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Epidural electrical stimulation (EES) has emerged as a promising therapy for restoring motor function in patients with paralysis. A primary challenge in this therapy lies in identifying feasible stimulation parameters in huge selection space for different movements, given the limited understanding of the precise alignment between stimulation and corresponding neuromuscular performance. We aimed to develop a computational framework that predicts neuromuscular performance under EES and thereby reduces the need for extensive in-clinic parameter searches. We implanted purpose-designed 32-contact epidural interfaces in two individuals with motor-complete spinal cord injury and reconstructed personalized spinal anatomies from medical imaging. Finite element simulations and axonal recruitment modeling were integrated with machine learning to establish a predictive mapping between stimulation parameters and muscle responses. A dimensionality-reduction Bayesian optimization algorithm was subsequently applied to identify compact sets of stimulation parameters targeting specific motor objectives, and selected configurations were validated through clinical testing. This study is an interim report of an ongoing registered clinical trial (Closed-loop Functional Spinal Cord Stimulation in Patients with Spinal Cord Injury, ClinicalTrials.gov Identifier: NCT04969042), sponsored by Beijing PINS Medical Co., Ltd. Here we present purpose-designed 32-contact epidural neural interfaces that enabled two individuals with spinal cord injury to regain lower-limb motor function. The hybrid predictive model demonstrated strong quantitative agreement with experimentally measured muscle responses (mean squared error = 0.0096). Algorithm-guided parameter recommendations comprising 180 configurations outperformed both the historical dataset (1,602 configurations) and conventional bipolar settings across four functional objectives. Clinical validation further confirmed that the recorded muscle activations were in close agreement with model predictions. The AI-aided computational framework can serve as a reliable and feasible agent for evaluating and recommending effective EES parameters. By bridging anatomical modeling with functional outcomes, this approach offers a practical pathway toward optimizing neuromodulation therapies and advancing the development of personalized treatment strategies for individuals with spinal cord injury. People with spinal cord injury often lose the ability to move their legs because the connection between the brain and spinal cord is damaged. Over recent decades, epidural electrical stimulation—delivering pulses of electricity to the spinal cord—has been shown to help restore leg movement. However, finding the proper stimulation settings for each person is usually time-consuming and depends on trial and error. In this study, we designed and manufactured a 32-contact spinal implant and implanted it in two people with spinal cord injury. We also developed a personalized hybrid model that combines computer simulations and neural-network predictions to estimate how different stimulation settings affect muscle activity. An optimization algorithm then recommends parameter sets for specific movements, and these recommendations were tested in the clinic. By automating and personalizing parameter selection, this approach can reduce the testing burden on patients and clinicians and help enable more tailored neuromodulation treatments.

Introduction: Electronic nicotine delivery systems (ENDSs), also known as e-cigarettes or vapes, have shown popularity among the adolescent population. Compared to adults, less is known regarding the impacts of ENDS and nicotine on the adolescent brain. Adolescent research related to nicotine and other illicit substances can be difficult due to the requirement of parent/guardian consent, adolescent hesitancy for disclosure of product use, and the continually evolving vaping and nicotine products on the market. Despite these challenges, further research is needed to explore the impact of ENDS on the developing adolescent brain. The objective of the study was to evaluate reward sensitivity and cognitive flexibility in the adolescent population using functional magnetic resonance imaging (fMRI) through a probabilistic reversal learning task. Methods: This pilot study recruited participants aged 13-19 years old to complete fMRI testing. We specifically adapted a probabilistic reversal learning task that was previously used to measure reward sensitivity and cognitive flexibility in adults (including nicotine users). We were unable to recruit enough ENDS users to complete the planned analysis; therefore, we evaluated non-users as proof of concept for the use of the probabilistic reversal learning task in adolescents to support future research. Participants completed four blocks of a probabilistic reversal learning task, each lasting 6 min. During each block of the task, blood-oxygenation-level-dependent (BOLD) fMRI images were collected. The reward sensitivity and cognitive flexibility contrasts of parameter estimates were entered into a group analysis model. Due to the small sample size and exploratory nature of the study, we were interested in computing population-level estimates of brain activation that could be attributed to reward sensitivity (win-stay minus lose-stay trials) and cognitive flexibility (lose-shift trials minus lose-stay trials). Results: A total of twelve participants completed fMRI testing-ten non-users, one intermittent user, one regular user. Four of these participants (three non-users and one intermittent user) were excluded from the fMRI analysis due to excessive head movement and/or poor task performance. With the seven remaining non-users, we found no evidence of significant BOLD activation when strictly controlling the Type I error rate. Using a more liberal statistical threshold that did not control the Type I error rate, both contrasts resulted in suprathreshold clusters in occipital and posterior parietal regions, and the reward sensitivity contrast also resulted in suprathreshold clusters in the prefrontal cortex (bilateral middle occipital gyrus). Discussion/Conclusions: We did not find statistically significant BOLD activation, which is likely due to the small sample size. Suprathreshold clusters using the liberal statistical threshold may be feasible for use as regions of interest in future studies using this task. Notably, the prefrontal regions where the reward sensitivity contrast exceeded the liberal statistical threshold in our study were similar to those observed in previous studies of reward sensitivity in adults (including nicotine users) and adolescents. This pilot study explores the use of an fMRI reward-learning paradigm in the adolescent population, which can serve as a catalyst for future research related to nicotine use.

The Awareness, Care, and Treatment In Obesity maNagement Asia Pacific (ACTION APAC) online survey identified perceptions, attitudes, and barriers to effective obesity care among People with Obesity (PwO) and Health Care Professionals (HCP) across nine APAC countries. Here, we present findings from Indonesia. This was a cross-sectional, observational, descriptive survey in PwO (≥18-year-old) with self-reported body mass index of ≥25 kg/m2 and HCPs who spent ≥50% of their time in direct patient care. The survey was conducted between 20 April, 2022 to 11 May, 2022. The questionnaires were approved by the institutional review board as per local regulations. A total of 1,000 PwO and 200 HCPs completed the survey. Notable differences were observed among PwO and HCPs in acknowledging obesity as a chronic disease (54% PwO and 90% HCPs), considering weight loss as PwO responsibility (91% PwO and 17% HCPs) and in agreeing that PwO were motivated to lose weight (76% PwO and 50% HCPs). Almost, two-thirds (67%) of PwO perceived themselves as either overweight or normal weight while only 30% discussed weight with their HCPs in the past five years. Financial concerns (45%) and assuming self-responsibility for weight loss (43%) were cited as the top reasons for not discussing. Only 53% HCPs initiated weight conversations, as they believed that PwO were either not motivated (55%) or not able to lose weight (51%). When discussed, most (68%) HCPs recommended lifestyle changes. Our study identified gaps in understanding obesity as a disease and its management among PwO and HCPs, highlighting a need for increased awareness to improve obesity care in Indonesia.

The gradual recruitment of tortuous medial collagen fibers underlies the nonlinear behavior of arteries within the physiological loading regime, while adventitial collagen fibers are hypothesized to act primarily as a protective element during supraphysiological loading events, such as balloon angioplasty. We examined five human cerebral artery specimens using multiphoton microscopy to image adventitial collagen during progressive supraphysiological uniaxial testing to failure. Fiber angles, tortuosity, and sublayer location were quantified for 3467 fibers across the adventitial thickness. A mixed-effects regression model assessed the effects of strain, tortuosity, sublayer index, and their interactions on circumferential fiber alignment. Higher strain significantly decreased fiber angles (p<0.001), indicating greater alignment, while higher tortuosity reduced alignment (p<0.01) and diminished aligning effects of strain (p<0.001). Sublayer position was also significant (p<0.001), with adventitial fibers closer to the media being more aligned. With increasing stretch, adventitial fibers first lose tortuosity. At higher stretch (&#x3bb;&#x2217;&#x2248;1.25&#xb1;0.09, &#x3c3;&#x2217;&#x2248;0.92&#xb1;0.27MPa), internal elastic lamina (IEL) tearing and adjacent medial fiber rupture occur, followed by circumferential adventitial fiber alignment. However, in this cohort (mean age 73.4&#xb1;7.9 years), realignment was observed after multiple transverse IEL and medial tears had occurred. These findings provide quantitative, layer- and sublayer-specific evidence of a two-stage adventitial response, highlighting the coupled influence of loading, tortuosity, and wall depth on fiber alignment, and underscoring the need for high-fidelity models that explicitly incorporate layer-specific fiber architecture and failure mechanisms.

Ongoing climatic changes and their future projections indicate that native conifer tree species would lose their suitable climatic niches in central Europe by the end of century. Maintaining productivity and carbon sequestration capacity in managed forests may require focusing on alternative tree species, including non-native ones. In this study we investigated productivity traits of seven grand fir (Abies grandis (Douglas ex. D. Don) Lindl.) provenances at two common garden testing sites in Poland to examine the extent at which variation could be attributed to climatic adaptation, and to the response to climatic transfer distances. Productivity per unit land area varied significantly between two sites and among tested provenances. The observed patterns of variation pointed to increasing performance of populations with milder climate and more favorable climatic moisture availability at their origin, indicating adaptation of local populations. Seed sources from Vancouver Island, the Olympic Peninsula, and the Cascades of Washington should be prioritized for planting in conditions of central Europe. The use of grand fir provenances in afforestation and reforestation programs must be closely aligned with climatic matching, especially with respect to moisture availability, for maximizing productivity and enhancing structural diversity of managed forests in central Europe in a changing climate.

In-vivo chemical cross-linking combined with mass spectrometry analysis (XL-MS) enables the direct capture of protein-protein interactions (PPIs) within their native cellular environment. This platform provides a unique capability to capture weak or transient interactions in near-native contexts, complementing other large-scale methods that may lose these associations during cell lysis or purification. The workflow involves selection of suitable chemical cross-linkers to stabilize PPIs in biological samples, ranging from organelles and cells to whole tissues. This is followed by careful sample preparation, high-resolution mass spectrometry (MS) analysis and computational identification of cross-linked peptides. Continuous advancements at each stage of this workflow have enhanced the sensitivity, throughput and accuracy of the technique. A pivotal development has been the design of novel multifunctional cross-linkers featuring improved cell permeability, MS-cleavable sites, enrichment tags and multisite reactivity. Furthermore, recent advances in MS instrumentation, data acquisition strategies and computational software have increased the depth and reliability of cross-link identification. This review focuses on general workflows and recent innovations that accelerate the impact of in-vivo XL-MS, highlighting experimental strategies for proteome-wide PPI mapping. The successful standardization of methodology would enable widespread acceptance and application of XL-MS to address diverse and complex biological questions.

Hundreds of proteins and lipid species give HDLs (high-density lipoproteins) their polydispersity and multifunctionality. Studies have shown that plasma levels of HDL cholesterol (HDL-C) and apo AI (apolipoprotein AI), as well as HDL particle measures recorded by nuclear magnetic resonance spectroscopy, are associated with many clinical end points, including cardiovascular disease, diabetes, chronic kidney disease, and infections. These conditions all share inflammation as a pathogenic process. HDL particles and their specific components interfere with several steps in the inflammatory process. (1) They prevent dysmetabolism and eliminate or inactivate the causes and triggers of inflammation, including infectious agents, cholesterol, and oxidized lipids. (2) They modulate the activity of cellular and humoral components of innate and acquired immune systems. (3) They help limit or repair tissue damage or systemic homeostatic disturbances caused by inflammation. However, confrontation with the causes of inflammation and the organism's additional responses to inflammation can modify HDL's composition and components so that these particles lose or gain beneficial or adverse properties, respectively. Therefore, HDL particles are components of host defense and remain interesting targets for managing multiple inflammatory diseases beyond atherosclerosis.

Decapping Scavenger (DcpS) enzyme was initially identified by its ability to hydrolyze the cap structure resulting from mRNA decay. Human DcpS is an established target for acute myeloid leukemia (AML) and hepatic metastasis. Recently, the protein has been linked to neuronal development regulation and implicated in certain developmental neurological disorders. Here we demonstrate for the first time that DcpS of the human and C. elegans nematode origin undergoes misfolding in vitro, leading to the formation of amyloid-like fibrils. Additionally, the DcpSINS15 insertional mutant linked to the Al-Raqad syndrome exhibited accelerated fibril aggregation kinetics compared to the wild type protein. Importantly, we demonstrate that the DcpS species investigated in this study undergo liquid-liquid phase separation (LLPS), which appears to lead in turn to amyloid formation. We propose that the LLPS phase transition underlies the intricate kinetics (e.g. lack of a clearly-resolved lag phase) of the misfolding process. As the physiological implications of the here-reported propensity of DcpS to lose its biological function through the coupled LLPS-fibrillization transition remain to be elucidated, this work lays the groundwork for further studies on this phenomenon and provides a potential link between DcpS aggregation and disease-associated loss of function.

Spontaneous pregnancy loss is the most common pregnancy complication; 15-25% of clinically confirmed pregnancies end in miscarriage, and when early, undetected pregnancy losses are included, the miscarriage rate can reach as high as 30-60% of all pregnancies. Women who lose their babies in the early stages of pregnancy often experience this as a bereavement. However, in Lithuania, 95.2% of women who had experienced a miscarriage and participated in the study did not receive any psychological support; only 4% of those surveyed stated that they did not need it. However, both in Lithuania and abroad, there is still a lack of research on women's emotional state following a spontaneous pregnancy loss and the impact of interventions on it. Research question: What experiences emerge in the thematic analysis of women who have experienced a spontaneous miscarriage? A qualitative study was conducted using the inductive thematic analysis method. The study participants underwent a 10-session group art therapy programme. After each art therapy session, the study participants reflected on their experiences related to their miscarriage by analyzing the drawings they had created. Verbal data from the reflections were recorded, then transcribed and analysed according to identified themes. The research participants were four women who had experienced a spontaneous pregnancy loss. The study analyses the reflections of three women who participated in all sessions. The thematic analysis revealed four themes characterising the women's core experiences of spontaneous pregnancy loss: defensiveness, the grieving process, a complicated relationship with oneself and others, and awareness and finding meaning.

Autoimmune diseases arise when B and T lymphocytes lose tolerance to self. Yet in most disorders, the underlying molecular determinants, including autoantibodies, epitopes and lymphocyte clones that drive tissue injury remain undefined. Rapid-onset obesity with hypothalamic dysfunction, hypoventilation and autonomic dysregulation (ROHHAD) is a rare and often fatal pediatric neuroendocrine syndrome with strong evidence of antigen-driven paraneoplastic autoimmunity, including association with the intracellular autoantigen ZSCAN1. However, the effector immune circuit and the epitope-level determinants operating within the hypothalamus and brainstem have remained unknown. To address this challenge in ROHHAD and more broadly in autoimmune disease, we developed the Autoimmune Epitope and immunoGlobulin/Immune-receptor identification System (AEGIS), an integrated framework that links immune repertoires to their cognate self-epitopes. AEGIS combines B cell and T cell receptor profiling from sites of tissue injury with high-resolution epitope mapping, direct sequencing of antigen-specific autoantibodies, in silico antibody-antigen folding, selection, and T cell antigen discovery. Applied to a deeply phenotyped child with ROHHAD, AEGIS revealed a compartmentalized, clonally restricted immune response in which brain-deposited IgG and expanded cerebrospinal fluid B cell and CD4 T cell clonotypes converged on shared ZSCAN1 epitopes, resolved to minimal determinants and peptide-MHC ligands. These findings provide a clone- and epitope-linked mechanistic map of ROHHAD autoimmunity and establish a generalizable framework for identifying candidate pathogenic clones and antigens across diverse autoimmune diseases.

The aim of this study was to determine if people with MS (pwMS) experience a different income development from controls, and if so, at what age, and at what time in the disease course. We examined income development for pwMS compared to matched controls in a Norwegian cohort. We assessed the impact of both age and time from diagnosis on income using linear mixed-effects models. Men with MS (mwMS) had, on average, a lower income trajectory compared to controls at an earlier age than women with MS (wwMS) (49 vs. 55&#x2009;years). For men, the gap was increasing throughout the entire working age, while women were catching up with their controls close to retirement age. Although the absolute difference from controls is larger for mwMS than wwMS from age 50, the difference between the sexes is only statistically significant from age 60. The income increase rate was lower for both mwMS and wwMS compared to controls after being diagnosed with MS. For mwMS, the difference is evident 2&#x2009;years after diagnosis, and for wwMS, 5&#x2009;years after diagnosis. The average income loss experienced by mwMS was double that of women from 6&#x2009;years after diagnosis, but the difference was not statistically significant when comparing the sexes. PwMS have lower income development than controls. Men lose income earlier in life and earlier in the disease course than women.

Throughout the world, peer review serves as the cornerstone of the scientific enterprise, providing rigorous quality control and building the confidence that underpins progress for both science and society. Without such a robust process, scientists and the general public would rapidly lose the ability to distinguish groundbreaking advances from noise, which undermines policy decisions, research translation, and most importantly, public trust in science. Sadly, that is exactly what has been happening in Australia.

The circadian &#x223c;24h timing system coordinates physiological and metabolic processes to anticipate daily environmental changes, yet how molecular clock-driven signals interface with redox signalling to shape health across the life course remain incompletely understood. Redox homeostasis encompasses the adaptive maintenance of a biological steady state through the regulation of reduction-oxidation (redox) reactions. Redox reactions are vital in maintaining cellular functions, from regulating cellular proliferation and differentiation to detoxification of harmful substances and metabolic regulation. This adaptive homeostasis allows cells and tissues to transiently adapt to fluctuating levels of internal and external environmental stressors and build stress resilience to potential damaging stimuli. As we age, our baseline stress-protective systems rise, and our cells and tissues lose the ability to transiently and temporally increase their adaptive capacity further, leading to chronic redox shifts in pathophysiological direction and increased susceptibility to disease and frailty. Here we integrate circadian timing, NRF2 signalling and redox balance into a unified circadian-NRF2-redox axis as a life course framework for maintaining health from development through ageing. We propose that circadian clocks regulate NRF2 activity through rhythmic modulation of various redox-sensitive transcriptional and post-translational co-regulators, kinases and miRNAs, thereby shaping the amplitude and timing of antioxidant and metabolic responses. Conversely, NRF2-driven transcriptional programmes modulate mitochondrial function, glutathione synthesis and xenobiotic defence in a time-of-day manner, reinforcing circadian robustness in tissues with high oxidative flux. The bidirectional interplay between circadian clocks and NRF2-driven redox adaptations generates predictable redox oscillations that gate energy metabolism, cellular repair and immune responses, influencing susceptibility to chronic diseases, from metabolic and cardiorespiratory to neurodegenerative diseases and cancer. We review evidence from in vitro and in vivo experimental models and human studies showing that circadian/NRF/redox misalignments, whether from shiftwork, light pollution, irregular sleep or chronic feeding, amplify oxidative stress and diminish adaptive responses, accelerating health decline with age. We propose that lifestyle interventions that realign circadian timing (consistent sleep/wake or feeding/fasting schedules) and pharmacological strategies that enhance NRF2 activity can restore redox balance and improve disease risk profiles, highlighting a unifying target to predict health trajectories and promote lifelong health. Understanding redox-circadian interactions will help optimise person-centred chronomedicine approaches for advocating preventative health across the life course and for designing smarter therapeutic treatments for redox-based diseases, utilising time-of-day administration of drug treatments and clinical interventions.

Hospital supply rooms are dense, vertically complex environments where clinicians may lose time locating items. Existing text-based inventory logs require mental translation from alphanumeric codes to physical space, adding cognitive load during time-sensitive tasks. Despite growing use of digital twins in health care, this technology has been underreported in supply room navigation. The objective of this study is to describe the design and feasibility of a browser-based three-dimensional (3D) digital twin system providing spatial guidance for locating supplies in a hospital clean supply room. A digital twin, defined here as a virtual interactive replica of a physical environment, was developed using React and Three.js to model a telemetry unit clean supply room. The system renders more than 100 storage bins using instanced rendering. Users search via a text interface; the system highlights the target bin and animates the camera to its position. The prototype achieved sub-10-ms search response times and loaded in under 1&#x2009;second on standard hospital hardware. Two coresidents completed informal prototype walkthroughs over a 2-week period; these observations were anecdotal and were not part of a formal usability study. A 3D digital twin approach to supply room navigation is technically feasible using open-source web technologies at zero licensing cost and addresses spatial cognition challenges in dense health care storage environments. Formal usability evaluation is needed to quantify clinical effects.

Background and objectives Malignant cells reprogram their metabolism. Glutamine is a major biosynthetic precursor apart from glucose in various cancers. Glutaminase 1 (kidney type) is the rate limiting enzyme in glutamine metabolism, which is increased in cancers of prostate, breast, colorectum, ovary and oral squamous cell. We aimed to evaluate the intensity and extent of immunohistochemical expression of glutaminase1 in various grades of oral squamous cell carcinoma (OSCC) and investigate whether any association exists between the glutaminase 1expression with staging, grading and tumour infiltrating lymphocytes. Methods This retrospective analysis included 98 formalin-fixed, paraffin-embedded tissue blocks of clinically and histopathologically confirmed cases of OSCC. One section was stained with haematoxylin and eosin and the other, immunohistochemically for glutaminase 1(GLS1). Staging, grading, tumour infiltrating lymphocytes were evaluated for their relation with GLS1 immunoscore. Results Statistically significant association was noted between GLS1 immunointensity (P<0.001) immunoextent (P<0.001) and the immunoscore (P=0.007) with the worsening grades of OSCC. There was no significant association between TNM staging P<0.61) and tumour infiltrating lymphocytes with GLS1 immunoscore (P=0.30). Interpretation and conclusions Glutaminase 1 expression increases with worsening grade of OSCC signifying an altered metabolic phenotype as the cancer cells lose differentiation.

Living systems self-organize in ways that conventional physical frameworks based on forces, energies, and continuous fields cannot fully capture. Processes like gene regulation and cellular decision-making involve rule-based logic and computational interactions. Here, the concept of non-equilibrium capacity (NEC) is introduced to denote the finite capacity of living systems to generate and sustain life-associated dynamics-the very capacity that defines viability-and whose irreversible loss constitutes death. I argue that two lines of inquiry are especially promising for understanding why this capacity is inevitably lost. First, experiments that slow or suspend all cellular processes reveal "low speed limits" below which life collapses. Second, generalized cellular automata, in which cells interact over diffusion-defined neighborhoods and follow discrete rules, provide a framework to understand how order emerges or persists. Together, these approaches suggest a new grammar of biology that complements energy-based physics and explains how living systems sustain and ultimately lose their NEC.