bluuebunny/crossref_metadata_2025 huggingface dataset:
Discovery-2: an interactive resource for the rational selection and comparison of putative drug target proteins in malaria
Authors: Mpangase Phelelani T , Szolkiewicz Michal J , le Grange Misha , Smit Jeanré H , Burger Pieter B , Joubert Fourie
Published: March 2013

Background

Drug resistance to anti-malarial compounds remains a serious problem, with resistance to newer pharmaceuticals developing at an alarming rate. The development of new anti-malarials remains a priority, and the rational selection of putative targets is a key element of this process. Discovery-2 is an update of the original Discovery in silico resource for the rational selection of putative drug target proteins, enabling researchers to obtain information for a protein which may be useful for the selection of putative drug targets, and to perform advanced filtering of proteins encoded by the malaria genome based on a series of molecular properties.

Methods

An updated in silico resource has been developed where researchers are able to mine information on malaria proteins and predicted ligands, as well as perform comparisons to the human and mosquito host characteristics. Protein properties used include: domains, motifs, EC numbers, GO terms, orthologs, protein-protein interactions, protein-ligand interactions. Newly added features include drugability measures from ChEMBL, automated literature relations and links to clinical trial information. Searching by chemical structure is also available.

Results

The updated functionality of the Discovery-2 resource is presented, together with a detailed case study of the Plasmodium falciparum S-adenosyl-L-homocysteine hydrolase (PfSAHH) protein. A short example of a chemical search with pyrimethamine is also illustrated.

Conclusion

The updated Discovery-2 resource allows researchers to obtain detailed properties of proteins from the malaria genome, which may be of interest in the target selection process, and to perform advanced filtering and selection of proteins based on a relevant range of molecular characteristics.
Electrical and optical properties of Al-doped ZnO and ZnAl2O4 films prepared by atomic layer deposition
Authors: Hou Qiongqiong , Meng Fanjie , Sun Jiaming
Published: March 2013

ZnO/Al2O3 multilayers were prepared by alternating atomic layer deposition (ALD) at 150°C using diethylzinc, trimethylaluminum, and water. The growth process, crystallinity, and electrical and optical properties of the multilayers were studied with a variety of the cycle ratios of ZnO and Al2O3 sublayers. Transparent conductive Al-doped ZnO films were prepared with the minimum resistivity of 2.4 × 10−3 Ω·cm at a low Al doping concentration of 2.26%. Photoluminescence spectroscopy in conjunction with X-ray diffraction analysis revealed that the thickness of ZnO sublayers plays an important role on the priority for selective crystallization of ZnAl2O4 and ZnO phases during high-temperature annealing ZnO/Al2O3 multilayers. It was found that pure ZnAl2O4 film was synthesized by annealing the specific composite film containing alternative monocycle of ZnO and Al2O3 sublayers, which could only be deposited precisely by utilizing ALD technology.
Prevalence of porcine enterovirus 9 in pigs in Middle and Eastern China
Authors: Yang Shixing , Wang Yan , Shen Quan , Zhang Wen , Hua Xiuguo
Published: March 2013

Little information on the epidemiology and pathogenicity of porcine enterovirus 9 (PEV-9) is available. The present study investigated the prevalence of PEV-9 in pig populations in middle and eastern China using reverse transcriptase (RT)-PCR. All 14 sampled farms were positive for PEV-9 and the overall prevalence of infection in the studied pigs was 8.3% (37/447). There was a higher frequency of infection in pigs aged 10–15 weeks (12/119, 10.1%) than in pigs aged >20 weeks (5/103, 4.9%). A 313 nucleotide sequence from the 5′-UTR region of 37 Chinese PEV-9 positive samples had 96.1-100% sequence homology. On phylogenetic analysis, sequences clustered into two major groups, from which two representative strains were selected to determine the complete RNA-dependent RNA polymerase (RdRp) gene sequence. Phylogenetic analysis based on the RdRp gene suggested that PEV-9 strains from China formed a new subgroup. Piglets were inoculated orally with the PEV-9 strain identified in this study. Although most experimental pigs showed no clinical signs, almost all carried PEV-9 in one or more tissues after 6 days post-inoculation. The results of tissue histologic examination suggested that PEV9 can cause pathological changes in cerebrum and lung.
Preclinical Studies of Low Back Pain
Authors: Strong Judith A , Xie Wenrui , Bataille Feguens J , Zhang Jun-Ming
Published: March 2013

Chronic low back pain is a major cause of disability and health care costs. Current treatments are inadequate for many patients. A number of preclinical models have been developed that attempt to mimic aspects of clinical conditions that contribute to low back pain. These involve application of nucleus pulposus material near the lumbar dorsal root ganglia (DRG), chronic compression of the DRG, or localized inflammation of the DRG. These models, which are primarily implemented in rats, have many common features including behavioral hypersensitivity of the hindpaw, enhanced excitability and spontaneous activity of sensory neurons, and locally elevated levels of inflammatory mediators including cytokines. Clinically, epidural injection of steroids (glucocorticoids) is commonly used when more conservative treatments fail, but clinical trials evaluating these treatments have yielded mixed results. There are relatively few preclinical studies of steroid effects in low back pain models. One preclinical study suggests that the mineralocorticoid receptor, also present in the DRG, may have pro-inflammatory effects that oppose the activation of the glucocorticoid receptor. Although the glucocorticoid receptor is the target of anti-inflammatory steroids, many clinically used steroids activate both receptors. This could be one explanation for the limited effects of epidural steroids in some patients. Additional preclinical research is needed to address other possible reasons for limited efficacy of steroids, such as central sensitization or presence of an ongoing inflammatory stimulus in some forms of low back pain.
Infratentorial benign cystic meningioma mimicking a hemangioblastoma radiologically and a pilocytic astrocytoma intraoperatively: a case report
Authors: Guan Tan Kheng , Pancharatnam Devaraj , Chandran Hari , Hooi Teoh Kean , Kumar Gnana , Ganesan Dharmendra
Published: March 2013

Introduction

Cystic meningiomas are rare variants of meningiomas; they can pose a radiological diagnostic dilemma.

Case presentation

We present a rare case of a 30-year-old Chinese woman with a histopathological diagnosis of infratentorial cystic meningioma (World Health Organization Grade 1) in which the features in imaging modalities were suggestive of a hemangioblastoma. Intraoperatively, however, the gross macroscopic features were more in keeping with a pilocytic astrocytoma.

Conclusion

In benign cystic meningiomas, particularly the infratentorial variety, radiological findings utilizing the various imaging modalities and intraoperative impressions may not be reflective of or in keeping with the final histopathological diagnosis.
Evaluation of Greek psychiatric reforms: methodological issues
Authors: Loukidou Evangelia , Mastroyannakis Anastasios , Power Tracey , Thornicroft Graham , Craig Tom , Bouras Nick
Published: March 2013

Over the last three decades significant efforts have been made in many European countries to move away from a mental health system dominated by institutional care towards one whereby the main emphasis is on providing care and support within the community. Although the time of starting the reforms, their pace, the political context, and the exact objectives varies substantially across Europe, practically all countries have been undergoing such major reforms aimed at establishing services in the community to replace institutional based care. Each country makes its own decisions about the necessary mental health services taking into account a range of factors including population needs, level of resources, flexibility and coordination of organizational structures, as well as local culture. These factors become an integral element of a national mental health policy and action plan, closely linked with national public health strategies.

Greece has been modernizing an outdated mental health system, which was based on institutional care, over the last 20 years, by developing community-based mental health care. This article describes the methodology used for the evaluation of the Psychargos programme of the mental health reforms in Greece. Various forms of community-based mental health services have been developed including supported living facilities, community mental health centres and employment opportunities.
Challenges for malaria elimination in Zanzibar: pyrethroid resistance in malaria vectors and poor performance of long-lasting insecticide nets
Authors: Haji Khamis A , Khatib Bakari O , Smith Stephen , Ali Abdullah S , Devine Gregor J , Coetzee Maureen , Majambere Silas
Published: March 2013

Background

Long-lasting insecticide treated nets (LLINs) and indoor residual house spraying (IRS) are the main interventions for the control of malaria vectors in Zanzibar. The aim of the present study was to assess the susceptibility status of malaria vectors against the insecticides used for LLINs and IRS and to determine the durability and efficacy of LLINs on the island.

Methods

Mosquitoes were sampled from Pemba and Unguja islands in 2010–2011 for use in WHO susceptibility tests. One hundred and fifty LLINs were collected from households on Unguja, their physical state was recorded and then tested for efficacy as well as total insecticide content.

Results

Species identification revealed that over 90% of the Anopheles gambiae complex was An. arabiensis with a small number of An. gambiae s.s. and An. merus being present. Susceptibility tests showed that An. arabiensis on Pemba was resistant to the pyrethroids used for LLINs and IRS. Mosquitoes from Unguja Island, however, were fully susceptible to all pyrethroids tested. A physical examination of 150 LLINs showed that two thirds were damaged after only three years in use. All used nets had a significantly lower (p < 0.001) mean permethrin concentration of 791.6 mg/m2 compared with 944.2 mg/m2 for new ones. Their efficacy decreased significantly against both susceptible An. gambiae s.s. colony mosquitoes and wild-type mosquitoes from Pemba after just six washes (p < 0.001).

Conclusion

The sustainability of the gains achieved in malaria control in Zanzibar is seriously threatened by the resistance of malaria vectors to pyrethroids and the short-lived efficacy of LLINs. This study has revealed that even in relatively well-resourced and logistically manageable places like Zanzibar, malaria elimination is going to be difficult to achieve with the current control measures.
Preventing food allergy: protocol for a rapid systematic review
Authors: de Silva Debra , Panesar Sukhmeet S , Thusu Sundeep , Rader Tamara , Halken Susanne , Muraro Antonella , Sheikh Aziz
Published: March 2013

Background

The European Academy of Allergy and Clinical Immunology is developing guidelines about how to prevent and manage food allergy. As part of the guidelines development process, a systematic review is planned to examine published research about the prevention of food allergy. This systematic review is one of seven inter‐linked evidence syntheses that are being undertaken in order to provide a state‐of‐the‐art synopsis of the current evidence base in relation to epidemiology, prevention, diagnosis and clinical management, and impact on quality of life, which will be used to inform clinical recommendations. The aim of this systematic review will be to assess the effectiveness of approaches for the primary prevention of food allergy.

Methods

Seven bibliographic databases will be searched from their inception to September 30, 2012 for systematic reviews, randomized controlled trials, quasi‐randomized controlled trials, controlled clinical trials, controlled before‐and‐after studies, interrupted time series and cohort studies. Cohort studies will be included due to an inability to randomize with interventions such as breastfeeding. Studies that focused on the development of either food sensitization (a proxy measure) or food allergy will also be eligible for inclusion. Studies will be critically appraised using the Critical Appraisal Skills Program and Cochrane Risk of Bias tools, as appropriate.

Discussion

There is a lack of rigorous evidence to support recommendations about how to prevent the development of food allergy. It would appear that it is important to see the prevention of food allergy in the context of individual, family and wider factors that may influence its development. There is much left to learn about preventing food allergy, and this is a priority given the high societal and healthcare costs involved. This systematic review will help to further this learning.
Microarray‐based component‐resolved diagnosis of latex allergy: isolated IgE‐mediated sensitization to latexprofilin Hev b8 may act as confounder
Authors: Schuler Sarah , Ferrari Giovanni , Schmid‐Grendelmeier Peter , Harr Thomas
Published: March 2013

Immediate type allergy to latex is still a widespread problem. Latex‐allergic patients undergoing diagnostic and operative medical procedures are at risk of potentially life‐threatening reactions. Accurate diagnostic methods are therefore crucial. The aim of this retrospective study was to discriminate between sensitization and relevant allergy to latex based on an easy and suitable diagnostic approach. In 14 patients with clinical symptoms and 27 controls, latex skin prick tests (SPT), IgE against latex (CAP) and serological component resolved specific latex‐allergen determination (Hev b1, b3, b5, b6, b7, b8, b9, b10, b11) based on ImmunoCAP ISAC were performed. SPT correlated very well with clinically manifest latex‐allergy demonstrating a high specificity (95%) (and a low sensitivity). However, CAP levels to crude latex could not safely discriminate between purely sensitized and latex‐allergic patients. The majority of patients mono‐sensitized to the latex profilin Hev b8 did not suffer from any relevant symptoms upon contact with latex. However, in two patients with latex‐allergy diagnosed by elevated specific IgE only sensitized against Hev b8, additional sensitization to carbohydrate cross‐reactive determinants (CCD) was found. In the case of positive serum IgE against latex and negative SPT, component‐resolved diagnosis including IgE against specific latex‐proteins, specially Hev b8, and carbohydrate cross‐reactive determinants (CCD) is a useful tool to discriminate between latex‐sensitization and latex‐allergy.
The impact of diurnal variation on induced sputum cell counts in healthy adults
Authors: Davidson Warren J , Wong Lisa E , The Stephanie , Leigh Richard
Published: March 2013

Background

Induced sputum cell counts are a non‐invasive, reliable method for evaluating the presence, type, and degree of inflammation in the airways of the lungs. Current reference values for induced sputum cell counts in healthy adults do not account for the effects of circadian rhythm, including diurnal variation. The objective of this study was to describe the diurnal variation in induced sputum cell counts, compared between early morning and late afternoon, in healthy adult individuals.

Methods

100 healthy adult subjects with no history of lung disease and normal bronchial reactivity proceeded with induced sputum testing at 7 am and 4 pm on different days. The order of testing was randomized. The cytotechnologist preparing and performing the cell counts was blinded to the sample collection time and subject characteristics.

Results

65 subjects were included in the final analyses. There was no significant change in the total and differential sputum cell counts between the 7 am and 4 pm collections. There was good inter‐observer agreement with respect to differential sputum cell count interpretation.

Conclusions

This is the largest study to assess the variation in induced sputum cell counts in healthy adult subjects at different times of the day. We found no significant change in total and differential sputum cell counts between the 7 am and 4 pm collection time points. This is in contrast to studies in asthmatics that demonstrated a circadian variation in sputum cell counts and other markers of inflammation, suggesting that fluctuations in airway inflammatory cells during the day are a disease‐specific effect.
The effect of cyclodextrin-solubilized curcuminoids on amyloid plaques in Alzheimer transgenic mice: brain uptake and metabolism after intravenous and subcutaneous injection
Authors: Quitschke Wolfgang W , Steinhauff Nicole , Rooney Jean
Published: March 2013

Introduction

Curcuminoids may improve pathological conditions associated with Alzheimer's disease. However, their therapeutic potential is limited by their exceedingly low bioavailability after oral administration. A method to deliver solubilized curcuminoids by injection was evaluated in Alzheimer transgenic mice.

Methods

Amyloid protein precursor (APP)SWE, PS1dE9 mice were intravenously or subcutaneously injected at weekly intervals between the ages of 4 and 12 months with serum- or cyclodextrin-solubilized curcuminoids to assess their potential for plaque prevention. Alternatively, mice between the ages of 11 and 12 months were intravenously injected with cyclodextrin-solubilized curcuminoids at biweekly intervals to evaluate their ability to eliminate existing plaques. Plasma and brain levels of curcuminoids and their metabolites were also determined after subcutaneous and intravenous injection.

Results

Weekly long-term injections did not result in a significant plaque load reduction. However, intravenous injection of cyclodextrin-solubilized curcuminoids at higher curcuminoid concentrations and at a biweekly frequency between the ages of 11 and 12 months reduced the plaque load to approximately 70% of the control value. After intravenous injection, plasma levels of 100 μM curcuminoids and brain levels of 47 nmol/g could initially be achieved that declined to essentially undetectable levels within 20 minutes. The primary curcuminoid metabolites in plasma were the conjugates of glucuronide or sulfate and hexahydrocurcuminoids as reduction products. In the brain, both hexahydrocurcuminoids and octahydrocurcuminoids were detected as major metabolites. After subcutaneous injection, maximal curcuminoid plasma levels of 23 μM and brain levels of 8 nmol/g were observed at 30 minutes after injection and curcuminoids remained detectable for 2 to 3 h.

Conclusion

Curcuminoids are rapidly metabolized after injection and their effect on reducing plaque load associated with Alzheimer's disease may be dependent on the frequency of administration.
The secreted AdamTS-A metalloprotease is required for collective cell migration
Authors: Ismat Afshan , Cheshire Alan M. , Andrew Deborah J.
Published: March 2013

Members of the ADAMTS family of secreted metalloproteases play crucial roles in modulating the extracellular matrix (ECM) in development and disease. Here, we show that ADAMTS-A, the Drosophila ortholog of human ADAMTS 9 and ADAMTS 20, and of C. elegans GON-1, is required for cell migration during embryogenesis. AdamTS-A is expressed in multiple migratory cell types, including hemocytes, caudal visceral mesoderm (CVM), the visceral branch of the trachea (VBs) and the secretory portion of the salivary gland (SG). Loss of AdamTS-A causes defects in germ cell, CVM and VB migration and, depending on the tissue, AdamTS-A functions both autonomously and non-autonomously. In the highly polarized collective of the SG epithelium, loss of AdamTS-A causes apical surface irregularities and cell elongation defects. We provide evidence that ADAMTS-A is secreted into the SG lumen where it functions to release cells from the apical ECM, consistent with the defects observed in AdamTS-A mutant SGs. We show that loss of the apically localized protocadherin Cad99C rescues the SG defects, suggesting that Cad99C serves as a link between the SG apical membrane and the secreted apical ECM component(s) cleaved by ADAMTS-A. Our analysis of AdamTS-A function in the SG suggests a novel role for ADAMTS proteins in detaching cells from the apical ECM, facilitating tube elongation during collective cell migration.
Nanotechnology-supported THz medical imaging
Authors: Stylianou Andreas , Talias Michael A
Published: March 2013

Over the last few decades, the achievements and progress in the field of medical imaging have dramatically enhanced the early detection and treatment of many pathological conditions. The development of new imaging modalities, especially non-ionising ones, which will improve prognosis, is of crucial importance. A number of novel imaging modalities have been developed but they are still in the initial stages of development and serious drawbacks obstruct them from offering their benefits to the medical field. In the 21st century, it is believed that nanotechnology will highly influence our everyday life and dramatically change the world of medicine, including medical imaging. Here we discuss how nanotechnology, which is still in its infancy, can improve Terahertz (THz) imaging, an emerging imaging modality, and how it may find its way into real clinical applications. THz imaging is characterised by the use of non-ionising radiation and although it has the potential to be used in many biomedical fields, it remains in the field of basic research. An extensive review of the recent available literature shows how the current state of this emerging imaging modality can be transformed by nanotechnology. Innovative scientific concepts that use nanotechnology-based techniques to overcome some of the limitations of the use of THz imaging are discussed. We review a number of drawbacks, such as a low contrast mechanism, poor source performance and bulky THz systems, which characterise present THz medical imaging and suggest how they can be overcome through nanotechnology. Better resolution and higher detection sensitivity can also be achieved using nanotechnology techniques.
Ouabain inhibition of Na/K-ATPase across the retina prevents signed refractive compensation to lens-induced defocus, but not default ocular growth in young chicks
Authors: Murphy Melanie J , Crewther Sheila Gillard
Published: March 2013

Purpose: The relevance of retinal integrity and energy pathways to ocular growth and induction of refractive errors has seldom been investigated. Thus, we used ouabain to target the channels that are essential for the maintenance of membrane potentials in cells, sodium potassium ATPase (Na/K-ATPase), to examine refractive compensation and ocular growth in response to lens-induced defocus in the chick.

Methods:  A single intravitreal injection of 1 mM ouabain in dimethyl sulfoxide (DMSO) carrier or DMSO alone was followed by monocular defocus with positive or negative 10 D lens (or no lens) from post-hatching days 5-9 under 12/12 hr light/dark conditions. Biometry and dark-adapted flash and electroretinography (ERG) were conducted on day 9, followed by immunohistological analyses.

Results: Ouabain inhibited differential ocular growth and refractive compensation to signed defocus compared to DMSO. By 4-days post-ouabain injection all components of the typical ERG responses to light had been eliminated, and widespread histological damage was apparent, though some ‘default state’ ocular growth was measurable. Immunohistochemistry demonstrated reduction in the specialized water channel Aquaporin 4 (AQP4) expression and increased evidence of caspase 3 expression (a cell death associated protein) in ouabain-treated eyes compared with DMSO alone.

Conclusion: The current study demonstrates that blockade of photoreceptor and inner retinal responses to light onset and offset by ouabain inhibits differential refractive compensation to optical blur, but does not prevent ocular growth.
Polycistronic transcription of fused cassettes and identification of translation initiation signals in an unusual gene cassette array from Pseudomonas aeruginosa
Authors: Fonseca Érica L. , Vicente Ana Carolina Paulo
Published: March 2013

The gene cassettes found in class 1 integrons are generally promoterless units composed by an open reading frame (ORF), a short 5’ untranslated region (UTR) and a 3’ recombination site (attC). Fused gene cassettes are generated by partial or total loss of the attC from the first cassette in an array, creating a fusion with the ORF from the next cassette. These structures are rare and little is known about their mechanisms of mobilization and expression. The aim of this study was to evaluate the dynamic of mobilization and transcription of the gcu14-blaGES-1/aacA4 gene cassette array, which harbours a fused gene cassette represented by blaGES-1/aacA4. The cassette array was analyzed by Northern blot and real-time reverse transcription-polymerase chain reaction (RT-PCR) in order to assess the transcription mechanism of blaGES-1/aacA4 fused cassette. Also, inverse polymerase chain reactions (PCR) were performed to detect the free circular forms of gcu14, blaGES-1 and aacA4. The Northern blot and real time RT-PCR revealed a polycistronic transcription, in which the fused cassette blaGES-1/aacA4 is transcribed as a unique gene, while gcu14 (with a canonical attC recombination site) has a monocistronic transcription. The gcu14 cassette, closer to the weak configuration of cassette promoter (Pc), had a higher transcription level than blaGES-1/aacA4, indicating that the cassette position impacts the transcript amounts. The presence of ORF-11 at attI1, immediately preceding gcu14, and of a Shine-Dalgarno sequence upstream blaGES-1/aacA4 composes a scenario for the occurrence of array translation. Inverse PCR generated amplicons corresponding to gcu14, gcu14-aacA4 and gcu14-blaGES-1/aacA4 free circular forms, but not to blaGES-1 and aacA4 alone, indicating that the GES-1 truncated attC is not substrate of integrase activity and that these genes are mobilized together as a unique cassette. This study was original in showing the transcription of fused cassettes and in correlating cassette position with transcription.
Orthopaedic challenges in Ancient Egypt
Authors: Colton C.
Published: March 2013

Ancient Egypt was a highly developed agrarian society with a massive civil engineering capability. Trauma and skeletal disease were common and vestiges of the evidence for that survive, largely in the form of hieratic images and papyri dedicated to the practice of medicine. The earliest treatise on trauma is the Edwin Smith papyrus, possibly the work of Imhotep. This study details some remarkable examples of musculoskeletal pathology including fatal open fractures, foot deformity of Tutankhamun, and the earliest recorded instances of child abuse.
What's at Stake in the Lives of People With Intellectual Disability? Part II: Recommendations for Naming, Defining, Diagnosing, Classifying, and Planning Supports
Authors: Luckasson Ruth , Schalock Robert L.
Published: March 2013

This article focuses on recommendations for naming, defining, diagnosing, classifying, and planning supports for individuals with intellectual disability (ID). The article provides an overview of the essential questions addressed by the respective functions and provides a series of specific recommendations that address the high stakes involved for people with ID, their families, and the field of ID.
The Law's Understanding of Intellectual Disability As a Disability
Authors: Ellis James W.
Published: March 2013

Intellectual disability (ID) is differently yet validly described by different professions. Legal professionals find it most useful to consider ID as a disability rather than a disorder. Because the law regulates the actions of individuals in a society and the actions of society on an individual, the law's concern in dealing with a person with ID is almost always with that person's functional abilities and limitations in society. This concern is reflected in various aspects of criminal and civil law, although the methods of assessing those functional abilities and limitations have changed considerably over time. The law has not always been wise or humane in its treatment of people with ID, but its focus on functional abilities and limitations allows us to assist people with ID to use their abilities and participate in society to their fullest potential.
Beyond Terminology: The Policy Impact of a Grassroots Movement
Authors: Ford Marty , Acosta Annie , Sutcliffe T. J.
Published: March 2013

This article discusses the history of the grassroots movement led by self-advocates and their families to replace the stigmatizing term mental retardation with intellectual disability in federal statute. It also describes recent and pending changes in federal regulations and policy to adopt the new terminology for Social Security and Medicaid.
Definition of Intellectual Disability in Criminal Court Cases
Authors: Olley J. Gregory
Published: March 2013

Definitions and associated descriptions of the condition now commonly known as intellectual disability serve many functions. The Atkins v. Virginia U.S. Supreme Court decision (2002) has called attention to the importance of clear, objective, and measureable wording of the definition. This article discusses the potential for misunderstanding and misinterpretation of such words as ability and cognitive, the importance of clarifying the role of measurement error and sociocultural factors, and the noncausal relationship between impairment in intelligence and adaptive behavior.
Considering Context: An Integrative Concept for Promoting Outcomes in the Intellectual Disability Field
Authors: Shogren Karrie A.
Published: March 2013

In light of the rapid evolution of research, policy, and practice in the intellectual disability (ID) field resulting from shifts in our conceptualization of disability and in frameworks for the diagnosis and classification of ID, systematic consideration of the multiple, interrelated contextual factors that impact research, policy, and practice are necessary to achieve valued outcomes for individuals with disabilities, their families, and society. The purpose of this article is to introduce a recently developed consensus definition of context and elaborate on application of this definition to research, practice, and policy in the ID field, with a specific focus on how context may be able to serve as an integrative concept to support the attainment of valued outcomes in the disability field for individuals with disabilities, their families, and society.
Gestational Diabetes Mellitus
Authors: Coustan Donald R
Published: March 2013

BACKGROUND

Gestational diabetes mellitus, defined as diabetes diagnosed during pregnancy that is not clearly overt diabetes, is becoming more common as the epidemic of obesity and type 2 diabetes continues. Newly proposed diagnostic criteria will, if adopted universally, further increase the prevalence of this condition. Much controversy surrounds the diagnosis and management of gestational diabetes.

CONTENT

This review provides information regarding various approaches to the diagnosis of gestational diabetes and the recommendations of a number of professional organizations. The implications of gestational diabetes for both the mother and the offspring are described. Approaches to self-monitoring of blood glucose concentrations and treatment with diet, oral medications, and insulin injections are covered. Management of glucose metabolism during labor and the postpartum period are discussed, and an approach to determining the timing of delivery and the mode of delivery is outlined.

This review provides an overview of current controversies as well as current recommendations for gestational diabetes care.
ZRT1Harbors an Excess of Nonsynonymous Polymorphism and Shows Evidence of Balancing Selection inSaccharomyces cerevisiae
Authors: Engle Elizabeth K , Fay Justin C
Published: March 2013

Estimates of the fraction of nucleotide substitutions driven by positive selection vary widely across different species. Accounting for different estimates of positive selection has been difficult, in part because selection on polymorphism within a species is known to obscure a signal of positive selection among species. While methods have been developed to control for the confounding effects of negative selection against deleterious polymorphism, the impact of balancing selection on estimates of positive selection has not been assessed. In Saccharomyces cerevisiae, there is no signal of positive selection within protein coding sequences as the ratio of nonsynonymous to synonymous polymorphism is higher than that of divergence. To investigate the impact of balancing selection on estimates of positive selection, we examined five genes with high rates of nonsynonymous polymorphism in S. cerevisiae relative to divergence from S. paradoxus. One of the genes, the high-affinity zinc transporter ZRT1 showed an elevated rate of synonymous polymorphism indicative of balancing selection. The high rate of synonymous polymorphism coincided with nonsynonymous divergence among three haplotype groups, among which we found no detectable differences in ZRT1 function. Our results implicate balancing selection in one of five genes exhibiting a large excess of nonsynonymous polymorphism in yeast. We conclude that balancing selection is a potentially important factor in estimating the frequency of positive selection across the yeast genome.
Influence of Steroid Hormone Signaling on Life Span Control byCaenorhabditis elegansInsulin-Like Signaling
Authors: Dumas Kathleen J , Guo Chunfang , Shih Hung-Jen , Hu Patrick J
Published: March 2013

Sterol-sensing nuclear receptors and insulin-like growth factor signaling play evolutionarily conserved roles in the control of aging. In the nematode Caenorhabditis elegans, bile acid-like steroid hormones known as dafachronic acids (DAs) influence longevity by binding to and regulating the activity of the conserved nuclear receptor DAF-12, and the insulin receptor (InsR) ortholog DAF-2 controls life span by inhibiting the FoxO transcription factor DAF-16. How the DA/DAF-12 pathway interacts with DAF-2/InsR signaling to control life span is poorly understood. Here we specifically investigated the roles of liganded and unliganded DAF-12 in life span control in the context of reduced DAF-2/InsR signaling. In animals with reduced daf-2/InsR activity, mutations that either reduce DA biosynthesis or fully abrogate DAF-12 activity shorten life span, suggesting that liganded DAF-12 promotes longevity. In animals with reduced DAF-2/InsR activity induced by daf-2/InsR RNAi, both liganded and unliganded DAF-12 promote longevity. However, in daf-2/InsR mutants, liganded and unliganded DAF-12 act in opposition to control life span. Thus, multiple DAF-12 activities influence life span in distinct ways in contexts of reduced DAF-2/InsR signaling. Our findings establish new roles for a conserved steroid signaling pathway in life span control and elucidate interactions among DA biosynthetic pathways, DAF-12, and DAF-2/InsR signaling in aging.
A Whole Genome Screen for Minisatellite Stability Genes in Stationary-Phase Yeast Cells
Authors: Alver Bonnie , Jauert Peter A , Brosnan Laura , O’Hehir Melissa , VanderSluis Benjamin , Myers Chad L , Kirkpatrick David T
Published: March 2013

Repetitive elements comprise a significant portion of most eukaryotic genomes. Minisatellites, a type of repetitive element composed of repeat units 15−100 bp in length, are stable in actively dividing cells but change in composition during meiosis and in stationary-phase cells. Alterations within minisatellite tracts have been correlated with the onset of a variety of diseases, including diabetes mellitus, myoclonus epilepsy, and several types of cancer. However, little is known about the factors preventing minisatellite alterations. Previously, our laboratory developed a color segregation assay in which a minisatellite was inserted into the ADE2 gene in the yeast Saccharomyces cerevisiae to monitor alteration events. We demonstrated that minisatellite alterations that occur in stationary-phase cells give rise to a specific colony morphology phenotype known as blebbing. Here, we performed a modified version of the synthetic genetic array analysis to screen for mutants that produce a blebbing phenotype. Screens were conducted using two distinctly different minisatellite tracts: the ade2-min3 construct consisting of three identical 20-bp repeats, and the ade2-h7.5 construct, consisting of seven-and-a-half 28-bp variable repeats. Mutations in 102 and 157 genes affect the stability of the ade2-min3 and ade2-h7.5 alleles, respectively. Only seven hits overlapped both screens, indicating that different factors regulate repeat stability depending upon minisatellite size and composition. Importantly, we demonstrate that mismatch repair influences the stability of the ade2-h7.5 allele, indicating that this type of DNA repair stabilizes complex minisatellites in stationary phase cells. Our work provides insight into the factors regulating minisatellite stability.
A Functional Comparison of the 3xP3 Promoter by Recombinase-Mediated Cassette Exchange in Drosophila and a Tephritid Fly, Anastrepha suspensa
Authors: Schetelig Marc F , Handler Alfred M
Published: March 2013

Transposable elements are widely used as vectors for integrating transgenes into the genome of insects. However, the random nature of transposon vector integrations often results in mutations and makes transgene expression subject to variable genomic position effects. This makes reliable quantitative comparisons of different transgenes difficult and development of highly fit transgenic strains laborious. Tools for site-specific transgene targeting are essential for functional genomic comparisons and to develop the most advanced transgenic insect strains for applied use. Here we describe a recombinase-mediated cassette exchange gene targeting system based on Cre/loxP that is highly efficient in Drosophila, and for the first time in a non-drosophilid, the tephritid fly, Anastrepha suspensa. This system allowed a comparison of the Drosophila constitutive polyubiquitin promoter and the artificial 3xP3 tissue-specific promoter in the same genomic context within each species, showing that the widely used 3xP3 promoter is apparently nonfunctional in the tephritid fly.
Activation-Induced Cytidine Deaminase Does Not Impact Murine Meiotic Recombination
Authors: Cortesao Catarina S , Freitas Raquel F , Barreto Vasco M
Published: March 2013

Activation-induced cytidine deaminase (AID) was first described as the triggering enzyme of the B-cell−specific reactions that edit the immunoglobulin genes, namely somatic hypermutation, gene conversion, and class switch recombination. Over the years, AID was also detected in cells other than lymphocytes, and it has been assigned additional roles in the innate defense against transforming retroviruses, in retrotransposition restriction and in DNA demethylation. Notably, AID expression was found in germline tissues, and in heterologous systems it can induce the double-strand breaks required for the initiation of meiotic recombination and proper gamete formation. However, because AID-deficient mice are fully fertile, the molecule is not essential for meiosis. Thus, the remaining question that we addressed here is whether AID influences the frequency of meiotic recombination in mice. We measured the recombination events in the meiosis of male and female mice F1 hybrids of C57BL/6J and BALB/c, in Aicda+/+ and Aicda−/− background by using a panel of single-nucleotide polymorphisms that distinguishes C57BL/6J from BALB/c genome across the 19 autosomes. In agreement with the literature, we found that the frequency of recombination in the female germline was greater than in male germline, both in the Aicda+/+ and Aicda−/− backgrounds. No statistical difference was found in the average recombination events between Aicda+/+ and Aidca−/− animals, either in females or males. In addition, the recombination frequencies between single-nucleotide polymorphisms flanking the immunoglobulin heavy and immunoglobulin kappa loci was also not different. We conclude that AID has a minor impact, if any, on the overall frequency of meiotic recombination.
Inferring Gene Function and Network Organization in Drosophila Signaling by Combined Analysis of Pleiotropy and Epistasis
Authors: Carter Gregory W
Published: March 2013

High-throughput genetic interaction screens have enabled functional genomics on a network scale. Groups of cofunctional genes commonly exhibit similar interaction patterns across a large network, leading to novel functional inferences for a minority of previously uncharacterized genes within a group. However, such analyses are often unsuited to cases with a few relevant gene variants or sparse annotation. Here we describe an alternative analysis of cell growth signaling using a computational strategy that integrates patterns of pleiotropy and epistasis to infer how gene knockdowns enhance or suppress the effects of other knockdowns. We analyzed the interaction network for RNAi knockdowns of a set of 93 incompletely annotated genes in a Drosophila melanogaster model of cellular signaling. We inferred novel functional relationships between genes by modeling genetic interactions in terms of knockdown-to-knockdown influences. The method simultaneously analyzes the effects of partially pleiotropic genes on multiple quantitative phenotypes to infer a consistent model of each genetic interaction. From these models we proposed novel candidate Ras inhibitors and their Ras signaling interaction partners, and each of these hypotheses can be inferred independent of network-wide patterns. At the same time, the network-scale interaction patterns consistently mapped pathway organization. The analysis therefore assigns functional relevance to individual genetic interactions while also revealing global genetic architecture.
The Biotinidase Gene Variants Registry: A Paradigm Public Database
Authors: Procter Melinda , Wolf Barry , Crockett David K , Mao Rong
Published: March 2013

The BTD gene codes for production of biotinidase, the enzyme responsible for helping the body reuse and recycle the biotin found in foods. Biotinidase deficiency is an autosomal recessively inherited disorder resulting in the inability to recycle the vitamin biotin and affects approximately 1 in 60,000 newborns. If untreated, the depletion of intracellular biotin leads to impaired activities of the biotin-dependent carboxylases and can result in cutaneous and neurological abnormalities in individuals with the disorder. Mutations in the biotinidase gene (BTD) alter enzymatic function. To date, more than 165 mutations in BTD have been reported. Our group has developed a database that characterizes the known mutations and sequence variants in BTD. (http://arup.utah.edu/database/BTD/BTD_welcome.php). All sequence variants have been verified for their positions within the BTD gene and designated according to standard nomenclature suggested by Human Genome Variation Society (HGVS). In addition, we describe the change in the protein, indicate whether the variant is a known or likely mutation vs. a benign polymorphism, and include the reference that first described the alteration. We also indicate whether the alteration is known to be clinically pathological based on an observation of a known symptomatic individual or predicted to be pathological based on enzymatic activity or putative disruption of the protein structure. We incorporated the published phenotype to help establish genotype-phenotype correlations and facilitate this process for those performing mutation analysis and/or interpreting results. Other features of this database include disease information, relevant links about biotinidase deficiency, reference sequences, ability to query by various criteria, and the process for submitting novel variations. This database is free to the public and will be updated quarterly. This database is a paradigm for formulating databases for other inherited metabolic disorders.
How Biochemical Constraints of Cellular Growth Shape Evolutionary Adaptations in Metabolism
Authors: Berkhout Jan , Bosdriesz Evert , Nikerel Emrah , Molenaar Douwe , de Ridder Dick , Teusink Bas , Bruggeman Frank J
Published: March 2013

Evolutionary adaptations in metabolic networks are fundamental to evolution of microbial growth. Studies on unneeded-protein synthesis indicate reductions in fitness upon nonfunctional protein synthesis, showing that cell growth is limited by constraints acting on cellular protein content. Here, we present a theory for optimal metabolic enzyme activity when cells are selected for maximal growth rate given such growth-limiting biochemical constraints. We show how optimal enzyme levels can be understood to result from an enzyme benefit minus cost optimization. The constraints we consider originate from different biochemical aspects of microbial growth, such as competition for limiting amounts of ribosomes or RNA polymerases, or limitations in available energy. Enzyme benefit is related to its kinetics and its importance for fitness, while enzyme cost expresses to what extent resource consumption reduces fitness through constraint-induced reductions of other enzyme levels. A metabolic fitness landscape is introduced to define the fitness potential of an enzyme. This concept is related to the selection coefficient of the enzyme and can be expressed in terms of its fitness benefit and cost.
Suppression of Chromosome Healing and Anticheckpoint Pathways in Yeast Postsenescence Survivors
Authors: Lai Xianning , Heierhorst Jörg
Published: March 2013

Telomere repeat-like sequences at DNA double-strand breaks (DSBs) inhibit DNA damage signaling and serve as seeds to convert DSBs to new telomeres in mutagenic chromosome healing pathways. We find here that the response to seed-containing DSBs differs fundamentally between budding yeast (Saccharomyces cerevisiae) cells that maintain their telomeres via telomerase and so-called postsenescence survivors that use recombination-based alternative lengthening of telomere (ALT) mechanisms. Whereas telomere seeds are efficiently elongated by telomerase, they remain remarkably stable without de novo telomerization or extensive end resection in telomerase-deficient (est2Δ, tlc1Δ) postsenescence survivors. This telomere seed hyper-stability in ALT cells is associated with, but not caused by, prolonged DNA damage checkpoint activity (RAD9, RAD53) compared to telomerase-positive cells or presenescent telomerase-negative cells. The results indicate that both chromosome healing and anticheckpoint activity of telomere seeds are suppressed in yeast models of ALT pathways.
Effect of heat stress on the physiological processes of wheat
Authors: Balla K. , Karsai I. , Bencze S. , Kiss T. , Veisz O.
Published: March 2013

Stress tolerance is associated with the activation of antioxidant compounds and enzyme systems that are capable of neutralising the reactive oxygen species (ROS) continually produced in response to stress. The present experiment was designed to compare the heat tolerance of four winter wheat varieties in the shooting and grain-filling stages by investigating changes detected in antioxidant enzyme activity and yield components in response to heat stress.Heat treatment was found to cause a significant rise in the activity of the glutathione-S-transferase and catalase enzymes, while there was usually a less intense decline in the activity of guaiacol peroxidase.An analysis of yield data revealed that heat stress had a more pronounced effect during grain filling in this experiment than at the beginning of shooting, as shown by the greater reduction in thousand-kernel weight and yield.