Miracle-dz/UniFAR-FTUs huggingface dataset:
Interactions between the hippocampus and fronto‐parietal regions during memory encoding in early childhood

The neural mechanisms underlying memory encoding have received much attention in the literature. Research in adults and school‐age children suggest that the hippocampus and cortical regions in both frontal and parietal areas are involved in successful formation of memories. Overall, the hippocampus has been shown to interact with fronto‐parietal regions to collaboratively support successful memory encoding for both individual items as well as item details (such as the source or color in which the item was originally encountered). To date, only one study has investigated neural regions engaged during memory encoding in children younger than 8 years of age, which is unfortunate since early childhood is a period of dramatic improvement in memory. This previous study indicated that both the hippocampus and cortical regions are involved during the encoding of subsequently remembered item details (i.e., sources). However, this study reported few interactions between these regions, and it did not explore item memory at a more general level. To fill these gaps, this article reanalyzed data from the previous report, aiming to examine the neural correlates of item memory during encoding in early childhood (4–8 years) and interactions between the hippocampus and fronto‐parietal regions during encoding. Consistent with research in older individuals, both the hippocampus and fronto‐parietal regions were found to participate in item memory encoding. Additionally, functional connectivity between hippocampus and fronto‐parietal regions was significantly related to both subsequent item memory and subsequent source memory. Taken together, these findings suggest that not only the activation of individual brain regions (hippocampus and fronto‐parietal regions) but also the functional connections between these regions are important for memory encoding. These data add to the growing literature providing insight into how the hippocampus and cortical regions interact to support memory during development.
The Chicken Pan-Genome Reveals Gene Content Variation and a Promoter Region Deletion in IGF2BP1 Affecting Body Size

Abstract Domestication and breeding have reshaped the genomic architecture of chicken, but the retention and loss of genomic elements during these evolutionary processes remain unclear. We present the first chicken pan-genome constructed using 664 individuals, which identified an additional approximately 66.5-Mb sequences that are absent from the reference genome (GRCg6a). The constructed pan-genome encoded 20,491 predicated protein-coding genes, of which higher expression levels are observed in conserved genes relative to dispensable genes. Presence/absence variation (PAV) analyses demonstrated that gene PAV in chicken was shaped by selection, genetic drift, and hybridization. PAV-based genome-wide association studies identified numerous candidate mutations related to growth, carcass composition, meat quality, or physiological traits. Among them, a deletion in the promoter region of IGF2BP1 affecting chicken body size is reported, which is supported by functional studies and extra samples. This is the first time to report the causal variant of chicken body size quantitative trait locus located at chromosome 27 which was repeatedly reported. Therefore, the chicken pan-genome is a useful resource for biological discovery and breeding. It improves our understanding of chicken genome diversity and provides materials to unveil the evolution history of chicken domestication.
Dephosphorylation of annexin A2 by protein phosphatase 1 regulates endothelial cell barrier

Annexin A2 (ANXA2) is a multifunctional protein expressed in nearly all human tissues and cell types, playing a role in various signaling pathways. It is subjected to phosphorylation, but no specific protein phosphatase has been identified in its posttranslational regulation yet. Using pull‐down assay followed by liquid chromatography–mass spectrometry analysis we found that ANXA2 interacts with TIMAP (TGF‐beta‐inhibited membrane‐associated protein) in pulmonary artery endothelial cells. TIMAP is highly expressed in endothelial cells, where it acts as a regulatory and targeting subunit of protein phosphatase 1 (PP1). TIMAP plays an important role in the regulation of the endothelial barrier maintenance through the dephosphorylation of its several substrate proteins. In the present work, phosphorylation of Ser25 side chain in ANXA2 by protein kinase C (PKC) was shown both in vivo and in vitro. Phosphorylation level of ANXA2 at Ser25 increased greatly by inhibition of PP1 and by depletion of its regulatory subunit, TIMAP, implying a role of this PP1 holoenzyme in the dephosphorylation of ANXA2. Immunofluorescence staining and subcellular fractionations revealed a diffuse subcellular localization for the endogenous ANXA2, but phospho‐Ser25 ANXA2 was mainly detected in the membrane. ANXA2 depletion lowered the basal endothelial barrier and inhibited cell migration, but had no significant effect on cell proliferation or viability. ANXA2 depleted cells failed to respond to PMA treatment, indicating an intimately involvement of phospho‐ANXA2 in PKC signaling. Moreover, phosphorylation of ANXA2 disrupted its interaction with S100A10 suggesting a phosphorylation dependent multiple regulatory role of ANXA2 in endothelial cells. Our results demonstrate the pivotal role of PKC‐ANXA2‐PP1 pathway in endothelial cell signaling, especially in barrier function and cell migration.
Investigating the spectral features of the brain meso‐scale structure at rest

Recent studies provide novel insights into the meso‐scale organization of the brain, highlighting the co‐occurrence of different structures: classic assortative (modular), disassortative, and core‐periphery. However, the spectral properties of the brain meso‐scale remain mostly unexplored. To fill this knowledge gap, we investigated how the meso‐scale structure is organized across the frequency domain. We analyzed the resting state activity of healthy participants with source‐localized high‐density electroencephalography signals. Then, we inferred the community structure using weighted stochastic block‐model (WSBM) to capture the landscape of meso‐scale structures across the frequency domain. We found that different meso‐scale modalities co‐exist and are diversely organized over the frequency spectrum. Specifically, we found a core‐periphery structure dominance, but we also highlighted a selective increase of disassortativity in the low frequency bands (<8 Hz), and of assortativity in the high frequency band (30–50 Hz). We further described other features of the meso‐scale organization by identifying those brain regions which, at the same time, (a) exhibited the highest degree of assortativity, disassortativity, and core‐peripheriness (i.e., participation) and (b) were consistently assigned to the same community, irrespective from the granularity imposed by WSBM (i.e., granularity‐invariance). In conclusion, we observed that the brain spontaneous activity shows frequency‐specific meso‐scale organization, which may support spatially distributed and local information processing.
Towards PET imaging of the dynamic phenotypes of microglia

There is increasing evidence showing the heterogeneity of microglia activation in neuroinflammatory and neurodegenerative diseases. It has been hypothesized that pro‐inflammatory microglia are detrimental and contribute to disease progression, while anti‐inflammatory microglia play a role in damage repair and remission. The development of therapeutics targeting the deleterious glial activity and modulating it into a regenerative phenotype relies heavily upon a clearer understanding of the microglia dynamics during disease progression and the ability to monitor therapeutic outcome in vivo. To that end, molecular imaging techniques are required to assess microglia dynamics and study their role in disease progression as well as to evaluate the outcome of therapeutic interventions. Positron emission tomography (PET) is such a molecular imaging technique, and provides unique capabilities for non‐invasive quantification of neuroinflammation and has the potential to discriminate between microglia phenotypes and define their role in the disease process. However, several obstacles limit the possibility for selective in vivo imaging of microglia phenotypes mainly related to the poor characterization of specific targets that distinguish the two ends of the microglia activation spectrum and lack of suitable tracers. PET tracers targeting translocator protein 18 kDa (TSPO) have been extensively explored, but despite the success in evaluating neuroinflammation they failed to discriminate between microglia activation statuses. In this review, we highlight the current knowledge on the microglia phenotypes in the major neuroinflammatory and neurodegenerative diseases. We also discuss the current and emerging PET imaging targets, the tracers and their potential in discriminating between the pro‐ and anti‐inflammatory microglia activation states.
Phase Separation of MAGI2-Mediated Complex Underlies Formation of Slit Diaphragm Complex in Glomerular Filtration Barrier

Visual Abstract Significance Statement Slit diaphragms between podocytes play a critical role in maintaining the filtration function in kidney. At each slit diaphragm there is an electron-dense junctional plaque crucial for slit diaphragm integrity and podocyte signal transduction. However, the molecular basis underlying slit diaphragm assembly is not well understood. Here, we demonstrate that MAGI2, a unique MAGUK family scaffold protein at slit diaphragm, can autonomously undergo liquid-liquid phase separation. Multivalent interactions among the MAGI2-Dendrin-CD2AP complex drive the formation of the slit diaphragm condensates at physiologic conditions. The reconstituted slit diaphragm condensates can effectively enrich Nephrin. A nephrotic syndrome–associated mutation of MAGI2 interferes with slit diaphragm condensate formation, leading to impaired recruitment of Nephrin. Therefore, the electron-dense slit diaphragm assembly might form via phase separation of the slit diaphragm complex. Background Slit diaphragm is a specialized adhesion junction between the opposing podocytes, establishing the final filtration barrier to urinary protein loss. At the cytoplasmic insertion site of each slit diaphragm there is an electron-dense and protein-rich cellular compartment that is essential for slit diaphragm integrity and signal transduction. Mutations in genes that encode components of this membrane-less compartment have been associated with glomerular diseases. However, the molecular mechanism governing formation of compartmentalized slit diaphragm assembly remains elusive. Methods We systematically investigated the interactions between key components at slit diaphragm, such as MAGI2, Dendrin, and CD2AP, through a combination of biochemical, biophysical, and cell biologic approaches. Results We demonstrated that MAGI2, a unique MAGUK family scaffold protein at slit diaphragm, can autonomously undergo liquid-liquid phase separation. Multivalent interactions among the MAGI2-Dendrin-CD2AP complex drive the formation of the highly dense slit diaphragm condensates at physiologic conditions. The reconstituted slit diaphragm condensates can effectively recruit Nephrin. A nephrotic syndrome–associated mutation of MAGI2 interfered with formation of the slit diaphragm condensates, thus leading to impaired enrichment of Nephrin. Conclusions Key components at slit diaphragm (e.g., MAGI2 and its complex) can spontaneously undergo phase separation. The reconstituted slit diaphragm condensates can be enriched in adhesion molecules and cytoskeletal adaptor proteins. Therefore, the electron-dense slit diaphragm assembly might form via phase separation of core components of the slit diaphragm in podocytes.
Epidemiology of pyogenic liver abscesses in Germany: Analysis of incidence, risk factors and mortality rate based on routine data from statutory health insurance

Abstract Background Pyogenic liver abscesses (PLAs) represent potentially life‐threatening abdominal conditions that require immediate diagnosis and therapy. European and American incidence figures vary between one and 15 per 100,000 per year. Structured epidemiological data for European countries are not available. Objective To systematically characterize the epidemiology and clinical outcome of PLA in Germany. Methods In representative statutory health insurance data from four million people in 2013–2019, the prevalence and incidence with clinical coding of International Statistical Classification of Diseases and Related Health Problems (ICD)‐10 code K75.0 were selected (n = 1118). Furthermore, demographics, relevant comorbidities, hospitalizations, mortality and complications were determined within one year. Results The incidence of PLA was approximately seven per 100,000. The average age at diagnosis was 66 years; 65% were male. Of these, biliary disease was documented in over 60% and infectious intestinal diseases were found in 21% within the same or previous calendar year. PLA patients had high comorbidity indices. Liver transplant status, malignancies of the liver and biliary system, liver cirrhosis and pancreatitis were strongly associated. Intensive care was documented in 27% of PLA cases. Nine percent died within 12 months, most with an underlying malignant disease. Conclusion Pyogenic liver abscess is a rare disease with high morbidity. Predisposing and risk factors include intestinal and biliary diseases as well as hepatic malignancies. Further research should focus on PLA therapy within prospective surveys and controlled clinical trials.
Vascular and Collagen Target: A Rational Approach to Hypertrophic Scar Management

Significance: Hypertrophic scarring is a challenging issue for patients and clinicians. The prevalence of hypertrophic scarring can be up to 70% after burns, and patients suffer from pain, itching, and loss of joint mobility. To date, the exact mechanisms underlying hypertrophic scar formation are unclear, and clinical options remain limited. Recent Advances: Several studies have demonstrated that pathological scars are a type of hyperactive vascular response to wounding. Scar regression has been found to be accompanied by microvessel occlusion, which causes severe hypoxia, malnutrition, and endothelial dysfunction, suggesting the essential roles of microvessels in scar regression. Therefore, interventions that target the vasculature, such as intense pulsed light, pulsed dye lasers, vascular endothelial growth factor antibodies, and Endostar, represent potential treatments. In addition, the mass of scar-associated collagen is usually not considered by current treatments. However, collagen-targeted therapies such as fractional CO2 laser and collagenase have shown promising outcomes in scar treatment. Critical Issues: Traditional modalities used in current clinical practice only partially target scar-associated microvessels or collagen. As a result, the effectiveness of current treatments is limited and is too often accompanied by undesirable side effects. The formation of scars in the early stage is mainly affected by microvessels, whereas the scars in later stages are mostly composed of residual collagen. Traditional therapies do not utilize specific targets for scars at different stages. Therefore, more precise treatment strategies are needed. Future Directions: Scars should be classified as either “vascular-dominant” or “collagen-dominant” before selecting a treatment. In this way, strategies that are vascular-targeted, collagen-targeted, or a combination thereof could be recommended to treat scars at different stages.
Chocolate consumption and all-cause and cause-specific mortality in a US population: a post hoc analysis of the PLCO cancer screening trial

Few studies with mixed results have examined the association between chocolate consumption and mortality. We aimed to examine this association in a US population. A population-based cohort of 91891 participants aged 55 to 74 years was identified. Chocolate consumption was assessed via a food frequency questionnaire. Cox regression was used to estimate risk estimates. After an average follow-up of 13.5 years, 19586 all-cause deaths were documented. Compared with no regular chocolate consumption, the maximally adjusted hazard ratios of all-cause mortality were 0.89 [95% confidence interval (CI) 0.84–0.94], 0.84 (95% CI 0.79–0.90), 0.86 (95% CI 0.81–0.93), and 0.87 (95% CI 0.82–0.93) for >0–0.5 servings/week, >0.5–1 serving/week, >1–2 servings/week, and >2 servings/week, respectively (Ptrend = 0.009). A somewhat stronger inverse association was observed for mortality from cardiovascular disease and Alzheimer’s disease. A nonlinear dose–response pattern was found for all-cause and cardiovascular mortality (all Pnonlinearity < 0.01), with the lowest risk observed at chocolate consumption of 0.7 servings/week and 0.6 servings/week, respectively. The favorable associations with all-cause and cardiovascular mortality were found to be more pronounced in never smokers than in current or former smokers (all Pinteraction < 0.05). In conclusion, chocolate consumption confers reduced risks of mortality from all causes, cardiovascular disease, and Alzheimer’s disease in this US population.
Bioprinting of dual ECM scaffolds encapsulating limbal stem/progenitor cells in active and quiescent statuses

Limbal stem cell deficiency and corneal disorders are among the top global threats for human vision. Emerging therapies that integrate stem cell transplantation with engineered hydrogel scaffolds for biological and mechanical support are becoming a rising trend in the field. However, methods for high-throughput fabrication of hydrogel scaffolds, as well as knowledge of the interaction between limbal stem/progenitor cells (LSCs) and the surrounding extracellular matrix (ECM) are still much needed. Here, we employed digital light processing (DLP)-based bioprinting to fabricate hydrogel scaffolds encapsulating primary LSCs and studied the ECM-dependent LSC phenotypes. The DLP-based bioprinting with gelatin methacrylate (GelMA) or hyaluronic acid glycidyl methacrylate (HAGM) generated microscale hydrogel scaffolds that could support the viability of the encapsulated primary rabbit LSCs (rbLSCs) in culture. Immunocytochemistry and transcriptional analysis showed that the encapsulated rbLSCs remained active in GelMA-based scaffolds while exhibited quiescence in the HAGM-based scaffolds. The primary human LSCs encapsulated within bioprinted scaffolds showed consistent ECM-dependent active/quiescent statuses. Based on these results, we have developed a novel bioprinted dual ECM ‘Yin-Yang’ model encapsulating LSCs to support both active and quiescent statues. Our findings provide valuable insights towards stem cell therapies and regenerative medicine for corneal reconstruction.
Characterizing the Low-Dose Effects of Methylmercury on the Early Stages of Embryo Development Using Cultured Human Embryonic Stem Cells

Background: Global concerns of methylmercury (MeHg) exposure have been raised, especially on its effects on pregnant women. Recent epidemiological studies have revealed associations between maternal blood/hair MeHg concentrations, adverse pregnancy outcomes, and developmental deficits. However, the underlying mechanisms remain unclear. Objectives: In this study, we characterized the effects of MeHg exposure on undifferentiated human embryonic stem cells (hESCs) and extrapolated the effects to human embryonic development. Methods: hESCs were exposed to 0, 1, 5, 10, 50, 100 or 200nM MeHg for 24 h or 6 d. Cell adherence and colony formation and expansion were examined under the microscope. Cell attachment, viability/proliferation, apoptosis, stress response, cell cycle, autophagy, and expression of cell lineage marker genes and proteins were measured at the end of exposures. Results: Our results indicated that exposure to nanomolar concentrations of MeHg was associated with a) higher levels of reactive oxygen species (ROS) and hemeoxygenase-1 (HO-1), suggesting increased stress and adaptive responses; b) lower cellular adhesion, viability/proliferation, and colony formation and expansion; c) higher levels of apoptosis, reflected by higher cleaved caspase-3 expression and Annexin V binding; d) higher levels of cytoskeleton protein α-tubulin expression; e) higher rates of G1/S phase cell cycle arrest; and f) autophagy inhibition, as shown by a lower LC3BII/LC3BI ratio and accumulation of SQSTM1 (p62). These outcomes were accompanied by higher expressions of self-renewal genes or proteins or both, including OCT4, SOX2, NANOG, and cytokine receptor IL6ST, as well as pluripotency and the cell fate regulator cyclin D1. Discussion: These results revealed that under the selection pressure of exposure to low doses of MeHg, some hESCs underwent apoptosis, whereas others adapted and survived with enhanced self-renewal gene expression and specific morphological phenotypes. Findings from the present study provide in vitro evidence that low doses of MeHg adversely affect hESCs when exposed during a period of time that models embryonic pre-, during, and early postimplantation stages. https://doi.org/10.1289/EHP7349
Clinical and linguistic validation of Polish version of Pulmonary Embolism Quality of Life Questionnaire: disease-specific quality of life questionnaire for patients after acute pulmonary embolism.

INTRODUCTION Acute venous thromboembolism involving deep vein thrombosis and/or pulmonary embolism (PE) has a broad array of early and long-term complications including recurrent episodes, bleeding complications related to anticoagulant treatment, persisting dyspnea or poor physical capacity, post-thrombotic syndrome, and chronic thromboembolic pulmonary hypertension. The underestimated sequala is decreased quality of life (QoL) [1–3]. Questionnaires for assessing QoL after an episode of acute PE were developed in several languages, however, there is none in Polish. The Pulmonary Embolism Quality of Life Questionnaire (PEmb-QoL) fits very well in the modern approach to the holistic management of PE and was proven to be a good instrument to detect and measure the intensity of symptoms and physical functioning. PEmb-QoL was first developed in Dutch and translated into English (2009). It was later validated in several languages: French (2014), German (2015), Norwegian (2015), and Chinese (2018) [4–8]. In this paper, we report the results of the validation of this questionnaire in Polish.