Search Results (15)

Alterations to post-translational crosslinking modifications in the extracellular matrix (ECM) are known to drive the pathogenesis of fibrotic diseases, including idiopathic pulmonary fibrosis (IPF). Thus, the methodology for measuring crosslinking dynamics is valuable for understanding disease progression. The existing crosslinking analysis sample preparation and liquid chromatography tandem mass spectrometry (LC-MS/MS) methods are typically labor-intensive and time-consuming which limits throughput. We, therefore, developed a rapid approach minimizing specialized equipment and hands-on time. The LC-MS/MS sample analysis time was reduced to two minutes per sample. We then improved the analytical integrity of the method by developing a novel surrogate matrix approach for the dihydroxylysinonorleucine (DHLNL) crosslink. By modifying sample preparation, we prepared a tissue-based surrogate matrix with undetectable levels of endogenous DHLNL, providing a strategy for quantifying this crosslink with a more relevant standard matrix. We then applied this rapid methodology to evaluating crosslinking in lung fibrosis. We showed an increase in DHLNL in human IPF lung relative to healthy donors, as well as in a fibrotic mouse model. Finally, we demonstrated that this increase in DHLNL could be mitigated with an anti-fibrotic compound, suggesting that this assay has potential for evaluating pharmaceutical compound efficacy. Full article

Walking is crucial for independence and quality of life. This study leverages wrist-worn sensor data from UK Biobank participants to establish normative daily-life walking data, stratified by age and sex, to provide benchmarks for research and clinical practice. The Watch Walk digital biomarkers were developed, validated, and applied to 92,022 participants aged 45–79 who wore a wrist sensor for at least three days. Normative data were collected for daily-life walking speed, step-time variability, step count, and 17 other gait and sleep biomarkers. Test–retest reliability was calculated, and associations with sex, age, self-reported walking pace, and mobility problems were examined. Population mean maximal and usual walking speeds were 1.49 and 1.15 m/s, respectively. The daily step count was 7749 steps, and step regularity was 65%. Women walked more regularly but slower than men. Walking speed, step count, longest walk duration, and step regularity decreased with age. Walking speed is associated with sex, age, self-reported pace, and mobility problems. Test–retest reliability was good to excellent (ICC ≥ 0.80). This study provides large-scale normative data and benchmarks for wrist-sensor-derived digital gait and sleep biomarkers from real-world data for future research and clinical applications. Full article

Parenteral nutrition (PN) is a life-sustaining method to provide adequate nutrients to patients unable to receive oral or enteral nutrition. PN typically contains a mixture of macro- and micro-nutrients, although the lipid composition has been identified as a concern for liver disease. Therefore, the study of the intravenous lipid emulsion (ILE) prescribing practices in home-based PN (HPN) patients and whether differing lipid PN alters liver function tests (LFTs) is needed. Methods: A retrospective study of monthly LFTs from a random sample of 105 adult HPN patients in the U.S. over a 6-month period was conducted. Patients were receiving olive oil/soy oil (n = 53, Clinolipid), mixed ILE (n = 39, SMOF Lipid), soy oil (SO; n = 4, Intralipid), or none (n = 7). LFTs monitored were alkaline phosphatase (ALP), alanine transaminase (ALT), aspartate transaminase (AST), and total bilirubin (T Bili). Results: No differences were observed in baseline LFTs across groups (all, p > 0.25, η² < 0.04), nor were there differences in age, body mass index, days of PN, or mean PN volume (all, p > 0.36, η² < 0.05). There were no significant interactions between ILE type and time (all p > 0.64, η_p² < 0.03), no effect of ILE type (all p > 0.60, η_p² < 0.03), and no effect of time (all p > 0.69, η_p² < 0.01) in terms of LFTs. Average LFTs over six months were also not different between ILE types (all p > 0.30, η² < 0.04). Conclusion: These findings suggested that patients were mostly prescribed mixed or ILE PN containing more than one lipid source and that differing ILEs in long-term HPN patients did not alter LFTs over a six-month period. Full article

Accelerometers worn by animals produce distinct behavioral signatures, which can be classified accurately using machine learning methods such as random forest decision trees. The objective of this study was to identify accelerometer signal separation among parsimonious behaviors. We achieved this objective by (1) describing functional differences in accelerometer signals among discrete behaviors, (2) identifying the optimal window size for signal pre-processing, and (3) demonstrating the number of observations required to achieve the desired level of model accuracy,. Crossbred steers (Bos taurus indicus; n = 10) were fitted with GPS collars containing a video camera and tri-axial accelerometers (read-rate = 40 Hz). Distinct behaviors from accelerometer signals, particularly for grazing, were apparent because of the head-down posture. Increasing the smoothing window size to 10 s improved classification accuracy (p < 0.05), but reducing the number of observations below 50% resulted in a decrease in accuracy for all behaviors (p < 0.05). In-pasture observation increased accuracy and precision (0.05 and 0.08 percent, respectively) compared with animal-borne collar video observations. Full article

The great diversity of color patterns observed among amphibians is largely explained by the differentiation of relatively few pigment cell types during development. Mexican axolotls present a variety of color phenotypes that span the continuum from leucistic to highly melanistic. The melanoid axolotl is a Mendelian variant characterized by large numbers of melanophores, proportionally fewer xanthophores, and no iridophores. Early studies of melanoid were influential in developing the single-origin hypothesis of pigment cell development, wherein it has been proposed that all three pigment cell types derive from a common progenitor cell, with pigment metabolites playing potential roles in directing the development of organelles that define different pigment cell types. Specifically, these studies identified xanthine dehydrogenase (XDH) activity as a mechanism for the permissive differentiation of melanophores at the expense of xanthophores and iridophores. We used bulked segregant RNA-Seq to screen the axolotl genome for melanoid candidate genes and identify the associated locus. Dissimilar frequencies of single-nucleotide polymorphisms were identified between pooled RNA samples of wild-type and melanoid siblings for a region on chromosome 14q. This region contains gephyrin (Gphn), an enzyme that catalyzes the synthesis of the molybdenum cofactor that is required for XDH activity, and leukocyte tyrosine kinase (Ltk), a cell surface signaling receptor that is required for iridophore differentiation in zebrafish. Wild-type Ltk crispants present similar pigment phenotypes to melanoid, strongly implicating Ltk as the melanoid locus. In concert with recent findings in zebrafish, our results support the idea of direct fate specification of pigment cells and, more generally, the single-origin hypothesis of pigment cell development. Full article

DNA glycosylases promote genomic stability by initiating base excision repair (BER) in both the nuclear and mitochondrial genomes. Several of these enzymes have overlapping substrate recognition, through which a degree of redundancy in lesion recognition is achieved. For example, OGG1 and NEIL1 both recognize and release the imidazole-ring-fragmented guanine, FapyGua as part of a common overall pathway to cleanse the genome of damaged bases. However, these glycosylases have many differences, including their differential breadth of substrate specificity, the contrasting chemistries through which base release occurs, the subsequent steps required to complete the BER pathway, and the identity of specific protein-binding partners. Beyond these differences, the complexities and differences of their in vivo biological roles have been primarily elucidated in studies of murine models harboring a knockout of Neil1 or Ogg1, with the diversity of phenotypic manifestations exceeding what might have been anticipated for a DNA glycosylase deficiency. Pathologies associated with deficiencies in nuclear DNA repair include differential cancer susceptibilities, where Ogg1-deficient mice are generally refractory to carcinogenesis, while deficiencies in Neil1-deficient mice confer cancer susceptibility. In contrast to NEIL1, OGG1 functions as a key transcription factor in regulating inflammation and other complex gene cascades. With regard to phenotypes attributed to mitochondrial repair, knockout of either of these genes results in age- and diet-induced metabolic syndrome. The adverse health consequences associated with metabolic syndrome can be largely overcome by expression of a mitochondrial-targeted human OGG1 in both wild-type and Ogg1-deficient mice. The goal of this review is to compare the roles that NEIL1 and OGG1 play in maintaining genomic integrity, with emphasis on insights gained from not only the diverse phenotypes that are manifested in knockout and transgenic mice, but also human disease susceptibility associated with polymorphic variants. Full article

Detection of Clostridioides difficile toxins in patients with gastroenteritis has increasingly been accomplished through the use of enteric multiplex syndromic panels. Comparisons of the performance of these panels to both direct-from-stool (DFS) and culture-enriched stools followed by polymerase chain reaction (PCR) methods in pediatric populations are limited. Here, we compare the performance of the Luminex xTAG^® Gastrointestinal Pathogen Panel (GPP) to our DFS in-house real-time PCR (DFS RT-PCR) assay for the detection of C. difficile toxin gene, tcdB, using 2641 stool specimens collected from children enrolled in the Alberta Provincial Pediatric EnTeric Infection Team (APPETITE) study in Alberta, Canada. We used culture enrichment followed by in-house RT-PCR to resolve discordant results between the two assays. We found excellent agreement (k = 0.89) between the GPP and our DFS RT-PCR assay: the positive percent agreement between the two assays was 97%, and the negative percent agreement was 99%. GPP, a multi-analyte platform can easily be implemented into a routine diagnostic laboratory for detecting enteric pathogens including C. difficile. Full article

Pre-eclampsia is a leading cause of maternal and perinatal morbidity and mortality. The burden of disease lies mainly in low-middle income countries. The aim of this project is to establish a pre-eclampsia biobank in South Africa to facilitate research in the field of pre-eclampsia with a focus on phenotyping severe disease.The approach of our biobank is to collect biological specimens, detailed clinical data, tests, and biophysical examinations, including magnetic resonance imaging (MRI) of the brain, MRI of the heart, transcranial Doppler, echocardiography, and cognitive function tests.Women diagnosed with pre-eclampsia and normotensive controls are enrolled in the biobank at admission to Tygerberg University Hospital (Cape Town, South Africa). Biological samples and clinical data are collected at inclusion/delivery and during the hospital stay. Special investigations as per above are performed in a subset of women. After two months, women are followed up by telephonic interviews. This project aims to establish a biobank and database for severe organ complications of pre-eclampsia in a low-middle income country where the incidence of pre-eclampsia with organ complications is high. The study integrates different methods to investigate pre-eclampsia, focusing on improved understanding of pathophysiology, prediction of organ complications, and potentially future drug evaluation and discovery. Full article

HIV-1 infection rapidly leads to a loss of the proliferative response of memory CD4+ T lymphocytes, when cultured with recall antigens. We report here that CD73 expression defines a subset of resting memory CD4+ T cells in peripheral blood, which highly express the α-chain of the IL-7 receptor (CD127), but not CD38 or Ki-67, yet are highly proliferative in response to mitogen and recall antigens, and to IL-7, in vitro. These cells also preferentially express CCR5 and produce IL-2. We reasoned that CD73+ memory CD4+ T cells decrease very early in HIV-1 infection. Indeed, CD73+ memory CD4+ T cells comprised a median of 7.5% (interquartile range: 4.5–10.4%) of CD4+ T cells in peripheral blood from healthy adults, but were decreased in primary HIV-1 infection to a median of 3.7% (IQR: 2.6–6.4%; p = 0.002); and in chronic HIV-1 infection to 1.9% (IQR: 1.1–3%; p < 0.0001), and were not restored by antiretroviral therapy. Moreover, we found that a significant proportion of CD73+ memory CD4+ T cells were skewed to a gut-homing phenotype, expressing integrins α4 and β7, CXCR3, CCR6, CD161 and CD26. Accordingly, 20% of CD4+ T cells present in gut biopsies were CD73+. In HIV+ subjects, purified CD73+ resting memory CD4+ T cells in PBMC were infected with HIV-1 DNA, determined by real-time PCR, to the same level as for purified CD73-negative CD4+ T cells, both in untreated and treated subjects. Therefore, the proliferative CD73+ subset of memory CD4+ T cells is disproportionately reduced in HIV-1 infection, but, unexpectedly, their IL-7 dependent long-term resting phenotype suggests that residual infected cells in this subset may contribute significantly to the very long-lived HIV proviral DNA reservoir in treated subjects. Full article

Trees in residential landscapes provide many benefits, but can injure persons and damage property when they fail. In hurricane-prone regions like Florida, USA, the regular occurrence of hurricanes has provided an opportunity to assess factors that influence the likelihood of wind-induced tree failure and develop species failure profiles. We assessed open-grown trees in Naples, Florida, following the passage of Hurricane Irma in September 2017 to determine the effect of relevant factors on the degree of damage sustained by individual trees. Of 4034 assessed individuals (n = 15 species), 74% sustained no damage, 4% sustained only minor damage (i.e., minimal corrective pruning needed), 6% sustained significant damage (i.e., major corrective pruning needed), and 15% were whole-tree failures (i.e., overturned trees or trees requiring removal). The proportion of individuals in each damage category varied among species, stem diameter at 1.4 m above ground, and the presence of utility lines, which was a proxy for maintenance. We compared our results with the findings of seven previous hurricanes in the region to explore species’ resilience in hurricanes. Full article

Several technologies can be used for measuring strains of soft materials under high rate impact conditions. These technologies include high speed tensile test, split Hopkinson pressure bar test, digital image correlation and high speed X-ray imaging. However, none of these existing technologies can produce a continuous 3D spatial strain distribution in the test specimen. Here we report a novel passive strain sensor based on poly(dimethyl siloxane) (PDMS) elastomer with covalently incorporated spiropyran (SP) mechanophore to measure impact induced strains. We have shown that the incorporation of SP into PDMS at 0.25 wt% level can adequately measure impact strains via color change under a high strain rate of 1500 s⁻¹ within a fraction of a millisecond. Further, the color change is fully reversible and thus can be used repeatedly. This technology has a high potential to be used for quantifying brain strain for traumatic brain injury applications. Full article

The Seismic Research Centre (SRC), formerly known as the Seismic Research Unit (SRU), of the University of the West Indies is located on the island of Trinidad in the Eastern Caribbean. The centre has been operating its volcanological and seismological surveillance network since 1953. Since that time, the network has been upgraded five times resulting in five generations of seismic network topologies (i.e., Classes). Class 1 consisted of autonomously operated photographic recording stations, a purely analogue configuration. From Class 2 to Class 5 (current class) the network has continuously grown in scope, sophistication and capability. The evolution of the network was carried out using a combination of state-of-the-art instruments as well as trailing edge technology (e.g., analogue transmission) used in a manner that allows for sustainability. In this way, the network has been able to address the scientific and technical challenges associated with operating in an island arc subduction zone which is exposed to other natural hazards such as hurricanes. To counter its operational constrains the SRC has developed several strategies, which contribute to: (i) expand the network to meet the demand for more timely and accurate surveillance of geohazards, (ii) broaden the range of monitoring techniques (e.g., cGPS, geochemical), (iii) capture research grade scientific data and (iv) reduce operational costs. Full article

Lutein (L) and zeaxanthin (Z) are two xanthophyll carotenoids that have antioxidant and anti-inflammatory properties. Previous work has demonstrated their importance for eye health and preventing diseases such as age-related macular degeneration. An emerging literature base has also demonstrated the importance of L and Z in cognition, neural structure, and neural efficiency. The present study aimed to better understand the mechanisms by which L and Z relate to cognition, in particular, visual–spatial processing and decision-making in older adults. We hypothesized that markers of higher levels of L and Z would be associated with better neural efficiency during a visual–spatial processing task. L and Z were assessed via standard measurement of blood serum and retinal concentrations. Visual–spatial processing and decision-making were assessed via a judgment of line orientation task (JLO) completed during a functional magnetic resonance imaging (fMRI) scan. The results demonstrated that individuals with higher concentrations of L and Z showed a decreased blood-oxygen-level dependent (BOLD) signal during task performance (i.e., “neural efficiency”) in key areas associated with visual–spatial perception, processing, decision-making, and motor coordination, including the lateral occipital cortex, occipital pole, superior and middle temporal gyri, superior parietal lobule, superior and middle frontal gyri, and pre- and post-central gyri. To our knowledge, this is the first investigation of the relationship of L and Z to visual–spatial processing at a neural level using in vivo methodology. Our findings suggest that L and Z may impact brain health and cognition in older adults by enhancing neurobiological efficiency in a variety of regions that support visual perception and decision-making. Full article

Pulmonary hypertension (PH) is an enigmatic vascular disorder characterized by pulmonary vascular remodeling and increased pulmonary vascular resistance, ultimately resulting in pressure overload, dysfunction, and failure of the right ventricle. Current medications for PH do not reverse or prevent disease progression, and current diagnostic strategies are suboptimal for detecting early-stage disease. Thus, there is a substantial need to develop new diagnostics and therapies that target the molecular origins of PH. Emerging investigations have defined metabolic aberrations as fundamental and early components of disease manifestation in both pulmonary vasculature and the right ventricle. As such, the elucidation of metabolic dysregulation in pulmonary hypertension allows for greater therapeutic insight into preventing, halting, or even reversing disease progression. This review will aim to discuss (1) the reprogramming and dysregulation of metabolic pathways in pulmonary hypertension; (2) the emerging therapeutic interventions targeting these metabolic pathways; and (3) further innovation needed to overcome barriers in the treatment of this devastating disease. Full article

This paper explores the use of Web 2.0 technologies for collaborative learning in a higher education context. A review of the literature exploring the strengths and weaknesses of Web 2.0 technology is presented, and a conceptual model of a Web 2.0 community of inquiry is introduced. Two Australian case studies are described, with an ex-poste evaluation of the use of Web 2.0 tools. Conclusions are drawn as to the potential for the use of Web 2.0 tools for collaborative e-learning in higher education. In particular, design and integration of Web 2.0 tools should be closely related to curriculum intent and pedagogical requirements, care must be taken to provide clear guidance on both expected student activity and learning expectations, and there is a clear need to develop, support and encourage strong interaction both between teachers and students, and amongst the students themselves. Full article