In economic literature, economic complexity is typically approximated on the basis of an economy’s gross export structure. However, in times of ever increasingly integrated global value chains, gross ...exports may convey an inaccurate image of a country’s economic performance since they also incorporate foreign value-added and double-counted exports. Thus, I introduce a new empirical approach approximating economic complexity based on a country’s value-added export structure. This approach leads to substantially different complexity rankings compared to established metrics. Moreover, the explanatory power of GDP per capita growth rates for a sample of 40 lower-middle- to high-income countries is considerably higher, even if controlling for typical growth regression covariates.
•This article proposes to approximate economic complexity based on an economy’s value-added export structure.•Complexity rankings differ substantially compared to established metrics based on gross exports.•Its explanatory power of GDP per capita growth in a first-differenced growth model is higher, controlling for typical covariates.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Enhancing immune cell functions in tumors remains a major challenge in cancer immunotherapy. Hypoxia is a common feature of solid tumors, and cells adapt by upregulating the transcription factor ...HIF-1α. Here, we defined the transcriptional landscape of mouse tumor-infiltrating natural killer (NK) cells by using single-cell RNA sequencing. Conditional deletion of Hif1a in NK cells resulted in reduced tumor growth, elevated expression of activation markers, effector molecules, and an enriched NF-κB pathway in tumor-infiltrating NK cells. Interleukin-18 (IL-18) from myeloid cells was required for NF-κB activation and the enhanced anti-tumor activity of Hif1a−/− NK cells. Extended culture with an HIF-1α inhibitor increased human NK cell responses. Low HIF1A expression was associated with high expression of IFNG in human tumor-infiltrating NK cells, and an enriched NK-IL18-IFNG signature in solid tumors correlated with increased overall patient survival. Thus, inhibition of HIF-1α unleashes NK cell anti-tumor activity and could be exploited for cancer therapy.
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•Hif1a deficiency in NK cells reduces tumor growth•Single-cell RNA sequencing reveals activated Hif1a−/− NK cells in tumor•IL-18 drives high NF-κB, Iκbζ, and Ifng expression in tumor HIF1a−/− NK cells•An NK-IL18-IFNGhi signature correlates with increased survival in cancer patients
Ni et al. define the transcriptional landscape of tumor-infiltrating NK cells using single-cell RNA sequencing. They find that the transcription factor HIF-1α suppresses IL-18-driven NF-κB signaling and anti-tumor activity of tumor-infiltrating NK cells. Extended inhibition of HIF-1α in mouse or human NK cells unleashes potent NK cell effector function.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
‘Angiodiversity’ refers to the structural and functional heterogeneity of endothelial cells (EC) along the segments of the vascular tree and especially within the microvascular beds of different ...organs. Organotypically differentiated EC ranging from continuous, barrier-forming endothelium to discontinuous, fenestrated endothelium perform organ-specific functions such as the maintenance of the tightly sealed blood–brain barrier or the clearance of macromolecular waste products from the peripheral blood by liver EC-expressed scavenger receptors. The microvascular bed of the liver, composed of discontinuous, fenestrated liver sinusoidal endothelial cells (LSEC), is a prime example of organ-specific angiodiversity. Anatomy and development of LSEC have been extensively studied by electron microscopy as well as linage-tracing experiments. Recent advances in cell isolation and bulk transcriptomics or single-cell RNA sequencing techniques allowed the identification of distinct LSEC molecular programs and have led to the identification of LSEC subpopulations. LSEC execute homeostatic functions such as fine tuning the vascular tone, clearing noxious substances from the circulation, and modulating immunoregulatory mechanisms. In recent years, the identification and functional analysis of LSEC-derived angiocrine signals, which control liver homeostasis and disease pathogenesis in an instructive manner, marks a major change of paradigm in the understanding of liver function in health and disease. This review summarizes recent advances in the understanding of liver vascular angiodiversity and the functional consequences resulting thereof.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
•Assessment of network consequences of stroke opens new perspectives, but beware of pitfalls.•Insights into network plasticity after stroke have suggested novel targets for therapy.•Network-states ...may help identify individualized treatment approaches for patients.
Stroke has long been regarded as focal disease with circumscribed damage leading to neurological deficits. However, advances in methods for assessing the human brain and in statistics have enabled new tools for the examination of the consequences of stroke on brain structure and function. Thereby, it has become evident that stroke has impact on the entire brain and its network properties and can therefore be considered as a network disease. The present review first gives an overview of current methodological opportunities and pitfalls for assessing stroke-induced changes and reorganization in the human brain. We then summarize principles of plasticity after stroke that have emerged from the assessment of networks. Thereby, it is shown that neurological deficits do not only arise from focal tissue damage but also from local and remote changes in white-matter tracts and in neural interactions among wide-spread networks. Similarly, plasticity and clinical improvements are associated with specific compensatory structural and functional patterns of neural network interactions. Innovative treatment approaches have started to target such network patterns to enhance recovery. Network assessments to predict treatment response and to individualize rehabilitation is a promising way to enhance specific treatment effects and overall outcome after stroke.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Postnatal liver development is characterized by hepatocyte growth, proliferation, and functional maturation. Notably, canonical Wnt signaling in hepatocytes has been identified as an important ...regulator of final adult liver size and metabolic liver zonation. The cellular origin of Wnt ligands responsible for homeostatic liver/body weight ratio (LW/BW) remained unclear, which was also attributable to a lack of suitable endothelial Cre driver mice. To comprehensively analyze the effects of hepatic angiocrine Wnt signaling on liver development and metabolic functions, we used endothelial subtype‐specific Stab2‐Cre driver mice to delete Wls from hepatic endothelial cells (HECs). The resultant Stab2‐Cretg/wt;Wlsfl/fl (Wls‐HECKO) mice were viable, but showed a significantly reduced LW/BW. Specifically, ablation of angiocrine Wnt signaling impaired metabolic zonation in the liver, as shown by loss of pericentral, β‐catenin‐dependent target genes such as glutamine synthase (Glul), RhBg, Axin2, and cytochrome P450 2E1, as well as by extended expression of periportal genes such as arginase 1. Furthermore, endothelial subtype‐specific expression of a c‐terminally YFP‐tagged Wls fusion protein in Wls‐HECKO mice (Stab2‐Cretg/wt;Wlsfl/fl;Rosa26:Wls‐YFPfl/wt Wls‐rescue) restored metabolic liver zonation. Interestingly, lipid metabolism was altered in Wls‐HECKO mice exhibiting significantly reduced plasma cholesterol levels, while maintaining normal plasma triglyceride and blood glucose concentrations. On the contrary, zonal expression of Endomucin, LYVE1, and other markers of HEC heterogeneity were not altered in Wls‐HECKO livers. Conclusion: Angiocrine Wnt signaling controls liver growth as well as development of metabolic liver zonation in mice, whereas intrahepatic HEC zonation is not affected. (Hepatology 2017).
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Background: Despite recent significant progress in the development of automatic sleep staging methods, building a good model still remains a big challenge for sleep studies with a small cohort due to ...the data-variability and data-inefficiency issues. This work presents a deep transfer learning approach to overcome these issues and enable transferring knowledge from a large dataset to a small cohort for automatic sleep staging. Methods: We start from a generic end-to-end deep learning framework for sequence-to-sequence sleep staging and derive two networks as the means for transfer learning. The networks are first trained in the source domain (i.e. the large database). The pretrained networks are then finetuned in the target domain (i.e. the small cohort) to complete knowledge transfer. We employ the Montreal Archive of Sleep Studies (MASS) database consisting of 200 subjects as the source domain and study deep transfer learning on three different target domains: the Sleep Cassette subset and the Sleep Telemetry subset of the Sleep-EDF Expanded database, and the Surrey-cEEGrid database. The target domains are purposely adopted to cover different degrees of data mismatch to the source domains. Results: Our experimental results show significant performance improvement on automatic sleep staging on the target domains achieved with the proposed deep transfer learning approach. Conclusions: These results suggest the efficacy of the proposed approach in addressing the above-mentioned data-variability and data-inefficiency issues. Significance: As a consequence, it would enable one to improve the quality of automatic sleep staging models when the amount of data is relatively small.<xref ref-type="fn" rid="fn1"> 1 1
The source code and the pretrained models are published at https://github.com/pquochuy/sleep_transfer_learning .
Angiocrine signaling by liver sinusoidal endothelial cells (LSECs) regulates hepatic functions such as growth, metabolic maturation, and regeneration. Recently, we identified GATA4 as the master ...regulator of LSEC specification during development. Herein, we studied the role of endothelial GATA4 in the adult liver and in hepatic pathogenesis.
We generated adult Clec4g-icretg/0xGata4fl/fl (Gata4LSEC-KO) mice with LSEC-specific depletion of Gata4. Livers were analyzed by histology, electron microscopy, immunohistochemistry/immunofluorescence, in situ hybridization, and LSECs were isolated for gene expression profiling, ChIP- and ATAC-sequencing. Partial hepatectomy was performed to assess regeneration. We used choline-deficient, l-amino acid-defined (CDAA) diet and chronic carbon tetrachloride exposure to model liver fibrosis. Human single cell RNA-seq data sets were analyzed for endothelial alterations in healthy and cirrhotic livers.
Genetic Gata4 deficiency in LSECs of adult mice caused perisinusoidal liver fibrosis, hepatopathy and impaired liver regeneration. Sinusoidal capillarization and LSEC-to-continuous endothelial transdifferentiation were accompanied by a profibrotic angiocrine switch involving de novo endothelial expression of hepatic stellate cell-activating cytokine PDGFB. Increased chromatin accessibility and amplification by activated MYC mediated angiocrine Pdgfb expression. As observed in Gata4LSEC-KO livers, CDAA diet-induced perisinusoidal liver fibrosis was associated with GATA4 repression, MYC activation and a profibrotic angiocrine switch in LSECs. Comparison of CDAA-fed Gata4LSEC-KO and control mice demonstrated that endothelial GATA4 indeed protects against dietary-induced perisinusoidal liver fibrosis. In human cirrhotic livers, GATA4-positive LSECs and endothelial GATA4 target genes were reduced, while non-LSEC endothelial cells and MYC target genes including PDGFB were enriched.
Endothelial GATA4 protects against perisinusoidal liver fibrosis by repressing MYC activation and profibrotic angiocrine signaling at the chromatin level. Therapies targeting the GATA4/MYC/PDGFB/PDGFRβ axis offer a promising strategy for prevention and treatment of liver fibrosis.
The liver vasculature is supposed to play a major role in the development of liver fibrosis and cirrhosis, which can lead to liver failure and liver cancer. Herein, we discovered that structural and transcriptional changes induced by genetic deletion of the transcription factor GATA4 in the hepatic endothelium were sufficient to cause liver fibrosis. Activation of the transcription factor MYC and de novo expression of the “angiocrine” growth factor PDGFB were identified as downstream drivers of fibrosis and as potential therapeutic targets for this potentially fatal disease.
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•Genetic endothelial Gata4 deletion leads to liver fibrosis and hepatopathy.•Gata4 deficiency causes profibrotic angiocrine signaling via endothelial PDGFB.•Increased chromatin accessibility and activated MYC mediate Pdgfb expression in LSECs.•Dietary liver fibrosis causes dysregulation of the endothelial GATA4/MYC/PDGFB axis.•In human cirrhosis, single-cell data implicate the GATA4/PDGFB axis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
To support the recovery of disability and the reduced functional capacity influencing the independence of daily life after focal brain lesions like stroke, the application of noninvasive brain ...stimulation (NIBS) by repetitive transcranial magnetic stimulation or transcranial electric stimulation has been found useful in the last decades. Still, a positive influence on the recovery seems to be restricted to specific subgroups of patients. Therefore, a closer look on individual parameters influencing the recovery course and the effect of NIBS is needed.
Neuroimaging studies investigated alterations in neuronal network settings during the recovery process from stroke and can explain a relevant amount of variance in residual motor function. In this regard for instance, the microstructural integrity of the corticospinal tract and its influence on cortical and subcortical functional and structural connectivity alterations shows a relevant impact on individual recovery from the acute to the chronic state.
Based on this understanding, a 'one-suits-all' NIBS strategy for clinical application appears insufficient and understanding of therapeutic susceptibility to NIBS gained from structural and functional imaging studies will help to develop patient-tailored NIBS-based interventional strategies towards precision medicine, as a promising future prospective within this field.
Nanobodies are highly valuable tools for numerous bioanalytical and biotechnical applications. Here, we report the characterization of a nanobody that binds a short peptide epitope with extraordinary ...affinity. Structural analysis reveals an unusual binding mode where the extended peptide becomes part of a β-sheet structure in the nanobody. This interaction relies on sequence-independent backbone interactions augmented by a small number of specificity-determining side chain contacts. Once bound, the peptide is fastened by two nanobody side chains that clamp it in a headlock fashion. Exploiting this unusual binding mode, we generated a novel nanobody-derived capture and detection system. Matrix-coupled nanobody enables the fast and efficient isolation of epitope-tagged proteins from prokaryotic and eukaryotic expression systems. Additionally, the fluorescently labeled nanobody visualizes subcellular structures in different cellular compartments. The high-affinity-binding and modifiable peptide tag of this system renders it a versatile and robust tool to combine biochemical analysis with microscopic studies.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Miller-Dieker syndrome (MDS) is caused by a heterozygous deletion of chromosome 17p13.3 involving the genes LIS1 and YWHAE (coding for 14.3.3ε) and leads to malformations during cortical development. ...Here, we used patient-specific forebrain-type organoids to investigate pathological changes associated with MDS. Patient-derived organoids are significantly reduced in size, a change accompanied by a switch from symmetric to asymmetric cell division of ventricular zone radial glia cells (vRGCs). Alterations in microtubule network organization in vRGCs and a disruption of cortical niche architecture, including altered expression of cell adhesion molecules, are also observed. These phenotypic changes lead to a non-cell-autonomous disturbance of the N-cadherin/β-catenin signaling axis. Reinstalling active β-catenin signaling rescues division modes and ameliorates growth defects. Our data define the role of LIS1 and 14.3.3ε in maintaining the cortical niche and highlight the utility of organoid-based systems for modeling complex cell-cell interactions in vitro.
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•Homogeneous forebrain-type organoids reflect early cortical development in vitro•MDS-derived organoids show reduced expansion rate caused by premature neurogenesis•MDS-derived organoids exhibit alterations in cortical niche architecture•Niche disruption leads to a non-cell-autonomous disturbance of β-catenin signaling
Using Miller-Dieker-syndrome-specific iPSC-derived forebrain-type organoid cultures, Iefremova et al. find that a disturbance of cortical niche signaling leads to alterations in N-cadherin/β-catenin signaling that result in a non-cell-autonomous expansion defect of ventricular zone radial glia cells.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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