HSCB, a co-chaperone in mitochondrial iron-sulfur cluster biogenesis, is a novel candidate gene for congenital sideroblastic anemia

Congenital sideroblastic anemias (CSA) are inherited diseases resulting from defects in heme biosynthesis, mitochondrial iron-sulfur cluster (ISC) assembly, or mitochondrial translation. CSAs are characterized by pathological iron deposits in the mitochondria of bone marrow erythroblasts. Recently the Fleming Lab at Boston Children’s Hospital has reported mutations in HSPA9, a chaperone involved in ISC assembly, as a cause of nonsyndromic CSA. Here we identified a CSA patient harboring two variants in HSCB, encoding a binding partner of HSPA9: a paternally inherited promoter variant (c-134C>A) and a maternally inherited frameshift variant (T87fs) predicted to result in a truncated protein. To better understand the pathophysiology of these variants, we investigated HSCB protein expression and function in patient-derived skin fibroblasts. Patient fibroblasts show evidence of decreased HSCB protein levels. shRNA targeting HSCB was employed to specifically suppress HSCB expression in the K562 erythroid-like cell line model. shRNA-infected K562 cells presented with perturbed iron homeostasis, a shift to glycolytic energy production, and diminished hemoglobinization. Targeted deletion of murine Hscb is embryonic lethal prior day E7.0. Tissue-specific lox-Cre transgenic lines, including Vav-, EpoR- and Mx-Cre demonstrate that Hscb is essential for hematopoiesis and erythropoiesis. Mutant mice present with hematopoietic defects similar to the index patient. Vav-Cre animals die prior to post-natal day 9 with decreased red cell counts, white cell counts, and decreased hemoglobin compared to wild-type animals. Floxed-null EpoR-Cre animals die before embryonic day 13. To excise Hscb specifically in the hematopoietic compartment of adult animals, conditional Mx-Cre animals were generated through bone marrow transplantation and temporally induced with polyinosinic-polycytidylic acid treatment. The animals died 22 days post-injection with decreased red blood cells, white blood cells, hemoglobin, and an overall decline in hematopoiesis of the bone marrow. These data demonstrate that HSCB is required for erythropoiesis and hematopoiesis and that the patient mutations are a pathogenic cause of CSA

A Wolf in Sheep���s Clothing? An analysis of student engagement with virtual learning environments.

The article is freely available on-line via The Higher Education Academy website.The growth in the use of virtual learning environments to support learning and teaching should be accompanied by research to examine their effectiveness. The aim of this study was twofold: a) To explore the views, opinions and experiences of student engagement or non-engagement in online learning activities; b) To use this knowledge to develop learning and teaching strategies that enhance student engagement with online learning activities. Focus groups were conducted with students studying leisure and tourism degree programmes to explore reasons for usage and non-usage of the online activities in the Wolverhampton Online Learning Framework (WOLF). Results identified issues related to student awareness, motivation, behaviour and learning approaches, assessment and technical factors. Findings from the study have implications for practice, including how to enhance the relevance of information, technical factors, enhancing awareness and links with assessment

Anaemia prevalence and factors associated with haemoglobin change following radiotherapy in individuals with cancers at the Ocean Road Cancer Institute in Tanzania

Background: Despite the fact that anaemia is common worldwide, limited studies have been done in most developing countries to estimate its prevalence and factors associated with haemoglobin change in patients with cancers receiving radiotherapy.               Methods: This was a descriptive cross-sectional study conducted at the Ocean Road Cancer Institute in Dar es salaam, Tanzania. All individuals with cancers who were admitted in the wards for radiation treatment from August to December 2013 were included. Information on social-clinical characteristics, cancer type and associated factors as well as haemoglobin level before and after radiation were obtained. The prevalence of anaemia was determined as a proportion and linear regression was used to determine factors associated with haemoglobin change.Results: A total of 230 study subjects were available for analysis, of whom 82% were females. The overall mean age was 50±14 years. Most of the subjects (44%) were residing in the coastal regions, 50% had never attended school and 77% had no formal employment. The overall prevalence of anaemia was 77% before and 82% after radiotherapy. Multivariate linear regression analysis revealed that history of blood transfusion (beta-coefficient= 1.193; p=0.004) was the only factor associated with absolute change in haemoglobin.Conclusion: The prevalence of anaemia was high, regardless of the cancer type. Blood transfusion appeared to have a positive change in haemoglobin following radiotherapy. Awareness should be increased to provide early detection of the condition with appropriate corrective measures

Engaging the networked learner : theoretical and practical issues

The nature of learning and teaching in higher education has changed significantly in recent years. The emergence of social media and technologies has had a profound impact upon learner engagement and tutors have had to adapt their learning and teaching strategies accordingly. The thesis discusses the author’s published body of research and presents a pedagogical framework for engaging the networked learner. The framework is based upon three perspectives that have emerged from the author’s research. Firstly, different learning paradigms should be acknowledged when developing pedagogical approaches to using learning technologies. Secondly, the thesis discusses how the author’s research on learning technologies, including VLEs and iPod technologies, should embrace networked communities and learner empowerment. Thirdly, the research on learning approaches is discussed which acknowledges different learning behaviours and the adoption of differentiated methods in learning and teaching. Whilst discussing the evolving nature of the learning environment, the pedagogical framework draws together each of the aforementioned perspectives. The framework raises a number of factors for engaging the networked learner. A set of practical guidelines based around institutional, tutor and learner perspectives are discussed and underpin the application of the framework. The thesis concludes with theoretical observations on learning and learning theory and presents limitations and areas for further research.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Customizable Operating Systems

A customizable operating system is one that can adapt to improve its functionality or performance. The need for customizable and application-specific operating systems has been recognized for many years, but they have yet to appear in the commercial market. This paper explores the notion of operating system customizability and examines the limits of existing approaches. The paper begins by surveying system structuring approaches for the safe and efficient execution of customizable operating systems. Then it discusses the burden that existing approaches impose on application software, and explores techniques for reducing this burden. Finally, support for customizability in the Synthetix project is described and illustrated through two examples: a dynamically specialized file system read call, and an adaptive Internet-based MPEG video player

Adsorption and release behavior of chemicals from microplastics during environmental aging

Plastics are widely used in daily life due to their flexibility, durability and low cost. Due to their global usage, and poor handling at all stages of use from manufacture to disposal, an increasing quantity of microplastic debris has been detected in aquatic environments. As microplastics are composed of a wide range of chemical additives (e.g., plasticizers, flame retardants, fillers, etc.), with those chemicals are not tightly bound into the polymer, they can be released into the environment, and furthermore, due to the hydrophobicity of microplastics, contaminants present environment might be adsorbed by microplastics. Microplastics have been shown to undergo extensive aging after physical abrasion, UV irradiation, biodegradation, etc. The aging effect is an important process that determines the transport and transformation of microplastics in the environment, as well as their interactions with environmental contaminants. This study investigates the aging mechanism, factors affect the aging process, and evaluates how aging of microplastics (including UV irradiation, biofilms colonization, natural aging) affects their surface properties, adsorption/desorption performance, presence of additives, etc. Generally, the oxygen-containing groups on the surface of microplastics increase after aging, and sometimes the surface brightness and colour-difference are changed (e.g., yellowing). Together with the changes in surface roughness, all of them directly or indirectly affect the adsorption/desorption performance of bisphenols (typical endocrine-disrupting chemicals) on microplastics. The interaction mechanisms involved H-bonding, π-π interaction, hydrophobicity interaction, electrostatic interaction. In addition, suspect screening analysis suggested that additives (e.g., antioxidants, light stabilizers, plasticizers) might be vital in controlling the aging process, and the aging of microplastics affects the present of additives, leading to the changes of leaching behavior of additives from microplastics to the aquatic environment. This study combined both laboratory and field work, providing direct evidence of microplastic particles aging processes and their potential environmental risks due as a transport vector and exposure medium

Yabi: An online research environment for grid, high performance and cloud computing

Background There is a significant demand for creating pipelines or workflows in the life science discipline that chain a number of discrete compute and data intensive analysis tasks into sophisticated analysis procedures. This need has led to the development of general as well as domain-specific workflow environments that are either complex desktop applications or Internet-based applications. Complexities can arise when configuring these applications in heterogeneous compute and storage environments if the execution and data access models are not designed appropriately. These complexities manifest themselves through limited access to available HPC resources, significant overhead required to configure tools and inability for users to simply manage files across heterogenous HPC storage infrastructure. Results In this paper, we describe the architecture of a software system that is adaptable to a range of both pluggable execution and data backends in an open source implementation called Yabi. Enabling seamless and transparent access to heterogenous HPC environments at its core, Yabi then provides an analysis workflow environment that can create and reuse workflows as well as manage large amounts of both raw and processed data in a secure and flexible way across geographically distributed compute resources. Yabi can be used via a web-based environment to drag-and-drop tools to create sophisticated workflows. Yabi can also be accessed through the Yabi command line which is designed for users that are more comfortable with writing scripts or for enabling external workflow environments to leverage the features in Yabi. Configuring tools can be a significant overhead in workflow environments. Yabi greatly simplifies this task by enabling system administrators to configure as well as manage running tools via a web-based environment and without the need to write or edit software programs or scripts. In this paper, we highlight Yabi's capabilities through a range of bioinformatics use cases that arise from large-scale biomedical data analysis. Conclusion The Yabi system encapsulates considered design of both execution and data models, while abstracting technical details away from users who are not skilled in HPC and providing an intuitive drag-and-drop scalable web-based workflow environment where the same tools can also be accessed via a command line. Yabi is currently in use and deployed at multiple institutions and is available at http://ccg.murdoch.edu.au/yabi

Impact of WHO guidelines on trends in HIV testing and ART initiation among children living with HIV in Zambia.

BACKGROUND: About 13 years since the introduction of antiretroviral therapy (ART) for children living with HIV (CLHIV) in Zambia, HIV/AIDS testing and treatment guidelines for children have evolved over the years with limited documentation of long-term trends in the numbers testing HIV positive and initiating ART. We examined trends in HIV testing and ART initiation in Zambia. METHODS: We conducted a retrospective cohort study using routinely collected patient level data from 496 health facilities across Zambia. We used Poisson regression to derive incident rate ratios and 95% confidence intervals (95% CI) for background characteristics and used a Cuzick non-parametric test for trends to test the 13-year trends. Median time from testing to ART initiation in days and incidence rates were derived using life tables in survival analysis. We used multi-level random effects Poisson regression model to determine variations in time from HIV testing to ART initiation by facility. RESULTS: Overall, the cumulative proportion of the children who tested positive and initiated antiretroviral therapy (ART for HIV) from 2004 to 2017 was 69% (n = 99 592). During the period under review proportions of ART initiation increased from 52% in 2004-2006 to 97% in 2016-2017 (P < 0.001) and time from testing to ART initiation reduced from a median of 17 days IQR (1-161) in 2004 to one day IQR (1-14), P < 0.001 in 2016-2017. CLHIV were 15 times more likely to be initiated on ART in 2016-17 compared to period 2004-6 (IRR = 15.2, 95% CI 14.7-15.7). Time to ART initiation increased with age and was higher in rural health facilities compared to urban facilities. About 11% of the variability in time to ART initiation in children could be attributed to differences between facilities. CONCLUSIONS: The substantial increase in ART initiation and reduction in time to ART initiation among CLHIV identified in this study, reflects improvements in the paediatric HIV programme in Zambia in relation to health care delivery and adherence to national testing and treatment guidelines that were adapted from WHO guidelines. However, age-related differentials in rates of ART initiation suggests that urgent interventions are needed to sustain and further improve programme performance

Most women diagnosed with cervical cancer by a visual screening program in Tanzania completed treatment: evidence from a retrospective cohort study

Abstract Background Visual inspection with acetic acid (VIA) to identify and treat pre-cancerous lesions is effective for cervical cancer prevention. Screening programs also facilitate screening and diagnosis of invasive cancers that must be referred for radiation therapy or chemotherapy. This study compared characteristics of women diagnosed with invasive cervical cancer by a VIA screening program who did and did not follow up for treatment and who did and did not complete treatment at the Ocean Road Cancer Institute (ORCI), Dar es Salaam, Tanzania. Methods We conducted a retrospective cohort study of ORCI screening referrals from the period November 2002 to June 2011. Women referred for treatment of invasive disease (n = 980) were identified from an existing database of all women attending the screening clinic during this period (n = 20,131) and matched to a dataset of all cervical cancer patients attending ORCI in this period (n = 8,240). Treatment information was abstracted from patient records of women who followed up. Records of a random sample (n = 333) of unscreened patients were reviewed for disease stage. Results Of the 980 women referred women, 829 (84.6%) sought treatment. Most of those women (82.8%) completed their prescribed radiation. Lower disease stage, having a skilled occupation, residence in Dar es Salaam, and younger age were independently associated with loss to follow-up. Higher disease stage, residence in Dar es Salaam, older age, and later year of first treatment appointment were independently associated with incomplete treatment among those who followed up. Significantly more screened women had stage 1 disease (14.0%) than unscreened women (7.8%). Conclusions Most women referred from the screening clinic completed treatment for their cancer at ORCI. Some of those lost to follow-up may have sought treatment elsewhere. In most cases, the screening clinic appears to facilitate diagnosis and treatment, rather than screening, for women with invasive cervical cancer.http://deepblue.lib.umich.edu/bitstream/2027.42/109468/1/12889_2013_Article_7027.pd

The elevated Curie temperature and half-metallicity in the ferromagnetic semiconductor Lax_{x}Eu1−x_{1-x}O

Here we study the effect of La doping in EuO thin films using SQUID magnetometry, muon spin rotation ($\mu$SR), polarized neutron reflectivity (PNR), and density functional theory (DFT). The $\mu$SR data shows that the La$_{0.15}$Eu$_{0.85}$O is homogeneously magnetically ordered up to its elevated $T_{\rm C}$. It is concluded that bound magnetic polaron behavior does not explain the increase in $T_{\rm C}$ and an RKKY-like interaction is consistent with the $\mu$SR data. The estimation of the magnetic moment by DFT simulations concurs with the results obtained by PNR, showing a reduction of the magnetic moment per La$_{x}$Eu$_{1-x}$O for increasing lanthanum doping. This reduction of the magnetic moment is explained by the reduction of the number of Eu-4$f$ electrons present in all the magnetic interactions in EuO films. Finally, we show that an upwards shift of the Fermi energy with La or Gd doping gives rise to half-metallicity for doping levels as high as 3.2 %.Comment: 7 pages, 11 figure