York University Libraries' Open Access Author Fund

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York University Libraries have directed a small portion of their collections budget in support of an open access author fund to cover Author Processing Charges for York researchers who wish to publish their work in open access journals. Please apply as early as possible as once the annual allocation has been expended, no further requests can be considered until the following fiscal year.

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Open Access
Integrative Genomics Reveals the Genetics and Evolution of the Honey Bee’s Social Immune System
(Oxford University Press, 2019) Harpur, Brock; Guarna, Maria Marta; Huxter, Elizabeth; Higo, Heather; Moon, Kyung-Mee; Hoover, Shelley; Ibrahim, Abdullah; Melathopoulos, Andony; Desai, Suresh; Currie, Rob; Pernal, Stephen; Foster, Leonard; Zayed, Amro
Social organisms combat pathogens through individual innate immune responses or through social immunity—behaviors among individuals that limit pathogen transmission within groups. Although we have a relatively detailed understanding of the genetics and evolution of the innate immune system of animals, we know little about social immunity. Addressing this knowledge gap is crucial for understanding how life-history traits influence immunity, and identifying if trade-offs exist between innate and social immunity. Hygienic behavior in the Western honey bee, Apis mellifera, provides an excellent model for investigating the genetics and evolution of social immunity in animals. This heritable, colony-level behavior is performed by nurse bees when they detect and remove infected or dead brood from the colony. We sequenced 125 haploid genomes from two artificially selected highly hygienic populations and a baseline unselected population. Genomic contrasts allowed us to identify a minimum of 73 genes tentatively associated with hygienic behavior. Many genes were within previously discovered QTLs associated with hygienic behavior and were predictive of hygienic behavior within the unselected population. These genes were often involved in neuronal development and sensory perception in solitary insects. We found that genes associated with hygienic behavior have evidence of positive selection within honey bees (Apis), supporting the hypothesis that social immunity contributes to fitness. Our results indicate that genes influencing developmental neurobiology and behavior in solitary insects may have been co-opted to give rise to a novel and adaptive social immune phenotype in honey bees.
Open Access
Ten simple rules for writing statistical book reviews
(PLOS, 2019-01-24) Lortie, Christopher
Statistical books can provide deep insights into statistics and software. There are, however, many resources available to the practitioner. Book reviews have the capacity to function as a critical mechanism for the learner to assess the merits of engaging in part, in full, or at all with a book. The “ten simple rules” format, pioneered in computational biology, was applied here to writing effective book reviews for statistics because of the wide breadth of offerings in this domain, including topical introductions, computational solutions, and theory. Learning by doing is a popular paradigm in statistics and computation, but there is still a niche for books in the pedagogy of self-taught and instruction-based learning. Primarily, these rules ensure that book reviews function as a form of short syntheses to inform and guide readers in deciding to use a specific book relative to other options for resolving statistical challenges.
Open Access
Importance of safety climate, teamwork climate and demographics: understanding nurses, allied health professionals and clerical staff perceptions of patient safety
(BMJ, 2018-11-28) Zaheer, Shahram; Ginsburg, Liane; Wong, Hannah; Thomson, Kelly; Bain, Lorna
Background: There is growing evidence regarding the importance of contextual factors for patient/staff outcomes and the likelihood of successfully implementing safety improvement interventions such as checklists; however, certain literature gaps still remain—for example, lack of research examining the interactive effects of safety constructs on outcomes. This study has addressed some of these gaps, together with adding to our understanding of how context influences safety. Purpose: The impact of staff perceptions of safety climate (ie, senior and supervisory leadership support for safety) and teamwork climate on a self-reported safety outcome (ie, overall perceptions of patient safety (PS)) were examined at a hospital in Southern Ontario. Methods: Cross-sectional survey data were collected from nurses, allied health professionals and unit clerks working on intensive care, general medicine, mental health or emergency department. Results: Hierarchical regression analyses showed that perceptions of senior leadership (p<0.001) and teamwork (p<0.001) were significantly associated with overall perceptions of PS. A non-significant association was found between perceptions of supervisory leadership and the outcome variable. However, when staff perceived poorer senior leadership support for safety, the positive effect of supervisory leadership on overall perceptions of PS became significantly stronger (p<0.05). Practice implications: Our results suggest that leadership support at one level (ie, supervisory) can substitute for the absence of leadership support for safety at another level (ie, senior level). While healthcare organisations should recruit into leadership roles and retain individuals who prioritise safety and possess adequate relational competencies, the field would now benefit from evidence regarding how to build leadership support for PS. Also, it is important to provide on-site workshops on topics (eg, conflict management) that can strengthen working relationships across professional and unit boundaries.
Open Access
Female Mice Have Higher Angiogenesis in Perigonadal Adipose Tissue Than Males in Response to High-Fat Diet
(Frontiers, 2018-10-23) Rudnicki, Martina; Abdifarkosh, Ghoncheh; Rezvan, Omid; Nwadozi, Emmanuel; Roudier, Emilie; Haas, Tara
Background: Impaired capillary growth (angiogenesis) in skeletal muscle and adipose tissue contributes to the development of metabolic disorders in obese males. This association remains unexplored in females, despite mounting evidence that endothelial cells have sex-specific transcriptional profiles. Therefore, herein we assessed whether males and females show distinct angiogenic capacities in response to diet-induced obesity. Methods: Age-matched male and female mice were fed normal chow or high-fat obesogenic diets for 16 weeks. At the end of diet period, systemic glucose disposal was assessed as well as insulin sensitivity of skeletal muscle and visceral adipose tissue. Capillary content and the expression of angiogenic regulators were also evaluated in these tissues. Results: When placed on a high-fat diet, female mice gained less weight than males and showed a metabolic phenotype similar to NC-fed mice, contrasting with the impaired whole-body glucose metabolism observed in high-fat-fed males. However, high-fat-feeding elevated serum lipid levels similarly in male and female mice. Although skeletal muscle of high-fat–fed female mice had higher insulin sensitivity than male counterparts, no sex difference was detected in muscle capillarization. Metabolic functions of perigonadal white adipose tissue (pgWAT) were retained in high-fat-fed females, as evidenced by smaller adipocytes with preserved insulin sensitivity, greater responsiveness to isoproterenol, higher expression of Adiponectin and a lower ratio of Leptin:Adiponectin mRNA. An enhanced browning phenotype was detected in HF-fed female adipocytes with upregulation of Ucp1 expression. PgWAT from high-fat-fed females also showed augmented capillary number and expression of endothelial cell markers, which was associated with elevated mRNA levels of pro-angiogenic mediators, including vascular endothelial growth factor A (Vegfa) and its receptor (Vegfr2), the Notch ligand Jagged-1 (Jag1) and Angiopoietin-2 (Angpt2). Conclusion: Taken together, our findings provide novel evidence that visceral adipose tissue of female mice display greater levels of pro-angiogenic factors and vascularity than males in response to high-fat diet. This phenotype is associated with preserved metabolic homeostasis at both tissue and systemic levels. Our study discloses that a thus-far-unappreciated sex-specific difference in the regulation of adipose angiogenesis may contribute to an individual’s susceptibility to developing adipose dysfunction and obesity-related metabolic disturbances.
Open Access
A proof of concept application of aptachain: ligand-induced self-assembly of a DNA aptamer
(Royal Society of Chemistry, 2019-01-14) Neves, Miguel A.D.; Slavkovic, Sladjana; Reinstein, Oren; Shoara, Aron Amin; Johnson, Philip
A challenge for the use of aptamers as biosensors is how to signal the occurrence of their ligand binding event into a signal that can be exploited in a detection scheme. Here, we present the concept of “aptachain” formation, where an aptamer is split into two overlapping or staggered strands and assembles into an extended oligomer upon ligand binding. This assembly of aptamers can then be used as a way to detect ligand binding by the aptamer. As an example of this concept, we employed the cocaine-binding aptamer as a model system, used its ability to tightly bind quinine and demonstrated its capability in a gold nanoparticle-based biosensing application. We used isothermal titration calorimetry to demonstrate that, when split into two overlapping DNA strands, the aptamer remains functional. Size-exclusion chromatography showed that the quinine-bound oligos form a larger assembly of aptamer units than in the absence of ligand. Finally, we used the oligomer forming ability of the aptachain oligos in a biosensor application for quinine that brings gold nanoparticles closer together resulting in a shift in their plasmonic resonance to a longer wavelength and an observed colour shift. We propose that splitting aptamers into overlapping strands that form oligomers in the presence of a ligand, aptachain formation, will be generally applicable to aptamers and prove useful in a variety of biotechnology applications.
Open Access
Models of Concurrent Disorder Service: Policy, Coordination, and Access to Care
(Frontiers, 2019-02-19) Wiktorowicz, Mary; Abdulle, Aber; Di Pierdomenico, Kaitlin; Boamah, Sheila A.
Background: Societal capacity to address the service needs of persons with concurrent mental health and substance-use disorders has historically been challenging given a traditionally siloed approach to mental health and substance-use care. As different approaches to care for persons with concurrent disorders emerge, a limited understanding of current models prevails. The goal of this paper is to explore these challenges along with promising models of coordinated care across Canadian provinces. Materials and methods: A scoping review of policies, service coordination and access issues was undertaken involving a review of the formal and gray literature from 2000 to 2018. The scoping review was triangulated by an analysis of provincial auditor general reports. Results: Models of concurrent disorders service were found to have evolved unevenly. Challenges related to the implementation of models of collaborative care and local networks that foster service coordination and policy accountability were found to inhibit integrated care. Conclusion: Emergent models of coordinated care were found to include collaborative care, regional networks with centralized access to care, clinical information-sharing, cross-training, improved scope of care to include psychologists and alignment of physician incentives with patient needs to better support patient care.
Open Access
Glycoprotein Hormone Receptor Knockdown Leads to Reduced Reproductive Success in Male Aedes aegypti
(Frontiers, 2019) Rocco, David; Garcia, Ana S.G.; Scudeler, Elton; dos Santos, Daniela C.; Nobrega, Rafael H.; Paluzzi, Jean-Paul
Glycoprotein hormone receptors mediate a diverse range of physiological functions in vertebrate and invertebrate organisms. The heterodimeric glycoprotein hormone GPA2/GPB5 and its receptor LGR1, constitute a recently discovered invertebrate neuroendocrine signaling system that remains to be functionally characterized. We previously reported that LGR1 is expressed in the testes of adult Aedes aegypti mosquitoes, where its immunoreactivity is particularly regionalized. Here, we show that LGR1 immunoreactivity is associated with the centriole adjunct of spermatids and is observed transiently during spermatogenesis in mosquitoes, where it may act to mediate the regulation of flagellar development. RNA interference to downregulate LGR1 expression was accomplished by feeding mosquito larvae with bacteria that produced LGR1-specific dsRNA, which led to defects in spermatozoa, characterized with shortened flagella. LGR1 knockdown mosquitoes also retained ∼60% less spermatozoa in reproductive organs and demonstrated reduced fertility compared to controls. To date, the endocrine regulation of spermatogenesis in mosquitoes remains an understudied research area. The distribution of LGR1 and detrimental effects of its knockdown on spermatogenesis in A. aegypti indicates that this heterodimeric glycoprotein hormone signaling system contributes significantly to the regulation of male reproductive biology in this important disease-vector.
Open Access
An Embedded Systems Perspective in Conceptualizing Canada’s Healthcare Sustainability
(MDPI, 2019) Tsasis, Peter; Agrawal, Nirupama; Guriel, Natalie
Healthcare sustainability has been dominated by a strong fiscal orientation. In an era of budget cuts and staff reductions, the financial challenges in Canadian healthcare are immediate and must be addressed. However, an independent focus on financial viability is too narrow a framing; too limited to allow for the kind of creative, novel, and even radical thinking that is required to fundamentally alter the current course of healthcare in Canada and internationally. Prospects for solving the current financial challenges are likely to be greatly enhanced if we simultaneously account for the broad and interrelated dimensions of sustainability. What would a healthcare system look like if sustainability were adopted as the focal and principal goal? And what might a “deep” sustainability orientation imply for how we think about and manage healthcare systems? This analysis is informed by the notion that healthcare systems are fully contained within the societal system, which is itself fully contained within the broader ecological system. This model, which foregrounds nature as the most fundamental and important system, has both greater ecological validity and particular relevance to the healthcare context given the interdependence between the health of natural systems and the health of humans. Our understanding of nature in relation to health may be key to solving or at least reducing the economic burden of healthcare. A multidimensional systems orientation thus has the potential to unveil new modes of thinking that highlight intersectoral relations, communications, collaboration, and cross-boundary learning for improved health and wellbeing, healthcare performance, and sustainability.
Open Access
Conservation Genomics of the Declining North American Bumblebee Bombus terricola Reveals Inbreeding and Selection on Immune Genes
(Frontiers Media, 2018-08-10) Kent, Clement; Dey, Alivia; Patel, Harshilkumar; Tsvetkov, Nadejda; Tiwari, Tanushree; MacPhail, Victoria J.; Gobeil, Yann; Harpur, Brock; Gurtowski, James; Schatz, Michael; Colla, Sheila R.; Zayed, Amro
The yellow-banded bumblebee Bombus terricola was common in North America but has recently declined and is now on the IUCN Red List of threatened species. The causes of B. terricola’s decline are not well understood. Our objectives were to create a partial genome and then use this to estimate population data of conservation interest, and to determine whether genes showing signs of recent selection suggest a specific cause of decline. First, we generated a draft partial genome (contig set) for B. terricola, sequenced using Pacific Biosciences RS II at an average depth of 35×. Second, we sequenced the individual genomes of 22 bumblebee gynes from Ontario and Quebec using Illumina HiSeq 2500, each at an average depth of 20×, which were used to improve the PacBio genome calls and for population genetic analyses. The latter revealed that several samples had long runs of homozygosity, and individuals had high inbreeding coefficient F, consistent with low effective population size. Our data suggest that B. terricola’s effective population size has decreased orders of magnitude from pre-Holocene levels. We carried out tests of selection to identify genes that may have played a role in ameliorating environmental stressors underlying B. terricola’s decline. Several immune-related genes have signatures of recent positive selection, which is consistent with the pathogen-spillover hypothesis for B. terricola’s decline. The new B. terricola contig set can help solve the mystery of bumblebee decline by enabling functional genomics research to directly assess the health of pollinators and identify the stressors causing declines.
Open Access
Sexual communal motivation in couples coping with low sexual interest/arousal: Associations with sexual well-being and sexual goals
(PLOS, 2019-07-17) Hogue, Jacqueline; Rosen, Natalie O.; Bockaj, Amanda; Impett, Emily; Muise, Amy
Women coping with female sexual interest/arousal disorder (FSIAD) report lower sexual and relationship satisfaction compared to healthy controls. In community samples, high sexual communal strength (i.e., the motivation to meet a partner’s sexual needs) is associated with higher sexual desire and satisfaction, but high unmitigated sexual communion (i.e., the prioritization of a partner’s needs to the exclusion of one’s own needs) is associated with lower sexual satisfaction. People higher in sexual communal strength report engaging in sex for approach goals (i.e., to enhance intimacy in their relationship), but not for avoidance goals (i.e., to avert conflict or a partner’s disappointment) and this is one reason why they report greater sexual desire. In the current sample of 97 women diagnosed with FSIAD and their partners we investigated the association between sexual communal strength and unmitigated sexual communion and sexual well-being (i.e., sexual desire, sexual satisfaction and sexual distress) and sexual goals (i.e., approach and avoidance goals). Women who reported higher sexual communal strength were more likely to pursue sex for approach goals and their partner reported greater sexual satisfaction. When partners reported higher sexual communal strength, they reported higher sexual desire, but when they reported higher unmitigated sexual communion, they reported higher sexual distress. Additional associations emerged for couples who engage in sex more (compared to less) frequently. Our findings demonstrate that being motivated to meet a partner’s sexual needs is associated with greater sexual well-being for couples coping with FSIAD, but when this motivation involves neglecting one’s own needs, people do not report greater sexual well-being and instead, partners report higher sexual distress.
Open Access
The fast contribution of visual-proprioceptive discrepancy to reach aftereffects and proprioceptive recalibration
(PLOS, 2018-07-17) Ruttle, Jennifer E.; 't Hart, Bernard; Henriques, Denise
Adapting reaches to altered visual feedback not only leads to motor changes, but also to shifts in perceived hand location; “proprioceptive recalibration”. These changes are robust to many task variations and can occur quite rapidly. For instance, our previous study found both motor and sensory shifts arise in as few as 6 rotated-cursor training trials. The aim of this study is to investigate one of the training signals that contribute to these rapid sensory and motor changes. We do this by removing the visuomotor error signals associated with classic visuomotor rotation training; and provide only experience with a visual-proprioceptive discrepancy for training. While a force channel constrains reach direction 30o away from the target, the cursor representing the hand unerringly moves straight to the target. The resulting visual-proprioceptive discrepancy drives significant and rapid changes in no-cursor reaches and felt hand position, again within only 6 training trials. The extent of the sensory change is unexpectedly larger following the visual-proprioceptive discrepancy training. Not surprisingly the size of the reach aftereffects is substantially smaller than following classic visuomotor rotation training. However, the time course by which both changes emerge is similar in the two training types. These results suggest that even the mere exposure to a discrepancy between felt and seen hand location is a sufficient training signal to drive robust motor and sensory plasticity.
Open Access
What image features guide lightness perception?
(Association for Research in Vision and Ophthalmology (ARVO), 2018-12-04) Kim, Minjung; Gold, Jason M.; Murray, Richard F.
Lightness constancy is the ability to perceive black and white surface colors under a wide range of lighting conditions. This fundamental visual ability is not well understood, and current theories differ greatly on what image features are important for lightness perception. Here we measured classification images for human observers and four models of lightness perception to determine which image regions influenced lightness judgments. The models were a high-pass-filter model, an oriented difference-of-Gaussians model, an anchoring model, and an atmospheric-link-function model. Human and model observers viewed three variants of the argyle illusion (Adelson, 1993) and judged which of two test patches appeared lighter. Classification images showed that human lightness judgments were based on local, anisotropic stimulus regions that were bounded by regions of uniform lighting. The atmospheric-link-function and anchoring models predicted the lightness illusion perceived by human observers, but the high-pass-filter and oriented-difference-of-Gaussians models did not. Furthermore, all four models produced classification images that were qualitatively different from those of human observers, meaning that the model lightness judgments were guided by different image regions than human lightness judgments. These experiments provide a new test of models of lightness perception, and show that human observers' lightness computations can be highly local, as in low-level models, and nevertheless depend strongly on lighting boundaries, as suggested by midlevel models.
Open Access
Factors Associated with Premenstrual Syndrome and its Different Symptom Domains among University Students in Lebanon
(ClinMed International Library, 2018-04-21) Costanian, Christy; Akiki, Zeina; Rabah, Zeinab; Daou, Safaa; Assaad, Shafika
Objectives: This study aimed to estimate the prevalence and examine the characteristics of premenstrual syndrome (PMS) among female university students. It also aimed to determine the factors associated with the affective and somatic domains of PMS. Methods: This cross sectional study was conducted among 2115 Lebanese female university students, who completed questionnaires on PMS symptoms and other factors. PMS was defined according to the “American College of Obstetricians and Gynecologists” criteria. Bivariate and multivariable associations between PMS, PMS affective and somatic domains respectively and other covariates were conducted using logistic regression. Results: Almost 63% of participants reported having PMS with 42.5% having severe PMS. The most common affective and somatic symptoms were “angry outbursts” and “abdominal bloating” respectively. Obesity, having unemployed fathers, caffeine consumption (coffee/tea), and pain medication use, and sleeping pill use were significantly associated with PMS. Among these factors, caffeine consumption, and medication use for pain were associated with PMS affective domain while BMI, caffeine consumption, and medication use for pain were related to PMS somatic domain. Conclusion: The proportion of Lebanese females with PMS and affective and somatic symptoms are notably high. These findings highlight the importance of weight management to minimize PMS symptoms.
Open Access
Interventions to Promote Patient Utilization of Cardiac Rehabilitation: Cochrane Systematic Review and Meta-Analysis
(MDPI, 2019-02-05) Santiago de Araújo Pio, Carolina; Chaves, Gabriela; Davies, Philippa; Taylor, Rod; Grace, Sherry L.
Too few patients utilize cardiac rehabilitation (CR), despite its benefits. The Cochrane review assessing the effectiveness of interventions to increase CR utilization (enrolment, adherence, and completion) was updated. A search was performed through July 2018 of the Cochrane and MEDLINE (Medical Literature Analysis and Retrieval System Online) databases, among other sources. Randomized controlled trials in adults with myocardial infarction, angina, revascularization, or heart failure were included. Interventions had to aim to increase utilization of comprehensive phase II CR. Two authors independently performed all stages of citation processing. Following the random-effects meta-analysis, meta-regression was undertaken to explore the impact of pre-specified factors. Twenty-six trials with 5299 participants were included (35.8% women). Low-quality evidence showed an effect of interventions in increasing enrolment (risk ratio (RR) = 1.27, 95% confidence interval (CI) = 1.13–1.42). Meta-regression analyses suggested that the intervention deliverer (nurse or allied healthcare provider, p = 0.02) and delivery format (face-to-face, p = 0.01) were influential in increasing enrolment. There was low-quality evidence that interventions to increase adherence were effective (standardized mean difference (SMD) = 0.38, 95% CI = 0.20–0.55), particularly where remotely-offered (SMD = 0.56, 95% CI = 0.36–0.76). There was moderate-quality evidence that interventions to increase program completion were effective (RR = 1.13, 95% CI = 1.02–1.25). There are effective interventions to increase CR utilization, but more research is needed to establish specific, implementable materials and protocols, particularly for completion.
Open Access
Barriers to cardiac rehabilitation delivery in a low-resource setting from the perspective of healthcare administrators, rehabilitation providers, and cardiac patients
(Biomed Central, 2019-09-02) Sérvio, Thaianne Cavalcante; Britto, Raquel; Lima de Melo Ghisi, Gabriela; da Silva, Lilian Pinto; Duarte Novais Silva, Luciana; Lima, Márcia Maria Oliveira; Pereira, Danielle Aparecida Gomes; Grace, Sherry L.
Background: Despite clinical practice guideline recommendations that cardiovascular disease patients participate, cardiac rehabilitation (CR) programs are highly unavailable and underutilized. This is particularly true in low-resource settings, where the epidemic is at its’ worst. The reasons are complex, and include health system, program and patient-level barriers. This is the first study to assess barriers at all these levels concurrently, and to do so in a lowresource setting. Methods: In this cross-sectional study, data from three cohorts (healthcare administrators, CR coordinators and patients) were triangulated. Healthcare administrators from all institutions offering cardiac services, and providers from all CR programs in public and private institutions of Minas Gerais state, Brazil were invited to complete a questionnaire. Patients from a random subsample of 12 outpatient cardiac clinics and 11 CR programs in these institutions completed the CR Barriers Scale. Results: Thirty-two (35.2%) healthcare administrators, 16 (28.6%) CR providers and 805 cardiac patients (305 [37.9%] attending CR) consented to participate. Administrators recognized the importance of CR, but also the lack of resources to deliver it; CR providers noted referral is lacking. Patients who were not enrolled in CR reported significantly greater barriers related to comorbidities/functional status, perceived need, personal/family issues and access than enrollees, and enrollees reported travel/work conflicts as greater barriers than non-enrollees (all p < 0.01). Conclusions: The inter-relationship among barriers at each level is evident; without resources to offer more programs, there are no programs to which physicians can refer (and hence inform and encourage patients to attend), and patients will continue to have barriers related to distance, cost and transport. Advocacy for services is needed. Keywords: Health care services, Cardiac rehabilitation, Cardiac care facilities, Attitude of health personnel
Open Access
Early myopathy in Duchenne muscular dystrophy is associated with elevated mitochondrial H2O2 emission during impaired oxidative phosphorylation
(Wiley, 2019-04-02) Hughes, Meghan C.; Ramos, Sofhia V.; Turnbull, Patrick C.; Rebalka, Irena A.; Cao, Andrew; Monaco, Cynthia M.F.; Varah, Nina E.; Edgett, Brittany; Huber, Jason; Tadi, Peyman; Delfinis, Luca J.; Schlattner, U.; Simpson, Jeremy; Hawke, Thomas; Perry, Christopher
Background Muscle wasting and weakness in Duchenne muscular dystrophy (DMD) causes severe locomotor limitations and early death due in part to respiratory muscle failure. Given that current clinical practice focuses on treating secondary complications in this genetic disease, there is a clear need to identify additional contributions in the aetiology of this myopathy for knowledge‐guided therapy development. Here, we address the unresolved question of whether the complex impairments observed in DMD are linked to elevated mitochondrial H2O2 emission in conjunction with impaired oxidative phosphorylation. This study performed a systematic evaluation of the nature and degree of mitochondrial‐derived H2O2 emission and mitochondrial oxidative dysfunction in a mouse model of DMD by designing in vitro bioenergetic assessments that attempt to mimic in vivo conditions known to be critical for the regulation of mitochondrial bioenergetics. Methods Mitochondrial bioenergetics were compared with functional and histopathological indices of myopathy early in DMD (4 weeks) in D2.B10‐DMDmdx/2J mice (D2.mdx)—a model that demonstrates severe muscle weakness. Adenosine diphosphate's (ADP's) central effect of attenuating H2O2 emission while stimulating respiration was compared under two models of mitochondrial‐cytoplasmic phosphate exchange (creatine independent and dependent) in muscles that stained positive for membrane damage (diaphragm, quadriceps, and white gastrocnemius). Results Pathway‐specific analyses revealed that Complex I‐supported maximal H2O2 emission was elevated concurrent with a reduced ability of ADP to attenuate emission during respiration in all three muscles (mH2O2: +17 to +197% in D2.mdx vs. wild type). This was associated with an impaired ability of ADP to stimulate respiration at sub‐maximal and maximal kinetics (−17 to −72% in D2.mdx vs. wild type), as well as a loss of creatine‐dependent mitochondrial phosphate shuttling in diaphragm and quadriceps. These changes largely occurred independent of mitochondrial density or abundance of respiratory chain complexes, except for quadriceps. This muscle was also the only one exhibiting decreased calcium retention capacity, which indicates increased sensitivity to calcium‐induced permeability transition pore opening. Increased H2O2 emission was accompanied by a compensatory increase in total glutathione, while oxidative stress markers were unchanged. Mitochondrial bioenergetic dysfunctions were associated with induction of mitochondrial‐linked caspase 9, necrosis, and markers of atrophy in some muscles as well as reduced hindlimb torque and reduced respiratory muscle function. Conclusions These results provide evidence that Complex I dysfunction and loss of central respiratory control by ADP and creatine cause elevated oxidant generation during impaired oxidative phosphorylation. These dysfunctions may contribute to early stage disease pathophysiology and support the growing notion that mitochondria are a potential therapeutic target in this disease.
Open Access
Space and time in episodic memory: Effects of linearity and directionality on memory for spatial location and temporal order in children and adults
(PLOS, 2018-11-08) Pathman, Thanujeni; Coughlin, Christine; Ghetti, Simona
Episodic memory is a critical capacity that involves remembering past events along with their spatial and temporal contexts. Relatively little is known about the relations between spatial and temporal information in long-term memory in children or adults. The present research examined the influence of the mental timeline (linear horizontal display extending from the left to right direction for English speakers) on memory for events and their spatial and temporal features in 7-year-olds, 9-year-olds, 11-year-olds and young adults (N = 146). During encoding, participants studied triplets of objects, varying on two dimensions of the mental timeline: linearity (whether objects were presented in linear succession or not) and direction (whether objects were presented from left-to-right or right-to-left). After a delay, during retrieval, participants were tested on their memory for individual objects, and either the spatial location or temporal order of the objects. We found that overall accuracy for spatial location was higher than accuracy for temporal order, and there was a parallel developmental trajectory for both these aspects of memory. Across age groups we found that memory for temporal order, but not spatial location, was influenced by linearity and direction (i.e., match to mental timeline). Thus, in both children and adults the spatiotemporal mental timeline supported memory for temporal order, converging with predictions generated within domains of language and thought and enhancing our understanding of how space and time are represented in the mind.
Open Access
Erythropoietin inhibits chemotherapy-induced cell death and promotes a senescence-like state in leukemia cells
(Springer, 2019-01-08) Pham, Thuc-Nghi Duc; Ma, Weili; Miller, David; Kazakova, Lidia; Benchimol, Samuel
There are conflicting reports on the adverse effects of erythropoietin (EPO) for the management of cancer-associated anemia. The recognition that erythropoietin receptors (EPORs) are expressed outside the erythroid lineage and concerns that erythropoiesis-stimulating agents (ESAs) may cause tumors to grow and increase the risk of venous thromboembolism have resulted in substantially fewer cancer patients receiving ESA therapy to manage myelosuppressive chemotherapy. In this study, we found that EPO suppresses p53-dependent apoptosis induced by genotoxic (daunorubicin, doxorubicin, and γ-radiation) and non-genotoxic (nutlin-3a) agents and induces a senescence-like state in myeloid leukemia cells. EPO interferes with stress-dependent Mdm2 downregulation and leads to the destabilization of p53 protein. EPO selectively modulates the expression of p53 target genes in response to DNA damage preventing the induction of a number of noncoding RNAs (ncRNAs) previously associated with p53-dependent apoptosis. EPO also enhances the expression of the cyclin-dependent kinase inhibitor p21WAF1 and promotes recruitment of p53 to the p21 promoter. In addition, EPO antagonizes Mcl-1 protein degradation in daunorubicin-treated cells. Hence, EPO signaling targets Mcl-1 expression and the p53-Mdm2 network to promote tumor cell survival.
Open Access
Thermoelectric Nanocomposite Foams Using Non-Conducting Polymers with Hybrid 1D and 2D Nanofillers
(MDPI, 2018-09-18) Aghelinejad, Mohammadmehdi; Leung, Siu Ning
A facile processing strategy to fabricate thermoelectric (TE) polymer nanocomposite foams with non-conducting polymers is reported in this study. Multilayered networks of graphene nanoplatelets (GnPs) and multi-walled carbon nanotubes (MWCNTs) are deposited on macroporous polyvinylidene fluoride (PVDF) foam templates using a layer-by-layer (LBL) assembly technique. The open cellular structures of foam templates provide a platform to form segregated 3D networks consisting of one-dimensional (1D) and/or two-dimensional (2D) carbon nanoparticles. Hybrid nanostructures of GnP and MWCNT networks synergistically enhance the material system’s electrical conductivity. Furthermore, the polymer foam substrates possess high porosity to provide ultra-low thermal conductivity without compromising the electrical conductivity of the TE nanocomposites. With an extremely low GnP loading (i.e., ~1.5 vol.%), the macroporous PVDF nanocomposites exhibit a thermoelectric figure-of-merit of ~10−3. To the best of our knowledge, this ZT value is the highest value reported for organic TE materials using non-conducting polymers and MWCNT/GnP nanofillers. The proposed technique represents an industrially viable approach to fabricate organic TE materials with enhanced energy conversion efficiencies. The current study demonstrates the potential to develop light-weight, low-cost, and flexible TE materials for green energy generation.
Open Access
Women in clinical trials: a review of policy development and health equity in the Canadian context
(Biomed Central, 2019-04-15) Yakerson, Alla
Health equity in pharmaceutical research is concerned with creating equal opportunities for men and women to partake in clinical trials. Equitable representation is imperative for determining the safety, effectiveness, and tolerance of drugs for all consumers. Historically, women have been excluded from participating in clinical research leading to a lack of knowledge regarding drug effects and their consequences. This paper examines the changes made since the implementation of Canadian policies on the representation of women in clinical trials, the analysis of sex and gender, as well as the discourses that are prominent among researchers. A feminist ethics framework is used to examine the structures that endeavor to elucidate women’s involvement in trials, as experienced under extensive patriarchal history. Scholarly literature and Canadian government policy documents are used to explore the development of clinical trials as pertaining to sex and gender. Findings suggest that women continue to be underrepresented or excluded from important research, highlighting ongoing ethical and justice concerns. Improvement recommendations for policies are outlined. Keywords: Women, Clinical trials, Underrepresentation, Feminism, Sex, Gender, Policy