Quantifying slope-channel coupling in an active gully and fan complex at Tarndale, Waipaoa catchment, New Zealand

Two RIEGL LMS‐Z420i scanner surveys (November 2007 and November 2008) of the Tarndale Gully complex and its associated fan were used to generate a digital elevation model (DEM) of difference in order to quantify gully‐fan‐channel connectivity. The Te Weraroa Stream, into which the first order Tarndale system feeds, is buffered from sediment generated by the gully complex by a fan. Sediment yields and the role of the fan in buffering Te Weraroa Stream are inferred from the TLS of the entire complex. DEM analysis suggests that c.25% of material derived from the gully is buffered from the stream by being stored in the fan. This figure was applied to fan behaviour since December 2004, mapped on nine successive occasions using detailed GPS surveys to get a longer‐term picture of sediment supply within the system and appraise a qualitative assessment of connectivity constructed on the basis of fan behaviour alone

Pseudohomozygous dysfibrinogenemia

Abstract Hypodysfibrinogenemia (HD) is a heterogeneous disorder in which plasma fibrinogen antigen and function are both reduced but discordant. This report addresses the key clinical question of whether genetic analysis enables clinically useful subclassification of patients with HD. We report a new case and identify a further eight previously documented cases that have the laboratory features of HD but biallelic inheritance of quantitative and qualitative fibrinogen gene variants. The cases displayed both bleeding and thrombosis and sometimes had undetectable fibrinogen activity. In all cases, the predicted effect of the coinherited variants is reduced levels of circulating fibrinogen that is all dysfunctional. We propose the term pseudohomozygous dysfibrinogenemia for this subtype of recessively inherited HD that is distinct from the more commonly recognized monoallelic HD caused by a single fibrinogen gene variant

Nuclear hyaluronidase 2 drives alternative splicing of CD44 pre-mRNA to determine profibrotic or antifibrotic cell phenotype

The cell surface protein CD44 is involved in diverse physiological processes, and its aberrant function is linked to various pathologies such as cancer, immune dysregulation, and fibrosis. The diversity of CD44 biological activity is partly conferred by the generation of distinct CD44 isoforms through alternative splicing. We identified an unexpected function for the ubiquitous hyaluronan-degrading enzyme, hyaluronidase 2 (HYAL2), as a regulator of CD44 splicing. Standard CD44 is associated with fibrotic disease, and its production is promoted through serine-arginine–rich (SR) protein–mediated exon exclusion. HYAL2 nuclear translocation was stimulated by bone morphogenetic protein 7, which inhibits the myofibroblast phenotype. Nuclear HYAL2 displaced SR proteins from the spliceosome, thus enabling HYAL2, spliceosome components (U1 and U2 small nuclear ribonucleoproteins), and CD44 pre-mRNA to form a complex. This prevented double-exon splicing and facilitated the inclusion of CD44 exons 11 and 12, which promoted the accumulation of the antifibrotic CD44 isoform CD44v7/8 at the cell surface. These data demonstrate previously undescribed mechanisms regulating CD44 alternative splicing events that are relevant to the regulation of cellular phenotypes in progressive fibrosis

Lack of change in CA1 dendritic spine density or clustering in rats following training on a radial-arm maze task [version 2; peer review: 2 approved]

Background: Neuronal plasticity is thought to underlie learning and memory formation. The density of dendritic spines in the CA1 region of the hippocampus has been repeatedly linked to mnemonic processes. Both the number and spatial location of the spines, in terms of proximity to nearest neighbour, have been implicated in memory formation. To examine how spatial training impacts synaptic structure in the hippocampus, Lister-Hooded rats were trained on a hippocampal-dependent spatial task in the radial-arm maze. Methods: One group of rats were trained on a hippocampal-dependent spatial task in the radial arm maze. Two further control groups were included: a yoked group which received the same sensorimotor stimulation in the radial-maze but without a memory load, and home-cage controls. At the end of behavioural training, the brains underwent Golgi staining. Spines on CA1 pyramidal neuron dendrites were imaged and quantitatively assessed to provide measures of density and distance from nearest neighbour. Results: There was no difference across behavioural groups either in terms of spine density or in the clustering of dendritic spines. Conclusions: Spatial learning is not always accompanied by changes in either the density or clustering of dendritic spines on the basal arbour of CA1 pyramidal neurons when assessed using Golgi imaging

Hyaluronidase-2 regulates RhoA signalling, myofibroblast contractility and other key pro-fibrotic myofibroblast functions

Hyaluronidase-2 (HYAL2) is a weak, acid-active hyaluronan-degrading enzyme that is broadly expressed in somatic tissues. Aberrant HYAL2 expression is implicated in diverse pathology. However, a significant proportion of HYAL2 is enzymatically inactive, thus the mechanisms through which HYAL2 dysregulation influences pathobiology is unclear. Recently, non-enzymatic HYAL2 functions have been described and our group has shown that nuclear HYAL2 can influence mRNA splicing to prevent myofibroblast differentiation. Myofibroblasts drive fibrosis, thereby promoting progressive tissue damage and leading to multimorbidity. This study identifies a novel HYAL2 cytoplasmic function in myofibroblasts that is unrelated to its enzymatic activity. In fibroblasts and myofibroblasts HYAL2 interacts with the small GTPase signaling molecule, RhoA. Transforming Growth Factor (TGF)-β1-driven fibroblast-to-myofibroblast differentiation promotes HYAL2 cytoplasmic re-localization to bind to the actin cytoskeleton. Cytoskeletal-bound HYAL2 functions as a key regulator of downstream RhoA signaling and influences pro-fibrotic myofibroblast functions including myosin light-chain kinase (MLCK) mediated myofibroblast contractility, myofibroblast migration, myofibroblast collagen/fibronectin deposition, as well as connective tissue growth factor (CTGF/CCN2) and matrix metalloproteinase-2 (MMP2) expression. These data demonstrate that in certain biological contexts the non-enzymatic effects of HYAL2 are critical in orchestrating RhoA signaling and downstream pathways that are important for full pro-fibrotic myofibroblast functionality. In conjunction with previous data demonstrating the influence of HYAL2 on RNA splicing, these findings begin to explain the broad biological effects of HYAL2

Coupling undetected sensing modes by quantum erasure

The effect known as ``induced coherence without induced emission'' has spawned a field dedicated to imaging with undetected photons (IUP), where photons from two distinct photon-pair sources interfere if their outputs are made indistinguishable. The indistinguishability is commonly achieved in two setups. Induced coherence IUP (IC-IUP) has only the idler photons from the first source passing through the second, whilst nonlinear interferometry (NI-IUP) has both signal and idler photons from the first source passing through the second and can be simpler to implement. In both cases, changes in the idler path between sources can be detected by measuring the interference fringes in the signal path in a way that allows image information to be moved between different wavelengths. Here we model and implement a novel setup that uses a polarization state quantum eraser approach to move continuously between IC-IUP and NI-IUP operation. We find excellent agreement between experiment and theory in the low-gain or quantum regime. The system also provides a new route for optimizing IUP interference by using controllable quantum erasure to balance the interferometer

Carnegie Supernova Project-II: Extending the Near-Infrared Hubble Diagram for Type Ia Supernovae to z∼0.1z\sim0.1

The Carnegie Supernova Project-II (CSP-II) was an NSF-funded, four-year program to obtain optical and near-infrared observations of a "Cosmology" sample of $\sim100$ Type Ia supernovae located in the smooth Hubble flow ($0.03 \lesssim z \lesssim 0.10$). Light curves were also obtained of a "Physics" sample composed of 90 nearby Type Ia supernovae at $z \leq 0.04$ selected for near-infrared spectroscopic time-series observations. The primary emphasis of the CSP-II is to use the combination of optical and near-infrared photometry to achieve a distance precision of better than 5%. In this paper, details of the supernova sample, the observational strategy, and the characteristics of the photometric data are provided. In a companion paper, the near-infrared spectroscopy component of the project is presented.Comment: 43 pages, 10 figures, accepted for publication in PAS

iPrevent®: a tailored, web-based, decision support tool for breast cancer risk assessment and management

We aimed to develop a user-centered, web-based, decision support tool for breast cancer risk assessment and personalized risk management. Using a novel model choice algorithm, iPrevent® selects one of two validated breast cancer risk estimation models (IBIS or BOADICEA), based on risk factor data entered by the user. Resulting risk estimates are presented in simple language and graphic formats for easy comprehension. iPrevent® then presents risk-adapted, evidence-based, guideline-endorsed management options. Development was an iterative process with regular feedback from multidisciplinary experts and consumers. To verify iPrevent®, risk factor data for 127 cases derived from the Australian Breast Cancer Family Study were entered into iPrevent®, IBIS (v7.02), and BOADICEA (v3.0). Consistency of the model chosen by iPrevent® (i.e., IBIS or BOADICEA) with the programmed iPrevent® model choice algorithm was assessed. Estimated breast cancer risks from iPrevent® were compared with those attained directly from the chosen risk assessment model (IBIS or BOADICEA). Risk management interventions displayed by iPrevent® were assessed for appropriateness. Risk estimation model choice was 100% consistent with the programmed iPrevent®logic. Discrepant 10-year and residual lifetime risk estimates of >1% were found for 1 and 4 cases, respectively, none was clinically significant (maximal variation 1.4%). Risk management interventions suggested by iPrevent® were 100% appropriate. iPrevent® successfully integrates the IBIS and BOADICEA risk assessment models into a decision support tool that provides evidence-based, risk-adapted risk management advice. This may help to facilitate precision breast cancer prevention discussions between women and their healthcare providers

The effects of time-restricted eating and weight loss on bone metabolism and health: a 6-month randomized controlled trial.

OBJECTIVE This study explored the impact of time-restricted eating (TRE) versus standard dietary advice (SDA) on bone health. METHODS Adults with ≥1 component of metabolic syndrome were randomized to TRE (ad libitum eating within 12 hours) or SDA (food pyramid brochure). Bone turnover markers and bone mineral content/density by dual energy x-ray absorptiometry were assessed at baseline and 6-month follow-up. Statistical analyses were performed in the total population and by weight loss response. RESULTS In the total population (n = 42, 76% women, median age 47 years [IQR: 31-52]), there were no between-group differences (TRE vs. SDA) in any bone parameter. Among weight loss responders (≥0.6 kg weight loss), the bone resorption marker β-carboxyterminal telopeptide of type I collagen tended to decrease after TRE but increase after SDA (between-group differences p = 0.041), whereas changes in the bone formation marker procollagen type I N-propeptide did not differ between groups. Total body bone mineral content decreased after SDA (p = 0.028) but remained unchanged after TRE (p = 0.31) in weight loss responders (between-group differences p = 0.028). Among nonresponders (<0.6 kg weight loss), there were no between-group differences in bone outcomes. CONCLUSIONS TRE had no detrimental impact on bone health, whereas, when weight loss occurred, it was associated with some bone-sparing effects compared with SDA