Journal Articles

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    Pattern Formation in a Spatially Extended Model of Pacemaker Dynamics in Smooth Muscle Cells.
    (Springer Nature Switzerland AG on behalf of the Society for Mathematical Biology, 2022-07-08) Fatoyinbo HO; Brown RG; Simpson DJW; van Brunt B
    Spatiotemporal patterns are common in biological systems. For electrically coupled cells, previous studies of pattern formation have mainly used applied current as the primary bifurcation parameter. The purpose of this paper is to show that applied current is not needed to generate spatiotemporal patterns for smooth muscle cells. The patterns can be generated solely by external mechanical stimulation (transmural pressure). To do this we study a reaction-diffusion system involving the Morris-Lecar equations and observe a wide range of spatiotemporal patterns for different values of the model parameters. Some aspects of these patterns are explained via a bifurcation analysis of the system without coupling - in particular Type I and Type II excitability both occur. We show the patterns are not due to a Turing instability and that the spatially extended model exhibits spatiotemporal chaos. We also use travelling wave coordinates to analyse travelling waves.
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    Antigen-specific cytotoxic T lymphocytes target airway CD103+ and CD11b+ dendritic cells to suppress allergic inflammation
    (Nature Publishing Group, 2016-01) Daniels NJ; Hyde E; Ghosh S; Seo K; Price KM; Hoshino K; Kaisho T; Okada T; Ronchese F
    Allergic airway inflammation is driven by the recognition of inhaled allergen by T helper type 2 (Th2) cells in the airway and lung. Allergen-specific cytotoxic T lymphocytes (CTLs) can strongly reduce airway inflammation, however, the mechanism of their inhibitory activity is not fully defined. We used mouse models to show that allergen-specific CTLs reduced early cytokine production by Th2 cells in lung, and their subsequent accumulation and production of interleukin (IL)-4 and IL-13. In addition, treatment with specific CTLs also increased the proportion of caspase+ dendritic cells (DCs) in mediastinal lymph node (MLN), and decreased the numbers of CD103+ and CD11b+ DCs in the lung. This decrease required expression of the cytotoxic mediator perforin in CTLs and of the appropriate MHC-antigen ligand on DCs, suggesting that direct CTL-DC contact was necessary. Lastly, lung imaging experiments revealed that in airway-challenged mice XCR1-GFP+ DCs, corresponding to the CD103+ DC subset, and XCR1-GFP− CD11c+ cells, which include CD11b+ DCs and alveolar macrophages, both clustered in the areas surrounding the small airways and were closely associated with allergen-specific CTLs. Thus, allergen-specific CTLs reduce allergic airway inflammation by depleting CD103+ and CD11b+ DC populations in the lung, and may constitute a mechanism through which allergic immune responses are regulated.
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    Clinical risk factors, bone density and fall history in the prediction of incident fracture among men and women
    (2013) Edwards MH; Jameson K; Denison H; Harvey NC; Sayer AA; Dennison EM; Cooper C
    The FRAX(tr) algorithm uses clinical risk factors (CRF) and bone mineral density (BMD) to predict fracture risk but does not include falls history in the calculation. Using results from the Hertfordshire Cohort Study, we examined the relative contributions of CRFs, BMD and falls history to fracture prediction. We studied 2299 participants at a baseline clinic that included completion of a health questionnaire and anthropometric data. A mean of 5.5years later (range 2.9-8.8years) subjects completed a postal questionnaire detailing fall and fracture history. In a subset of 368 men and 407 women, bone densitometry was performed using a Hologic QDR 4500 instrument. There was a significantly increased risk of fracture in men and women with a previous fracture. A one standard deviation drop in femoral neck BMD was associated with a hazards ratio (HR) of incident fracture (adjusted for CRFs) of 1.92 (1.04-3.54) and 1.77 (1.16-2.71) in men and women respectively. A history of any fall since the age of 45years resulted in an unadjusted HR of fracture of 7.31 (3.78-14.14) and 8.56 (4.85-15.13) in men and women respectively. In a ROC curve analysis, the predictive capacity progressively increased as BMD and previous falls were added into an initial model using CRFs alone. Falls history is a further independent risk factor for fracture. Falls risk should be taken into consideration when assessing whether or not to commence medication for osteoporosis and should also alert the physician to the opportunity to target falls risk directly.
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    Feeding experience affects the behavioral response of polyphagous gypsy moth caterpillars to herbivore-induced poplar volatiles
    (Springer Verlag (Germany), 2016-05) McCormick AL; Reinecke A; Gershenzon J; Unsicker S
    Plant volatiles influence host selection of herbivorous insects. Since volatiles often vary in space and time, herbivores (especially polyphagous ones) may be able to use these compounds as cues to track variation in host plant quality based on their innate abilities and previous experience. We investigated the behavioral response of naïve (fed on artificial diet) and experienced (fed on poplar) gypsy moth (Lymantria dispar) caterpillars, a polyphagous species, towards constitutive and herbivore-induced black poplar (Populus nigra) volatiles at different stages of herbivore attack. In Y-tube olfactometer assays, both naïve and experienced caterpillars were attracted to constitutive volatiles and volatiles released after short-term herbivory (up to 6 hr). Naïve caterpillars also were attracted to volatiles released after longer-term herbivory (24-30 hr), but experienced caterpillars preferred the odor of undamaged foliage. A multivariate statistical analysis comparing the volatile emission of undamaged plants vs. plants after short and longer-term herbivory, suggested various compounds as being responsible for distinguishing between the odors of these plants. Ten compounds were selected for individual testing of caterpillar behavioral responses in a four-arm olfactometer. Naïve caterpillars spent more time in arms containing (Z)-3-hexenol and (Z)-3-hexenyl acetate than in solvent permeated arms, while avoiding benzyl cyanide and salicyl aldehyde. Experienced caterpillars avoided benzyl cyanide and preferred (Z)-3-hexenyl acetate and the homoterpene (E)-4,8-dimethyl-1,3,7-nonatriene (DMNT) over solvent. Only responses to DMNT were significantly different when comparing experienced and naïve caterpillars. The results show that gypsy moth caterpillars display an innate behavioral response towards constitutive and herbivore-induced plant volatiles, but also that larval behavior is plastic and can be modulated by previous feeding experience.
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    Recall of mobile phone usage and laterality in young people: The multinational Mobi-Expo study.
    (Elsevier B.V., 26/04/2018) Goedhart G; van Wel L; Langer CE; de Llobet Viladoms P; Wiart J; Hours M; Kromhout H; Benke G; Bouka E; Bruchim R; Choi K-H; Eng A; Ha M; Huss A; Kiyohara K; Kojimahara N; Krewski D; Lacour B; 't Mannetje A; Maule M; Migliore E; Mohipp C; Momoli F; Petridou ET; Radon K; Remen T; Sadetzki S; Sim M; Weinmann T; Cardis E; Vrijheid M; Vermeulen R
    OBJECTIVE: To study recall of mobile phone usage, including laterality and hands-free use, in young people. METHODS: Actual mobile phone use was recorded among volunteers aged between 10 and 24 years from 12 countries by the software application XMobiSense and was compared with self-reported mobile phone use at 6 and 18 months after using the application. The application recorded number and duration of voice calls, number of text messages, amount of data transfer, laterality (% of call time the phone was near the right or left side of the head, or neither), and hands-free usage. After data cleaning, 466 participants were available for the main analyses (recorded vs. self-reported phone use after 6 months). RESULTS: Participants were on average 18.6 years old (IQR 15.2-21.8 years). The Spearman correlation coefficients between recorded and self-reported (after 6 months) number and duration of voice calls were 0.68 and 0.65, respectively. Number of calls was on average underestimated by the participants (adjusted geometric mean ratio (GMR) self-report/recorded = 0.52, 95% CI = 0.47-0.58), while duration of calls was overestimated (GMR=1.32, 95%, CI = 1.15-1.52). The ratios significantly differed by country, age, maternal educational level, and level of reported phone use, but not by time of the interview (6 vs. 18 months). Individuals who reported low mobile phone use underestimated their use, while individuals who reported the highest level of phone use were more likely to overestimate their use. Individuals who reported using the phone mainly on the right side of the head used it more on the right (71.1%) than the left (28.9%) side. Self-reported left side users, however, used the phone only slightly more on the left (53.3%) than the right (46.7%) side. Recorded percentage hands-free use (headset, speaker mode, Bluetooth) increased with increasing self-reported frequency of hands-free device usage. Frequent (≥50% of call time) reported headset or speaker mode use corresponded with 17.1% and 17.2% of total call time, respectively, that was recorded as hands-free use. DISCUSSION: These results indicate that young people can recall phone use moderately well, with recall depending on the amount of phone use and participants' characteristics. The obtained information can be used to calibrate self-reported mobile use to improve estimation of radiofrequency exposure from mobile phones.
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    The aetiology of wobbly possum disease: Reproduction of the disease with purified nidovirus.
    (2016-04) Giles J; Perrott M; Roe W; Dunowska M
    The objective of this study was to investigate a role of a recently discovered marsupial nidovirus in the development of a neurological disease, termed wobbly possum disease (WPD), in the Australian brushtail possum (Trichosurus vulpecula). Four possums received 1 mL of a standard inoculum that had been prepared from tissues of WPD-affected possums, 4 possums received 1.8 mL (1 × 10(6) TCID50) of a cell lysate from inoculated cultures, and 4 possums received 1 mL (× 10(7) TCID50) of a purified WPD isolate. All but one possum that received infectious inocula developed neurological disease and histopathological lesions characteristic for WPD. High levels of viral RNA were detected in livers from all possums that received infectious inocula, but not from control possums. Altogether, our data provide strong experimental evidence for the causative involvement of WPD virus in development of a neurological disease in infected animals.
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    Preferential sites for intramolecular glucosepane cross-link formation in type I collagen: A thermodynamic study
    (Elsevier, 1/06/2015) Collier TA; Nash A; Birch HL; de Leeuw NH
    The extracellular matrix (ECM) undergoes progressive age-related stiffening and loss of proteolytic digestibility due to an increase in concentration of advanced glycation end products (AGEs). The most abundant AGE, glucosepane, accumulates in collagen with concentrations over 100 times greater than all other AGEs. Detrimental collagen stiffening properties are believed to play a significant role in several age-related diseases such as osteoporosis and cardiovascular disease. Currently little is known of the potential location of covalently cross-linked glucosepane formation within collagen molecules; neither are there reports on how the respective cross-link sites affect the physical and biochemical properties of collagen. Using fully atomistic molecular dynamics simulations (MD) we have identified six sites where the formation of a covalent intra-molecular glucosepane cross-link within a single collagen molecule in a fibrillar environment is energetically favourable. Identification of these favourable sites enables us to align collagen cross-linking with experimentally observed changes to the ECM. For example, formation of glucosepane was found to be energetically favourable within close proximity of the Matrix Metalloproteinase-1 (MMP1) binding site, which could potentially disrupt collagen degradation.
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    Unilateral perivertebral fibrosis associated with lordosis, kyphosis and scoliosis (LKS) in farmed Chinook salmon in New Zealand.
    (27/10/2016) Munday JS; Perrott MR; Symonds JE; Walker SP; Lovett B; Preece MA; Davie PS
    Vertebral column lordosis, kyphosis and scoliosis (LKS) can result in downgrading of farmed Chinook salmon Oncorhynchus tshawytscha in New Zealand. No cause of LKS has been identified. Radiography and histology were used to quantify LKS and perivertebral fibrosis in 27 fish with LKS visible at harvest and 30 visually normal fish from 3 New Zealand farms. Radiographic LKS was present in all 27 fish with LKS and in 18 of 30 fish without visible LKS. Quantification of the radiographic severity revealed significantly higher radiographic severity scores in fish with visible LKS (mean ± SD = 5.89 ± 2.41) than in fish with no visible, but radiographic LKS (1.44 ± 0.86, p < 0.001). The most frequent histological finding was unilateral perivertebral fibrosis that often extended into the horizontal septum and adjacent myomeres resulting in separation or loss of myocytes. Fibrosis was visible in all fish with LKS and in 12 of 30 fish without visible LKS. Fibrosis scores were higher in fish with visible LKS (3.32 ± 1.71) than in fish without visible LKS (0.35 ± 0.57, p < 0.001). The radiographic LKS severity scores were significantly correlated to the fibrosis scores (R2 = 0.59 p < 0.001) in the fish. Histology of other tissues revealed multifocal inflammation within muscle, peripheral connective tissues and myocardium which were considered most likely incidental in these fish. In this study, LKS was consistently and significantly associated with perivertebral fibrosis, suggesting that perivertebral fibrosis is an important process in the development of LKS. Further research to determine the cause of the fibrosis is required.
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    Genomic signatures of cooperation and conflict in the social amoeba
    (1/01/2015) Ostrowski EA; Shen Y; Tian X; Sucgang R; Jiang H; Qu J; Katoh-Kurasawa M; Brock DA; Dinh C; Lara-Garduno F; Lee SL; Kovar CL; Dinh HH; Korchina V; Jackson LR; Patil S; Han Y; Chaboub L; Shaulsky G; Muzny DM; Worley KC; Gibbs RA; Richards S; Kuspa A; Strassmann JE; Queller DC
    © 2015 Elsevier Ltd. Summary Cooperative systems are susceptible to invasion by selfish individuals that profit from receiving the social benefits but fail to contribute. These so-called "cheaters" can have a fitness advantage in the laboratory, but it is unclear whether cheating provides an important selective advantage in nature. We used a population genomic approach to examine the history of genes involved in cheating behaviors in the social amoeba Dictyostelium discoideum, testing whether these genes experience rapid evolutionary change as a result of conflict over spore-stalk fate. Candidate genes and surrounding regions showed elevated polymorphism, unusual patterns of linkage disequilibrium, and lower levels of population differentiation, but they did not show greater between-species divergence. The signatures were most consistent with frequency-dependent selection acting to maintain multiple alleles, suggesting that conflict may lead to stalemate rather than an escalating arms race. Our results reveal the evolutionary dynamics of cooperation and cheating and underscore how sequence-based approaches can be used to elucidate the history of conflicts that are difficult to observe directly.
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    Single-molecule folding mechanisms of the apo- and Mg(2+)-bound states of human neuronal calcium sensor-1
    (Biophysical Society, 7/07/2015) Naqvi MM; Heidarsson PO; Rodriguez Otazo M; Mossa A; Kragelund BB; Cecconi C
    Neuronal calcium sensor-1 (NCS-1) is the primordial member of a family of proteins responsible primarily for sensing changes in neuronal Ca(2+) concentration. NCS-1 is a multispecific protein interacting with a number of binding partners in both calcium-dependent and independent manners, and acting in a variety of cellular processes in which it has been linked to a number of disorders such as schizophrenia and autism. Despite extensive studies on the Ca(2+)-activated state of NCS proteins, little is known about the conformational dynamics of the Mg(2+)-bound and apo states, both of which are populated, at least transiently, at resting Ca(2+) conditions. Here, we used optical tweezers to study the folding behavior of individual NCS-1 molecules in the presence of Mg(2+) and in the absence of divalent ions. Under tension, the Mg(2+)-bound state of NCS-1 unfolds and refolds in a three-state process by populating one intermediate state consisting of a folded C-domain and an unfolded N-domain. The interconversion at equilibrium between the different molecular states populated by NCS-1 was monitored in real time through constant-force measurements and the energy landscapes underlying the observed transitions were reconstructed through hidden Markov model analysis. Unlike what has been observed with the Ca(2+)-bound state, the presence of Mg(2+) allows both the N- and C-domain to fold through all-or-none transitions with similar refolding rates. In the absence of divalent ions, NCS-1 unfolds and refolds reversibly in a two-state reaction involving only the C-domain, whereas the N-domain has no detectable transitions. Overall, the results allowed us to trace the progression of NCS-1 folding along its energy landscapes and provided a solid platform for understanding the conformational dynamics of similar EF-hand proteins.