Interactions of Lysenin Channels with Sn\u3csup\u3e2+\u3c/sup\u3e Ions

Lysenin, a pore-forming toxin extracted from the red earthworm E. fetida, inserts large conductance channels in artificial and natural lipid membranes containing sphingomyelin. Based on prior reports showing that lysenin channels interact with many multivalent metals by employing a ligand-gated mechanism, we hypothesized that lysenin channels might similarly interact with Sn2+ ions in water-aqueous solutions. Our investigations were conducted on lysenin channels reconstituted in planar bilayer lipid membranes composed of Asolectin, Sphingomyelin, and Cholesterol and bathed by buffered electrolyte solutions. The electrical measurements were performed with an Axopatch 200B electrophysiology amplifier in a voltage clamp setting. The conductance of the channel-containing membranes was assessed from IV plots recorded in response to ramp voltages. Our results show that Sn2+ addition diminishes the membrane’s conductance in a concentration-dependent and cooperative manner. Single channel measurements allowed the identification of a ligand-gated mechanism responsible for the reduced conductance. Additionally, precipitation of Sn2+ ions by phosphate addition restored the original conductance, suggesting a reversible gating mechanism. These results are anticipated to contribute to a better understanding of the physiological role of lysenin channels and lead to applications that rely on the controlled passage of ions and molecules through natural and artificial lipid membranes

"She's a dog at the end of the day": guide dog owners' perspectives on the behaviour of their guide dog

A guide dog is a domestic dog (Canis familiaris) that is specifically educated to provide mobility support to a blind or visually impaired owner. Current dog suitability assessments focus on behavioural traits, including: trainability, reactivity or attention to environmental stimuli, low aggressiveness, fearfulness and stress behaviour, energy levels, and attachment behaviour. The aim of this study was to find out which aspects of guide dog behaviour are of key importance to guide dog owners themselves. Sixty-three semi-structured interview surveys were carried out with guide dog owners. Topics included the behaviour of their guide dog both within and outside their working role, and also focused on examples of behaviour which might be considered outside a guide dog owner’s typical expectations. Both positive and negative examples and situations were covered. This allowed for the discovery of new perspectives and emerging themes on living and working with a guide dog. Thematic analysis of the results reveals that a dog’s safe behaviour in the face of traffic was the most important positive aspect of a guide dog’s behaviour and pulling or high tension on the lead and /or harness was the most discussed negative aspect. Other aspects of guide dog behaviour were highlighted as particularly pleasing or disappointing by owners including attentiveness to the task, work, environment and owner; confidence in work and decision making (with confident dogs resulting in confident owners) obedience and control; calmness and locating objectives. The results reveal important areas of behaviour that are not currently considered priorities in guide dog assessments; these key areas were consistency of behaviour, the dog’s maturity and the dog’s behaviour in relation to children. The survey revealed a large range in what owners considered problematic or pleasing behaviours and this highlights the heterogeneity in guide dog owners and the potential multifarious roles of the guide dog. This study contributes to the literature on which behaviour is considered appropriate or inappropriate in dogs and on the nature of human-animal interactions

Poikilocytosis of Angora goats is associated with erythrocyte density and reticulocytosis

Angora goats in South Africa experience several syndromes that result in notable morbidity and mortality in juveniles and adults, but not kids. Insight into their causes is hampered by the lack of normal reference values for this breed, and the present study therefore aimed to characterise (1) differences in the haematology of healthy kids at birth and weaning, and (2) the haematology of apparently healthy yearlings. Selected variables were measured by blood smear analysis, and complete blood counts were performed using an ADVIA 2120i. Variables at 1, 11, and 20 weeks of age were compared using the Friedman test and associations between variables of yearlings were determined by correlation analysis. In kids, red blood cell count, mean corpuscular haemoglobin concentration (MCHC), and poikilocytosis increased over time, while mean corpuscular haemoglobin (MCH) and mean corpuscular volume (MCV) decreased. Yearlings displayed a lower MCHC, and higher haemoglobin distribution width than previously reported for goats, and these were positively correlated with poikilocytosis, as were reticulocyte counts. White cell counts of yearlings exceeded normal values previously reported for goats, with some individuals displaying remarkably high mature neutrophil counts. Changes in haemoglobin variant expression or cation and water fluxes are possible explanations for the findings in kids, while in yearlings, the associations between MCHC, HDW, poikilocytosis, and reticulocytosis suggest alterations in red cell hydration in adulthood that are associated with increased red cell turnover. These findings may prove informative in the further investigation of various clinical syndromes in this population.The South African Medical Research Council (SAMRC) Centre for Tuberculosis Research; The Harry Crossley Foundation; The Faculty of Medicine and Health Sciences Undergraduate Research Project Fund of Stellenbosch University.http://www.jsava.co.zaam2024Companion Animal Clinical StudiesSDG-03:Good heatlh and well-bein

Refining the Primrose syndrome phenotype: A study of five patients with ZBTB20 de novo variants and a review of the literature

Primrose syndrome is a rare autosomal dominant condition caused by heterozygous missense variants within ZBTB20. Through an exome sequencing approach (as part of the Deciphering Developmental Disorders [DDD] study) we have identified five unrelated individuals with previously unreported, de novo ZBTB20 pathogenic missense variants. All five missense variants targeted the C2H2 zinc finger domains. This genotype‐up approach has allowed further refinement of the Primrose syndrome phenotype. Major characteristics (>90% individuals) include an intellectual disability (most frequently in the moderate range), a recognizable facial appearance and brain MRI abnormalities, particularly abnormalities of the corpus callosum. Other frequent clinical associations (in 50–90% individuals) include sensorineural hearing loss (83%), hypotonia (78%), cryptorchidism in males (75%), macrocephaly (72%), behavioral issues (56%), and dysplastic/hypoplastic nails (57%). Based upon these clinical data we discuss our current management of patients with Primrose syndrom

Teaching higher education staff to understand and support autistic students: evaluation of a novel training program

BackgroundAutistic students are particularly vulnerable to stressors within a university environment and are more likely to experience poor mental health than their non-autistic peers. Students’ experiences of stigma from staff and peers, and the masking behaviors they deploy to minimize it, can also result in worsening mental health. Despite these concerns, there is a lack of tailored support for autistic students at university. The current project assesses a co-created training course for university staff focused on debunking stereotypes, educating about the autistic experience at university, mental health presentation among autistic individuals, and practical strategies to improve interactions with autistic students.MethodsThe Autism Stigma and Knowledge Questionnaire [ASK-Q] was administered before and after the training, to examine changes in trainees’ understanding and acceptance of autism and autistic people. Post-training interviews and surveys were also conducted with trainees, covering the impact the training has had on their perceptions of autism, the strategies they found beneficial, and how they will use the materials in future.ResultsThere were no statistically significant differences between pre- and post-training scores on the ASK-Q, likely due to ceiling effects as pre-training scores were high. Thematic analysis of interviews identified five themes: value of lived experience; developing nuanced, in-depth knowledge of autism; training as acceptable and feasible; links to professional practice; and systemic barriers.ConclusionAlthough ceiling effects meant there were no changes to participant’s knowledge about autism and autistic people statistically, the qualitative data reveals the extensive benefits they gained from taking part in the training programs. Scoring highly on the ASK-Q did not mean that people could not learn important new information and benefit from the course. This more nuanced understanding of autism led to practical changes in their practice. Listening to and learning from autistic people was seen as particularly important, highlighting the value of co-production. Our results also emphasize the need for varied approaches to evaluating training effectiveness, as reliance on quantitative data alone would have missed the subtler, but impactful, changes our participants experienced. This has important implications for professional practice, both within higher education and more broadly

Identification of the first ATRIP-deficient patient and novel mutations in ATR define a clinical spectrum for ATR-ATRIP Seckel Syndrome

A homozygous mutational change in the Ataxia-Telangiectasia and RAD3 related (ATR) gene was previously reported in two related families displaying Seckel Syndrome (SS). Here, we provide the first identification of a Seckel Syndrome patient with mutations in ATRIP, the gene encoding ATR-Interacting Protein (ATRIP), the partner protein of ATR required for ATR stability and recruitment to the site of DNA damage. The patient has compound heterozygous mutations in ATRIP resulting in reduced ATRIP and ATR expression. A nonsense mutational change in one ATRIP allele results in a C-terminal truncated protein, which impairs ATR-ATRIP interaction; the other allele is abnormally spliced. We additionally describe two further unrelated patients native to the UK with the same novel, heterozygous mutations in ATR, which cause dramatically reduced ATR expression. All patient-derived cells showed defective DNA damage responses that can be attributed to impaired ATR-ATRIP function. Seckel Syndrome is characterised by microcephaly and growth delay, features also displayed by several related disorders including Majewski (microcephalic) osteodysplastic primordial dwarfism (MOPD) type II and Meier-Gorlin Syndrome (MGS). The identification of an ATRIP-deficient patient provides a novel genetic defect for Seckel Syndrome. Coupled with the identification of further ATR-deficient patients, our findings allow a spectrum of clinical features that can be ascribed to the ATR-ATRIP deficient sub-class of Seckel Syndrome. ATR-ATRIP patients are characterised by extremely severe microcephaly and growth delay, microtia (small ears), micrognathia (small and receding chin), and dental crowding. While aberrant bone development was mild in the original ATR-SS patient, some of the patients described here display skeletal abnormalities including, in one patient, small patellae, a feature characteristically observed in Meier-Gorlin Syndrome. Collectively, our analysis exposes an overlapping clinical manifestation between the disorders but allows an expanded spectrum of clinical features for ATR-ATRIP Seckel Syndrome to be define

The Mock LISA Data Challenges: from Challenge 3 to Challenge 4

The Mock LISA Data Challenges are a program to demonstrate LISA data-analysis capabilities and to encourage their development. Each round of challenges consists of one or more datasets containing simulated instrument noise and gravitational waves from sources of undisclosed parameters. Participants analyze the datasets and report best-fit solutions for the source parameters. Here we present the results of the third challenge, issued in Apr 2008, which demonstrated the positive recovery of signals from chirping Galactic binaries, from spinning supermassive--black-hole binaries (with optimal SNRs between ~ 10 and 2000), from simultaneous extreme-mass-ratio inspirals (SNRs of 10-50), from cosmic-string-cusp bursts (SNRs of 10-100), and from a relatively loud isotropic background with Omega_gw(f) ~ 10^-11, slightly below the LISA instrument noise.Comment: 12 pages, 2 figures, proceedings of the 8th Edoardo Amaldi Conference on Gravitational Waves, New York, June 21-26, 200

Expanding the genotypic spectrum of TXNL4A variants in Burn‐McKeown syndrome

From Wiley via Jisc Publications RouterHistory: received 2021-09-06, rev-recd 2021-10-21, accepted 2021-10-23, pub-electronic 2021-11-05Article version: VoRPublication status: PublishedFunder: Biotechnology and Biological Sciences Research Council; Id: http://dx.doi.org/10.13039/501100000268; Grant(s): BB/N000358/1Funder: Health Education England Genomics Education ProgrammeFunder: Medical Research Council; Id: http://dx.doi.org/10.13039/501100007155; Grant(s): 1916606Funder: National Institute for Health Manchester Biomedical Research Centre; Grant(s): IS‐BRC‐1215‐20007Abstract: The developmental disorder Burn‐McKeown Syndrome (BMKS) is characterised by choanal atresia and specific craniofacial features. BMKS is caused by biallelic variants in the pre‐messenger RNA splicing factor TXNL4A. Most patients have a loss‐of‐function variant in trans with a 34‐base pair (bp) deletion (type 1 Δ34) in the promoter region. Here, we identified two patients with BMKS. One individual has a TXNL4A c.93_94delCC, p.His32Argfs *21 variant combined with a type 1 Δ34 promoter deletion. The other has an intronic TXNL4A splice site variant (c.258‐3C>G) and a type 1 Δ34 promoter deletion. We show the c.258‐3C>G variant and a previously reported c.258‐2A>G variant, cause skipping of the final exon of TXNL4A in a minigene splicing assay. Furthermore, we identify putative transcription factor binding sites within the 56 bp of the TXNL4A promoter affected by the type 1 and type 2 Δ34 and use dual luciferase assays to identify a 22 bp repeated motif essential for TXNL4A expression within this promoter region. We propose that additional variants affecting critical transcription factor binding nucleotides within the 22 bp repeated motif could be relevant to BMKS aetiology. Finally, our data emphasises the need to analyse the non‐coding sequence in individuals where a single likely pathogenic coding variant is identified in an autosomal recessive disorder consistent with the clinical presentation

Priorities for social science and humanities research on the challenges of moving beyond animal-based food systems

Increasingly high-profile research is being undertaken into the socio-environmental challenges associated with the over-production and consumption of food from animals. Transforming food systems to mitigate climate change and hidden hunger, ensure food security and good health all point to reducing animal-based foods as a key lever. Moving beyond animal-based food systems is a societal grand challenge requiring coordinated international research by the social sciences and humanities. A 'selective openness' to this range of disciplines has been observed within multi-discipline research programmes designed to address societal grand challenges including those concerned with the sustainability of food systems, inhibiting the impact of social sciences and humanities. Further, existing research on animal-based foods within these disciplines is largely dispersed and focused on particular parts of food systems. Inspired by the 'Sutherland Method' this paper discusses the results of an iterative research prioritisation process carried out to enhance capacity, mutual understanding and impact amongst European social sciences and humanities researchers. The process produced 15 research questions from an initial list of 100 and classified under the following five themes: (1) debating and visioning food from animals; (2) transforming agricultural spaces; (3) framing animals as food; (4) eating practices and identities; and (5) governing transitions beyond animal-based food systems. These themes provide an important means of making connections between research questions that invite and steer research on key challenges in moving beyond animal-based food systems. The themes also propose loci for future transdisciplinary research programmes that join researchers from the natural sciences, social sciences, and humanities and stakeholders from beyond academia to develop cooperative research and implementation initiatives. The experiences gained from the prioritisation process draw attention to the value of spending time to discuss and collaboratively steer research enquiry into emergent and controversial matters of concern. Fundamental, ethical questions around the continuation or complete cessation of the use of animals for food was a key tension. The positioning of research towards these questions affects not only the framing of the research area but also the partners with whom the research can be carried out and for whom it may be of benefit.peerReviewe