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SH3 domains selectively activate the PI3 kinase through non-conventional tertiary contacts
No full textPhosphoinositide-3 kinase (PI3K) is a central regulator of cellular metabolism and survival, and its dysregulation is implicated in major human diseases, particularly cancer. The p85 regulatory subunit of PI3K uses its C-terminal domains to stabilise the catalytic p110 subunit in an inhibited state. Certain Src homology 3 (SH3) domains activate p110 by binding to the proline-rich (PR) 1 motif at the N-terminus of p85. How this interaction leads to PI3K activation remains unclear. Moreover, the low specificity of SH3 domains raises the question about how they can selectively control PI3K activation. Combining structural, biophysical, and functional methods, we demonstrate that both questions are linked: PI3K-activating SH3 domains form additional ‘tertiary’ interactions with the C-terminal domains of p85, relieving p110 inhibition. SH3 domains lacking these tertiary contacts may bind p85 with similar affinity but fail to activate PI3K. Thus, p85 employs a selection mechanism that discriminates based on binding mode rather than binding strength, preventing nonspecific activation rather than nonspecific binding. This mechanism conveys a functional selectivity to SH3 domains that are otherwise considered promiscuous. These insights establish a mechanistic framework that will help to predict, modulate, and therapeutically target SH3-driven PI3K activation in disease
Drought stress modulates the molecular response of Arabidopsis plants to root-knot nematode infection
Get PDFPlants are exposed to multiple concurrent stresses under field conditions that can include a combination of biotic and abiotic factors. Drought stress and plant parasitic nematodes are among the most damaging stress factors limiting plant growth and production. Plants have developed complex and specific responses to combined biotic and abiotic stresses, which differ from their responses to individual stresses. Therefore, there is an imperative need to understand plant responses to multiple stresses as a central avenue for development of robust plants with the ability to sustain growth and crop production in times of global climate change. RNA-Seq analysis was performed on Arabidopsis plants to investigate the transcriptomic responses to infection with the root-knot nematode Meloidogyne incognita and drought stress either individually or concurrently. Arabidopsis plants activated a unique suite of genes in response to the joint stress, which significantly differed from the response to either individual stress. Among these differentially expressed genes, AZELAIC ACID INDUCED1 (AZI1), SMALL AUXIN UPREGULATED RNA 71 (SAUR71), and DISEASE RELATED NONSPECIFIC LIPID TRANSFER PROTEIN 1 (DRN1) may play important roles in plant responses to concurrent drought stress and root-knot nematode infection. The expression of AZI1, which is involved in priming defences via systemic acquired resistance, was uniquely upregulated in Arabidopsis leaves in response to the combined stress. SAUR71, which is a member of the largest family of primary auxin response genes, was induced solely in response to combined stress. In contrast, the expression of DRN1, a member of the non-specific lipid-transfer protein family, was strongly suppressed in Arabidopsis roots by combined drought stress and nematode infection. When Arabidopsis plants are exposed to multiple stresses simultaneously, their defence and adaptation mechanisms become more complex, leading to the induction of a wide range of morphological and molecular changes that enable them to cope with combined stress conditions
ENGAGE: Analyzing the value of virtual reality in a patient-centric immersive learning program in myasthenia gravis for healthcare professionals
Get PDFBackground: Myasthenia gravis (MG) is a chronic autoimmune neuromuscular disease characterized by muscle weakness that can significantly impact patients’ lives. Recent patient-led research highlighted a disconnect between healthcare professionals (HCPs) and patients, emphasizing the need for effective and empathetic patient–HCP dialogue and shared decision-making (SDM). The power of virtual reality (VR) to increase empathy and provide impactful learning experiences has been established. This outcome evaluation assessed the ability of VR to improve HCPs’ knowledge, attitudes and empathy in MG, aiming to strengthen patient–HCP communication and facilitate SDM.
Methods: The ENGAGE educational pilot program comprised a needs assessment, a VR-based intervention and an outcome evaluation. Content for the VR intervention was developed using a patient-centric approach integrating patient and HCP voices. The VR module simulated “a day in the life of Julia,” a virtual patient with MG, allowing HCPs to experience MG symptoms and their impact on a patient’s life. The experience was implemented in hospital-based workshops. The outcome evaluation included surveys assessing Moore’s Levels 2–4, the Theoretical Domains Framework (TDF), and SDM, and was supplemented by semi-structured interviews. Quantitative and qualitative data were analyzed using SPSS Statistics and thematic analysis, respectively.
Results: Eighty-seven HCPs completed the VR experience across 12 workshops. Sixty HCPs participated in the outcome evaluation survey, and 10 participated in interviews. HCPs reported high satisfaction with the immersive learning, citing its relevance and ease of use. Based on survey responses, HCPs’ most important learnings were a “better understanding of the impact of MG on patients’ lives” (n/N = 46/60) and “developing empathy for how a patient with MG might feel” (n/N = 37/60). HCPs expressed commitment to changing their practice. Quantitative analysis revealed significant improvements in most TDF domains and SDM post-intervention, with the TDF domain “beliefs about capabilities” emerging as the strongest predictor of SDM.
Conclusion: Our study found that the immersive VR intervention effectively increased HCP empathy, knowledge and attitudes in MG care. The program’s patient-centric design ensured content relevance. These findings suggest that VR-based learning is a valuable tool for medical education and the improvement of SDM, particularly in rare diseases like MG
Factors influencing the decision to accept or decline aortic valve replacement for asymptomatic aortic stenosis: a nested longitudinal qualitative substudy of the EASY-AS randomised trial
Get PDFOBJECTIVE: To examine how patients and family members decide whether to accept a highly invasive intervention (aortic valve replacement (AVR)) when their condition (aortic stenosis (AS)) is asymptomatic and its course uncertain.
DESIGN: Nested, longitudinal, qualitative substudy of an ongoing randomised controlled trial (RCT) (NCT04204915) testing early intervention (EI) versus watchful waiting (WW) in patients with asymptomatic severe AS.
SETTING: Six select UK sites of the RCT.
PARTICIPANTS: Select participants of the RCT, their next-of-kin and some who declined RCT participation.
RESULTS: 73 interviews were conducted, with 41 participants. Few knew much about AS before diagnosis. Uncertainty and the need for reliable information regarding symptoms and progress was a significant problem. While some expressed unease at a major intervention for an asymptomatic condition, there were no outright objections to the idea. Those who declined participation in the RCT did so for personal reasons, for example, their home circumstances did not permit the required period of recovery or they felt too old to risk intervention. Reasons for accepting early intervention included the belief that the condition was serious and likely to deteriorate, and so better to have the intervention before such deterioration, as well as avoiding long waiting lists. Trusting clinicians' judgement played a part in some decisions. Patients also wanted choice in the type of intervention received. The longitudinal interviews (n=32) showed satisfaction in the early intervention group despite some problems in the the early recovery phase, especially for those undergoing surgical AVR.
CONCLUSIONS: Where evidence supports major intervention for an asymptomatic condition, patients are likely to accept the offer, although personal circumstances play an important role in decision-making. Where a condition is not well known to the public, such as AS, patients rely on clinicians and other resources to help decide. Liaison with patient groups in developing shared decision-making resources may help with complex decisions.
TRIAL REGISTRATION NUMBER: NCT04204915
Bracing AdoleScent Idiopathic Scoliosis after skeletal maturity (BASIS 2): study protocol for a randomized controlled trial within a larger trial
Get PDFAims
Adolescent idiopathic scoliosis affects 0.2% to 0.5% of adolescents, often requiring bracing to reduce the risk of curve progression. While bracing is typically discontinued at skeletal maturity, significant curve progression can occur afterwards, potentially necessitating surgery. The Bracing AdoleScent Idiopathic Scoliosis (BASIS) 2 study, nested within the larger BASIS trial, aims to evaluate the efficacy of prolonged full-time and night-time bracing beyond skeletal maturity in reducing curve progression. The aim is to determine if six months of additional bracing at normal prescription, after skeletal maturity, significantly reduces curve progression and is acceptable to patients with adolescent idiopathic scoliosis who were successfully treated with bracing.
Methods
This multicentre, prospective, parallel group, pragmatic, open-label, randomized controlled superiority trial will recruit participants from the BASIS study who reach skeletal maturity with a curve < 50°. Participants will be randomized 1:1 to either continue bracing for six months or cease bracing immediately.
Outcomes
The primary outcome is curve progression from baseline to two years post-skeletal maturity. Secondary outcomes include radiological measures, patient bracing experience and any preferences, and cost-effectiveness. The sample size is estimated at 228 participants. Results will be disseminated through peer-reviewed publications, conference presentations, and to study participants
The timing and nature of marine ecosystem recovery following the Permian-Triassic mass extinction
Get PDFThe Permian-Triassic mass extinction (PTME; c. 252 million years ago) was the most devastating extinction event of the Phanerozoic, resulting in up to 90% of marine animal species becoming extinct and profound ecological changes from Palaeozoic to Mesozoic faunas. The eruption of the Siberian Traps Large Igneous Province caused a cascade of environmental effects such as extreme warming, ocean anoxia and acidification which collapsed Permian ecosystems and delayed recovery in the Early Triassic. However, uncertainty remains regarding the temporal dynamics and nature of ecological recovery following the PTME. Models attribute a slow stepwise recovery within marine communities, from primary producers to top predators, reattaining pre-extinction levels of ecological complexity by the Middle Triassic. However, global empirical data indicates the rapid recovery of multiple trophic levels albeit in the form of top-heavy, unstable Early Triassic ecosystems. Further research promises exciting opportunities to apply community ecology models to ever improving databases of fossil ecosystems spanning multiple palaeolatitudes to test fundamental questions regarding the nature and timing of recovery and whether it really was “recovery” back to pre-extinction states; or “restructuring” to new baselines of ecosystem complexity more reflective of modern marine ecosystems
Non-antiarrhythmic pharmacotherapy in cardio-renal-metabolic disease and incident atrial fibrillation:a trial meta-analysis
Get PDFBACKGROUND AND AIMS: Atrial fibrillation (AF) disease burden is increasing. Pharmacotherapy of cardio-renal-metabolic diseases may prevent incident AF. This meta-analysis estimates the effect of different pharmacotherapies on risk of incident AF across cardio-renal-metabolic diseases. METHODS: The Medline, Embase, and Cochrane Central databases were searched to 7 October 2025 for randomized clinical trials (RCTs) comparing the effect of a non-antiarrhythmic cardio-renal-metabolic medication with control or another agent for incident AF. Random-effects meta-analysis using the Mantel-Haenszel method, with between-study variance estimated using the DerSimonian-Laird method, was performed to synthesize risk ratios (RR) with 95% confidence intervals (CI). RESULTS: Two hundred and forty-nine RCTs involving 745 041 patients were included, of which 207 identified AF through adverse event reports, 161 were placebo-controlled, and 15 had AF as a pre-specified endpoint. In placebo-controlled trials, significant differences in incident AF were observed with treatment of heart failure with reduced ejection fraction with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers (RR 0.69, 95% CI 0.60-0.80), mineralocorticoid receptor antagonists (RR 0.62, 95% CI 0.43-0.90), and sodium-glucose co-transporter 2 (SGLT2) inhibitors (RR 0.62, 95% CI 0.44-0.87); treatment of chronic kidney disease with SGLT2 inhibitors (RR 0.53, 95% CI 0.33-0.85); and treatment of obesity with glucagon-like peptide-1 receptor agonists (RR 0.79, 95% CI 0.63-0.99). However, the number of AF events per trial was low and none were adequately powered for incident AF. CONCLUSIONS: Prospective RCTs with AF as a pre-specified outcome should be integrated into the design of future trials of cardio-renal-metabolic medications to determine whether they reduce incident AF
Ground state-based quantum feature maps
Get PDFWe introduce a quantum data embedding protocol based on the preparation of a ground state of a parameterized Hamiltonian. We analyze the corresponding quantum feature map, recasting it as an adiabatic state preparation procedure with Trotterized evolution. We compare the properties of underlying quantum models with ubiquitous Fourier-type quantum models and show that ground state embeddings can be described effectively by a spectrum with a degree that grows rapidly with the number of qubits, corresponding to a large model capacity. We observe that the spectrum contains massive frequency degeneracies and the weighting coefficients for the modes are highly structured, thus limiting model expressivity. Our results provide a step toward understanding models based on quantum data and contribute to fundamental knowledge needed for building efficient quantum machine learning (QML) protocols. As non-trivial embeddings are crucial for designing QML protocols that cannot be simulated classically, our findings guide the search for high-capacity quantum models that can largely outperform classical models
Continuous-wave quantum light control via engineered Rydberg-induced dephasing
Get PDFWe analyze several implementations of all-optical single-photon transistors (SPTs) operating in the continuous-wave (cw) regime, as presented in the companion paper [Phys. Rev. A 113, L011701 (2026)]. The devices rely on ensembles of Rydberg atoms interacting via van der Waals interactions. Under electromagnetically induced transparency (EIT), a weak probe field is fully transmitted through the atomic ensemble in the absence of control photons. Exciting a collective Rydberg state with a single control photon breaks the EIT condition, thereby strongly suppressing the probe transmission. We show how collective Rydberg interactions in an atomic ensemble, confined either in an optical cavity or in free space, give rise to two distinct probe-induced dephasing mechanisms. These processes localize the control excitations, extend their lifetimes, and increase the device efficiency. We characterize the SPTs in terms of control-photon absorption probability and probe gain, supported by numerical simulations of realistic one- and three-dimensional ensembles. The proposed cw devices complement previously demonstrated SPTs and broaden the toolbox of quantum light manipulation circuitry
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