Putting pharmaceuticals into the wider context of challenges to fish populations in rivers

The natural range of fish species in our rivers is related to flow, elevation, temperature, local habitat and connectivity. For over 2000 years, humans have altered to varying degrees the river habitat. In the past 200 years, we added to the environmental disruption by discharging poorly treated sewage, nutrients and industrial waste into our rivers. For many rivers, the low point arrived during the period of 1950s–1970s, when rapid economic development overrode environmental concerns and dissolved oxygen concentrations dropped to zero. In these more enlightened times, gross river pollution is a thing of the past in the Developed World. However, persistent legacy chemical contaminants can be found in fish long after their discharge ceased. Changes in habitat quality and morphology caused and continue to cause the disappearance of fish species. The range of fish stressors has now increased as temperatures rise, and non-native fish introductions bring new diseases. The threat from pharmaceuticals to fish populations remains hypothetical, and no studies have yet linked change in fish populations to exposure

A dynamic ubiquitin equilibrium couples proteasomal activity to chromatin remodeling

Protein degradation, chromatin remodeling, and membrane trafficking are critically regulated by ubiquitylation. The presence of several coexisting ubiquitin-dependent processes, each of crucial importance to the cell, is remarkable. This brings up questions on how the usage of this versatile regulator is negotiated between the different cellular processes. During proteotoxic stress, the accumulation of ubiquitylated substrates coincides with the depletion of ubiquitylated histone H2A and chromatin remodeling. We show that this redistribution of ubiquitin during proteotoxic stress is a direct consequence of competition for the limited pool of free ubiquitin. Thus, the ubiquitin cycle couples various ubiquitin-dependent processes because of a rate-limiting pool of free ubiquitin. We propose that this ubiquitin equilibrium may allow cells to sense proteotoxic stress in a genome-wide fashion

Metastable liquid lamellar structures in binary and ternary mixtures of Lennard-Jones fluids

We have carried out extensive equilibrium molecular dynamics (MD) simulations to investigate the Liquid-Vapor coexistence in partially miscible binary and ternary mixtures of Lennard-Jones (LJ) fluids. We have studied in detail the time evolution of the density profiles and the interfacial properties in a temperature region of the phase diagram where the condensed phase is demixed. The composition of the mixtures are fixed, 50% for the binary mixture and 33.33% for the ternary mixture. The results of the simulations clearly indicate that in the range of temperatures $78 < T < 102 ^{\rm o}$K, --in the scale of argon-- the system evolves towards a metastable alternated liquid-liquid lamellar state in coexistence with its vapor phase. These states can be achieved if the initial configuration is fully disordered, that is, when the particles of the fluids are randomly placed on the sites of an FCC crystal or the system is completely mixed. As temperature decreases these states become very well defined and more stables in time. We find that below $90 ^{\rm o}$K, the alternated liquid-liquid lamellar state remains alive for 80 ns, in the scale of argon, the longest simulation we have carried out. Nonetheless, we believe that in this temperature region these states will be alive for even much longer times.Comment: 18 Latex-RevTex pages including 12 encapsulated postscript figures. Figures with better resolution available upon request. Accepted for publication in Phys. Rev. E Dec. 1st issu

Mutational spectrum of the succinate semialdehyde dehydrogenase (ALDH5A1) gene and functional analysis of 27 novel disease-causing mutations in patients with SSADH deficiency

Succinate semialdehyde dehydrogenase (SSADH; ALlDH5A1) deficiency, a rare metabolic disorder that disrupts the normal degradation of GABA, gives rise to a highly heterogeneous neurological phenotype ranging from mild to very severe. The nature of the mutation has so far been reported in patients from six families world wide and eight different mutations were described. Here we report the mutational spectrum in 48 additional unrelated families of different geographic origin. We detected 27 novel mutations at the cDNA level, of which 26 could be attributed to changes at the genomic level. Furthermore, six mutations were detected that did not strongly affect SSADH activity when expressed in HEK 293 cells and are considered nonpathogenic allelic variants. Twenty of the mutations were only found in one family. The spectrum of disease-causing mutations from all patients sequenced thus far consists of 25 point mutations, four small insertions, and five small deletions. Seven of these mutations affect splice junctions, seven are nonsense mutations, and 12 are missense mutations. Although there were no mutational hotspots or prevalent mutations responsible for a significant number of cases, 14 out of 37 (38%) of the missense alleles were present in exon 4 or 5. With one exception, the missense mutations we consider to be causative of SSADH deficiency reduced the SSADH activity to less than 5% of the normal activity in our in vitro expression system. This indicates that residual expression is not likely to be an important factor contributing to the large phenotypic differences observed among different families and even among siblings, suggesting that other modifying factors are of great importance in disease pathology. (C) 2003 Wiley,Liss, Inc

The low-density/high-density liquid phase transition for model globular proteins

The effect of molecule size (excluded volume) and the range of interaction on the surface tension, phase diagram and nucleation properties of a model globular protein is investigated using a combinations of Monte Carlo simulations and finite temperature classical Density Functional Theory calculations. We use a parametrized potential that can vary smoothly from the standard Lennard-Jones interaction characteristic of simple fluids, to the ten Wolde-Frenkel model for the effective interaction of globular proteins in solution. We find that the large excluded volume characteristic of large macromolecules such as proteins is the dominant effect in determining the liquid-vapor surface tension and nucleation properties. The variation of the range of the potential only appears important in the case of small excluded volumes such as for simple fluids. The DFT calculations are then used to study homogeneous nucleation of the high-density phase from the low-density phase including the nucleation barriers, nucleation pathways and the rate. It is found that the nucleation barriers are typically only a few $k_{B}T$ and that the nucleation rates substantially higher than would be predicted by Classical Nucleation Theory.Comment: To appear in Langmui

Ethical Considerations of Using Machine Learning for Decision Support in Occupational Health:An Example Involving Periodic Workers' Health Assessments

Purpose Computer algorithms and Machine Learning (ML) will be integrated into clinical decision support within occupational health care. This will change the interaction between health care professionals and their clients, with unknown consequences. The aim of this study was to explore ethical considerations and potential consequences of using ML based decision support tools (DSTs) in the context of occupational health. Methods We conducted an ethical deliberation. This was supported by a narrative literature review of publications about ML and DSTs in occupational health and by an assessment of the potential impact of ML-DSTs according to frameworks from medical ethics and philosophy of technology. We introduce a hypothetical clinical scenario from a workers' health assessment to reflect on biomedical ethical principles: respect for autonomy, beneficence, non-maleficence and justice. Results Respect for autonomy is affected by uncertainty about what future consequences the worker is consenting to as a result of the fluctuating nature of ML-DSTs and validity evidence used to inform the worker. A beneficent advisory process is influenced because the three elements of evidence based practice are affected through use of a ML-DST. The principle of non-maleficence is challenged by the balance between group-level benefits and individual harm, the vulnerability of the worker in the occupational context, and the possibility of function creep. Justice might be empowered when the ML-DST is valid, but profiling and discrimination are potential risks. Conclusions Implications of ethical considerations have been described for the socially responsible design of ML-DSTs. Three recommendations were provided to minimize undesirable adverse effects of the development and implementation of ML-DSTs

Factors affecting metal mobilisation during oxidation of sulphidic, sandy wetland substrates

Most metals accumulate as sulphides under anoxic conditions in wetland substrates, reducing their bioavailability due to the solubility of metal sulphides. However, upon oxidation of these sulphides when the substrate is occasionally oxidised, metals can be released from the solid phase to the pore water or overlaying surface water. This release can be affected by the presence of carbonates, organic matter and clay. We compared changes of Cd, Cu and Zn mobility (CaCl2 extraction) during oxidation of a carbonate-rich and a carbonate-poor sulphidic, sandy wetland substrate. In addition, we studied how clay with low and high cation sorption capacity (bentonite and kaolinite, respectively) and organic matter (peat) can counteract Cd, Cu and Zn release during oxidation of both carbonate-rich and carbonate-poor sulphidic sediments. CaCl2-extractability of Cu, a measure for its availability, is low in both carbonate-poor and carbonate-rich substrates, whereas its variability is high. The availability of Cd and Zn is much higher and increases when peat is supplied to carbonate-poor substrates. A strong reduction of Cd and Zn extractability is observed when clay is added to carbonate-poor substrates. This reduction depends on the clay type. Most observations could be explained taking into account pH differences between treatments, with kaolinite resulting in a lower pH in comparison to bentonite. These pH differences affect the presence and characteristics of dissolved organic carbon and the metal speciation, which in turns affects the interaction of metals with the solid soil phase. In carbonate-rich substrates, Cd and Zn availability is lower and the effects of peat and clay amendment are less clear. The latter can also be attributed to the high pH and lack of pH differences between treatments