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Cardiogenesis relies on the precise spatiotemporal coordination of multiple progenitor populations. Understanding the specification and differentiation of these distinct progenitor pools during human embryonic development is crucial for advancing our knowledge of congenital cardiac malformations and designing new regenerative therapies. By combining genetic labelling, single-cell transcriptomics, and ex vivo human-mouse embryonic chimeras we uncovered that modulation of retinoic acid signaling instructs human pluripotent stem cells to form heart field-specific progenitors with distinct fate potentials. In addition to the classical first and second heart fields, we observed the appearance of juxta-cardiac field progenitors giving rise to both myocardial and epicardial cells. Applying these findings to stem-cell based disease modelling we identified specific transcriptional dysregulation in first and second heart field progenitors derived from stem cells of patients with hypoplastic left heart syndrome. This highlights the suitability of our in vitro differentiation platform for studying human cardiac development and disease. The heart is formed from several spatiotemporally distinct progenitor pools during development. Here they show that modulation of retinoic acid signaling can instruct human pluripotent stems cells into heart progenitors that are useful for studying human development and disease.

Background PPCS deficiency disorder (PPCS DD) is an ultra-rare, autosomal recessive form of dilated cardiomyopathy (DCM) caused by pathogenic variants in PPCS, which encodes the enzyme catalyzing the second step in the coenzyme A (CoA) biosynthesis pathway. To date, only six patients worldwide have been identified. Methods Whole-exome sequencing was performed to identify pathogenic PPCS variants in affected individuals. Protein stability was assessed by Western blotting. CoA levels were quantified using a microplate-based assay in patient-derived fibroblasts, cardiac progenitor cells, and cardiomyocytes. Functional evaluation of cardiac cells and engineered heart patches was conducted to investigate contractile performance and arrhythmogenicity. Pantethine was tested as a potential therapeutic agent both in vitro and through long-term clinical follow-up in patients. Results Causative PPCS variants are identified in six individuals with DCM and variable associated features, including neuromuscular and neurological symptoms. Identified variants lead to reduced PPCS protein stability and decreased cellular CoA levels. Cardiac cells exhibit impaired contractility and arrhythmias, which are partially rescued by pantethine treatment. Clinically, patients receiving pantethine show sustained improvement over time. Conclusions Our study expands the genetic and clinical spectrum of PPCS deficiency disorder, identifying six new cases with diverse phenotypes. Functional investigations reveal reduced CoA levels and dysfunction in patient-derived cardiac cells. Pantethine treatment shows promise in partially rescuing DCM phenotypes, both in vitro and in patients. However, complete reversal may require early intervention. These findings underscore the importance of timely diagnosis and treatment in PPCS DD. Future research should focus on optimizing pantethine supplementation and exploring additional therapies to enhance CoA levels and cardiac function in affected individuals. Zhang, Dorn, Gnutti et al. identify pathogenic PPCS variants in people with PPCS deficiency disorder. Cardiac cells exhibit impaired contractility and arrhythmias, which is partially rescued by pantethine treatment. Plain language summary PPCS deficiency disorder is an extremely rare inherited disease that causes heart muscle weakness (dilated cardiomyopathy) and other symptoms. It results from changes in a gene involved in making coenzyme A (CoA), a vital molecule for cell energy. This study identified six new patients with the condition and investigated how these gene changes affect heart function. Researchers used patient cells and lab-grown heart tissues to study the disease and tested pantethine, a compound that helps increase CoA levels. They found that pantethine improved heart cell function and showed positive effects in treated patients. These results highlight the importance of early diagnosis and treatment. In the future, therapies such as pantethine could offer hope for improving heart health in affected individuals.

Cardiomyocytes (CMs) derived from human induced pluripotent stem cells (hiPSCs) represent an excellent in vitro model in cardiovascular research. Changes in their action potential (AP) dynamics convey information that is essential for disease modeling, drug screening and toxicity evaluation. High-throughput optical AP recordings utilizing intramolecular Förster resonance energy transfer (FRET) of the voltage-sensitive fluorescent protein (VSFP) have emerged as a substitute or complement to the resource-intensive patch clamp technique. Here, we functionally validated our recently generated voltage indicator hiPSC lines stably expressing CAG-promoter-driven VSFP in the AAVS1 safe harbor locus. By combining subtype-specific cardiomyocyte differentiation protocols, we established optical AP recordings in ventricular, atrial, and nodal CMs in 2D monolayers using fluorescence microscopy. Moreover, we achieved high-throughput optical AP measurements in single hiPSC-derived CMs in a 3D context. Overall, this system greatly expands the spectrum of possibilities for high-throughput, non-invasive and long-term AP analyses in cardiovascular research and drug discovery.

The epicardium, the mesothelial envelope of the vertebrate heart, is the source of multiple cardiac cell lineages during embryonic development and provides signals that are essential to myocardial growth and repair. Here we generate self-organizing human pluripotent stem cell-derived epicardioids that display retinoic acid-dependent morphological, molecular and functional patterning of the epicardium and myocardium typical of the left ventricular wall. By combining lineage tracing, single-cell transcriptomics and chromatin accessibility profiling, we describe the specification and differentiation process of different cell lineages in epicardioids and draw comparisons to human fetal development at the transcriptional and morphological levels. We then use epicardioids to investigate the functional cross-talk between cardiac cell types, gaining new insights into the role of IGF2/IGF1R and NRP2 signaling in human cardiogenesis. Finally, we show that epicardioids mimic the multicellular pathogenesis of congenital or stress-induced hypertrophy and fibrotic remodeling. As such, epicardioids offer a unique testing ground of epicardial activity in heart development, disease and regeneration. The lineage of human epicardium is studied using time course single-cell analysis of epicardioids.

Cardiogenesis relies on the precise spatiotemporal coordination of multiple progenitor populations. Understanding the specification and differentiation of these distinct progenitor pools during human embryonic development is crucial for advancing our knowledge of congenital cardiac malformations and designing new regenerative therapies. By combining genetic labelling, single-cell transcriptomics, and ex vivo human-mouse embryonic chimeras we uncovered that modulation of retinoic acid signaling instructs human pluripotent stem cells to form heart field-specific progenitors with distinct fate potentials. In addition to the classical first and second heart fields, we observed the appearance of juxta-cardiac field progenitors giving rise to both myocardial and epicardial cells. Applying these findings to stem-cell based disease modelling we identified specific transcriptional dysregulation in first and second heart field progenitors derived from stem cells of a patient with hypoplastic left heart syndrome. This highlights the suitability of our in vitro differentiation platform for studying human cardiac development and disease.

Clues from the epidemiology of schizophrenia, such as the increased risk in those born in winter/spring, have led to the hypothesis that prenatal vitamin D deficiency may increase the risk of later schizophrenia. We wish to explore this hypothesis in a large Danish case-control study (n = 2602). The concentration of 25 hydroxyvitamin D (25OHD) was assessed from neonatal dried blood samples. Incidence rate ratios (IRR) were calculated when examined for quintiles of 25OHD concentration. In addition, we examined statistical models that combined 25OHD concentration and the schizophrenia polygenic risk score (PRS) in a sample that combined the new sample with a previous study (total n = 3464; samples assayed and genotyped between 2008-2013). Compared to the reference (fourth) quintile, those in the lowest quintile (<20.4 nmol/L) had a significantly increased risk of schizophrenia (IRR = 1.44, 95%CI: 1.12–1.85). None of the other quintile comparisons were significantly different. There was no significant interaction between 25OHD and the PRS. Neonatal vitamin D deficiency was associated with an increased risk for schizophrenia in later life. These findings could have important public health implications related to the primary prevention of schizophrenia.

Human neuroscience has always been pushing the boundary of what is measurable. During the last decade, concerns about statistical power and replicability – in science in general, but also specifically in human neuroscience – have fueled an extensive debate. One important insight from this discourse is the need for larger samples, which naturally increases statistical power. An alternative is to increase the precision of measurements, which is the focus of this review. This option is often overlooked, even though statistical power benefits from increasing precision as much as from increasing sample size. Nonetheless, precision has always been at the heart of good scientific practice in human neuroscience, with researchers relying on lab traditions or rules of thumb to ensure sufficient precision for their studies. In this review, we encourage a more systematic approach to precision. We start by introducing measurement precision and its importance for well-powered studies in human neuroscience. Then, determinants for precision in a range of neuroscientific methods (MRI, M/EEG, EDA, Eye-Tracking, and Endocrinology) are elaborated. We end by discussing how a more systematic evaluation of precision and the application of respective insights can lead to an increase in reproducibility in human neuroscience.

Online record access (ORA) is being increasingly implemented internationally. Despite reported benefits for patients, health care professionals (HCPs) have raised concerns about potential disadvantages. To date, no review has examined the empirical evidence on whether and how documentation changes following the introduction of patients' ORA. This scoping review aimed to examine potential subjective and objective changes in HCPs' documentation after using patients' ORA. A scoping review was conducted using a methodological framework for scoping reviews and data from 4 electronic databases. Studies examining objective and subjective changes in clinical documentation following the implementation of ORA, specifically those related to actual use experiences (rather than previous expectations), up to July 2023, were included. We used the Mixed Methods Appraisal Tool to assess the quality of the included studies. The narrative synthesis and reporting of findings were guided by the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews). Of the 3143 papers screened, 42 (1.34%) were included in this review. The included studies mainly used qualitative methods and were predominantly published after 2016 in the United States. The included studies were conducted in different settings (inpatient and outpatient) and clinical areas (somatic, mental health, and other). In total, 8 studies analyzed clinical notes, while the remaining studies focused on the experiences of patients, HCPs, and other stakeholders with ORA. Objectively, a decrease in complexity, an increase in readability, and a change in the emotional tone of the clinical notes were observed. The length of the clinical notes was observed to change both objectively and subjectively, although the direction of this change was inconclusive. However, many HCPs also reported writing notes that were less open and more restrictive to protect sensitive or hypothetical information. While for some HCPs the implementation of ORA made the clinical notes a less efficient and valuable working tool, others perceived that ORA opened up new therapeutic opportunities through direct contact with patients. The question of whether an inherently uniform clinical note can meet the diverse needs of different health care stakeholders remains unresolved, highlighting the challenges of standardizing practices in this complex sector. While ORA may encourage HCPs to make their clinical notes more patient friendly, it may also compromise the integrity of documentation by omitting sensitive findings and expert judgment, which can put patients at risk and lead to errors that increase the risk of malpractice. Given the limitations of digital documentation in fostering trust, it is imperative to prioritize meaningful patient-HCP interactions. The use of compensatory measures, such as parallel documentation and restricted access to clinical notes, indicates systemic problems and suggests that current practices are suboptimal. RR2-10.2196/46722.

Location, specific topography, and hydrographic setting together with climate change and strong anthropogenic pressure are the main factors shaping the biogeochemical functioning and thus also the ecological status of the Baltic Sea. The recent decades have brought significant changes in the Baltic Sea. First, the rising nutrient loads from land in the second half of the 20th century led to eutrophication and spreading of hypoxic and anoxic areas, for which permanent stratification of the water column and limited ventilation of deep-water layers made favourable conditions. Since the 1980s the nutrient loads to the Baltic Sea have been continuously decreasing. This, however, has so far not resulted in significant improvements in oxygen availability in the deep regions, which has revealed a slow response time of the system to the reduction of the land-derived nutrient loads. Responsible for that is the low burial efficiency of phosphorus at anoxic conditions and its remobilization from sediments when conditions change from oxic to anoxic. This results in a stoichiometric excess of phosphorus available for organic-matter production, which promotes the growth of N2-fixing cyanobacteria and in turn supports eutrophication. This assessment reviews the available and published knowledge on the biogeochemical functioning of the Baltic Sea. In its content, the paper covers the aspects related to changes in carbon, nitrogen, and phosphorus (C, N, and P) external loads, their transformations in the coastal zone, changes in organic-matter production (eutrophication) and remineralization (oxygen availability), and the role of sediments in burial and turnover of C, N, and P. In addition to that, this paper focuses also on changes in the marine CO2 system, the structure and functioning of the microbial community, and the role of contaminants for biogeochemical processes. This comprehensive assessment allowed also for identifying knowledge gaps and future research needs in the field of marine biogeochemistry in the Baltic Sea.

Background: Cerebral small vessel disease (SVD) is associated with increased risk of stroke and dementia. Progressive damage to the cerebral microvasculature may also trigger angiogenic processes to promote vessel repair. Elevated levels of circulating endothelial progenitor cells (EPCs) and pro-angiogenic signaling proteins are observed in response to vascular injury. We aimed to examine circulating levels of EPCs and proangiogenic proteins in older adults with evidence of SVD. Methods: Older adults (ages 55–90) free of dementia or stroke underwent venipuncture and brain magnetic resonance imaging (MRI). Flow cytometry quantified circulating EPCs as the number of cells in the lymphocyte gate positively expressing EPC surface markers (CD34+CD133+CD309+). Plasma was assayed for proangiogenic factors (VEGF-A, VEGF-C, VEGF-D, Tie-2, and Flt-1). Total SVD burden score was determined based on MRI markers, including white matter hyperintensities, cerebral microbleeds and lacunes. Results: Sixty-four older adults were included. Linear regression revealed that older adults with higher circulating EPC levels exhibited greater total SVD burden [β = 1.0 × 10 5 , 95% CI (0.2, 1.9), p = 0.019], after accounting for age and sex. Similarly, a positive relationship between circulating VEGF-D and total SVD score was observed, controlling for age and sex [β = 0.001, 95% CI (0.000, 0.001), p = 0.048]. Conclusion: These findings suggest that elevated levels of circulating EPCs and VEGF-D correspond with greater cerebral SVD burden in older adults. Additional studies are warranted to determine whether activation of systemic angiogenic growth factors and EPCs represents an early attempt to rescue the vascular endothelium and repair damage in SVD.