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Triple Agonism Based Therapies for Obesity
No full textPurpose of the Review Glucagon-like peptide 1 (GLP-1) receptor agonists (RA) have transformed obesity and type 2 diabetes (T2D) management. Tirzepatide, the first dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) RA approved for both conditions, has paved the way for next-generation incretin-based therapies. Among these, triple agonists targeting GLP-1, GIP, and glucagon receptors represent a promising next step. This review outlines the rationale for their development and summarizes clinical trial data, focusing on retatrutide, the most advanced candidate. Recent Findings Retatrutide is the first triple agonist (acting on GLP-1/GIP/glucagon receptors) with published phase 2 data in people with obesity as well as in people with T2D. Retatrutide achieved up to 24.2% mean weight loss after 48 weeks in individuals with obesity and 16.9% in those with T2D after 36 weeks. In the T2D study, HbA1c improved by 2.2%, with 82% of participants reaching HbA1c ≤ 6.5%. Retatrutide also improved multiple cardiometabolic parameters, including blood pressure, lipids, waist circumference, and liver fat (82% reduction in hepatic steatosis). Gastrointestinal symptoms were the most common side effects; no major safety concerns were observed. A comprehensive phase 3 program is ongoing to evaluate efficacy, safety, and cardiovascular/renal outcomes in people with obesity and/or T2D. Other unimolecular triple agonists and combination regimens involving tirzepatide with additional mono agonists are also in development. Summary Retatrutide, a triple agonist now in phase 3 trials, has the potential to become the most effective pharmacological treatment for obesity while also offering substantial benefits in T2D management and other cardiometabolic risk factors.</p
Deciphering Clonal Somatic Alterations Associated with Homologous Recombination Deficiency and Synthetic Lethality in Mesothelioma
No full textMesothelioma is a rare and incurable form of cancer that arises in the the parietal pleura. With limited treatment options, particularly in the relapsed setting, there is a need to identify novel precision medicines that exploit genetic differences. Homologous recombination deficiency (HRD) is often present in mesothelioma, where a synthetically lethal relationship can be formed by treating with PARP inhibitors (PARPi). With no current biomarker of sensitivity, this current study aimed to explore the promise of PARPi treatment in mesothelioma and understand the causations of sensitivity.Ex vivo mesothelioma patient-derived explants (PDEs) were treated with varying doses of the PARPi rucaparib and niraparib. Multiplex immunofluorescence (mIF) staining showed PARPi can induce double-strand break (DSB) formation and cell death, and proposed responses of the targeted treatment. DNA damage response (DDR) related genes and SLFN11 were shown not to predict PARPi sensitivity, despite expectations.While, transcriptomic data showed inflammatory responses, primarily IFN-α and IFN-γ responses, were significantly associated with PARPi responders across all mesothelioma models following gene set enrichment analysis (GSEA). Given that PARPi are proinflammatory this provides a plausible explanation as to why these pathways were upregulated, providing a favourable environment for response. This also supports the combination of PARPi with immune checkpoint inhibitors (ICIs), providing a synergistic relationship to increase the therapeutic efficacy of both drugs. Moreover, these findings have shown that PARPi are a feasible option as a novel second-line therapy in the relapsed setting of mesothelioma, with potential to use cisplatin response as a surrogate of sensitivity based on some of these results.</p
Population genomics and molecular epidemiology of wheat powdery mildew in Europe
No full textAgricultural diseases are a major threat to sustainable food production. Yet, for many pathogens we know exceptionally little about their epidemiological and population dynamics, and this knowledge gap is slowing the development of efficient control strategies. Here we study the population genomics and molecular epidemiology of wheat powdery mildew, a disease caused by the biotrophic fungus Blumeria graminis forma specialis tritici (Bgt). We sampled Bgt across two consecutive years, 2022 and 2023, and compiled a genomic dataset of 415 Bgt isolates from 22 countries in Europe and surrounding regions. We identified a single epidemic unit in the north of Europe, consisting of a highly homogeneous population. Conversely, the south of Europe hosts smaller local populations which are less interconnected. In addition, we show that the population structure can be largely predicted by the prevalent wind patterns. We identified several loci that were under selection in the recent past, including fungicide targets and avirulence genes. Some of these loci are common between populations, while others are not, suggesting different local selective pressures. We reconstructed the evolutionary history of one of these loci, AvrPm17, coding for an effector recognized by the wheat receptor Pm17. We found evidence for a soft sweep on standing genetic variation. Multiple AvrPm17 haplotypes, which can partially escape recognition by Pm17, spread rapidly throughout the continent upon its introduction in the early 2000s. We also identified a new virulent variant, which emerged more recently and can evade Pm17 resistance altogether. Overall, we highlight the potential of genomic surveillance in resolving the evolutionary and epidemiological dynamics of agricultural pathogens, as well as in guiding control strategies.</p
Gravitational lensing in gamma-ray bursts
No full textGravitationally lensed gamma-ray bursts (GRBs) offer critical advantages over other lensed sources. They can be detected via continuously operating detectors covering most of the sky. They offer extremely high time resolution to determine lensing delays and find short time delays accurately. They are detectable across most of the visible Universe. However, they are also rare and frequently poorly localized. In this article, we review searches for gravitational lensing in GRBs and comment on promising avenues for the future. We note that the highly structured jets in GRBs can show variations on sufficiently small scales that, unlike lensing of most transient sources, gravitational lensing in GRBs may not be achromatic. Such behaviour would weaken the stringent requirements for identifying lensed bursts but would also make robust identification of lensing more challenging. A continuously running search that could identify candidate lensed events in near real-time would enable afterglow searches with current and near-future wide-field optical/infrared surveys that could yield the first unambiguous detection of a lensed GRB. The new generation of sensitive X-ray and γ-ray detectors, such as the Einstein Probe and SVOM, will complement Swift and significantly enhance the number of well-localized γ-ray and X-ray transients. Tuned strategies could dramatically improve the probability of observing a lensed GRB.
This article is part of the Theo Murphy meeting issue ‘Multi-messenger gravitational lensing (Part 1)’.</p
Parental Perspectives on the Educational Journeys of their Children with Down Syndrome: Starting Points for Cultural Change
No full textRecent UK research into parental perspectives of the education of their children with Down syndrome (DS) indicates that at primary level many are educated in mainstream schools but fewer at secondary level. Surveys provide an overview of parental satisfaction with the education of their children with DS but further qualitative data are needed on parental perspectives of their child’s educational journey over time, to provide insight into causative factors for positive and negative experiences. A framework for understanding the educational experiences of this population was devised using previous research and theories of funds of knowledge and local understanding. Situated within an interpretive paradigm, the research design assumes that knowledge can be gained from experience. The research aim was to gain insights from parental accounts of educational journeys of learners with DS, to inform a consistently positive experience of education for these children. The narrative methodology was informed by elements of life history. Unstructured interviews were conducted online with ten parents of children with DS, mainly between April and June 2021. Transcripts were analysed using reflexive thematic analysis (RTA). The parental narratives yielded a wealth of data regarding systemic issues. Participants’ proactivity was critical in achieving positive educational experiences for their children. Rich insights into underlying attitudes, values and beliefs also indicated where cultural change was needed. A fundamental implication of these findings for education professionals is that to create the best possible educational experiences for children with DS we need to foster attitudes based on presumptions of belonging, competence and a professional willingness to learn. The data also indicated that attitudinal change needs to reach beyond educational establishments, to challenge societal values and promote recognition of intrinsic human worth.</p
Comparison of Online Peer‐Assisted Learning and Faculty‐Led Teaching for Short Answer Questions
No full textIntroductionPeer‐assisted learning (PAL) is a well‐recognised pedagogical approach in medical education; however, research on its effectiveness in online settings remains limited. Multiple‐choice questions have been the predominant method for assessing PAL outcomes, despite Short Answer Questions (SAQs) being the superior tool for evaluating knowledge. This study compares online peer and faculty teaching in enhancing medical students' higher‐order thinking skills and assesses students' perceptions of these methods.MethodsThird‐year medical students undergoing surgical placements were consented and recruited for the study. Three pre‐defined cohorts were randomised to the following arms: no intervention (n = 41), online PAL teaching (n = 37) and online faculty teaching (n = 35). Peer teaching was delivered by fourth‐year students (n = 6) and faculty teaching by Clinical Teaching Fellows (CTFs) (n = 6). Academic outcomes were assessed using end‐of‐block SAQ formatives, and teaching quality was evaluated using the validated SEEQ questionnaire. Knowledge gain and self‐perceived confidence were assessed through pre‐ and post‐session tests, validated with a reference group of learners.ResultsConsent for SAQ exam scores was obtained from n = 19 (no intervention), n = 29 (PAL) and n = 21 (CTF). No significant differences were seen between the groups (p = 0.650). SEEQ completion was n = 24 (PAL) and n = 30 (CTF). CTF tutors received significantly higher ratings in domains of Learning (p = 0.017) and Group Interaction (p = 0.036). Pre‐ and post‐session tests showed no significant differences in scores (p = 0.957) or self‐perceived confidence ratings (p = 0.454).ConclusionThis study shows that online PAL is a viable alternative to faculty‐led teaching for enhancing SAQ skills and knowledge acquisition. However, faculty‐led teaching offers a superior educational experience.</p
‘The Good Place’: investigating the social responsibility image of countries and its impact on the attractiveness of highly skilled workers
No full textAbstract
This article aims to bridge the gap between corporate social responsibility and place branding literature by (1) examining the nature and dimensions of the social responsibility image of countries (SRIC), (2) developing a scale for SRIC and (3) measuring its impact on nation brand identification and intention to apply for a job. Leveraging social identity theory, associative network theory and selection–attraction–attrition theory, the study employs a mixed method approach comprising semi-structured interviews, focus groups and a survey with UK and Italian highly skilled workers. Findings reveal the complexity of this multidimensional concept which integrates economic, ethical and environmental factors. SRIC exerts a significant impact on both nation brand identification and intention to apply for a job vacancy. Based on the results, organisations and governments interested in luring the best candidates should work in partnership to develop adequate programmes and a consistent narrative that highlight economic, ethical and environmental responsibilities of the place.</p
The Day-long, Repeating GRB 250702B: A Unique Extragalactic Transient
No full textγ-ray bursts (GRBs) are singular outbursts of high-energy radiation with durations typically lasting from milliseconds to minutes and, in extreme cases, a few hours. They are attributed to the catastrophic outcomes of stellar-scale events and, as such, are not expected to recur. Here, we present observations of the exceptional GRB 250702B (formerly GRB 250702BDE) which triggered the Fermi GRB monitor on three occasions over several hours, and which was detected in soft X-rays by the Einstein Probe several hours before the γ-ray triggers (EP 250702a). We present the discovery of an extremely red infrared counterpart of the event with the Very Large Telescope, as well as radio observations from MeerKAT. Hubble Space Telescope observations pinpoint the source to a nonnuclear location in a host galaxy with complex morphology, implying GRB 250702B is an extragalactic event. The multiwavelength counterpart is well described with standard afterglow models at a relatively low redshift z ∼ 0.3, but the prompt emission does not readily fit within the expectations for either collapsar or merger-driven GRBs. Indeed, a striking feature of the multiple prompt outbursts is that the third occurs at an integer multiple of the interval between the first two. Although not conclusive, this could be indicative of periodicity in the progenitor system. We discuss several possible scenarios to explain the exceptional properties of the burst, which suggest that either a very unusual collapsar or the tidal disruption of a white dwarf by an intermediate-mass black hole are plausible explanations for this unprecedented GRB.</p
Powerful Nuclear Outflows and Circumgalactic Medium Shocks Driven by the Most Luminous Known Obscured Quasar in the Universe
No full textWe report integral field spectroscopy observations with the Near-Infrared Spectrograph on board the James Webb Space Telescope, targeting the 60 kpc environment surrounding the most luminous obscured quasar known at z = 4.6. We detect ionized gas filaments on 40 kpc scales connecting a network of merging galaxies, likely to form a cluster. We find regions of low ionization consistent with large-scale shock excitation surrounding the central dust-obscured quasar, out to distances nearly 8 times the effective stellar radius of the quasar host galaxy. In the nuclear region, we find an ionized outflow driven by the quasar with velocities reaching 13,000 km s−1, one of the fastest discovered to date, with an outflow rate of 2000 M ⊙ yr−1 and a kinetic luminosity of 6 × 1046 erg s−1, resulting in a coupling efficiency between the bolometric luminosity of the quasar and the outflow of 5%. The kinetic luminosity of the outflow is sufficient to power the turbulent motion of the gas on galactic and circumgalactic scales, and is likely the primary driver of the radiative shocks on interstellar medium and circumgalactic medium scales. This provides compelling evidence supporting long-standing theoretical predictions that powerful quasar outflows are a main driver in regulating the heating and accretion rate of gas onto massive central cluster galaxies.</p
Data for "Anti-Breast Cancer Stem Cell Activity of Titanocene Complexes of Non-Steroidal Anti-Inflammatory Drugs"
No full textTitanocene(IV)-NSAID complexes Cp2Ti(mefenamate)2 (4) and Cp2Ti(flufenamate)2 (5) show enhanced redox stability and potent cytotoxicity against breast cancer stem cells (CSCs), with 5 rivaling salinomycin and cisplatin. Complex 5 induces DNA damage and apoptosis, and its nanoparticle encapsulation improves biocompatibility. This is the first report targeting breast CSCs with titanocene-based metallodrugs.</p