In vivo base editing extends lifespan of a humanized mouse model of prion disease.

Prion disease is a fatal neurodegenerative disease caused by the misfolding of prion protein (PrP) encoded by the PRNP gene. While there is currently no cure for the disease, depleting PrP in the brain is an established strategy to prevent or stall templated misfolding of PrP. Here we developed in vivo cytosine and adenine base strategies delivered by adeno-associated viruses to permanently modify the PRNP locus to achieve PrP knockdown in the mouse brain.

Microcomputed tomographic analysis of the trabecular and cortical architecture of the proximal femur and hip bone of cats and small breed dogs.

This study aims to provide an initial database to gain more detailed knowledge of the trabecular and cortical bone structure of pelvic and femur bones in cats and smaller dogs. Additionally, the bony microarchitecture between cats and smaller dogs was compared to identify possible differences between those species. These findings could potentially improve the development of non-cemented total hip replacement (THR).

Site-Specific Modification of Native IgGs with Flexible Drug-Load.

Homogeneous, site-specifically conjugated antibodies have shown to result in antibody-drug conjugates (ADCs) with improved efficacy and tolerability compared to stochastically conjugated ADCs. However, precisely controlling the drug load as well as attaching multiple payload moieties to the antibody remains challenging. Here, we demonstrate the simple and direct modification of native IgG-antibodies at the residue glutamine 295 (Q295) without the need for any protein engineering with flexible drug-to-antibody ratios of one or multiple payloads.

Specific EEG resting state biomarkers in FXS and ASD.

Background: Fragile X syndrome (FXS) and autism spectrum disorder (ASD) are neurodevelopmental conditions that often have a substantial impact on daily functioning and quality of life. FXS is the most common cause of inherited intellectual disability (ID) and the most common monogenetic cause of ASD. Previous literature has shown that electrophysiological activity measured by electroencephalogram (EEG) during resting state is perturbated in FXS and ASD.

Synthetic mRNAs Containing Minimalistic Untranslated Regions Are Highly Functional In Vitro and In Vivo.

Synthetic mRNA produced by in vitro transcription (ivt mRNA) is the active pharmaceutical ingredient of approved anti-COVID-19 vaccines and of many drugs under development. Such synthetic mRNA typically contains several hundred bases of non-coding "untranslated" regions (UTRs) that are involved in the stabilization and translation of the mRNA. However, UTRs are often complex structures, which may complicate the entire production process.

Differential functionality of fluoropyrimidine nucleosides for safe cancer therapy.

Chemotherapies are standard care for most cancer types. Pyrimidine analogs including 5-fluorouracil, cytosine arabinoside, 5-azacytidine, and gemcitabine are effective drugs that are utilized as part of a number of anticancer regimens. However, their lack of cell-specificity results in severe side effects.

Ecological stress memory in wood architecture of two Neotropical hickory species from central-eastern Mexico.

Background: Drought periods are major evolutionary triggers of wood anatomical adaptive variation in Lower Tropical Montane Cloud Forests tree species. We tested the influence of historical drought events on the effects of ecological stress memory on latewood width and xylem vessel traits in two relict hickory species (Carya palmeri and Carya myristiciformis) from central-eastern Mexico. We hypothesized that latewood width would decrease during historical drought years, establishing correlations between growth and water stress conditions, and that moisture deficit during past tree growth between successive drought events, would impact on wood anatomical features.

A Basic Method for Formulating mRNA-Lipid Nanoparticle Vaccines in the Lab.

During recent years, RNA therapeutics have begun to make a substantial impact in the clinic, with the approval of the siRNA-based therapeutic Patisiran in 2018, and of the two mRNA SARS-CoV-2 vaccines, BNT162b2 and mRNA-1273 in 2021. A key to the success of these therapeutics lies in the lipid-based delivery system. The therapeutic RNAs are encapsulated in lipid nanoparticles (LNPs), which protect against enzymatic degradation and efficiently deliver the RNA across the cell membrane into the cytosol.

Design and Synthesis of Circular RNA Expression Vectors.

The recent success of the synthetic mRNA-based anti-COVID-19 vaccines has demonstrated the broad potential of the mRNA platform for applications in medicine, thanks to the combined efforts of a small community that has vastly improved key determinants such as design and formulation of synthetic mRNA during the past three decades. However, the cost of production and sensitivity to enzymatic degradation are still limiting the broader application of synthetic mRNA for therapeutic applications. The increased interest in mRNA-based technologies has spurred a renaissance for circular RNA (circRNA), as the lack of free 5' and 3' ends substantially increases resistance against enzymatic degradation in biological systems and does not require expensive cap analogs, as translation is controlled by an Internal Ribosome Entry Site (IRES) sequence.

The Pediatric Autism Research Cohort (PARC) Study: protocol for a patient-oriented prospective study examining trajectories of functioning in children with autism.

Introduction: The developmentally variable nature of autism poses challenges in providing timely services tailored to a child's needs. Despite a recent focus on longitudinal research, priority-setting initiatives with stakeholders highlighted the importance of studying a child's day-to-day functioning and social determinants of health to inform clinical care. To address this, we are conducting a pragmatic multi-site, patient-oriented longitudinal investigation: the (.

Development of ISB 1442, a CD38 and CD47 bispecific biparatopic antibody innate cell modulator for the treatment of multiple myeloma.

Antibody engineering can tailor the design and activities of therapeutic antibodies for better efficiency or other advantageous clinical properties. Here we report the development of ISB 1442, a fully human bispecific antibody designed to re-establish synthetic immunity in CD38+ hematological malignancies. ISB 1442 consists of two anti-CD38 arms targeting two distinct epitopes that preferentially drive binding to tumor cells and enable avidity-induced blocking of proximal CD47 receptors on the same cell while preventing on-target off-tumor binding on healthy cells.

Web-based Prototype for Graphical Exploration of FHIR® Questionnaire Responses.

The evaluation of clinical questionnaires is an important part of gaining knowledge in empirical research. The electronically captured responses are encoded in a standard format such as HL7 FHIR® that facilitates data exchange and systems interoperability. However, this also complicates access of the information to explore and interpret the results without appropriate tools.

Qualitative study exploring the perspectives of emerging adults with type 1 diabetes after transfer to adult care from a paediatric diabetes centre in Montreal, Canada.

Introduction: Among youth living with type 1 diabetes (T1D), the increasing demands to diabetes self-care and medical follow-up during the transition from paediatric to adult care has been associated with greater morbidity and mortality. Inadequate healthcare support for youth during the transition care period could exacerbate psychosocial risks and difficulties that are common during emerging adulthood. The current investigation sought to explore the post-transfer perceptions of emerging adults living with T1D relating to their transition to adult care.

Diabetes duration, perceived comfort with self-management and glycaemic control in adolescents with type 1 diabetes: A cross-sectional study.

Aims: Evidence is lacking on whether diabetes duration is associated with type 1 diabetes (T1D) self-management during late adolescence before transfer from paediatric to adult care. We examined associations of diabetes duration with dimensions of perceived comfort with diabetes self-management (self-efficacy, transition readiness, diabetes distress) and glycaemic control in late adolescence.

Methods: Using a cross-sectional design, we conducted a secondary analysis of baseline data of adolescents (ages 16-17 years) with T1D followed at paediatric diabetes academic hospitals in Montreal and enrolled in the Group Education Trial to Improve Transition (GET-IT-T1D).

GERNERMED++: Semantic annotation in German medical NLP through transfer-learning, translation and word alignment.

We present a statistical model, GERNERMED++, for German medical natural language processing trained for named entity recognition (NER) as an open, publicly available model. We demonstrate the effectiveness of combining multiple techniques in order to achieve strong results in entity recognition performance by the means of transfer-learning on pre-trained deep language models (LM), word-alignment and neural machine translation, outperforming a pre-existing baseline model on several datasets. Due to the sparse situation of open, public medical entity recognition models for German texts, this work offers benefits to the German research community on medical NLP as a baseline model.

Annotated dataset creation through large language models for non-english medical NLP.

Obtaining text datasets with semantic annotations is an effortful process, yet crucial for supervised training in natural language processing (NLP). In general, developing and applying new NLP pipelines in domain-specific contexts for tasks often requires custom-designed datasets to address NLP tasks in a supervised machine learning fashion. When operating in non-English languages for medical data processing, this exposes several minor and major, interconnected problems such as the lack of task-matching datasets as well as task-specific pre-trained models.

Associations of Diabetes-related and Health-related Quality of Life With Glycemic Levels in Adolescents With Type 1 Diabetes Preparing to Transition to Adult Care.

Objectives: As adolescents with type 1 diabetes (T1D) progress to adulthood, they assume responsibility for diabetes self-management while dealing with competing life demands, decreasing parental support, and the transfer to adult care. Lower perceived quality of life (QOL) may hamper diabetes management, which is associated with suboptimal glycemic levels. Our objective was to determine associations of diabetes- and health-related QOL with glycemic management (glycated hemoglobin [A1C]) in adolescents with T1D before their transfer to adult care.

German Medical Named Entity Recognition Model and Data Set Creation Using Machine Translation and Word Alignment: Algorithm Development and Validation.

Background: Data mining in the field of medical data analysis often needs to rely solely on the processing of unstructured data to retrieve relevant data. For German natural language processing, few open medical neural named entity recognition (NER) models have been published before this work. A major issue can be attributed to the lack of German training data.

DrNote: An open medical annotation service.

In the context of clinical trials and medical research medical text mining can provide broader insights for various research scenarios by tapping additional text data sources and extracting relevant information that is often exclusively present in unstructured fashion. Although various works for data like electronic health reports are available for English texts, only limited work on tools for non-English text resources has been published that offers immediate practicality in terms of flexibility and initial setup. We introduce DrNote, an open source text annotation service for medical text processing.

Low-cost prosthetic feet for underserved populations: A comparison of gait analysis and mechanical stiffness.

Background: Lower-limb loss is an ongoing cause of disability throughout the world. Despite advancements in prosthetic technologies, there are numerous underserved populations in need of effective low-cost prosthetic foot options.

Objective: To evaluate the biomechanical performance of several low-cost prosthetic feet, using a combination of instrumented gait analysis and mechanical stiffness testing.

Transcriptomic analysis of isolated and pooled human postmortem cerebellar Purkinje cells in autism spectrum disorders.

At present, the neuronal mechanisms underlying the diagnosis of autism spectrum disorder (ASD) have not been established. However, studies from human postmortem ASD brains have consistently revealed disruptions in cerebellar circuitry, specifically reductions in Purkinje cell (PC) number and size. Alterations in cerebellar circuitry would have important implications for information processing within the cerebellum and affect a wide range of human motor and non-motor behaviors.

RNA with chemotherapeutic base analogues as a dual-functional anti-cancer drug.

Nanoparticles of different sizes formulated with unmodified RNA and Protamine differentially engage Toll-like Receptors (TLRs) and activate innate immune responses . Here, we report that similar differential immunostimulation that depends on the nanoparticle sizes is induced in wild type as well as in humanized mice. In addition, we found that the schedule of injections strongly affects the magnitude of the immune response.

MeCP2 heterochromatin organization is modulated by arginine methylation and serine phosphorylation.

Rett syndrome is a human intellectual disability disorder that is associated with mutations in the X-linked gene. The epigenetic reader MeCP2 binds to methylated cytosines on the DNA and regulates chromatin organization. We have shown previously that Rett syndrome missense mutations are impaired in chromatin binding and heterochromatin reorganization.