Hyperactive delta isoform of PI3Kinase enables long distance regeneration of adult rat corticospinal tract.

Neurons in the central nervous system (CNS) lose regenerative potential with maturity, leading to minimal corticospinal tract (CST) axon regrowth after spinal cord injury (SCI). In young rodents, knockdown of PTEN, which antagonises PI3K signalling by hydrolysing PIP3, promotes axon regeneration following SCI. However, this effect diminishes in adults, potentially due to lower PI3K activation leading to reduced PIP3.

Prevalence and determinants of metabolic syndrome in 2338 childhood cancer survivors: A Dutch Childhood Cancer Survivor LATER 2 study.

Background: Because the occurrence of metabolic syndrome (MetS) might contribute to childhood cancer survivor's excess risk of cardiovascular disease, the authors assessed the prevalence and determinants of MetS in the Dutch Childhood Cancer Survivor Study (DCCSS-LATER2) cohort.

Methods: In total, 2338 adult childhood cancer survivors (CCS) were cross-sectionally assessed for the prevalence of MetS, using the Lifelines cohort (N = 132,226 adults without a history of cancer) as references. The prevalence of MetS was clinically assessed using existing classifications, as well as an alternative method using dual-energy x-ray absorptiometry fat% instead of waist circumference to define abdominal adiposity.

High SARS-CoV-2 antibody levels after three consecutive BNT162b2 booster vaccine doses in nursing home residents.

Background: As older age and having certain comorbidities can influence humoral responses to vaccination, we studied antibody responses after the COVID-19 booster campaigns in nursing home (NH) residents.

Methods: In a two year longitudinal study with Dutch NH residents (n = 107), aged 50 years and over, we monitored antibody responses in serum prior to and after vaccination with a third, fourth BNT162b2 (wild-type; WT), and a BNT162b2 bivalent (WT/OMI BA.1) fifth vaccine.

Transitioning to residency: a qualitative study exploring residents' perspectives on strategies for adapting to residency.

Background: The transition to residency (TTR) goes along with new opportunities for learning and development, which can also be challenging, despite the availability of preparation courses designed to ease the transition process. Although the TTR highly depends on the organization, individual combined with organizational strategies that advance adaptation are rarely investigated. This study explores residents' strategies and experiences with organizational strategies to help them adapt to residency.

Recording practices of body mass index, overweight and obesity by Dutch general practitioners: an observational study.

Background: Routine body mass index (BMI) recording in electronic health records (EHR) could support general practitioners (GPs) in managing patients with obesity. This study aimed to evaluate recording practices of BMI, overweight, and obesity in adults including subgroup analysis of age, sex, and comorbidities in primary care in the Netherlands.

Methods: An observational study of individuals aged ≥ 18 years and registered between 2007 and 2023, using routine healthcare data from the Extramural LUMC Academic Network (ELAN) in the Netherlands.

Inspecting the external world: Memory capacity, but not memory self-efficacy, predicts offloading in working memory.

Individuals with memory impairments may need to rely often on the external world (i.e. offloading).

Predictors of Tinnitus Symptom Relief With Hearing Aids in a European Multicenter Study.

Objectives: Hearing aids (HAs) are a widely accepted first-line treatment option for individuals suffering from both hearing loss and chronic tinnitus. Though HAs are highly effective at improving speech understanding, their effectiveness in ameliorating tinnitus symptoms is less clear. In recent years, several investigators have reported on attempts to predict HAs effectiveness on tinnitus symptoms using an array of variables.

An ultra-conserved poison exon in the Tra2b gene encoding a splicing activator is essential for male fertility and meiotic cell division.

The cellular concentrations of splicing factors (SFs) are critical for controlling alternative splicing. Most serine and arginine-enriched (SR) protein SFs regulate their own concentration via a homeostatic feedback mechanism that involves regulation of inclusion of non-coding 'poison exons' (PEs) that target transcripts for nonsense-mediated decay. The importance of SR protein PE splicing during animal development is largely unknown despite PE ultra-conservation across animal genomes.

Orthogonal validation of PROTAC mediated degradation of the integral membrane proteins EGFR and c-MET.

Dysregulation of integral membrane proteins (IMPs) has been linked to a myriad of diseases, making these proteins an attractive target in drug research. Whilst PROTAC technology has had a significant impact in scientific research, its application to IMPs is still limited. Limitations of the traditional approach of immunoblotting in PROTAC research include the low throughput compared to other methods, as well as a lack of spatial information for the target.

The transcriptional repressor HEY2 regulates mitochondrial oxidative respiration to maintain cardiac homeostasis.

Energy deprivation and metabolic rewiring of cardiomyocytes are widely recognized hallmarks of heart failure. Here, we report that HEY2 (a Hairy/Enhancer-of-split-related transcriptional repressor) is upregulated in hearts of patients with dilated cardiomyopathy. Induced Hey2 expression in zebrafish hearts or mammalian cardiomyocytes impairs mitochondrial respiration, accompanied by elevated ROS, resulting in cardiomyocyte apoptosis and heart failure.

Immunoassay detection of multiphosphorylated tau proteoforms as cerebrospinal fluid and plasma Alzheimer's disease biomarkers.

Different forms of phosphorylated tau (p-tau) have shown strong potential as Alzheimer's disease (AD) biomarkers in both cerebrospinal fluid (CSF) and plasma. We hypothesized that p-tau proteoforms simultaneously phosphorylated at two different sites may have an increased diagnostic value compared with tau phosphorylated at a single site. Here, we developed two immunoassays detecting CSF and plasma tau simultaneously phosphorylated at both T181 and T231 (p-tau181&231) and at T217 and T231 (p-tau217&231).

Passive and active suppression of transduced noise in silicon spin qubits.

Addressing and mitigating decoherence sources plays an essential role in the development of a scalable quantum computing system, which requires low gate errors to be consistently maintained throughout the circuit execution. While nuclear spin-free materials, such as isotopically purified silicon, exhibit intrinsically promising coherence properties for electron spin qubits, the omnipresent charge noise, when converted to magnetic noise under a strong magnetic field gradient, often hinders stable qubit operation within a time frame comparable to the data acquisition time. Here, we demonstrate both open- and closed-loop suppression techniques for the transduced noise in silicon spin qubits, resulting in a more than two-fold (ten-fold) improvement of the inhomogeneous coherence time (Rabi oscillation quality) that leads to a single-qubit gate fidelity of over 99.

Molecular and spatial analysis of tertiary lymphoid structures in Sjogren's syndrome.

Tertiary lymphoid structures play important roles in autoimmune and non-autoimmune conditions. While many of the molecular mechanisms involved in tertiary lymphoid structure formation have been identified, the cellular sources and temporal and spatial relationship remain unknown. Here we use combine single-cell RNA-sequencing, spatial transcriptomics and proteomics of minor salivary glands of patients with Sjogren's disease and Sicca Syndrome, with ex-vivo functional studies to construct a cellular and spatial map of key components involved in the formation and function of tertiary lymphoid structures.

Current State of the Neuroscience of Fear Extinction and Its Relevance to Anxiety Disorders.

The elucidation of the functional neuroanatomy of human fear, or threat, extinction has started in the 2000s by a series of enthusiastically greeted functional magnetic resonance imaging (fMRI) studies that were able to translate findings from rodent research about an involvement of the ventromedial prefrontal cortex (vmPFC) and the hippocampus in fear extinction into human models. Enthusiasm has been painfully dampened by a meta-analysis of human fMRI studies by Fullana and colleagues in 2018 who showed that activation in these areas is inconsistent, sending shock waves through the extinction research community. The present review guides readers from the field (as well as non-specialist readers desiring safe knowledge about human extinction mechanisms) during a series of exposures with corrective information.

Multiparametric MRI and artificial intelligence in predicting and monitoring treatment response in bladder cancer.

Bladder cancer is the 10th most common and 13th most deadly cancer worldwide, with urothelial carcinomas being the most common type. Distinguishing between non-muscle-invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC) is essential due to significant differences in management and prognosis. MRI may play an important diagnostic role in this setting.

European consensus on endoscopic surgery for bilateral vocal fold immobility: classification and nomenclature.

Introduction: There are inconsistencies in how different endoscopic procedures to manage Bilateral Vocal Fold Immobility (BVFI) have been described in the literature. This limits our ability to compare functional outcomes. There is no unifying international terminology available that precisely describes the anatomical boundaries and extent of the different types of treatment.

The hidden role of heterotrophic bacteria in early carbonate diagenesis.

Microbial impacts on early carbonate diagenesis, particularly the formation of Mg-carbonates at low temperatures, have long eluded scientists. Our breakthrough laboratory experiments with two species of halophilic aerobic bacteria and marine carbonate grains reveal that these bacteria created a distinctive protodolomite (disordered dolomite) rim around the grains. Scanning Electron Microscopy (SEM) and X-ray Diffraction (XRD) confirmed the protodolomite formation, while solid-state nuclear magnetic resonance (NMR) revealed bacterial interactions with carboxylated organic matter, such as extracellular polymeric substances (EPS).

The impact of common and rare genetic variants on bradyarrhythmia development.

To broaden our understanding of bradyarrhythmias and conduction disease, we performed common variant genome-wide association analyses in up to 1.3 million individuals and rare variant burden testing in 460,000 individuals for sinus node dysfunction (SND), distal conduction disease (DCD) and pacemaker (PM) implantation. We identified 13, 31 and 21 common variant loci for SND, DCD and PM, respectively.

Cross-species comparison reveals that Hmga1 reduces H3K27me3 levels to promote cardiomyocyte proliferation and cardiac regeneration.

In contrast to adult mammalian hearts, the adult zebrafish heart efficiently replaces cardiomyocytes lost after injury. Here we reveal shared and species-specific injury response pathways and a correlation between Hmga1, an architectural non-histone protein, and regenerative capacity, as Hmga1 is required and sufficient to induce cardiomyocyte proliferation and required for heart regeneration. In addition, Hmga1 was shown to reactivate developmentally silenced genes, likely through modulation of H3K27me3 levels, poising them for a pro-regenerative gene program.

Mechanical regulation of macrophage metabolism by allograft inflammatory factor 1 leads to adverse remodeling after cardiac injury.

Myocardial infarction (MI) mobilizes macrophages, the central protagonists of tissue repair in the infarcted heart. Although necessary for repair, macrophages also contribute to adverse remodeling and progression to heart failure. In this context, specific targeting of inflammatory macrophage activation may attenuate maladaptive responses and enhance cardiac repair.

Learning to hear again with alternating cochlear frequency allocations.

Traditionally, the place-pitch 'tonotopically' organized auditory neural pathway was considered to be hard-wired. Cochlear implants restore hearing by arbitrarily mapping frequency-amplitude information. This study shows that recipients, after a long period of sound deprivation, preserve a level of auditory plasticity, enabling them to swiftly and concurrently learn speech understanding with two alternating, distinct frequency maps.