Invariant classification and the generalised invariant formalism: conformally flat pure radiation metrics, with zero cosmological constant

Metrics obtained by integrating within the generalised invariant formalism are structured around their intrinsic coordinates, and this considerably simplifies their invariant classification and symmetry analysis. We illustrate this by presenting a simple and transparent complete invariant classification of the conformally flat pure radiation metrics (except plane waves) in such intrinsic coordinates; in particular we confirm that the three apparently non-redundant functions of one variable are genuinely non-redundant, and easily identify the subclasses which admit a Killing and/or a homothetic Killing vector. Most of our results agree with the earlier classification carried out by Skea in the different Koutras-McIntosh coordinates, which required much more involved calculations; but there are some subtle differences. Therefore, we also rework the classification in the Koutras-McIntosh coordinates, and by paying attention to some of the subtleties involving arbitrary functions, we are able to obtain complete agreement with the results obtained in intrinsic coordinates. In particular, we have corrected and completed statements and results by Edgar and Vickers, and by Skea, about the orders of Cartan invariants at which particular information becomes available.Comment: Extended version of GRG publication, with some typos etc correcte

Epigenetic Telomere Protection by Drosophila DNA Damage Response Pathways

Analysis of terminal deletion chromosomes indicates that a sequence-independent mechanism regulates protection of Drosophila telomeres. Mutations in Drosophila DNA damage response genes such as atm/tefu, mre11, or rad50 disrupt telomere protection and localization of the telomere-associated proteins HP1 and HOAP, suggesting that recognition of chromosome ends contributes to telomere protection. However, the partial telomere protection phenotype of these mutations limits the ability to test if they act in the epigenetic telomere protection mechanism. We examined the roles of the Drosophila atm and atr-atrip DNA damage response pathways and the nbs homolog in DNA damage responses and telomere protection. As in other organisms, the atm and atr-atrip pathways act in parallel to promote telomere protection. Cells lacking both pathways exhibit severe defects in telomere protection and fail to localize the protection protein HOAP to telomeres. Drosophila nbs is required for both atm- and atr-dependent DNA damage responses and acts in these pathways during DNA repair. The telomere fusion phenotype of nbs is consistent with defects in each of these activities. Cells defective in both the atm and atr pathways were used to examine if DNA damage response pathways regulate telomere protection without affecting telomere specific sequences. In these cells, chromosome fusion sites retain telomere-specific sequences, demonstrating that loss of these sequences is not responsible for loss of protection. Furthermore, terminally deleted chromosomes also fuse in these cells, directly implicating DNA damage response pathways in the epigenetic protection of telomeres. We propose that recognition of chromosome ends and recruitment of HP1 and HOAP by DNA damage response proteins is essential for the epigenetic protection of Drosophila telomeres. Given the conserved roles of DNA damage response proteins in telomere function, related mechanisms may act at the telomeres of other organisms

Updated Clinical Classification of Pulmonary Hypertension

In 1998, a clinical classification of pulmonary hypertension (PH) was established, categorizing PH into groups which share similar pathological and hemodynamic characteristics and therapeutic approaches. During the 5th World Symposium held in Nice, France, in 2013, the consensus was reached to maintain the general scheme of previous clinical classifications. However, modifications and updates especially for Group 1 patients (pulmonary arterial hypertension [PAH]) were proposed. The main change was to withdraw persistent pulmonary hypertension of the newborn (PPHN) from Group 1 because this entity carries more differences than similarities with other PAH subgroups. In the current classification, PPHN is now designated number 1. Pulmonary hypertension associated with chronic hemolytic anemia has been moved from Group 1 PAH to Group 5, unclear/multifactorial mechanism. In addition, it was decided to add specific items related to pediatric pulmonary hypertension in order to create a comprehensive, common classification for both adults and children. Therefore, congenital or acquired left-heart inflow/outflow obstructive lesions and congenital cardiomyopathies have been added to Group 2, and segmental pulmonary hypertension has been added to Group 5. Last, there were no changes for Groups 2, 3, and 4

Targeting the mitochondrial VDAC in hepatocellular carcinoma using a polyclonal antibody-conjugated to a nitrosyl ruthenium complex

The rational design of anti-cancer agents includes a new approach based on ruthenium complexes that can act as nitric oxide (NO) donor agents against specific cellular targets. One of the most studied classes of those compounds is based on bis(bipyridine) ruthenium fragment and its derivative species. In this work, we present the chemical and cytotoxicity properties against the liver hepatocellular carcinoma cell line HepG2 of cis-[RuII(NO+)Cl(dcbpy)2]2− conjugated to a polyclonal antibody IgG (anti-VDAC) recognizing a cell surface marker. UV–visible bands of the ruthenium complex were assigned with the aid of density functional theory, which also allowed estimation of the structures that explain the biological effects of the ruthenium complex–IgG conjugate. The interaction of cis-[RuII(NO+)Cl(dcbpy)2]3− with mitochondria was evaluated due to the potential of these organelles as anti-cancer targets, and considering they interact with the anti-VDAC antibody. The cytotoxicity of cis-[RuII(NO+)Cl(dcbpy)2]3−-anti-VDAC antibody was up to 80% greater in comparison to the free cis-[RuII(NO+)Cl(dcbpy)2]3− complex. We suggest that this effect is due to site-specific interaction of the complex followed by NO release.Fil: Ramos, Loyanne C. B.. Universidade de Sao Paulo; BrasilFil: Rodrigues, Fernando P.. Universidade de Sao Paulo; BrasilFil: Biazzotto, Juliana C.. Universidade de Sao Paulo; BrasilFil: de Paula Machado, Sergio. Universidade Federal do Rio de Janeiro; BrasilFil: Slep, Leonardo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química, Física de los Materiales, Medioambiente y Energía. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química, Física de los Materiales, Medioambiente y Energía; ArgentinaFil: Hamblin, Michael R.. Harvard Medical School; Estados UnidosFil: da Silva, Roberto S.. Harvard Medical School; Estados Unidos. Universidade de Sao Paulo; Brasi

Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia

BACKGROUND: Most patients with familial primary pulmonary hypertension have defects in the gene for bone morphogenetic protein receptor II (BMPR2), a member of the transforming growth factor beta (TGF-beta) superfamily of receptors. Because patients with hereditary hemorrhagic telangiectasia may have lung disease that is indistinguishable from primary pulmonary hypertension, we investigated the genetic basis of lung disease in these patients. METHODS: We evaluated members of five kindreds plus one individual patient with hereditary hemorrhagic telangiectasia and identified 10 cases of pulmonary hypertension. In the two largest families, we used microsatellite markers to test for linkage to genes encoding TGF-beta-receptor proteins, including endoglin and activin-receptor-like kinase 1 (ALK1), and BMPR2. In subjects with hereditary hemorrhagic telangiectasia and pulmonary hypertension, we also scanned ALK1 and BMPR2 for mutations. RESULTS: We identified suggestive linkage of pulmonary hypertension with hereditary hemorrhagic telangiectasia on chromosome 12q13, a region that includes ALK1. We identified amino acid changes in activin-receptor-like kinase 1 that were inherited in subjects who had a disorder with clinical and histologic features indistinguishable from those of primary pulmonary hypertension. Immunohistochemical analysis in four subjects and one control showed pulmonary vascular endothelial expression of activin-receptor-like kinase 1 in normal and diseased pulmonary arteries. CONCLUSIONS: Pulmonary hypertension in association with hereditary hemorrhagic telangiectasia can involve mutations in ALK1. These mutations are associated with diverse effects, including the vascular dilatation characteristic of hereditary hemorrhagic telangiectasia and the occlusion of small pulmonary arteries that is typical of primary pulmonary hypertension

Optimization and analysis of a quantitative real-time PCR-based technique to determine microRNA expression in formalin-fixed paraffin-embedded samples

<p>Abstract</p> <p>Background</p> <p>MicroRNAs (miRs) are non-coding RNA molecules involved in post-transcriptional regulation, with diverse functions in tissue development, differentiation, cell proliferation and apoptosis. miRs may be less prone to degradation during formalin fixation, facilitating miR expression studies in formalin-fixed paraffin-embedded (FFPE) tissue.</p> <p>Results</p> <p>Our study demonstrates that the TaqMan Human MicroRNA Array v1.0 (Early Access) platform is suitable for miR expression analysis in FFPE tissue with a high reproducibility (correlation coefficients of 0.95 between duplicates, p < 0.00001) and outlines the optimal performance conditions of this platform using clinical FFPE samples. We also outline a method of data analysis looking at differences in miR abundance between FFPE and fresh-frozen samples. By dividing the profiled miR into abundance strata of high (Ct<30), medium (30≤Ct≤35), and low (Ct>35), we show that reproducibility between technical replicates, equivalent dilutions, and FFPE <it>vs</it>. frozen samples is best in the high abundance stratum. We also demonstrate that the miR expression profiles of FFPE samples are comparable to those of fresh-frozen samples, with a correlation of up to 0.87 (p < 0.001), when examining all miRs, regardless of RNA extraction method used. Examining correlation coefficients between FFPE and fresh-frozen samples in terms of miR abundance reveals correlation coefficients of up to 0.32 (low abundance), 0.70 (medium abundance) and up to 0.97 (high abundance).</p> <p>Conclusion</p> <p>Our study thus demonstrates the utility, reproducibility, and optimization steps needed in miR expression studies using FFPE samples on a high-throughput quantitative PCR-based miR platform, opening up a realm of research possibilities for retrospective studies.</p

Paleoenvironmental and diagenetic evolution of the Aptian Pre-Salt succession in Namibe Basin (Onshore Angola)

The Aptian Pre-Salt sedimentary succession cropping out in Cangulo palaeovalley onshore Namibe Basin (Angola) was studied by a combination of field and analytical techniques to constrain the sedimentary and diagenetic evolution of the uppermost sag sequence of the South Atlantic passive margin. Field observations allows definition of four transgressive-regressive cycles characterised by fluvial to tidal-influenced mixed clastic-carbonate and carbonate-dominated deposits, that locally show evidence of evaporite dissolution; highlighting that evaporite deposition started earlier than deposition of the regional South Atlantic Loeme-Bambata evaporite formations. Two separate pre-salt carbonate units have been differentiated within the Cangulo Fm; i) a lower transitional to marginal marine, and ii) a younger upper non-marine freshwater travertine system, that is documented for the first time in the west African margin. Transgressive-regressive cycles control the early diagenesis of the tidal carbonates that include dolomitization due to mixing fluids during transgressions, and karstification due to evaporite dissolution by meteoric water circulation during regressive events. Clastic supply appears to have been completely shut down during carbonate deposition, suggesting major climatic change associated with carbonate deposition. During the lowstand between the two carbonate units, fluid flow through Cangulo palaeovalley was re-established resulting in extensive karstification and formation of a large-scale erosional unconformity that is interpreted to be time equivalent to an intra Chela-Cuvo Fm. event. The top of the studied succession corresponds to the transgressive deposits of the Bambata evaporites that are not preserved in the Cangulo palaeovalley due to its erosion but are regionally developed. The results of this study can be directly linked to along strike age equivalent Pre-Salt successions cropping out in the Namibe, Benguela and Kwanza basins, and directly offshore Angola and Brazil using well and seismic data. These new data shed important new light and constraints on the depositional and diagenetic evolution of the complex Pre-Salt reservoir systems of the South Atlantic, and the depositional and bathymetric setting at the time of onset of the main south Atlantic evaporite deposition.publishedVersio

Simulating complex patient populations with hierarchical learning effects to support methods development for post-market surveillance

Funding Information: This work was funded by a grant from the National Heart, Lung, and Blood Institute (NHLBI; grant number 1R01HL149948). The funding agency was not involved in the design of the study, collection and analysis of data, interpretation of results, or writing of the manuscript. Publisher Copyright: © 2023, The Author(s).Peer reviewedPublisher PD

Peripheral Blood Gene Expression as a Novel Genomic Biomarker in Complicated Sarcoidosis

Sarcoidosis, a systemic granulomatous syndrome invariably affecting the lung, typically spontaneously remits but in ∼20% of cases progresses with severe lung dysfunction or cardiac and neurologic involvement (complicated sarcoidosis). Unfortunately, current biomarkers fail to distinguish patients with remitting (uncomplicated) sarcoidosis from other fibrotic lung disorders, and fail to identify individuals at risk for complicated sarcoidosis. We utilized genome-wide peripheral blood gene expression analysis to identify a 20-gene sarcoidosis biomarker signature distinguishing sarcoidosis (n = 39) from healthy controls (n = 35, 86% classification accuracy) and which served as a molecular signature for complicated sarcoidosis (n = 17). As aberrancies in T cell receptor (TCR) signaling, JAK-STAT (JS) signaling, and cytokine-cytokine receptor (CCR) signaling are implicated in sarcoidosis pathogenesis, a 31-gene signature comprised of T cell signaling pathway genes associated with sarcoidosis (TCR/JS/CCR) was compared to the unbiased 20-gene biomarker signature but proved inferior in prediction accuracy in distinguishing complicated from uncomplicated sarcoidosis. Additional validation strategies included significant association of single nucleotide polymorphisms (SNPs) in signature genes with sarcoidosis susceptibility and severity (unbiased signature genes - CX3CR1, FKBP1A, NOG, RBM12B, SENS3, TSHZ2; T cell/JAK-STAT pathway genes such as AKT3, CBLB, DLG1, IFNG, IL2RA, IL7R, ITK, JUN, MALT1, NFATC2, PLCG1, SPRED1). In summary, this validated peripheral blood molecular gene signature appears to be a valuable biomarker in identifying cases with sarcoidoisis and predicting risk for complicated sarcoidosis.</p