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BackgroundEarly identification of deficits in our ability to perceive odors is important as many normal (i.e., aging) and pathological (i.e., sinusitis, viral, neurodegeneration) processes can result in diminished olfactory function. To realistically enable population-level measurements of olfaction, validated olfaction tests must be capable of being administered outside the research laboratory and clinical setting.AimThe purpose of this study was to determine the feasibility of remotely testing olfactory performance using a test that was developed with funding from the National Institutes of Health as part of a ready-to-use, non-proprietary set of measurements useful for epidemiologic studies (NIH Toolbox Odor ID Test).Materials and methodsEligible participants older than 39 years and active (within 6 months) in the Brain Health Registry (BHR), an online cognitive assessment platform which connects participants with researchers, were recruited for this study. Interested participants were mailed the NIH Toolbox Odor ID Test along with instructions on accessing a website to record their responses. Data obtained from subjects who performed the test at home was compared to the normative data collected when the NIH Toolbox Odor ID Test was administered by a tester in a research setting and validated against the Smell Identification Test. The age-range and composition of the population ensured we had the ability to observe both age-related decline and gender-related deficits in olfactory ability, as shown in the experimental setting.ResultsWe observed that age-associated olfactory decline and gender-associated performance was comparable to performance on the administered test. Self-administration of this test showed the age-related loss in olfactory acuity, F(4, 1156)=14.564, pConclusionThese results indicate that the NIH Toolbox Odor ID Test is an appropriate instrument for self-administered assessment of olfactory performance. The ability to self-administer an inexpensive olfactory test increases its utility for inclusion in longitudinal epidemiological studies and when in-person testing is not feasible.

Asymptomatic carriage of Staphylococcus aureus is a major risk factor for subsequent clinical infection. Diminishing returns from mitigation efforts emphasize the need to better understand colonization, spread, and transmission of this opportunistic pathogen. While contact with other people presents opportunities for pathogen exposure and transmission, diversity of social connections may be protective against pathogens such as the common cold. This study examined whether social relationship resources, including the amount and diversity of social contacts, are associated with S. aureus colonization. Participants were community members (N = 443; 68% Hispanic) in naturally occurring social groups in southwestern Arizona. Four types of social relationships and loneliness were assessed, and samples from the skin, nose and throat were obtained to ascertain S. aureus colonization. Overall S. aureus prevalence was 64.8%. Neither the amount nor the diversity of social contacts were associated with S. aureus colonization. The concurrent validity of the social relationship assessments was supported by their moderate intercorrelations and by their positive association with self-rated health. The results suggest that the association of social network diversity and susceptibility to the common cold does not extend to S. aureus colonization. Conversely, colonization prevalence was not higher among those with more social contacts. The latter pattern suggests that social transmission may be relatively infrequent or that more intimate forms of social interaction may drive transmission and colonization resulting in high community prevalence of S. aureus colonization. These data inform communicable disease control efforts.

BackgroundThe number of oral anticancer medications has increased over the past few decades, opening new possibilities in cancer care and improving convenience for patients and caregivers. However, adherence levels continue to be suboptimal, potentially jeopardizing therapeutic benefits. Poor adherence levels may indicate gaps in current strategies and interventions aimed at enhancing medication adherence and the extent to which they address the complex and multi-faceted medication management needs of patients and their caregivers. Beyond commonly understood barriers (e.g., forgetting to take medications), adherence interventions must address systemic barriers that may not be fully appreciated by members of the healthcare system. This scoping review aims to apply a systems framework (human factors engineering framework) to examine system elements targeted by adherence enhancing interventions.MethodsStudies published in English, reporting adherence interventions for oral anticancer medications with adherence and/or persistence as primary outcome measures will be included in this review. We will search the following electronic databases with no limits on dates: Ovid MEDLINE, Cochrane Library, Web of Science Core Collection, Embase, CINAHL Complete, PsycInfo, and Scopus. Two reviewers will independently screen study titles and abstracts for inclusion with a third reviewer adjudicating conflicts. Full text of included articles will be used to extract information on systemic barriers targeted by adherence interventions as well as information about intervention type, outcomes, and study characteristics. Extracted information will be synthesized to generate a summary of work system factors targeted by adherence interventions.DiscussionThrough application of a systems-based approach, this scoping review is expected to shed light on the complex and multifaceted nature of factors influencing adherence to oral anticancer agents. The review may also identify areas that are ripe for further research.

Certain exercises could overload the osteoarthritic knee. We developed an exercise program from yoga postures with a minimal knee adduction moment for knee osteoarthritis. The purpose was to compare the effectiveness of this biomechanically-based yoga exercise (YE), with traditional exercise (TE), and a no-exercise attention-equivalent control (NE) for improving pain, self-reported physical function and mobility performance in women with knee osteoarthritis.Single-blind, three-arm randomized controlled trial.Community in Southwestern Ontario, Canada.A convenience sample of 31 women with symptomatic knee osteoarthritis was recruited through rheumatology, orthopaedic and physiotherapy clinics, newspapers and word-of-mouth.Participants were stratified by disease severity and randomly allocated to one of three 12-week, supervised interventions. YE included biomechanically-based yoga exercises; TE included traditional leg strengthening on machines; and NE included meditation with no exercise. Participants were asked to attend three 1-hour group classes/sessions each week.Primary outcomes were pain, self-reported physical function and mobility performance. Secondary outcomes were knee strength, depression, and health-related quality of life. All were assessed by a blinded assessor at baseline and immediately following the intervention.The YE group demonstrated greater improvements in KOOS pain (mean difference of 22.9 [95% CI, 6.9 to 38.8; p = 0.003]), intermittent pain (mean difference of -19.6 [95% CI, -34.8 to -4.4; p = 0.009]) and self-reported physical function (mean difference of 17.2 [95% CI, 5.2 to 29.2; p = 0.003]) compared to NE. Improvements in these outcomes were similar between YE and TE. However, TE demonstrated a greater improvement in knee flexor strength compared to YE (mean difference of 0.1 [95% CI, 0.1 to 0.2]. Improvements from baseline to follow-up were present in quality of life score for YE and knee flexor strength for TE, while both also demonstrated improvements in mobility. No improvement in any outcome was present in NE.The biomechanically-based yoga exercise program produced clinically meaningful improvements in pain, self-reported physical function and mobility in women with clinical knee OA compared to no exercise. While not statistically significant, improvements in these outcomes were larger than those elicited from the traditional exercise-based program. Though this may suggest that the yoga program may be more efficacious for knee OA, future research studying a larger sample is required.ClinicalTrials.gov (NCT02370667).

The mouse double minute 1 (Mdm1) gene was first reported and cloned in mouse tumor cell lines as an oncogene candidate. Later, it was found that mutation of Mdm1 might cause age-related retinal degeneration 2 in mice by genetic linkage analysis. Additionally, the MDM1 protein was found to be expressed in the centrosomes, cilia, and the nucleus of multiciliated tracheal epithelial cells in mice. These observations suggest that MDM1 may have some basal functions in cell physiology. However, the evolutionary history of this gene and its expression during embryonic development remain largely unexplored.Using molecular phylogenetic analysis, we found that the MDM1 gene encoded an evolutionarily conserved protein across all metazoans. We also found that the MDM1 gene was in a conserved synteny in vertebrates. In almost all the species that were analyzed, there was only one MDM1 gene based on current genome annotations. Since vertebrate genomes underwent two to three rounds of whole-genome duplications around the origin of the vertebrates, it is interesting that only one MDM1 ohnolog was retained. This observation implies that other MDM1 ohnologs were lost after the whole-genome duplications. Furthermore, using whole-mount in situ hybridization, we found that mdm1 was expressed in the forebrain, nephric ducts, and tail buds during zebrafish early embryonic development.MDM1 is an evolutionary conserved gene, and its homologous genes can be traced back to basal metazoan lineages. In vertebrates, the MDM1 gene is in a conserved synteny and there is only one MDM1 ohnolog suggesting it is a "duplication-resistant" gene. Its expression patterns in early zebrafish embryos indicate that mdm1 may play important roles in the development of the central nervous system, kidneys, and hematopoietic system.

[This corrects the article DOI: 10.1371/journal.pone.0135053.].

BACKGROUND:Personal lubricant use is common during anal intercourse. Some water-based products with high osmolality and low pH can damage genital and rectal tissues, and the polymer polyquaternium 15 (PQ15) can enhance HIV replication in vitro. This has raised concerns that lubricants with such properties may increase STD/HIV infection risk, although in vivo evidence is scarce. We use a macaque model to evaluate rectal cytotoxicity and SHIV infection risk after use of a highly osmolar (>8,000 mOsm/kg) water-based lubricant with pH of 4.4, and containing PQ15. METHODS:Cytotoxicity was documented by measuring inflammatory cytokines and epithelial tissue sloughing during six weeks of repeated, non-traumatic lubricant or control buffer applications to rectum and anus. We measured susceptibility to SHIVSF162P3 infection by comparing virus doses needed for rectal infection in twenty-one macaques treated with lubricant or control buffer 30 minutes prior to virus exposure. RESULTS:Lubricant increased pro-inflammatory cytokines and tissue sloughing while control buffer (phosphate buffered saline; PBS) did not. However, the estimated AID50 (50% animal infectious dose) was not different in lubricant- and control buffer-treated macaques (p = 0.4467; logistic regression models). CONCLUSIONS:Although the test lubricant caused acute cytotoxicity in rectal tissues, it did not increase susceptibility to infection in this macaque model. Thus neither the lubricant-induced type/extent of inflammation nor the presence of PQ15 affected infection risk. This study constitutes a first step in the in vivo evaluation of lubricants with regards to HIV transmission.

Because sequence information is now available for the 648bp barcode region of cytochrome c oxidase 1 (COI) from more than 400,000 animal species, this gene segment can be used to probe patterns of mitochondrial evolution. The present study examines levels of amino acid substitution and the frequency of indels in COI from 4177 species of arachnids, including representatives from all 16 orders and 43% of its families (267/625). It examines divergences at three taxonomic levels-among members of each order to an outgroup, among families in each order and among BINs, a species proxy, in each family. Order Distances vary fourfold (0.10-0.39), while the mean of the Family Distances for the ten orders ranges fivefold (0.07-0.35). BIN Distances show great variation, ranging from 0.01 or less in 12 families to more than 0.25 in eight families. Patterns of amino acid substitution in COI are generally congruent with previously reported variation in nucleotide substitution rates in arachnids, but provide some new insights, such as clear rate acceleration in the Opiliones. By revealing a strong association between elevated rates of nucleotide and amino acid substitution, this study builds evidence for the selective importance of the rate variation among arachnid lineages. Moreover, it establishes that groups whose COI genes have elevated levels of amino acid substitution also regularly possess indels, a dramatic form of protein reconfiguration. Overall, this study suggests that the mitochondrial genome of some arachnid groups is dynamic with high rates of amino acid substitution and frequent indels, while it is 'locked down' in others. Dynamic genomes are most prevalent in arachnids with short generation times, but the possible impact of breeding system deserves investigation since many of the rapidly evolving lineages reproduce by haplodiploidy, a mode of reproduction absent in 'locked down' taxa.

Although mites are one of the most abundant and diverse groups of arthropods, they are rarely targeted for detailed biodiversity surveys due to taxonomic constraints. We address this gap through DNA barcoding, evaluating acarine diversity at Churchill, Manitoba, a site on the tundra-taiga transition. Barcode analysis of 6279 specimens revealed nearly 900 presumptive species of mites with high species turnover between substrates and between forested and non-forested sites. Accumulation curves have not reached an asymptote for any of the three mite orders investigated, and estimates suggest that more than 1200 species of Acari occur at this locality. The coupling of DNA barcode results with taxonomic assignments revealed that Trombidiformes compose 49% of the fauna, a larger fraction than expected based on prior studies. This investigation demonstrates the efficacy of DNA barcoding in facilitating biodiversity assessments of hyperdiverse taxa.

Animals in the natural world continuously encounter learning experiences of varying degrees of novelty. New neurons in the hippocampus are especially responsive to learning associations between novel events and more cells survive if a novel and challenging task is learned. One might wonder whether new neurons would be rescued from death upon each new learning experience or whether there is an internal control system that limits the number of cells that are retained as a function of learning. In this experiment, it was hypothesized that learning a task that was similar in content to one already learned previously would not increase cell survival. We further hypothesized that in situations in which the cells are rescued hippocampal theta oscillations (3-12 Hz) would be involved and perhaps necessary for increasing cell survival. Both hypotheses were disproved. Adult male Sprague-Dawley rats were trained on two similar hippocampus-dependent tasks, trace and very-long delay eyeblink conditioning, while recording hippocampal local-field potentials. Cells that were generated after training on the first task were labeled with bromodeoxyuridine and quantified after training on both tasks had ceased. Spontaneous theta activity predicted performance on the first task and the conditioned stimulus induced a theta-band response early in learning the first task. As expected, performance on the first task correlated with performance on the second task. However, theta activity did not increase during training on the second task, even though more cells were present in animals that had learned. Therefore, as long as learning occurs, relatively small changes in the environment are sufficient to increase the number of surviving neurons in the adult hippocampus and they can do so in the absence of an increase in theta activity. In conclusion, these data argue against an upper limit on the number of neurons that can be rescued from death by learning.

Non-coding RNAs have raised a lot of interest because of their capabilities to perform enzymatic reactions and regulate gene expression in various ways. Human Accelerated Region 1 (HAR1) has been identified during the search for highly conserved regions in mammalian genomes, over one hundred base pairs long, and with high rates of substitution in the human genome. Its potential for coding for a protein is very minimal. However, the HAR1 transcript has been computationally predicted to have a stable secondary structure. Previous structure-probing experiments have suggested that the majority of differences between human and chimp constructs are in helices, designated C and D. For this reason, a 47nt construct consisting of the C and D helices along with two additional C-G pairs was synthesized, purified, and crystallized, and its x-ray structure is reported in this study. The final structure is an artificial dimer, with a bulge that forms different conformations on each monomer. This bulge has been observed in predicted secondary structures, footprinting assays, enzymatic degradation assays, NMR studies, in silico studies, and in this crystalized dimer structure. It is proposed that the HAR1 transcript is a non-coding RNA that interacts with an unknown binding partner responsible for brain development through this inherent structural motif of bulged adenosines.

Microglia are the primary immune cell in the brain and are postulated to play important roles outside of immunity. Administration of the dual colony-stimulating factor 1 receptor (CSF1R)/c-Kit kinase inhibitor, PLX3397, to adult mice results in the elimination of ~99% of microglia, which remain eliminated for as long as treatment continues. Upon removal of the inhibitor, microglia rapidly repopulate the entire adult brain, stemming from a central nervous system (CNS) resident progenitor cell. Using this method of microglial elimination and repopulation, the role of microglia in both healthy and diseased states can be explored. Here, we examine the responsiveness of newly repopulated microglia to an inflammatory stimulus, as well as determine the impact of these cells on behavior, cognition, and neuroinflammation. Two month-old wild-type mice were placed on either control or PLX3397 diet for 21 d to eliminate microglia. PLX3397 diet was then removed in a subset of animals to allow microglia to repopulate and behavioral testing conducted beginning at 14 d repopulation. Finally, inflammatory profiling of the microglia-repopulated brain in response to lipopolysaccharide (LPS; 0.25 mg/kg) or phosphate buffered saline (PBS) was determined 21 d after inhibitor removal using quantitative real time polymerase chain reaction (RT-PCR), as well as detailed analyses of microglial morphologies. We find mice with repopulated microglia to perform similarly to controls by measures of behavior, cognition, and motor function. Compared to control/resident microglia, repopulated microglia had larger cell bodies and less complex branching in their processes, which resolved over time after inhibitor removal. Inflammatory profiling revealed that the mRNA gene expression of repopulated microglia was similar to normal resident microglia and that these new cells appear functional and responsive to LPS. Overall, these data demonstrate that newly repopulated microglia function similarly to the original resident microglia without any apparent adverse effects in healthy adult mice.

People with knee osteoarthritis may benefit from exercise prescriptions that minimize knee loads in the frontal plane. The primary objective of this study was to determine whether a novel 12-week strengthening program designed to minimize exposure to the knee adduction moment (KAM) could improve symptoms and knee strength in women with symptomatic knee osteoarthritis. A secondary objective was to determine whether the program could improve mobility and fitness, and decrease peak KAM during gait. The tertiary objective was to evaluate the biomechanical characteristics of this yoga program. In particular, we compared the peak KAM during gait with that during yoga postures at baseline. We also compared lower limb normalized mean electromyography (EMG) amplitudes during yoga postures between baseline and follow-up. Primary measures included self-reported pain and physical function (Knee injury and Osteoarthritis Outcome Score) and knee strength (extensor and flexor torques). Secondary measures included mobility (six-minute walk, 30-second chair stand, stair climbing), fitness (submaximal cycle ergometer test), and clinical gait analysis using motion capture synchronized with electromyography and force measurement. Also, KAM and normalized mean EMG amplitudes were collected during yoga postures. Forty-five women over age 50 with symptomatic knee osteoarthritis, consistent with the American College of Rheumatology criteria, enrolled in our 12-week (3 sessions per week) program. Data from 38 were analyzed (six drop-outs; one lost to co-intervention). Participants experienced reduced pain (mean improvement 10.1–20.1 normalized to 100; p