ATP Reception and Chemosensory Adaptation in \u3c/i\u3eTetrahymena thermophila\u3c/i\u3e

Micromolar concentrations of adenosine triphosphate (ATP) and its non-hydrolyzable analog β- γ -methylene ATP are both effective depolarizing chemorepellents in Tetrahymena thermophila. Chemorepellent behavior consists of repeated bouts of backward swimming (avoidance reactions) that can easily be quantified to provide a convenient bioassay for purinergic reception studies. Chemosensory adaptation occurs following prolonged exposure (10 min) to the repellents, and cells regain normal swimming behavior. Adaptation is specific since cells that are behaviorally adapted to either ATP or β- γ -methylene ATP still retain full responsiveness to the chemorepellents GTP and lysozyme. However, cross adaptation occurs between ATP and β- γ -methylene ATP, suggesting that they involve the same receptor. Behavioral sensitivity to both ATP and β- γ -methylene ATP is increased by the addition of Na+, but addition of either Ca2+ or Mg2+ dramatically decreases the response to ATP. These ionic effects are correlated with in vivo ATP hydrolysis, suggesting that divalent ions decrease purinergic sensitivity by activating a Ca2+- or Mg2+-dependent ecto-ATPase to hydrolyze the ATP signal. In vivo [32P]ATP binding studies and Scatchard analysis suggest that the behavioral adaptation is due to a decrease in the number of surface binding sites, as represented by decreased Bmax values. All these changes are reversible (de-adaptation) after 12 min in a repellent-free buffer. Electrophysiological analysis showed that both β- γ -methylene ATP (10 micromol l-1) and ATP (500 micromol l-1) elicited sustained, reversible depolarizations while GTP (10 micromol l-1) produced a transient depolarization, suggesting that the chemosensory response pathways for ATP and GTP reception may differ. There may be separate ATP and GTP receptors since ATP and GTP responses do not cross-adapt and ‘cold’ (unlabeled) GTP is not a good inhibitor of [32P]ATP binding. These results suggests that T. thermophila possess high-affinity surface receptors for ATP that are down-regulated during chemosensory adaptation. These ATP receptors may act as chemorepellent receptors to enable T. thermophila to recognize recently lysed cells and avoid a possibly deleterious situation. This is the simplest eukaryotic organism to show an electrophysiological response to external ATP

Patterns of genomic loss of heterozygosity predict homologous recombination repair defects in epithelial ovarian cancer

Background: Defects in BRCA1, BRCA2, and other members of the homologous recombination pathway have potential therapeutic relevance when used to support agents that introduce or exploit double-stranded DNA breaks. This study examines the association between homologous recombination defects and genomic patterns of loss of heterozygosity (LOH). Methods: Ovarian tumours from two independent data sets were characterised for defects in BRCA1,BRCA2, and RAD51C, and LOH profiles were generated. Publically available data were downloaded for a third independent data set. The same analyses were performed on 57 cancer cell lines. Results: Loss of heterozygosity regions of intermediate size were observed more frequently in tumours with defective BRCA1 or BRCA2 (P=10−11). The homologous recombination deficiency (HRD) score was defined as the number of these regions observed in a tumour sample. The association between HRD score and BRCA deficiency was validated in two independent ovarian cancer data sets (P=10−5 and 10−29), and identified breast and pancreatic cell lines with BRCA defects. Conclusion: The HRD score appears capable of detecting homologous recombination defects regardless of aetiology or mechanism. This score could facilitate the use of PARP inhibitors and platinum in breast, ovarian, and other cancers

When the path is never shortest: a reality check on shortest path biocomputation

Shortest path problems are a touchstone for evaluating the computing performance and functional range of novel computing substrates. Much has been published in recent years regarding the use of biocomputers to solve minimal path problems such as route optimisation and labyrinth navigation, but their outputs are typically difficult to reproduce and somewhat abstract in nature, suggesting that both experimental design and analysis in the field require standardising. This chapter details laboratory experimental data which probe the path finding process in two single-celled protistic model organisms, Physarum polycephalum and Paramecium caudatum, comprising a shortest path problem and labyrinth navigation, respectively. The results presented illustrate several of the key difficulties that are encountered in categorising biological behaviours in the language of computing, including biological variability, non-halting operations and adverse reactions to experimental stimuli. It is concluded that neither organism examined are able to efficiently or reproducibly solve shortest path problems in the specific experimental conditions that were tested. Data presented are contextualised with biological theory and design principles for maximising the usefulness of experimental biocomputer prototypes.Comment: To appear in: Adamatzky, A (Ed.) Shortest path solvers. From software to wetware. Springer, 201

A systematic review of dedicated models of care for emergency urological patients

Available online 26 June 2020Objective: To systematically evaluate the spectrum of models providing dedicated resources for emergency urological patients (EUPs). Methods: A search of Cochrane, Embase, Medline and grey literature from January 1, 2000 to March 26, 2019 was performed using methods pre-published on PROSPERO. Reporting followed Preferred Reporting Items for Systematic Review and meta-analysis guidelines. Eligible studies were articles or abstracts published in English describing dedicated models of care for EUPs, which reported at least one secondary outcome. Studies were excluded if they examined pathways dedicated only to single presentations, such as torsion, or outpatient solutions, such as rapid access clinics. The primary outcome was the spectrum of models. Secondary outcomes were time-to-theatre, length of stay, complications and cost. Results: Seven studies were identified, totalling 487 patients. Six studies were conference abstracts, while one study was of full-text length but published in grey literature. Four distinct models were described. These included consultant urologists allocated solely to the care of EUPs (“Acute Urological Unit”) or dedicated registrars or operating theatres (“Hybrid structures”). In some services, EUPs bypassed emergency department assessment and were referred directly to urology (“Urological Assessment Unit”) or were managed by other dedicated means. Allocating services to EUPs was associated with reduced time-to-theatre, length of stay and hospital cost, and improved supervision of junior medical staff. Conclusion: Multiple dedicated models of care exist for EUPs. Low-level evidence suggests these may improve outcomes for patients, staff and hospitals. Higher quality studies are required to explore patient outcomes and minimum requirements to establish these models.Ned Kinnear, Matheesha Herath, Dylan Barnett, Derek Hennessey, Christopher Dobbins, Tarik Sammour, James Moor

Non-state space: The strategic ejection of dangerous and high maintenance urban space

Some commentators have characterised so-called ‘no-go’ areas as sites in which the exercise of authority is prevented. Here we suggest that many such spaces are produced by state, policing and citizen repertoires that aim to minimise the costs and risks of engaging, supporting and servicing such spaces and their populations. In this article we locate strategies of public spending, policing and political action that offer a governing logic in which neighbourhoods are essentially subtracted from the constitution of the city. During such designations the assurances of citizenship, vitality of civic institutions and presence of policing may be partially or wholly suspended. We present a framework for the identification of such strategies in which these forms of social, political and spatial exiting are described as being autotomic in nature – spaces that are ejected in order to avoid losses or further damage to the body politic of the city in ways akin to the response of certain animals that protect themselves from predation by shedding a limb or body part. This term adds force and depth to assessments of the ways in which both temporary and more sustained exits by policing, management and state servicing are designed in order to avoid responsibility over, or engagement with, spaces that are deemed a threat in order to maintain the integrity of the remaining, included city

Evolution of associative learning in chemical networks

Organisms that can learn about their environment and modify their behaviour appropriately during their lifetime are more likely to survive and reproduce than organisms that do not. While associative learning – the ability to detect correlated features of the environment – has been studied extensively in nervous systems, where the underlying mechanisms are reasonably well understood, mechanisms within single cells that could allow associative learning have received little attention. Here, using in silico evolution of chemical networks, we show that there exists a diversity of remarkably simple and plausible chemical solutions to the associative learning problem, the simplest of which uses only one core chemical reaction. We then asked to what extent a linear combination of chemical concentrations in the network could approximate the ideal Bayesian posterior of an environment given the stimulus history so far? This Bayesian analysis revealed the ’memory traces’ of the chemical network. The implication of this paper is that there is little reason to believe that a lack of suitable phenotypic variation would prevent associative learning from evolving in cell signalling, metabolic, gene regulatory, or a mixture of these networks in cells

New Results from the Cryogenic Dark Matter Search Experiment

Using improved Ge and Si detectors, better neutron shielding, and increased counting time, the Cryogenic Dark Matter Search (CDMS) experiment has obtained stricter limits on the cross section of weakly interacting massive particles (WIMPs) elastically scattering from nuclei. Increased discrimination against electromagnetic backgrounds and reduction of neutron flux confirm WIMP-candidate events previously detected by CDMS were consistent with neutrons and give limits on spin-independent WIMP interactions which are >2X lower than previous CDMS results for high WIMP mass, and which exclude new parameter space for WIMPs with mass between 8-20 GeV/c^2.Comment: 4 pages, 4 figure

Enzyme Sequence and Its Relationship to Hyperbaric Stability of Artificial and Natural Fish Lactate Dehydrogenases

The cDNAs of lactate dehydrogenase b (LDH-b) from both deep-sea and shallow living fish species, Corphaenoides armatus and Gadus morhua respectively, have been isolated, sequenced and their encoded products overproduced as recombinant enzymes in E. coli. The proteins were characterised in terms of their kinetic and physical properties and their ability to withstand high pressures. Although the two proteins are very similar in terms of their primary structure, only 21 differences at the amino acid level exist between them, the enzyme from the deep-sea species has a significantly increased tolerance to pressure and a higher thermostability. It was possible to investigate whether the changes in the N-terminal or C-terminal regions played a greater role in barophilic adaptation by the construction of two chimeric enzymes by use of a common restriction site within the cDNAs. One of these hybrids was found to have even greater pressure stability than the recombinant enzyme from the deep-living fish species. It was possible to conclude that the major adaptive changes to pressure tolerance must be located in the N-terminal region of the protein. The types of changes that are found and their spatial location within the protein structure are discussed. An analysis of the kinetic parameters of the enzymes suggests that there is clearly a trade off between Km and kcat values, which likely reflects the necessity of the deep-sea enzyme to operate at low temperatures

Forty years studying British politics : the decline of Anglo-America

The still present belief some 40 years ago that British politics was both exceptional and superior has been replaced by more theoretically sophisticated analyses based on a wider and more rigorously deployed range of research techniques, although historical analysis appropriately remains important. The American influence on the study of British politics has declined, but the European Union dimension has not been fully integrated. The study of interest groups has been in some respects a fading paradigm, but important questions related to democratic health have still to be addressed. Public administration has been supplanted by public policy, but economic policy remains under-studied. A key challenge for the future is the study of the management of expectations