Craig Goch Report No. 10 The effect of density on mortality in juvenile Atlantic salmon (Salmo salar L.)

Le Cren (1973) suggested that the most likely population-regulating process in salmonid populations is density-dependent territorial behaviour. Thus, in trout (Salmo trutta L.) populations aggressive territorial behaviour was manifested in density-dependent mortality and the size of the adult stock was largely dependent on the area of suitable rearing ground for the fry (Le Cren, 1973). Ricker (1954) also concluded that in most fish populations compensatory mortality in the juvenile stages, rather than in the mature stock, was of greatest importance as a regulator of population size. The nature of such regulating mechanisms in juvenile populations is, therefore, of fundamental importance in the understanding of the dynamics of fish populations and the implementation of management policies. This paper considers mortality rates of young Atlantic salmon (Salmo salar L.) in the upper catchment of the R. Wye over a two year period. The work forms part of a broader study of fish populations in the R. Wye

Craig Goch Report No. 9 Mass mortalities of adult salmon (Salmo salar L.) in the R. Wye, 1976

The physical, biological and chemical conditions leading to a mass mortality of adult salmon (Salmo salar L.) in the lower reaches of the R. Wye are described. As a result of sunny and low flow conditions during late June, 1976, water temperatures increased to a maximum of 27.6oC and accelerated the decay of substantial plant stands, the growth of which had been enhanced by the prevailing conditions: this resulted in severe de-oxygenation of the water. It is concluded that the low oxygen concentration in the water at this time was the principal factor in causing mass mortalities of fish and was probably accentuated by high water temperatures

Assessing cognitive dysfunction in Parkinson's disease: An online tool to detect visuo-perceptual deficits.

BackgroundPeople with Parkinson's disease (PD) who develop visuo-perceptual deficits are at higher risk of dementia, but we lack tests that detect subtle visuo-perceptual deficits and can be performed by untrained personnel. Hallucinations are associated with cognitive impairment and typically involve perception of complex objects. Changes in object perception may therefore be a sensitive marker of visuo-perceptual deficits in PD.ObjectiveWe developed an online platform to test visuo-perceptual function. We hypothesised that (1) visuo-perceptual deficits in PD could be detected using online tests, (2) object perception would be preferentially affected, and (3) these deficits would be caused by changes in perception rather than response bias.MethodsWe assessed 91 people with PD and 275 controls. Performance was compared using classical frequentist statistics. We then fitted a hierarchical Bayesian signal detection theory model to a subset of tasks.ResultsPeople with PD were worse than controls at object recognition, showing no deficits in other visuo-perceptual tests. Specifically, they were worse at identifying skewed images (P < .0001); at detecting hidden objects (P = .0039); at identifying objects in peripheral vision (P < .0001); and at detecting biological motion (P = .0065). In contrast, people with PD were not worse at mental rotation or subjective size perception. Using signal detection modelling, we found this effect was driven by change in perceptual sensitivity rather than response bias.ConclusionsOnline tests can detect visuo-perceptual deficits in people with PD, with object recognition particularly affected. Ultimately, visuo-perceptual tests may be developed to identify at-risk patients for clinical trials to slow PD dementia. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society

Covalent Proximity Scanning of a Distal Cysteine to Target PI3Kα

Covalent protein kinase inhibitors exploit currently noncatalytic cysteines in the adenosine 5′-triphosphate (ATP)-binding site via electrophiles directly appended to a reversible-inhibitor scaffold. Here, we delineate a path to target solvent-exposed cysteines at a distance >10 Å from an ATP-site-directed core module and produce potent covalent phosphoinositide 3-kinase α (PI3Kα) inhibitors. First, reactive warheads are used to reach out to Cys862 on PI3Kα, and second, enones are replaced with druglike warheads while linkers are optimized. The systematic investigation of intrinsic warhead reactivity (kchem), rate of covalent bond formation and proximity (kinactand reaction space volume Vr), and integration of structure data, kinetic and structural modeling, led to the guided identification of high-quality, covalent chemical probes. A novel stochastic approach provided direct access to the calculation of overall reaction rates as a function of kchem, kinact, Ki, and Vr, which was validated with compounds with varied linker lengths. X-ray crystallography, protein mass spectrometry (MS), and NanoBRET assays confirmed covalent bond formation of the acrylamide warhead and Cys862. In rat liver microsomes, compounds 19 and 22 outperformed the rapidly metabolized CNX-1351, the only known PI3Kα irreversible inhibitor. Washout experiments in cancer cell lines with mutated, constitutively activated PI3Kα showed a long-lasting inhibition of PI3Kα. In SKOV3 cells, compounds 19 and 22 revealed PI3Kβ-dependent signaling, which was sensitive to TGX221. Compounds 19 and 22 thus qualify as specific chemical probes to explore PI3Kα-selective signaling branches. The proposed approach is generally suited to develop covalent tools targeting distal, unexplored Cys residues in biologically active enzymes

Craig Goch Report No. 10 The effect of density on mortality in juvenile Atlantic salmon (Salmo salar L.)

Le Cren (1973) suggested that the most likely population-regulating process in salmonid populations is density-dependent territorial behaviour. Thus, in trout (Salmo trutta L.) populations aggressive territorial behaviour was manifested in density-dependent mortality and the size of the adult stock was largely dependent on the area of suitable rearing ground for the fry (Le Cren, 1973). Ricker (1954) also concluded that in most fish populations compensatory mortality in the juvenile stages, rather than in the mature stock, was of greatest importance as a regulator of population size. The nature of such regulating mechanisms in juvenile populations is, therefore, of fundamental importance in the understanding of the dynamics of fish populations and the implementation of management policies. This paper considers mortality rates of young Atlantic salmon (Salmo salar L.) in the upper catchment of the R. Wye over a two year period. The work forms part of a broader study of fish populations in the R. Wye

Craig Goch Report No. 9 Mass mortalities of adult salmon (Salmo salar L.) in the R. Wye, 1976

The physical, biological and chemical conditions leading to a mass mortality of adult salmon (Salmo salar L.) in the lower reaches of the R. Wye are described. As a result of sunny and low flow conditions during late June, 1976, water temperatures increased to a maximum of 27.6oC and accelerated the decay of substantial plant stands, the growth of which had been enhanced by the prevailing conditions: this resulted in severe de-oxygenation of the water. It is concluded that the low oxygen concentration in the water at this time was the principal factor in causing mass mortalities of fish and was probably accentuated by high water temperatures

Craig Goch Report No. 11 The behaviour and budgets of selected ions in the Wye Catchment

The river Wye, 250 km long and draining a predominantly rural catchment of 4183 km2, rises in mid-Wales (677m O.D.) and flows to the Severn Estuary (Fig 1). Samples for chemical analysis were obtained from sites 1 to 14 at two-week intervals over the period April 1975 to July 1976 and from site 15 at weekly intervals from 1973

Assessing cognitive dysfunction in Parkinson's disease: an online tool to detect visuo-perceptual deficits

Background: People with Parkinson's disease (PD) who develop visuo‐perceptual deficits are at higher risk of dementia, but we lack tests that detect subtle visuo‐perceptual deficits and can be performed by untrained personnel. Hallucinations are associated with cognitive impairment and typically involve perception of complex objects. Changes in object perception may therefore be a sensitive marker of visuo‐perceptual deficits in PD. Objective: We developed an online platform to test visuo‐perceptual function. We hypothesised that (1) visuo‐perceptual deficits in PD could be detected using online tests, (2) object perception would be preferentially affected, and (3) these deficits would be caused by changes in perception rather than response bias. Methods: We assessed 91 people with PD and 275 controls. Performance was compared using classical frequentist statistics. We then fitted a hierarchical Bayesian signal detection theory model to a subset of tasks. Results: People with PD were worse than controls at object recognition, showing no deficits in other visuo‐perceptual tests. Specifically, they were worse at identifying skewed images (P  < .0001); at detecting hidden objects (P  = .0039); at identifying objects in peripheral vision (P  < .0001); and at detecting biological motion (P  = .0065). In contrast, people with PD were not worse at mental rotation or subjective size perception. Using signal detection modelling, we found this effect was driven by change in perceptual sensitivity rather than response bias. Conclusions: Online tests can detect visuo‐perceptual deficits in people with PD, with object recognition particularly affected. Ultimately, visuo‐perceptual tests may be developed to identify at‐risk patients for clinical trials to slow PD dementia. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society

Craig Goch Report No. 11 The behaviour and budgets of selected ions in the Wye Catchment

The river Wye, 250 km long and draining a predominantly rural catchment of 4183 km2, rises in mid-Wales (677m O.D.) and flows to the Severn Estuary (Fig 1). Samples for chemical analysis were obtained from sites 1 to 14 at two-week intervals over the period April 1975 to July 1976 and from site 15 at weekly intervals from 1973