In Vivo Selection of S/MAR Sequences to Favour AAV Episomal Maintenance in Dividing Cells.

Adeno-associated viral (AAV) vector-mediated gene therapy has emerged as a promising alternative to liver transplantation for monogenic metabolic hepatic diseases. AAVs are non-integrative vectors that are maintained primarily as episomes in quiescent cells like adult hepatocytes. This quality, while advantageous from a safety perspective due to a decreased risk of insertional mutagenesis, becomes a disadvantage when treating dividing cells, as it inevitably leads to the loss of the therapeutic genome.

Therapeutic Efficacy of the Inositol D-Pinitol as a Multi-Faceted Disease Modifier in the 5×FAD Humanized Mouse Model of Alzheimer's Amyloidosis.

Background/objectives: Alzheimer's disease (AD), a leading cause of dementia, lacks effective long-term treatments. Current therapies offer temporary relief or fail to halt its progression and are often inaccessible due to cost. AD involves multiple pathological processes, including amyloid beta (Aβ) deposition, insulin resistance, tau protein hyperphosphorylation, and systemic inflammation accelerated by gut microbiota dysbiosis originating from a leaky gut.

Comparison of Performance for Cochlear-Implant Listeners Using Audio Processing Strategies Based on Short-Time Fast Fourier Transform or Spectral Feature Extraction.

Objectives: We compared sound quality and performance for a conventional cochlear-implant (CI) audio processing strategy based on short-time fast-Fourier transform (Crystalis) and an experimental strategy based on spectral feature extraction (SFE). In the latter, the more salient spectral features (acoustic events) were extracted and mapped into the CI stimulation electrodes. We hypothesized that (1) SFE would be superior to Crystalis because it can encode acoustic spectral features without the constraints imposed by the short-time fast-Fourier transform bin width, and (2) the potential benefit of SFE would be greater for CI users who have less neural cross-channel interactions.

A spatial threshold for astrocyte calcium surge.

Astrocytes are active cells involved in brain function through the bidirectional communication with neurons, in which astrocyte calcium plays a crucial role. Synaptically evoked calcium increases can be localized to independent subcellular domains or expand to the entire cell, i.e.

Efficient Transfer of Chirality in Complex Hybrid Materials and Impact on Chirality-induced Spin Selectivity.

Transfer of chirality, or transmission of asymmetric information from one system to another, plays an essential role in fundamental biological and chemical processes and, therefore, is essential for life. This phenomenon also holds immense potential in spintronics in the context of chirality-induced spin selectivity (CISS). In the CISS, the spatial arrangement of chiral molecules influences the spin state of electrons during the charge-transfer processes.

Superior Vena Cava Isolation With Cryoballoon in AF Ablation: Randomized CAVAC AF Trial.

Background: Superior vena cava (SVC) has been considered a specific trigger in atrial fibrillation development.

Methods: We investigated the efficacy and safety of combining cryoballoon pulmonary vein isolation (PVI) with SVC ablation compared with PVI alone in 100 patients with paroxysmal or non-long-standing persistent atrial fibrillation. Patients were randomly assigned to either the PVI+SVC ablation group or the PVI-only group.

Weight and metabolic changes with long-acting cabotegravir and rilpivirine or bictegravir/emtricitabine/tenofovir alafenamide.

Background: Modest weight and lipid changes have been observed in cabotegravir plus rilpivirine long-acting (CAB+RPV LA) Phase 3/3b studies. The SOLAR study included standardized evaluations of weight and metabolic changes in people living with HIV switching to CAB+RPV LA dosed every 2 months (Q2M) vs. continuing bictegravir/emtricitabine/tenofovir (BIC/FTC/TAF).

Influence of agarose in semi-IPN hydrogels for sustained Polymyxin B release.

Hydrogels (HGs) are 3-D polymeric networks with high water content, making them appropriate for biomedical applications such as drug delivery systems. This study examines the impact of agarose in semi-interpenetrating polymer networks (Semi-IPNs) based on poly(acrylic acid) (p(AA)), N, N' Methylenebis(acrylamide) (MBA) and agarose (AGA) on the sustained release of Polymyxin B (PolB). Agarose incorporation improved the mechanical strength, swelling behavior and drug retention capacity of the HG.

Osteomalacia: A Challenging Diagnosis Adverse Event Associated with Intravenous Ferric Carboxymaltose-A Case Report.

Hypophosphatemia resulting from intravenous iron treatment has become an increasingly concerning syndrome in recent years. We report the case of a 66-year-old male patient with a medical history of ankylosing spondylitis (AS), Crohn's disease, and chronic iron deficiency. Following intravenous iron infusions of ferric carboxymaltose, the patient developed diffuse bone pain and multiple bone fractures.

Post mortem validation and mechanistic study of UCB-J in progressive supranuclear palsy patients' brains.

Introduction: Progressive supranuclear palsy (PSP) is a devastating 4R tauopathy affecting motor functions and is often misdiagnosed/underdiagnosed due to a lack of specific biomarkers. Synaptic loss is an eminent feature of tauopathies including PSP. Novel synaptic positron emission tomography tracer UCB-J holds great potential for early diagnosis; however, there is a substantial knowledge gap in terms of the mechanism and the extent and nature of synaptic loss in PSP.

Transposable element exonization generates a reservoir of evolving and functional protein isoforms.

Alternative splicing enhances protein diversity in different ways, including through exonization of transposable elements (TEs). Recent transcriptomic analyses identified thousands of unannotated spliced transcripts with exonizing TEs, but their contribution to the proteome and biological relevance remains unclear. Here, we use transcriptome assembly, ribosome profiling, and proteomics to describe a population of 1,227 unannotated TE exonizing isoforms generated by mRNA splicing and recurrent in human populations.

Neutralizing GDF-15 can overcome anti-PD-1 and anti-PD-L1 resistance in solid tumours.

Cancer immunotherapies with antibodies blocking immune checkpoint molecules are clinically active across multiple cancer entities and have markedly improved cancer treatment. Yet, response rates are still limited, and tumour progression commonly occurs. Soluble and cell-bound factors in the tumour microenvironment negatively affect cancer immunity.

Diagnosis, treatment, and follow-up of patients with hypophosphatasia.

Introduction: Hypophosphatasia is a rare inherited systemic metabolic disorder, with an estimated prevalence in the severe forms of the disease of 1/100.000-1/300.000, that affects the typical architecture of bone, leading to defective mineralization during growth and remodeling.

Corticotropin-Releasing Factor Modulates Binge-Like Ethanol Drinking in a Sex-Dependent Manner: Impact of Amygdala Deletion and Inhibition of a Central Amygdala to Lateral Hypothalamus Circuit.

Background: Binge alcohol drinking is a dangerous behavior that can contribute to the development of more severe alcohol use disorder. Importantly, the rate and severity of alcohol use disorder has historically differed between men and women, suggesting that there may be sex differences in the central mechanisms that modulate alcohol (ethanol) consumption. Corticotropin-releasing factor (CRF) is a centrally expressed neuropeptide that has been implicated in the modulation of binge-like ethanol intake, and emerging data highlight sex differences in CRF systems.

Palbociclib plus letrozole in estrogen receptor-positive advanced/recurrent endometrial cancer: Double-blind placebo-controlled randomized phase II ENGOT-EN3/PALEO trial.

Purpose: The CDK4/6 inhibitor palbociclib inhibits cyclin A, which is overexpressed in endometrial cancer. Combining palbociclib with endocrine therapy improves efficacy in hormone receptor-positive breast cancer. We investigated palbociclib combined with endocrine therapy for estrogen receptor-positive advanced/recurrent endometrial cancer.

Astragalus polysaccharide/carboxymethyl chitosan/sodium alginate based electroconductive hydrogels for diabetic wound healing and muscle function assessment.

Natural polysaccharides with excellent biocompatibility are considered ideal materials for repairing diabetic foot ulcer. However, diabetic foot ulcer is often accompanied by decreased muscle function, even resulting in muscle atrophy. During wound repair, monitoring muscle function at the wound site in real time can identify the decreased muscle strength timely, which is crucial for precise wound rehabilitation.

Rewording Theoretical Predictions at Colliders with Vacuum Amplitudes.

We propose multiloop vacuum amplitudes in the loop-tree duality (LTD) as the optimal building blocks for efficiently assembling theoretical predictions at high-energy colliders. This hypothesis is strongly supported by the manifestly causal properties of the LTD representation of a vacuum amplitude. The vacuum amplitude in LTD, acting as a kernel, encodes all the final states contributing to a given scattering or decay process through residues in the on-shell energies of the internal propagators.

Design of tunable hyaluronic acid and O'-carboxymethyl chitosan formulations for the minimally invasive delivery of multifunctional therapies targeting rheumatoid arthritis.

The development of injectable, dual-component formulations based on natural-based polysaccharides is a promising strategy for the localized treatment of rheumatoid arthritis (RA). In the present study, biomimetic formulations consisting of aldehyde-functionalized hyaluronic acid (AHA) and O-carboxymethyl chitosan (OCC) were developed, presenting rapid in situ gelation rates and finely tunable physicochemical properties. These two properties allowed for the controlled delivery of anti-inflammatory, antioxidant, and pro-regenerative agents (i.

Acrylamide: An approach to its knowledge and importance for roasted coffee.

Acrylamide (AA) has been classified as a toxic, harmful, and carcinogenic substance since 2002, and therefore it is currently widely studied. When functional amino and carbonyl groups of asparagine and reducing sugars are condensed into Schiff bases, they are transformed into AA molecules at temperatures >120 °C. This mechanism is known as the Maillard reaction and is considered the main AA pathway.

KeyGAN: Synthetic keystroke data generation in the context of digital phenotyping.

Objective: This paper aims to introduce and assess KeyGAN, a generative modeling-based keystroke data synthesizer. The synthesizer is designed to generate realistic synthetic keystroke data capturing the nuances of fine motor control and cognitive processes that govern finger-keyboard kinematics, thereby paving the way to support biomarker development for psychomotor impairment due to neurodegeneration.

Methods: KeyGAN is designed with two primary objectives: (i) to ensure high realism in the synthetic distributions of the keystroke features and (ii) to analyze its ability to replicate the subtleties of natural typing for enhancing biomarker development.

ALBA proteins facilitate cytoplasmic YTHDF-mediated reading of m6A in Arabidopsis.

N6-methyladenosine (mA) exerts many of its regulatory effects on eukaryotic mRNAs by recruiting cytoplasmic YT521-B homology-domain family (YTHDF) proteins. Here, we show that in Arabidopsis thaliana, the interaction between mA and the major YTHDF protein ECT2 also involves the mRNA-binding ALBA protein family. ALBA and YTHDF proteins physically associate via a deeply conserved short linear motif in the intrinsically disordered region of YTHDF proteins and their mRNA target sets overlap, with ALBA4 binding sites being juxtaposed to mA sites.