Role of the unique N-terminal domain of CtBP2 in determining the subcellular localisation of CtBP family proteins

BACKGROUND: CtBP1 and CtBP2 are transcriptional co-repressors that modulate the activity of a large number of transcriptional repressors via the recruitment of chromatin modifiers. Many CtBP-regulated proteins are involved in pathways associated with tumorigenesis, including TGF-beta and Wnt signalling pathways and cell cycle regulators such as RB/p130 and HDM2, as well as adenovirus E1A. CtBP1 and CtBP2 are highly similar proteins, although evidence is emerging that their activity can be differentially regulated, particularly through the control of their subcellular localisation. CtBP2s from diverse species contain a unique N-terminus, absent in CtBP1 that plays a key role in controlling the nuclear-cytoplasmic distribution of the protein.RESULTS: Here we show that amino acids (a.a.) 4-14 of CtBP2 direct CtBP2 into an almost exclusively nuclear distribution in cell lines of diverse origins. Whilst this sequence contains similarity to known nuclear localisation motifs, it cannot drive nuclear localisation of a heterologous protein, but rather has been shown to function as a p300 acetyltransferase-dependent nuclear retention sequence. Here we define the region of CtBP2 required to co-operate with a.a. 4-14 to promote CtBP2 nuclear accumulation as being within a.a. 1-119. In addition, we show that a.a. 120-445 of CtBP2 can also promote CtBP2 nuclear accumulation, independently of a.a. 4-14. Finally, CtBP1 and CtBP2 can form heterodimers, and we show that the interaction with CtBP2 is one mechanism whereby CtBP1 can be recruited to the nucleus.CONCLUSION: Together, these findings represent key distinctions in the regulation of the functions of CtBP family members that may have important implications as to their roles in development, and cell differentiation and survival.<br/

Incorporating psychology into cyber security education: A pedagogical approach

The role of the human in cyber security is well acknowledged. Many cyber security incidents rely upon targets performing specific behavioural actions, such as opening a link within a phishing email. Cyber adversaries themselves are driven by psychological processes such as motivation, group dynamics and social identity. Furthermore, both intentional and unintentional insider threats are associated with a range of psychological factors, including cognitive load, mental wellbeing, trust and interpersonal relations. By incorporating psychology into cyber security education, practitioners will be better equipped with the skills they need to address cyber security issues. However, there are challenges in doing so. Psychology is a broad discipline, and many theories, approaches and methods may have little practical significance to cyber security. There is a need to sift through the literature to identify what can be applied to cyber security. There are also pedagogical differences in how psychology and cyber security are taught and also psychological differences in the types of student that may typically study psychology and cyber security. To engage with cyber security students, it is important that these differences are identified and positively addressed. Essential to this endeavor is the need to discuss and collaborate across the two disciplines. In this paper, we explore these issues and discuss our experiences as psychology and cyber security academics who work across disciplines to deliver psychology education to cyber security students, practitioners and commercial clients

‘Dead people don’t claim’: A psychopolitical autopsy of UK austerity suicides

One of the symptoms of post financial crisis austerity in the UK has been an increase in the numbers of suicides, especially by people who have experienced welfare reform. This article develops and utilises an analytic framework of psychopolitical autopsy to explore media coverage of ‘austerity suicide’ and to take seriously the psychic life of austerity (internalisation, shame, anxiety), embedding it in a context of social dis-ease. Drawing on three distinct yet interrelated areas of literature (the politics of affect and psychosocial dynamics of welfare, post and anti-colonial psychopolitics, and critical suicidology), the article aims to better understand how austerity ‘kills’. Key findings include understanding austerity suicides as embedded within an affective economy of the anxiety caused by punitive welfare retrenchment, the stigmatisation of being a recipient of benefits, and the internalisation of market logic that assigns value through ‘productivity’ and conceptualises welfare entitlement as economic ‘burden’. The significance of this approach lies in its ability to widen analytic framing of suicide from an individual and psychocentric focus, to illuminate culpability of government reforms while still retaining the complexity of suicide, and thus to provide relevant policy insights about welfare reform

A mitochondria-targeted mass spectrometry probe to detect glyoxals: implications for diabetes

The glycation of protein and nucleic acids that occurs as a consequence of hyperglycaemia disrupts cell function and contributes to many pathologies, including those associated with diabetes and aging. Intracellular glycation occurs following the generation of the reactive 1,2-dicarbonyls methylglyoxal and glyoxal and disruption to mitochondrial function is associated with hyperglycemia. However, the contribution of these reactive dicarbonyls to mitochondrial damage in pathology is unclear due to uncertainties about their levels within mitochondria in cells and in vivo. To address this we have developed a mitochondria-targeted reagent (MitoG) designed to assess the levels of mitochondrial dicarbonyls within cells. MitoG comprises a lipophilic triphenylphosphonium cationic function, which directs the molecules to mitochondria within cells and an o-phenylenediamine moiety that reacts with dicarbonyls to give distinctive and stable products. The extent of accumulation of these diagnostic heterocyclic products can be readily and sensitively quantified by liquid chromatography-tandem mass spectrometry (LC-MS/MS), enabling changes to be determined. Using the MitoG-based analysis we assessed the formation of methylglyoxal and glyoxal in response to hyperglycaemia in cells in culture and in the Akita mouse model of diabetes in vivo. These findings indicated that the levels of methylglyoxal and glyoxal within mitochondria increase during hyperglycaemia in both cells and in vivo, suggesting that they can contribute to the pathological mitochondrial dysfunction that occurs in diabetes and aging

An EMA analysis of the effect of increasing word length on consonant production in apraxia of speech: A case study

The effect of increasing word length on the articulatory dynamics (i.e. duration, distance, maximum acceleration, maximum deceleration, and maximum velocity) of consonant production in acquired apraxia of speech was investigated using electromagnetic articulography (EMA). Tongue-tip and tongue-back movement of one apraxic patient was recorded using the AG-200 EMA system during word-initial consonant productions in one, two, and three syllable words. Significantly deviant articulatory parameters were recorded for each of the target consonants during one, two, and three syllables words. Word length effects were most evident during the release phase of target consonant productions. The results are discussed with respect to theories of speech motor control as they relate to AOS

Cultural theory and the dynamics of organizational change: the response of housing associations in London to the Housing Act 1988

The aim of this article is to consider the most effective way of conceptualizing a sector that has undergone radical change: the UK voluntary housing sector. The article considers existing accounts of housing associations and classifies these into five analytically distinct groups: practitioners, historical accounts, managerialist approaches, network theorists and institutionalist accounts. The main contention is that each of these is limited in explanatory potential, primarily due to their neglect of culture. This article proposes a more detailed framework for developing an understanding of the substantial changes affecting housing associations since the 1980s; that offered by "grid-group cultural theory". The article provides longitudinal qualitative data obtained from London housing associations to support the contention that organizational change can most usefully be understood by reference to the cultural themes of hierarchy and individualism. The article contends that cultural theory offers the opportunity to develop a systematic analysis that accounts for institutional history and organizational differentiation

Using virtual reality in criminological research

Since the pioneering early studies of the 1990s hinted at its promise as a research method, virtual reality (VR) technology has increasingly been used by social scientists. Given recent developments that have greatly enhanced realism, reduced costs, and increased possibilities for application, VR seems well on its way to become an established research tool in the social sciences. However, as with other ethodological innovations, the field of criminology hasbeen slow to catch on. To address this gap, this article explores the potential of VR as a tool for crime research. It provides readers with a brief and non-technical description of VR and its main elements and reviews severalapplications of VR in social scientific research that are potentially relevant for criminologists. By way of illustration, we identify and discuss in more detail different areas in which we think the field of criminology can particularly benefit from VR and offer suggestions for research. Some of the equipment available on the consumer market is also reviewed.In conjunction, the different sections should equip readers interested in applying VR in their own research with a fundamental understanding of what it entails and how it can be applied

Facial-muscle weakness, speech disorders and dysphagia are common in patients with classic infantile Pompe disease treated with enzyme therapy

Classic infantile Pompe disease is an inherited generalized glycogen storage disorder caused by deficiency of lysosomal acid α-glucosidase. If left untreated, patients die before one year of age. Although enzyme-replacement therapy (ERT) has significantly prolonged lifespan, it has also revealed new aspects of the disease. For up to 11 years, we investigated the frequency and consequences of facial-muscle weakness, speech disorders and dysphagia in long-term survivors. Sequential photographs were used to determine the timing and severity of facial-muscle weakness. Using standardized articulation tests and fibreoptic endoscopic evaluation of swallowing, we investigated speech and swallowing function in a subset of patients. This study included 11 patients with classic infantile Pompe disease. Median age at the start of ERT was 2.4 months (range 0.1-8.3 months), and median age at the end of the study was 4.3 years (range 7.7 months −12.2 years). All patients developed facial-muscle weakness before the age of 15 months. Speech was studied in four patients. Articulation was disordered, with hypernasal resonance and reduced speech intelligibility in all four. Swallowing function was studied in six patients, the most important findings being ineffective swallowing with residues of food (5/6), penetration or aspiration (3/6), and reduced pharyngeal and/or laryngeal sensibility (2/6). We conclude that facial-muscle weakness, speech disorders and dysphagia are common in long-term survivors receiving ERT for classic infantile Pompe disease. To improve speech and reduce the risk for aspiration, early treatment by a speech therapist and regular swallowing assessments are recommended

SARS-CoV-2 neutralizing antibodies: Longevity, breadth, and evasion by emerging viral variants.

The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) antibody neutralization response and its evasion by emerging viral variants and variant of concern (VOC) are unknown, but critical to understand reinfection risk and breakthrough infection following vaccination. Antibody immunoreactivity against SARS-CoV-2 antigens and Spike variants, inhibition of Spike-driven virus-cell fusion, and infectious SARS-CoV-2 neutralization were characterized in 807 serial samples from 233 reverse transcription polymerase chain reaction (RT-PCR)-confirmed Coronavirus Disease 2019 (COVID-19) individuals with detailed demographics and followed up to 7 months. A broad and sustained polyantigenic immunoreactivity against SARS-CoV-2 Spike, Membrane, and Nucleocapsid proteins, along with high viral neutralization, was associated with COVID-19 severity. A subgroup of "high responders" maintained high neutralizing responses over time, representing ideal convalescent plasma donors. Antibodies generated against SARS-CoV-2 during the first COVID-19 wave had reduced immunoreactivity and neutralization potency to emerging Spike variants and VOC. Accurate monitoring of SARS-CoV-2 antibody responses would be essential for selection of optimal responders and vaccine monitoring and design