A hydrogeomorphic assessment of twenty-first century floods in the UK

The occurrence of devastating floods in the British uplands during the first two decades of the twenty-first century poses two key questions: (1) are recent events unprecedented in terms of their frequency and magnitude; and (2) is climate and/or land-use change driving the apparent upturn in flooding? Conventional methods of analysing instrumental flow records cannot answer these questions because upland catchments are usually ungauged, and where records do exist they rarely provide more than 30-40 years of data. In this paper we analyse all lichen-dated upland flood records in the United Kingdom (UK) to establish the longer-term context and causes of recent severe flooding. Our new analysis of torrential sedimentary deposits shows that twenty-first century floods are not unprecedented in terms of both their frequency (they were more frequent before 1960) and magnitude (the biggest events occurred during the seventeenth-nineteenth centuries). However, in some areas recent floods have either equalled or exceeded the largest historical events. The majority of recent floods have been triggered by torrential summer downpours related to a marked negative phase of the summer North Atlantic Oscillation (NAO) between 2007 and 2012. It is of concern that historical data suggests there is far more capacity in the North Atlantic climate system to produce wetter and more prolonged flood-rich periods than hitherto experienced in the twenty-first century. Looking forwards, an increased likelihood of weather extremes due to climate change means that geomorphological based flood series extensions must be placed at the centre of flood risk assessment in the UK uplands and in similar areas worldwide. © 2016 John Wiley & Sons, Ltd

Geomorphological records of extreme floods and their relationship to decadal-scale climate change

Extreme rainfall and flood events in steep upland catchments leave geomorphological traces of their occurrence in the form of boulder berms, debris cones, and alluvial fans. Constraining the age of these features is critical to understanding (i) landscape evolution in response to past, present, and future climate changes; and (ii) the magnitude–frequency of extreme, ungauged floods in small upland catchments. This research focuses on the Cambrian Mountains of Wales, UK, where lichenometric dating of geomorphological features and palaeohydrological reconstructions is combined with climatological data and documentary flood records. Our new data from Wales highlight a distinct flood-rich period between 1900 and 1960, similar to many other UK lichen-dated records. However, this study sheds new light on the underlying climatic controls on upland flooding in small catchments. Although floods can occur in any season, their timing is best explained by the Summer North Atlantic Oscillation (SNAO) and shifts between negative (wetter than average conditions with regular cyclonic flow and flooding) and positive phases (drier than average conditions with less frequent cyclonic flow and flooding), which vary from individual summers to decadal and multidecadal periods. Recent wet summer weath-er, flooding, and boulder-berm deposition in the UK (2007–2012) are related to a pronounced negative phase shift of the SNAO. There is also increasing evidence that recent summer weather extremes in the mid-latitudes may be related to Arctic amplification and rapid sea ice loss. If this is the case, continuing and future climate change is likely to mean that (i) unusual weather patterns become more frequent; and (ii) upland UK catchments will experience heightened flood risk and significant geomorphological changes

A review of the status and range expansion of common carp (Cyprinus carpio L.) in Ireland

Although common carp are known to have been present in Ireland since the early 17th century, historically the species’ distribution was extremely localised. Owing to the popularity of carp as a sport fish in more recent times, it was suspected that the species range had expanded. Distribution maps were constructed from records in the published literature and consultations with both angling and governmental bodies, facilitating a review of the temporal changes in the range and distribution of carp from 1950 to the present day. There has been a significant increase in the range of distribution of carp, by order of 302% in the national 10 km grid-square network. The characteristic pattern of extinction and colonisation of carp in Irish water bodies clearly indicates that the species has not spread by natural dispersal but rather by human-mediated transfers, which are the mechanism for the species’ range expansion. While carp has been able to establish self-sustaining populations in Ireland, these remain restricted to smaller, often land-locked, water bodies. Future climatic warming and the increasing popularity of carp as an angling quarry may facilitate further range expansion, both naturally and human mediated

Incorporating sedimentological data in UK flood frequency estimation

This study presents a new analytical framework for combining historical flood data derived from sedimentological records with instrumental river flow data to increase the reliability of flood risk assessments. Historical flood records were established for two catchments through re-analysis of sedimentological records; the Nant Cwm-du, a small, steep upland catchment in the Cambrian Mountains of Wales, and a piedmont reach of the River Severn in mid Wales. The proposed framework is based on maximum likelihood and least-square estimation methods in combination with a Generalised Logistic distribution; this enables the sedimentological data to be combined effectively with existing instrumental river flow data. The results from this study are compared to results obtained using existing industry standard methods based solely on instrumental data. The comparison shows that inclusion of sedimentological data can have an important impact on flood risk estimates, and that the methods are sensitive to assumptions made in the conversion of the sedimentological records into flood flow data. As current industry standard methods for flood risk analysis are known to be highly uncertain, the ability to include additional evidence of past flood events derived from sedimentological records as demonstrated in this study can have a significant impact on flood risk assessments

Biomarker-driven phenotyping in Parkinson's disease: A translational missing link in disease-modifying clinical trials

Past clinical trials of putative neuroprotective therapies have targeted PD as a single pathogenic disease entity. From an Oslerian clinicopathological perspective, the wide complexity of PD converges into Lewy bodies and justifies a reductionist approach to PD: A single-mechanism therapy can affect most of those sharing the classic pathological hallmark. From a systems-biology perspective, PD is a group of disorders that, while related by sharing the feature of nigral dopamine-neuron degeneration, exhibit unique genetic, biological, and molecular abnormalities, which probably respond differentially to a given therapeutic approach, particularly for strategies aimed at neuroprotection. Under this model, only biomarker-defined, homogenous subtypes of PD are likely to respond optimally to therapies proven to affect the biological processes within each subtype. Therefore, we suggest that precision medicine applied to PD requires a reevaluation of the biomarker-discovery effort. This effort is currently centered on correlating biological measures to clinical features of PD and on identifying factors that predict whether various prodromal states will convert into the classical movement disorder. We suggest, instead, that subtyping of PD requires the reverse view, where abnormal biological signals (i.e., biomarkers), rather than clinical definitions, are used to define disease phenotypes. Successful development of disease-modifying strategies will depend on how relevant the specific biological processes addressed by an intervention are to the pathogenetic mechanisms in the subgroup of targeted patients. This precision-medicine approach will likely yield smaller, but well-defined, subsets of PD amenable to successful neuroprotection.Fil: Espay, Alberto J.. University of Cincinnati; Estados UnidosFil: Schwarzschild, Michael A.. Massachusetts General Hospital; Estados UnidosFil: Tanner, Caroline M.. University of California; Estados UnidosFil: Fernandez, Hubert H.. Cleveland Clinic; Estados UnidosFil: Simon, David K.. Harvard Medical School; Estados UnidosFil: Leverenz, James B.. Cleveland Clinic; Estados UnidosFil: Merola, Aristide. University of Cincinnati; Estados UnidosFil: Chen Plotkin, Alice. University of Pennsylvania; Estados UnidosFil: Brundin, Patrik. Van Andel Research Institute. Center for Neurodegenerative Science; Estados UnidosFil: Kauffman, Marcelo Andres. Universidad Austral; Argentina. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Ramos Mejía"; ArgentinaFil: Erro, Roberto. Universita di Verona; Italia. University College London; Reino UnidoFil: Kieburtz, Karl. University of Rochester Medical Center; Estados UnidosFil: Woo, Daniel. University of Cincinnati; Estados UnidosFil: Macklin, Eric A.. Massachusetts General Hospital; Estados UnidosFil: Standaert, David G.. University of Alabama at Birmingahm; Estados UnidosFil: Lang, Anthony E.. University of Toronto; Canad

Effect Of Gender On T-Cell Proliferative Responses To Myelin Proteolipid Protein Antigens In Patients With Multiple Sclerosis And Controls

Multiple sclerosis (MS) is an inflammatory demyelinating disorder of the central nervous system. Gender influences both susceptibility to MS, with the disease being more common in women, and the clinical course of disease, with an increased proportion of males developing the primary progressive form of the disease. The basis for these differences may include genetic and immunological factors, and the immunological differences between men and women may be influenced by the effects of the sex hormones. Over several years we have collected blood from MS patients and controls, and measured T-cell responses to myelin proteolipid protein (PLP) and myelin basic protein (MBP) and have shown increased responses to PLP in MS patients compared to healthy controls and patients with other neurological diseases. In the present study we analyzed data from over 500 individuals, to determine whether there are differences between males and females in their responses to PLP and MBP. We found that there was higher frequency of increased T-cell reactivity to immunodominant PLP peptides in women than in men, particularly in non-MS individuals. We suggest that this may be relevant to the higher prevalence of MS in women

Orthorhombic distortion on Li intercalation in anatase

Published versio

Predicting drug pharmacokinetics and effect in vascularized tumors using computer simulation

In this paper, we investigate the pharmacokinetics and effect of doxorubicin and cisplatin in vascularized tumors through two-dimensional simulations. We take into account especially vascular and morphological heterogeneity as well as cellular and lesion-level pharmacokinetic determinants like P-glycoprotein (Pgp) efflux and cell density. To do this we construct a multi-compartment PKPD model calibrated from published experimental data and simulate 2-h bolus administrations followed by 18-h drug washout. Our results show that lesion-scale drug and nutrient distribution may significantly impact therapeutic efficacy and should be considered as carefully as genetic determinants modulating, for example, the production of multidrug-resistance protein or topoisomerase II. We visualize and rigorously quantify distributions of nutrient, drug, and resulting cell inhibition. A main result is the existence of significant heterogeneity in all three, yielding poor inhibition in a large fraction of the lesion, and commensurately increased serum drug concentration necessary for an average 50% inhibition throughout the lesion (the IC50 concentration). For doxorubicin the effect of hypoxia and hypoglycemia (“nutrient effect”) is isolated and shown to further increase cell inhibition heterogeneity and double the IC50, both undesirable. We also show how the therapeutic effectiveness of doxorubicin penetration therapy depends upon other determinants affecting drug distribution, such as cellular efflux and density, offering some insight into the conditions under which otherwise promising therapies may fail and, more importantly, when they will succeed. Cisplatin is used as a contrast to doxorubicin since both published experimental data and our simulations indicate its lesion distribution is more uniform than that of doxorubicin. Because of this some of the complexity in predicting its therapeutic efficacy is mitigated. Using this advantage, we show results suggesting that in vitro monolayer assays using this drug may more accurately predict in vivo performance than for drugs like doxorubicin. The nonlinear interaction among various determinants representing cell and lesion phenotype as well as therapeutic strategies is a unifying theme of our results. Throughout it can be appreciated that macroscopic environmental conditions, notably drug and nutrient distributions, give rise to considerable variation in lesion response, hence clinical resistance. Moreover, the synergy or antagonism of combined therapeutic strategies depends heavily upon this environment

Modeling Evolutionary Dynamics of Epigenetic Mutations in Hierarchically Organized Tumors

The cancer stem cell (CSC) concept is a highly debated topic in cancer research. While experimental evidence in favor of the cancer stem cell theory is apparently abundant, the results are often criticized as being difficult to interpret. An important reason for this is that most experimental data that support this model rely on transplantation studies. In this study we use a novel cellular Potts model to elucidate the dynamics of established malignancies that are driven by a small subset of CSCs. Our results demonstrate that epigenetic mutations that occur during mitosis display highly altered dynamics in CSC-driven malignancies compared to a classical, non-hierarchical model of growth. In particular, the heterogeneity observed in CSC-driven tumors is considerably higher. We speculate that this feature could be used in combination with epigenetic (methylation) sequencing studies of human malignancies to prove or refute the CSC hypothesis in established tumors without the need for transplantation. Moreover our tumor growth simulations indicate that CSC-driven tumors display evolutionary features that can be considered beneficial during tumor progression. Besides an increased heterogeneity they also exhibit properties that allow the escape of clones from local fitness peaks. This leads to more aggressive phenotypes in the long run and makes the neoplasm more adaptable to stringent selective forces such as cancer treatment. Indeed when therapy is applied the clone landscape of the regrown tumor is more aggressive with respect to the primary tumor, whereas the classical model demonstrated similar patterns before and after therapy. Understanding these often counter-intuitive fundamental properties of (non-)hierarchically organized malignancies is a crucial step in validating the CSC concept as well as providing insight into the therapeutical consequences of this model