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DNA demethylating agents suppress preclinical models of synovial sarcoma
No full textSynovial sarcoma is an aggressive soft tissue cancer driven by the chimeric SS18::SSX fusion oncoprotein, which disrupts chromatin remodeling by combining two antagonistic transcriptional regulators. SS18 participates in BAF complexes that open chromatin, while the SSX genes are cancer-testis antigens that interface with chromatin decorated with monoubiquitinated histone H2A placed by Polycomb repressive complexes (PRCs) activity. Because KDM2B brings PRC to unmethylated CpG islands, it is plausible that methylation directly determines the distribution of SS18::SSX to target loci. Given that synovial sarcoma is also characterized by a peculiarly low DNA hypomethylation profile, we hypothesized that further disturbance of DNA methylation would have a negative impact on synovial sarcoma growth. DNMT1 disruption by CRISPR/Cas9 targeting or pharmacologic inhibition with cytidine analogs 5-aza-2ʹ-deoxycytidine (decitabine) and 5-azacytidine led to decreased genome-wide methylation, redistribution of SS18::SSX, and altered gene expression profiles, most prominently including upregulation of tumor suppressor genes, immune-related genes, and mesenchymal differentiation-related genes. These drugs suppressed growth of synovial sarcoma cell lines and drove cytoreduction in mouse genetic models. DNMT1 inhibitors, already approved for treating myelodysplastic syndromes, warrant further clinical investigation for synovial sarcoma as repurposed, targeted treatments exploiting a vulnerability in the intrinsic biology of this cancer
Calix[4]arene-supported trigonal and square prisms of Mn and Na
No full textThe heterometallic tricapped trigonal prism [MnIII3Na6(TBC[4])3(CO3)(Cl)(dmso)7]·5MeCN ([Mn3Na6]; 1·5MeCN) and the related heterometallic tetracapped square prism [MnIII4MnII2Na6(bisTBC[4])2(CO3)2(Cl)2(dmf)8(MeOH)1.2(H2O)0.8]·6MeCN ([Mn6Na6]; 2·6MeCN), are isolated using p-tBu-calix[4]arene (H4TBC[4]) and 2,2′-bis-p-tBu-calix[4]arene (H8-bisTBC[4]), respectively. In the former the MnIII ions sit in the TBC[4] polyphenolic pockets, forming three Mn-TBC[4] metalloligands that cap the square faces of the prism, whose vertices contain the six Na ions. Introduction of the bis-calix[4]arene enables expansion of the main building block from three Mn-TBC[4] metalloligands in 1 to four Mn-TBC[4] metalloligands in 2. The result is the formation of a square prism of Na/MnII ions, with four of the square faces capped with MnIII ions. Dc magnetic susceptibility and magnetisation measurements reveal paramagnetism in 1 and weak antiferromagnetic exchange interactions in 2.</p
Circulating microRNAs associated with immune competence in Angus cattle
No full textAn immune competence (IC) trait has been developed in livestock to combat infectious diseases through selective breeding. Here, we investigate whether circulating host-encoded microRNAs (miRNAs) are associated with immune responses to a commercial multivalent clostridial and leptospiral vaccine in Australian Angus steers, a proxy measure for IC. A total of 332 animals from 2 herds in New South Wales, Australia-Herd 1 (n = 168) and Herd 2 (n = 164)-were IC phenotyped on the day of yard weaning. Within a herd, animals were ranked by their antibody- (Ab-IR) and cell-mediated (Cell-IR) immune responses, and animals identified as "high" or "low" were in the top or bottom 7% of animals for each, respectively. A total of 47 steers that were identified as either low Cell-IR (n = 12), high Cell-IR (n = 11), low Ab-IR (n = 12), or high Ab-IR (n = 12) were selected for miRNA analysis. The IC score, a weighted average incorporating both Ab-IR and Cell-IR rankings, was calculated for selected steers. Our results indicate that the IC phenotype is associated with differences in circulating miRNA profiles. Linear regression modeling identified a potential association between pre-vaccination miR-150 levels and IC scores, while logistic regression modeling suggested that pre-vaccination miR-150 may differentiate IC high and low steers. Machine learning classification models further identified a 5-miRNA signature (miR-192, miR-150, miR-2285co, miR-155, and let-7a-5p) that classified high IC steers with 94% accuracy in this dataset. The findings of this pilot study suggest that circulating miRNAs warrant further investigation as potential predictors of immune response to vaccination and may provide insights into miRNA-regulated pathways involved in vaccine-induced immunity.</p
Variant Creutzfeldt-Jakob disease in UK children after 27 years of active prospective surveillance
No full textOBJECTIVE: To determine whether any children in the UK had variant Creutzfeldt-Jakob disease (vCJD).DESIGN: This active prospective epidemiological study used the British Paediatric Surveillance Unit, asking UK paediatricians to notify all childhood cases of progressive intellectual and neurological deterioration (PIND), a group that would include all cases of vCJD. Clinical data were obtained by questionnaire or via a site visit. An independent expert group classified the cases. If vCJD was suspected, referral to the National Creutzfeldt-Jakob Disease Research and Surveillance Unit was recommended.RESULTS: Between May 1997 and April 2024 (27 years), 5222 children were notified. There were four groups. (1) 2540 were 'not cases'-they did not meet the case definition or there were notification errors. (2) 2367 had a known underlying diagnosis other than vCJD; the group contained more than 220 different diseases. (3) 309 had no diagnosis to explain their deterioration; there was evidence that none of these cases had vCJD. (4) There were six cases of vCJD: two males and four females. They developed symptoms between 1998 and 2000, aged 12-15 years, and the last two died in 2003. Their clinical features were similar to those of adults. Four were classified as definite vCJD and two as probable vCJD.CONCLUSIONS: This study has provided unique data about neurodegenerative diseases in UK children. There is no reliable vCJD screening test; so for 27 years, the PIND study has provided reassurance that childhood vCJD cases were not missed. New vCJD cases with the methionine/valine genotype could appear.</p
Designing Exchangeopoly: A boardgame to explore value exchange within communities
No full textIn this pictorial, we discuss the design of Exchangeopoly, a boardgame developed to investigate exchanges between people in communities when they help each other out. Such exchanges are often acts of kindness for forms of volunteering that are not remunerated financially and are built on social capital. The boardgame scaffolded explorations of scenarios with participants where informal altruistic interactions in their communities are tokenised, rewarded and incentivised. We focus on the designed-in features and considerations that went into the visual and material production of the game and its gameplay mechanics. We discuss how Exchangeopoly was a valuable method that surfaced existing and speculated practices of exchange, and supported participants to explore the opportunities and problems of representing and rewarding such interactions. We contribute insights about the usefulness of exchangeopoly as a tool to explore scenarios and surface tensions about tokenisation in community value exchange
Future of money and HCI
No full textMoney and financial activities reflect social connections and societal norms. Collaborative financial activities and decision-making are highly common in our day-to-day activities. However, existing financial technologies (fintech) are often limited to individual-centric approaches and goals. Recent HCI work has repeatedly noted the need for creating new interaction strategies and design paradigms to better support our financial behaviors, habits, and goals. However, there has not been much concrete work yet, specifically when it comes to supporting collaborative behaviors and social norms that underpin much of our daily financial activities. In this in-person workshop, we will bring together an interdisciplinary group of researchers interested in reshaping the current landscape of digital money and fintech with a focus on social and collaborative interactions. Specifically, we will identify limitations of existing fintech approaches and potential strategies to address these limitations. We will also discuss key challenges for fintech design and development, including collaboration, privacy, agency, trust, and accessibility. The workshop will lead to identifying novel HCI research and implementation directions focusing on the future of financial technologies.</p
Quantification of carotid artery plaque and peri-vascular adipose tissue attenuation on computed tomography
No full textAimsQuantitative assessment of carotid artery plaque on computed tomography (CT) may identify high-risk phenotypes associated with culprit lesions and subsequent ischaemic stroke or transient ischaemic attack.Methods and resultsCarotid CT angiography was performed in 48 patients with acute ischaemic stroke or transient ischaemic attack within 21 days. Quantitative plaque assessment was performed in the proximal 6 cm of the internal and external carotid artery, distal 6 cm of the common carotid artery, and residual common carotid artery. Semi-automated quantification included assessment of non-calcified, calcified, low-attenuation, and total plaque, area and diameter stenosis, and peri-vascular adipose tissue attenuation. In 48 patients (mean age 71 ± 11 years, 67% male), 96 vessels were assessed with 30 (31%) identified as culprit vessels. Culprit internal carotid arteries had greater area [83 (65, 94) vs. 64 (55, 77)%] and diameter [56 (39, 74) vs. 32 (21, 48)%] stenosis and more non-calcified [563 (413, 965) vs. 428 (283 649) mm3, P = 0.04], low-attenuation [33.7 (6.9, 72.4) vs. 16.3 (3.35, 54.3) mm3, P = 0.01], and total [699 (455, 1057) vs. 492 (311, 809), P = 0.04] plaque. There was no difference in calcified plaque or peri-vascular adipose tissue attenuation between culprit and non-culprit internal carotid arteries. There were no differences in quantitative plaque or peri-vascular adipose tissue attenuation in the external carotid artery or common carotid artery.ConclusionCarotid atherosclerotic plaque characteristics are the principal features associated with culprit plaques with little or no demonstrable relationship with calcified plaque or increased peri-vascular adipose tissue attenuation
Rodent chronic variable stress procedures: a disjunction between stress entity and impact on behaviour
No full textBackground Chronic variable stress (CVS) procedures are widely used to model depression in laboratory mice and rats. In order to explore how study design might impact experimental outcomes, we systematically documented characteristics of study design in a series of published rodent CVS studies and, in a subset of studies, measured effect sizes in the behavioural tests used to evaluate the effects of CVS. We hypothesised that CVS procedures that were longer or involved more stressors would be associated with larger effect sizes in five commonly used behavioural tests: the sucrose preference test (SPT), the tail suspension test (TST), the forced swim test (FST), the open field test (OFT) and the elevated plus maze (EPM). We also hypothesised that effect sizes would positively correlate between the behavioural tests that are believed to measure the same consequences of CVS. Methods We searched PubMed for articles using CVS procedures with mice or rats and systematically documented the duration (the length of the CVS procedure), burden (the total number of stressors experienced by the animal) and diversity (the total number of different types of stressors used) of the CVS procedures used. We also systematically documented the design of the behavioural tests used to evaluate the effects of CVS in each study and calculated the effect sizes obtained in these tests. To ask whether effects sizes in these tests correlated with characteristics of the CVS procedure used, we used a linear model of the effect of duration, burden and diversity on the effect size then calculated the Euclidean distance between studies’ characteristics and correlated those with the differences in effect size between studies. To explore whether effect sizes correlated between different behavioural tests, we calculated a pairwise Pearson correlation. Results We observed that most studies used a unique CVS procedure. In contrast to our hypothesis, the most evident impact of CVS procedure design was on FST effect sizes where longer-duration CVS procedures with more diverse types of stressors were associated with a smaller effect size in behavioural tests. When exploring correlations between behavioural test effect sizes, we found a positive correlation between effects sizes in the TST and FST, and in the OFT and EPM, but the strongest positive correlations were between the EPM and TST, and between the EPM and FST.Conclusion We did not find evidence for a strong relationship between the design of CVS procedures and the effect sizes seen in the behavioural tests used to evaluate these procedures. When we explored correlations in effect sizes between different behavioural tests, we uncovered complex relationships that are not necessarily in concordance with current understanding of what these tests measure. Accordingly, our data raise scientific questions around the design of CVS procedures used and the behavioural tests used to evaluate them.<br/
No train but gain:Language arithmetic for training-free language adapters enhancement
No full textModular deep learning is the state-of-the-art solution for lifting the curse of multilinguality, preventing the impact of negative interference and enabling cross-lingual performance in Multilingual Pre-trained Language Models. However, a trade-off of this approach is the reduction in positive transfer learning from closely related languages. In response, we introduce a novel method called language arithmetic, which enables training-free post-processing to address this limitation. Extending the task arithmetic framework, we apply learning via addition to the language adapters, transitioning the framework from a multi-task to a multilingual setup. The effectiveness of the proposed solution is demonstrated on three downstream tasks in a MAD-X-based set of cross-lingual schemes, acting as a post-processing procedure. Language arithmetic consistently improves the baselines with significant gains, especially in the most challenging case of zero-shot application. Our code and models are available at https://github.com/mklimasz/language-arithmetic
Development and validation of a novel approach for quantifying dimensions of the lateral ligaments in human ankle dissections
No full textThe lateral ankle ligaments, composed of the anterior talofibular (ATFL), calcaneofibular (CFL), and posterior talofibular ligaments (PTFL) are frequently subject to injury. While conservative and surgical treatment methods have had some positive outcomes, high rates of re-injury, chronic ankle instability, and pain remain, prompting the investigation of tissue-engineered applications in the treatment of lateral ligament injuries. In order for tissue-engineered construct design to be undertaken, a complete understanding of the native anatomy of the lateral ankle ligaments must be obtained. To date, substantial data exist on the anatomical structure of the lateral ankle ligaments, particularly surrounding their dimensions throughout movements of the ankle complex. Despite this, current literature does not consider the dynamic nature of the lateral ankle ligaments when assessing true ligament length nor the ability of ligaments to stretch and recoil throughout joint movement. Existing methodologies for measuring the lateral ankle ligaments commonly use instruments with limited flexibility and simply measure the distance between attachment points, not accounting for any degree of relaxation within the ligament. Therefore, this study aims to establish a new methodology that considers the curvatures and form of the lateral ankle ligaments throughout all movements of the ankle complex. Cadaveric dissection was performed on 21 ankles to fully expose the lateral ankle ligaments. The full length of the ATFL, CFL, and PTFL was measured following a newly developed ‘String for Dynamic Tissue’ (SDT) method. Flax-coated wax string was aligned and moulded to the surface and curves of each ligament from the most proximal attachment point to the most distal attachment point, along the same plane and cut to size. Measurements for each ligament were assessed throughout all degrees of movement of the ankle complex: plantarflexion, dorsiflexion, inversion, eversion, and neutral. A digital calliper was used to measure the exact string length, representing both the relaxed and taut ligament's full ligament length. Across all samples, the full length of the ATFL ranged between 21.20 and 33.80 mm (n = 20) throughout all movements of the ankle complex. Measurements of the CFL ranged between 28.66 and 44.44 mm (n = 21), while full-length measurements of the PTFL ranged from 27.90 to 39.80 mm (n = 21). Ligament dimensions of the relaxed ligament were greater when compared to the current literature, while dimensions of the taut ligament closely resembled data currently available. The SDT method not only enables accurate measurement and assessment of non-linear structures but also highlights the importance of considering complete structural form, emphasizing the need to move beyond merely measuring the linear distance between two points. This method will have multiple applications within the anatomical and biomechanical fields and across a range of tissue types and locations
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