Biofilm-induced bioclogging produces sharp interfaces in hyporheic flow, redox conditions, and microbial community structure

Riverbed sediments host important biogeochemical processes that play a key role in nutrient dynamics. Sedimentary nutrient transformations are mediated by bacteria in the form of attached biofilms. The influence of microbial metabolic activity on the hydrochemical conditions within the hyporheic zone is poorly understood. We present a hydrobiogeochemical model to assess how the growth of heterotrophic and autotrophic biomass affects the transport and transformation of dissolved nitrogen compounds in bedform-induced hyporheic zones. Coupling between hyporheic exchange, nitrogen metabolism, and biomass growth leads to an equilibrium between permeability reduction and microbial metabolism that yields shallow hyporheic flows in a region with low permeability and high rates of microbial metabolism near the stream-sediment interface. The results show that the bioclogging caused by microbial growth can constrain rates and patterns of hyporheic fluxes and microbial transformation rate in many streams

A necessary condition for dispersal driven growth of populations with discrete patch dynamics

We revisit the question of when can dispersal-induced coupling between discrete sink populations cause overall population growth? Such a phenomenon is called dispersal driven growth and provides a simple explanation of how dispersal can allow populations to persist across discrete, spatially heterogeneous, environments even when individual patches are adverse or unfavourable. For two classes of mathematical models, one linear and one non-linear, we provide necessary conditions for dispersal driven growth in terms of the non-existence of a common linear Lyapunov function, which we describe. Our approach draws heavily upon the underlying positive dynamical systems structure. Our results apply to both discrete- and continuous-time models. The theory is illustrated with examples and both biological and mathematical conclusions are drawn

MDM2 antagonists boost antitumor effect of androgen withdrawal: implications for therapy of prostate cancer

<p>Abstract</p> <p>Background</p> <p>Hormone therapy is the standard of care for newly diagnosed or recurrent prostate cancers. It uses anti-androgen agents, castration, or both to eliminate cancer promoting effect of testicular androgen. The p53 tumor suppressor controls a major pathway that can block cell proliferation or induce apoptosis in response to diverse forms of oncogenic stress. Activation of the p53 pathway in cancer cells expressing wild-type p53 has been proposed as a novel therapeutic strategy and recently developed MDM2 antagonists, the nutlins, have validated this in preclinical models of cancer. The crosstalk between p53 and androgen receptor (AR) signaling suggest that p53 activation could augment antitumor outcome of androgen ablation in prostate cancer. Here, we test this hypothesis <it>in vitro </it>and <it>in vivo </it>using the MDM2 antagonist, nutlin-3 and the p53 wild-type prostate cancer cell line, LNCaP.</p> <p>Results</p> <p>Using charcoal-stripped serum as a cellular model of androgen deprivation, we show an increased apoptotic effect of p53 activation by nutlin-3a in the androgen-dependent LNCaP cells and to a lesser extent in androgen-independent but responsive 22Rv1 cell line. This effect is due, at least in part, to an enhanced downregulation of AR expression by activated p53. In vivo, androgen deprivation followed by two weeks of nutlin administration in LNCaP-bearing nude mice led to a greater tumor regression and dramatically increased survival.</p> <p>Conclusions</p> <p>Since majority of prostate tumors express wild-type p53, its activation by MDM2 antagonists in combination with androgen depletion may offer an efficacious new approach to prostate cancer therapy.</p

The recognition of collagen and triple-helical toolkit peptides by MMP-13: sequence specificity for binding and cleavage.

Remodeling of collagen by matrix metalloproteinases (MMPs) is crucial to tissue homeostasis and repair. MMP-13 is a collagenase with a substrate preference for collagen II over collagens I and III. It recognizes a specific, well-known site in the tropocollagen molecule where its binding locally perturbs the triple helix, allowing the catalytic domain of the active enzyme to cleave the collagen α chains sequentially, at Gly(775)-Leu(776) in collagen II. However, the specific residues upon which collagen recognition depends within and surrounding this locus have not been systematically mapped. Using our triple-helical peptide Collagen Toolkit libraries in solid-phase binding assays, we found that MMP-13 shows little affinity for Collagen Toolkit III, but binds selectively to two triple-helical peptides of Toolkit II. We have identified the residues required for the adhesion of both proMMP-13 and MMP-13 to one of these, Toolkit peptide II-44, which contains the canonical collagenase cleavage site. MMP-13 was unable to bind to a linear peptide of the same sequence as II-44. We also discovered a second binding site near the N terminus of collagen II (starting at helix residue 127) in Toolkit peptide II-8. The pattern of binding of the free hemopexin domain of MMP-13 was similar to that of the full-length enzyme, but the free catalytic subunit bound none of our peptides. The susceptibility of Toolkit peptides to proteolysis in solution was independent of the very specific recognition of immobilized peptides by MMP-13; the enzyme proved able to cleave a range of dissolved collagen peptides.This work was supported by a British Heart Foundation programme grant, RG/009/003/27122, and peptide synthesis, by grants from Medical Research Council and Wellcome Trust.This is the author accepted manuscript. The final version can be found on the publisher's website at: http://www.jbc.org/content/early/2014/07/09/jbc.M114.58344

Voretigene Neparvovec for Treating Inherited Retinal Dystrophies Caused by RPE65 Gene Mutations: An Evidence Review Group Perspective of a NICE Highly Specialised Technology Appraisal

The UK National Institute for Health and Care Excellence (NICE) considered evidence for voretigene neparvovec (VN; Luxturna®) for the treatment of RPE65-mediated inherited retinal dystrophies (IRD) within its highly specialised technology programme. This paper summarises the evidence provided by the company; the appraisal of the evidence by the Peninsula Technology Appraisal Group, who were commissioned to act as the independent evidence review group (ERG); and the development of the NICE guidance by the appraisal committee. The evidence presented by the company highlighted the significant lifelong burden of IRD for patients and carers. Evidence to support the effectiveness of VN was lacking, but the available evidence showed a modest, sustained improvement across a variety of vision-related outcomes. While patients would remain visually impaired, the committee considered that VN would prevent further deterioration in vision. The modelling approach used by the company had a number of limitations and relied heavily upon a large volume of clinical expert input to produce cost-effectiveness estimates with large uncertainty around long-term effectiveness. The ERG’s main concerns revolved around these long-term outcomes and the plausibility of utility values. The NICE committee were convinced that the clinical benefits of VN were important and an appropriate use of national health service resources within a specialised service. The committee concluded that a high unmet need existed in patients with RPE65-mediated IRD and that VN represents a step change in the management of this condition

Planum temporale asymmetry in people who stutter

Previous studies have reported that the planum temporale - a language-related structure that normally shows a leftward asymmetry - had reduced asymmetry in people who stutter (PWS) and reversed asymmetry in those with severe stuttering. These findings are consistent with the theory that altered language lateralization may be a cause or consequence of stuttering. Here, we re-examined these findings in a larger sample of PWS. We evaluated planum temporale asymmetry in structural MRI scans obtained from 67 PWS and 63 age-matched controls using: 1) manual measurements of the surface area; 2) voxel-based morphometry to automatically calculate grey matter density. We examined the influences of gender, age, and stuttering severity on planum temporale asymmetry. The size of the planum temporale and its asymmetry were not different in PWS compared with Controls using either the manual or the automated method. Both groups showed a significant leftwards asymmetry on average (about one-third of PWS and Controls showed rightward asymmetry). Importantly, and contrary to previous reports, the degree of asymmetry was not related to stuttering severity. In the manual measurements, women who stutter had a tendency towards rightwards asymmetry but men who stutter showed the same degree of leftwards asymmetry as male Controls. In the automated measurements, Controls showed a significant increase in leftwards asymmetry with age but this relationship was not observed in PWS. We conclude that reduced planum temporale asymmetry is not a prominent feature of the brain in PWS and that the asymmetry is unrelated to stuttering severity. [Abstract copyright: Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

The Autobot-WQ: A portable, low-cost autosampler to provide new insight into urban spatio-temporal water quality dynamics

Urbanization and the increase in urban land cover are growing concerns associated with numerous negative impacts on surface water quality. Currently, many emerging contaminants are difficult to measure with no field deployable sensors currently available. Hence, discrete grab samples are required for subsequent laboratory analysis. To capture the spatiotemporal variability in pollution pulses, autosamplers can be used, but commercial offerings are both expensive and have a large footprint. This can be problematic in urban environments where there is a high density of point source inputs and risk of vandalism or theft. Here, we present a small and robust low-cost autosampler that is ideally suited for deployment in urban environments. The design is based on “off the shelf” open-source hardware components and software and requires no prior engineering, electronics, or computer programming experience to build. The autosampler uses a small peristaltic pump to enable collection of 14 small volume samples (50 mL) and is housed in a small footprint camera case. To illustrate the technology, we present two use cases for rapid sampling of stormwater pulses of: 1) an urban river channel and 2) green roof runoff. When compared with a commercial autosampler, our device showed comparable results and enabled us to capture temporal dynamics in key water quality parameters (e.g., dissolved organic matter) following rain events in an urban stream. Water quality differences associated with differing green roof design/maintenance regimes (managed and unmanaged vegetation) were captured using the autosampler, highlighting how unmanaged vegetation has a greater potential for mitigating the rapid runoff and peaked pollutant inputs associated with impervious surfaces. These two case studies show that our portable autosampler provides capacity to improve understanding of the impact of urban design and infrastructure on water quality and can lead to the development of more effective mitigation solutions. Finally, we discuss opportunities for further technical refinement of our autosampler and applications to improve environmental monitoring. We propose a holistic monitoring approach to address some of the outstanding challenges in urban areas and enable monitoring to shift from discrete point sources towards characterization of catchment or network scale dynamics

Organizational Principles of Hyporheic Exchange Flow and Biogeochemical Cycling in River Networks Across Scales

Hyporheic zones increase freshwater ecosystem resilience to hydrological extremes and global environmental change. However, current conceptualizations of hyporheic exchange, residence time distributions, and the associated biogeochemical cycling in streambed sediments do not always accurately explain the hydrological and biogeochemical complexity observed in streams and rivers. Specifically, existing conceptual models insufficiently represent the coupled transport and reactivity along groundwater and surface water flow paths, the role of autochthonous organic matter in streambed biogeochemical functioning, and the feedbacks between surface-subsurface ecological processes, both within and across spatial and temporal scales. While simplified approaches to these issues are justifiable and necessary for transferability, the exclusion of important hyporheic processes from our conceptualizations can lead to erroneous conclusions and inadequate understanding and management of interconnected surface water and groundwater environments. This is particularly true at the landscape scale, where the organizational principles of spatio-temporal dynamics of hyporheic exchange flow (HEF) and biogeochemical processes remain largely uncharacterized. This article seeks to identify the most important drivers and controls of HEF and biogeochemical cycling based on a comprehensive synthesis of findings from a wide range of river systems. We use these observations to test current paradigms and conceptual models, discussing the interactions of local-to-regional hydrological, geomorphological, and ecological controls of hyporheic zone functioning. This improved conceptualization of the landscape organizational principles of drivers of HEF and biogeochemical processes from reach to catchment scales will inform future river research directions and watershed management strategies

Inferring transient dynamics of human populations from matrix non-normality

This is the final version of the article. Available from Springer Verlag via the DOI in this record.In our increasingly unstable and unpredictable world, population dynamics rarely settle uniformly to long-term behaviour. However, projecting period-by-period through the preceding fluctuations is more data-intensive and analytically involved than evaluating at equilibrium. To efficiently model populations and best inform policy, we require pragmatic suggestions as to when it is necessary to incorporate short-term transient dynamics and their effect on eventual projected population size. To estimate this need for matrix population modelling, we adopt a linear algebraic quantity known as non-normality. Matrix non-normality is distinct from normality in the Gaussian sense, and indicates the amplificatory potential of the population projection matrix given a particular population vector. In this paper, we compare and contrast three well-regarded metrics of non-normality, which were calculated for over 1000 age-structured human population projection matrices from 42 European countries in the period 1960 to 2014. Non-normality increased over time, mirroring the indices of transient dynamics that peaked around the millennium. By standardising the matrices to focus on transient dynamics and not changes in the asymptotic growth rate, we show that the damping ratio is an uninformative predictor of whether a population is prone to transient booms or busts in its size. These analyses suggest that population ecology approaches to inferring transient dynamics have too often relied on suboptimal analytical tools focussed on an initial population vector rather than the capacity of the life cycle to amplify or dampen transient fluctuations. Finally, we introduce the engineering technique of pseudospectra analysis to population ecology, which, like matrix non-normality, provides a more complete description of the transient fluctuations than the damping ratio. Pseudospectra analysis could further support non-normality assessment to enable a greater understanding of when we might expect transient phases to impact eventual population dynamics.This work was funded by Wellcome Trust New Investigator 103780 to TE, who is also funded by NERC Fellowship NE/J018163/1. JB gratefully acknowledges the ESRC Centre for Population Change ES/K007394/1