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Objectives To study normative thresholds and latencies for click and tone-burst auditory brainstem response (TB-ABR) for air and bone conduction in normal infants and those discharged from neonatal intensive care units, who passed newborn hearing screening and follow-up distortion product otoacoustic emission. An evoked potential system (Vivosonic Integrity) that incorporates Bluetooth electrical isolation and Kalman-weighted adaptive processing to improve signal to noise ratios was employed for this study. Results were compared with other published data. Design One hundred forty-five infants who passed two-stage hearing screening with transient-evoked otoacoustic emission or automated auditory brainstem response were assessed with clicks at 70 dB nHL and threshold TB-ABR. Tone bursts at frequencies between 500 and 4000 Hz were used for air and bone conduction auditory brainstem response testing using a specified staircase threshold search to establish threshold levels and wave V peak latencies. Results Median air conduction hearing thresholds using TB-ABR ranged from 0 to 20 dB nHL, depending on stimulus frequency. Median bone conduction thresholds were 10 dB nHL across all frequencies, and median air-bone gaps were 0 dB across all frequencies. There was no significant threshold difference between left and right ears and no significant relationship between thresholds and hearing loss risk factors, ethnicity, or gender. Older age was related to decreased latency for air conduction. Compared with previous studies, mean air conduction thresholds were found at slightly lower (better) levels, while bone conduction levels were better at 2000 Hz and higher at 500 Hz. Latency values were longer at 500 Hz than previous studies using other instrumentation. Sleep state did not affect air or bone conduction thresholds. Conclusions This study demonstrated slightly better wave V thresholds for air conduction than previous infant studies. The differences found in the present study, while statistically significant, were within the test step size of 10 dB. This suggests that threshold responses obtained using the Kalman weighting software were within the range of other published studies using traditional signal averaging, given step-size limitations. Thresholds were not adversely affected by variable sleep states.

Background The renin-angiotensin system (RAS) plays an important role in regulating blood pressure and controlling sodium levels in the blood. Hyperactivity of this system has been linked to numerous conditions including hypertension, kidney disease, and congestive heart failure. Three classes of drugs have been developed to inhibit RAS. In this study, we provide a structure-based analysis of the effect of single nucleotide variants (SNVs) on the interaction between renin and angiotensinogen with the aim of revealing important residues and potentially damaging variants for further inhibitor design purposes. Objectives To identify SNVs that have functional and potentially damaging effects on the renin-angiotensinogen complex and to use computational approaches to investigate how SNVs might have damaging effects. Methods A comprehensive set of all known SNVs in the renin and angiotensinogen proteins was extracted from the HUMA database. This dataset was filtered by removing synonymous and missense variants and using the VAPOR pipeline to predict which variants were likely to be deleterious. Variants in the filtered dataset were modeled into the renin-angiotensinogen complex using MODELLER and subjected to molecular dynamics simulations using GROMACS. The residue interaction networks of the resultant trajectories were analyzed using graph theory. Conclusions This research identified important SNVs in the interface of RAS and showed how they might affect the function of the proteins. For instance, the mutant complex containing the variant P40L in angiotensinogen caused instability in the complex, indicating that this mutation plays an important role in disrupting the interaction between renin and angiotensinogen. The mutant complex containing the SNV A188V in renin was shown to have significantly increased fluctuation in the residue interaction networks. D104N in renin, associated with renal tubular dysgenesis, caused increased rigidity in the protein complex comparison to the wild type, which probably in turn negatively affects the function of RAS.

With the completion of the human genome project at the beginning of the 21st century, the biological sciences entered an unprecedented age of data generation, and made its first steps toward an era of personalized medicine. This abundance of sequence data has led to the proliferation of numerous sequence-based techniques for associating variation with disease, such as genome-wide association studies and candidate gene association studies. However, these statistical methods do not provide an understanding of the functional effects of variation. Structure-based drug discovery and design is increasingly incorporating structural bioinformatics techniques to model and analyze protein targets, perform large scale virtual screening to identify hit to lead compounds, and simulate molecular interactions. These techniques are fast, cost-effective, and complement existing experimental techniques such as high throughput sequencing. In this paper, we discuss the contributions of structural bioinformatics to drug discovery, focusing particularly on the analysis of nonsynonymous single nucleotide polymorphisms. We conclude by suggesting a protocol for future analyses of the structural effects of nonsynonymous single nucleotide polymorphisms on proteins and protein complexes.

The purpose of this study was to evaluate pressurised wideband acoustic immittance (WAI) tests in children with Down syndrome (DS) and in typically developing children (TD) for prediction of conductive hearing loss (CHL) and patency of pressure equalising tubes (PETs).Audiologic diagnosis was determined by audiometry in combination with distortion-product otoacoustic emissions, 0.226 kHz tympanometry and otoscopy. WAI results were compared for ears within diagnostic categories (Normal, CHL and PET) and between groups (TD and DS).Children with DS (n = 40; mean age 6.4 years), and TD children (n = 48; mean age 5.1 years) were included.Wideband absorbance was significantly lower at 1-4 kHz in ears with CHL compared to NH for both TD and DS groups. In ears with patent PETs, wideband absorbance and group delay (GD) were larger than in ears without PETs between 0.25 and 1.5 kHz. Wideband absorbance tests were performed similarly for prediction of CHL and patent PETs in TD and DS groups.Wideband absorbance and GD revealed specific patterns in both TD children and those with DS that can assist in detection of the presence of significant CHL, assess the patency of PETs, and provide frequency-specific information in the audiometric range.

The completion of the human genome project at the beginning of the 21st century, along with the rapid advancement of sequencing technologies thereafter, has resulted in exponential growth of biological data. In genetics, this has given rise to numerous variation databases, created to store and annotate the ever-expanding dataset of known mutations. Usually, these databases focus on variation at the sequence level. Few databases focus on the analysis of variation at the 3D level, that is, mapping, visualizing, and determining the effects of variation in protein structures. Additionally, these Web servers seldom incorporate tools to help analyze these data. Here, we present the Human Mutation Analysis (HUMA) Web server and database. HUMA integrates sequence, structure, variation, and disease data into a single, connected database. A user-friendly interface provides click-based data access and visualization, whereas a RESTful Web API provides programmatic access to the data. Tools have been integrated into HUMA to allow initial analyses to be carried out on the server. Furthermore, users can upload their private variation datasets, which are automatically mapped to public data and can be analyzed using the integrated tools. HUMA is freely accessible at https://huma.rubi.ru.ac.za.

Aim Pressure related skin injuries (including ulceration, skin/epithelial stripping, and combination injuries) have historically been neglected within neonatal research. Although anecdotal evidence, wound reviews and isolated case studies have been published; there is limited research specific to neonatal pressure injuries despite this population being, arguably, the most vulnerable patient group. The objective of this study was to investigate specific rates of neonatal skin breakdown from pressure including locations, stages, and etiology associated with tissue damage. Methods A descriptive cohort study was conducted in North Queensland's Tertiary perinatal center over a 2-year period. Prevalence audits for pressure injuries to the skin were conducted (including epithelial stripping) and incorporated categorization of with degree of tissue breakdown between Stage 1–4. A modified risk assessment and prevalence tool was utilized in this study. Results 247 neonatal patients were reviewed during the study period, of these infants, 77/247 were identified as having a skin injury (a prevalence rate of 31.2%). In total, 107 injuries were identified with the mean number of 1.4 injuries (range 1–4, SD 0.71). The mean gestational age was 28 weeks (range 22–41 weeks, SD 4.1 weeks) and the mean birth weight was 1155 g (range 445–2678 g, SD 620 g). Factors identified as contributing to pressure injuries included indwelling vascular catheters (22.4%), non-invasive continuous positive airway pressure delivery devices (14.0%), oxygen saturation and temperature probes (17.8.%). 31.8% of injuries could not be associated with a specific risk factor. Conclusions Neonates are undeniably at risk for pressure injuries however; it is still unclear which proportions of injuries are entirely preventable. Further development of a risk assessment and prevalence tool will provide practitioners with insight into the specific risk factors applicable for neonatal pressure injuries. Additional studies with larger patient groups will more accurately update practice related to pressure injury prevention and management in neonatal units; as well as critically evaluate the adverse affects of routine care processes that unintentionally harm the skin of these fragile patients.

Summary Molecular dynamics (MD) determines the physical motions of atoms of a biological macromolecule in a cell-like environment and is an important method in structural bioinformatics. Traditionally, measurements such as root mean square deviation, root mean square fluctuation, radius of gyration, and various energy measures have been used to analyze MD simulations. Here, we present MD-TASK, a novel software suite that employs graph theory techniques, perturbation response scanning, and dynamic cross-correlation to provide unique ways for analyzing MD trajectories. Availability and implementation MD-TASK has been open-sourced and is available for download from https://github.com/RUBi-ZA/MD-TASK, implemented in Python and supported on Linux/Unix.

Binding of echovirus 11 strain 207 (EV11-207) to Caco-2 monolayers results in rapid transfer of the virus to tight junctions prior to uptake. Using a confocal microscopy based-method, this study quantified the spatiotemporal distribution of actin during the time course of infection by EV11-207 in Caco-2 polarized cells. It was found that binding of EV11-207 to the apical surface resulted in rapid rearrangement of the actin cytoskeleton, concomitant with transport of the virus particles to tight junctions. By interfering with the actin network dynamics, the virus remained trapped at the cell surface, leading to abortion of infection. In addition, it was observed that at 4 h post-infection, concomitant with the detection of virus replication, actin filament was depolymerized and degraded. Finally, it was shown that the mechanisms leading to loss of actin were independent of viral genome synthesis, indicating a potential role for the viral protein synthesis seen in late infection. These data confirmed a previous study on the requirement for an intact actin cytoskeleton for EV11-207 to infect cells and reinforce the notion of actin cytoskeleton subversion by picornaviruses during infection in polarized epithelial cells.

There are a variety of relatively new, and some old and persisting, empirical issues confronting scholars of credentialing. Success in understanding these matters will be aided by greater theoretical and methodological precision and sophistication, and by avoidance of morality-driven assumptions about these topics. This paper discusses both promising and problematic aspects of current credentialing research.

Feline calicivirus (FCV) is a major causative agent of respiratory disease in cats. It is also one of the few cultivatable members of the family Caliciviridae. It has recently been reported that FCV binding is in part due to interaction with junction adhesion molecule-A. This report describes the characterization of additional receptor components for FCV. Chemical treatment of cells with sodium periodate showed that FCV recognized carbohydrate moieties on the surface of permissive cells. Enzymic treatment with Vibrio cholerae neuraminidase demonstrated that sialic acid was a major determinant of virus binding. Further characterization using linkage-specific lectins from Maackia amurensis and Sambucus nigra revealed that FCV recognized sialic acid with an α2,6 linkage. Using various proteases and metabolic inhibitors, it was shown that α2,6-linked sialic acid recognized by FCV is present on an N-linked glycoprotein.

Background Natural products (NPs) are important to the drug discovery process. NP research efforts are expanding world-wide and South Africa is no exception to this. While freely-accessible small molecule databases, containing compounds isolated from indigenous sources, have been established in a number of other countries, there is currently no such online database in South Africa. Description The current research presents a South African natural compound database, named SANCDB. This is a curated and fully-referenced database containing compound information for 600 natural products extracted directly from journal articles, book chapters and theses. There is a web interface to the database, which is simple and easy to use, while allowing for compounds to be searched by a number of different criteria. Being fully referenced, each compound page contains links to the original referenced work from which the information was obtained. Further, the website provides a submission pipeline, allowing researchers to deposit compounds from their own research into the database. Conclusions SANCDB is currently the only web-based NP database in Africa. It aims to provide a useful resource for the in silico screening of South African NPs for drug discovery purposes. The database is supported by a submission pipeline to allow growth by entries from researchers. As such, we currently present SANCDB the starting point of a platform for a community-driven, curated database to further natural products research in South Africa. SANCDB is freely available at https://sancdb.rubi.ru.ac.za/. Electronic supplementary material The online version of this article (doi:10.1186/s13321-015-0080-8) contains supplementary material, which is available to authorized users.

Feline calicivirus is a major causative agent of respiratory disease in cats. It is also one of the few cultivatable members of Caliciviridae . We have examined the entry process of feline calicivirus (FCV). An earlier study demonstrated that acidification in endosomes may be required. We have confirmed this observation and expanded upon it, demonstrating, using drugs to inhibit the various endocytic pathways and dominant-negative mutants, that FCV infects cells via clathrin-mediated endocytosis. We have also observed that FCV permeabilizes cell membranes early during infection to allow the coentry of toxins such as α-sarcin. Inhibitors of endosome acidification such as chloroquine and bafilomycin A1 blocked this permeabilization event, demonstrating that acidification is required for uncoating of the genome and access to the cytoplasm.

A rich literature on public policy abounds in social gerontology and related gerontology curriculum. However, much less emphasis has been placed on public policy in the geriatric education curriculum. This article discusses the need for a greater infusion of public policy into training modules and core curriculum of geriatric education. The view is presented that public policy is, by its nature, a valuable area for interdisciplinary study, cutting across the discipline-specific areas of geriatric education. This emphasis is particularly acute and timely, given rising social and political criticism of safety net programs for the elderly such as Medicare, Medicaid, and Social Security. Public policy curriculum design will be suggested as well as intervention strategies of use to public health professionals.

Background: Although pockets of bioinformatics excellence have developed in Africa, generally, large-scale genomic data analysis has been limited by the availability of expertise and infrastructure. H3ABioNet, a pan-African bioinformatics network, was established to build capacity specifically to enable H3Africa (Human Heredity and Health in Africa) researchers to analyze their data in Africa. Since the inception of the H3Africa initiative, H3ABioNet’s role has evolved in response to changing needs from the consortium and the African bioinformatics community.Objectives: H3ABioNet set out to develop core bioinformatics infrastructure and capacity for genomics research in various aspects of data collection, transfer, storage, and analysis.Methods and Results: Various resources have been developed to address genomic data management and analysis needs of H3Africa researchers and other scientific communities on the continent. NetMap was developed and used to build an accurate picture of network performance within Africa and between Africa and the rest of the world, and Globus Online has been rolled out to facilitate data transfer. A participant recruitment database was developed to monitor participant enrollment, and data is being harmonized through the use of ontologies and controlled vocabularies. The standardized metadata will be integrated to provide a search facility for H3Africa data and biospecimens. Because H3Africa projects are generating large-scale genomic data, facilities for analysis and interpretation are critical. H3ABioNet is implementing several data analysis platforms that provide a large range of bioinformatics tools or workflows, such as Galaxy, the Job Management System, and eBiokits. A set of reproducible, portable, and cloud-scalable pipelines to support the multiple H3Africa data types are also being developed and dockerized to enable execution on multiple computing infrastructures. In addition, new tools have been developed for analysis of the uniquely divergent African data and for downstream interpretation of prioritized variants. To provide support for these and other bioinformatics queries, an online bioinformatics helpdesk backed by broad consortium expertise has been established. Further support is provided by means of various modes of bioinformatics training.Conclusions: For the past 4 years, the development of infrastructure support and human capacity through H3ABioNet, have significantly contributed to the establishment of African scientific networks, data analysis facilities, and training programs. Here, we describe the infrastructure and how it has affected genomics and bioinformatics research in Africa.HighlightsH3ABioNet is building capacity to enable analysis of genomic data in Africa.Infrastructure has been built for clinical and genomic data storage, management, and analysis.New algorithms and pipelines for African genomic data analysis have been developed.Data are being harmonized using ontologies to enable easy search and retrieval.Genomics training is implemented using various online and face-to-face approaches.

The basis of social support that provides political legitimacy for age-related public policy is being called into question. Critics focus on the rapid growth of entitlement benefits for older people, both in terms of utilization and costs. Some have even suggested that if the current levels of spending are not curbed, we will sacrifice the economic legacy of our children. Programs being specifically targeted for criticism are Medicaid, Medicare, and Social Security. This article presents an issues overview of these programs in the context of current calls for reform. It suggests that aging public policy can be usefully taught and analyzed from the perspective of two conflicting schools of thought, which hold widely disparate views - the devolutionists and the safety netters. Devolutionists would tightly curtail the sustaining federal role in providing benefits to the elderly, while safety netters maintain that the federal government's role is indispensable. Relative deprivation theory, as advanced by Gurr...

We investigated whether small RNA (sRNA) sequenced from field-collected mosquitoes and chironomids (Diptera) can be used as a proxy signature of viral prevalence within a range of species and viral groups, using sRNAs sequenced from wild-caught specimens, to inform total RNA deep sequencing of samples of particular interest. Using this strategy, we sequenced from adult Anopheles maculipennis s.l. mosquitoes the apparently nearly complete genome of one previously undescribed virus related to chronic bee paralysis virus, and, from a pool of Ochlerotatus caspius and Oc. detritus mosquitoes, a nearly complete entomobirnavirus genome. We also reconstructed long sequences (1503-6557 nt) related to at least nine other viruses. Crucially, several of the sequences detected were reconstructed from host organisms highly divergent from those in which related viruses have been previously isolated or discovered. It is clear that viral transmission and maintenance cycles in nature are likely to be significantly more complex and taxonomically diverse than previously expected. © 2013 Cook et al.

Termination codon readthrough is utilized as a mechanism of expression of a growing number of viral and cellular proteins, but in many cases the mRNA signals that promote readthrough are poorly characterized. Here, we investigated the readthrough signal of Colorado tick fever virus (CTFV) segment 9 RNA (Seg-9). CTFV is the type-species of the genus Coltivirus within the family Reoviridae and is a tick-borne, double-stranded, segmented RNA virus. Seg-9 encodes a 36-kDa protein VP9, and by readthrough of a UGA stop codon, a 65-kDa product, VP9′. Using a reporter system, we defined the minimal sequence requirements for readthrough and confirmed activity in both mammalian and insect cell-free translation systems, and in transfected mammalian cells. Mutational analysis revealed that readthrough was UGA specific, and that the local sequence context around the UGA influenced readthrough efficiency. Readthrough was also dependent upon a stable RNA stem–loop structure beginning eight bases downstream from the UGA codon. Mutational analysis of this stem–loop revealed a requirement for the stem region but not for substructures identified within the loop. Unexpectedly, we were unable to detect a ribosomal pause during translation of the CTFV signal, suggesting that the mechanism of readthrough, at least at this site, is unlikely to be dependent upon RNA secondary-structure induced ribosomal pausing at the recoded stop codon.