Enantioselective reduction of α,β-dehydro-α-amido carboxylic acid derivatives to optically active amido carboxylic acid derivatives has been carried out using whole-cell overexpressing ene-reductases (EREDs). The reduced products were obtained with good yields and excellent enantiomeric excesses of >99%. Among the enzymes tested, Seqenzym ene-reductase E4671 proved to be the most effective, accommodating methyl ester, free amide, and diverse N-protecting groups, as well as β-unsubstituted, β-methyl, and β-ethyl substituted substrates. Notably, the reaction is readily scalable.

Axially chiral biaryls are privileged motifs in catalysis, bioactive molecules, and materials, and arynes should in principle provide concise access to these valuable scaffolds. However, the high reactivity, fleeting lifetime, and neutral character of arynes make selective catalytic control, particularly enantiocontrol, exceptionally challenging. As a result, existing aryne-based approaches to axial chirality have relied on stoichiometric chiral information rather than catalytic asymmetric induction. Herein, we disclose the first catalytic enantioselective construction of axial chiral biaryls from arynes through a palladium-catalyzed atroposelective [2 + 2 + 2] cycloaddition with internal and terminal arylalkynes. Enabled by a newly developed chiral P,N-ligand, (R)-JiaPhos, this transformation achieves efficient and stereocontrolled aryne capture even with only a slight excess of aryne precursor, affording structurally diverse axially chiral biaryls in high yields with excellent chemo- and enantioselectivities. Notably, this reaction exhibits a remarkably broad scope, accommodating tri- and tetra-ortho-substituted biaryls and both carboaryl and heteroaryl partners, and enabling access to C-C, C-N, and C-B axial chirality. Moreover, representative phosphine oxide products were readily transformed into a MOP ligand and a chiral DavePhos analogue by reduction, further underscoring the practical utility of this method.

Penetrating orocutaneous and oropharyngeal fistulas (POFs) are difficult to treat due to continuous oral muscle movement and saliva leakage, and persistent bacterial infection and inflammation in the oral environment. However, healing biomaterials that can simultaneously block the penetrating wound, exert antibacterial and anti-inflammatory effects and degrade timely to accommodate fistula closure are rarely reported. Here, we report an organic-inorganic hybrid hydrogel termed MPMQb@gel, which exhibits robust mechanical strength, flexibility, and adhesion ability, enabling effective POF blockage. It consists of hemiaminal structure-containing polymeric hydrogel and Mn-polydopamine nanoparticles cross-linked via aldehyde-amine condensation. Triggered by excessive reactive oxygen species (ROS) in the POF microenvironment, MPMQb@gel gradually degrades and releases Mn[2+], quercetin (Que), and basic fibroblast growth factor (bFGF) to achieve synergistic antibacterial, anti-inflammatory and pro-healing effects. In a New Zealand rabbit model of severe POF infection, this hybrid hydrogel realized complete POF healing within 12 days with administration every 4 days, markedly faster than commercial iodoform gauze-treated group. RNA sequencing and mechanistic analysis reveal that MPMQb@gel suppresses Th1 and Th17 cell differentiation, inhibit the Th17/IL-17-associated signaling axis and modulate the TLR2/STAT3 pathway to promote a stable immune microenvironment, thereby attenuating the inflammatory response and ultimately promoting POF repair. Collectively, by addressing the critical challenge of reconciling wound contraction with the requirement for durable occlusion through a controllably biodegradable organic-inorganic hybrid hydrogel, this work offers a transformative therapeutic strategy for POFs and penetrating wounds.

The widespread adoption of wearable ECG devices has driven an explosive growth of long-term, multi-lead ECG data. However, clinical analysis and model development remain constrained by the excessive cost of data annotation, a limitation particularly pronounced in conventional deep learning methods that rely on labeled information. Approach. To address the problem of label scarcity in wearable ECG measurement scenarios, this paper proposes a self-supervised learning method for ECG based on intervention-based attribution alignment, aiming to improve the model's analytical performance on sparsely labeled ECG signals using unlabeled data. Our method integrates an intervention-inspired operation into the contrastive learning framework: it extracts compact representations from unlabeled data on one hand, and employs feature intervention to learn view-invariant mechanisms on the other, thereby reducing dependency on labeled data for target tasks. Main results. Experimental results on four public ECG datasets demonstrate that the proposed method achieves performance on par with state-of-the-art approaches in typical tasks such as arrhythmia classification, while utilizing only a fraction of the annotated samples. Significance. The findings indicate that our method effectively accommodates the multi-scenario monitoring characteristics of wearable devices, offering a practical solution to alleviate ECG data annotation burdens and advance the efficient analysis of long-term ECG signals.

A comparative study on hemicircular tibial plateau leveling osteotomy (hTPLO) and TPLO for correcting cranial cruciate ligament (CCL) ruptures at excessive tibial plateau angles (eTPAs) was performed with a specially fabricated hTPLO saw blade (hemicircular) and TPLO saw blade (quartercircular), respectively. Ten 3D-printed bone models with eTPAs (TPA > 40°), were resized to accommodate the respective saw blade shape for each method. Cranial closing wedge osteotomy (CCWO) combined with TPLO was also performed. Distances of segment rotation below the patellar tendon insertion (PTI) and differences between anatomical and mechanical axes after correction were measured. The TPAs of the bone models were 46.06 ± 4.40° (40.0-50.7°). Postoperative TPAs of hTPLO, TPLO, and TPLO combined with CCWO were 4.93 ± 1.025°, 4.52 ± 0.085°, and 4.17 ± 1.128°, respectively. Rotation distances from the PTI were 0.46 ± 2.153 mm, 8.67 ± 2.318 mm, and 1.13 ± 1.796 mm, respectively. hTPLO showed significantly less movement of the segment below the PTI than TPLO with or without CCWO (p < 0.01). Differences between anatomical and mechanical axes after hTPLO and TPLO with or without CCWO were 5.74 ± 2.231°, 6.43 ± 2.105°, and 5.16 ± 2.465°, respectively. Within the limitations of this model-based study, hTPLO demonstrated geometric feasibility for correction of excessive tibial plateau angles and was associated with less rotational displacement of the proximal tibial segment relative to the patellar tendon insertion than conventional TPLO and TPLO combined with CCWO. Further cadaveric, biomechanical, and clinical studies are required to evaluate its safety and clinical applicability.

Transcatheter aortic valve replacement (TAVR) has extended its use to low-surgical-risk populations, yet long-term comparative data against surgical aortic valve replacement (SAVR) are still limited, particularly concerning durability and the need for reintervention. We conducted a search of PubMed/MEDLINE, Embase, CENTRAL, and ClinicalTrials.gov through March 2026 for randomized trials comparing TAVR with SAVR in patients with low surgical risk and severe aortic stenosis, specifically those with at least three years of follow-up. Outcomes were pooled as risk ratios (RR) using Mantel-Haenszel random-effects models, and durability and mortality outcomes were analyzed as time-to-event hazard ratios (HR) to accommodate different follow-up durations. Prespecified subgroup analyses by valve platform were performed. Four trials involving 3,014 patients (follow-up ranging from 3 to 10 years) were included. Cardiovascular mortality (HR 1.11, 95% CI 0.86-1.42; P = 0.43) and all-cause stroke (HR 1.09, 95% CI 0.73-1.64; P = 0.67) did not differ significantly between TAVR and SAVR. Aortic valve reintervention was higher with TAVR in risk-ratio analysis (RR 1.58, 95% CI 1.16-2.16) but did not reach statistical significance in the prespecified time-to-event analysis (HR 1.29, 95% CI 0.81-2.05). The excess reintervention risk was confined to the self-expanding valve platform. Permanent pacemaker implantation was significantly more frequent after TAVR (RR 2.08, 95% CI 1.48-2.93; P < 0.0001), with a significant interaction by valve platform (self-expanding RR 2.57 vs balloon-expandable RR 1.40; P = 0.02 for interaction). Bioprosthetic valve failure showed a nonsignificant trend favoring TAVR (HR 0.80, 95% CI 0.54-1.17). The only available 10-year randomized data (NOTION trial) showed significantly less severe structural valve deterioration with TAVR than with SAVR. The results suggest that TAVR and SAVR are equivalent in terms of cardiovascular mortality and stroke outcomes. However, pacemaker implantation rates were higher with TAVR and were strongly dependent on the valve platform used. The observed excess in reinterventions was confined to self-expanding valves and did not show robust support in the time-to-event analysis. The unique 10-year data from the self-expanding platform indicate less severe structural valve deterioration compared to SAVR, suggesting that durability should not be generalized across different device families. These findings advocate for individualized, platform-aware decision-making in clinical practice.

Large congenital melanocytic nevi (LCMN) of the face can pose significant functional, esthetic, and psychosocial challenges in childhood. In selected patients, staged excision offers a practical reconstructive strategy when primary closure is not feasible without distortion of nearby facial landmarks. We report the management of a child with a facial LCMN using a planned multistage surgical approach aimed at lesion removal while preserving contour and minimizing scar burden. The lesion was excised sequentially over three procedures, with careful attention given to relaxed skin tension lines and facial esthetic units. When required, adjunctive reconstruction was performed to optimize closure and support tissue healing. This approach allowed a gradual reduction in the nevus, improved tissue accommodation, and avoidance of excessive tension on the surrounding skin. Postoperative recovery was uncomplicated, and the final esthetic outcome was satisfactory for both the patient and parents. Staged excision was selected over tissue expansion and skin grafting because it allowed progressive lesion reduction while preserving adjacent facial landmarks and minimizing donor-site morbidity. This technical case highlights the importance of individualized surgical planning, preservation of facial esthetic units, and staged scar placement when managing large facial congenital melanocytic nevi in pediatric patients. The educational value of the report lies in illustrating the decision-making process used to balance lesion removal, esthetic outcomes, and long-term surveillance in a challenging facial location.

Elemental antimony (Sb) enables ultrafast crystallization but suffers from poor amorphous stability. Here, we report a Sb/GaSb4 homojunction-like architecture in which chemically similar yet electronically distinct interfaces regulate phase-change behavior. Increasing interfacial density markedly elevates the crystallization temperature and enhances data retention, accompanied by delayed crystallization and preserved layered structures. We further identify an interfacial sequestration-expulsion mechanism: adjacent Sb layers suppress excess-Sb expulsion from the GaSb4 matrix, while Ga promotes Sb accommodation and thermally driven redistribution, stabilizing Sb-rich local environments. As a result, devices achieve 5 ns switching, >10[5] endurance cycles, and low resistance drift. Moreover, interfacial-density scaling enables linear conductance modulation, supporting both high-speed memory and neuromorphic functionality. These findings establish interface-engineered homojunction-like structures as an effective strategy to mitigate phase-change trade-offs and enable multifunctional electronics.

Frailty is a clinical syndrome of reduced physiological reserve in older adults for which no pharmacological treatment exists and whose cellular basis remains incompletely defined. As life expectancy rises without a comparable extension of healthspan, the absence of a mechanistic account able to guide targeted intervention is a growing clinical problem. The dominant model of primary mitochondrial bioenergetic insufficiency does not accommodate several features of the phenotype. Among the conditions most strongly associated with frailty in aging, obesity, particularly when coupled with sarcopenia, stands out for its rising prevalence and the depth of its systemic metabolic consequences. Drawing on a recent multi-omics characterisation of skeletal muscle in sarcopenic obesity and on the convergent literature in aging metabolism, organelle communication, and redox biology, we propose a complementary framework in which the proximate cellular abnormality of frailty is energetic congestion, a chronic mismatch between substrate input, energetic demand, and the capacity to dispatch the resulting flux through demand-driven oxidative metabolism. In this view the mitochondrion is not failing because fuel is scarce, but because energetic demand declines below the rate at which substrate continues to be delivered, so that substrate persists in relative rather than absolute excess, while mitochondrial adaptability is progressively impaired. The resulting cycle is self-amplifying, anchored in reverse electron transport, and generalises across skeletal muscle, adipose tissue, liver, heart and brain. Strategies that re-engage demand-driven metabolic flux through AMPK activation, substrate restriction, mild mitochondrial uncoupling, modulation of endoplasmic reticulum stress, and clearance of irreversibly congested cells are predicted to produce more durable benefits than energy supplementation, with structured exercise as the prototype of demand-driven recoupling. This perspective offers a path toward a precision pharmacology of frailty grounded in molecular stratification of patients.

Cognitive and computational modeling has been used as a method to understand the processes underlying behavior in humans and other animals. A common approach in this field involves the use of theoretically constructed cognitive models, such as reinforcement learning models. However, human and animal decision-making often deviates from the predictions of these theoretical models. To capture characteristics that these cognitive models fail to account for, recurrent neural networks (RNNs) have been increasingly used to model choice behavior involving reinforcement learning. RNNs can capture how choice probabilities change depending on past experience. In this work, we demonstrate that RNNs can improve future choice predictions by capturing individual differences on the basis of past behavior, even when a single model is fit across the entire population. We refer to this capacity as the individual difference tracking (IDT) property. While the IDT property might be useful for prediction, it may introduce excessive flexibility when RNNs are used as benchmarks for predictive accuracy. We investigate the nature of the IDT property through simulation studies and examine how it affects the interpretation of predictive accuracy when RNNs are used as benchmarks for cognitive models. We also present examples using real-world data. Through these analyses, we discuss practical considerations and limitations in using RNNs as benchmarks for cognitive models.

Mediation analysis is a powerful tool for exploring the causal relationships between exposures and outcomes that are mediated by intermediate variables. In this paper, we propose a flexible Bayesian mediation analysis framework to accommodate zero-inflated mediators, compatible with a wide range of outcome distributions. This novel technique employs Bayesian models for both the mediator and the outcome, utilizing Markov Chain Monte Carlo algorithms for parameter estimation. While addressing the challenges posed by an excess of zeros, we further decompose the mediation effects into components influenced by either the probability of zero or the mean of the non-zero distribution in the mediator. An associated R package mediationBayes (https://github.com/jhcuibst/mediationBayes.git) has been developed to facilitate the application of this framework. Through comprehensive simulation studies, we demonstrate that our method outperforms alternatives in terms of the accuracy of point estimates, coverage probabilities, and the precision of the mediation effects decomposition. We further illustrate the practical applicability of our method by conducting an analysis on the REasons for Geographic And Racial Differences in Stroke Study to investigate the mediating influence of smoking pack-years on the association between educational levels and incident hypertension, where mediation effects are quantified on a risk ratio scale for binary outcomes.

The fundamental challenge in all-solid-state batteries (ASSBs) lies in regulating the dynamic reconstruction of solid-solid interfaces under electro-chemo-mechanical conditions. Currently, no mechanism exists to reconcile the conflicting requirements of structural stability and rapid ion transport for high-capacity silicon (Si) anodes: expansion-accommodated encapsulation strategies preserve integrity but block interparticle ionic contact, while intrinsic electrochemical sintering restores conduction but creates excessive agglomeration that fractures the electrode. Here, we propose a stress-lensed electrochemical sintering (SLES) strategy to guide selective interfacial bonding by depositing Si conformally into a porous carbon host, specifically utilizing its high-curvature pore entrances as geometric constrictions. During cycling, these constrictions act as "stress lenses", concentrating the volumetric expansion stress of Si precisely at interparticle contacts. This focused mechanical energy locally lowers the atomic diffusion barrier, guiding the formation of a robust, percolating Si network while preserving internal voids to buffer volume changes. The resulting Si-SLES anode resolves the stability-transport conflict, achieving ∼100% capacity retention after 100 cycles with superior rate capability and demonstrating practical viability in full cells over 700 cycles.