Anti-α-glucose-based glycan IgM antibodies predict relapse activity in multiple sclerosis after the first neurological event

Background There is no specific serum-based biomarker for the diagnosis or prognosis of relapsing-remitting multiple sclerosis (RRMS). Objective We investigated whether levels of IgM antibodies to Glc(alpha 1,4) Glc(alpha) (GAGA4) or to a panel of four glucose-based glycans could differentiate MS from other neurological diseases (OND) or predict risk of early relapse following first presentation (FP) of RRMS. Methods Retrospective analysis of 440 sera samples of three cohorts: A) FP-RRMS (n = 44), OND (n = 44); B) FP-RRMS (n = 167), OND (n = 85); and C) FP (n = 100). Anti-GAGA4 IgM levels were measured by enzyme immunoassay in cohort-A and cohort-B. Cohort-C IgM antibodies to glucose-based glycan panel were measured by immunofluorescence. Results FP-RRMS had higher levels of anti-GAGA4 IgM than OND patients (cohort-A, P = 0.01; cohort-B, P = 0.0001). Sensitivity and specificity were 27% and 97% for cohort-A; and 26% and 90% for cohort-B, respectively. In cohort-C, 58 patients experienced early relapse (= 24 months), and 11 did not experience second attack during follow-up. Kaplan-Meier curves demonstrated decrease in time to next relapse for patients positive for the antibody panel (P = 0.02, log rank). Conclusions Serum anti-GAGA4 IgM discerns FP-RRMS patients from OND patients. Higher levels of serum anti-alpha-glucose IgM in FP patients predict imminent early relapse. Multiple Sclerosis 2009; 15: 422-430. http://msj.sagepub.co

Innate Immune Recognition of Yersinia pseudotuberculosis Type III Secretion

Specialized protein translocation systems are used by many bacterial pathogens to deliver effector proteins into host cells that interfere with normal cellular functions. How the host immune system recognizes and responds to this intrusive event is not understood. To address these questions, we determined the mammalian cellular response to the virulence-associated type III secretion system (T3SS) of the human pathogen Yersinia pseudotuberculosis. We found that macrophages devoid of Toll-like receptor (TLR) signaling regulate expression of 266 genes following recognition of the Y. pseudotuberculosis T3SS. This analysis revealed two temporally distinct responses that could be separated into activation of NFκB- and type I IFN-regulated genes. Extracellular bacteria were capable of triggering these signaling events, as inhibition of bacterial uptake had no effect on the ensuing innate immune response. The cytosolic peptidoglycan sensors Nod1 and Nod2 and the inflammasome component caspase-1 were not involved in NFκB activation following recognition of the Y. pseudotuberculosis T3SS. However, caspase-1 was required for secretion of the inflammatory cytokine IL-1β in response to T3SS-positive Y. pseudotuberculosis. In order to characterize the bacterial requirements for induction of this novel TLR-, Nod1/2-, and caspase-1-independent response, we used Y. pseudotuberculosis strains lacking specific components of the T3SS. Formation of a functional T3SS pore was required, as bacteria expressing a secretion needle, but lacking the pore-forming proteins YopB or YopD, did not trigger these signaling events. However, nonspecific membrane disruption could not recapitulate the NFκB signaling triggered by Y. pseudotuberculosis expressing a functional T3SS pore. Although host cell recognition of the T3SS did not require known translocated substrates, the ensuing response could be modulated by effectors such as YopJ and YopT, as YopT amplified the response, while YopJ dampened it. Collectively, these data suggest that combined recognition of the T3SS pore and YopBD-mediated delivery of immune activating ligands into the host cytosol informs the host cell of pathogenic challenge. This leads to a unique, multifactorial response distinct from the canonical immune response to a bacterium lacking a T3SS

Systematic Review of Potential Health Risks Posed by Pharmaceutical, Occupational and Consumer Exposures to Metallic and Nanoscale Aluminum, Aluminum Oxides, Aluminum Hydroxide and Its Soluble Salts

Aluminum (Al) is a ubiquitous substance encountered both naturally (as the third most abundant element) and intentionally (used in water, foods, pharmaceuticals, and vaccines); it is also present in ambient and occupational airborne particulates. Existing data underscore the importance of Al physical and chemical forms in relation to its uptake, accumulation, and systemic bioavailability. The present review represents a systematic examination of the peer-reviewed literature on the adverse health effects of Al materials published since a previous critical evaluation compiled by Krewski et al. (2007). Challenges encountered in carrying out the present review reflected the experimental use of different physical and chemical Al forms, different routes of administration, and different target organs in relation to the magnitude, frequency, and duration of exposure. Wide variations in diet can result in Al intakes that are often higher than the World Health Organization provisional tolerable weekly intake (PTWI), which is based on studies with Al citrate. Comparing daily dietary Al exposures on the basis of “total Al”assumes that gastrointestinal bioavailability for all dietary Al forms is equivalent to that for Al citrate, an approach that requires validation. Current occupational exposure limits (OELs) for identical Al substances vary as much as 15-fold. The toxicity of different Al forms depends in large measure on their physical behavior and relative solubility in water. The toxicity of soluble Al forms depends upon the delivered dose of Al+ 3 to target tissues. Trivalent Al reacts with water to produce bidentate superoxide coordination spheres [Al(O2)(H2O4)+ 2 and Al(H2O)6 + 3] that after complexation with O2•−, generate Al superoxides [Al(O2•)](H2O5)]+ 2. Semireduced AlO2• radicals deplete mitochondrial Fe and promote generation of H2O2, O2 • − and OH•. Thus, it is the Al+ 3-induced formation of oxygen radicals that accounts for the oxidative damage that leads to intrinsic apoptosis. In contrast, the toxicity of the insoluble Al oxides depends primarily on their behavior as particulates. Aluminum has been held responsible for human morbidity and mortality, but there is no consistent and convincing evidence to associate the Al found in food and drinking water at the doses and chemical forms presently consumed by people living in North America and Western Europe with increased risk for Alzheimer\u27s disease (AD). Neither is there clear evidence to show use of Al-containing underarm antiperspirants or cosmetics increases the risk of AD or breast cancer. Metallic Al, its oxides, and common Al salts have not been shown to be either genotoxic or carcinogenic. Aluminum exposures during neonatal and pediatric parenteral nutrition (PN) can impair bone mineralization and delay neurological development. Adverse effects to vaccines with Al adjuvants have occurred; however, recent controlled trials found that the immunologic response to certain vaccines with Al adjuvants was no greater, and in some cases less than, that after identical vaccination without Al adjuvants. The scientific literature on the adverse health effects of Al is extensive. Health risk assessments for Al must take into account individual co-factors (e.g., age, renal function, diet, gastric pH). Conclusions from the current review point to the need for refinement of the PTWI, reduction of Al contamination in PN solutions, justification for routine addition of Al to vaccines, and harmonization of OELs for Al substances

Renewed and emerging concerns over the production and emission of ozone-depleting substances

Stratospheric ozone depletion, first observed in the 1980s, has been caused by the increased production and use of substances such as chlorofluorocarbons (CFCs), halons and other chlorine-containing and bromine-containing compounds, collectively termed ozone-depleting substances (ODSs). Following controls on the production of major, long-lived ODSs by the Montreal Protocol, the ozone layer is now showing initial signs of recovery and is anticipated to return to pre-depletion levels in the mid-to-late twenty-first century, likely 2050–2060. These return dates assume widespread compliance with the Montreal Protocol and, thereby, continued reductions in ODS emissions. However, recent observations reveal increasing emissions of some controlled (for example, CFC-11, as in eastern China) and uncontrolled substances (for example, very short-lived substances (VSLSs)). Indeed, the emissions of a number of uncontrolled VSLSs are adding significant amounts of ozone-depleting chlorine to the atmosphere. In this Review, we discuss recent emissions of both long-lived ODSs and halogenated VSLSs, and how these might lead to a delay in ozone recovery. Continued improvements in observational tools and modelling approaches are needed to assess these emerging challenges to a timely recovery of the ozone layer

Observation of triple J/ψ meson production in proton-proton collisions

Data availability: Tabulated results are provided in the HEPData record for this analysis71. Release and preservation of data used by the CMS Collaboration as the basis for publications is guided by the CMS policy as stated in CMS data preservation, re-use and open access policy.Code availability: The CMS core software is publically available at https://github.com/cms-sw/cmssw.Copyright . Protons consist of three valence quarks, two up-quarks and one down-quark, held together by gluons and a sea of quark-antiquark pairs. Collectively, quarks and gluons are referred to as partons. In a proton-proton collision, typically only one parton of each proton undergoes a hard scattering – referred to as single-parton scattering – leaving the remainder of each proton only slightly disturbed. Here, we report the study of double- and triple-parton scatterings through the simultaneous production of three J/ψ mesons, which consist of a charm quark-antiquark pair, in proton-proton collisions recorded with the CMS experiment at the Large Hadron Collider. We observed this process – reconstructed through the decays of J/ψ mesons into pairs of oppositely charged muons – with a statistical significance above five standard deviations. We measured the inclusive fiducial cross-section to be 272+141−104(stat)±17(syst)fb, and compared it to theoretical expectations for triple-J/ψ meson production in single-, double- and triple-parton scattering scenarios. Assuming factorization of multiple hard-scattering probabilities in terms of single-parton scattering cross-sections, double- and triple-parton scattering are the dominant contributions for the measured process.SCOAP3.Change history: 27 February 2023A Correction to this paper has been published: https://doi.org/10.1038/s41567-023-01992-

Measurements of the Higgs boson production cross section and couplings in the W boson pair decay channel in proton-proton collisions at s\sqrt{s} = 13 TeV

A preprint version of the article is available at arXiv:2206.09466v2 [hep-ex], https://arxiv.org/abs/2206.09466v2 . Comments: Replaced with the published version. Added the journal reference and the DOI. All the figures and tables can be found at httpS://cms-results.web.cern.ch/cms-results/public-results/publications/HIG-20-013 (CMS Public Pages). Report number: CMS-HIG-20-013, CERN-EP-2022-120.Production cross sections of the standard model Higgs boson decaying to a pair of W bosons are measured in proton-proton collisions at a center-of-mass energy of 13 TeV. The analysis targets Higgs bosons produced via gluon fusion, vector boson fusion, and in association with a W or Z boson. Candidate events are required to have at least two charged leptons and moderate missing transverse momentum, targeting events with at least one leptonically decaying W boson originating from the Higgs boson. Results are presented in the form of inclusive and differential cross sections in the simplified template cross section framework, as well as couplings of the Higgs boson to vector bosons and fermions. The data set collected by the CMS detector during 2016-2018 is used, corresponding to an integrated luminosity of 138 fb^−1. The signal strength modifier μ, defined as the ratio of the observed production rate in a given decay channel to the standard model expectation, is measured to be μ = 0.95 +0.10−0.09. All results are found to be compatible with the standard model within the uncertainties.SCOAP3

A portrait of the Higgs boson by the CMS experiment ten years after the discovery

A Correction to this paper has been published (18 October 2023) : https://doi.org/10.1038/s41586-023-06164-8.Data availability: Tabulated results are provided in the HEPData record for this analysis. Release and preservation of data used by the CMS Collaboration as the basis for publications is guided by the CMS data preservation, re-use and open acess policy.Code availability: The CMS core software is publicly available on GitHub (https://github.com/cms-sw/cmssw).In July 2012, the ATLAS and CMS collaborations at the CERN Large Hadron Collider announced the observation of a Higgs boson at a mass of around 125 gigaelectronvolts. Ten years later, and with the data corresponding to the production of a 30-times larger number of Higgs bosons, we have learnt much more about the properties of the Higgs boson. The CMS experiment has observed the Higgs boson in numerous fermionic and bosonic decay channels, established its spin–parity quantum numbers, determined its mass and measured its production cross-sections in various modes. Here the CMS Collaboration reports the most up-to-date combination of results on the properties of the Higgs boson, including the most stringent limit on the cross-section for the production of a pair of Higgs bosons, on the basis of data from proton–proton collisions at a centre-of-mass energy of 13 teraelectronvolts. Within the uncertainties, all these observations are compatible with the predictions of the standard model of elementary particle physics. Much evidence points to the fact that the standard model is a low-energy approximation of a more comprehensive theory. Several of the standard model issues originate in the sector of Higgs boson physics. An order of magnitude larger number of Higgs bosons, expected to be examined over the next 15 years, will help deepen our understanding of this crucial sector.BMBWF and FWF (Austria); FNRS and FWO (Belgium); CNPq, CAPES, FAPERJ, FAPERGS, and FAPESP (Brazil); MES and BNSF (Bulgaria); CERN; CAS, MoST, and NSFC (China); MINCIENCIAS (Colombia); MSES and CSF (Croatia); RIF (Cyprus); SENESCYT (Ecuador); MoER, ERC PUT and ERDF (Estonia); Academy of Finland, MEC, and HIP (Finland); CEA and CNRS/IN2P3 (France); BMBF, DFG, and HGF (Germany); GSRI (Greece); NKFIH (Hungary); DAE and DST (India); IPM (Iran); SFI (Ireland); INFN (Italy); MSIP and NRF (Republic of Korea); MES (Latvia); LAS (Lithuania); MOE and UM (Malaysia); BUAP, CINVESTAV, CONACYT, LNS, SEP, and UASLP-FAI (Mexico); MOS (Montenegro); MBIE (New Zealand); PAEC (Pakistan); MES and NSC (Poland); FCT (Portugal); MESTD (Serbia); MCIN/AEI and PCTI (Spain); MOSTR (Sri Lanka); Swiss Funding Agencies (Switzerland); MST (Taipei); MHESI and NSTDA (Thailand); TUBITAK and TENMAK (Turkey); NASU (Ukraine); STFC (United Kingdom); DOE and NSF (USA). Individuals have received support from the Marie-Curie programme and the European Research Council and Horizon 2020 Grant, contract Nos. 675440, 724704, 752730, 758316, 765710, 824093, 884104, and COST Action CA16108 (European Union); the Leventis Foundation; the Alfred P. Sloan Foundation; the Alexander von Humboldt Foundation; the Belgian Federal Science Policy Office; the Fonds pour la Formation à la Recherche dans l’Industrie et dans l’Agriculture (FRIA-Belgium); the Agentschap voor Innovatie door Wetenschap en Technologie (IWT-Belgium); the F.R.S.-FNRS and FWO (Belgium) under the “Excellence of Science – EOS” – be.h project n. 30820817; the Beijing Municipal Science & Technology Commission, No. Z191100007219010; the Ministry of Education, Youth and Sports (MEYS) of the Czech Republic; the Stavros Niarchos Foundation (Greece); the Deutsche Forschungsgemeinschaft (DFG), under Germany’s Excellence Strategy – EXC 2121 “Quantum Universe” – 390833306, and under project number 400140256 - GRK2497; the Hungarian Academy of Sciences, the New National Excellence Program - ÚNKP, the NKFIH research grants K 124845, K 124850, K 128713, K 128786, K 129058, K 131991, K 133046, K 138136, K 143460, K 143477, 2020-2.2.1-ED-2021-00181, and TKP2021-NKTA-64 (Hungary); the Council of Science and Industrial Research, India; the Latvian Council of Science; the Ministry of Education and Science, project no. 2022/WK/14, and the National Science Center, contracts Opus 2021/41/B/ST2/01369 and 2021/43/B/ST2/01552 (Poland); the Fundação para a Ciência e a Tecnologia, grant CEECIND/01334/2018 (Portugal); the National Priorities Research Program by Qatar National Research Fund; MCIN/AEI/10.13039/501100011033, ERDF “a way of making Europe”, and the Programa Estatal de Fomento de la Investigación Científica y Técnica de Excelencia María de Maeztu, grant MDM-2017-0765 and Programa Severo Ochoa del Principado de Asturias (Spain); the Chulalongkorn Academic into Its 2nd Century Project Advancement Project, and the National Science, Research and Innovation Fund via the Program Management Unit for Human Resources & Institutional Development, Research and Innovation, grant B05F650021 (Thailand); the Kavli Foundation; the Nvidia Corporation; the SuperMicro Corporation; the Welch Foundation, contract C-1845; and the Weston Havens Foundation (USA)

Search for light Higgs bosons from supersymmetric cascade decays in pp collisions at √s=13TeV

A search is reported for pairs of light Higgs bosons (H1) produced in supersymmetric cascade decays in f inal states with small missing transverse momentum. A data set of LHC pp collisions collected with the CMS detector at √s = 13TeV and corresponding to an integrated lumi nosity of 138fb−1 is used. The search targets events where both H1 bosons decay into b¯b pairs that are reconstructed as large-radius jets using substructure techniques. No evi dence is found for an excess of events beyond the back ground expectations of the standard model (SM). Results from the search are interpreted in the next-to-minimal super symmetric extension of the SM, where a “singlino” of small mass leads to squark and gluino cascade decays that can pre dominantly end in a highly Lorentz-boosted singlet-like H1 andasinglino-likeneutralinoofsmalltransversemomentum. Upperlimitsaresetontheproductofthesquarkorgluinopair production cross section and the square of the b¯b branching fraction of the H1 in a benchmark model containing almost mass-degenerategluinosandlight-flavoursquarks.Underthe assumption of an SM-like H1 → b¯b branching fraction, H1 bosonswithmassesintherange40–120GeVarisingfromthe decays of squarks or gluinos with a mass of 1200–2500GeV are excluded at 95% confidence level.SCOA