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The perioperative period is crucial for determining postoperative tumor recurrence and metastasis. Various factors in postoperative lesions can diminish the therapeutic effect of conventional chemoradiotherapy, while emerging immunotherapy is restricted. The combination use of inflammatory inhibitors during treatment is also controversial. Here, a modular microneedle prepared from engineered keratin proteins is reported, which spatially and temporally differentiates the microenvironment of immune cell activation required for immunotherapy from that of wound healing. The recombinant keratin-84-T-based needle root layer, mainly retained in the epidermis, facilitated dendritic cell recruitment to achieve maximum antigen presentation of loaded vaccines. Meanwhile, the recombinant keratin-81-1Aα-based needle tip layer, located within the dermis, rapidly mitigated inflammatory responses while promoting tissue repair and regeneration. Unlike simply mixing immunotherapy and wound treatment, this spatiotemporal segmentation approach maximized the efficacy of immune therapeutics while promoting wound healing, making it suitable for application throughout the perioperative period., (© 2025 Wiley‐VCH GmbH.)

Background: Social isolation and loneliness have detrimental impacts on health, especially for older adults. During the COVID-19 pandemic, physical access to third places (e.g., coffee shops, libraries) decreased due to the closure of non-essential destinations and personal risk assessments. Older adults reported adopting information and communication technology (ICT) during pandemic lockdowns. ICT-mediated socializing may have different impacts on loneliness than in-person equivalents. Understanding access to social connection and their distinct relationships to the built environment and health for older Chinese migrants is critical to supporting equitable, healthy aging in a post-COVID world., Methods: Using a survey of older Chinese migrants in the Greater Toronto Area (GTA) during the extended COVID-19 lockdown, we investigate how community mobility and ICT use, two mechanisms of socializing, relate to the built environment and influence loneliness (De Jong Gierveld 6-item scale), as well as mental and physical health (SF-12). Specifically, we use a structural equation model to test a theoretical framework of older adult social isolation., Results: Our model demonstrates the importance of community mobility for reducing feelings of loneliness, while ICT use is significantly related to better physical health. Both community mobility and ICT use have significant, although opposite, relationships to transit density., Conclusions: Results indicate that ICT use might have limited ability to reduce loneliness and support mental health when mobility is limited. Addressing older migrants' barriers to community mobility is critical to reducing feelings of loneliness., Competing Interests: Declarations. Ethics approval and consent to participate: We received ethical approval prior to data collection from the University of Toronto Research Ethics Board (protocol #00038958). Informed consent was obtained from all participants. Consent for publication: Not Applicable. Competing interests: The authors declare no competing interests. Authors’ information: The first author (AD) does not speak Mandarin Chinese, the language used to collect all data for this study. The survey instruments, consents, etc. were translated by BL, a native Mandarin speaker. XM and ZL, who are both native Mandarin speakers, commented on the final translation of materials., (© 2025. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background & Aims: The mechanisms underlying the regulation of hepatocyte non-receptor tyrosine kinases in metabolic dysfunction-associated steatohepatitis (MASH) remain largely unclear., Methods: Hepatocyte-specific overexpression or deletion and anti-protein tyrosine kinase 2 beta (PYK2) or anti-TRAF6-binding protein (T6BP) crosslinking were utilized to study fatty liver protection by T6BP. A P-PTC (peptide-proteolysis targeting chimera) degrades PYK2 to block MASH progression., Results: We found that T6BP is a novel and critical suppressor of PYK2 that reduces hepatic lipid accumulation, pro-inflammatory factor release, and pro-fibrosis production. Mechanistic evidence suggests that T6BP directly targets PYK2 and prevents its N-terminal FERM domain-triggered dimerization, disrupting downstream PYK2-JNK signaling hyperactivation. Additionally, T6BP favorably recruits CBL, a particular E3 ubiquitin ligase targeting PYK2, to form a complex and degrade PYK2. T6BP (F1), a core fragment of T6BP, directly blocks N-terminal FERM domain-associated dimerization of PYK2, followed by T6BP-recruiting CBL-mediated PYK2 degradation in a typical T6BP-dependent manner when the tiny fragment is specifically expressed using thyroxine binding globulin (TBG) vectors. This inhibits the progression of MASH, MASH-related hepatocellular carcinoma, and metabolic syndrome in dietary rodent models. We devised, and validated in animal models, the first-ever P-PTC based on the core segment of T6BP, as a ligand for the targeted recruitment of CBL, that could be used to target metabolic disorders like MASH., Conclusions: Our study uncovered a previously unknown mechanism, with T6BP identified as a key suppressor of steatosis. This, alongside the discovery of crucial T6BP-based fragments that interrupt PYK2 dimerization hold much promise for the treatment of MASH., Impact and Implications: Excessive high-energy diet ingestion is critical in driving steatohepatitis via regulation of hepatocyte non-receptor tyrosine kinases. The mechanisms underlying the regulation of hepatocyte PYK2 in metabolic dysfunction-associated steatohepatitis remain largely unclear. Here, we found that T6BP as a critical fatty liver eliminator could be used for the development of promising therapeutic options. Additionally, vital T6BP-based pharmacon fragments that impede PYK2 dimerization have been found, offering new and effective treatments for advanced fatty liver symptoms and complications., Competing Interests: Conflict of interest Authors declare that they have no competing interests. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2024 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Objectives: To develop robust variants of L-threonine aldolases (L-TAs), potent catalysts for synthesizing asymmetric β-hydroxy-α-amino acids, it is necessary to identify critical residues beyond the known active site residues., Results: Through virtual screening, a neglected residue Asn305, was identified as critical for catalytic efficiency. Subsequent site-saturation mutagenesis led to a potent variant N305R which exhibited excellent conversions of 88% conv (87% de ) and 80% conv (94% de ) for the synthesis of L-threo-phenylserine and L-threo-4-fluorophenylserine respectively. This variant not only outperformed the template enzyme, but also represented a promising L-TA for synthesizing the two β-hydroxy-α-amino acids. It was suggested that Arg305 of the variant N305R generated strong cation-arene interaction and electrostatic force with the intermediates, leading to strengthened binding, enhanced L-threo favored orientation and wider entrance., Conclusions: Our work not only provided an excellent variant N305R, but also suggested the crucial function of a neglected residue Asn305, which offered valuable experiences for other L-TA studies., Competing Interests: Declarations. Competing interest: The authors have no relevant financial or non-financial interests to disclose. Ethical approval: This article does not contain any studies involving human participants or animals. Consent to participate: Not applicable. Consent to publish: All authors agree to publish this work., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Background: In England, the number of takeaway food outlets ('takeaways') has been increasing for over two decades. Takeaway management zones around schools are an effective way to restrict the growth of new takeaways but their impacts on population health have not been estimated., Methods: To model the impact of takeaway management zones on health, we used estimates of change in and exposure to takeaways (across home, work, and commuting buffers) based on a previous evaluation suggesting that 50% of new outlets were prevented from opening because of management zones. Based on previous cross-sectional findings, we estimated changes in body mass index (BMI) from changes in takeaway exposure, from 2018 to 2040. We used PRIMEtime, a proportional multistate lifetable model, and BMI change to estimate the impact of the intervention, in a closed-cohort of adults (25-64 years), on incidence of 12 non-communicable diseases, obesity prevalence, quality-adjusted life years (QALYs), and healthcare costs saved by 2040 in six local authorities (LAs) across the rural-urban spectrum in England (Wandsworth, Manchester, Blackburn with Darwen, Sheffield, North Somerset, and Fenland)., Results: By 2031, compared to no intervention, reductions in outlet exposure ranged from 3 outlets/person in Fenland to 28 outlets/person in Manchester. This corresponded to mean per person reductions in BMI of 0.08 and 0.68 kg/m 2 , respectively. Relative to no intervention, obesity prevalence was estimated to be reduced in both sexes in all LAs, including by 2.3 percentage points (PP) (95% uncertainty interval:2.9PP, 1.7PP) to 1.5PP (95%UI:1.9PP, 1.1PP) in males living in Manchester and Wandsworth by 2040, respectively. Model estimates showed reductions in incidence of disease, including type II diabetes (e.g. 964 (95% UI: 1565, 870) fewer cases/100,000 population for males in Manchester)), cardiovascular diseases, asthma, certain cancers, and low back pain. Savings in healthcare costs (millions) ranged from £1.65 (95% UI: £1.17, £2.25)/100,000 population in North Somerset to £2.02 (95% UI: £1.39, £2.83)/100,000 population in Wandsworth. Gains in QALYs/100,000 person were broadly similar across LAs., Conclusions: Takeaway management zones in England have the potential to meaningfully contribute towards reducing obesity prevalence and associated healthcare burden in the adult population, at the local level and across the rural-urban spectrum., Competing Interests: Declarations Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. For the purpose of open access, the author has applied a Creative Commons Attribution (CC BY) licence to any Author Accepted Manuscript version arising. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Background: Neighbourhood exposure to takeaways can contribute negatively to diet and diet-related health outcomes. Urban planners within local authorities (LAs) in England can modify takeaway exposure through denying planning permission to new outlets in management zones around schools. LAs sometimes refer to these as takeaway "exclusion zones". Understanding the long-term impacts of this intervention on the takeaway retail environment and health, an important policy question, requires methods to forecast future takeaway growth and subsequent population-level exposure to takeaways. In this paper we describe a novel two-stage method to achieve this., Methods: We used historic data on locations of takeaways and a time-series auto-regressive integrated moving average (ARIMA) model, to forecast numbers of outlets within management zones to 2031, based on historical trends, in six LAs with different urban/rural characteristics across England. Forecast performance was evaluated based on root mean squared error (RMSE) and mean absolute scaled error (MASE) scores in time-series cross-validation. Using travel-to-work data from the 2011 UK census, we then translated these forecasts of the number of takeaways within management zones into population-level exposures across home, work and commuting domains., Results: Our ARIMA models outperformed exponential smoothing equivalents according to RMSE and MASE. The model was able to forecast growth in the count of takeaways up to 2031 across all six LAs, with variable growth rates by RUC (min-max: 39.4-79.3%). Manchester (classified as a non-London urban with major conurbation LA) exhibited the highest forecast growth rate (79.3%, 95% CI 61.6, 96.9) and estimated population-level takeaway exposure within management zones, increasing by 65.5 outlets per capita to 148.2 (95% CI 133.6, 162.7) outlets. Overall, urban (vs. rural) LAs were forecast stronger growth and higher population exposures., Conclusions: Our two-stage forecasting approach provides a novel way to estimate long-term future takeaway growth and population-level takeaway exposure. While Manchester exhibited the strongest growth, all six LAs were forecast marked growth that might be considered a risk to public health. Our methods can be used to model future growth in other types of retail outlets and in other areas., Competing Interests: Declarations Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)