Spy1 Levels Predict Sensitivity of Refractory Multiple Myeloma to Therapy

Multiple myeloma (MM) is an aggressive hematopoietic malignancy with a poor prognosis that is caused by the abnormal growth of plasma cells in the bone marrow. Cyclin-dependent kinase inhibitors (CKIs) have been explored as a possible treatment for MM, with limited clinical success. We postulate that the cyclin-like protein, Spy1 (SPDYA), which is capable of overriding cell-cycle checkpoints, may play a role in limiting therapeutic effectiveness. To support this hypothesis, we have found that Spy1 is highly expressed in MM patient samples and human cell lines. We aim to explore the role that Spy1 plays in CKI resistance in MM using a variety of in vitro and in vivo techniques. Firstly, we intend to create and optimize an in vitro platform to study MM using patient samples collected from clinicians at Windsor Regional Hospital. Using this culture, and human cell lines, we intend to investigate the methylation status of Spy1 and other MM genes in Spy1 overexpression and knockout conditions to see the effects of epigenetic regulation. Then, we will perform drug and toxicity assays with standard CKIs using our Spy1 overexpression and knock-down lines to observe response to CKIs, expecting lines with higher Spy1 to demonstrate increased therapy resistance. Finally, our cells with manipulated Spy1 levels will be injected into zebrafish to test the effects of CKIs in vivo. Collectively, we aim to explore the role Spy1 may play in resistance to CKI therapy in MM, to improve disease understanding and identify areas treatments may be improved

Impact of the relationship between managers and board of directors on performance of agricultural cooperatives

Abstract Cooperatives operate under a business model that creates unique challenges in financial management, governance, strategy, and communication. There have been a number of efforts to identify challenges, critical issues and success factors for agricultural cooperatives. One of the issues agricultural cooperatives are facing is the relationship between managers and the board of directors. Directors in a cooperative occupy a crucial position between members and hired management. Acting as a group, directors set the objectives for the cooperative and decide what the cooperative will do while the general manager decides how it can best be done, subject to board review. Success of a cooperative mainly depends on good board/ manager relationships. This study was focused on evaluation of impact of the relationship between the board of directors and managers on performance of agricultural cooperatives. Data originated from a mail survey and personal interviews among managers and chairmen of agricultural cooperatives in Texas. The results showed that size of the cooperative had negative impact on performance while more frequent engagement of the managers in strategic planning, higher level of managers' job satisfaction, and organizational commitment positively affect the profitability of a cooperative

Requirements for Point of Care Devices using Use Case Maps

Point of Care (PoC) testing (diagnosis) is a method for bringing medical laboratories to a patient’s home to conduct diagnostic tests so that the patient does not need to go to the doctor or laboratory in person. PoC testing reduces the burden on expensive laboratory setups and provides management of patient care in cost effective manner. The design and development of the PoC device and the associated infrastructure must be done with extreme rigor, as the PoC system meets the definition of a mission critical or safety critical system. Requirements creation and management are the key processes for ensuring that a highly reliable and low defect PoC system is developed since accurate PoC testing-based diagnosis is an essential process improvement for remote patient care management. It is important that the requirements be specified accurately, completely and without any ambiguity so that the PoC device can be designed and developed with minimal errors. This provides physicians a vehicle to diagnose patients with drastically increased reliability. This paper explains how Use Case Maps (UCM), a modeling technique, can help to sufficiently model requirement specifications for a PoC system development. It illustrates PoC functional requirements and security requirements in terms of the UCM representation. DOI: 10.17762/ijritcc2321-8169.150616

Reviews

The following publications have been reviewed by the mentioned authors;Ideas Bank Design Technology: Designing & Making Book 1 - reviewed by Robert BowenAztecs - Your Move - reviewed by Bridget A. EganChanging Technology - reviewed by John Hill & Elizabeth WrightElectronic Circuits and Components/ The Parts Gallery - reviewed by Mark HudsonGCSE Design and Technology: Resistant Materials - reviewed by John DurrellGlobal contexts: an introduction for design and technology teachers - reviewed by Anne RiggsScience Resources for Key Stage 2: SATIS 8-14 Technology - reviewed by Richard AgerScience Resources for Key Stage 2: SATIS 8-14 Health - reviewed by Richard AgerScience Resources for Key Stage 2: SATIS 8-14 Materials/Transport/Environment - reviewed by Robert BowenTechnology an Enterprising Approach - reviewed by Dr Ron RichieUnderstanding Electronic Circuits CD-ROM - reviewed by Dr Rowland Dye and Phil NormanTextiles and Technology - reviewed by Jillian MellorArt and Design 97 - reviewed by Andy Brecko

Prevalence of Disorders Recorded in Dogs Attending Primary-Care Veterinary Practices in England

Purebred dog health is thought to be compromised by an increasing occurence of inherited diseases but inadequate prevalence data on common disorders have hampered efforts to prioritise health reforms. Analysis of primary veterinary practice clinical data has been proposed for reliable estimation of disorder prevalence in dogs. Electronic patient record (EPR) data were collected on 148,741 dogs attending 93 clinics across central and south-eastern England. Analysis in detail of a random sample of EPRs relating to 3,884 dogs from 89 clinics identified the most frequently recorded disorders as otitis externa (prevalence 10.2%, 95% CI: 9.1-11.3), periodontal disease (9.3%, 95% CI: 8.3-10.3) and anal sac impaction (7.1%, 95% CI: 6.1-8.1). Using syndromic classification, the most prevalent body location affected was the head-and-neck (32.8%, 95% CI: 30.7-34.9), the most prevalent organ system affected was the integument (36.3%, 95% CI: 33.9-38.6) and the most prevalent pathophysiologic process diagnosed was inflammation (32.1%, 95% CI: 29.8-34.3). Among the twenty most-frequently recorded disorders, purebred dogs had a significantly higher prevalence compared with crossbreds for three: otitis externa (P = 0.001), obesity (P = 0.006) and skin mass lesion (P = 0.033), and popular breeds differed significantly from each other in their prevalence for five: periodontal disease (P = 0.002), overgrown nails (P = 0.004), degenerative joint disease (P = 0.005), obesity (P = 0.001) and lipoma (P = 0.003). These results fill a crucial data gap in disorder prevalence information and assist with disorder prioritisation. The results suggest that, for maximal impact, breeding reforms should target commonly-diagnosed complex disorders that are amenable to genetic improvement and should place special focus on at-risk breeds. Future studies evaluating disorder severity and duration will augment the usefulness of the disorder prevalence information reported herein

Evidence for Positive Selection in Putative Virulence Factors within the Paracoccidioides brasiliensis Species Complex

Paracoccidioides brasiliensis is a dimorphic fungus that is the causative agent of paracoccidioidomycosis, the most important prevalent systemic mycosis in Latin America. Recently, the existence of three genetically isolated groups in P. brasiliensis was demonstrated, enabling comparative studies of molecular evolution among P. brasiliensis lineages. Thirty-two gene sequences coding for putative virulence factors were analyzed to determine whether they were under positive selection. Our maximum likelihood–based approach yielded evidence for selection in 12 genes that are involved in different cellular processes. An in-depth analysis of four of these genes showed them to be either antigenic or involved in pathogenesis. Here, we present evidence indicating that several replacement mutations in gp43 are under positive balancing selection. The other three genes (fks, cdc42 and p27) show very little variation among the P. brasiliensis lineages and appear to be under positive directional selection. Our results are consistent with the more general observations that selective constraints are variable across the genome, and that even in the genes under positive selection, only a few sites are altered. We present our results within an evolutionary framework that may be applicable for studying adaptation and pathogenesis in P. brasiliensis and other pathogenic fungi

Empirical Comparison of Simple Sequence Repeats and Single Nucleotide Polymorphisms in Assessment of Maize Diversity and Relatedness

While Simple Sequence Repeats (SSRs) are extremely useful genetic markers, recent advances in technology have produced a shift toward use of single nucleotide polymorphisms (SNPs). The different mutational properties of these two classes of markers result in differences in heterozygosities and allele frequencies that may have implications for their use in assessing relatedness and evaluation of genetic diversity. We compared analyses based on 89 SSRs (primarily dinucleotide repeats) to analyses based on 847 SNPs in individuals from the same 259 inbred maize lines, which had been chosen to represent the diversity available among current and historic lines used in breeding. The SSRs performed better at clustering germplasm into populations than did a set of 847 SNPs or 554 SNP haplotypes, and SSRs provided more resolution in measuring genetic distance based on allele-sharing. Except for closely related pairs of individuals, measures of distance based on SSRs were only weakly correlated with measures of distance based on SNPs. Our results suggest that 1) large numbers of SNP loci will be required to replace highly polymorphic SSRs in studies of diversity and relatedness and 2) relatedness among highly-diverged maize lines is difficult to measure accurately regardless of the marker system

The genomes of two key bumblebee species with primitive eusocial organization

Background: The shift from solitary to social behavior is one of the major evolutionary transitions. Primitively eusocial bumblebees are uniquely placed to illuminate the evolution of highly eusocial insect societies. Bumblebees are also invaluable natural and agricultural pollinators, and there is widespread concern over recent population declines in some species. High-quality genomic data will inform key aspects of bumblebee biology, including susceptibility to implicated population viability threats. Results: We report the high quality draft genome sequences of Bombus terrestris and Bombus impatiens, two ecologically dominant bumblebees and widely utilized study species. Comparing these new genomes to those of the highly eusocial honeybee Apis mellifera and other Hymenoptera, we identify deeply conserved similarities, as well as novelties key to the biology of these organisms. Some honeybee genome features thought to underpin advanced eusociality are also present in bumblebees, indicating an earlier evolution in the bee lineage. Xenobiotic detoxification and immune genes are similarly depauperate in bumblebees and honeybees, and multiple categories of genes linked to social organization, including development and behavior, show high conservation. Key differences identified include a bias in bumblebee chemoreception towards gustation from olfaction, and striking differences in microRNAs, potentially responsible for gene regulation underlying social and other traits. Conclusions: These two bumblebee genomes provide a foundation for post-genomic research on these key pollinators and insect societies. Overall, gene repertoires suggest that the route to advanced eusociality in bees was mediated by many small changes in many genes and processes, and not by notable expansion or depauperation

Recombinant human complement component C2 produced in a human cell line restores the classical complement pathway activity in-vitro: an alternative treatment for C2 deficiency diseases

Background: Complement C2 deficiency is the most common genetically determined complete complement deficiency and is associated with a number of diseases. Most prominent are the associations with recurrent serious infections in young children and the development of systemic lupus erythematosus (SLE) in adults. The links with these diseases reflect the important role complement C2 plays in both innate immunity and immune tolerance. Infusions with normal fresh frozen plasma for the treatment of associated disease have demonstrated therapeutic effects but so far protein replacement therapy has not been evaluated. Results: Human complement C2 was cloned and expressed in a mammalian cell line. The purity of recombinant human C2 (rhC2) was greater than 95% and it was characterized for stability and activity. It was sensitive to C1s cleavage and restored classical complement pathway activity in C2-deficient serum both in a complement activation ELISA and a hemolytic assay. Furthermore, rhC2 could increase C3 fragment deposition on the human pathogen Streptococcus pneumoniae in C2-deficient serum to levels equal to those with normal serum. Conclusions: Taken together these data suggest that recombinant human C2 can restore classical complement pathway activity and may serve as a potential therapeutic for recurring bacterial infections or SLE in C2-deficient patients

Effects of Irritant Chemicals on Aedes aegypti Resting Behavior: Is There a Simple Shift to Untreated “Safe Sites”?

Aedes aegypti, the primary vector mosquito of dengue virus, typically lives near or inside human dwellings, and feeds preferentially on humans. The control of this mosquito vector remains the most important dengue prevention method. The use of chemicals at levels toxic to mosquitoes is currently the only confirmed effective adult vector control strategy with interventions usually applied following epidemic onset. However, research indicates that sub-lethal chemical approaches to prevent human-vector contact at the house level exist: contact irritancy and spatial repellency. The optimum efficacy of an intervention based on contact irritant actions of chemicals will, however, require full knowledge of variables that will influence vector resting behavior and thereby chemical uptake from treated sources. Here we characterize the resting patterns of female Ae. aegypti on two material types at various dark:light surface area coverage ratios and contrast configurations under chemical-free and treated conditions using a laboratory behavioral assay. Change in resting behavior between baseline and treatment conditions was quantified to determine potential negative effects of untreated surfaces (“safe sites”) when irritant responses are elicited. We show that treatment of preferred resting sites with known irritant compounds do not stimulate mosquitoes to move to safe sites after making contact with treated surfaces