Function, regulation and pathological roles of the Gab/DOS docking proteins

Since their discovery a little more than a decade ago, the docking proteins of the Gab/DOS family have emerged as important signalling elements in metazoans. Gab/DOS proteins integrate and amplify signals from a wide variety of sources including growth factor, cytokine and antigen receptors as well as cell adhesion molecules. They also contribute to signal diversification by channelling the information from activated receptors into signalling pathways with distinct biological functions. Recent approaches in protein biochemistry and systems biology have revealed that Gab proteins are subject to complex regulation by feed-forward and feedback phosphorylation events as well as protein-protein interactions. Thus, Gab/DOS docking proteins are at the centre of entire signalling subsystems and fulfil an important if not essential role in many physiological processes. Furthermore, aberrant signalling by Gab proteins has been increasingly linked to human diseases from various forms of neoplasia to Alzheimer's disease

Abnormal Leg Muscle Latencies and Relationship to Dyscoordination and Walking Disability after Stroke

The purpose was to determine timing characteristics of leg muscle latencies for patients following stroke (>12 months) who had persistent coordination and gait deficits, and to determine the relationships among abnormal latencies, dyscoordination, and gait deficits. We compared nine healthy controls and 27 stroke survivors. Surface electromyography measured activation and deactivation latencies of knee flexor and extensor muscles during a ballistic knee flexion task, consistency of latencies across repetitions, and close coupling between agonist and antagonist muscle latencies. We measured Fugl-Meyer (FM) coordination and the functional gait measure, six minute walk test (6MWT). For stroke subjects, there were significant delays of muscle activation and deactivation, abnormal inconsistency, and abnormal decoupled agonist and antagonist activations. There was good correlation between activation latencies and FM and 6MWT. Results suggest abnormal timing characteristics underlie coordination impairment and dysfunctional gait. These abnormal muscle activation and deactivation timing characteristics are important targets for rehabilitation

python-ags4: A Python library to read, write, and validate AGS4 geodata files

Data gathered from geotechnical, geoenvironmental, and geophysical investigations can be broadly described as “geodata”. The AGS4 data format (Association of Geotechnical and Geoenvironmental Specialists, 2011, 2017, 2021b, 2022) is one of the most widely used data transmittal formats for geodata and is used across the world. It is a plain text format consisting of multiple tables of comma-separated values, tied together with a robust data schema and a comprehensive suite of validation rules. The basic structure of an AGS4 file is shown in Figure 1. Figure 1: Simplified schematic of AGS4 data structure Source: Association of Geotechnical and Geoenvironmental Specialists (2022) python-ags4 is a Python library that provides functionality to read, write, and validate AGS4 geodata files. It provides users with a gateway to access the full power of the Python ecosystem to explore, analyze, and visualize geodata. Pandas DataFrame (The pandas development team, 2020) is the primary data structure used within the library, therefore it can handle relatively large datasets reasonably fast. The data validation module checks the file for compliance with the validation rules and provides a detailed error report. An example error report is shown in Figure 2

Succession of physiological stages hallmarks the transcriptomic response of the fungus Aspergillus niger to lignocellulose.

BackgroundUnderstanding how fungi degrade lignocellulose is a cornerstone of improving renewables-based biotechnology, in particular for the production of hydrolytic enzymes. Considerable progress has been made in investigating fungal degradation during time-points where CAZyme expression peaks. However, a robust understanding of the fungal survival strategies over its life time on lignocellulose is thereby missed. Here we aimed to uncover the physiological responses of the biotechnological workhorse and enzyme producer Aspergillus niger over its life time to six substrates important for biofuel production.ResultsWe analysed the response of A. niger to the feedstock Miscanthus and compared it with our previous study on wheat straw, alone or in combination with hydrothermal or ionic liquid feedstock pretreatments. Conserved (substrate-independent) metabolic responses as well as those affected by pretreatment and feedstock were identified via multivariate analysis of genome-wide transcriptomics combined with targeted transcript and protein analyses and mapping to a metabolic model. Initial exposure to all substrates increased fatty acid beta-oxidation and lipid metabolism transcripts. In a strain carrying a deletion of the ortholog of the Aspergillus nidulans fatty acid beta-oxidation transcriptional regulator farA, there was a reduction in expression of selected lignocellulose degradative CAZyme-encoding genes suggesting that beta-oxidation contributes to adaptation to lignocellulose. Mannan degradation expression was wheat straw feedstock-dependent and pectin degradation was higher on the untreated substrates. In the later life stages, known and novel secondary metabolite gene clusters were activated, which are of high interest due to their potential to synthesize bioactive compounds.ConclusionIn this study, which includes the first transcriptional response of Aspergilli to Miscanthus, we highlighted that life time as well as substrate composition and structure (via variations in pretreatment and feedstock) influence the fungal responses to lignocellulose. We also demonstrated that the fungal response contains physiological stages that are conserved across substrates and are typically found outside of the conditions with high CAZyme expression, as exemplified by the stages that are dominated by lipid and secondary metabolism

The Lancet Oral Health Series – implications for oral and dental research

No abstract available

Standardisation of rates using logistic regression: a comparison with the direct method

<p>Abstract</p> <p>Background</p> <p>Standardisation of rates in health services research is generally undertaken using the direct and indirect arithmetic methods. These methods can produce unreliable estimates when the calculations are based on small numbers. Regression based methods are available but are rarely applied in practice. This study demonstrates the advantages of using logistic regression to obtain smoothed standardised estimates of the prevalence of rare disease in the presence of covariates.</p> <p>Methods</p> <p>Step by step worked examples of the logistic and direct methods are presented utilising data from BETS, an observational study designed to estimate the prevalence of subclinical thyroid disease in the elderly. Rates calculated by the direct method were standardised by sex and age categories, whereas rates by the logistic method were standardised by sex and age as a continuous variable.</p> <p>Results</p> <p>The two methods produce estimates of similar magnitude when standardising by age and sex. The standard errors produced by the logistic method were lower than the conventional direct method.</p> <p>Conclusion</p> <p>Regression based standardisation is a practical alternative to the direct method. It produces more reliable estimates than the direct or indirect method when the calculations are based on small numbers. It has greater flexibility in factor selection and allows standardisation by both continuous and categorical variables. It therefore allows standardisation to be performed in situations where the direct method would give unreliable results.</p

A “Calvinist” Theory of Matter? Burgersdijk and Descartes on res extensa

In the Dutch debates on Cartesianism of the 1640s, a minority believed that some Cartesian views were in fact Calvinist ones. The paper argues that, among others, a likely precursor of this position is the Aristotelian Franco Burgersdijk (1590-1635), who held a reductionist view of accidents and of the essential extension of matter on Calvinist grounds. It seems unlikely that Descartes was unaware of these views. The claim is that Descartes had two aims in his Replies to Arnauld: to show the compatibility of res extensa and the Catholic transubstantiation but also to differentiate the res extensa from some views of matter explicitly defended by some Calvinists. The association with Calvinism will be eventually used polemically against Cartesianism, for example in France. The paper finally suggests that, notwithstanding the points of conflict, the affinities between the theologically relevant theories of accidents, matter and extension ultimately facilitated the dissemination of Cartesianism among the Calvinists

A robust methodology to subclassify pseudokinases based on their nucleotide-binding properties

Protein kinase-like domains that lack conserved residues known to catalyse phosphoryl transfer, termed pseudokinases, have emerged as important signalling domains across all kingdoms of life. Although predicted to function principally as catalysis-independent protein-interaction modules, several pseudokinase domains have been attributed unexpected catalytic functions, often amid controversy. We established a thermal-shift assay as a benchmark technique to define the nucleotide-binding properties of kinase-like domains. Unlike in vitro kinase assays, this assay is insensitive to the presence of minor quantities of contaminating kinases that may otherwise lead to incorrect attribution of catalytic functions to pseudokinases. We demonstrated the utility of this method by classifying 31 diverse pseudokinase domains into four groups: devoid of detectable nucleotide or cation binding; cation-independent nucleotide binding; cation binding; and nucleotide binding enhanced by cations. Whereas nine pseudokinases bound ATP in a divalent cation-dependent manner, over half of those examined did not detectably bind nucleotides, illustrating that pseudokinase domains predominantly function as non-catalytic protein-interaction modules within signalling networks and that only a small subset is potentially catalytically active. We propose that henceforth the thermal-shift assay be adopted as the standard technique for establishing the nucleotide-binding and catalytic potential of kinase-like domains