerbated when combined with other aggravating factors like smoking or inhaled substance abuse, which by themselves can suppress one or more components of the MCC system. This review discusses the pathophysiological mechanisms that lead to MCC suppression in people living with HIV who also smoke tobacco or abuse illicit drugs

Death is Different. Death Sentencing is Not.

This paper investigates the conditional demands of Death-Is-Different jurisprudence in the United States criminal justice system and argues that the dissonance between the need for heightened protections in capital sentencing and the reality of our capital-sentencing institutions ultimately renders the death penalty, as it currently exists in our society, impermissible. This claim is substantiated in three parts: first, through an analysis of foundational death penalty decisions from the Supreme Course, which condemn the arbitrary nature of capital juries while simultaneously justifying their constitutional necessity as sentencing agents; second, through an examination of the development of Death-Is-Different jurisprudence and its conceptual implications for the application of the death penalty; and finally, through an identification of the faults that render capital juries unable to meet the protective standard that America\u27s Death-Is-Different principle requires

Ghost Athletes: A Subversion of Gender Equity and Violation of Title IX

Title IX of the Education Amendments to the 1964 Civil Rights Act established a three-prong test to determine whether or not educational institutions are providing female and male students with equal opportunities for athletic participation. Under the proportionality prong of the test, schools must demonstrate that their overall percentages of female and male athletes are substantially proportionate to their respective enrollment percentages. However, to circumvent the financial costs needed to increase female participation, many schools use roster manipulation to artificially inflate their proportionality numbers. This thesis investigates the practice of using ‘ghost athletes’ on women’s team rosters to artificially achieve Title IX compliant gender proportionality statistics. It analyzes the practice against scholarly research, legal arguments, and relevant Title IX court precedent to argue that it violates Title IX. Relying on expert literature, an autoethnography of my own experience with ‘ghost athletes’ on the University of Pennsylvania varsity women’s fencing team during the 2017-2018 season, and Title IX jurisprudence, this thesis demonstrates that ‘ghost athletes’ do not constitute genuine athletic participation opportunities and cause significant (and legally-relevant) harm to female athletes. The research presented supports the finding that using ‘ghost athletes’ to inflate female participation numbers subverts the intentions of equality underlining Title IX and violates the federal statute

Rearrangements of Alpha-Halosilanes and Conformational Analysis of Silanes.

A number of (alpha)-halosilanes, some which are chiral at carbon, have been prepared. Lewis acid-catalyzed rearrangements and thermal rearrangements were performed on ((alpha)-chloroethyl)diphenylmethylsilane. Both the rearrangements proceed cleanly; the major product is formed by the migration of the phenyl group from silicon to carbon. The rearranged product mixture was subjected to a Kumada-type oxidation in which the silicon-carbon is cleaved stereospecifically. Thus the principle has been established that a clean rearrangement can be carried out in a manner which will allow determination of the stereochemistry at the carbon center. Preliminary kinetic studies of the thermolysis of ((alpha)-chlorobenzyl)dimethylphenylsilanes containing p-substituents in the benzyl group were done. The relative ease of rearrangement was found to be p-MeOC(,6)H(,4) \u3e p-t-BuC(,6)H(,4) \u3e C(,6)H(,5), indicating that electron donating groups at carbon assist the rearrangement. This observation is consistent with several mechanistic possibilities which involve positive charge generation at the carbon (alpha) to silicon and concurrent negative charge on silicon forming an \u27inverse ylide\u27. The rotational potential function and structures of 1,4 disilabutane (DSB), propylsilane (PS), ethylmethylsilane (EMS) allylsilane and 1,2 disilacyclobutane have been examined by means of ab initio (3-21G((,*))) and molecular mechanics technique. The two methods yield virtually identical relative conformational energies and barrier heights. For three silanes, DSB, PS, EMS, there exists a butane-like rotational potential exists with gauche and anti energy minima. In the case of EMS equi-energetic gauche and anti conformers are suggested. Very good agreement is found between the electron diffraction and MM2 structures of allylsilane. The minimal energy conformer occurs at a torsion angle of 103(DEGREES). Hyperconjugation may explain this result. In the case of 1,2 bistrimethylsilylcyclohexane conformational energies of various conformers was calculated by means of the molecular mechanics method, and the results were compared with the conformational energies of 1,2 di-t-butylcyclohexane. The 3-21G((,*)) basis set is superior to other similar or smaller basis sets for evaluating structures and conformational properties of silanes. The silane force field developed by Frierson and Allinger represents a valid and useful tool for silane conformational/structural studies

The Influence of Hand Position on Prior Entry

Attended information is perceived quicker than unattended information. This is known as prior entry. When making judgments on the temporal order of two successive stimuli, performance is influenced based on attention. We were interested in whether this same attentional shift would occur when we adopt a crossed hands posture. Typically when making these tactile temporal order judgments, performance declines when the hands are crossed. This may be due to a greater influence of the external environment in the crossed posture. We investigated this by providing an exogenous visual cue at one or both of the hands prior to making judgments about the temporal order of two successive vibrations. This was completed with the hands crossed and uncrossed. In Experiment 1 responses were to which stimulus occurred first. In Experiment 2 participants responded to which stimulus occurred second. Changing the response requirement did not influence overall performance. In both experiments we observed prior entry that was in the same direction for both crossed and uncrossed postures. The size of the prior entry effect was larger when the hands were crossed. We remap tactile information quickly to external coordinates, however we are less certain of the hand’s location.ThesisMaster of Science (MSc

Soluble adenylyl cyclase mediates hydrogen peroxide-induced changes in epithelial barrier function

BACKGROUND: Elevated H(2)O(2) levels are associated with inflammatory diseases and H(2)O(2) exposure is known to disrupt epithelial barrier function, leading to increased permeability and decreased electrical resistance. In normal human bronchial epithelial (NHBE) cells, fully differentiated at the air liquid interface (ALI), H(2)O(2) activates an autocrine prostaglandin pathway that stimulates transmembrane adenylyl cyclase (tmAC) as well as soluble adenylyl cyclase (sAC), but the role of this autocrine pathway in H(2)O(2)-mediated barrier disruption is not entirely clear. METHODS: To further characterize the mechanism of H(2)O(2)-induced barrier disruption, NHBE cultures were treated with H(2)O(2) and evaluated for changes in transepithelial resistance and mannitol permeability using agonist and inhibitors to dissect the pathway. RESULTS: A short (<10 min) H(2)O(2) treatment was sufficient to induce resistance and permeability changes that occurred 40 min to 1 h later and the changes were partially sensitive to EP1 but not EP4 receptor antagonists. EP1 receptors were localized to the apical compartment of NHBE. Resistance and permeability changes were sensitive to inhibition of sAC but not tmAC and were partially blocked by PKA inhibition. Pretreatment with a PLC inhibitor or an IP3 receptor antagonist reduced changes in resistance and permeability suggesting activation of sAC occurred through increased intracellular calcium. CONCLUSION: The data support an important role for prostaglandin activation of sAC and PKA in H(2)O(2)-induced barrier disruption. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12931-016-0329-4) contains supplementary material, which is available to authorized users

Investigation of Energy Modelling Methods of Multiple Fidelities: A Case Study

Building energy modelling has become an integral part of building design due to energy consumption concerns in sustainable buildings. As such, energy modelling methods have evolved to the point of including higher-order physics, complex interconnected components and sub-systems. Despite advances in computer capacity, the cost of generating and running complex energy simulations makes it impractical to rely exclusively on such higher fidelity energy modelling for exploring a large set of design alternatives. This challenge of exploring a large set of alternatives efficiently might be overcome by using surrogate models to generalize across the large design space from an evaluation of a sparse subset of design alternatives by higher fidelity energy modelling or by using a set of multi-fidelity models in combination to efficiently evaluate the design space. Given there exists a variety of building energy modelling methods for energy estimation, multi-fidelity modelling could be a promising approach for broad exploration of design spaces to identify sustainable building designs. Hence, this study investigates energy estimates from three energy modelling methods (modified bin, degree day, EnergyPlus) over a range of design variables and climatic regions. The goal is to better understand how their outputs compare to each other and whether they might be suitable for a multi-fidelity modelling approach. The results show that modified bin and degree day methods yield energy use estimates of similar magnitude to each other but are typically higher than results from EnergyPlus. The differences in the results were traced, as expected, to the heating and cooling end-uses, and specifically to the heat gain and heat loss through opaque (i.e., walls, floors, roofs) and window surfaces. The observed trends show the potential for these methods to be used for multi-fidelity modelling, thereby allowing building designers to broadly consider and compare more design alternatives earlier in the design process

A dual function TAR Decoy serves as an anti-HIV siRNA delivery vehicle

The TAR RNA of HIV was engineered as an siRNA delivery vehicle to develop a combinatorial therapeutic approach. The TAR backbone was found to be a versatile backbone for expressing siRNAs. Upon expression in human cells, pronounced and specific inhibition of reporter gene expression was observed with TARmiR. The resulting TARmiR construct retained its ability to bind Tat and mediate RNAi. TARmiR was able to inhibit HIV gene expression as a TAR decoy and by RNA interference when challenged with infectious proviral DNA. The implications of this dual function therapeutic would be discussed

Cellular stress responses and dysfunctional Mitochondrial–cellular senescence, and therapeutics in chronic respiratory diseases

The abnormal inflammatory responses due to the lung tissue damage and ineffective repair/resolution in response to the inhaled toxicants result in the pathological changes associated with chronic respiratory diseases. Investigation of such pathophysiological mechanisms provides the opportunity to develop the molecular phenotype-specific diagnostic assays and could help in designing the personalized medicine-based therapeutic approaches against these prevalent diseases. As the central hubs of cell metabolism and energetics, mitochondria integrate cellular responses and interorganellar signaling pathways to maintain cellular and extracellular redox status and the cellular senescence that dictate the lung tissue responses. Specifically, as observed in chronic obstructive pulmonary disease (COPD) and pulmonary fibrosis, the mitochondria-endoplasmic reticulum (ER) crosstalk is disrupted by the inhaled toxicants such as the combustible and emerging electronic nicotine-delivery system (ENDS) tobacco products. Thus, the recent research efforts have focused on understanding how the mitochondria-ER dysfunctions and oxidative stress responses can be targeted to improve inflammatory and cellular dysfunctions associated with these pathologic illnesses that are exacerbated by viral infections. The present review assesses the importance of these redox signaling and cellular senescence pathways that describe the role of mitochondria and ER on the development and function of lung epithelial responses, highlighting the cause and effect associations that reflect the disease pathogenesis and possible intervention strategies

Chemically Modified Oligonucleotides Modulate an Epigenetically Varied and Transient Form of Transcription Silencing of HIV-1 in Human Cells

Small noncoding RNAs (ncRNAs) have been shown to guide epigenetic silencing complexes to target loci in human cells. When targeted to gene promoters, these small RNAs can lead to long-term stable epigenetic silencing of gene transcription. To date, small RNAs have been shown to modulate transcriptional gene silencing (TGS) of human immunodeficiency virus type 1 (HIV-1) as well as several other disease-related genes, but it has remained unknown as to what extent particular chemistries can be used to generate single-stranded backbone-modified oligonucleotides that are amenable to this form of gene targeting and regulation. Here, we present data indicating that specific combinations of backbone modifications can be used to generate single-stranded antisense oligonucleotides that can functionally direct TGS of HIV-1 in a manner that is however, independent of epigenetic changes at the target loci. Furthermore, this functionality appears contingent on the absence of a 5′ phosphate in the oligonucleotide. These data suggest that chemically modified oligonucleotide based approaches could be implemented as a means to regulate gene transcription in an epigenetically independent manner