Search

We present the first spectroscopic ALMA follow-up for a pilot sample of nine radio-selected near-IR-dark galaxies in the COSMOS field. These sources were initially selected as radio-detected sources (S3 GHz > 12.65 μJy) without an optical or near-IR (NIR) counterpart in the COSMOS2015 catalog (Ks ≳ 24.7 mag), and just three of them were subsequently detected in the deeper COSMOS2020. Several studies highlighted that this selection could provide a population of highly dust-obscured, massive, and star-bursting galaxies. With these new ALMA observations, we assess the spectroscopic redshifts of this pilot sample of sources and improve the quality of the physical properties estimated through SED-fitting. Moreover, we measure the quantity of molecular gas inside these galaxies and forecast their potential evolutionary path, finding that the radio-selected NIR-dark galaxies might likely represent a population of high-z progenitors of the massive and passive galaxies that were discovered at z ∼ 3. Finally, we present some initial constraints on the kinematics of the interstellar medium within the analyzed galaxies, reporting a high fraction (∼55%) of double-peaked lines that can be interpreted as the signature of a rotating structure in our targets or as the presence of major mergers in our sample. The results we present here show the scientific potential of (sub)mm observations for this elusive population of galaxies and highlight the potential contribution of these sources to the evolution of the massive and passive galaxies at high z. [ABSTRACT FROM AUTHOR]

The unprecedented number of gravitational lenses expected from new-generation facilities such as the ESA Euclid telescope and the Vera Rubin Observatory makes it crucial to rethink our classical approach to lens-modelling. In this paper, we present lemon (Lens Modelling with Neural networks): a new machine-learning algorithm able to analyse hundreds of thousands of gravitational lenses in a reasonable amount of time. The algorithm is based on a Bayesian Neural Network : a new generation of neural networks able to associate a reliable confidence interval to each predicted parameter. We train the algorithm to predict the three main parameters of the singular isothermal ellipsoid model (the Einstein radius and the two components of the ellipticity) by employing two simulated data sets built to resemble the imaging capabilities of the Hubble Space Telescope and the forthcoming Euclid satellite. In this work, we assess the accuracy of the algorithm and the reliability of the estimated uncertainties by applying the network to several simulated data sets of 104 images each. We obtain accuracies comparable to previous studies present in the current literature and an average modelling time of just ∼0.5 s per lens. Finally, we apply the lemon algorithm to a pilot data set of real lenses observed with HST during the SLACS program, obtaining unbiased estimates of their SIE parameters. The code is publicly available on GitHub (https://github.com/fab-gentile/LEMON). [ABSTRACT FROM AUTHOR]

We present a sample of 16 likely strong gravitational lenses identified in the VST Optical Imaging of the CDFS and ES1 fields (VOICE survey) using convolutional neural networks (CNNs). We train two different CNNs on composite images produced by superimposing simulated gravitational arcs on real Luminous Red Galaxies observed in VOICE. Specifically, the first CNN is trained on single-band images and more easily identifies systems with large Einstein radii, while the second one, trained on composite RGB images, is more accurate in retrieving systems with smaller Einstein radii. We apply both networks to real data from the VOICE survey, taking advantage of the high limiting magnitude (26.1 in the r band) and low PSF FWHM (0.8 arcsec in the r band) of this deep survey. We analyse ∼21 200 images with magr < 21.5, identifying 257 lens candidates. To retrieve a high-confidence sample and to assess the accuracy of our technique, nine of the authors perform a visual inspection. Roughly 75 per cent of the systems are classified as likely lenses by at least one of the authors. Finally, we assemble the LIVE sample (Lenses In VoicE) composed by the 16 systems passing the chosen grading threshold. Three of these candidates show likely lensing features when observed by the Hubble Space Telescope. This work represents a further confirmation of the ability of CNNs to inspect large samples of galaxies searching for gravitational lenses. These algorithms will be crucial to exploit the full scientific potential of forthcoming surveys with the Euclid satellite and the Vera Rubin Observatory. [ABSTRACT FROM AUTHOR]

Oxidative stress and lipid peroxidation (LPO) induced by inflammation, excess metal storage and excess caloric intake cause generalized DNA damage, producing genotoxic and mutagenic effects. The consequent deregulation of cell homeostasis is implicated in the pathogenesis of a number of malignancies and degenerative diseases. Reactive aldehydes produced by LPO, such as malondialdehyde, acrolein, crotonaldehyde and 4-hydroxy-2-nonenal, react with DNA bases, generating promutagenic exocyclic DNA adducts, which likely contribute to the mutagenic and carcinogenic effects associated with oxidative stress-induced LPO. However, reactive aldehydes, when added to tumor cells, can exert an anticancerous effect. They act, analogously to other chemotherapeutic drugs, by forming DNA adducts and, in this way, they drive the tumor cells toward apoptosis. The aldehyde-DNA adducts, which can be observed during inflammation, play an important role by inducing epigenetic changes which, in turn, can modulate the inflammatory process. The pathogenic role of the adducts formed by the products of LPO with biological macromolecules in the breaking of immunological tolerance to self antigens and in the development of autoimmunity has been supported by a wealth of evidence. The instrumental role of the adducts of reactive LPO products with self protein antigens in the sensitization of autoreactive cells to the respective unmodified proteins and in the intermolecular spreading of the autoimmune responses to aldehyde-modified and native DNA is well documented. In contrast, further investigation is required in order to establish whether the formation of adducts of LPO products with DNA might incite substantial immune responsivity and might be instrumental for the spreading of the immunological responses from aldehyde-modified DNA to native DNA and similarly modified, unmodified and/or structurally analogous self protein antigens, thus leading to autoimmunity. [ABSTRACT FROM AUTHOR]

As current research illuminates the dynamic interplay between the innate and acquired immune responses, the interaction and communication between these two arms has yet to be fully investigated. Polymorphonuclear neutrophils (PMNs) and interferon-γ (IFN-γ) are known critical components of innate and acquired immunity, respectively. However, recent studies have demonstrated that these two components are not entirely isolated. Treatment of PMNs with IFN-γ elicits a variety of responses depending on stimuli and environmental conditions. These responses include increased oxidative burst, differential gene expression, and induction of antigen presentation. Many of these functions have been overlooked in PMNs, which have long been classified as terminal phagocytic cells incapable of protein synthesis. As this review reports, the old definition of the PMN is in need of an update, as these cells have demonstrated their ability to mediate the transition between the innate and acquired immune responses. [ABSTRACT FROM AUTHOR]

Exposure of Chinese hamster ovary, mouse adrenal cortex tumor (Y-l), THP-1 and U-937 cells and human erythrocytes to adenylate-cyclase-containing urea extracts of Bordetella pertussis (strain 114) organisms promotes the formation of large concentrations of intracellular cAMP. Accumulation is dependent on dose and temperature, with significant accumulation occurring at 4°C, and is virtually instantaneous, with a doubling at 1 min. There is an absolute Ca2+ requirement but external caimodulin (the activator of cyclase activity) has no effect except in erythrocytes and U-937 cells, where it reduces cAMP accumulation. However, calmodulin antagonists inhibit cAMP accumulation. In Y-I adrenal cells the urea-extract adenylate cyclase stimulates steroidogenesis. Anti-(B. pertussis) antibodies inhibit cyclase activity and prevent further cAMP accumulation after 10 min in cells previously exposed to urea extract. The same effect is obtained by washing. This suggests that a portion of the cyclase is associated with cells in a form not accessible to antibody or washing but accessible to substrate, which we interpret as internalized enzyme with a short lifetime. Continuing cAMP accumulation thus appears to need a continuing source of external cyclase. lnhibitors of the effect of diphtheria toxin, such as NH4Cl, methylamine, chloroquin or monensin, have no inhibitory effect on the accumulation of intracelluar cAMP promoted by the internalized adenylate cyclase of urea extracts of B. pertussis organisms. We conclude that entry of the cyclase into cells is not by receptor-mediated endocytosis. [ABSTRACT FROM AUTHOR]

The sites and the sequence of the proteolytic cleavages of bovine, human and rat thyroglobulin, during the limited proteolysis with thermolysin and trypsin, were determined by sequencing the NH2 termini of the peptides produced and comparing them to the cDNA-derived sequences of bovine, human and rat thyroglobulin included residues 240, 502, 993, 1218, 1784 with thermolysin, and 240, 520, 1142, 1783, 2515 with trypsin. Cleavage sites of human thyroglobulin included residues 503, 982, 990, 1405, 1831 with thermolysin, and 522, 1627, 2513 with trypsin. Those of rat thyroglobulin included residues 501, 1776, 1784 with thermolysin, and 522, 1771, 1825, 2515 with trypsin (numbered as in bovine thyroglobulin). Thus, thyroglobulin from various species presents well localized and conserved regions particularly sensitive to protcolysis. The most sensitive region extended for 30 residues after residue 500. Another major cluster of cleavages was centered around residue 1800: this region was only partially sensitive in human thyroglobulin. A conserved tryptic site lay at the COOH terminus of the molecule. Most cleavage sites occurred within the inserted sequences that disrupt the Cys-rich, tandem repeats of thyroglobulin and either contain or are located near exon-intron junction. Several cleavage sites lay in proximity of early iodinated or hormonogenic tyrosyl residues or of putative N-linked glycosylation sites. While a predominantly –-type secondary structure and a rigid three-dimensional structure were interspersed in the regions surrounding the cleavage sites. These data demonstrate the existence of conserved regions of thyroglobulin inherently sensitive to proteolysis, which most likely represent solvent-exposed regions of the primary structure, possibly forming loops at the surface of thyroglobulin. [ABSTRACT FROM AUTHOR]

Purpose: To assess age at 1st central retinal vein occlusion (CRVO) in carriers ≤ 45 years old of the methylenetetrahydrofolate reductase (MTHFR) C667T genotype compared to heterozygous and wild type, and to identify predictors of age at CRVO. Methods: Retrospective cohort study consisting of 18 MTHFR TT, 23 MTHFR TC and 28 MTHFR CC participants; information regarding age, sex, age at CRVO, history of dyslipidaemia, hypertension, smoking and plasma HC measured by immunoassay were collected. Results: Age at CRVO was lower in MTHFR TT than MTHFR TC and CC (32 ± 6 vs 38 ± 5 vs 37 ± 6 years, respectively, p = 0.005); plasma HC was higher in MTHFR TT than in the other genotypes [14.4 (10.8, 19.6) vs 10.4 ((8.6,12.5) vs 8.5 ((7.5,9.8) μmol/l, p = 0.0002). Smoking (cigarettes/day) independently predicted age at CRVO (p = 0.039) and plasma HC (p = 0.005); smoking status (yes/no) predicted ischemic CRVO (p = 0.01) that was more common in the MTHFR TT group (p = 0.006). Conclusions: Carriers of the MTHFR TT genotype ≤ 45 years old develop their 1st CRVO on average 5 years earlier than the MTHFR CC genotype; smoking contributes to the prematurity and severity of CRVO in MTHFR TT carriers. [ABSTRACT FROM AUTHOR]

About 12 billion years ago, the Universe was first experiencing light again after the dark ages, and galaxies filled the environment with stars, metals, and dust. How efficient was this process? How fast did these primordial galaxies form stars and dust? We can answer these questions by tracing the star formation rate density (SFRD) back to its widely unknown high-redshift tail, traditionally observed in the near-infrared (NIR), optical, and UV bands. Thus, objects with a large amount of dust were missing. We aim to fill this knowledge gap by studying radio-selected NIR-dark (RS-NIRdark) sources, i.e., sources not having a counterpart at UV-to-NIR wavelengths. We widen the sample of Talia et al. from 197 to 272 objects in the Cosmic Evolution Survey (COSMOS) field, including also photometrically contaminated sources, which were previously excluded. Another important step forward consists in the visual inspection of each source in the bands from u * to MIPS 24 μ m. According to their "environment" in the different bands, we are able to highlight different cases of study and calibrate an appropriate photometric procedure for the objects affected by confusion issues. We estimate that the contribution of RS-NIRdark sources to the cosmic SFRD at 3 < z < 5 is ∼10%–25% of that based on UV-selected galaxies. [ABSTRACT FROM AUTHOR]

To evaluate the intima media thickness of carotid arteries (IMT) and its clinical, laboratory and treatment correlates in Behcet's disease (BD). Systematic search of EMBASE and PubMed databases from January 2016 to October 2022; we employed random effect meta-analyses for continuous outcomes and Peto's odds ratio for rare events. The meta-analysis included 36 case control studies: the IMT was greater in BD (n = 1103) than in controls (n = 832) (p < 0.0001) with wide heterogeneity (I2 = 86.9%); a sensitivity analysis that included mean age of BD participants, gender, disease duration and activity, atherogenic index of plasma, blood pressure, C-reactive protein, ethnicity, smoking status, anti-inflammatory and immune suppressive agents, revealed that male gender, mean age of participants and azathioprine use (the latter two in inverse fashion) partly explained the heterogeneity variance (p = 0.02, p = 0.005, and p = 0.01). The IMT was greater in vascular (n = 114) than in non-vascular BD (n = 214) (p = 0.006). BD patients (n = 782) had a greater pooled prevalence of carotid plaques than controls (n = 537) (13.1% vs. 2.97%, p < 0.0001). Subclinical carotid artery atherosclerosis represents a vascular feature of BD, independently of the traditional cardiovascular risk factors. The inverse correlations between IMT, age and azathioprine use suggest that thicker carotid arteries at disease onset eventually regress with immune suppressive treatment: this assumption needs verification on adequately designed clinical trials. [ABSTRACT FROM AUTHOR]

A growing number of far-infrared (FIR) bright sources completely invisible in deep extragalactic optical surveys hint at an elusive population of z > 4 dusty, star-forming galaxies. Cycle 1 JWST surveys are now detecting their rest-frame optical light, which provides key insight into their stellar properties and statistical constraints on the population as a whole. This work presents the JWST Near Infrared Camera (NIRCam) counterpart from the COSMOS-Web survey to an FIR SCUBA-2 and Atacama Large Millimeter/submillimeter Array (ALMA) source, AzTECC71, which was previously undetected at wavelengths shorter than 850 μ m. AzTECC71, among the reddest galaxies in COSMOS-Web with F277W − F444W ∼ 0.9, is undetected in NIRCam/F150W and F115W and fainter in F444W than other submillimeter galaxies identified in COSMOS-Web by 2–4 magnitudes. This is consistent with the system having both a lower stellar mass and higher redshift than the median dusty, star-forming galaxy. With deep ground- and space-based upper limits combined with detections in F277W, F444W, and the FIR including ALMA Band 6, we find a high probability (99%) that AzTECC71 is at z > 4 with z phot = 5.7 − 0.7 + 0.8 . This galaxy is massive ( log M * / M ⊙ ∼ 10.7) and infrared-luminous ( log L IR / L ⊙ ∼ 12.7), comparable to other optically undetected but FIR-bright dusty, star-forming galaxies at z > 4. This population of luminous, infrared galaxies at z > 4 is largely unconstrained but comprises an important bridge between the most extreme dust-obscured galaxies and more typical high-redshift star-forming galaxies. If further FIR-selected galaxies that drop out of the F150W filter in COSMOS-Web have redshifts z > 4 like AzTECC71, then the volume density of such sources may be ∼3–10 × greater than previously estimated. [ABSTRACT FROM AUTHOR]

We investigate the ability of human 'expert' classifiers to identify strong gravitational lens candidates in Dark Energy Survey like imaging. We recruited a total of 55 people that completed more than 25 per cent of the project. During the classification task, we present to the participants 1489 images. The sample contains a variety of data including lens simulations, real lenses, non-lens examples, and unlabelled data. We find that experts are extremely good at finding bright, well-resolved Einstein rings, while arcs with g -band signal to noise less than ∼25 or Einstein radii less than ∼1.2 times the seeing are rarely recovered. Very few non-lenses are scored highly. There is substantial variation in the performance of individual classifiers, but they do not appear to depend on the classifier's experience, confidence or academic position. These variations can be mitigated with a team of 6 or more independent classifiers. Our results give confidence that humans are a reliable pruning step for lens candidates, providing pure and quantifiably complete samples for follow-up studies. [ABSTRACT FROM AUTHOR]

Thrombosis associated with thrombocytopaenia is an apparent paradox that is present across a wide spectrum of disorders. While thrombocytopaenia has been a controversial clinical classification criterion for APS, as initial reports failed to demonstrate a relation between low platelet count with other clinical or laboratory manifestations of the syndrome, recent data highlight the association between mild–moderate thrombocytopaenia and the risk of thrombosis. Although aPL antibodies may induce platelet activation in vitro , additional stimuli may contribute to their activation in vivo , among which are reactive oxygen and nitrogen species and lipid peroxidation products, which are elevated in patients with APS; an excess of the same stimuli may induce megakaryocyte and platelet apoptosis that leads to decreased platelet production and increased destruction, resulting ultimately in thrombocytopaenia. Herein we provide a novel plausible framework involving free radicals that could add to the understanding of the thrombocytopaenia–thrombosis paradox in APS. [ABSTRACT FROM AUTHOR]

To investigate whether age at first presentation of pure peripheral arterial thrombosis (PAT) in lower and upper limbs and in the splanchnic circulation occurs earlier in carriers of the methylenetetrahydrofolate reductase (MTHFR) T677T genotype compared to the heterozygous and wild type and to identify predictors of a possible earlier onset. Retrospective cohort study on 27 MTHFR TT, 29 MTHFR TC and 29 MTHFR CC participants; data regarding age, sex, age at PAT, clinical history (dyslipidaemia, hypertension, smoking, obesity) and homocysteine (HC) measured by immunoassay were collected. Age at PAT was lower in MTHFR TT than MTHFR TC and CC (43 ± 9 vs 47 ± 9 vs 51 ± 4 years, respectively, p = 0.02); plasma HC was higher in MTHFR TT than in the other groups (25 ± 19 vs 12.7 ± 6.7 vs 11.3 ± 3.3 μmol/l, respectively, p < 0.001) while the activated partial thromboplastin ratio (aPTTr) was lower in MTHFR TT than in other genotypes (0.90 ± 0.10 vs 0.97 ± 0.12 vs 0.97 ± 0.08 μmol/L p < 0.001). Among categorical variables, MTHFR TT and dyslipidaemia independently predicted age at AT (p = 0.01 & p = 0.03, respectively) whereas among the continuous variables HC independently predicted age at PAT (p = 0.02) as well as the aPTTr (p = 0.001); smoking predicted lower limb PAT (p = 0.005). MTHFR TT carriers develop their first PAT an average of 4 and 8 years earlier than MTHF CT and CC genotypes; MTHFR TT, dyslipidaemia and plasma HC contribute to the prematurity of the PAT while the interplay between elevated HC and smoking may affect type of arterial district occlusion. [ABSTRACT FROM AUTHOR]

Background and Aim: Age at portal vein thrombosis (PVT) in liver cirrhosis (LC) carriers of the methylene tetrahydrofolate reductase (MTHFR) rs1801133 (C → T667 transition) polymorphism has never been addressed; we compared age at PVT in LC patients genotyped for the MTHFR and explored the interrelated clinical and laboratory factors predicting age at PVT. Approach and Results: Retrospective cross-sectional cohort study. PVT participants: MTHFR CC n = 36, MTHFR CT n = 53, MTHFR TT n = 19; age, sex, age at PVT, Child–Pugh score, rs1799963 PT polymorphisms (G → A 20,210 transition), plasma HC and natural anticoagulants available for all participants. Age at PVT was lower in MTHFR TT than CT and CC (56 ± 13 vs. 57 ± 13 vs. 64 ± 9 years, p = 0.001); median (IQR) plasma HC was higher in MTHFR TT than in the other groups [(17 (9.4, 23.3) vs 13 (8,14.7) vs 11 (8.9, 12.7) μmol/l, p = 0.03)]. MTHFR TT, male gender and protein C predicted age at PVT (p = 0.02, p = 0.04 and p = 0.08); MTHFR TT and Child–Pugh score predicted plasma HC (p = 0.005 and p = 0.01) as well as low plasma protein C (p < 0.0001 and p = 0.0002). Plasma HC inversely related to protein C in the MTHFR TT group (p < 0.0001). Compound MTHFR TT with PT GA had lower age at PVT compared to MTHFR TT alone (49 ± 18 vs 58 ± 12 years). Conclusions: MTHFR TT anticipates PVT associated with LC by an average of 8 years; MTHFR TT associates with severity of liver disease and to high plasma HC; the latter may contribute to the prematurity of PVT by interfering with the anticoagulant activity of protein C. [ABSTRACT FROM AUTHOR]

Background: Several autoimmune skin disorders are characterised by an increased risk of thrombosis, with bollous pemphigoid carrying a higher risk than pemphigus vulgaris (PV). We describe the case of a middle aged gentleman who developed recurrent venous thromboembolism despite adequate oral anticoagulation during very active PV that required escalation of treatment to bring the disease under control. Case presentation: In May 2014 a 49 year gentleman was admitted for widespread mucocutaneous blistering diagnosed as PV by histology and immunofluorescence. After 6 weeks of treatment with systemic steroids and azathioprine the patient developed pulmonary emboli and started oral anticoagulation with warfarin. In late September, the patient re-presented with a severe flare of PV and a recurrent deep vein thrombosis despite oral anticoagulation within therapeutic range. Warfarin was changed to subcutaneous low molecular heparin in therapeutic dose while treatment for pemphigus was escalated: first azathioprine was switched to mycophenolate mofetil and the steroids dose increased; then due to poor response, intravenous immunoglobulins were given for three courses and finally he received four infusions of Rituximab that induced sustained remission. In April 2015 the dose of mycophenolate was decreased but anticoagulation was continued until the beginning of July 2015 to ensure that decreasing immune suppression did not allow the emergence of another flare with attendant thrombotic risk. Conclusion: The case highlights the risk of thrombosis and re-thrombosis in aggressive PV and demands further clinical research in this area to assess the need for thromboprophylaxis in aggressive bollous skin disease. [ABSTRACT FROM AUTHOR]

Introduction/objective: The relationship between autoimmune haemolytic anaemia (AIHA) and antiphospholipid antibodies (aPL) has never been addressed via a meta-analysis in the paediatric age group. We evaluated the link between AIHA and aPL in childhood systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS). Methods: EMBASE and PubMed were screened from inception to May 2020 and Peto's odds ratio for rare events was employed for the between group comparisons. Results: The meta-analysis included 11 articles for a total of 575 children: the pooled prevalence of AIHA was greater in (1) IgG aCL–positive than IgG aCL–negative children (39.7% vs 20.9%, p = 0.005); (2) in APS-positive than APS-negative SLE children (36.8% vs 13.2%, p = 0.01); and (3) in SLE-related APS than in primary APS children (53% vs 16.2%, p = 0.008). Conclusions: The pooled prevalence of AIHA is greatest in SLE with aPL/APS, low-moderate in SLE without aPL/APS, and lowest in primary APS. Key Points • Antiphospholipid antibodies strongly relate to autoimmune haemolytic anaemia. • Autoimmune haemolytic anaemia is more common in systemic lupus erythematosus with antiphospholipid antibodies. [ABSTRACT FROM AUTHOR]

Introduction: The relationship between autoimmune hemolytic anemia and antiphospholipid antibodies (aPL) and/or antiphospholipid syndrome has never been systematically addressed. Methods: Systematic review of EMBASE and PubMed databases performed according to PRISMA guidelines from inception to March 2020; meta‐analysis performed by Peto's odds ratio for rare events. Findings Forty‐five studies with different outcomes met the inclusion/exclusion criteria. The pooled prevalence (PP) of IgG anticardiolipin antibodies (aCL) positivity was greater in end‐stage renal disease (ESRD) than controls (20.2% vs. 2.6%, P = 0.001, I2 >80%; I2 = heterogeneity), particularly in hemodialysis patients (18.3% vs. 8%, I2 = 0%). The PP of lupus anticoagulant was greater in ESRD than controls (8.7% vs. 0.2%, P < 0.0001, I2 = 0%). The standardized mean difference of IgG aCL favored ESRD rather than controls (P < 0.0001, I2 =97%). The PP of fistula occlusion was greater in IgG aCL‐positive patients than negative patients (39% vs. 27%, I2 =97%); the PP of IgG aCL positivity was greater in patients with fistula occlusion than without fistula occlusion (26.9% vs. 23.2%, P = 0.01, I2 =72%); the same applied to the PP of lupus anticoagulant positivity (23% vs. 0.3%, P < 0.0001, I2 = 0%). The standardized mean difference of IgG aCL favored fistula occlusion (P = 0.004, I2 = 91%). Discussion Lupus anticoagulant relates to ESRD regardless of management whereas IgG aCL relates specifically to ESRD on hemodialysis, but only lupus anticoagulant associates with fistula occlusion. The expression of aPL as patients positive for aPL rather than as titers precludes further assumptions on the relationship. [ABSTRACT FROM AUTHOR]

Prothrombin fragment F1 + 2 (F1 + 2) and thrombin–antithrombin (TAT) have been assessed in antiphospholipid syndrome (APS) but without evaluating a direct relationship with antiphospholipid (aPL) antibody titers. This article aims to investigate a direct relationship between aPL and F1 + 2 and perform a systematic review and meta-analysis of F1 + 2 and TAT in APS. Systematic search was performed using EMBASE and PubMed databases from January 1982 to December 2018 and random effects meta-analyses for continuous outcomes. This is a cross-sectional case–control study; immunoglobulin G/immunoglobulin M (IgG/IgM) anticardiolipin (aCL) anti-β 2 -glycoprotein-I, antiprothrombin (aPT) antibodies, F1 + 2, and lupus anticoagulants (LA) were measured in 25 thrombotic primary APS (PAPS), 9 nonthrombotic carriers of aPL, and 18 controls. The significant effect size (ES) for F1 + 2 between aPL +ve and aPL −ve systemic lupus erythematosus (SLE) and between aPL +ve SLE and control displayed high heterogeneity. The significant ES for F1 + 2 between aPL −ve SLE and controls displayed no heterogeneity. The ES for TAT between aPL +ve and aPL −ve SLE patients and between aPL −ve SLE and controls was low, without heterogeneity. Mean F1 + 2 was greater in PAPS ( p  < 0.0001), inversely correlated with IgG aCL, IgM aPT, and LA ( p  = 0.001, 0.03, and 0.01, respectively), though only IgG aCL negatively predicted F1 + 2 ( p  = 0.01). IgG aCL inversely predicts F1 + 2. IgG aCL positivity introduces heterogeneity in the F1 + 2 ES, whereas the lack of heterogeneity in the ES for TAT may indicate poor TAT formation in aPL +ve group. Thus, F1 + 2 measurements may be unfounded as already demonstrated for TAT in the 1990s. [ABSTRACT FROM AUTHOR]

Systemic sclerosis (SSc) is a multisystem autoimmune disease: characterised from the clinical side by progressive vasculopathy and fibrosis of the skin and different organs and from the biochemical side by fibroblast deregulation with excessive production of collagen and increased expression of nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4). The latter contributes to an overproduction of reactive oxygen species that through an autocrine loop maintains NOX4 in a state of activation. Reactive oxygen and nitrogen species are implicated in the origin and perpetuation of several clinical manifestations of SSc having vascular damage in common; attempts to dampen oxidative and nitrative stress through different agents with antioxidant properties have not translated into a sustained clinical benefit. Objective of this narrative review is to describe the origin and clinical implications of oxidative and nitrative stress in SSc, with particular focus on the central role of NOX4 and its interactions, to re-evaluate the antioxidant approaches so far used to limit disease progression, to appraise the complexity of antioxidant treatment and to touch on novel pathways elements of which may represent specific treatment targets in the not so distant future. [ABSTRACT FROM AUTHOR]

Aim.To investigate possible abnormalities of vasoactive compounds, nitrative stress, and antioxidant activity of paraoxonase (PONa) in human hepatopulmonary syndrome (HPS), we determined endothelin-1 (ET), nitric oxide (NOx) metabolites, PONa alongside crude plasma nitrotyrosine (NT) as surrogate marker of nitrative stress.Material and methods.Liver cirrhosis (LC) patients with HPS (n= 12) were matched by age, sex, and Child–Pugh score to LC patients without HPS (n= 15) and to healthy controls (CTR) (n= 15); plasma NO2−(nitrite) (vascular metabolite), NO3−(nitrate) (inflammatory metabolite), and PONa were determined by a colorimetric assay, ET, and NT by immunoassays.Results.HPS patients showed higher level of ET (p= 0.0002), NO2−(p= 0.002), NO3−(p= 0.0001), NT (p< 0.0001), and lower PONa (p= 0.0004) than CTR;post-hocanalysis revealed greater ET (p< 0.05) and NO3−(p< 0.005) in LC patients with HPS than in LC patients without HPS. NT correlated to Child–Pugh score within HPS (p= 0.04) and LC (p= 0.02).Conclusion.Our HPS patients are characterized by elevated plasma levels of ET and NOx metabolites and lower PONa. Reduced PONa alongside elevated NO3−and NT suggests that defective antioxidation may favor nitrative stress and both may be implicated in the pathogenesis of HPS. [ABSTRACT FROM AUTHOR]

Significance: Oxidative stress provokes the peroxidation of polyunsaturated fatty acids in cellular membranes, leading to the formation of aldheydes that, due to their high chemical reactivity, are considered to act as second messengers of oxidative stress. Among the aldehydes formed during lipid peroxidation (LPO), 4-hydroxy-2-nonenal (HNE) is produced at a high level and easily reacts with both low-molecular-weight compounds and macromolecules, such as proteins and DNA. In particular, HNE-protein adducts have been extensively investigated in diseases characterized by the pathogenic contribution of oxidative stress, such as cancer, neurodegenerative, chronic inflammatory, and autoimmune diseases. Recent Advances: In this review, we describe and discuss recent insights regarding the role played by covalent adducts of HNE with proteins in the development and evolution of those among the earlier mentioned disease conditions in which the functional consequences of their formation have been characterized. Critical Issues: Results obtained in recent years have shown that the generation of HNE-protein adducts can play important pathogenic roles in several diseases. However, in some cases, the generation of HNE-protein adducts can represent a contrast to the progression of disease or can promote adaptive cell responses, demonstrating that HNE is not only a toxic product of LPO but also a regulatory molecule that is involved in several biochemical pathways. Future Directions: In the next few years, the refinement of proteomical techniques, allowing the individuation of novel cellular targets of HNE, will lead to a better understanding the role of HNE in human diseases. Antioxid. Redox Signal. 22, 1681-1702. [ABSTRACT FROM AUTHOR]

A tryptic fragment (b5TR,NR), encompassing residues 2515-2750, was isolated from a low-iodine (0.26% by mass) bovine thyroglobulin, by limited proteolysis with trypsin and preparative, continuous-elution SDS-PAGE. The fragment was digested with Asp-N endoproteinase and analyzed by reverse-phase HPLC electrospray ionization quadrupole time-of-flight mass spectrometry, revealing the formation of: 3-monoiodotyrosine and dehydroalanine from Tyr2522; 3-monoiodotyrosine from Tyr2555 and Tyr2569; 3-monoiodotyrosine and 3,5-diiodotyrosine from Tyr2748. The data presented document, by direct mass spectrometric identifications, efficient iodophenoxyl ring transfer from monoiodinated hormonogenic donor Tyr2522 and efficient mono- and diiodination of hormonogenic acceptor Tyr2748, under conditions which permitted only limited iodination of Tyr2555 and Tyr2569, in low-iodine bovine thyroglobulin. The present study thereby provides: (1) a rationale for the preferential synthesis of T3 at the carboxy-terminal end of thyroglobulin, at low iodination level; (2) confirmation for the presence of an interspecifically conserved hormonogenic donor site in the carboxy-terminal domain of thyroglobulin; (3) solution for a previous uncertainty, concerning the precise location of such donor site in bovine thyroglobulin. [ABSTRACT FROM AUTHOR]

We localized the site of type D (chondroitin 6-sulfate) oligosaccharide unit addition to human thyroglobulin (hTg). hTg was chromatographically separated into chondroitin 6-sulfate-containing (hTg-CS) and chondroitin 6-sulfate-devoid (hTg-CS0) molecules on the basis of their D-glucuronic acid content. In an ample number of hTg preparations, the fraction of hTg-CS in total hTg ranged from 32.0 to 7 1.6%. By exploiting the electrophoretic mobility shift and metachromasia conferred by chondroitin 6-sulfate upon the products of limited proteolysis of hTg, chondroitin 6-sulfate was first restricted to a carboxyl-terminal region, starting at residue 2514. A single chondroitin 6-sulfate-containing nonapeptide was isolated in pure form from the products of digestion of hTg with endoproteinase Glu-C, and its sequence was determined as LTAGXGLRE (residues 2726-2734, X being Ser2730 linked to the oligosaccharide chain). In an in vitro assay of enzymatic iodination, hTg-CS produced higher yields of 3,5,5′-triiodothyronine (T3) (171%) and 3,5,3′,5′ -tetraiodothyronine (T4) (134%) than hTg-CS0. Unfractionated hTg behaved as hTg-CS. Thus, chondroitin 6-sulfate addition to a subset of hTg molecules enhanced the overall level of T4 and, in particular, T3 formation. Furthermore, the chondroitin 6-sulfate oligosaccharide unit of hTg-CS protected peptide bond Lys2714-Gly2715 from proteolysis, during the limited digestion of hTg-CS with trypsin. These findings provide insights into the molecular mechanism of regulation of the hormonogenic efficiency and of the T4/T3 ratio in hTg. The potential implications in the ability of hTg to function as an autoantigen and into the pathogenesis of thyroidal and extra-thyroidal manifestations of autoimmune thyroid disease are discussed. [ABSTRACT FROM AUTHOR]

Methylation in vivo is a post-translational modification observed in several organisms belonging to eucarya, bacteria, and archaea. Although important implications of this modification have been demonstrated in several eucaryotes, its biological role in hyperthermophillc archaea is far from being understood. The aim of this work is to clarify some effects of methylation on the properties of β-glycosidase from Sulfolobus solfataricus, by a structural comparison between the native, methylated protein and its unmethylated counterpart, recombinantly expressed in Escherichia coli. Analysis by Fourier transform infrared spectroscopy indicated similar secondary structure contents for the two forms of the protein. However, the study of temperature perturbation by Fourier transform infrared spectroscopy and turbidimetry evidenced denaturation and aggregation events moro pronounced in recombinant than in native β-glycosidase. Red Nile fluorescence analysis revealed significant differences of surface hydrophobicity between the two forms of the protein. Unlike the native enzyme, which dissociated into SDS-rosistant dimers upon exposure to the detergent, the recombinant enzyme partially dissociated into monomers. By electrospray mapping, the methylation sites of the native protein were identified. A computational analysis of β-glycosidase three-dimensional structuro and comparisons with other proteins from S. solfataricus revealed analogies in the localization of methylation sites in terms of secondary structural elements and overall topology. These observations suggest a role for the methylation of lysyl residues, located in selected domains, in the thermal stabilization of β-giycosidase from S. solfataricus. [ABSTRACT FROM AUTHOR]

The perturbation induced by mono- and divalent cations on the thermophilicity and thermostability of Solfolobus solfataricus β-glycosidase, a hyperthermophilic tetrameric enzyme, has been investigated by spectroscopic and computational simulation methods to ascertain the Hofmeister effects on two strategic protein regions identified previously. Specifically, (1) an extra segment (83–124), present only in the sequence of hyperthermophilic glycosidases and recognized as an important thermostability determinant for the enzyme structure; and (2) a restricted area of the subunit interface responsible for the quaternary structure maintenance. Mono- and divalent cations inhibit to a different extent the β-glycosidase activity, whose kinetic constants show an apparent competitive inhibition of the catalytic process that reflects the Hofmeister order. The thermostability is also affected by the nature and charge of the cations, reaching maximal effects for the case of Mg[sup 2+]. Fourier transform infrared spectroscopy has revealed very small changes in the protein secondary structure in the presence of the investigated cations at 20 °C, while large effects on the protein melting temperatures are observed. Computational analysis of the enzyme structure has identified negative patches on the accessible surface of the two identified regions. Following the Hofmeister series, cations weaken the existing electrostatic network that links the extra segment to the remaining protein matrix. In particular, the perturbing action of cations could involve the ionic pair interactions E107–R245 and E109–R185, thus leading to a local destructuring of the extra segment as a possible starting event for thermal destabilization. A detailed investigation of the electrostatic network at the A–C intermolecular interface of Sβgly after energy minimization suggests that cations could cause a strong attenuation of the ion pair interactions E474–K72 and D473–R402, with consequent partial dissociation of the tetrameric structure. [ABSTRACT FROM AUTHOR]

Alzheimer's disease is a neurodegenerative disorder whose pathological mechanisms, despite recent advances, are not fully understood. However, the deposition of beta amyloid -peptide and neuroinflammation, which is probably aggravated by dysbiotic microbiota, seem to play a key role. Anti-Gal are the most abundant xenoreactive natural antibodies. They are supposed to stem from immunization against the gut microbiota and have been implicated in the pathogenesis of several diseases, including multiple sclerosis. These antibodies target the alpha-Gal epitope, expressed on the terminal sugar units of glycoprotein or glycolipid of all mammals except apes, Old World monkeys and humans. The alpha-Gal is constitutively expressed in several bacteria constituting the brain microbiota, and alpha-Gal-like epitopes have been detected in gray matter, amyloid plaque, neurofibrillary tangles and corpora amylacea of the human brain, suggesting a potential link between anti-Gal and Alzheimer's disease etiopathogenesis. For the first time, our study searched for possible alterations of anti-Gal immunoglobulin levels in Alzheimer's disease patients. IgG and IgM blood levels were significantly lower, and IgA significantly higher in patients than in healthy subjects. These results suggest that such immunoglobulins might be implicated in Alzheimer's disease pathogenesis and open new scenarios in the research for new biomarkers and therapeutic strategies. [ABSTRACT FROM AUTHOR]

Abstract: We describe a case of brainstem infection by Listeria monocytogenes with right oculomotor palsy and lip drop, facial hypoesthesia, left arm paresthesia, positive blood culture, and sterile liquor in a 63-year-old man. Magnetic resonance imaging revealed an isolated mesencephalic lesion. Localization of this kind accounted for 3% of 111 cases reviewed. [Copyright &y& Elsevier]

The relationship between antiphospholipid antibodies (aPL) and autoimmune haemolytic anaemia (AIHA) has never been systematically addressed. The aim of this study is to assess the link between aPL and AIHA in adult systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS). This study performed an EMBASE/PubMed search from inception to June 2019 and meta-analysis using Peto's odds ratios. The pooled prevalence (PP) of IgG/IgM anticardiolipin (aCL) and lupus anticoagulant (LA) was greater in AIHA +ve than AIHA −ve patients (34.7% vs. 27.6%, p = 0.03; 33.3% vs. 21.8%, p < 0.0001; 20.9% vs. 8.3%, p = 0.01). The PP of AIHA was greater in: (1) IgG and IgM aCL +ve than −ve patients (21.8% vs. 11.1%, p = 0.001 and 18.7% vs. 6.3%, p < 0.0001), (2) in SLE related APS than in primary APS patients (22.8% vs. 3.9% p < 0.0001), (3) in APS +ve than APS −ve SLE patients (23.2% vs. 8.4%, p = 0.01), and (4) in thrombotic APS than non-thrombotic APS/SLE patients (26.8% vs. 10%, p = 0.03). The PP of IgG/IgM aCL and LA was greater in DAT +ve than DAT −ve patients (42.4% vs. 12.8%, p < 0.0001; 26.2% vs. 12.8%, p = 0.03 and 29.2% vs. 15.7%, p = 0.004 respectively). It was found that AIHA prevalence is maximal in SLE with aPL/APS, low-moderate in SLE without aPL and minimal in PAPS. Moreover, AIHA is rightly included among the classification criteria for SLE but not for APS/aPL. The significance of an isolated DAT positivity remains unclear in this setting [ABSTRACT FROM AUTHOR]