Efficient targeting to storage granules of human proinsulins with altered propeptide domain.

In neuronal and endocrine cells, peptide hormones are selectively segregated into storage granules, while other proteins are exported continuously without storage. Sorting of hormones by cellular machinery involves the recognition of specific structural domains on prohormone molecules. Since the propeptide of insulin is known to play an important role in its three-dimensional structure, it is reasonable to speculate that targeting of proinsulin to storage granules would require a functional connecting peptide. To test this hypothesis, we constructed two mutations in human proinsulin with different predicted structures. In one mutation, Ins delta C, the entire C peptide was deleted, resulting in an altered insulin in which the B and the A chains are joined contiguously. In the other mutation, Ins/IGF, the C peptide of proinsulin was replaced with the unrelated 12-amino acid connecting peptide of human insulin-like growth factor-I; this substitution should permit correct folding of the B and A chains to form a tertiary structure similar to that of proinsulin. By several biochemical and morphological criteria, we found that Ins/IGF is efficiently targeted to storage granules, suggesting that the C peptide of proinsulin does not contain necessary sorting information. Unexpectedly, Ins delta C, which presumably cannot fold properly, is also targeted to granules at a high efficiency. These results imply that either the targeting machinery can tolerate changes in the tertiary structure of transported proteins, or that the B and A chains of insulin can form a relatively intact three-dimensional structure even in the absence of C peptide

Work-life Balance: Experiences of Women in the Australian Construction Industry

Considerable changes in Australian lifestyles and the relationship between work and family life over recent decades have lead to the progressive entry of women into the workforce. Their increased numbers in the workplace have led many women to have a stronger voice to demand benefits to help them balance their work and life responsibilities. The accompanying shifts in the traditional roles of men and women have raised new issues for employers. In an effort to meet the changing needs of todayâs workforce, many organisations now implement work-family or work-life programs. While women in the workforce face various barriers the primary focus of this paper is on the conflicting demands of career and family life for women in male dominated industry of construction. The paper will draw on exploratory research to examine the career barriers faced by women in the Australian construction industry and compare them to those identified in the literature by women in the British construction industry (eg Fielden, Davidson, Gale and Davey 2001; Gale 1994). The paper puts forward Australian results that support the research findings in Britain that claim that despite lack of work-family or work-life programs women who choose to work within the industry are highly satisfied with their choice

A critical review of manual therapy use for headache disorders: Prevalence, profiles, motivations, communication and self-reported effectiveness

© 2017 The Author(s). Background: Despite the expansion of conventional medical treatments for headache, many sufferers of common recurrent headache disorders seek help outside of medical settings. The aim of this paper is to evaluate research studies on the prevalence of patient use of manual therapies for the treatment of headache and the key factors associated with this patient population. Methods: This critical review of the peer-reviewed literature identified 35 papers reporting findings from new empirical research regarding the prevalence, profiles, motivations, communication and self-reported effectiveness of manual therapy use amongst those with headache disorders. Results: While available data was limited and studies had considerable methodological limitations, the use of manual therapy appears to be the most common non-medical treatment utilized for the management of common recurrent headaches. The most common reason for choosing this type of treatment was seeking pain relief. While a high percentage of these patients likely continue with concurrent medical care, around half may not be disclosing the use of this treatment to their medical doctor. Conclusions: There is a need for more rigorous public health and health services research in order to assess the role, safety, utilization and financial costs associated with manual therapy treatment for headache. Primary healthcare providers should be mindful of the use of this highly popular approach to headache management in order to help facilitate safe, effective and coordinated care

Current evidence for spinal X-ray use in the chiropractic profession: A narrative review

© 2018 The Author(s). The use of routine spinal X-rays within chiropractic has a contentious history. Elements of the profession advocate for the need for routine spinal X-rays to improve patient management, whereas other chiropractors advocate using spinal X-rays only when endorsed by current imaging guidelines. This review aims to summarise the current evidence for the use of spinal X-ray in chiropractic practice, with consideration of the related risks and benefits. Current evidence supports the use of spinal X-rays only in the diagnosis of trauma and spondyloarthropathy, and in the assessment of progressive spinal structural deformities such as adolescent idiopathic scoliosis. MRI is indicated to diagnose serious pathology such as cancer or infection, and to assess the need for surgical management in radiculopathy and spinal stenosis. Strong evidence demonstrates risks of imaging such as excessive radiation exposure, overdiagnosis, subsequent low-value investigation and treatment procedures, and increased costs. In most cases the potential benefits from routine imaging, including spinal X-rays, do not outweigh the potential harms. The use of spinal X-rays should not be routinely performed in chiropractic practice, and should be guided by clinical guidelines and clinician judgement

Phagocytosis in the brain: homeostasis and disease

Microglia are resident macrophages of the central nervous system and significantly contribute to overall brain function by participating in phagocytosis during development, homeostasis, and diseased states. Phagocytosis is a highly complex process that is specialized for the uptake and removal of opsonized and non-opsonized targets, such as pathogens, apoptotic cells, and cellular debris. While the role of phagocytosis in mediating classical innate and adaptive immune responses has been known for decades, it is now appreciated that phagocytosis is also critical throughout early neural development, homeostasis, and initiating repair mechanisms. As such, modulating phagocytic processes has provided unexplored avenues with the intent of developing novel therapeutics that promote repair and regeneration in the CNS. Here, we review the functional consequences that phagocytosis plays in both the healthy and diseased CNS, and summarize how phagocytosis contributes to overall pathophysiological mechanisms involved in brain injury and repair

Accelerating epistasis analysis in human genetics with consumer graphics hardware

BACKGROUND: Human geneticists are now capable of measuring more than one million DNA sequence variations from across the human genome. The new challenge is to develop computationally feasible methods capable of analyzing these data for associations with common human disease, particularly in the context of epistasis. Epistasis describes the situation where multiple genes interact in a complex non-linear manner to determine an individual's disease risk and is thought to be ubiquitous for common diseases. Multifactor Dimensionality Reduction (MDR) is an algorithm capable of detecting epistasis. An exhaustive analysis with MDR is often computationally expensive, particularly for high order interactions. This challenge has previously been met with parallel computation and expensive hardware. The option we examine here exploits commodity hardware designed for computer graphics. In modern computers Graphics Processing Units (GPUs) have more memory bandwidth and computational capability than Central Processing Units (CPUs) and are well suited to this problem. Advances in the video game industry have led to an economy of scale creating a situation where these powerful components are readily available at very low cost. Here we implement and evaluate the performance of the MDR algorithm on GPUs. Of primary interest are the time required for an epistasis analysis and the price to performance ratio of available solutions. FINDINGS: We found that using MDR on GPUs consistently increased performance per machine over both a feature rich Java software package and a C++ cluster implementation. The performance of a GPU workstation running a GPU implementation reduces computation time by a factor of 160 compared to an 8-core workstation running the Java implementation on CPUs. This GPU workstation performs similarly to 150 cores running an optimized C++ implementation on a Beowulf cluster. Furthermore this GPU system provides extremely cost effective performance while leaving the CPU available for other tasks. The GPU workstation containing three GPUs costs $2000 while obtaining similar performance on a Beowulf cluster requires 150 CPU cores which, including the added infrastructure and support cost of the cluster system, cost approximately$82,500. CONCLUSION: Graphics hardware based computing provides a cost effective means to perform genetic analysis of epistasis using MDR on large datasets without the infrastructure of a computing cluster

Covering Problems for Partial Words and for Indeterminate Strings

We consider the problem of computing a shortest solid cover of an indeterminate string. An indeterminate string may contain non-solid symbols, each of which specifies a subset of the alphabet that could be present at the corresponding position. We also consider covering partial words, which are a special case of indeterminate strings where each non-solid symbol is a don't care symbol. We prove that indeterminate string covering problem and partial word covering problem are NP-complete for binary alphabet and show that both problems are fixed-parameter tractable with respect to $k$, the number of non-solid symbols. For the indeterminate string covering problem we obtain a $2^{O(k \log k)} + n k^{O(1)}$-time algorithm. For the partial word covering problem we obtain a $2^{O(\sqrt{k}\log k)} + nk^{O(1)}$-time algorithm. We prove that, unless the Exponential Time Hypothesis is false, no $2^{o(\sqrt{k})} n^{O(1)}$-time solution exists for either problem, which shows that our algorithm for this case is close to optimal. We also present an algorithm for both problems which is feasible in practice.Comment: full version (simplified and corrected); preliminary version appeared at ISAAC 2014; 14 pages, 4 figure

Auditory cognition and perception of action video game players

A training method to improve speech hearing in noise has proven elusive, with most methods failing to transfer to untrained tasks. One common approach to identify potentially viable training paradigms is to make use of cross-sectional designs. For instance, the consistent finding that people who chose to avidly engage with action video games as part of their normal life also show enhanced performance on non-game visual tasks has been used as a foundation to test the causal impact of such game play via true experiments (e.g., in more translational designs). However, little work has examined the association between action video game play and untrained auditory tasks, which would speak to the possible utility of using such games to improve speech hearing in noise. To examine this possibility, 80 participants with mixed action video game experience were tested on a visual reaction time task that has reliably shown superior performance in action video game players (AVGPs) compared to non-players (≤ 5 h/week across game categories) and multi-genre video game players (> 5 h/week across game categories). Auditory cognition and perception were tested using auditory reaction time and two speech-in-noise tasks. Performance of AVGPs on the visual task replicated previous positive findings. However, no significant benefit of action video game play was found on the auditory tasks. We suggest that, while AVGPs interact meaningfully with a rich visual environment during play, they may not interact with the games’ auditory environment. These results suggest that far transfer learning during action video game play is modality-specific and that an acoustically relevant auditory environment may be needed to improve auditory probabilistic thinking

Spatially Uniform ReliefF (SURF) for computationally-efficient filtering of gene-gene interactions

<p>Abstract</p> <p>Background</p> <p>Genome-wide association studies are becoming the de facto standard in the genetic analysis of common human diseases. Given the complexity and robustness of biological networks such diseases are unlikely to be the result of single points of failure but instead likely arise from the joint failure of two or more interacting components. The hope in genome-wide screens is that these points of failure can be linked to single nucleotide polymorphisms (SNPs) which confer disease susceptibility. Detecting interacting variants that lead to disease in the absence of single-gene effects is difficult however, and methods to exhaustively analyze sets of these variants for interactions are combinatorial in nature thus making them computationally infeasible. Efficient algorithms which can detect interacting SNPs are needed. ReliefF is one such promising algorithm, although it has low success rate for noisy datasets when the interaction effect is small. ReliefF has been paired with an iterative approach, Tuned ReliefF (TuRF), which improves the estimation of weights in noisy data but does not fundamentally change the underlying ReliefF algorithm. To improve the sensitivity of studies using these methods to detect small effects we introduce Spatially Uniform ReliefF (SURF).</p> <p>Results</p> <p>SURF's ability to detect interactions in this domain is significantly greater than that of ReliefF. Similarly SURF, in combination with the TuRF strategy significantly outperforms TuRF alone for SNP selection under an epistasis model. It is important to note that this success rate increase does not require an increase in algorithmic complexity and allows for increased success rate, even with the removal of a nuisance parameter from the algorithm.</p> <p>Conclusion</p> <p>Researchers performing genetic association studies and aiming to discover gene-gene interactions associated with increased disease susceptibility should use SURF in place of ReliefF. For instance, SURF should be used instead of ReliefF to filter a dataset before an exhaustive MDR analysis. This change increases the ability of a study to detect gene-gene interactions. The SURF algorithm is implemented in the open source Multifactor Dimensionality Reduction (MDR) software package available from <url>http://www.epistasis.org</url>.</p

Investigation of SLA4A3 as a candidate gene for human retinal disease.

SLC4A3 has been shown to cause retinal degeneration in a genetically engineered knockout mouse, and in a naturally occurring form of canine progressive retinal atrophy considered to be the equivalent of retinitis pigmentosa in humans (RP). This study was undertaken to investigate if SLC4A3 coding variants were implicated in human retinal degeneration. SLC4A3 exons were amplified and sequenced in 200 patients with autosomal recessive retinal degeneration who had no known molecular diagnosis for their condition, which included 197 unrelated individuals with suspected RP and three individuals with other forms of retinal disease. Three rare variants were identified that were predicted to be potentially pathogenic, however each variant was heterozygous in a single patient and therefore not considered disease-causing in isolation. Of these three variants, SNP-3 was the rarest, with an allele frequency of 7.06 x 10(-5) (>46,000 exomes from the ExAC database). In conclusion, no compound heterozygous or homozygous potentially pathogenic variants were identified that would account for recessive RP or retinal degeneration in this cohort, however the possibility remains that the rare variants identified could be acting with as yet undiscovered mutations in introns or regulatory regions. SLC4A3 remains an excellent candidate gene for human retinal degeneration, and with the advent of whole exome and whole genome sequencing of cohorts of molecularly unsolved patients with syndromic and non-syndromic forms of retinal degeneration, SLC4A3 may yet be implicated in human disease