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Abstract Background Restraining or slowing ageing hallmarks at the cellular level have been proposed as a route to increased organismal lifespan and healthspan. Consequently, there is great interest in anti-ageing drug discovery. However, this currently requires laborious and lengthy longevity analysis. Here, we present a novel screening readout for the expedited discovery of compounds that restrain ageing of cell populations in vitro and enable extension of in vivo lifespan. Methods Using Illumina methylation arrays, we monitored DNA methylation changes accompanying long-term passaging of adult primary human cells in culture. This enabled us to develop, test, and validate the CellPopAge Clock, an epigenetic clock with underlying algorithm, unique among existing epigenetic clocks for its design to detect anti-ageing compounds in vitro. Additionally, we measured markers of senescence and performed longevity experiments in vivo in Drosophila, to further validate our approach to discover novel anti-ageing compounds. Finally, we bench mark our epigenetic clock with other available epigenetic clocks to consolidate its usefulness and specialisation for primary cells in culture. Results We developed a novel epigenetic clock, the CellPopAge Clock, to accurately monitor the age of a population of adult human primary cells. We find that the CellPopAge Clock can detect decelerated passage-based ageing of human primary cells treated with rapamycin or trametinib, well-established longevity drugs. We then utilise the CellPopAge Clock as a screening tool for the identification of compounds which decelerate ageing of cell populations, uncovering novel anti-ageing drugs, torin2 and dactolisib (BEZ-235). We demonstrate that delayed epigenetic ageing in human primary cells treated with anti-ageing compounds is accompanied by a reduction in senescence and ageing biomarkers. Finally, we extend our screening platform in vivo by taking advantage of a specially formulated holidic medium for increased drug bioavailability in Drosophila. We show that the novel anti-ageing drugs, torin2 and dactolisib (BEZ-235), increase longevity in vivo. Conclusions Our method expands the scope of CpG methylation profiling to accurately and rapidly detecting anti-ageing potential of drugs using human cells in vitro, and in vivo, providing a novel accelerated discovery platform to test sought after anti-ageing compounds and geroprotectors.

Background: Intra-lenticular foreign bodies are rare in veterinary medicine and uncommon in human medicine. Approximately 50% of perforating ocular injuries in canines have lenticular involvement. Treatment choices include conservative management and surgical options. Retained intra-lenticular foreign body with delayed removal has not been reported in animals. Case Description: A 3-year-old, male neutered Lurcher presented with right sided ocular discomfort and a sealed full-thickness corneal perforation. Full ophthalmic examination could not be performed at the initial presentation due to miosis. Recrudescence of anterior uveitis was seen post-drug cessation. Re-evaluation of the eye with a mydriatic pupil revealed an intra-lenticular foreign body. Surgical removal via phacoemulsification was performed eight weeks after initial perforating injury. The eye remains visual, comfortable, and normotensive 50 months post-operatively. Conclusion: This is the first report of an encapsulated, retained intra-lenticular foreign body with delayed removal in a dog. Mydriasis and repeat examinations are of crucial importance when evaluating eyes post perforation. [Open Vet J 2023; 13(10.000): 1379-1384]

Background: Only 27 cases of equine conjunctival haemangiosarcoma have been reported in the literature over the past 37 years. Out of these, 22% of cases were lost to follow-up, 52% were euthanised and 26% survived. A scarcity of cases and information is available for this rarely seen conjunctival tumour. Aim: To describe the clinical features, management, and outcome for conjunctival hemangiosarcoma in seven horses in the UK. Methods: Optivet medical records were reviewed for equine cases seen, or advised on, with a histopathological diagnosis of conjunctival haemangiosarcoma between January 2013 and March 2023. Medical records were accessed for details of signalment, history, management, and follow-up. Histopathology was used to confirm the diagnosis of haemangiosarcoma and assess the surgical margins. Immunohistochemistry was performed in a minority of cases with poorly differentiated solid tumours to support vascular lineage. Results: Seven eyes from 7 horses (5 geldings and 2 mares) with a mean age of 16 years and median of 18 years (range 10-21 years) met the criteria. Serosanguinous discharge was seen in 6 eyes. All eyes were managed surgically; 4 by exenteration and 3 by conjunctivectomy/keratectomy. Adjunctive cryotherapy was performed in 2 eyes. Metastatic disease in the ipsilateral parotid salivary gland, confirmed with histopathology, was seen in 1 horse. Surgical margins were clear in all but 1 eye. Solar elastosis was noted in 5 eyes. All horses were healthy at the last follow-up (0.2 – 5 years, mean 2.9 years, median 2 years). Conclusion: Equine conjunctival haemangiosarcoma is rare. Serosanguinous ocular discharge is a common clinical sign. Early surgical excision is highly effective. Solar elastosis is a common histopathological feature, suggesting a role for UV-light in the pathogenesis. [Open Vet J 2023; 13(10.000): 1366-1378]

Abstract Understanding the effects of temperature on ecological and evolutionary processes is crucial for generating future climate adaptation scenarios. Using experimental evolution, we evolved the model ciliate Tetrahymena thermophila in an initially novel high temperature environment for more than 35 generations, closely monitoring population dynamics and morphological changes. We observed initially long lag phases in the high temperature environment that over about 26 generations reduced to no lag phase, a strong reduction in cell size and modifications in cell shape at high temperature. When exposing the adapted populations to their original temperature, most phenotypic traits returned to the observed levels in the ancestral populations, indicating phenotypic plasticity is an important component of this species thermal stress response. However, persistent changes in cell size were detected, indicating possible costs related to the adaptation process. Exploring the molecular basis of thermal adaptation will help clarify the mechanisms driving these phenotypic responses.

Abstract Epigenetic clocks comprise a set of CpG sites whose DNA methylation levels measure subject age. These clocks are acknowledged as a highly accurate molecular correlate of chronological age in humans and other vertebrates. Also, extensive research is aimed at their potential to quantify biological aging rates and test longevity or rejuvenating interventions. Here, we discuss key challenges to understand clock mechanisms and biomarker utility. This requires dissecting the drivers and regulators of age-related changes in single-cell, tissue- and disease-specific models, as well as exploring other epigenomic marks, longitudinal and diverse population studies, and non-human models. We also highlight important ethical issues in forensic age determination and predicting the trajectory of biological aging in an individual.

The Research Collaboratory for Structural Bioinformatics Protein Data Bank (RCSB PDB), funded by the United States National Science Foundation, National Institutes of Health, and Department of Energy, supports structural biologists and Protein Data Bank (PDB) data users around the world. The RCSB PDB, a founding member of the Worldwide Protein Data Bank (wwPDB) partnership, serves as the US data center for the global PDB archive housing experimentally-determined three-dimensional (3D) structure data for biological macromolecules. As the wwPDB-designated Archive Keeper, RCSB PDB is also responsible for the security of PDB data and weekly update of the archive. RCSB PDB serves tens of thousands of data depositors (using macromolecular crystallography, nuclear magnetic resonance spectroscopy, electron microscopy, and micro-electron diffraction) annually working on all permanently inhabited continents. RCSB PDB makes PDB data available from its research-focused web portal at no charge and without usage restrictions to many millions of PDB data consumers around the globe. It also provides educators, students, and the general public with an introduction to the PDB and related training materials through its outreach and education-focused web portal. This review article describes growth of the PDB, examines evolution of experimental methods for structure determination viewed through the lens of the PDB archive, and provides a detailed accounting of PDB archival holdings and their utilization by researchers, educators, and students worldwide.

This article adapts an existing experimental protocol for assessing individuals’ ability to transfer knowledge across instrumental and pavlovian learning stages. The protocol (Transfer of Control using differential outcomes learning) is adapted to fit social contexts wherein the pavlovian learning phase is modulated so that individuals are able to observe, and potentially learn from, the stimulus associated with reinforcing outcomes presented to another (observable) individual. Transfer of Control concerns participants combining knowledge of learned instrumental and pavlovian (stimulus, response, outcome) associations in order to ground the learning of new associations. The article describes the theoretical and procedural underpinnings of a novel Social Transfer of Control methodology. The use of such a methodology is two-fold: i) to serve as a guide to researchers interested in evaluating how individuals can learn from others in a partially observable setting, i.e. when behavioural and reinforcing outcome information is hidden, and bring to bear this knowledge on their own instrumental decision making; ii), to facilitate investigation of the routes of cognitive and emotional empathy, with potential applications for educational and clinical settings. • Three stage Transfer of Control behavioural methodology is adapted to include a social (pavlovian) learning stage. • Hypotheses can be tested that concern learning rewarding instrumental responses achieved by observation of others’ emotionally expressive reactions to differentially rewarding outcomes. • Methodological and validation considerations for evaluating the above are presented

This article contains performance data, questionnaire ratings, and EEG data from a differential outcomes learning task from two experiments. In both experiments, the standard differential outcomes learning task was extended to involve a social dimension, in order to capture how people can learn from others by observation. In Experiment 1 (N = 20), using a within-subjects design, participants learned pairings of image stimuli in four conditions: 1) individual-differential outcomes, 2) individual-non-differential outcomes, 3) social-differential outcomes, and 4) social-non-differential outcomes. The social condition had a screen-captured video recording of the outcomes (but not the actions themselves) of another person performing the task. During the task, the performance of the participants was measured. After the task, participants rated their experience in a questionnaire. The procedure for Experiment 2 (N = 33) was similar to Experiment 1, but with a stronger social manipulation using a video of another person's face showing facial expressions reflecting the outcomes. In addition, EEG was measured while performing the task. For more insight, please see Vicarious value learning: Knowledge transfer through affective processing on a social differential outcomes task (Rittmo et al., 2020).

Abstract Background Environmental influences fluctuate throughout the life course of an organism. It is therefore important to understand how the timing of exposure impacts molecular responses. Herein, we examine the responses of two key molecular markers of dietary stress, namely variant-specific methylation at ribosomal DNA (rDNA) and small RNA distribution, including tRNA fragments, in a mouse model of protein restriction (PR) with exposure at pre- and/or post-weaning. Results We first confirm that pre-weaning PR exposure modulates the methylation state of rDNA in a genotype-dependent manner, whereas post-weaning PR exposure has no such effect. Conversely, post-weaning PR induces a shift in small RNA distribution, but there is no effect in the pre-weaning PR model. Intriguingly, mice exposed to PR throughout their lives show neither of these two dietary stress markers, similar to controls. Conclusions The results show that the timing of the insult affects the nature of the molecular response but also, critically, that ‘matching’ diet exposure either side of weaning eliminates the stress response at the level of rDNA methylation and small RNA in sperm.

Abstract Background Mammalian species exhibit a wide range of lifespans. To date, a robust and dynamic molecular readout of these lifespan differences has not yet been identified. Recent studies have established the existence of ageing-associated differentially methylated positions (aDMPs) in human and mouse. These are CpG sites at which DNA methylation dynamics show significant correlations with age. We hypothesise that aDMPs are pan-mammalian and are a dynamic molecular readout of lifespan variation among different mammalian species. Results A large-scale integrated analysis of aDMPs in six different mammals reveals a strong negative relationship between rate of change of methylation levels at aDMPs and lifespan. This relationship also holds when comparing two different dog breeds with known differences in lifespans. In an ageing cohort of aneuploid mice carrying a complete copy of human chromosome 21, aDMPs accumulate far more rapidly than is seen in human tissues, revealing that DNA methylation at aDMP sites is largely shaped by the nuclear trans-environment and represents a robust molecular readout of the ageing cellular milieu. Conclusions Overall, we define the first dynamic molecular readout of lifespan differences among mammalian species and propose that aDMPs will be an invaluable molecular tool for future evolutionary and mechanistic studies aimed at understanding the biological factors that determine lifespan in mammals.

The incidence of type 1 diabetes is increasing, potentially implicating non-genetic factors. Here the authors conduct an epigenome-wide association study in disease-discordant twins and find increased DNA methylation variability at genes associated with immune cell metabolism and the cell cycle.

Summary: Senescence is a cellular phenotype present in health and disease, characterized by a stable cell-cycle arrest and an inflammatory response called senescence-associated secretory phenotype (SASP). The SASP is important in influencing the behavior of neighboring cells and altering the microenvironment; yet, this role has been mainly attributed to soluble factors. Here, we show that both the soluble factors and small extracellular vesicles (sEVs) are capable of transmitting paracrine senescence to nearby cells. Analysis of individual cells internalizing sEVs, using a Cre-reporter system, show a positive correlation between sEV uptake and senescence activation. We find an increase in the number of multivesicular bodies during senescence in vivo. sEV protein characterization by mass spectrometry (MS) followed by a functional siRNA screen identify interferon-induced transmembrane protein 3 (IFITM3) as being partially responsible for transmitting senescence to normal cells. We find that sEVs contribute to paracrine senescence. : Borghesan et al. show that the soluble fraction and small extracellular vesicles (sEVs) mediate paracrine senescence. RNA sequencing and loxP reporter systems confirm sEV-mediated paracrine senescence, while preventing sEV release averts senescence. Mass spectrometry and functional analysis show that the IFN protein, IFITM3, is partially responsible for this phenotype. Keywords: exosomes, small extracellular vesicles, EV, paracrine senescence, OIS, DDIS, aging, interferon, IFITM3, fragilis

Hepatocellular cancer (HCC) is increasing dramatically in incidence in Europe and the United States due mainly to the hepatitis C epidemic and, to a lesser extent, increased body mass index of the population. In the fairly recent past, HCC was largely considered as untreatable due to detection mainly at late stages and lack of effective drugs for treatment. Several advances have led to changes in the prognosis of HCC. Screening of high-risk populations has allowed for earlier detection in some studies. If found at an early stage, liver transplantation not only cures the usual underlying cirrhosis but has cure rates for HCC in the range of 60% in recent series. Larger lesions can sometimes be cured by partial hepatic resection assuming the remaining liver is not too damaged to sustain liver functions after surgery. Vaccination for hepatitis B has led to reduction in the incidence of HCC. Significant improvements in antiviral treatments for both hepatitis B and hepatitis C may be having an impact on the incidence of HCC as well. It is still generally held that a finding of metastases precludes cure of HCC. We here report the case of a patient who presented with a large HCC in the context of occult hepatitis C infection. The primary tumor was resected. Over a year later, he developed a lung metastasis that was resected as well. He has not shown recurrence for 6 years since the metastasectomy. We review the recent literature on resection of lung metastases from HCC.

Introduction: This study compared the effects of vasopressin via tibial intraosseous (IO) and intravenous (IV) routes on maximum plasma concentration (Cmax), the time to maximum concentration (Tmax), return of spontaneous circulation (ROSC), and time to ROSC in a hypovolemic cardiac arrest model. Methods: This study was a randomized prospective, between-subjects experimental design. A computer program randomly assigned 28 Yorkshire swine to one of four groups: IV (n=7), IO tibia (n=7), cardiopulmonary resuscitation (CPR) + defibrillation (n=7), and a control group that received just CPR (n=7). Ventricular fibrillation was induced, and subjects remained in arrest for two minutes. CPR was initiated and 40 units of vasopressin were administered via IO or IV routes. Blood samples were collected at 0.5, 1, 1.5, 2, 2.5, 3, and 4 minutes. CPR and defibrillation were initiated for 20 minutes or until ROSC was achieved. We measured vasopressin concentrations using highperformance liquid chromatography. Results: There was no significant difference between the IO and IV groups relative to achieving ROSC (p=1.0) but a significant difference between the IV compared to the CPR+ defibrillation group (p=0.031) and IV compared to the CPR-only group (p=0.001). There was a significant difference between the IO group compared to the CPR+ defibrillation group (p=0.031) and IO compared to the CPR-only group (p=0.001). There was no significant difference between the CPR + defibrillation group and the CPR group (p=0.127). There was no significant difference in Cmax between the IO and IV groups (p=0.079). The mean ± standard deviation of Cmax of the IO group was 58,709±25,463pg/mL compared to the IV group, which was 106,198±62,135pg/mL. There was no significant difference in mean Tmax between the groups (p=0.084). There were no significant differences in odds of ROSC between the tibial IO and IV groups. Conclusion: Prompt access to the vascular system using the IO route can circumvent the interruption in treatment observed with attempting conventional IV access. The IO route is an effective modality for the treatment of hypovolemic cardiac arrest and may be considered first line for rapid vascular access.

Energy models have been widely applied to the analysis of energy system decarbonisation to assess the options and costs of a transition to a low carbon supply. However, questions persist as to whether they are able to effectively represent and assess heat decarbonisation pathways for the buildings sector. A range of limitations have been identified, including a poor spatio-temporal resolution, limited representation of behaviour, and restricted representation of the full technical option set. This paper undertakes a review of existing energy models for heat decarbonisation in the UK, applying the novel perspective of energy system architecture (ESA). A set of ESA-related features are identified (including evolvability, flexibility, robustness, and feasibility), and models are reviewed against these features. The review finds that a range of models exist that have strengths across different features of ESA, suggesting that multiple modelling approaches are needed in order to adequately address the heat decarbonisation challenge. However, opportunities to improve existing models and develop new approaches also exist, and a research agenda is therefore proposed.

Human genetic studies have emphasised the dominant contribution of pancreatic islet dysfunction to development of Type 2 Diabetes (T2D). However, limited annotation of the islet epigenome has constrained efforts to define the molecular mechanisms mediating the, largely regulatory, signals revealed by Genome-Wide Association Studies (GWAS). We characterised patterns of chromatin accessibility (ATAC-seq, n = 17) and DNA methylation (whole-genome bisulphite sequencing, n = 10) in human islets, generating high-resolution chromatin state maps through integration with established ChIP-seq marks. We found enrichment of GWAS signals for T2D and fasting glucose was concentrated in subsets of islet enhancers characterised by open chromatin and hypomethylation, with the former annotation predominant. At several loci (including CDC123, ADCY5, KLHDC5) the combination of fine-mapping genetic data and chromatin state enrichment maps, supplemented by allelic imbalance in chromatin accessibility pinpointed likely causal variants. The combination of increasingly-precise genetic and islet epigenomic information accelerates definition of causal mechanisms implicated in T2D pathogenesis.

Whether they are considered discrete or dimensional, emotions are ’embodied’ phenomena [...]

Social robots are expected gradually to be used by more and more people in a wider range of settings, domestic as well as professional. As a consequence, the features and quality requirements on human⁻robot interaction will increase, comprising possibilities to communicate emotions, establishing a positive user experience, e.g., using touch. In this paper, the focus is on depicting how humans, as the users of robots, experience tactile emotional communication with the Nao Robot, as well as identifying aspects affecting the experience and touch behavior. A qualitative investigation was conducted as part of a larger experiment. The major findings consist of 15 different aspects that vary along one or more dimensions and how those influence the four dimensions of user experience that are present in the study, as well as the different parts of touch behavior of conveying emotions.

Abstract In the second of our series of articles celebrating peer reviewers, we talk to Robert Lowe, who is a Lecturer in computational biology at Queen Mary University of London, UK, and a valued reviewer for Genome Biology.

We here present results and analysis from a study of affective tactile communication between human and humanoid robot (the NAO robot). In the present work, participants conveyed eight emotions to the NAO via touch. In this study, we sought to understand the potential for using a wearable affective (tactile) interface, or WAffI. The aims of our study were to address the following: (i) how emotions and affective states can be conveyed (encoded) to such a humanoid robot, (ii) what are the effects of dressing the NAO in the WAffI on emotion conveyance and (iii) what is the potential for decoding emotion and affective states. We found that subjects conveyed touch for longer duration and over more locations on the robot when the NAO was dressed with WAffI than when it was not. Our analysis illuminates ways by which affective valence, and separate emotions, might be decoded by a humanoid robot according to the different features of touch: intensity, duration, location, type. Finally, we discuss the types of sensors and their distribution as they may be embedded within the WAffI and that would likely benefit Human-NAO (and Human-Humanoid) interaction along the affective tactile dimension.

In this article, we discuss our recent work in elucidating the mode-of-action of compounds used in traditional medicine including Ayurvedic medicine. Using computational (′in silico′) approach, we predict potential targets for Ayurvedic anti-cancer compounds, obtained from the Indian Plant Anticancer Database given its chemical structure. In our analysis, we observed that: (i) the targets predicted can be connected to cancer pathogenesis i.e. steroid-5-alpha reductase 1 and 2 and estrogen receptor-β, and (ii) predominantly hormone-dependent cancer targets were predicted for the anti-cancer compounds. Through the use of our in silico target prediction, we conclude that understanding how traditional medicine such as Ayurveda work through linking with the ′western′ understanding of chemistry and protein targets can be a fruitful avenue in addition to bridging the gap between the two different schools of thinking. Given that compounds used in Ayurveda have been tested and used for thousands of years (although not in the same approach as Western medicine), they can potentially be developed into potential new drugs. Hence, to further advance the case of Ayurvedic medicine, we put forward some suggestions namely: (a) employing and integrating novel analytical methods given the advancements of ′omics′ and (b) sharing experimental data and clinical results on studies done on Ayurvedic compounds in an easy and accessible way.

Evidence of a fabric performance gap has underlined the need for measurements of in situ building performance. Steady state co-heating tests have been used since the 1980s to measure whole building heat transfer coefficients, but are often cited as impractical due to their 2–4 week test duration and limited testing season. Despite this, the required conditions for testing and test duration have never been fully assessed. Analysis of field tests show that in 12 of 16 cases, a heat loss estimate to within 10% of the result achieved across a full test period can be achieved within just 72 h. These results are supported by simulated tests upon a wider range of dwellings and across wider environmental conditions. However, systematic errors may still exist, even in cases of convergence and cases with significant uncertainties may never converge. Simulated examples of traditional dwellings and those built in line with current building regulation limits may be tested for more than half the year. However, even when simulated with reduced uncertainties, dwellings with low heat loss and high solar gains, such Passivhaus dwellings and apartments, could be successfully tested for just 22% and 12% of a year respectively, demonstrating the limitations of the co-heating method in assessing such dwellings.

Morphological computing, at its core, entails that the morphology (shape + material properties) of an agent (a living organism or a machine) enables and constrains its possible (physical and social) interactions with the environment as well as its development, including its growth and reconfiguration [1]. [...]

European National Calculation Methods (NCM), such as the UK Standard Assessment Procedure (SAP), are used to make standardised and simplified assessments of building energy performance. These NCMs contain simplifications to aid ease of use and comparability of resulting Energy Performance Certificates (EPC). By comparing SAP with a modern, dynamic modelling system, this study quantifies internal temperatures and thereby heating energy consumption. Results show that for the considered test house SAP results correspond closely to a dynamic model using an idealistic heating system, with perfect control and instant responsiveness. However, the introduction of a dynamic, physically realistic gas fired boiler and water based heating system to the model results in a consistent increase in internal temperature (0.5 °C) and energy demand (by ca. 1000 kWh/a). Variation of further parameters within the dynamic model, controls and heat source size, are presented and compared to SAP results and assumptions. The inclusion of more realistic dynamics in building energy modelling for NCMs may provide a better basis for effective decision making with respect to a wide range of heating systems.

Native-speakerism is an ideology in English language teaching (ELT) in which so-called "native speaker" teachers, and the culture they are believed to represent, are perceived to be norm-providing both for the English language and for the ways in which English is taught around the world. While native-speakerism has been written on extensively, this study investigates one area in particular -- the prevalence of "centre" qualifications (those awarded by institutes in the political West) in "periphery" educational settings. By investigating the qualifications held by instructors (both "native" and "non-native" speakers) working on large ELT programs at three Japanese universities and comparing these data to the number of similar qualifications available in Japanese universities, the research shows a possible bias towards centre qualifications in two of the institutions, and an overall bias in the data as a whole. It is suggested that this may be indicative of a subtle native-speakerism at play in which Western methods and approaches are preferred or idealised over locally developed techniques.