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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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    Intra-molecular lysine-arginine derived advanced glycation end-product cross-linking in Type I collagen: A molecular dynamics simulation study.
    (2016-11) Collier TA; Nash A; Birch HL; de Leeuw NH
    Covalently cross-linked advanced glycation end products (AGE) are among the major post-translational modifications to proteins as a result of non-enzymatic glycation. The formation of AGEs has been shown to have adverse effects on the properties of the collagenous tissue; they are even linked to a number of age related disorders. Little is known about the sites at which these AGEs form or why certain sites within the collagen are energetically more favourable than others. In this study we have used a proven fully atomistic molecular dynamics approach to identify six sites where the formation of the intra-molecular 3-deoxyglucosone-derived imidazolium cross-link (DOGDIC) is energetically favourable. We have also conducted a comparison of these positions with those of the more abundant glucosepane cross-link, to determine any site preference. We show that when we consider both lysine and arginine AGEs, they exhibit a prevalence to form within the gap region of the collagen fibril.
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    Combined injection of rAAV with mannitol enhances gene expression in the rat brain
    (Cell Press, 6/09/2000) Mastakov M; Baer K; Xu R; Fitzsimons H; During M
    Recombinant adeno-associated viruses (rAAV) are highly efficient vectors for gene transfer into the central nervous system (CNS). However, a major hurdle for gene delivery to the mammalian brain is to achieve high-level transduction in target cells beyond the immediate injection site. Therefore, in addition to improvements in expression cassettes and viral titers, optimal injection parameters need to be defined. Here, we show that previous studies of somatic cell gene transfer to the mammalian brain have used suboptimal injection parameters, with even the lowest reported perfusion rates still excessively fast. Moreover, we evaluated the effect of local administration of mannitol to further enhance transgene expression and vector spread. Ultraslow microperfusion of rAAV, i.e., <33 nl/min, resulted in significantly higher gene expression and less injury of surrounding tissue than the previously reported rates of 100 nl/min or faster. Co-infusion of mannitol facilitated gene transfer to neurons, increasing both the total number and the distribution of transduced cells by 200-300%. Gene transfer studies in the CNS using rAAV should use very slow infusion rates and combined injection with mannitol to maximize transduction efficiency and spread.
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    Soil C, N, and P stocks evaluation under major land uses on China’s Loess Plateau
    (Society for Range Management, 1/03/2017) Chen X; Hou F; Matthew C; He XZ
    Loess Plateau covers 640 000 km2 in the central northern China. Despite a semiarid environment, harsh winters, and hot summers, agriculture has been practiced in this region for > 5 000 yr, and the food production systems are among China's oldest. The environment is fragile because the loessial soils are prone to erosion. Sound scientific information is therefore required to underpin future land use planning in the region. To this end, total soil organic carbon (SOC), N, and P stocks were measured in Huanxian County of the wider Loess Plateau, representing five major land use categories. Sites were sampled three times over 3 yr. In all, almost 2 800 soil analyses were performed. A feature of these soils is low SOC content in the A horizon but comparatively small decline with soil depth. For example, SOC levels for the 0-20 cm and 70-100 cmsoil depths averaged 6.1 and 4.1Mg ha-1, respectively. Alfalfa and rangeland sites had 5.1 Mg ha-1 (10%) more total than cropland and 7.5 t ha-1 (16%) more total SOC to 100-cm soil depth than the two silvopastoral sites. For total soil N (0- to 100-cm soil depth) the averages of alfalfa and RL siteswere 20% and 28%, respectively, higher than the cropland and silvopastoral site group means, although soil C, N, and P levels are very low, relative to those of typical soils elsewhere. When these observations are scaled up to a regional level, it can be calculated that a 5% shift in land use from cropping or silvopastoral systems to alfalfa-based systems could increase soil C sequestration by as many as 20 million t CO2 per yr, although some caution is needed in making extrapolations, as the present data are from a single locality on the Loess Plateau.
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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.
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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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    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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    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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    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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    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.