Hydroxychloroquine is associated with a lower risk of polyautoimmunity: data from the RELESSER Registry

OBJECTIVES: This article estimates the frequency of polyautoimmunity and associated factors in a large retrospective cohort of patients with SLE. METHODS: RELESSER (Spanish Society of Rheumatology Lupus Registry) is a nationwide multicentre, hospital-based registry of SLE patients. This is a cross-sectional study. The main variable was polyautoimmunity, which was defined as the co-occurrence of SLE and another autoimmune disease, such as autoimmune thyroiditis, RA, scleroderma, inflammatory myopathy and MCTD. We also recorded the presence of multiple autoimmune syndrome, secondary SS, secondary APS and a family history of autoimmune disease. Multiple logistic regression analysis was performed to investigate possible risk factors for polyautoimmunity. RESULTS: Of the 3679 patients who fulfilled the criteria for SLE, 502 (13.6%) had polyautoimmunity. The most frequent types were autoimmune thyroiditis (7.9%), other systemic autoimmune diseases (6.2%), secondary SS (14.1%) and secondary APS (13.7%). Multiple autoimmune syndrome accounted for 10.2% of all cases of polyautoimmunity. A family history was recorded in 11.8%. According to the multivariate analysis, the factors associated with polyautoimmunity were female sex [odds ratio (95% CI), 1.72 (1.07, 2.72)], RP [1.63 (1.29, 2.05)], interstitial lung disease [3.35 (1.84, 6.01)], Jaccoud arthropathy [1.92 (1.40, 2.63)], anti-Ro/SSA and/or anti-La/SSB autoantibodies [2.03 (1.55, 2.67)], anti-RNP antibodies [1.48 (1.16, 1.90)], MTX [1.67 (1.26, 2.18)] and antimalarial drugs [0.50 (0.38, 0.67)]. CONCLUSION: Patients with SLE frequently present polyautoimmunity. We observed clinical and analytical characteristics associated with polyautoimmunity. Our finding that antimalarial drugs protected against polyautoimmunity should be verified in future studies

Measurement of the Bottom-Strange Meson Mixing Phase in the Full CDF Data Set

We report a measurement of the bottom-strange meson mixing phase \beta_s using the time evolution of B0_s -> J/\psi (->\mu+\mu-) \phi (-> K+ K-) decays in which the quark-flavor content of the bottom-strange meson is identified at production. This measurement uses the full data set of proton-antiproton collisions at sqrt(s)= 1.96 TeV collected by the Collider Detector experiment at the Fermilab Tevatron, corresponding to 9.6 fb-1 of integrated luminosity. We report confidence regions in the two-dimensional space of \beta_s and the B0_s decay-width difference \Delta\Gamma_s, and measure \beta_s in [-\pi/2, -1.51] U [-0.06, 0.30] U [1.26, \pi/2] at the 68% confidence level, in agreement with the standard model expectation. Assuming the standard model value of \beta_s, we also determine \Delta\Gamma_s = 0.068 +- 0.026 (stat) +- 0.009 (syst) ps-1 and the mean B0_s lifetime, \tau_s = 1.528 +- 0.019 (stat) +- 0.009 (syst) ps, which are consistent and competitive with determinations by other experiments.Comment: 8 pages, 2 figures, Phys. Rev. Lett 109, 171802 (2012

Reward devaluation disrupts latent inhibition in fear conditioning

Three experiments explored the link between reward shifts and latent inhibition (LI). Using consummatory procedures, rewards were either downshifted from 32% to 4% sucrose (Experiments 1–2), or upshifted from 4% to 32% sucrose (Experiment 3). In both cases, appropriate unshifted controls were also included. LI was implemented in terms of fear conditioning involving a single tone-shock pairing after extensive tone-only preexposure. Nonpreexposed controls were also included. Experiment 1 demonstrated a typical LI effect (i.e., disruption of fear conditioning after preexposure to the tone) in animals previously exposed only to 4% sucrose. However, the LI effect was eliminated by preexposure to a 32%-to-4% sucrose devaluation. Experiment 2 replicated this effect when the LI protocol was administered immediately after the reward devaluation event. However, LI was restored when preexposure was administered after a 60- min retention interval. Finally, Experiment 3 showed that a reward upshift did not affect LI. These results point to a significant role of negative emotion related to reward devaluation in the enhancement of stimulus processing despite extensive nonreinforced preexposure experience

Validation of standardized data formats and tools for ground-level particle-based gamma-ray observatories

Ground-based gamma-ray astronomy is still a rather young field of research,with strong historical connections to particle physics. This is why mostobservations are conducted by experiments with proprietary data and analysissoftware, as it is usual in the particle physics field. However in recentyears, this paradigm has been slowly shifting towards the development and useof open-source data formats and tools, driven by upcoming observatories such asthe Cherenkov Telescope Array (CTA). In this context, a community-driven,shared data format (the gamma-astro-data-format or GADF) and analysis toolssuch as Gammapy and ctools have been developed. So far these efforts have beenled by the IACT community, leaving out other types of ground-based gamma-rayinstruments.We aim to show that the data from ground particle arrays, such asthe High-Altitude Water Cherenkov (HAWC) observatory, is also compatible withthe GADF and can thus be fully analysed using the related tools, in this caseGammapy. We reproduce several published HAWC results using Gammapy and dataproducts compliant with GADF standard. We also illustrate the capabilities ofthe shared format and tools by producing a joint fit of the Crab spectrumincluding data from six different gamma-ray experiments. We find excellentagreement with the reference results, a powerful check of both the publishedresults and the tools involved. The data from particle detector arrays such asthe HAWC observatory can be adapted to the GADF and thus analysed with Gammapy.A common data format and shared analysis tools allow multi-instrument jointanalysis and effective data sharing. Given the complementary nature of pointingand wide-field instruments, this synergy will be distinctly beneficial for thejoint scientific exploitation of future observatories such as the SouthernWide-field Gamma-ray Observatory and CTA.<br

Association of a single nucleotide polymorphism combination pattern of the Klotho gene with non-cardiovascular death in patients with chronic kidney disease

Chronic kidney disease (CKD) is associated with an elevated risk of all-cause mortality, with cardiovascular death being extensively investigated. However, non-cardiovascular mortality represents the biggest percentage, showing an evident increase in recent years. Klotho is a gene highly expressed in the kidney, with a clear influence on lifespan. Low levels of Klotho have been linked to CKD progression and adverse outcomes. Single nucleotide polymorphisms (SNPs) of the Klotho gene have been associated with several diseases, but studies investigating the association of Klotho SNPs with noncardiovascular death in CKD populations are lacking. The main aim of this study was to assess whether 11 Klotho SNPs were associated with non-cardiovascular death in a subpopulation of the National Observatory of Atherosclerosis in Nephrology (NEFRONA) study (n ¼ 2185 CKD patients). After 48 months of follow-up, 62 cardiovascular deaths and 108 non-cardiovascular deaths were recorded. We identified a high non-cardiovascular death risk combination of SNPs corresponding to individuals carrying the most frequent allele (G) at rs562020, the rare allele (C) at rs2283368 and homozygotes for the rare allele (G) at rs2320762 (rs562020 GG/AG þ rs2283368 CC/CT þ rs2320762 GG). Among the patients with the three SNPs genotyped (n ¼ 1016), 75 (7.4%) showed this combination. Furthermore, 95 (9.3%) patients showed a low-risk combination carrying all the opposite genotypes (rs562020 AA þ rs2283368 TT þ rs2320762 GT/TT). All the other combinations [n ¼ 846 (83.3%)] were considered as normal risk. Using competing risk regression analysis, we confirmed that the proposed combinations are independently associated with a higher fhazard ratio [HR] 3.28 [confidence interval (CI) 1.51-7.12]g and lower [HR 6 × 10- (95% CI 3.3 × 10--1.1 × 10-)] risk of suffering a non-cardiovascular death in the CKD population of the NEFRONA cohort compared with patients with the normal-risk combination. Determination of three SNPs of the Klotho gene could help in the prediction of non-cardiovascular death in CKD

HAWC Study of Very-High-Energy γ\gamma-ray Spectrum of HAWC J1844-034

Recently, the region surrounding eHWC J1842-035 has been studied extensively by gamma-ray observatories due to its extended emission reaching up to a few hundred TeV and potential as a hadronic accelerator. In this work, we use 1,910 days of cumulative data from the High Altitude Water Cherenkov (HAWC) observatory to carry out a dedicated systematic source search of the eHWC J1842-035 region. During the search we have found three sources in the region, namely, HAWC J1844-034, HAWC J1843-032, and HAWC J1846-025. We have identified HAWC J1844-034 as the extended source that emits photons with energies up to 175 TeV. We compute the spectrum for HAWC J1844-034 and by comparing with the observational results from other experiments, we have identified HESS J1843-033, LHAASO J1843-0338, and TASG J1844-038 as very-high-energy gamma-ray sources with a matching origin. Also, we present and use the multi-wavelength data to fit the hadronic and leptonic particle spectra. We have identified four pulsar candidates in the nearby region from which PSR J1844-0346 is found to be the most likely candidate due to its proximity to HAWC J1844-034 and the computed energy budget. We have also found SNR G28.6-0.1 as a potential counterpart source of HAWC J1844-034 for which both leptonic and hadronic scenarios are feasible.Comment: 13 pages, 9 figures, published in Ap

A Mitosis Block Links Active Cell Cycle with Human Epidermal Differentiation and Results in Endoreplication

How human self-renewal tissues co-ordinate proliferation with differentiation is unclear. Human epidermis undergoes continuous cell growth and differentiation and is permanently exposed to mutagenic hazard. Keratinocytes are thought to arrest cell growth and cell cycle prior to terminal differentiation. However, a growing body of evidence does not satisfy this model. For instance, it does not explain how skin maintains tissue structure in hyperproliferative benign lesions. We have developed and applied novel cell cycle techniques to human skin in situ and determined the dynamics of key cell cycle regulators of DNA replication or mitosis, such as cyclins E, A and B, or members of the anaphase promoting complex pathway: cdc14A, Ndc80/Hec1 and Aurora kinase B. The results show that actively cycling keratinocytes initiate terminal differentiation, arrest in mitosis, continue DNA replication in a special G2/M state, and become polyploid by mitotic slippage. They unambiguously demonstrate that cell cycle progression coexists with terminal differentiation, thus explaining how differentiating cells increase in size. Epidermal differentiating cells arrest in mitosis and a genotoxic-induced mitosis block rapidly pushes epidermal basal cells into differentiation and polyploidy. These observations unravel a novel mitosis-differentiation link that provides new insight into skin homeostasis and cancer. It might constitute a self-defence mechanism against oncogenic alterations such as Myc deregulation

Gamma/Hadron Separation with the HAWC Observatory

The High Altitude Water Cherenkov (HAWC) gamma-ray observatory observesatmospheric showers produced by incident gamma rays and cosmic rays with energyfrom 300 GeV to more than 100 TeV. A crucial phase in analyzing gamma-raysources using ground-based gamma-ray detectors like HAWC is to identify theshowers produced by gamma rays or hadrons. The HAWC observatory records roughly25,000 events per second, with hadrons representing the vast majority($>99.9\%$) of these events. The standard gamma/hadron separation technique inHAWC uses a simple rectangular cut involving only two parameters. This workdescribes the implementation of more sophisticated gamma/hadron separationtechniques, via machine learning methods (boosted decision trees and neuralnetworks), and summarizes the resulting improvements in gamma/hadron separationobtained in HAWC.<br

Biogenesis and Dynamics of Mitochondria during the Cell Cycle: Significance of 3′UTRs

Nowadays, we are facing a renaissance of mitochondria in cancer biology. However, our knowledge of the basic cell biology and on the timing and mechanisms that control the biosynthesis of mitochondrial constituents during progression through the cell cycle of mammalian cells remain largely unknown. Herein, we document the in vivo changes on mitochondrial morphology and dynamics that accompany cellular mitosis, and illustrate the following key points of the biogenesis of mitochondria during progression of liver cells through the cycle: (i) the replication of nuclear and mitochondrial genomes is synchronized during cellular proliferation, (ii) the accretion of OXPHOS proteins is asynchronously regulated during proliferation being the synthesis of β-F1-ATPase and Hsp60 carried out also at G2/M and, (iii) the biosynthesis of cardiolipin is achieved during the S phase, although full development of the mitochondrial membrane potential (ΔΨm) is attained at G2/M. Furthermore, we demonstrate using reporter constructs that the mechanism regulating the accretion of β-F1-ATPase during cellular proliferation is controlled at the level of mRNA translation by the 3′UTR of the transcript. The 3′UTR-driven synthesis of the protein at G2/M is essential for conferring to the daughter cells the original phenotype of the parental cell. Our findings suggest that alterations on this process may promote deregulated β-F1-ATPase expression in human cancer

Horizontal muon track identification with neural networks in HAWC

Nowadays the implementation of artificial neural networks in high-energyphysics has obtained excellent results on improving signal detection. In thiswork we propose to use neural networks (NNs) for event discrimination in HAWC.This observatory is a water Cherenkov gamma-ray detector that in recent yearshas implemented algorithms to identify horizontal muon tracks. However, thesealgorithms are not very efficient. In this work we describe the implementationof three NNs: two based on image classification and one based on objectdetection. Using these algorithms we obtain an increase in the number ofidentified tracks. The results of this study could be used in the future toimprove the performance of the Earth-skimming technique for the indirectmeasurement of neutrinos with HAWC.<br