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Mapping of endosomal proximity proteomes reveals Retromer as a hub for RAB GTPase regulation
Abstract Endosomal retrieval and recycling of integral cargo proteins is essential for cell and organism development and homeostasis and is orchestrated through a specialised endosomal nanodomain, the retrieval sub-domain. Sub-domain dysfunction is associated with human disease, but our mechanistic understanding of its function remains poorly described. Here, using proximity proteomics of retrieval sub-domain components Retromer and Retriever we identify mechanistic details of retrieval sub-domain composition and organization, including an unrecognised complexity in the interface with RAB GTPase switching. Combining X-ray crystallography and in silico predictions with biochemical and cellular analysis, we reveal that Retromer directly associates and recruits the RAB10 regulators DENND4A, DENND4C, TBC1D1, and TBC1D4, and the RAB35 regulator TBC1D13 to regulate retrieval sub-domain function. The retrieval sub-domain therefore constitutes a hub for integrating cargo recycling with the regulated switching of selected RAB GTPases. We propose this constitutes a major component of the neuroprotective role of the retrieval sub-domain.
DBRSNet: a dual-branch remote sensing image segmentation model based on feature interaction and multi-scale feature fusion
Association of serum Klotho with tinnitus prevalence, duration and severity: A cross-sectional study in middle-aged and older adults
Background As an anti-aging protein, although studies increasingly suggest that the Klotho plays a role in the auditory system, the link between serum Klotho levels and tinnitus remains poorly characterized. The aim of this study was to investigate the associations between serum Klotho levels and tinnitus focusing on prevalence, duration and severity in middle-aged and older adults. Methods We performed a population-based cross-sectional study of individuals in the National Health and Nutrition Examination Survey (NHANES) 2009–2012 and 2015–2016. Univariable and multivariable logistic regression was used to evaluate the relationship between serum Klotho levels and tinnitus, with adjustment for potential confounders and further age-stratified analyses. Restricted cubic splines were applied to assess potential non-linearity in the dose-response relationship. Furthermore, Subgroup and interaction analyses were conducted to assess the consistency of this association. Results In this research of 3280 individuals aged 40–79 years with a median age of 55 (IQR: 48, 62) and 48% male participants, the median serum Klotho level was 779.80pg/mL. Multivariable logistic regression uncovered consistent inverse associations between serum Klotho levels and tinnitus incidence across progressively adjusted models (ORs: 0.68–0.70, p = 0.009–0.01). Age-based stratified analyses suggested the strongest effect was observed in individuals aged 50–59 years (full model ORs: 0.55, p = 0.046). A marginally significant protective effect was observed in the 60–69 age group (unadjusted OR=0.62, 95% CI: 0.39–1.00, p = 0.050). Serum Klotho levels showed no significant correlation with tinnitus severity, while a potential association with the duration of tinnitus was observed (p = 0.058). Additionally, restricted cubic spline analysis revealed a linear inverse association between Klotho and tinnitus risk stratified by age (all p for nonlinear >0.15). Finally, subgroup and interaction analyses revealed no significant effect modification (all p-interaction >0.1). Conclusion Serum Klotho concentrations showed a consistent inverse association with tinnitus prevalence in US adults, with the strongest effect observed in individuals aged 50–69 years.
Effects of sacubitril/valsartan on hypertensive heart disease: the REVERSE-LVH randomized phase 2 trial
Mediating role of SII in the association between LC9 and overactive bladder
Low-cost computation for isolated sign language video recognition with multiple reservoir computing
Sign language recognition (SLR) has the potential to bridge communication gaps and empower hearing-impaired communities. To ensure the portability and accessibility of the SLR system, its implementation on a portable, server-independent device becomes imperative. This approach facilitates usage in areas without internet connectivity, addressing the need for data privacy protection. Although deep neural network models are potent, their efficacy is hindered by computational constraints on edge devices. This study delves into reservoir computing (RC), which is renowned for its edge-friendly characteristics. Through leveraging RC, our objective is to craft a cost-effective SLR system optimized for operation on edge devices with limited resources. To enhance the recognition capabilities of RC, we introduce multiple reservoirs with distinct leak rates, extracting diverse features from input videos. Prior to feeding sign language videos into the RC, we employ preprocessing via MediaPipe. This step involves extracting the coordinates of the signer’s body and hand locations, referred to as keypoints, and normalizing their spatial positions. This combined approach, which incorporates keypoint extraction via MediaPipe and normalization during preprocessing, enhances the SLR system’s robustness against complex background effects and varying signer positions. Experimental results demonstrate that the integration of MediaPipe and multiple reservoirs yields competitive outcomes compared with deep recurrent neural and echo state networks and promises significantly lower training times. Our proposed MRC achieved accuracies of 60.35%, 84.65%, and 91.51% for the top-1, top-5, and top-10, respectively, on the WLASL100 dataset, outperforming the deep learning-based approaches Pose-TGCN and Pose-GRU. Furthermore, because of the RC characteristics, the training time was shortened to 52.7 s, compared with 20 h for I3D and the competitive inference time.
Dominant end-tunneling effect in two distinct Luttinger liquids coexisting in one quantum wire
Cultural adaptation of the polish version of the brief pain inventory short form among the elderly
Abstract Demographic changes taking place in society require a holistic approach to the health problems of the elderly, including the chronic pain that often accompanies them in various disease entities. The aim of this study was to evaluate the psychometric properties of the Polish version of the Brief Pain Inventory-Short Form (BPI-SF) among the elderly. The study was conducted on a group of 181 patients of both genders, over 65 years of age, with pain lasting longer than 6 months, hospitalized in internal medicine and geriatric wards. Construct validity was assessed using principal component analysis (PCA) method with Quartimax rotation. The goodness of fit of the measurement model, the BPI-SF was based on, in the sample of Polish elderly was tested using the Confirmatory Factor Analysis (CFA). The reliability of the scale, in terms of its internal consistency, was estimated using the Cronbach alpha and Raykow’s Rho coefficients and by analysis of item-total correlation, applying the Kline criterion. The PCA revealed unidimensional structure in the BPI-SF the first factor of the solution was defined by all but two items of the scale. The reliability of the total score was 0.88 and remained at the same level after removing sleep position and average pain intensity from the subscales. Raykow’s Rho for the individual subscales was estimated at 0.78 for severity subscale, 0.66 for affective disturbances involving sleep and 0.82 excluding it, and 0.86 for activity-related difficulties. The Brief Pain Inventory-Short Form (BPI-SF), despite differences in psychometric properties with respect to the original results, may be applicable in monitoring the intensity of chronic non-cancer pain (pain associated with the musculoskeletal system and neuropathic pain) among the elderly as well as in the verification of functional status in daily clinical practice. Trial registration: Statutory research “Chronic pain in people over 65 years of age” K/ZDS/005733, conducted in 2015-2018.
Differentiation of HL-60 cells into primed neutrophils for the evaluation of antiapoptotic effects of poorly soluble nanoparticles
Background Neutrophil apoptosis is an important determinant of intensity and duration of neutrophilic inflammation. The interaction of poorly soluble nanoparticles with primed neutrophils can reduce their natural apoptosis rates. This reaction may contribute to pathogenic consequences of increased neutrophilic inflammation. Toxicological studies aiming to identify hazards of such materials with primary neutrophils are however challenging due to the short life span of these cells and a high donor to donor variability. Our purpose was the establishment of a culturable neutrophil-like cell line as a suitable model for studies of antiapoptotic effects of poorly soluble combustion-derived environmental nanoparticles. Therefore, differentiation protocols for the myeloid HL-60 cell line based on commonly used differentiation inducers all-trans retinoic acid (ATRA) and dimethyl sulfoxide (DMSO) were established and compared. Results The data demonstrate that only a combined cell treatment with ATRA and DMSO for a period of 5 days leads to the complete HL-60 differentiation with the typical neutrophil morphology and characteristic features of neutrophil maturation like cell cycle arrest, increase in differentiation marker CD11b, loss of proliferation marker CD71, and increased phagocytic capacity. Exposure of cells differentiated with ATRA + DMSO to carbon nanoparticles or proinflammatory cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) revealed a delay of apoptosis causally linked to intracellular reactive oxygen species (ROS). These data verified our earlier findings with human peripheral primed neutrophils from donors with slightly elevated proinflammatory blood plasma factors. Moreover, completely differentiated HL-60 cells possessed similar levels of L-selectin CD62L as neutrophils with primed immunophenotype, thus representing the biology of primed inflammatory neutrophils. Conclusion Neutrophil-like HL-60 cells differentiated according to our protocol could be an appropriate substitute cell line model for studies on the effects of inhalable nanomaterials on primed inflammatory neutrophils like lung neutrophils. For such toxicological studies our cell model is preferable to peripheral neutrophils, as blood neutrophils not always occur in a primed state and primed lung neutrophils from donors are not available for this purpose.
Structure and mechanism of the RalGAP tumor suppressor complex
Abstract The RalGAP (GTPase activating protein) complexes are negative regulators of the Ral GTPases and thus crucial components that counteract oncogenic Ras signaling. However, no structural information on the architecture of this tumor suppressor complex is available hampering a mechanistic understanding of its functionality. Here, we present a cryo-EM structure of RalGAP that reveals an extended 58 nm tetrameric architecture comprising two heterodimers of the RalGAPα and RalGAPβ subunits. We show that the catalytic domain of RalGAPα requires stabilization by a unique domain of RalGAPβ, providing the molecular basis for why RalGAP complexes are obligatory heterodimers. Formation of RalGAP tetramers is not required for activity in vitro, but essential for function of the complex in vivo. Structural analysis of RalGAP subunit variants reported in cancer patients suggests effects on complex formation and thus functional relevance, emphasizing the significance of the obtained structural information for medical research.
A closed loop fully automated wireless vagus nerve stimulation system
Abstract Vagus nerve stimulation (VNS) has been explored as a treatment for a range of conditions, including epilepsy, cardiovascular disorders, drug-resistant depression, chronic pain, and obesity. Conventionally, VNS is administered using an open-loop approach, in which trained personnel adjust stimulation parameters. Medical supervision is necessary to minimize adverse effects, such as severe bradycardia, which can significantly interfere with daily activities. This requirement limits the feasibility of VNS in unsupervised settings and highlights the need for an automated control system. To address this limitation, we introduce the fully automated wireless VNS (FAW-VNS) system, which dynamically adjusts stimulation parameters to maintain steady-state operation while minimizing bradycardia. The FAW-VNS system operates in real-time and consists of a biocompatible, miniaturized, wirelessly powered implant equipped with cuff electrodes; a handheld device for power delivery and stimulation protocol communication; a sensing patch to collect and transmit heart rate (HR) data; and a central control unit (CCU) that updates stimulation protocols based on the acquired physiological signals. In-vivo studies were conducted on four anesthetized pigs to validate the system’s ability to reach a steady-state response, achieving a controlled HR reduction within 2–4% of baseline during stimulation. This work lays the foundation for developing closed-loop, wireless implants for point-of-care applications.
Serum fibrinogen level and fibrinogen administration in patients with traumatic brain injury: A systematic review and meta-analysis protocol
Introduction Traumatic Brain Injury (TBI) is a leading cause of disability and death globally. It has a significant economic burden. Coagulopathy has been identified as one of the key factors contributing to the poor outcomes observed in TBI patients, and it has been theorised that the management of coagulopathy will improve patient outcomes. Low serum fibrinogen levels denote a coagulopathic state, and the therapeutic administration of fibrinogen has been proposed to correct this state. However, there is no consensus on its efficacy in patients with TBI. Hence, this systematic review and meta-analysis seeks to ascertain the prognostic value of serum fibrinogen levels in patients with TBI and assess the effect of fibrinogen administration on these patients. Methods Using the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) guidelines, we will perform a comprehensive search of Scopus, Medline, Embase and Cochrane Library to retrieve all original articles that investigate the prognostic value of fibrinogen levels and/or the effect of fibrinogen administration in TBI patients. Primary outcomes include functional outcome and mortality assessments such as the Glasgow Outcome Score and modified Rankin Score. Secondary outcomes include progressive intracranial haemorrhage/contusion and need for surgical intervention. Data collected will encompass participant demographics, measured fibrinogen levels, dose of fibrinogen administered and specified outcome measures. Conclusion Findings from this study, specifically the evidence if fibrinogen level has prognostic value and if fibrinogen administration improves patient outcomes, will help inform future TBI management. It will also enhance shared decision-making between healthcare professionals and patients if fibrinogen has a prognostic value, as this value could be used to communicate more effectively the expected prognosis post-TBI. Thus, TBI patient outcomes can be optimised accordingly. PROSPERO Registration Number CRD42024556497. Available from: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42024556497
Continuous structure modification of metal-organic framework glasses via halide salts
Abstract Melting and glass formation of metal-organic frameworks (MOFs) allow them to be processed into bulk materials. However, two major challenges remain: only a small fraction of MOF crystals undergo melting and glass-formation, and no well-established strategies exist for tuning MOF glass structures and properties. Here, we address both challenges through co-melting of zeolitic imidazole frameworks (ZIFs), a subset of MOFs, with heterocycle-based halide salts. The salt acts as a chemical “modifier”, akin to the role of alkali modifiers in traditional silicate glasses, e.g., allowing the melting of ZIF-8 that otherwise decomposes prior to melting. Through experimental and computational analyses, we show that the salts depolymerize the ZIFs, enabling continuous tuning of the fraction of bridging to non-bridging imidazolate linkers and, thereby, the thermal and mechanical properties. The proposed strategy enables diversification of MOF glass chemistry, tunable structures and properties, and ultimately an increased number of glass-forming MOFs with improved functionalities.
A hybrid deep learning model for sentiment analysis of COVID-19 tweets with class balancing
Abstract The widespread dissemination of misinformation and the diverse public sentiment observed during the COVID-19 pandemic highlight the necessity for accurate sentiment analysis of social media discourse. This study proposes a hybrid deep learning (DL) model that integrates Bidirectional Encoder Representations from Transformers (BERT) for contextual feature extraction with Long Short-Term Memory (LSTM) networks for sequential learning to classify COVID-19-related sentiments. To enhance data quality, advanced text preprocessing techniques, including Unicode normalization, contraction expansion, and emoji conversion, are applied. Additionally, to mitigate class imbalance, Random OverSampling (ROS) is employed, leading to significant improvements in model performance. Before applying ROS, the model exhibited lower accuracy and inconsistent performance across sentiment categories. After balancing the dataset, accuracy for binary classification increased to 92.10%, with corresponding precision, sensitivity, and specificity of 92.10%, 92.10%, and 91.50%, respectively. For three-class sentiment classification, accuracy improved to 89.47%, with precision, sensitivity, and specificity of 89.80%, 89.47%, and 94.10%, respectively. In five-class sentiment classification, accuracy reached 81.78%, with precision, sensitivity, and specificity of 82.19%, 81.78%, and 95.28%, respectively. These findings demonstrate the efficacy of combining deep learning-based sentiment analysis with advanced text preprocessing and class balancing techniques for accurately classifying public sentiment related to COVID-19 across multiple sentiment categories.
Emergency dispatchers as instructors of laypersons in unplanned out-of-hospital deliveries - Interdisciplinary qualitative study
Introduction Unplanned out-of-hospital delivery tasks are continuously increasing and are challenging to the emergency dispatcher, but there is scant research on them, especially from the perspective of instructing the layperson in delivery. In the Finnish model of one emergency response centre authority, the expertise of the emergency dispatcher is highlighted. However, it’s necessary to develop collaborative and transformative expertise and cooperation in the maternity care service system to respond to risky and unexpected childbirth events. This study adopts concepts from cultural-historical activity theory in the framework of object-oriented activity systems and negotiated knotworking. Our aim is to describe and analyse the perspectives of emergency dispatchers and laypersons when the emergency dispatcher instructs the layperson in handling an unplanned out-of-hospital delivery. Methods This is an interdisciplinary qualitative study. The study data consists of stories written by emergency dispatchers (n = 31) and semi-structured interviews with laypersons (n = 5). The data was collected using both the method of empathy-based stories and semi-structured interviews. The data was analysed using qualitative theory-driven content analysis, data-based theory-driven thematic analysis and text mining. Results The emergency dispatchers’ and laypersons’ descriptions of their actions in the examined delivery situations were structured as elements of activity systems. The thematic analysis produced two themes containing discursive characteristics of negotiated knotworking, which were (i) script innovations requiring midwifery competence and (ii) emotion work. Discussion The object of the emergency dispatcher’s actions was the physical wellbeing of the person giving birth and the newborn, while the layperson’s object was the childbirth experience, including the aforementioned and shared with the person giving birth. The formal script of childbirth services does not serve negotiated knotworking. Further, a midwife’s participation in an emergency call, including video consultation, is desired. The emergency dispatcher should respect the object-oriented conscious agency of the layperson, providing ad hoc information for childbirth.
Supramolecular dynamics-enhanced synergistic antifouling mechanisms for enhanced membrane antifouling and permeability
Abstract This study develops water treatment membranes using an innovative surface modifier comprising threaded supramolecular assemblies formed by hydrophilic cyclodextrin (CD) and low-surface-energy polydimethylsiloxane (PDMS). These supramolecular constructs establish dynamic hydrophilic and low-surface-energy heterogeneous microdomains that enhance synergistic resistance-release antifouling mechanisms. The modified membranes demonstrate better antifouling performance compared to conventional systems, particularly addressing the critical limitation of traditional membranes under low tangential flow conditions. The Brownian motion of the CDs sustains microdomain activity to prevent foulant accumulation in static environments, while tangential flow amplifies dynamic interactions to accelerate foulant detachment. The threading configuration of CDs along PDMS chains prevents water channel blockage caused by PDMS aggregation and facilitates water transport through the dynamic mobility of CDs. When separating bovine serum albumin solutions under an initial flux of 550 L·m−2·h−1 with 60 rpm stirring, the membrane exhibits merely 14.2% flux decline, highlighting its exceptional antifouling performance and permeability.
A text mining-based approach for comprehensive understanding of Chinese railway operational equipment failure reports
Expression of Concern: Magnitude and associated factors of disrespect and abusive care among laboring mothers at public health facilities in Borena District, South Wollo, Ethiopia
Long-term effect of temporary ART initiated during primary HIV-1 infection on viral persistence
Abstract Initiation of antiretroviral therapy (ART) during primary HIV-1 infection (PHI) has been proposed to limit the formation of HIV-1 reservoirs. However, it remains unknown whether temporary ART initiated during PHI has a long-term effect on viral persistence. Here, we longitudinally quantify HIV-1 persistence markers and immunological parameters in the participants (n = 64) of a randomized controlled trial comparing 24 or 60 weeks of temporary ART vs. no treatment during PHI, who subsequently (re)initiated ART during chronic HIV-1 infection (CHI) after a median period of 116 weeks without treatment (ISRCTN59497461). Levels of several HIV-1 persistence markers (cell-associated unspliced RNA, total DNA, and intact DNA) do not significantly differ and strongly positively correlate between early and CHI ART periods in the same participants. Early ART is associated with lower HIV-1 proviral sequence diversity and superior restoration of the CD4/CD8 ratio, as well as lower levels of monocyte activation markers, compared to CHI ART, in the same participants. At CHI ART, intact HIV-1 DNA negatively correlates with HIV-specific T-cell responses. Finally, levels of HIV-1 persistence markers during CHI ART are lower in participants who had been pre-treated during PHI, indicating a long-term suppressive effect of temporary early ART on the persistence of HIV-1 reservoir.