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Structural basis for Rep-mediated adeno-associated virus packaging
No full textAdeno-associated viruses (AAVs) are parvoviruses utilized as gene therapy vectors. However, the AAV packaging mechanism is unresolved at the molecular level, creating a bottleneck for vector manufacturing, safety, and efficacy. Here, cryo-EM structures of the Rep helicase packaging motor in complex with the packaging marker DNA (ITR) and the Rep-AAV8 capsid complex are presented. Rep-ITR complexes reveal dynamic oligomeric states on the DNA, elucidating the strand separation mechanism coupled to its ATPase cycle. We observe Rep preferentially bound to empty capsids, with a binding interface likely conserved across the virus family. This complex also unveils a cryptic capsid ATP-binding site which, alongside Rep binding, triggers structural rearrangements priming the capsid for packaging. Collectively, these findings advance the understanding of Rep-mediated packaging, with significant implications for parvovirus virology and viral vector design
Methoxyacetic acid exposure in rats induces N-butyrylglycinuria consistent with beta-oxidation impairment
No full textMethoxyacetic acid (MAA) is a testicular toxin that targets spermatocytes and round spermatids by disrupting mitochondrial function, leading to cellular energy depletion. Male Sprague-Dawley rats were given single oral doses of MAA (150 or 650 mg/kg), resulting in no mortality but transient toxicity signs and modest body weight effects, especially at the higher dose. Histopathology revealed dose- and time-dependent testicular damage, with selective germ cell necrosis by 48 h and extensive germ cell loss, spermatic giant cells, and epididymal inflammation observed in high-dose animals by 168 h. Metabolic analysis using high resolution ¹H NMR spectroscopy and OPLS-DA identified elevated urinary excretion of N-butyryl glycine, a marker of mitochondrial dysfunction and impaired β-oxidation. The persistence of N-butyryl glycine and altered energy metabolites up to 168 h indicates sustained mitochondrial stress and disruption of ATP-dependent processes essential for spermatogenesis. Moreover, the close structural similarity between methoxyacetic acid and butyrate raises the possibility that methoxyacetic acid interacts directly with enzymes involved in butyryl-CoA turnover during the terminal steps of β-oxidation in rodents
Evidence and methods from studies of symptom-assessment applications under real-world conditions: a scoping review
No full textPreprint versionBackground Symptom-assessment applications (SAAs) are widely used as patient-facing digital tools for triage and diagnostic support, yet most evaluations have relied on vignettebased designs that poorly reflect real-world use. Evidence generated under real-world conditions, where users experiencing symptoms enter their own information, remains fragmented and methodologically heterogeneous. Objective We conducted a PRISMA-ScR compliant scoping review to synthesise evidence from studies evaluating SAAs under real-world conditions and to characterise the methods used. Methods Searches of MEDLINE, Embase, Web of Science and medRxiv identified 20 eligible studies published between 2018 and 2025. The aims of the included studies can be clustered into three domains: (i) performance and safety, (ii) user characteristics and usability, and (iii) impact on decision-making and healthcare utilisation. Results Across studies, triage accuracy ranged from 34-85%, with a consistent tendency toward over-triage, that is, assigning a higher urgency than necessary. Reported safety concerns were uncommon but non-negligible, particularly at scale. Reported diagnostic accuracy varied widely depending on operationalisation and reference standards. Users were predominantly younger and female, and acceptability was generally high. Evidence on behavioural and system-level impact showed decreased healthcare utilization and a tendency towards lower perceived urgency, although the evidence remains limited. Methodologically, the studies varied substantially in sampling strategies, reference standards, matching procedures, and blinding, which limits comparability. Conclusions These findings indicate that while SAAs may provide comparatively safe triage advic
Trends in prescription drug coverage restrictions in Medicare, Medicaid, and commercial insurance plans, 2011-2019
No full textIntroduction
Access to prescription drugs is an enduring challenge in patient care. Payers often rely on coverage restrictions to balance access and cost.
Methods
We assessed coverage restrictions for a comprehensive set of branded retail drugs without generic competitors from 2011-2019 across the four largest US market segments (Medicare, Medicaid, employer-sponsored, and health insurance exchanges) using CMS and Managed Market Insight and Technology (MMIT) data.
Results
Between 2011-2019, for the nationally representative beneficiary, the share of drugs excluded from formularies increased from 7.5% to 13.4%, the share of drugs subject to administrative restrictions such as prior authorization or step therapy increased from 18.1% to 43.7%, and the share of drugs on non-preferred tiers decreased from 57.8% to 42.2%. The share of drugs with any coverage restriction increased from 69.7 to 79.0%. Health plans and drugs subject to federal coverage mandates saw much larger increases in prior authorization and increases in non-preferred status.
Conclusion
These dynamics suggest that future research should study the tradeoffs between partial and full coverage restrictions for patient utilization, spending, and wellbeing
Polymer electrodes in solid-state metal-ion batteries: an in-depth review on recent advances, challenges, and future prospects
No full textThe pursuit of next-generation rechargeable batteries that are lightweight, intrinsically safe, sustainable, and mechanically flexible has accelerated interest in all organic solid-state battery concepts based on conducting and redox-active polymers as electrode materials. While many redox polymers exhibit intrinsically low electronic conductivity, conducting polymers can provide substantial electronic transport, highlighting the need for a more nuanced understanding of structure–property relationships in polymer-based electrodes. The key challenges instead arise from polymer swelling in liquid or quasi-solid electrolytes, limited ionic/electronic percolation, and interfacial instabilities at polymer–electrolyte and polymer–current-collector interfaces. This review synthesizes fundamental principles of polymer electrochemistry, including charge transport, redox kinetics, and the evolution of conductivity in electrochemical environments. We critically evaluate major classes of polymer electrode materials, outlining their advantages, limitations, and the design strategies used to enhance performance through molecular engineering, cross-linking, composite formation, and interface modification. Special emphasis is placed on the transition from liquid to solid and quasi-solid electrolytes as a route to mitigate swelling, enhance safety, and stabilize interfacial chemistry. We outline the overarching vision for all-organic solid-state batteries that unite sustainability (bio-derived and recyclable components), intrinsic safety (non-flammable solid electrolytes), mechanical flexibility, and compatibility with low-energy manufacturing. By accurately framing the key challenges and highlighting the transformative potential of polymer-based electrochemical systems, this review provides a roadmap toward practical and scalable all-organic solid-state battery technologies
“How do I ...?”: procedural questions predominate student-LLM chatbot conversations
No full textPreprint versionLearning at scale often requires domain-specific automation such as assessment and feedback. An organization locked in to a general learning platform without these specialist automations limits its pedagogical offering. An ecosystem of interoperable, platformagnostic microservices for domain-specific automation would solve this problem. To develop an effective ecosystem , a standard interface (API) for education microservices is required. We propose an initial specification for a standard, platformindependent API for educational microservices, µEd. The API integrates functionality from existing systems in use at four institutions, which are adopting the new API. The API is initially specified for automation of feedback, assessment, and educational chatbots, with further service types envisaged in the future. The API specification provided here enables the development of an ecosystem of education microservices that will facilitate automation in more domains, to more users, providing a richer learning experience in a wide range of disciplines. CCS Concepts • General and reference → Computing standards, RFCs and guidelines; • Applied computing → Education
Prevalence of liver disease and liver transplantation in pediatric ZZ alpha-1 antitrypsin deficiency: a systematic review and meta-analysis
No full textBackground
Pediatric Pi*ZZ alpha-1 antitrypsin deficiency (A1ATD) can cause hepatocyte A1AT polymer retention and progressive liver injury, but estimates of childhood liver morbidity vary across studies and remain poorly defined.
Aim
To quantify liver-specific outcomes in pediatric Pi*ZZ A1ATD.
Methods
We systematically reviewed studies reporting liver-specific outcomes in children with confirmed Pi*ZZ/ZZ A1ATD (PROSPERO CRD42022335666). We extracted prevalence of fibrosis and cirrhosis, elevated liver enzymes, and liver transplantation. Random-effects meta-analysis pooled logit-transformed proportions (with sensitivity analyses assessing robustness to model assumptions).
Results
Thirteen studies including 398 children met inclusion criteria. Pooled prevalence was 41.3% (95% CI 29.6–54.0) for fibrosis and 17.3% (7.2–35.9) for cirrhosis, with substantial heterogeneity for cirrhosis (I2 78.6%). Liver transplantation prevalence was 10.7% (6.3–13.0). Elevated liver enzymes occurred in 43.0% (19.2–70.5) with high heterogeneity (I2 89.4%). Across cohorts, the proportion with elevated liver enzymes declined with increasing mean age, despite ongoing liver disease in reported histology-based outcomes.
Conclusions
Clinically important liver disease occurs in a substantial subset of children with Pi*ZZ A1ATD. Declining rates of elevated liver enzymes with age should not be interpreted as disease resolution. Standardized registries are needed for longitudinal surveillance, to identify disease modifiers, and to guide early intervention in this high-risk population
Subtypes estimation in single-cell multi-omics data via S-multi-SNE
No full textSingle-cell RNA sequencing (scRNA-seq) has rapidly become an essential method in modern biology, as it allows global characterisation of transcriptomics in individual cells from different tissues, or organisms. scRNA-seq data are collected from a single individual organism and they are composed as mRNA count matrices with rows representing the cells and columns the genes. New technologies further allow multi-omics data to be obtained on the same set of single cells.
In this paper, multi-SNE and S-multi-SNE, two multi-view dimensionality reduction approaches, are adapted for visualization and classification of cellular subtypes, two important challenges in the analysis of scRNA-seq data. S-multi-SNE has been adapted for cell subtype estimation of scRNA-seq data. In a series of experiments we illustrate that it is possible to identify cell subtypes by leveraging information from individuals from the same species, from different species, and when data are generated by different sequencing technologies. In the conducted analyses, we show that S-multi-SNE consistently outperformed several other machine learning techniques and, in most comparisons, surpassed existing reference-based single-cell classification algorithms.
We further illustrate how two single-cell multi-omics datasets, scATAC-seq and scRNA-seq, can be integrated together through S-multi-SNE for improved cell subtype identification
'Crazy Dog Moms'? Gendering relational dynamics, carework and pet parenting practices in multispecies Canadian homes
No full textopen access article
This article is from a project funded by a Canadian research council and led by the University of Guelph, Canada and colleagues in the Department of Family Relations and Applied Nutrition. Research groups involved were the FIDO lab, which focuses on human-animal connection, with an emphasis on kin networks which include both dogs and humans and The ReVision Centre for Art and Social Justice, an arts methodology research hub at the University of Guelph.Social scientists have begun to consider the importance of interspecies relationalities in homes, yet, the field of family studies has largely overlooked conceptualisations of families as multispecies. This paper contributes to research contesting this anthropocentrism by recognizing animal companions as family members implicated within domestic relationships. Drawing on the findings of twenty mobile and placed-based interviews and nine digital/multimedia stories, we explore caregiving in multispecies Canadian homes, with a focus on gendered dynamics and parental parallels within relationships. Gendered dynamics identified as themes in our dataset entailed: dogs as protectors of women, women driving dog acquisition, women’s closer relationships with dogs, and gendered companion animal care labour. Participants adopted parental discourses prominently by self-identifying as mothers or fathers to their dogs, referring to dogs as their babies, discussing divergent parental roles within households, dogs’ significance to empty nesters, and dogs as replacement or practice children. Our findings illustrate the ways men and women engage in canine carework differently and unevenly and display divergent gendered performances of canine companionship. We contribute to growing work at the intersection of family and animal studies which explores multispecies households and care labour, positioning companion animals within kin networks and challenging dominant humancentric research paradigms
Comparing low-cost monocentric and polycentric prosthetic knees: user satisfaction among persons with unilateral above- and through-knee amputations
No full textBackground: The International Committee of the Red Cross (ICRC) developed two low-cost prosthetic knees: monocentric (ICRC-MKJ) and polycentric (ICRC-PKJ), both intended solely for above-knee amputees. Independently, Imperial College London designed a low-cost polycentric knee (ICL-PKJ) for both above- and through-knee amputations. Because no affordable through-knee prostheses are currently available, clinics in LMICs often fit the ICRC-MKJ for through-knee amputees, even though it is designed exclusively for above-knee amputees.
Objectives: This study assesses user satisfaction with the ICRC-MKJ, ICRC-PKJ, and ICL-PKJ knees across individuals with unilateral transfemoral (UTF) and unilateral through-knee amputations (UTK).
Study design: Single Arm, Repeated-measures design.
Methods: 13 UTF (11 males, 2 females) and 5 UTK (males) consented to participate and trialed the three prosthetic knees. Each participant completed the Prosthesis Evaluation Questionnaire (PEQ) and Prosthesis Satisfaction Questionnaire (SAT-PRO) for each prosthesis. Results were compared.
Results: For UTF participants, ICL-PKJ scored 39% lower than ICRC-PKJ (p=0.007) in PEQ Sounds. The SAT-PRO perceived risk of harm score was higher with ICRC-MKJ (mean 33.3) than ICRC-PKJ (mean 53.9, p=0.014) and ICL-PKJ (mean 69.2, p=0.029). Aesthetics were rated higher for ICRC-MKJ (mean 87.2) than ICRC-PKJ (mean 66.7, p=0.046) and ICL-PKJ (mean 69.2, p=0.047). For UTK participants, PEQ Wellbeing increased by 37% with ICL-PKJ compared to their own ICRC-MKJ.
Conclusions: The findings emphasize the need for prosthetic solutions that meet the mobility needs and social considerations of individuals with limb loss. These results underscore the urgent need to develop affordable, dedicated through-knee prostheses to provide effective
options for through-knee amputees