Miracle-dz/UniFAR-FTUs huggingface dataset:
Mitochondrial Dysfunction Combined with High Calcium Load Leads to Impaired Antioxidant Defense Underlying the Selective Loss of Nigral Dopaminergic Neurons

Mitochondrial dysfunction is critically involved in Parkinson's disease, characterized by loss of dopaminergic neurons (DaNs) in the substantia nigra (SNc), whereas DaNs in the neighboring ventral tegmental area (VTA) are much less affected. In contrast to VTA, SNc DaNs engage calcium channels to generate action potentials, which lead to oxidant stress by yet unknown pathways. Mitochondrial dysfunction is critically involved in Parkinson's disease, characterized by loss of dopaminergic neurons (DaNs) in the substantia nigra (SNc), whereas DaNs in the neighboring ventral tegmental area (VTA) are much less affected. In contrast to VTA, SNc DaNs engage calcium channels to generate action potentials, which lead to oxidant stress by yet unknown pathways. To determine the molecular mechanisms linking calcium load with selective cell death in the presence of mitochondrial deficiency, we analyzed the mitochondrial redox state and the mitochondrial membrane potential in mice of both sexes with genetically induced, severe mitochondrial dysfunction in DaNs (MitoPark mice), at the same time expressing a redox-sensitive GFP targeted to the mitochondrial matrix. Despite mitochondrial insufficiency in all DaNs, exclusively SNc neurons showed an oxidized redox-system, i.e., a low reduced/oxidized glutathione (GSH-GSSG) ratio. This was mimicked by cyanide, but not by rotenone or antimycin A, making the involvement of reactive oxygen species rather unlikely. Surprisingly, a high mitochondrial inner membrane potential was maintained in MitoPark SNc DaNs. Antagonizing calcium influx into the cell and into mitochondria, respectively, rescued the disturbed redox ratio and induced further hyperpolarization of the inner mitochondrial membrane. Our data therefore show that the constant calcium load in SNc DaNs is counterbalanced by a high mitochondrial inner membrane potential, even under conditions of severe mitochondrial dysfunction, but triggers a detrimental imbalance in the mitochondrial redox system, which will lead to neuron death. Our findings thus reveal a new mechanism, redox imbalance, which underlies the differential vulnerability of DaNs to mitochondrial defects. SIGNIFICANCE STATEMENT Parkinson's disease is characterized by the preferential degeneration of dopaminergic neurons (DaNs) of the substantia nigra pars compacta (SNc), resulting in the characteristic hypokinesia in patients. Ubiquitous pathological triggers cannot be responsible for the selective neuron loss. Here we show that mitochondrial impairment together with elevated calcium burden destabilize the mitochondrial antioxidant defense only in SNc DaNs, and thus promote the increased vulnerability of this neuron population.
Laparoscopic Liver Resection Ameliorates the Postoperative Liver Function Impairment for Hepatocellular Carcinoma Patients

Supplemental Digital Content is available in the text. To study whether laparoscopic liver resection (LLR) is able to alleviate the postoperative liver function impairment for hepatocellular carcinoma patients, the clinical data of 103 patients were retrospectively analyzed, including 42 patients who underwent LLR and 61 patients who underwent open liver resection (OLR), during the period spanning from 2012 to 2017. The postoperative peak aspartate aminotransferase and alanine aminotransferase levels in the LLR group were significantly lower than those of the OLR group (209.76±189.516 vs. 262.55±181.19, P=0.046; 250.56±200.944 vs. 411.01±412.51, P=0.005, for aspartate aminotransferase and alanine aminotransferase, respectively). The recovering of postoperative total protein and albumin in the LLR group was faster than that in the OLR group, and the total protein and albumin levels on the postoperative day-5 were significantly higher in the LLR group than in the OLR group (62.528±9.427 vs. 57.87±6.101, P=0.019; 36.456±4.875 vs. 33.653±4.112, P=0.012, respectively). In conclusion, these data show that LLR alleviates postoperative liver function impairment and increases liver function recovery.
Yo-Yo Intermittent Recovery Level 1 Test for Estimation of Peak Oxygen Uptake: Use Without Restriction?

ABSTRACT Purpose: This study analyzed the physiological response during Yo-Yo Intermittent Recovery Level 1 (YYIR1) test and re-test by in-field ergospirometry and time-series analyses of respiratory parameters. Methods: Ten moderately trained males (23.4 ± 2.01 years, VO2peak= 56.81 ± 10.75 mL·kg−1·min−1) completed three running trials including two separate YYIR1 tests and an independent maximal performance running test with time-series analyses of gas exchange parameters. Physiological response was assessed during all tests by determination of blood lactate levels (including calculation of individual lactate threshold), heart rate, oxygen consumption and respiratory exchange ratio (RER). Results: Modeling of YYIR1 test mean VO2 uptake kinetics over all participants revealed that VO2 increased rapidly after the individual lactate threshold (11.49 ± 0.66 km∙h−1 at 3.83 ± 0.42 mmol∙L−1) was reached with ~95% VO2peak at ~50% of the test duration (test, VO2 50%= 95.17 ± 8.74% of VO2peak; re-test, VO2 50%= 96.78 ± 7.04% of VO2peak). However, and despite identical YYIR1 test performance (1568 ± 364.6 m vs. 1568 ± 449.7 m, CV = 4.59%), mean VO2peak during YYIR1 test was 8.81 ± 5.6% higher than YYIR1 re-test (p = .027). Importantly, correlation of VO2peak with YYIR1 test performance was weak (R2 = 0.28, p = .115). Conclusions: We conclude that the YYIR1 test should not be used to estimate VO2peak. Further studies on direct determination of gas exchange parameters during different YYI test variants are warranted.
Adhesion, motility and matrix-degrading gene expression changes in CSF-1-induced mouse macrophage differentiation

ABSTRACT Migratory macrophages play critical roles in tissue development, homeostasis and disease, so it is important to understand how their migration machinery is regulated. Whole-transcriptome sequencing revealed that CSF-1-stimulated differentiation of bone marrow-derived precursors into mature macrophages is accompanied by widespread, profound changes in the expression of genes regulating adhesion, actin cytoskeletal remodeling and extracellular matrix degradation. Significantly altered expression of almost 40% of adhesion genes, 60–86% of Rho family GTPases, their regulators and effectors and over 70% of extracellular proteases occurred. The gene expression changes were mirrored by changes in macrophage adhesion associated with increases in motility and matrix-degrading capacity. IL-4 further increased motility and matrix-degrading capacity in mature macrophages, with additional changes in migration machinery gene expression. Finally, siRNA-induced reductions in the expression of the core adhesion proteins paxillin and leupaxin decreased macrophage spreading and the number of adhesions, with distinct effects on adhesion and their distribution, and on matrix degradation. Together, the datasets provide an important resource to increase our understanding of the regulation of migration in macrophages and to develop therapies targeting disease-enhancing macrophages. Summary: Widespread and profound changes occur in the expression of adhesion, motility and matrix-degrading genes as macrophages differentiate under the influence of CSF-1; the roles of paxillin and leupaxin adhesion proteins are compared.
Long non-coding RNA PSMA3-AS1 promotes malignant phenotypes of esophageal cancer by modulating the miR-101/EZH2 axis as a ceRNA

Backgrounds: Emerging evidences has demonstrated that dysregulation of long non-coding RNAs (lncRNAs) is critically involved in esophageal squamous cell carcinoma (ESCC) progression. However, the function of lncRNA PSMA3-AS1 in ESCC is unclear. Therefore, we aimed to explore the functions and potential mechanisms of PSMA3-AS1 in ESCC cells progression. Results: Here, we found that PSMA3-AS1 expression was significantly up-regulated in ESCC tissues. Forced PSMA3-AS1 expression was correlated with tumor size, distant metastasis, and poor prognosis in ESCC patients. Functionally, PSMA3-AS1-overexpression promoted ESCC cells proliferation, invasion, and migration in vitro. Mechanistically, PSMA3-AS1 up-regulated EZH2 expression by competitively binding to miR-101. Conclusion: PSMA3-AS1 is significantly up-regulated in ESCC tissues, and the PSMA3-AS1/miR-101/EZH2 axis plays a critical role in ESCC progression. Taken together, our results may provide promising targets for ESCC therapy. Methods: PSMA3-AS1 and miR-101 expression were explored using qRT-PCR in ESCC tissues and cell lines. Immunohistochemistry assays were carried out to analyze EZH2 (enhancer of zeste homolog) protein expression. RIP, dual-luciferase reporter, fluorescence in situ hybridization, and biotin pull-down assays were used to detect the interactions of PSMA3-AS1, miR-101 and EZH2. The biological functions of PSMA3-AS1 in PSMA3-AS1-altered cells were explored using CCK-8, colony formation, wound healing, and transwell assays in vitro.
A high‐quality walnut genome assembly reveals extensive gene expression divergences after whole‐genome duplication

The common walnut Juglans regia and its related species in the genus Juglans are important economic trees, which have been widely grown for nut and wood productions in many counties. In the Juglans genus, there are ~21 diploid species all with 2n=32 chromosomes, which can be divided into four major sections based on phylogenetic analyses and fruit morphology - Cardiocaryon (e.g., J. cathayensis and J. mandshurica), Juglans (e.g., J. sigillata and the most popular one J. regia), Trachycaryon (e.g. J. cinerea) and Rhysocaryon (e.g., J. hindsii, J. nigra, and J. microcarpa) (Aradhya et al., 2017). For walnuts, the draft genome sequences of several Juglans species had been generated from second-generation sequencing platform (J. regia Chandler N50: 465Kb, Martınez-Garcıa et al., 2016; J. regia Chandler N50: 640Kb, Stevens et al., 2018).
Typology of coastal urban vulnerability under rapid urbanization

Coastal areas are urbanizing at unprecedented rates, particularly in low- and middle-income countries. Combinations of long-standing and emerging problems in these urban areas generate vulnerability for human well-being and ecosystems alike. This baseline study provides a spatially explicit global systematization of these problems into typical urban vulnerability profiles for the year 2000 using largely sub-national data. Using 11 indicator datasets for urban expansion, urban population growth, marginalization of poor populations, government effectiveness, exposures and damages to climate-related extreme events, low-lying settlement, and wetlands prevalence, a cluster analysis reveals a global typology of seven clearly distinguishable clusters, or urban profiles of vulnerability. Each profile is characterized by a specific data-value combination of indicators representing mechanisms that generate vulnerability. Using 21 studies for testing the plausibility, we identify seven key profile-based vulnerabilities for urban populations, which are relevant in the context of global urbanization, expansion, and climate change. We show which urban coasts are similar in this regard. Sensitivity and exposure to extreme climate-related events, and government effectiveness, are the most important factors for the huge asymmetries of vulnerability between profiles. Against the background of underlying global trends we propose entry points for profile-based vulnerability reduction. The study provides a baseline for further pattern analysis in the rapidly urbanizing coastal fringe as data availability increases. We propose to explore socio-ecologically similar coastal urban areas as a basis for sharing experience and vulnerability-reducing measures among them.
The Work and Social Adjustment Scale, Youth and Parent Versions: Psychometric Evaluation of a Brief Measure of Functional Impairment in Young People

The Work and Social Adjustment Scale (WSAS) is a brief global measure of functional impairment that is widely used in adult health. We have adapted the WSAS for its use in youth, the WSAS-Youth version (WSAS-Y) and WSAS-Parent version (WSAS-P). This study evaluated the psychometric properties of the scale. The internal consistency, factor structure, convergent and divergent validity, test–retest reliability and sensitivity to change of the WSAS-Y/P were studied in 525 children and adolescents with obsessive–compulsive disorder and related disorders receiving treatment. The internal consistency of the WSAS-Y/P was excellent across diagnostic groups and time-points. Exploratory factor analysis extracted a single-factor of functional impairment, explaining in excess of 85% of the variance. The test–retest reliability was adequate. The WSAS-Y/P correlated more strongly with other measures of functional impairment than with measures of symptom severity, indicating good convergent/divergent validity. Finally, the WSAS-Y/P was highly sensitive to change after treatment.
A canstatin-derived peptide provides insight into the role of Capillary Morphogenesis Gene 2 in angiogenic regulation and matrix uptake

Capillary Morphogenesis Gene 2 protein (CMG2) is a transmembrane, integrin-like receptor and the primary receptor for the anthrax toxin. In addition to its role as an anthrax toxin receptor, CMG2 has been repeatedly shown to play a role in angiogenic processes. However, the molecular mechanism mediating observed CMG2-related angiogenic effects has not been fully elucidated. Previous studies have found that CMG2 binds type IV collagen (Col-IV), a key component of the vascular basement membrane, as well as other ECM proteins. Currently, no link has been made between these CMG2-ECM interactions and angiogenesis; however, ECM fragments are known to play a role in regulating angiogenesis. Here, we further characterize the CMG2-Col-IV interaction and explore the effect of this interaction on angiogenesis. Using a peptide array, we observed that CMG2 preferentially binds peptide fragments of the NC1 (non-collagenous domain 1) domains of Col-IV. These domains are also known as the fragments arresten (from the α1 chain) and canstatin (from the α2 chain) and have documented antiangiogenic properties. A second peptide array was probed to map a putative binding epitope. A top hit from the initial array, a canstatin-derived peptide, binds to the CMG2 ligand-binding von Willebrand factor A (vWA) domain with sub-micromolar affinity (peptide S16, Kd = 400 ± 200 nM). This peptide competes with anthrax protective antigen (PA) for CMG2 binding, and does not bind CMG2 in the presence of EDTA. Together these data suggest that, like PA, S16 interacts with CMG2 at the metal-ion dependent adhesion site (MIDAS) of its vWA domain. We demonstrate that CMG2 specifically mediates endocytic uptake of S16, since CMG2-/- endothelial cells show markedly reduced S16 uptake, without reducing total endocytosis. Furthermore, we show that S16 reduces endothelial migration but not cell proliferation. Taken together, our data demonstrate that a Col IV-derived anti-angiogenic peptide acts via CMG2, suggesting a possible link between CMG2-Col IV interactions and angiogenesis.
Chronic exposure to diesel particles worsened emphysema and increased M2-like phenotype macrophages in a PPE-induced model

Chronic exposure to ambient levels of air pollution induces respiratory illness exacerbation by increasing inflammatory responses and apoptotic cells in pulmonary tissues. The ineffective phagocytosis of these apoptotic cells (efferocytosis) by macrophages has been considered an important factor in these pathological mechanisms. Depending on microenvironmental stimuli, macrophages can assume different phenotypes with different functional actions. M1 macrophages are recognized by their proinflammatory activity, whereas M2 macrophages play pivotal roles in responding to microorganisms and in efferocytosis to avoid the progression of inflammatory conditions. To verify how exposure to air pollutants interferes with macrophage polarization in emphysema development, we evaluated the different macrophage phenotypes in a PPE- induced model with the exposure to diesel exhaust particles. C57BL/6 mice received intranasal instillation of porcine pancreatic elastase (PPE) to induce emphysema, and the control groups received saline. Both groups were exposed to diesel exhaust particles or filtered air for 60 days according to the groups. We observed that both the diesel and PPE groups had an increase in alveolar enlargement, collagen and elastic fibers in the parenchyma and the number of macrophages, lymphocytes and epithelial cells in BAL, and these responses were exacerbated in animals that received PPE instillation prior to exposure to diesel exhaust particles. The same response pattern was found inCaspase-3 positive cell analysis, attesting to an increase in cell apoptosis, which is in agreement with the increase in M2 phenotype markers, measured by RT-PCR and flow cytometry analysis. We did not verify differences among the groups for the M1 phenotype. In conclusion, our results showed that both chronic exposure to diesel exhaust particles and PPE instillation induced inflammatory conditions, cell apoptosis and emphysema development, as well as an increase in M2 phenotype macrophages, and the combination of these two factors exacerbated these responses. The predominance of the M2-like phenotype likely occurred due to the increased demand for efferocytosis. However, M2 macrophage activity was ineffective, resulting in emphysema development and worsening of symptoms.
Preserving Symmetry and Degeneracy in the Localized Orbital Scaling Correction Approach.

Symmetry is a fundamental concept that plays a critical role in many chemical and physical phenomena and processes, which highlights the importance of theoretical methods to correctly handle symmetry. The recently developed localized orbital scaling correction (LOSC1) shows great improvement on the description of band gaps, photoemission spectra, and dissociation limits of cationic species. However, issues remain with LOSC1 in dealing with the symmetry and degeneracy of electronic states, which are also relevant to other methods using localization. In this work, we utilize a new method that deals with the physical-space and the energy-space localization on an equal footing. The resulting localized orbitals, i.e. orbitalets, are able to maintain more symmetry and the desired state degeneracy, which is important in calculating the electronic structure of both molecules and periodic bulk systems. Furthermore, the curvature matrix is redefined to improve potential energy curves for systems with stretched bonds, while retaining the correct dissociation limits. This new approach, termed LOSC2, includes only two fitting parameters. It maintains similar accuracy as LOSC1 over many properties, while overcomes LOSC1's deficiencies in symmetry and degeneracy. Our tests have shown that LOSC2 orbitalets possess the full- or sub-group of molecular symmetry if allowed, which preserves the state degeneracy. Tests on different sized planar annulenes, odd-numbered allenes, and triphenylene again verifies that LOSC2 is able to maintain the state degeneracy, while LOSC1 cannot. All the tests demonstrate the advantage of LOSC2 in the calculation of molecular systems and its potential for application to periodic bulk systems.
Identification and characterisation of differentially displayed transcripts in metastatic versus non-metastatic cells of the CSML cell line system.

Metastasis is a complex multistep process allowing otherwise localised tumour cells to migrate to other organs. To elucidate this mechanism further we compared the mRNA level of non-metastatic CSML-0 to metastatic CSML-100 and VMR-Li using differential display. This approach led to the identification of ten different genes differentially expressed between two closely related CSML cell lines. Cloning, sequencing and database analysis suggested the cloned fragments to be related to six genes with known coding sequence. MMTV, Collagen XI a 1 and PACE4 were found in CSML-0, while Cystatin C, Lamin C and Ly-6A/E were upregulated in CSML-100. Also four fragments, NN18 found in CSML-0 and NN9, NN30 and NN32 found in CSML-100, not related to any known gene were cloned. When tested against a panel of mouse tumour cell lines, a pattern of expression for Collagen XI a l , PACE4, Cy statin C, Lamin C, Ly-6A/E, NN9 and NN30 connecting these genes to the metastatic process were found. Cystatin C protein staining of cell lines and CSML tumour tissue further suggested an involvement of this proteinase inhibitor in tumour progression. This is the first report connecting PACE4 and Collagen XI a 1 to tumour progression and points to new proteins potentially.utilised by colonising cells. The NN30 gene fragment was selected for further identifieation and eharacterisation. The full-length clone revealed a 338 amino acid 39 kDa protein, lacking obvious . homologues in the EMBL database. We temporarily named this protein E30. In situ hybridisation and immunostainings demonstrated that this protein was highly expressed in epithelial cells, in testis and in ovary, in embryonic tissue as well as in extra embryonic. This gene is part of a previously undescribed gene family as indicated by human and C. elegans ESTs homologous to E30. Transfection of E30 into non-metastatic CSML-0 cells rendered these cells metastatic in 2 out of 3 mice in an experimental metastasis assay. Metastatic nodules were not only confined to the lung, but both mice produced liver metastasis. I therefore report the cloning of a gene expressed in epithelial cells and capable of inducing metastasis to the liver and lung.
Inhibition of BCL2 Family Members Increases the Efficacy of Copper Chelation in BRAFV600E-Driven Melanoma

This study unveils a novel collateral drug sensitivity elicited by combining copper chelators and BH3 mimetics for treatment of BRAFV600E mutation-positive melanoma. The principal unmet need in BRAFV600E-positive melanoma is lack of an adequate therapeutic strategy capable of overcoming resistance to clinically approved targeted therapies against oncogenic BRAF and/or the downstream MEK1/2 kinases. We previously discovered that copper (Cu) is required for MEK1 and MEK2 activity through a direct Cu–MEK1/2 interaction. Repurposing the clinical Cu chelator tetrathiomolybdate (TTM) is supported by efficacy in BRAFV600E-driven melanoma models, due in part to inhibition of MEK1/2 kinase activity. However, the antineoplastic activity of Cu chelators is cytostatic. Here, we performed high-throughput small-molecule screens to identify bioactive compounds that synergize with TTM in BRAFV600E-driven melanoma cells. Genetic perturbation or pharmacologic inhibition of specific members of the BCL2 family of antiapoptotic proteins (BCL-W, BCL-XL, and MCL1) selectively reduced cell viability when combined with a Cu chelator and induced CASPASE-dependent cell death. Further, in BRAFV600E-positive melanoma cells evolved to be resistant to BRAF and/or MEK1/2 inhibitors, combined treatment with TTM and the clinically evaluated BCL2 inhibitor, ABT-263, restored tumor growth suppression and induced apoptosis. These findings further support Cu chelation as a therapeutic strategy to target oncogene-dependent tumor cell growth and survival by enhancing Cu chelator efficacy with chemical inducers of apoptosis, especially in the context of refractory or relapsed BRAFV600E-driven melanoma. Significance: This study unveils a novel collateral drug sensitivity elicited by combining copper chelators and BH3 mimetics for treatment of BRAFV600E mutation-positive melanoma.