Factor scoring models of the Pittsburgh Sleep Quality Index: a comparative confirmatory factor analysis

The Pittsburgh Sleep Quality Index (PSQI) is a rigorously validated questionnaire with extensive use in sleep assessment. Findings from numerous factor analytic studies of the PSQI have been interpreted to support a heterogeneous factor structure model for the test. Nevertheless, the literature continues to lack a focused evaluation of whether this heterogeneous factor structure is justified. A consideration of this issue led to a conclusion that a closer analysis of the PSQI’s factor structure was merited. To address this need a comparative confirmatory factor analysis for assessing the performance of the accepted factors models of the PSQI was conducted. A sample of university students (n = 418), age = 20.92 ± 1.81 years, BMI = 23.30 ± 2.57 kg/m² completed the multi-structured sleep survey at Jamia Millia Islamia, New Delhi, India. Seventeen putative factor structures (three 1-Factor, eight 2-Factor, and six 3-Factor) of the PSQI from the existing literature were selected for analysis. Fourteen models (82.35%) had almost similar values for model fit indices. Two models were misfits, and one model was a poor fit. The two misfit models incorporated gender and age as covariates. The third poor fit model was used to produce a unique path diagram, which made it distinct from the remaining 16 models. The overlapping values in the fit range of the model fit indices did not support the often projected heterogeneous factor structures of the PSQI for the vast majority of the models.     

Seasonal Differences in Extinction and Colonization Drive Occupancy Dynamics of an Imperilled Amphibian

A detailed understanding of the population dynamics of many amphibian species is lacking despite concerns about declining amphibian biodiversity and abundance. This paper explores temporal patterns of occupancy and underlying extinction and colonization dynamics in a regionally imperiled amphibian species, the Northern leopard frog (Lithobates pipiens) in Alberta. Our study contributes to elucidating regional occupancy dynamics at northern latitudes, where climate extremes likely have a profound effect on seasonal occupancy. The primary advantage of our study is its wide geographic scale (60,000 km²) and the use of repeat visual surveys each spring and summer from 2009–2013. We find that occupancy varied more dramatically between seasons than years, with low spring and higher summer occupancy. Between spring and summer, colonization was high and extinction low; inversely, colonization was low and extinction high over the winter. The dynamics of extinction and colonization are complex, making conservation management challenging. Our results reveal that Northern leopard frog occupancy was constant over the last five years and thus there is no evidence of decline or recovery within our study area. Changes to equilibrium occupancy are most sensitive to increasing colonization in the spring or declining extinction in the summer. Therefore, conservation and management efforts should target actions that are likely to increase spring colonization; this could be achieved through translocations or improving the quality or access to breeding habitat. Because summer occupancy is already high, it may be difficult to improve further. Nevertheless, summer extinction could be reduced by predator control, increasing water quality or hydroperiod of wetlands, or increasing the quality or quantity of summer habitat.     

Sex differences in anthropoid mandibular canine lateral enamel formation

Previous research has demonstrated that great ape and macaque males achieve large canine crown sizes primarily through extended canine growth periods. Recent work has suggested, however, that platyrrhine males may achieve larger canine sizes by accelerating rather than prolonging growth. This study tested the hypothesis that the ontogenetic pathway leading to canine sexual dimorphism in catarrhines differs from that of platyrrhines. To test this hypothesis, males and females of several catarrhine genera (Hylobates, Papio, Macaca, Cercopithecus, and Cercocebus) and three platyrrhine genera (Cebus, Ateles, and Callicebus) were compared in the number and spacing of perikymata (enamel growth increments) on their canine crowns. In addition, perikymata periodicities (the number of days of growth perikymata represent) were determined for five genera (Hylobates, Papio, Macaca, Cebus, and Ateles) using previously published as well as original data gathered for this study. The central findings are as follows: 1) males have more perikymata than females for seven of eight genera (in five of the seven, the differences are statistically significant); 2) in general, the greater the degree of sexual dimorphism, the greater the sex difference in male and female perikymata numbers; 3) there is no evidence of a systematic sex difference in primate periodicities; and 4) there is some evidence that sex differences in enamel formation rates may make a minor contribution to canine sexual dimorphism in Papio and Cercopithecus. These findings strongly suggest that in both catarrhines and platyrrhines prolongation of male canine growth is the primary mechanism by which canine crown sexual dimorphism is achieved. Am J Phys Anthropol, 2009. © 2009 Wiley‐Liss, Inc.     

A critical perspective of the use of (13)C-isotopomer analysis by GCMS and NMR as applied to cardiac metabolism

The aim of this article is to provide a guide for metabolic physiologists and bioengineers to the combined use of gas chromatography-mass spectrometry (GCMS) and nuclear magnetic resonance (NMR) in stable isotope investigations in any biological systems. Building on our past experience with these two techniques, as applied separately to the investigation of citric acid metabolism in the ex vivo perfused rat heart we initiated a collaborative study for their critical evaluation. This article, which expands on our previous work (Mol. Cel. Biol., 2003), directly compares GCMS- and NMR-determined 13C-isotopomer and flux data obtained from ex vivo rat heart perfusion studies with 13C-substrates. Overall we have found excellent agreement between the 13C-enrichments of GCMS- and NMR-determined citric acid cycle metabolites (citrate, 2-ketoglutarate, succinate and malate) and glutamate; however the unlabeled component (M) was consistently underestimated by NMR. Despite this discrepancy there was reasonably good agreement in the relative fluxes of 13C-substrates through the citric acid cycle determined by the two techniques. Nevertheless, further investigations appear necessary before maximal advantage can be taken of the complementary 13C-isotopomer and flux data of GCMS and NMR for probing the dynamics of cellular metabolism.     

Nanoencapsulation of ABT-737 and camptothecin enhances their clinical potential through synergistic antitumor effects and reduction of systemic toxicity

The simultaneous delivery of multiple cancer drugs in combination therapies to achieve optimal therapeutic effects in patients can be challenging. This study investigated whether co-encapsulation of the BH3-mimetic ABT-737 and the topoisomerase I inhibitor camptothecin (CPT) in PEGylated polymeric nanoparticles (NPs) was a viable strategy for overcoming their clinical limitations and to deliver both compounds at optimal ratios. We found that thrombocytopenia induced by exposure to ABT-737 was diminished through its encapsulation in NPs. Similarly, CPT-associated leukopenia and gastrointestinal toxicity were reduced compared with the administration of free CPT. In addition to the reduction of dose-limiting side effects, the co-encapsulation of both anticancer compounds in a single NP produced synergistic induction of apoptosis in both in vitro and in vivo colorectal cancer models. This strategy may widen the therapeutic window of these and other drugs and may enhance the clinical efficacy of synergistic drug combinations.Colorectal cancer is the third most commonly occurring cancer worldwide. Despite advances in understanding the molecular basis of the disease and development of new therapeutic modalities, the 5-year overall survival for patients with late-stage disease remains poor.¹ Although new compounds are continually developed, the lack of efficacy at systemically tolerable doses frequently precludes their success in the clinic. Formulation and delivery strategies that can improve the narrow therapeutic window of such compounds have the potential to make significant advances in treatment regimens.ABT-737 is a small molecule that targets the BH3-binding hydrophobic cleft of antiapoptotic B-cell lymphoma (Bcl) proteins Bcl-2, Bcl-w and Bcl-X(L), which are frequently upregulated in tumors and strongly associated with chemoresistance.² As a single agent, ABT-737 is particularly potent against leukaemia/lymphoma cells and a range of small-cell lung carcinomas, causing complete regression of solid tumors in mouse models.³ Moreover, its orally bioavailable derivative, ABT-263, has shown potential clinical utility in combination therapies as it has been demonstrated to sensitize tumor types, including colorectal cancer cells, to a range of chemotherapies.⁴ However, the clinical evaluation of ABT-263 has revealed that its therapeutic effects are compromised by severe dose-dependent thrombocytopenia.^{5, 6, 7} Platelets normally survive in circulation for several days by maintaining elevated levels of Bcl-X(L), the inhibition of which by ABT-263/ABT-737 results in premature initiation of platelet apoptosis.^8,9 In spite of these issues, ABT-263 is still under clinical investigation in combination with frontline cytotoxic chemotherapies such as irinotecan and other therapies (Supplementary Table S1).Camptothecin (CPT) is a potent topoisomerase-I inhibitor; however, it is poorly soluble and rapidly hydrolyzed from a lactone to an inactive carboxylic acid in an aqueous environment, thus limiting its clinical applicability. Consequently, this has led to the development of derivatives such as irinotecan.¹⁰ Although irinotecan overcomes some of the pharmacokinetic problems associated with CPT, it has reduced inhibitory activity and still exhibits systemic toxicities such as neutropenia and dose-limiting diarrhea owing to the damage of the intestinal mucosa.¹¹Pharmaceutical formulations that improve the safety profile of potent anticancer drugs such as ABT-737/263 and CPT are urgently required. Drug-loaded nanotherapeutics are finding increasing application in a range of solid tumors, best exemplified by Doxil, a liposomal preparation of doxorubicin that reduces drug-associated myocardiotoxicity.¹² Such drug carriers can not only diminish adverse effects, but also simultaneously enhance tumor localization through the ability of nanosized particles to penetrate defective endothelial junctions in the tumor neovasculature – a phenomenon known as the enhanced permeability and retention (EPR) effect.¹³ Of note, a polymeric formulation of CPT, CRLX101, has been clinically evaluated, and it was demonstrated that the improved pharmacokinetics and tumor penetration of nanoparticle (NP)-based carriers observed in mouse models were maintained in patients,¹⁴ highlighting the therapeutic potential that new formulations hold for this parental molecule.Previously, we developed polymeric NPs encapsulating a range of drug types, formulated in FDA-approved poly-lactide-co-glycolide acid (PLGA).^{15, 16, 17} In the current investigation, we wished to examine the application of both CPT and ABT-737 in colorectal cancer models and determine if a nanodelivery system could be employed to elicit the synergistic efficacies of these agents. We show that nanoencapsulation of ABT-737 reduces thrombocytopenic effects, whereas nanoencapsulation of CPT inhibits its cytotoxic effects towards white blood cells and the gastrointestinal (GI) tract. Both drugs were successfully combined in a single NP formulation to elicit synergistic effects against colorectal cancer cells in vitro and in vivo; this highlights the potential of this approach and similar formulations for widening narrow therapeutic windows for the treatment of colorectal and other cancers with rationally selected drug combinations delivered at pre-determined synergistic concentrations.     

Bioengineering nisin to overcome the nisin resistance protein

The emergence and dissemination of antibiotic resistant bacteria is a major medical challenge. Lantibiotics are highly modified bacterially produced antimicrobial peptides that have attracted considerable interest as alternatives or adjuncts to existing antibiotics. Nisin, the most widely studied and commercially exploited lantibiotic, exhibits high efficacy against many pathogens. However, some clinically relevant bacteria express highly specific membrane‐associated nisin resistance proteins. One notable example is the nisin resistance protein that acts by cleaving the peptide bond between ring E and the adjacent serine 29, resulting in a truncated peptide with significantly less activity. We utilised a complete bank of bioengineered nisin (nisin A) producers in which the serine 29 residue has been replaced with every alternative amino acid. The nisin A S29P derivative was found to be as active as nisin A against a variety of bacterial targets but, crucially, exhibited a 20‐fold increase in specific activity against a strain expressing the nisin resistance protein. Another derivative, nisin PV, exhibited similar properties but was much less prone to oxidation. This version of nisin with enhanced resistance to specific resistance mechanisms could prove useful in the fight against antibiotic resistant pathogens.     

Bactericidal peptidoglycan recognition protein induces oxidative stress in Escherichia coli through a block in respiratory chain and increase in central carbon catabolism

Mammalian Peptidoglycan Recognition Proteins (PGRPs) kill both Gram‐positive and Gram‐negative bacteria through simultaneous induction of oxidative, thiol and metal stress responses in bacteria. However, metabolic pathways through which PGRPs induce these bactericidal stress responses are unknown. We screened Keio collection of Escherichia coli deletion mutants and revealed that deleting genes for respiratory chain flavoproteins or for tricarboxylic acid (TCA) cycle resulted in increased resistance of E. coli to PGRP killing. PGRP‐induced killing depended on the production of hydrogen peroxide, which required increased supply of NADH for respiratory chain oxidoreductases from central carbon catabolism (glycolysis and TCA cycle), and was controlled by cAMP‐Crp. Bactericidal PGRP induced a rapid decrease in respiration, which suggested that the main source of increased production of hydrogen peroxide was a block in respiratory chain and diversion of electrons from NADH oxidoreductases to oxygen. CpxRA two‐component system was a negative regulator of PGRP‐induced oxidative stress. By contrast, PGRP‐induced thiol stress (depletion of thiols) and metal stress (increase in intracellular free Zn²⁺ through influx of extracellular Zn²⁺) were mostly independent of oxidative stress. Thus, manipulating pathways that induce oxidative, thiol and metal stress in bacteria could be a useful strategy to design new approaches to antibacterial therapy.     

Building a Comprehensive Mill-Level Database for the Industrial Sectors Integrated Solutions (ISIS) Model of the U.S. Pulp and Paper Sector

Air emissions from the U.S. pulp and paper sector have been federally regulated since 1978; however, regulations are periodically reviewed and revised to improve efficiency and effectiveness of existing emission standards. The Industrial Sectors Integrated Solutions (ISIS) model for the pulp and paper sector is currently under development at the U.S. Environmental Protection Agency (EPA), and can be utilized to facilitate multi-pollutant, sector-based analyses that are performed in conjunction with regulatory development. The model utilizes a multi-sector, multi-product dynamic linear modeling framework that evaluates the economic impact of emission reduction strategies for multiple air pollutants. The ISIS model considers facility-level economic, environmental, and technical parameters, as well as sector-level market data, to estimate the impacts of environmental regulations on the pulp and paper industry. Specifically, the model can be used to estimate U.S. and global market impacts of new or more stringent air regulations, such as impacts on product price, exports and imports, market demands, capital investment, and mill closures. One major challenge to developing a representative model is the need for an extensive amount of data. This article discusses the collection and processing of data for use in the model, as well as the methods used for building the ISIS pulp and paper database that facilitates the required analyses to support the air quality management of the pulp and paper sector.     

The dawning of a 'Golden era' in lantibiotic bioengineering

There are many examples of highly modified antimicrobial peptides in nature, many of which are non-ribosomally synthesized. However, the bacterial lantibiotics are produced as gene-encoded pre-peptides that are subsequently modified by dedicated enzyme systems to form extraordinarily potent inhibitors. Consequently, they are much more amenable to bioengineering which could lead to the generation of a new arsenal of potent antimicrobials. However, although bioengineering of these compounds has been underway for at least two decades, significant progress has only been reported in recent years. This review charts these recent developments which suggest that we are entering a 'Golden era' of lantibiotic bioengineering.