The 'questionableness' of things: opening up the conversation

The authors show, through its structure and form, what it means to open up a collaborative conversation. This chapter developed from a number of conversations that took place at the Fourth International Conference on Value and Virtue in Practice-Based Research, the twin themes of which were 'openness' and 'criticality'. These chance and often fleeting conversations focused on ideas explored in the keynote address that Jon delivered at the conference, but spanned out into a wider discussion of the relevance of those ideas within different areas of professional practice

Using a Nearest-Neighbour, BERT-Based Approach for Scalable Clone Detection

Code clones can detrimentally impact software maintenance and manually detecting them in very large codebases is impractical. Additionally, automated approaches find detection of Type 3 and Type 4 (inexact) clones very challenging. While the most recent artificial deep neural networks (for example BERT-based artificial neural networks) seem to be highly effective in detecting such clones, their pairwise comparison of every code pair in the target system(s) is inefficient and scales poorly on large codebases. We therefore introduce SSCD, a BERT-based clone detection approach that targets high recall of Type 3 and Type 4 clones at scale (in line with our industrial partner's requirements). It does so by computing a representative embedding for each code fragment and finding similar fragments using a nearest neighbour search. SSCD thus avoids the pairwise-comparison bottleneck of other Neural Network approaches while also using parallel, GPU-accelerated search to tackle scalability. This paper details the approach and an empirical assessment towards configuring and evaluating that approach in industrial setting. The configuration analysis suggests that shorter input lengths and text-only based neural network models demonstrate better efficiency in SSCD, while only slightly decreasing effectiveness. The evaluation results suggest that SSCD is more effective than state-of-the-art approaches like SAGA and SourcererCC. It is also highly efficient: in its optimal setting, SSCD effectively locates clones in the entire 320 million LOC BigCloneBench (a standard clone detection benchmark) in just under three hours.Comment: 10 pages, 2 figures, 38th IEEE International Conference on Software Maintenance and Evolutio

Antibodies to Kv1 potassium channel-complex proteins leucine-rich, glioma inactivated 1 protein and contactin-associated protein-2 in limbic encephalitis, Morvan’s syndrome and acquired neuromyotonia

Antibodies that immunoprecipitate 125I-α-dendrotoxin-labelled voltage-gated potassium channels extracted from mammalian brain tissue have been identified in patients with neuromyotonia, Morvan’s syndrome, limbic encephalitis and a few cases of adult-onset epilepsy. These conditions often improve following immunomodulatory therapies. However, the proportions of the different syndromes, the numbers with associated tumours and the relationships with potassium channel subunit antibody specificities have been unclear. We documented the clinical phenotype and tumour associations in 96 potassium channel antibody positive patients (titres >400 pM). Five had thymomas and one had an endometrial adenocarcinoma. To define the antibody specificities, we looked for binding of serum antibodies and their effects on potassium channel currents using human embryonic kidney cells expressing the potassium channel subunits. Surprisingly, only three of the patients had antibodies directed against the potassium channel subunits. By contrast, we found antibodies to three proteins that are complexed with 125I-α-dendrotoxin-labelled potassium channels in brain extracts: (i) contactin-associated protein-2 that is localized at the juxtaparanodes in myelinated axons; (ii) leucine-rich, glioma inactivated 1 protein that is most strongly expressed in the hippocampus; and (iii) Tag-1/contactin-2 that associates with contactin-associated protein-2. Antibodies to Kv1 subunits were found in three sera, to contactin-associated protein-2 in 19 sera, to leucine-rich, glioma inactivated 1 protein in 55 sera and to contactin-2 in five sera, four of which were also positive for the other antibodies. The remaining 18 sera were negative for potassium channel subunits and associated proteins by the methods employed. Of the 19 patients with contactin-associated protein-antibody-2, 10 had neuromyotonia or Morvan’s syndrome, compared with only 3 of the 55 leucine-rich, glioma inactivated 1 protein-antibody positive patients (P < 0.0001), who predominantly had limbic encephalitis. The responses to immunomodulatory therapies, defined by changes in modified Rankin scores, were good except in the patients with tumours, who all had contactin-associated-2 protein antibodies. This study confirms that the majority of patients with high potassium channel antibodies have limbic encephalitis without tumours. The identification of leucine-rich, glioma inactivated 1 protein and contactin-associated protein-2 as the major targets of potassium channel antibodies, and their associations with different clinical features, begins to explain the diversity of these syndromes; furthermore, detection of contactin-associated protein-2 antibodies should help identify the risk of an underlying tumour and a poor prognosis in future patients

Cellular levels of p120 catenin function as a set point for cadherin expression levels in microvascular endothelial cells

The mechanisms by which catenins regulate cadherin function are not fully understood, and the precise function of p120 catenin (p120ctn) has remained particularly elusive. In microvascular endothelial cells, p120ctn colocalized extensively with cell surface VE-cadherin, but failed to colocalize with VE-cadherin that had entered intracellular degradative compartments. To test the possibility that p120ctn binding to VE-cadherin regulates VE-cadherin internalization, a series of approaches were undertaken to manipulate p120ctn availability to endogenous VE-cadherin. Expression of VE-cadherin mutants that competed for p120ctn binding triggered the degradation of endogenous VE-cadherin. Similarly, reducing levels of p120ctn using siRNA caused a dramatic and dose-related reduction in cellular levels of VE-cadherin. In contrast, overexpression of p120ctn increased VE-cadherin cell surface levels and inhibited entry of cell surface VE-cadherin into degradative compartments. These results demonstrate that cellular levels of p120ctn function as a set point mechanism that regulates cadherin expression levels, and that a major function of p120ctn is to control cadherin internalization and degradation

Anomalous transient uplift observed at the Lop Nor, China nuclear test site using satellite radar interferometry time-series analysis

Anomalous uplift is observed at the Lop Nor, China nuclear test site using ERS satellite SAR data. Using an InSAR time‐series analysis method, we show that an increase in absolute uplift with time is observed between 1997 and 1999. The signal is collocated with past underground nuclear tests. Due to the collocation in space with past underground tests we postulate a nuclear test‐related hydrothermal source for the uplift signal. A possible mechanism is presented that can account for the observed transient uplift and is consistent with documented thermal regimes associated with underground nuclear tests conducted at the Nevada National Security Site (NNSS) (formerly the Nevada Test Site)

Differential effect of lactate on synovial fibroblast and macrophage effector functions

IntroductionThe synovial membrane is the main site of inflammation in rheumatoid arthritis (RA). Here several subsets of fibroblasts and macrophages, with distinct effector functions, have been recently identified. The RA synovium is hypoxic and acidic, with increased levels of lactate as a result of inflammation. We investigated how lactate regulates fibroblast and macrophage movement, IL-6 secretion and metabolism via specific lactate transporters.MethodsSynovial tissues were taken from patients undergoing joint replacement surgery and fulfilling the 2010 ACR/EULAR RA criteria. Patients with no evidence of degenerative or inflammatory disease were used as control. Expression of the lactate transporters SLC16A1 and SLC16A3 on fibroblasts and macrophages was assessed by immunofluorescence staining and confocal microscopy. To test the effect of lactate in vitro we used RA synovial fibroblasts and monocyte-derived macrophages. Migration was assessed via scratch test assays or using trans-well inserts. Metabolic pathways were analysed by Seahorse analyser. IL-6 secretion was determined by ELISA. Bioinformatic analysis was performed on publicly available single cell and bulk RNA sequencing datasets.ResultsWe show that: i) SLC16A1 and SLC16A3 which regulate lactate intake and export respectively, are both expressed in RA synovial tissue and are upregulated upon inflammation. SLC16A3 is more highly expressed by macrophages, while SLC16A1 was expressed by both cell types. ii) This expression is maintained in distinct synovial compartments at mRNA and protein level. iii) Lactate, at the concentration found in RA joints (10 mM), has opposite effects on the effector functions of these two cell types. In fibroblasts, lactate promotes cell migration, IL-6 production and increases glycolysis. In contrast macrophages respond to increases in lactate by reducing glycolysis, migration, and IL-6 secretion.DiscussionIn this study, we provide the first evidence of distinct functions of fibroblasts and macrophages in presence of high lactate levels, opening new insights in understanding the pathogenesis of RA and offering novel potential therapeutic targets