Role of endothelial Raptor in abnormal arteriogenesis after lower limb ischemia in type-2 diabetes.

AIMS: Proper arteriogenesis after tissue ischemia is necessary to rebuild stable blood circulation; nevertheless, this process is impaired in type-2 diabetes mellitus (T2DM). Raptor, is a scaffold protein and a component of mammalian target of rapamycin complex 1 (mTORC1). However, the role of the endothelial Raptor in arteriogenesis under the conditions of T2DM remains unknown. This study investigated the role of endothelial Raptor in ischemia-induced arteriogenesis during T2DM. METHODS AND RESULTS: Although endothelial mTORC1 is hyperactive in T2DM, we observed a marked reduction in the expression of endothelial Raptor in two mouse models and in human vessels. Inducible endothelial-specific Raptor knockout severely exacerbated impaired hindlimb perfusion and arteriogenesis after hindlimb ischemic injury in 12-week high-fat diet fed mice. Additionally, we found that Raptor deficiency dampened vascular endothelial growth factor receptor 2 (VEGFR2) signaling in endothelial cells and inhibited VEGF-induced cell migration and tube formation in a PTP1B-dependent manner. Furthermore, mass spectrometry analysis indicated that Raptor interacts with neuropilin 1 (NRP1), the co-receptor of VEGFR2, and mediates VEGFR2 trafficking by facilitating the interaction between NRP1 and Synectin. Finally, we found that endothelial cell-specific overexpression of the Raptor mutant (loss of mTOR binding) reversed impaired hindlimb perfusion and arteriogenesis induced by endothelial Raptor knockout in high-fat diet fed mice. CONCLUSIONS: Collectively, our study demonstrated the crucial role of endothelial Raptor in promoting ischemia-induced arteriogenesis in T2DM by mediating VEGFR2 signaling. Thus, endothelial Raptor is a novel therapeutic target for promoting arteriogenesis and ameliorating perfusion in T2DM.

Investigating the Integration and the Long-Term Use of Smart Speakers in Older Adults' Daily Practices: Qualitative Study.

BACKGROUND: As smart speakers become more popular, there have been an increasing number of studies on how they may benefit older adults or how older adults perceive them. Despite the increasing ownership rates of smart speakers among older adults, studies that examine their integration and the long-term use in older adults' daily practices are scarce. OBJECTIVE: This study aims to uncover the integration of smart speakers into the daily practices of older adults over the long term, contributing to an in-depth understanding of maintained technology use among this demographic. METHODS: To achieve these objectives, the study interviewed 20 older adults who had been using smart speakers for over 6 months. These semistructured interviews enabled participants to share their insights and experiences regarding the maintained use of smart speakers in the long term. RESULTS: We identified 4 dimensions of the long-term use of smart speakers among older adults, including functional integration, spatial integration, cognitive integration, and semantic integration. For the functional integration of smart speakers, the study reported different types of use, including entertainment, information collection, medication reminders, companionship, environment modification, and emergency calls. For the spatial integration of smart speakers, the study showed older adults' agency in defining, changing, and reshaping daily practices through the spatial organization of smart speakers. For the cognitive integration of smart speakers, the findings showed the cognitive processes involved in adapting to and incorporating smart speakers into daily habits and routines. For the semantic integration of smart speakers, the findings revealed that older adults' enjoyable user experience and strong bonds with the device contributed to their acceptance of occasional functional errors. Finally, the study proposed several suggestions for designers and developers to better design smart speakers that promote maintainable use behaviors among older adults. CONCLUSIONS: On the basis of the findings, this study highlighted the importance of understanding how older adults use smart speakers and the practices through which they integrate them into their daily routines. The findings suggest that smart speakers can provide significant benefits for older adults, including increased convenience and improved quality of life. However, to promote maintainable use behaviors, designers and developers should consider more about the technology use contexts and the specific needs and preferences of older adults when designing these devices.

Non-invasive detection of lymphoma with circulating tumor DNA features and protein tumor markers.

Background: According to GLOBOCAN 2020, lymphoma ranked as the 9th most common cancer and the 12th leading cause of cancer-related deaths worldwide. Traditional diagnostic methods rely on the invasive excisional lymph node biopsy, which is an invasive approach with some limitations. Most lymphoma patients are diagnosed at an advanced stage since they are asymptomatic at the beginning, which has significantly impacted treatment efficacy and prognosis of the disease. Method: This study assessed the performance and utility of a newly developed blood-based assay (SeekInCare) for lymphoma early detection. SeekInCare utilized protein tumor markers and a comprehensive set of cancer-associated genomic features, including copy number aberration (CNA), fragment size (FS), end motif, and lymphoma-related virus, which were profiled by shallow WGS of cfDNA. Results: Protein marker CA125 could be used for lymphoma detection independent of gender, and the sensitivity was 27.8% at specificity of 98.0%. After integrating these multi-dimensional features, 77.8% sensitivity was achieved at specificity of 98.0%, while its NPV and PPV were both more than 92% for lymphoma detection. The sensitivity of early-stage (I-II) lymphoma was up to 51.3% (47.4% and 55.0% for stage I and II respectively). After 2 cycles of treatment, the molecular response of SeekInCare was correlated with the clinical outcome. Conclusion: In summary, a blood-based assay can be an alternative to detect lymphoma with adequate performance. This approach becomes particularly valuable in cases where obtaining tissue biopsy is difficult to obtain or inconclusive.

Co-designing community-level integral interventions for active ageing: a systematic review from the lens of community-based participatory research.

BACKGROUND: While community-level interventions for promoting active ageing have received increasing attention and there is a trend to leverage technology to support traditional physical or social interventions, little hands-on guidance exists for designing these integral interventions. This study aimed to examine the interventions reported in the literature guided by Community-Based Participatory Research (CBPR) principles. The goal is to extract insights that inform future practices in co-designing integral interventions for active ageing. METHODS: The systematic review focused on community-level interventions promoting active ageing that integrated physical, social, and digital elements, i.e., integral interventions. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. The included interventions were analysed abductively based on the CBPR principles. RESULTS: A total of 13 studies were included, and 24 design considerations were generated under eight categories. Further reflection identified the interrelated nature of these design considerations and pinpointed the gaps in current research. This study highlights the urgency and importance of sharing recruitment methods and resource allocation details, recording and reporting collaboration specifics, and disseminating findings to stakeholders beyond academia. CONCLUSIONS: This study offers valuable insights and practical guidance to researchers and practitioners developing community-level integral interventions for active ageing. The findings also serve as a starting point for accumulating knowledge and practice in co-designing integral interventions for active ageing at the community level. The next crucial phase involves evaluating these design considerations within real-world cases to assess their applicability and identify potential areas for improvement.

Identifying Human miRNA Target Sites via Learning the Interaction Patterns between miRNA and mRNA Segments.

miRNAs (microRNAs) target specific mRNA (messenger RNA) sites to regulate their translation expression. Although miRNA targeting can rely on seed region base pairing, animal miRNAs, including human miRNAs, typically cooperate with several cofactors, leading to various noncanonical pairing rules. Therefore, identifying the binding sites of animal miRNAs remains challenging. Because experiments for mapping miRNA targets are costly, computational methods are preferred for extracting potential miRNA-mRNA fragment binding pairs first. However, existing prediction tools can have significant false positives due to the prevalent noncanonical miRNA binding behaviors and the information-biased training negative sets that were used while constructing these tools. To overcome these obstacles, we first prepared an information-balanced miRNA binding pair ground-truth data set. A miRNA-mRNA interaction-aware model was then designed to help identify miRNA binding events. On the test set, our model (auROC = 94.4%) outperformed existing models by at least 2.8% in auROC. Furthermore, we showed that this model can suggest potential binding patterns for miRNA-mRNA sequence interacting pairs. Finally, we made the prepared data sets and the designed model available at http://cosbi2.ee.ncku.edu.tw/mirna_binding/download.

Ganglioside GM3 Protects Against Abdominal Aortic Aneurysm by Suppressing Ferroptosis.

BACKGROUND: Abdominal aortic aneurysm (AAA) is a potentially life-threatening vascular condition, but approved medical therapies to prevent AAA progression and rupture are currently lacking. Sphingolipid metabolism disorders are associated with the occurrence and development of AAA. It has been discovered that ganglioside GM3, a sialic acid-containing type of glycosphingolipid, plays a protective role in atherosclerosis, which is an important risk factor for AAA; however, the potential contribution of GM3 to AAA development has not been investigated. METHODS: We performed a metabolomics study to evaluated GM3 level in plasma of human patients with AAA. We profiled GM3 synthase (ST3GAL5) expression in the mouse model of aneurysm and human AAA tissues through Western blotting and immunofluorescence staining. RNA sequencing, affinity purification and mass spectrometry, proteomic analysis, surface plasmon resonance analysis, and functional studies were used to dissect the molecular mechanism of GM3-regulating ferroptosis. We conditionally deleted and overexpressed St3gal5 in smooth muscle cells (SMCs) in vivo to investigate its role in AAA. RESULTS: We found significantly reduced plasma levels of GM3 in human patients with AAA. GM3 content and ST3GAL5 expression were decreased in abdominal aortic vascular SMCs in patients with AAA and an AAA mouse model. RNA sequencing analysis showed that ST3GAL5 silencing in human aortic SMCs induced ferroptosis. We showed that GM3 interacted directly with the extracellular domain of TFR1 (transferrin receptor 1), a cell membrane protein critical for cellular iron uptake, and disrupted its interaction with holo-transferrin. SMC-specific St3gal5 knockout exacerbated iron accumulation at lesion sites and significantly promoted AAA development in mice, whereas GM3 supplementation suppressed lipid peroxidation, reduced iron deposition in aortic vascular SMCs, and markedly decreased AAA incidence. CONCLUSIONS: Together, these results suggest that GM3 dysregulation promotes ferroptosis of vascular SMCs in AAA. Furthermore, GM3 may constitute a new therapeutic target for AAA.

Wafer-scale organic-on-III-V monolithic heterogeneous integration for active-matrix micro-LED displays.

The organic thin-film transistor is advantageous for monolithic three-dimensional integration attributed to low temperature and facile solution processing. However, the electrical properties of solution deposited organic semiconductor channels are very sensitive to the substrate surface and processing conditions. An organic-last integration technology is developed for wafer-scale heterogeneous integration of a multi-layer organic material stack from solution onto the non-even substrate surface of a III-V micro light emitting diode plane. A via process is proposed to make the via interconnection after fabrication of the organic thin-film transistor. Low-defect uniform organic semiconductor and dielectric layers can then be formed on top to achieve high-quality interfaces. The resulting organic thin-film transistors exhibit superior performance for driving micro light emitting diode displays, in terms of milliampere driving current, and large ON/OFF current ratio approaching 1010 with excellent uniformity and reliability. Active-matrix micro light emitting diode displays are demonstrated with highest brightness of 150,000 nits and highest resolution of 254 pixels-per-inch.

Impact of social networks on fertilizer use efficiency in China: Evidence from kiwifruit production in Shaanxi province.

Improving fertilizer use efficiency (FUE) is an effective way to reduce the fertilizer use and non-point source pollution in agriculture production in China. Existing research related to fertilizer use efficiency ignores the impact of famers' social networks, which can significantly affect the fertilizer use and its efficiency. This paper analyzed the impact of social networks on fertilizer use efficiency and the mediator effect of green fertilization technology adoption, based on the calculation of fertilizer use efficiency of 569 kiwifruit farmers in Shaanxi province of China surveyed in 2021 by using stochastic frontier method. The results show that the FUE of kiwifruit production ranged within 0.1027-0.9945, with an average value of 0.333, which showed great variability, and fertilizer input had an average 66.7% reduction potential without reducing output. Social networks and its four dimensions all had a significant positive impact on FUE, in which network trust and network learning had a greater impact on FUE. Farmers' adoption of green fertilization technology played a positive mediator effect in the process of social networks influencing their fertilizer use efficiency, which was mainly promoted by network trust and learning. Farmers' experience in agricultural production, joining the cooperative, the quantity of village agricultural supply points had a significant positive impact on fertilizer use efficiency, while age and gentle of the head of household had a significant negative impact of fertilizer use efficiency. Planting scale had a U-shape impact on FUE. Policies aimed at improving FUE and reducing non-point source pollution should, therefore, focus on improving the social networks of farmers, especially young farmers, strengthening network trust, promoting network learning, network reciprocity and network interaction, strengthening the research and development and extension of green fertilization technology, encouraging farmers to join agricultural cooperative, improving village production conditions, guiding sustainable agricultural production.

Malat1 promotes macrophage-associated inflammation by increasing PPAR-γ methylation through binding to EZH2 in acute myocardial infarction.

The inflammatory microenvironment of macrophage plays an important role in acute myocardial infarction (AMI), but the regulatory mechanism is unknown. Here, we aimed to investigate the role of Malat1 on inflammation microenvironment of macrophage in AMI. Our study found that Malat1 expression was increased in AMI, which mainly expressed in macrophages. Malat1 inhibition improved collagen deposition and inflammation in infarcted heart. In vitro, Malat1 inhibition evidently reduced macrophage-associated inflammation. The results from ribonucleic acid pull-down (RNA pull-down) and RNA Immunoprecipitation (RIP) assay demonstrated that Malat1 directly binds to EZH2. Malat1 and EZH2 complex could increase histone H3K27me3 expression and further inhibit the production of PPAR-γ. In vivo, inhibition of Malat1 also leaded to the down-regulation of both EZH2 and H3K27me3, as well as up-regulation of PPAR-γ in infarcted heart. Therefore, these findings demonstrate a novel mechanism of Malat1 on inflammation microenvironment of macrophage in AMI, which provide a new target for its treatment.

Domesticating Social Alarm Systems in Nursing Homes: Qualitative Study of Differences in the Perspectives of Assistant Nurses.

BACKGROUND: New social alarm solutions are viewed as a promising approach to alleviate the global challenge of an aging population and a shortage of care staff. However, the uptake of social alarm systems in nursing homes has proven both complex and difficult. Current studies have recognized the benefits of involving actors such as assistant nurses in advancing these implementations, but the dynamics by which implementations are created and shaped in their daily practices and relations have received less attention. OBJECTIVE: Based on domestication theory, this paper aims to identify the differences in the perspectives of assistant nurses when integrating a social alarm system into daily practices. METHODS: We interviewed assistant nurses (n=23) working in nursing homes to understand their perceptions and practices during the uptake of social alarm systems. RESULTS: During the four domestication phases, assistant nurses were facing different challenges including (1) system conceptualization; (2) spatial employment of social alarm devices; (3) treatment of unexpected issues; and (4) evaluation of inconsistent competence in technology use. Our findings elaborate on how assistant nurses have distinct goals, focus on different facets, and developed diverse coping strategies to facilitate the system domestication in different phases. CONCLUSIONS: Our findings reveal a divide among assistant nurses in terms of domesticating social alarm systems and stress the potential of learning from each other to facilitate the whole process. Further studies could focus on the role of collective practices during different domestication phases to enhance the understanding of technology implementation in the contexts of complex interactions within a group.

Technology scripts in care practice: A case study of assistant nurses' use of a social alarm system in Swedish nursing homes.

Background: Technologies such as social alarm systems contain expectations about how they should be integrated and used in practice. These expectations, also called technology scripts, usually fail to consider all the complexity in care practice. Shifting the focus from technology scripts to care practice, this paper examines how a social alarm system is used in assistant nurses' care practices in nursing homes. Methods: The paper draws on observations of assistant nurses' daily tasks (32 h) and semi-structured interviews with assistant nurses (n = 12) in two Swedish nursing homes. The observation data were used to understand the care contexts and assistant nurses' technology-mediated care practices, while interviews were used to deeply understand assistant nurses' perceptions of the system, their care practices, and which aspects they considered during the provision of care. Findings: We show the complexities involved in integrating a social alarm system into care practices based on assistant nurses' situational and personal interpretations of both technology scripts and quality of care. The technology-mediated care practices consist of receiving alarms from residents, checking alarms via alarm phones, responding to alarms via alarm phones, checking specific residents' situations in person, documenting all finished alarms, and documenting some finished alarms. In these practices, the assistant nurses defined technology scripts according to their expected requirements and outcomes, and meanwhile considered the quality of care by evaluating the priority of practical, moral or relational care in the situations at hand. Through further negotiations with the defined scripts and the considered quality of care, the assistant nurses decided on the final way of following (or not following) specific scripts in practice. Conclusion: Results from our study portray the complexity of technology in care practices. The findings contribute to increased understanding of technology-mediated care practices in nursing homes, and research on technology scripts in institutional settings.

The atypical binding mechanism of second calcium on phospholipase A2 group IIE.

Secreted phospholipase A2s (sPLA2s) are calcium dependent enzymes involved in various biological events such as lipid metabolism and inflammation. We previously identified the second calcium (Ca2) binding site of human sPLA2 Group IIE (hGIIE) by structural study and suggested that Asn21 act as the switch of Ca2 binding to modulate the enzymatic activity, but the detailed Ca2 binding mechanism is still unclear. Combined with enzymatic assay, model analysis and calcium binding affinity data for mutated hGIIE proteins, we herein further demonstrate that the flexibly bound Ca2 is essential for the catalysis of hGIIE, unlike the stable binding of Ca2 in hGIIA that replenishes the calcium in the typical loop during the reaction. The atypical Ca2 binding feature of hGIIE will provide a better understanding on the catalytic mechanism of hGIIE.

Gut-inhabiting Clostridia build human GPCR ligands by conjugating neurotransmitters with diet- and human-derived fatty acids.

Human physiology is regulated by endogenous signalling compounds, including fatty acid amides (FAAs), chemical mimics of which are made by bacteria. The molecules produced by human-associated microbes are difficult to identify because they may only be made in a local niche or they require a substrate sourced from the host, diet or other microbes. We identified a set of uncharacterized gene clusters in metagenomics data from the human gut microbiome. These clusters were discovered to make FAAs by fusing exogenous fatty acids with amines. Using an in vitro assay, we tested their ability to incorporate 25 fatty acids and 53 amines known to be present in the human gut, from which the production of six FAAs was deduced (oleoyl dopamine, oleoyl tyramine, lauroyl tryptamine, oleoyl aminovaleric acid, α-linolenoyl phenylethylamine and caproyl tryptamine). These molecules were screened against panels of human G-protein-coupled receptors to deduce their putative human targets. Lauroyl tryptamine is found to be an antagonist to the immunomodulatory receptor EBI2 against its native oxysterol ligand (0.98 µM half-maximal inhibitory concentration), is produced in culture by Eubacterium rectale and is present in human faecal samples. FAAs produced by Clostridia may serve as a mechanism to modulate their host by mimicking human signalling molecules.

Discrepancies between Expected and Actual Implementation: The Process Evaluation of PERS Integration in Nursing Homes.

Recent studies prove that when implementing new technology technology-driven and one-size-fits-all approaches are problematic. This study focuses on the process of implementing personal emergency response system (PERS) at nursing homes. The aim is to understand why the implementation of PERS has not met initial expectations. Multiple methods were used in two Swedish nursing homes, including document analysis, questionnaires (n = 42), participant observation (67 h), and individual interviews (n = 12). A logic model was used to ascertain the discrepancies that emerged between expected and actual implementation, and the domestication theory was used to discuss the underlying meanings of the discrepancies. The discrepancies primarily focused on staff competence, system readiness, work routines, and implementation duration. Corresponding reasons were largely relevant to management issues regarding training, the procurement systems, individual and collective responsibilities as well as invisible work. The uptake of technology in daily practice is far more nuanced than a technology implementation plan might imply. We point out the importance of preparing for implementation, adjusting to new practices, and leaving space and time for facilitating implementation. The findings will be of use to implementers, service providers, and organizational managers to evaluate various measures in the implementation process, enabling them to perform technology implementation faster and more efficiently.

The Effect of Processing Donor Milk on Its Nutrient and Energy Content.

Background: The pasteurization is a mandatory step to inactivate pathogenic microorganisms of bank milk. For storage, freezing and thawing are necessary. The concentration of macronutrients and energy of bank milk could be influenced by these procedures which are routinely used in human milk bank. Research Aim: The aim of this study is to analyze the effect of bank milk processing (pasteurization and freezing/thawing) on the macronutrients (fat, protein, and carbohydrate) concentration and energy content. Materials and Methods: The samples of donor milk were collected and studied before/after pasteurization and after frozen for 3 months. Total 100 samples of bank milk were tested using an infrared analyzer. The measurements of fat, protein, carbohydrate, and energy were statistically analyzed by SPSS. Results: There was a prominent reduction of fat mean concentration following pasteurization and frozen (20.5% and 6.5%, respectively). The processing did not cause significant changes in protein content, but there were significant increase after pasteurization and decrease after frozen in carbohydrate (p < 0.05). Overall (postpasteurization and frozen storage), a 9.6% decrease was observed for energy content. Conclusion: This study revealed that the processing of bank milk (including Holder Pasteurization and frozen storage) decreased fat and energy content of human milk significantly, and this could not meet the specific needs of preterm infants.

Hydrogen production driven by formate oxidation in Shewanella oneidensis MR-1.

Shewanella oneidensis MR-1 is a potent hydrogen producer in the deficiency of exogenous electron acceptors. The electron transfer pathway for hydrogen production remains unclear, although enzymes for hydrogen production have been identified in S. oneidensis MR-1. In this study, we investigated the electron transfer pathway from formate to hydrogen, given that formate is commonly a key chemical for bacterial hydrogen production. We revealed that two formate dehydrogenases FdhA1B1C1 and FdhA2B2C2, rather than FdnGHI, played a dominant role in formate-driven hydrogen production. Menaquinone was indispensable for the electron transfer from formate to hydrogen, which excluded the presence of formate hydrogen-lyase in S. oneidensis MR-1. A previously proposed formate dehydrogenase subunit HydC was identified as a menaquinone-binding subunit of [FeFe] hydrogenase HydAB, and the hydABC operon is conserved in bacteria living in diverse environments. A formate exporter FocA and transcriptional regulator FhlA were identified for their effect on formate metabolism and hydrogen production. FhlA positively affected the metabolism of formate and hydrogen by regulating the expression of fdhA2B2C2, fdnGHI, focA, and dld-II. Overall, the electron transfer pathway deciphered in this work will facilitate the improvement of biohydrogen production by S. oneidensis MR-1.Key Points• The electron transfer pathway from formate to hydrogen in MR-1 is deciphered.• Menaquinone is indispensable for hydrogen production.• A cytochrome b subunit transfers electrons from menaquinone to [FeFe] hydrogenase.