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Found across all kingdoms of life, 2-keto acid dehydrogenase complexes possess prominent metabolic roles and form major regulatory sites. Although their component structures are known, their higher-order organization is highly heterogeneous, not only across species or tissues but also even within a single cell. Here, we report a cryo-EM structure of the fully active Chaetomium thermophilum pyruvate dehydrogenase complex (PDHc) core scaffold at 3.85 Å resolution (FSC = 0.143) from native cell extracts. By combining cryo-EM with macromolecular docking and molecular dynamics simulations, we resolve all PDHc core scaffold interfaces and dissect the residing transacetylase reaction. Electrostatics attract the lipoyl domain to the transacetylase active site and stabilize the coenzyme A, while apolar interactions position the lipoate in its binding cleft. Our results have direct implications on the structural determinants of the transacetylase reaction and the role of flexible regions in the context of the overall 10 MDa PDHc metabolon architecture. How is acetyl-CoA produced in the context of the endogenous, eukaryotic pyruvate dehydrogenase complex metabolon? Here the authors dissect the embedded transacetylase reaction through biochemical, cryo-EM, HADDOCKing and molecular dynamics methods.

Transcatheter aortic valve replacement (TAVR) has become a well-established treatment for severe aortic stenosis across all levels of surgical risk. While transfemoral access remains the default approach, complications arising from vascular access—especially in patients with peripheral artery disease (PAD)—pose significant challenges. Hostile vascular access, characterized by narrow vessel diameters, severe calcification, and tortuosity, complicates the procedure and necessitates alternative strategies. Recent advancements, such as intravascular lithotripsy (IVL), have shown promise in managing severely calcified arteries, improving the feasibility of transfemoral TAVR in patients previously considered ineligible. IVL uses pulsatile sonic waves to fragment arterial calcifications, enhancing vessel compliance and facilitating safe device delivery. Studies have demonstrated that IVL-assisted TAVR improves procedural success and reduces complications in patients with PAD. Additionally, orbital atherectomy, an adjunctive therapy targeting both concentric and eccentric calcifications, may complement the management of complex arterial calcification. The Hostile and passage–puncture scores offer valuable risk stratification tools for predicting vascular complications, aiding in better access site selection. Post-procedural echocardiography, particularly femoral artery sonography, may also play a role in detecting vascular complications early, enabling timely intervention. Finally, alternative access sites are increasingly being explored, with emerging data helping to guide the final access site decision. As TAVR continues to expand into lower risk populations, optimizing vascular access strategies remains essential to improving procedural outcomes. This review highlights the importance of preoperative imaging, endovascular techniques, and post-procedural monitoring in overcoming vascular challenges and ensuring successful TAVR outcomes.

Metabolites produced via traditional biochemical processes affect intracellular communication, inflammation, and malignancy. Unexpectedly, acetyl-CoA, α-ketoglutarate and palmitic acid, which are chemical species of reactions catalyzed by highly abundant, gigantic enzymatic complexes, dubbed as “metabolons”, have broad “nonmetabolic” signaling functions. Conserved unstructured regions within metabolons determine the yield of these metabolites. Unstructured regions tether functional protein domains, act as spatial constraints to confine constituent enzyme communication, and, in the case of acetyl-CoA production, tend to be regulated by intricate phosphorylation patterns. This review presents the multifaceted roles of these three significant metabolites and describes how their perturbation leads to altered or transformed cellular function. Their dedicated enzymatic systems are then introduced, namely, the pyruvate dehydrogenase (PDH) and oxoglutarate dehydrogenase (OGDH) complexes, and the fatty acid synthase (FAS), with a particular focus on their structural characterization and the localization of unstructured regions. Finally, upstream metabolite regulation, in which spatial occupancy of unstructured regions within dedicated metabolons may affect metabolite availability and subsequently alter cell functions, is discussed. 29SCgJ38h7YmLnprd51La4 Video abstract Graphical abstract

Background: Hypertension remains the leading global risk factor for cardiovascular morbidity and mortality, with suboptimal control rates despite guideline-directed therapies. Digital health and artificial intelligence (AI) technologies offer novel approaches for improving diagnosis, monitoring, and individualized treatment of hypertension. Objectives: To critically review the current landscape of AI-enabled digital tools for hypertension management, including emerging applications, implementation challenges, and future directions. Methods: A narrative review of recent PubMed-indexed studies (2019–2024) was conducted, focusing on clinical applications of AI and digital health technologies in hypertension. Emphasis was placed on real-world deployment, algorithmic explainability, digital biomarkers, and ethical/regulatory frameworks. Priority was given to high-quality randomized trials, systematic reviews, and expert consensus statements. Results: AI-supported platforms—including remote blood pressure monitoring, machine learning titration algorithms, and digital twins—have demonstrated early promise in improving hypertension control. Explainable AI (XAI) is critical for clinician trust and integration into decision-making. Equity-focused design and regulatory oversight are essential to prevent exacerbation of health disparities. Emerging implementation strategies, such as federated learning and co-design frameworks, may enhance scalability and generalizability across diverse care settings. Conclusions: AI-guided titration and digital twin approaches appear most promising for reducing therapeutic inertia, whereas cuffless blood pressure monitoring remains the least mature. Future work should prioritize pragmatic trials with equity and cost-effectiveness endpoints, supported by safeguards against bias, accountability gaps, and privacy risks.

Photosystem II (PSII) is essential for energy conversion during oxygenic photosynthesis in plants and algae. Chlorella ohadii , one of the fastest multiplying green algae, thrives under the harsh desert sun but lacks the standard PSII photoprotective mechanisms involving LhcSR/PsbS proteins or protein phosphorylation. Here, we present the cryo-EM structure of the PSII supercomplex from C. ohadii at 2.9 Å resolution, which is used to determine whether the exceptional resistance to desert conditions has a structural basis in PSII. The structure reveals a distinct PsbO isoform and additional subunits, PsbR and PsbY, which enhance core complex stability through extensive interactions. Furthermore, the trimeric light-harvesting complexes (LHCII) are bound to the PSII core by specific light-harvesting proteins whose down-regulation in response to high-light conditions implies a reduction in the number of bound LHCII trimers. These structural modifications, together with the high accumulation of specific polyamines in the thylakoid membrane, play a key role in maintaining PSII stability and photoprotection, allowing C. ohadii to survive in extreme conditions. Photosystem II drives photosynthesis, but how desert algae adapt to excess of light remains unclear. Here, authors present a cryo-EM structure of PSII from Chlorella ohadii , revealing structural features and antenna arrangements that may contribute to its stability.

Here we present the structure of mouse H-chain apoferritin at 2.7 Å (FSC = 0.143) solved by single particle cryogenic electron microscopy (cryo-EM) using a 200 kV device, the Thermo Fisher Glacios®. This is a compact, two-lens illumination system with a constant power objective lens, without any energy filters or aberration correctors, often thought of as a \"screening cryo-microscope\". Coulomb potential maps reveal clear densities for main chain carbonyl oxygens, residue side chains (including alternative conformations) and bound solvent molecules. We used a quasi-crystallographic reciprocal space approach to fit model coordinates to the experimental cryo-EM map. We argue that the advantages offered by (a) the high electronic and mechanical stability of the microscope, (b) the high emission stability and low beam energy spread of the high brightness Field Emission Gun (X-FEG), (c) direct electron detection technology and (d) particle-based Contrast Transfer Function (CTF) refinement have contributed to achieving high resolution. Overall, we show that basic electron optical settings for automated cryo-electron microscopy imaging can be used to determine structures approaching atomic resolution.

A revolutionary non-invasive method for the thorough evaluation of coronary artery disease (CAD) is fractional flow reserve (FFR) obtained from coronary computed tomography angiography (CCTA). Computed tomography-derived FFR (FFRCT) assesses both the anatomical and functional significance of coronary lesions simultaneously by utilizing sophisticated computational models, including computational fluid dynamics, machine learning (ML), and Artificial Intelligence (AI) methods. The technological development, validation research, clinical uses, and real-world constraints of FFRCT are compiled in this review. Large multicenter trials and registries consistently show that FFRCT is a reliable gatekeeper to invasive coronary angiography (ICA) and increases diagnostic accuracy significantly when compared to coronary Computed Tomography Angiography (CTA) alone, especially in patients with intermediate-risk anatomy. Additionally, FFRCT has demonstrated benefits in populations with in-stent restenosis (ISR) and in virtual procedural planning. Notwithstanding its advantages, the technique still requires high-quality imaging, and its practical application is constrained by expenses, processing requirements, and image distortions. Continuous developments in automation and deep learning should improve accessibility, effectiveness, and workflow integration in clinical settings. FFRCT is expected to become more and more important in the individualized treatment of CAD by minimizing unnecessary invasive procedures and improving patient selection for revascularization.

Background: Optimal endovascular strategy for lower limb peripheral artery disease (PAD) remains debated, particularly regarding 1-year restenosis. Aim: To evaluate the association between drug-coated balloon (DCB)-based angioplasty and 1-year restenosis compared with stent-based and plain balloon strategies in a real-world PAD cohort. Methods: We performed a single-center retrospective analysis of 283 consecutive patients (mean age 67.5 ± 11.2 years, 79% male) undergoing lower limb angioplasty between 2010 and 2023. Patients were treated with one of five strategies: direct stent, pre-dilatation + stent, stent + post-dilatation, DCB ± bailout stent, or plain old balloon angioplasty (POBA). Restenosis at 12 months (≥50% diameter reduction on Doppler, CT angiography, or angiography) was the primary endpoint. Kaplan-Meier curves and multivariable Cox regression adjusted for clinical and lesion characteristics were used. The prespecified main comparison was DCB ± stent versus non-DCB strategies. Results: Overall, 1-year restenosis occurred in 81 patients (28.7%). Restenosis rates were 15.4% with DCB ± stent versus 34.2%, 29.8%, 31.5%, and 38.1% with direct stent, pre-dilatation + stent, stent + post-dilatation, and POBA, respectively (p = 0.004). In adjusted analysis, DCB ± stent was associated with a lower hazard of restenosis compared with direct stent (HR 0.52; 95% CI 0.31–0.87), whereas POBA was associated with a higher hazard versus DCB ± stent (HR 1.89; 95% CI 1.01–3.53). Periprocedural complication rates were low and similar across groups (overall 6.3%). Conclusions: In this real-world PAD cohort, DCB-based angioplasty was independently associated with lower 1-year restenosis compared with stent-based and plain balloon strategies, without an excess of procedural complications. Given the observational design and lesion-driven strategy selection, these findings should be interpreted as hypothesis-generating but support broader use of DCB in appropriately selected lesions.

Background and Objectives: Access-site complications (ASCs) remain clinically relevant after peripheral endovascular procedures, particularly with large femoral sheaths and complex anatomy. While randomized coronary trials show non-inferiority of vascular closure devices (VCDs) versus manual compression (MC), real-world data in peripheral interventions performed under systematic ultrasound-guided access are limited. Materials and Methods: This retrospective single-center cohort included consecutive peripheral arterial revascularizations (2010–2023) performed via common femoral access under real-time ultrasound guidance. Hemostasis was achieved using MC or VCDs, categorized as collagen plug-based, suture-mediated, or clip-based systems. The primary endpoint was 30-day ASCs, defined as hematoma requiring management, pseudoaneurysm, bleeding requiring transfusion, access-site thrombosis/occlusion, arteriovenous fistula, or infection. The secondary endpoint was VCD failure, defined as unsuccessful hemostasis requiring adjunctive measures. Multivariable logistic regression adjusted for prespecified anatomical and procedural covariates, including sheath size > 6 Fr and puncture-site calcification. Results: Among 231 procedures, VCDs were used in 139 (60.2%) and MC in 92 (39.8%). ASC occurred in 28 cases (12.1%), with higher rates in the MC group compared with VCDs (18.5% vs. 9–14% across device types; p = 0.044). In adjusted analyses, MC (vs any VCD) (odds ratio [OR] 2.41, 95% confidence interval [CI] 1.06–5.47; p = 0.035), sheath size > 6 Fr, and puncture-site calcification were independently associated with ASCs. VCD failure occurred in 5 cases (3.6%) and was not observed with collagen plug-based devices. Conclusions: In this ultrasound-guided real-world peripheral cohort, VCD use was associated with lower 30-day ASC rates and low device failure rates compared with MC. Given the retrospective and non-randomized design, these findings should be considered hypothesis-generating and support individualized, imaging-guided strategies for femoral closure in peripheral interventions.

Background: Accurate operative risk stratification is essential for treatment selection in severe aortic stenosis. We developed an automated workflow using large language models (LLMs) to replicate Heart Team risk assessment. Methods: We retrospectively analyzed 231 consecutive patients with severe aortic stenosis evaluated by multidisciplinary Heart Teams (January 2022–December 2024). An automated system using GPT-4o was developed, comprising the following: (1) structured data extraction from clinical dossiers; (2) EuroSCORE II calculation via two methods (algorithmic vs. LLM-based); (3) clinical vignette generation; and (4) risk stratification comparing EuroSCORE-based thresholds versus guideline-integrated LLM approaches with/without EuroSCORE values. The primary endpoint was the risk stratification accuracy of each method compared to Heart Team decisions. Results: Mean age was 79.5 ± 7.7 years, with 58.4% female. The automated workflow processed patients in 32.6 ± 6.4 s. The LLM-calculated EuroSCORE II showed a lower mean difference from Heart Team values (−1.42%, 95% CI −2.32 to −0.53) versus algorithmic calculation (−1.88%, 95% CI −2.38 to −1.38). For risk stratification, the guideline-integrated LLM without EuroSCORE achieved the highest accuracy (90.0%) and AUC (0.93), outperforming both the EuroSCORE-based (accuracy 50.2% for high-risk, AUC 0.63) and guideline-integrated LLM with EuroSCORE approaches (accuracy 82.4%, AUC 0.76). However, systematic hallucinations occurred for cardiovascular risk factors when data were missing. Conclusions: LLMs accurately calculated EuroSCORE II and achieved 90% concordance with multidisciplinary Heart Team decisions. However, hallucinations, reproducibility concerns, and the absence of clinical outcome validation preclude direct clinical application.