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Exploring the mechanism of Shuangyu Granule in regulating immune-inflammatory responses in influenza through UPLC-Orbitrap-MS/MS, GC-MS, and network target analysis

Influenza, an acute respiratory infectious disease caused by the influenza virus, remains a significant challenge for prevention and treatment due to rapid viral mutation and high pathogenicity. Traditional Chinese Medicine (TCM), including Shuangyu Granule (SYKL), has demonstrated efficacy in managing influenza. This study aimed to systematically identify the chemical components of SYKL in vitro and its absorbed constituents in vivo, and to preliminarily explore its potential mechanism in regulating influenza-related immune inflammation. UPLC-Orbitrap-MS/MS and GC-MS were used to characterize SYKL’s chemical profile, identifying 148 in vitro components and 21 prototype absorbed blood components. Network target analysis, integrated with single-cell RNA sequencing (scRNA-seq) data from influenza patients, predicted that the absorbed components may target multiple immune-inflammatory regulatory genes across various immune cell types. Molecular docking suggested favorable predicted binding potential between these components and target proteins. Experimental validation using poly(I:C)-induced inflammatory models in both RAW264.7 macrophages and mouse bone marrow-derived macrophages (BMDMs) showed that the absorbed components—loganic acid, 8-epiloganic acid, calycosin, atractylodin, eucalyptol, secoxyloganin, and paeoniflorin—significantly reduced mRNA expression of immune-inflammatory genes (DUSP6, MAPKAPK2, NOD2) and inhibited secretion of TNF-α, IL-6, IL-8, and NO. These findings suggest that SYKL may alleviate influenza-associated inflammation through multi-component, multi-cell, and multi-target pathways, highlighting its potential in modulating excessive immune responses in influenza.

A standardized imaging and analysis workflow for quantitative evaluation of cutaneous neurofibromas in Nf1-KO mice

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder in which cutaneous neurofibromas (cNFs) represent one of the most common and burdensome manifestations. No approved pharmacological treatment exists. Preclinical studies are essential to evaluate candidate therapies, but reliable outcome and endpoint measures for cNFs in animal models remain limited. We developed and validated a standardized methodology to assess drug efficacy in the Prss56Cre Nf1-KO mouse model which recapitulates key features of cNFs. In this model, Nf1 inactivation and tdTomato (Tom) reporter expression were specifically targeted to Schwann cells (SCs) responsible for cNF development. This approach enables real-time monitoring, isolation, and manipulation of tumor SCs at any time. We defined macroscopic (tumor count, total Tom + fluorescent surface area, fluorescence intensity) and microscopic (cell-type composition defined by immunolabeling with a panel of specific markers, area quantification) endpoints, developed dedicated ImageJ scripts for automated image analysis, and compared the results with those obtained using the conventional manual method. Both automated measurements showed excellent reproducibility (ICC = 1) and strong correlation with manual analysis (Spearman’s coefficient > 0.90), while significantly reducing analysis time (up to 100-fold faster). Bland–Altman analyses confirmed the absence of systematic bias compared with manual scoring. The standardized image naming and metadata integration further facilitated data consolidation and statistical analysis. This validated approach provides a reliable, reproducible, and time-efficient framework for evaluating drug effects on cNFs in preclinical studies. It establishes a foundation for robust efficacy testing of candidate therapies, facilitates cross-study comparability, and accelerates therapeutic development and clinical translation.

Spatial Evolution of Coke in ZSM‐5 Catalysts During Methanol‐to‐Hydrocarbons Conversion Revealed by In Situ X‐Ray Photoelectron Spectroscopy

ABSTRACT Along with assessing chemical pathways, understanding the spatial evolution of deactivating coke species in zeolites is essential for enhancing their catalytic efficiency in processes for chemical and fuel production. In this study, synchrotron‐based in situ X‐ray photoemission spectroscopy experiments provide insights into the coke deposition on ZSM‐5 catalysts with different Si/Al ratios during methanol‐to‐hydrocarbons conversion, which is an industrially relevant reaction. Surface‐sensitive C 1s X‐ray photoemission spectroscopy with a probing depth ≈1 nm demonstrates that the less acidic ZSM‐5 zeolites exhibit a more pronounced coke accumulation on crystal surfaces and promote the formation of highly condensed, graphite‐like structures than the higher acidic ones. Analysis of coking kinetics, lattice deformation, and coke composition using Raman, in situ infrared, and operando UV‐vis spectroscopies further supports enhanced surface coking in low‐acidity, slowly deactivating catalysts and more prominent micropore coke formation in high‐acidity, fast‐deactivating catalysts. The results indicate that acid site density governs both the kinetics and the preferential location of coke, shedding light on the fundamental nanoscale processes underlying coke‐induced deactivation of zeolite catalysts.

3‐Deoxy‐3‐Fluoro Mannuronic Acid Alginates: Stereoselective Automated Synthesis and Conformational Behaviour

ABSTRACT Fluorination is a powerful strategy for the editing of glycans, creating bespoke tools to probe carbohydrate‐protein recognition and processing. Positioning the site for fluorination within a glycan is critical, whether examining bonding interactions or installing benign reporter capability. Herein, we study the effect of C‐3 fluorination of mannuronic acids in the assembly of β‐1,4‐ d ‐mannuronic acid alginate fragments and the effect of these point mutations on the conformational preference of the generated oligosaccharides. We explore the synthesis and glycosylating properties of a 3‐deoxy‐3‐fluoro d ‐mannuronate donor to establish that the C‐3 fluoride does not thwart the high β‐stereoselectivity of the mannuronate system. Subsequent deployment of these building blocks in automated glycan assembly enables the preparation of a small library of β‐ d ‐mannuronate oligosaccharides containing the C‐3‐F modification. Comprehensive NMR analysis shows that even though the 3‐deoxy‐3‐fluoro units disrupt the native inter‐residue C3‐OH•••O5 hydrogen bonds, the overall conformation remains in line with that of the native β‐1,4 mannuronic acid alginate. This indicates tolerance for this modification in these structural tools and provides an exciting foundation to study self‐assembly and enzymatic processing of β‐1,4 mannuronic acid oligosaccharides.

An automated approach to extracting head and brain circumference from MRI datasets

Head circumference is a fundamental biometric parameter for brain growth in both the clinical pediatric setting and in developmental neuroscience. However, the gold standard for obtaining head circumference by manual tape measurement is notoriously error-prone. Further, while it is known that the growth trajectories of head and brain differ over time, a systematic comparison of these two parameters as a function of age does not yet exist. We developed a new and automated algorithm for obtaining head and brain circumference from MRI data. The algorithm mimics manual head circumference measurement by placing a convex hull around axial slices which must intersect with predefined anatomical landmarks. Several differently-tilted iterations are run and results are combined. In addition to obtaining head circumference, the approach can also be applied to gray matter only, providing “brain circumference” (gray matter hull perimeter) at the same level as head circumference. To assess validity, we used T1-weighted 3D datasets (n = 153) with available, manually measured head circumference values (age range 0–226 months [0–18.8 years]). To assess test-retest reliability, a second dataset (n = 3 with 40 scans each) was used. When compared with the current gold standard (manual measure), high validity was demonstrated for the new approach, with no systematic bias. The algorithm also showed a very high reliability across multiple measurements. Developmental trajectories of both head and brain circumference were generated and compared. In summary, the algorithm represents a valid and reliable method for the automated determination of head as well as brain circumference. It offers an objective way to assess these parameters in retrospect and prospectively, and may shed light on specific clinical situations where they differ, such as in the presence of enlarged subarachnoid spaces.

Intrathecal pump refills at home or at the hospital: Protocol for a randomized controlled crossover trial—The IMPROVE study

Background Intrathecal drug delivery (IDD) offers a therapeutic option for patients suffering from refractory pain or severe spasticity. By allowing targeted and continuous infusion directly into the intrathecal space, IDD bypasses the blood-brain barrier and enhances therapeutic effectiveness of the drug. Following the implantation of an IDD pump, the most commonly performed postoperative maintenance procedure is the pump refill (at regular intervals). This process can be burdensome for patients, affects their comfort, and carries significant risks. The current aim of this study is to evaluate whether intrathecal pump refills performed at home provide a difference in patient comfort compared to refills conducted in the hospital. Methods The IMPROVE study is a monocentric, randomized controlled crossover trial, including 82 patients. For this study, each patient will undergo four intrathecal pump refill procedures (two at home and two in the outpatient clinic) allocated in a randomized order. The primary objective of this study is to determine whether at-home refills provide a difference in patient comfort compared to hospital-based refills. Secondary objectives include assessing differences in quality of life, pain, stress, anxiety, self-efficacy, caregiver burden, patient preferences, safety, and overall cost-effectiveness between the two settings. Patients will be followed over the course of four intrathecal pump refills, which is estimated to span approximately one year. Discussion Within the IMPROVE project, pump refills will be performed through hospital at home. If at-home intrathecal pump refills prove more comfortable for patients and cost-effective for society, this would strengthen the patient-centred care model and support adopting this approach as the new standard treatment for IDD patients. A graphical abstract is provided in the supplementary materials (S1 Fig). Trial registration Details on the study site can be found at ISRCTN with identifier: ISRCTN18031921; [href: https://doi.org/10.1186/ISRCTN18031921 ] https://doi.org/10.1186/ISRCTN18031921 . The trial was registered in the ISRCTN registry on 18 November 2025.

Lewis‐Base Coordination Enables Highly Dispersed Pt Cocatalyst on Pyrene‐Based MOFs for Enhanced Photocatalytic Hydrogen Evolution

ABSTRACT Rationally optimizing the coordination structures of Pt‐based cocatalysts to concurrently achieve enhanced charge separation/transfer and lowered reaction energy barriers is significant for photocatalysis. Herein, we engineered the coordination of Pt cocatalyst on pyrene‐based metal‐organic frameworks (MOFs) through grafting different Lewis‐base groups. The softness of the introduced groups directly determines their affinity for Pt precursors, allowing for precise tailoring of the electronic metal‐support interactions (EMSI) of Pt and MOFs, which leads to the distinct Pt coordination structures. These structural features accelerate charge separation/transfer by an established internal electric field and lower catalytic energy barriers enabled by the oxidized Pt surface, leading to significantly enhanced photocatalytic activity. Specifically, the ‐SH‐functionalized MOF (Pt/NU‐M), featuring strong EMSI, achieves atomic dispersion of Pt‐O/S coordination and delivers a superior hydrogen evolution rate of 5.68 mmol g cat −1  h −1 (405.71 mmol g pt −1  h −1 ) when using ascorbic acid as a sacrificial agent upon full‐spectrum light irradiation, which is about 16 times higher than that of the Pt/NU control and surpasses many reported MOF‐based materials. Notably, the catalyst maintains exceptional stability over 20 h of continuous operation. This work highlights Lewis‐base coordination for tailoring active sites and optimizing EMSI, providing new insights for rational catalyst design and related energy applications.

Editorial Note: A risk-averse sustainable perishable food supply chain considering production and delivery times with real-world application

Multicolor and Attenuated Light Intensity Responses in Protein Hydrogels Arising from Photoregulated Crosslink Dynamics

ABSTRACT Light‐responsive hydrogels enable noninvasive, precise, remote control over material properties with great biocompatibility, yet achieving multicolor addressability and dynamic regulation of mechanical properties remains challenging. Most systems rely on single photoswitches and regulate stiffness primarily through changes in crosslinking density. Here, we present a fully protein‐based hydrogel that combines multicolor light responsiveness with optical control of crosslink dynamics. The hydrogel includes two visible light‐responsive photoceptors: the cyanobacterial phytochrome Cph1, which enables reversible red/far‐red light‐controlled crosslinking, and CarH, which introduces irreversible green light‐induced gel‐sol transitions. Remarkably, Cph1‐based hydrogels exhibited an attenuated red light intensity response, forming stiffer networks under low‐intensity illumination than under high‐intensity light and show a subsequent dark‐adaptation with stiffening once red light illumination is stopped. This counterintuitive behavior arises from light‐driven bidirectional photoisomerization that modulates crosslink lifetimes without altering the photostationary state composition. Together, these findings establish orthogonally addressable reversible and irreversible crosslinks and photoregulated crosslink dynamics as new design principles for multicolor light‐responsive biomaterials.

Fetal sex programs immune architecture and cellular differentiation at the maternal–fetal interface in early human pregnancy

Enhancing missense variant classification in predicted intrinsically disordered regions

Classifying disease-causing missense variants in intrinsically disordered regions (IDRs) remains a significant challenge, with over 25% of known deleterious variants occurring in these regions. Existing in silico missense variant predictors that predict variant classification generally perform better in ordered regions of the protein, limiting their effectiveness. To address this, we developed a machine learning methodology that integrates global IDR conformation (gIDRc) features from ALBATROSS, phase separation (PS) features from BioPython, and 1024-dimensional protein embeddings from ProtTransBertBFD generated for both wild-type (WT) and mutant IDR sequences. IDR boundaries were defined using the AlphaFold-RSA predictions, which identifies disordered regions based on AlphaFold2 pLDDT scores and relative solvent accessibility. Using ClinVar variant classifications as ground truth, AlphaMissense, EVE, and ESM1b were the highest scoring unsupervised in silico missense predictors for IDR variants. Our baseline model, using only IDR-specific features achieved competitive performance on the hold-out test set with a PR-AUC of 0.817. Critically, when these IDR features were combined with these methods we saw significant overall improvement. The AlphaMissense-Enhanced model increased its PR-AUC from 0.807 to 0.919. Similarly, ESM1b-Enhanced improved PR-AUC from 0.679 to 0.845 and EVE increased from 0.591 to 0.910. These results demonstrate the effectiveness of our enhancements for classifying missense variants in IDRs and highlight its ability to complement existing in silico missense predictors.

Unlocking a Nitrosuccinate Lyase for Decarboxylative Enzymatic Hydronitration

ABSTRACT Nitro compounds are central to synthetic chemistry, yet mild and selective biocatalytic routes to these motifs remain elusive. We report an enzymatic strategy for the unique decarboxylative hydronitration of fumarate, achieved by repurposing the nitrosuccinate lyase CreD from the aspartase/fumarase superfamily for the synthetic direction. CreD from Streptomyces cremeus and three related bacterial homologues catalyze hydronitration using sodium nitrite salt with remarkable efficiency (turnover numbers up to 102,000) and high atom economy. With an already exceptionally broad functional group tolerance across the superfamily, this feature underscores a conserved yet adaptable activity landscape. Guided by comprehensive mutagenesis and computational analysis across all functionally distinct superfamily members, we uncovered key molecular determinants that govern nucleophile selectivity and preserve the structural integrity required for active tetramer assembly. We also define a diagnostic fingerprint for predicting hydronitration activity and propose a reaction mechanism supported by extensive QM/MM simulations. These molecular insights provide a foundation for expanding biocatalytic Michael‐type additions under environmentally benign aqueous conditions.

Effectiveness of liquorice gel as an adjunct to non-surgical periodontal therapy in chronic periodontitis: a randomized controlled, clinical and microbiological trial

Identifying cluster profiles based on barriers and facilitators to physical activity during COVID-19 confinement: A cross-sectional study using machine learning analysis

Social restrictions, such as confinement periods, tend to reduce physical activity (PA) levels. However, sociodemographic factors may influence specific barriers and facilitators to PA during such periods. This study aimed to identify cluster profiles of individuals based on barriers and facilitators to physical activity (PA) during COVID-19 confinement. Brazilian adults participated in a cross-sectional online survey. The questionnaire collected demographic data, PA levels, sedentary behavior (SB), and perceived barriers and facilitators for PA. During data preprocessing, correlated barriers and facilitators related to a similar topic were aggregated. Using machine learning analysis, the K-modes evaluated by the Silhouette Score were used for barriers and the ROCK evaluated by the Silhouette Score was used for facilitators. The barriers model produced well-defined profiles, whereas the facilitators model did not. The facilitator model generated clusters with multiple negative silhouette coefficients and exhibited a significantly less cohesive cluster structure. Therefore, only the barriers-based model was used for further analysis. The best model generated eight clusters, each named according to the most frequent barriers in the group, such as “Inactive depressive women”, “Active depressive women” and “Super active”. The depressive clusters presented more barriers to PA, three barriers each one. Significant differences in PA and SB were observed across clusters. This work highlights the novelty of using unsupervised machine learning to uncover latent subgroups based on multiple concurrent barriers. In conclusion, tailored home-based and outdoor strategies should be developed, particularly targeting individuals with depressive symptoms and those facing significant time constraints.

Synthesis of Cyclopropene‐Modified Fatty Acids Allows Single‐Cell Quantification of Uptake by Immune Cells

ABSTRACT Immune cell activity is strongly influenced by the nutrients present during activation. The effects of specific fatty acids (FAs) can be particularly complex, with them exerting diverse and sometimes opposing effects on immune cells. These functional differences are thought to stem from structural differences between the FAs, leading to altered cellular handling. However, chemical tools to directly probe these aspects remain limited. Here, we report the design and synthesis of saturated, unsaturated, and polyunsaturated cyclopropenyl fatty acids, each incorporating a minimal one‐carbon cyclopropene moiety as a bioorthogonal click handle. This motif enables rapid and live‐cell‐compatible labeling via the inverse electron‐demand Diels–Alder reaction, providing a versatile platform to trace FA behavior in biological systems. Application of these synthetic cyclopropenyl FAs in primary immune cell mixtures reveals distinct uptake patterns between different cell types, with polyunsaturated analogues showing strong uptake across all immune cell types. Complementary metabolic and proteomic analyses suggest that this uptake results in biological differences between high/low uptake immune populations, highlighting the utility of cyclopropenyl FA probes for dissecting lipid uptake in the context of immune cell biology.

Experimental study on crack initiation mechanism of loess containing non-penetrating fissures

Age-stratified prognostic performance of hematologic inflammatory indices for 30-day mortality in emergency department patients with PCR-confirmed COVID-19: A cohort study from the pre-vaccination pandemic era

Background During the pandemic era, rapid and accessible prognostic tools were essential to support clinical decision-making for emergency department (ED) patients presenting with acute infectious symptoms. Hematologic inflammatory indices derived from complete blood count (CBC) parameters, such as the systemic immune-inflammation index (SII), systemic inflammatory response index (SIRI), and pan-immune-inflammation value (PIV), have been increasingly investigated for risk stratification. This retrospective cohort study evaluated the age-stratified prognostic performance of these indices for 30-day mortality in ED patients during the pandemic period. Methods This retrospective cohort study included adults presenting to a tertiary-care ED between March 1 and May 31, 2020. All included patients were retrospectively confirmed to have SARS-CoV-2 infection by RT-PCR. CBC-derived inflammatory markers (SII, SIRI, and PIV) were calculated at admission. The primary outcome was 30-day mortality; the secondary outcome was ICU admission. Age-stratified analyses (<65 and ≥65 years) were performed. Receiver operating characteristic (ROC) analyses, area under the curve (AUC) values, optimal cut-offs, and negative predictive values (NPVs) were determined; logistic regression models assessed independent associations with mortality. Results A total of 2,778 PCR-confirmed patients were included (mean age 47.8 ± 16.2; 58.7% male). Thirty-day mortality was 6.2%. In the overall cohort, SII, SIRI, and PIV demonstrated modest prognostic performance for mortality (AUCs: 0.663, 0.659, and 0.649, respectively). In patients <65 years, performance improved particularly for SII (AUC 0.727), with SIRI and PIV yielding AUCs of 0.676 and 0.677, respectively. Among patients ≥65 years, discrimination was lower (SII: 0.570; SIRI: 0.604; PIV: 0.588). Formal DeLong testing confirmed statistically significant age-related attenuation for SII (ΔAUC = 0.159; P = 0.0055), with non-significant trends for SIRI and PIV. As an exploratory secondary outcome, direct ED-to-ICU admission occurred in 2.9% of patients; this endpoint primarily reflects the institutional pandemic-era pathway of low-threshold ward admission with subsequent ICU escalation upon clinical deterioration. All indices demonstrated high negative predictive values, particularly in younger patients, indicating potential utility for identifying lower-risk individuals during high-volume pandemic ED operations. Conclusions Hematologic inflammatory indices obtained at ED presentation demonstrated age-dependent prognostic performance for 30-day mortality, with SII showing good discrimination and high negative predictive value (98.9%) in patients younger than 65 years and reduced discriminatory performance in elderly patients. These readily available and cost-effective parameters may support rule-out decisions for younger adults in emergency settings, while in elderly patients clinical assessment and comorbidity profiling should be prioritized over inflammatory marker interpretation.

Integrated value iteration and simple games enable calibrated strategic coalition formation in social networks

Understanding support needs of African and African-Caribbean people living with dementia, their care partners and families, and impacts of delayed support: Identifying inclusive strategies to facilitate social care support: A study protocol

African and African-Caribbean (AAC) people living with dementia (PLWD) are a population at high risk of inequitable access to health and social care services, and have poor health and wellbeing outcomes. Research suggests they are likely to experience failings in care, be recognised by services late and at points of crisis, and are at increased risk of institutionalisation. This research aims to examine the experiences of AAC PLWD, their care partners and families of accessing social care services and support. Employing an intersectionality theoretical framework, this study will use a multi-method, flexible exploratory sequential design. An evidence synthesis using the JBI meta-aggregation approach, co-produced with AAC PLWD, their care partners, and families, will be conducted to synthesise existing evidence on the experiences of AAC PLWD, their care partners’ and families’ of support seeking in the UK. Narrative interviews will involve 3 sequential interviews conducted with 40 AAC PLWD (n = 10 per site), with opportunities for dyadic interviews with care partners and families. Ethnographic fieldwork will be conducted across 4 Local Authority sites within Adult Social Care teams (n = 30 days per site) to provide insight into institutional and organisational processes and cultures, and staff practices and engagement with PLWD. Artistic art workshops will be conducted to facilitate a diverse range of participant voices and support meaningful engagement for AAC PLWD at increased risk of isolation. Ethical approval has been obtained. Dissemination will include peer reviewed publications, conference presentations and free publicly available resources for health and social care professionals, third-sector partners, PLWD and their carer partners.

Water Radiolysis Enables CO ₂ ‐Activated Radical Recycling of Spent Lithium‐Ion Cathodes

ABSTRACT Conventional recycling of spent lithium‐ion batteries (LIBs) relies on energy‐intensive and complex processes that hinder sustainability. Here, we report a mild, efficient recycling strategy using programmable water radiolysis with CO 2 to establish an aqueous reductive radical platform. This radiolytic approach enables simultaneous cathode peeling, metal leaching, and component separation under ambient conditions, which is inaccessible to existing methods. Within minutes, high‐dose‐rate irradiation degrades the polymeric binder, enabling ∼99.5% active material recovery. Radiolytically generated CO 2 •− radicals reduce and leach transition metals (Co, Ni, Mn) and lithium with >96% efficiency. The dynamic pH evolution during irradiation precipitates transition metals in situ as carbonates while retaining Li + in solution, accomplishing one‐step separation. Regenerated cathodes deliver electrochemical performance comparable to commercial benchmarks. Techno‐economic analysis indicates this CO 2 ‐mediated radiolytic pathway offers a more sustainable, energy‐efficient, and cost‐effective route for battery recycling.