Characterization of the receptor binding sites of human leukemia inhibitory factor and creation of antagonists

Residues in human leukemia inhibitory factor (hLIF) crucial for binding to both the human LIF receptor (R) and gp130 were identified by analysis of alanine scanning mutants of hLIF in assays for both receptor binding and bioactivity. The region of hLIF most important for binding to the hLIF-R is composed of residues from the amino terminus of the D-helix, carboxyl terminus of the B-helix, and C-D loop. This site forms a distinct surface at the end of the four-helix bundle in the tertiary structure of the closely related murine LIF. The two residues of hLIF that contribute the majority of free energy for hLIF-R binding, Phe-156 and Lys-159 are surrounded by other residues which have only a moderate impact. This arrangement of a few key residues surrounded by less important ones is analogous to the functional binding epitope of human growth hormone for its receptor. A second region of hLIF that includes residues from the carboxyl terminus of the D-helix and A-B loop also had a weak influence on hLIF-R binding. Residues in hLIF from both the A- and C-helices are involved in binding the gp130 co-receptor. Abolition of the gp130 binding site in hLIF created antagonists of LIF action

An antagonist for the leukemia inhibitory factor receptor inhibits leukemia inhibitory factor, cardiotrophin-1, ciliary neurotrophic factor, and oncostatin M

The leukemia inhibitory factor receptor (LIF-R) is activated not only by LIF, but also by cardiotrophin-1, ciliary neurotrophic factor with its receptor, and oncostatin M (OSM). Each of these cytokines induces the hetero-oligomerization of LIF-R with gp130, a signal-transducing subunit shared with interleukin-6 and interleukin-11. The introduction of mutations into human LIF that reduced the affinity for gp130 while retaining affinity for LIF-R has generated antagonists for LIF. In the current study, a LIF antagonist that was free of detectable agonistic activity was tested for antagonism against the family of LIF-R ligands. On cells that express LIF-R and gp130, all LIF-R ligands were antagonized. On cells that also express OSM receptor, OSM was not antagonized, demonstrating that the antagonist is specific for LIF-R. Ligand-triggered tyrosine phosphorylation of both LIF-R and gp130 was blocked by the antagonist. The antagonist is therefore likely to work by preventing receptor oligomerization

Beyoncé’s Lemonade: She Dreams in Both Worlds

Beyoncé calls Lemonade a “visual album.” There’s been buzz about the image of Beyoncé smashing up cars, and a lot of talk about the autobiographical themes of the lyrics (lines like “better call Becky with the good hair” have been getting attention for the way they call out Jay Z’s mistress). But this 65-minute film’s songs, text and sound design haven’t been talked about in relation to its images. Lemonade’s unusual form—a long-play music video—gives it the capacity to draw connections between the personal pain of infidelity and America’s terrible history of racism. Twelve video clips are linked by brief passages comprised of poetry, visual tableaux and sound collage. These interludes lean toward avant-garde aesthetics. One thing avant garde aesthetics and music video share is the capacity to hold several vantage points in suspension. In Lemonade this capacity allows the work to embody opposites: love and hate, engagement and alienation, forgiveness and revenge

Canine mesenchymal stem cells are neurotrophic and angiogenic:an in vitro assessment of their paracrine activity

Mesenchymal stem cells (MSCs) have been used in cell replacement therapies for connective tissue damage, but also can stimulate wound healing through paracrine activity. In order to further understand the potential use of MSCs to treat dogs with neurological disorders, this study examined the paracrine action of adipose-derived canine MSCs on neuronal and endothelial cell models. The culture-expanded MSCs exhibited a MSC phenotype according to plastic adherence, cell morphology, CD profiling and differentiation potential along mesenchymal lineages. Treating the SH-SY5Y neuronal cell line with serum-free MSC culture-conditioned medium (MSC CM) significantly increased SH-SY5Y cell proliferation (P < 0.01), neurite outgrowth (P = 0.0055) and immunopositivity for the neuronal marker βIII-tubulin (P = 0.0002). Treatment of the EA.hy926 endothelial cell line with MSC CM significantly increased the rate of wound closure in endothelial cell scratch wound assays (P = 0.0409), which was associated with significantly increased endothelial cell proliferation (P < 0.05) and migration (P = 0.0001). Furthermore, canine MSC CM induced endothelial tubule formation in EA.hy926 cells in a soluble basement membrane matrix. Hence, this study has demonstrated that adipose-derived canine MSC CM stimulated neuronal and endothelial cells probably through the paracrine activity of MSC-secreted factors. This supports the use of canine MSC transplants or their secreted products in the clinical treatment of dogs with neurological disorders and provides some insight into possible mechanisms of action

Astroglial expression of the P-glycoprotein is controlled by intracellular CNTF

BACKGROUND: The P-glycoprotein (P-gp), an ATP binding cassette transmembrane transporter, is expressed by astrocytes in the adult brain, and is positively modulated during astrogliosis. In a search for factors involved in this modulation, P-gp overexpression was studied in long-term in vitro astroglial cultures. RESULTS: Surprisingly, most factors that are known to induce astroglial activation in astroglial cultures failed to increase P-gp expression. The only effective proteins were IFNγ and those belonging to the IL-6 family of cytokines (IL-6, LIF, CT-1 and CNTF). As well as P-gp expression, the IL-6 type cytokines - but not IFNγ - stimulated the expression of endogenous CNTF in astrocytes. In order to see whether an increased intracellular level of CNTF was necessary for induction of P-gp overexpression by IL-6 type cytokines, by the same cytokines analysis was carried out on astrocytes obtained from CNTF knockout mice. In these conditions, IFNγ produced increased P-gp expression, but no overexpression of P-gp was observed with either IL-6, LIF or CT-1, pointing to a role of CNTF in the intracellular signalling pathway leading to P-gp overexpression. In agreement with this suggestion, application of exogenous CNTF -which is internalised with its receptor - produced an overexpression of P-gp in CNTF-deficient astrocytes. CONCLUSIONS: These results reveal two different pathways regulating P-gp expression and activity in reactive astrocytes, one of which depends upon the intracellular concentration of CNTF. This regulation of P-gp may be one of the long searched for physiological roles of CNTF

Post-COVID-19 Adaptations; the Shifts Towards Online Learning, Hybrid Course Delivery and the Implications for Biosciences Courses in the Higher Education Setting

The Covid-19 pandemic has created challenges and caused disruption across the Higher Education sector; university campuses closed, and face-to-face teaching and assessment shifted to an online format. Learning from our students’ experience during this period will help us shape future hybrid delivery so that it best fits Bioscience students. This pedagogical study explored Aston University’s Bioscience students’ experiences of studying from home, and the impact of the lockdown on mental wellbeing and quality of life. 151 students completed an online survey during August 2020, which included open and closed questions. Analysis of survey data revealed that a majority of students reported positive experiences of online open-book assessments and most would welcome this format in the future. The majority of students faced no technical issues, predominantly stating that they also had good internet connectivity. Shifting to remote learning and online classrooms uncovered conflicting preferences; despite wanting more interactive lectures, only half of the students were comfortable interacting using video cameras. Free text responses provided an insight into how some students reported an inadequate home working space/environment and lacked necessary items such as a desk, highlighting how remote working may intensify social and digital inequality - particularly for students from more deprived households. Wider detrimental experiences of lockdown included dissatisfaction with access to healthcare, decreased concentration, sleeping difficulties and a decline in mental wellbeing. Education strategies going forward will need to address the mental health needs of students who have suffered during the pandemic. Our university, amongst others, is embracing hybrid course delivery, which could offer a solution to ensuring Bioscience students receive hands-on laboratory experience and face-to-face contact to remain motivated and benefit from the on-campus facilities and support, whilst allowing students some of the flexibility afforded by remote study. In the current competitive higher education market where student retention is key, it is important to consider student demographics and digital equity to ensure an appropriate approach is applied to cater for all students

Come to Daddy? Claiming Chris Cunningham for British Art Cinema

Twenty years after he came to prominence via a series of provocative, ground-breaking music videos, Chris Cunningham remains a troubling, elusive figure within British visual culture. His output – which includes short films, advertisements, art gallery commissions, installations, music production and a touring multi-screen live performance – is relatively slim, and his seemingly slow work rate (and tendency to leave projects uncompleted or unreleased) has been a frustration for fans and commentators, particularly those who hoped he would channel his interests and talents into a full-length ‘feature’ film project. There has been a diverse critical response to his musical sensitivity, his associations with UK electronica culture – and the Warp label in particular – his working relationship with Aphex Twin, his importance within the history of the pop video and his deployment of transgressive, suggestive imagery involving mutated, traumatised or robotic bodies. However, this article makes a claim for placing Cunningham within discourses of British art cinema. It proposes that the many contradictions that define and animate Cunningham's work – narrative versus abstraction, political engagement versus surrealism, sincerity versus provocation, commerce versus experimentation, art versus craft, a ‘British’ sensibility versus a transnational one – are also those that typify a particular terrain of British film culture that falls awkwardly between populism and experimentalism

Genotypic and antimicrobial characterisation of Propionibacterium acnes isolates from surgically excised lumbar disc herniations

The anaerobic skin commensal Propionibacterium acnes is an underestimated cause of human infections and clinical conditions. Previous studies have suggested a role for the bacterium in lumbar disc herniation and infection. To further investigate this, five biopsy samples were surgically excised from each of 64 patients with lumbar disc herniation. P. acnes and other bacteria were detected by anaerobic culture, followed by biochemical and PCR-based identification. In total, 24/64 (38%) patients had evidence of P. acnes in their excised herniated disc tissue. Using recA and mAb typing methods, 52% of the isolates were type II (50% of culture-positive patients), while type IA strains accounted for 28% of isolates (42% patients). Type III (11% isolates; 21% patients) and type IB strains (9% isolates; 17% patients) were detected less frequently. The MIC values for all isolates were lowest for amoxicillin, ciprofloxacin, erythromycin, rifampicin, tetracycline, and vancomycin (≤1mg/L). The MIC for fusidic acid was 1-2 mg/L. The MIC for trimethoprim and gentamicin was 2 to ≥4 mg/L. The demonstration that type II and III strains, which are not frequently recovered from skin, predominated within our isolate collection (63%) suggests that the role of P. acnes in lumbar disc herniation should not be readily dismissed. © 2013 Jess Rollason et al

Choreography, controversy and child sex abuse: Theoretical reflections on a cultural criminological analysis of dance in a pop music video

This article was inspired by the controversy over claims of ‘pedophilia!!!!’ undertones and the ‘triggering’ of memories of childhood sexual abuse in some viewers by the dance performance featured in the music video for Sia’s ‘Elastic Heart’ (2015). The case is presented for acknowledging the hidden and/or overlooked presence of dance in social scientific theory and cultural studies and how these can enhance and advance cultural criminological research. Examples of how these insights have been used within other disciplinary frameworks to analyse and address child sex crime and sexual trauma are provided, and the argument is made that popular cultural texts such as dance in pop music videos should be regarded as significant in analysing and tracing public perceptions and epistemologies of crimes such as child sex abuse