Oxidative phosphorylation selectively orchestrates tissue macrophage homeostasis

We are grateful to N.-G. Larsson, F. Sa´ nchez-Madrid, G. Sabio, R.D. Palmiter, E. Gottlieb, C.T.Moraes, and M.A. del Pozofor sharing essential reagents.We thank S. Iborra, his team, M. Sa´ nchez-A´ lvarez, I. Nikolic, and members of the D.S. laboratory for discussions and critical reading of the manuscript. We thank the staff at the CNIC technical units; foremost the animal, cellomics, histology, metabolomics, genomics,microscopy, and bioinformaticsfacilities; and the SIdI of the Universidad Auto´ noma de Madrid for technical support. This project was supported by the ‘‘la Caixa’’ Foundation (ID 100010434) Postdoctoral Junior Leader Fellowship code LCF/BQ/PR20/11770008 (S.K.W.); ‘‘la Caixa’’ Foundation (ID 100010434) INPhINIT Fellowship code LCF/BQ/IN17/11620074 (I.H.-M.); Spanish Ministry of Education FPU fellowship code FPU20/01418 (M.G.); Ministerio de Ciencia e Innovacio´ n (MCIN) PID2019-104233RB-100/AEI/10.13039/ 501100011033 (S.L.); and NIH grants P01AG049665-08, RO1A148190, and P01HL154998 (N.S.C.). The J.A.E. laboratory is supported by the CNIC and a grant by Ministerio de Ciencia, Innovacio´ n y Universidades (MCNU); Agencia Estatal de Investigacio´ n (AEI) and Fondo Europeo de Desarrollo Regional (FEDER) (RTI2018-099357-B-I00); the Biomedical Research Networking Center on Frailty and Healthy Ageing (CIBERFES-ISCiii-CB16/10/00289); and the HFSP agency (RGP0016/2018). Work in the D.S. laboratory is funded by the CNIC; by the European Union’s Horizon 2020 research and innovation program under grant agreement ERC-2016-Consolidator grant 725091; by Spanish Ministerio de Ciencia e Innovacio´ n PID2019-108157RB/AEI/ and CPP2021-008310/AEI/10.13039/ 501100011033; by Comunidad de Madrid (P2022/BMD-7333 INMUNOVARCM); and by ‘‘la Caixa’’ Foundation (LCF/PR/HR20/00075 and LCF/PR/HR22/ 00253). The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the MICINN, and the Pro CNIC Foundation and is a Severo Ochoa Center of Excellence (CEX2020-001041-S funded by MCIN/AEI/10.13039/501100011033).S

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Photography-based taxonomy is inadequate, unnecessary, and potentially harmful for biological sciences

The question whether taxonomic descriptions naming new animal species without type specimen(s) deposited in collections should be accepted for publication by scientific journals and allowed by the Code has already been discussed in Zootaxa (Dubois & Nemésio 2007; Donegan 2008, 2009; Nemésio 2009a–b; Dubois 2009; Gentile & Snell 2009; Minelli 2009; Cianferoni & Bartolozzi 2016; Amorim et al. 2016). This question was again raised in a letter supported by 35 signatories published in the journal Nature (Pape et al. 2016) on 15 September 2016. On 25 September 2016, the following rebuttal (strictly limited to 300 words as per the editorial rules of Nature) was submitted to Nature, which on 18 October 2016 refused to publish it. As we think this problem is a very important one for zoological taxonomy, this text is published here exactly as submitted to Nature, followed by the list of the 493 taxonomists and collection-based researchers who signed it in the short time span from 20 September to 6 October 2016

Study of the doubly charmed tetraquark T+cc

Quantum chromodynamics, the theory of the strong force, describes interactions of coloured quarks and gluons and the formation of hadronic matter. Conventional hadronic matter consists of baryons and mesons made of three quarks and quark-antiquark pairs, respectively. Particles with an alternative quark content are known as exotic states. Here a study is reported of an exotic narrow state in the D0D0π+ mass spectrum just below the D*+D0 mass threshold produced in proton-proton collisions collected with the LHCb detector at the Large Hadron Collider. The state is consistent with the ground isoscalar T+cc tetraquark with a quark content of ccu⎯⎯⎯d⎯⎯⎯ and spin-parity quantum numbers JP = 1+. Study of the DD mass spectra disfavours interpretation of the resonance as the isovector state. The decay structure via intermediate off-shell D*+ mesons is consistent with the observed D0π+ mass distribution. To analyse the mass of the resonance and its coupling to the D*D system, a dedicated model is developed under the assumption of an isoscalar axial-vector T+cc state decaying to the D*D channel. Using this model, resonance parameters including the pole position, scattering length, effective range and compositeness are determined to reveal important information about the nature of the T+cc state. In addition, an unexpected dependence of the production rate on track multiplicity is observed

Por la illustre cofradia del clero de la ciudad de Santiago, debajo del patrocinio de la Purissima Virge[n] Nuestra Señora, en el instante de su Inmaculada Concepcion venerada en la ... Cathedral ... del Señor Santiago ... con Don Francisco de Lamas, Alguacil Mayor de el Santo Oficio de Inquisicion de este Reyno de Galicia, sobre que se confirma la sent¯encia dada por los Inquisidores Apostolicos de este Tribunal, por la qual absolvieron à la Cofradia de la restitucion de vnas casas, y mandaron nombrasse segunda vez dentro de vn termino.

Tít. tomado del comienzo del textoTexto datado en Santiago, 21 de mayo de 1716 y asdo. por Benito Antonio FrayzSign.: A-F\p2\

Antioxidant responses and cellular adjustments to oxidative stress

Abstract Redox biological reactions are now accepted to bear the Janus faceted feature of promoting both physiological signaling responses and pathophysiological cues. Endogenous antioxidant molecules participate in both scenarios. This review focuses on the role of crucial cellular nucleophiles, such as glutathione, and their capacity to interact with oxidants and to establish networks with other critical enzymes such as peroxiredoxins. We discuss the importance of the Nrf2-Keap1 pathway as an example of a transcriptional antioxidant response and we summarize transcriptional routes related to redox activation. As examples of pathophysiological cellular and tissular settings where antioxidant responses are major players we highlight endoplasmic reticulum stress and ischemia reperfusion. Topologically confined redox-mediated post-translational modifications of thiols are considered important molecular mechanisms mediating many antioxidant responses, whereas redox-sensitive microRNAs have emerged as key players in the posttranscriptional regulation of redox-mediated gene expression. Understanding such mechanisms may provide the basis for antioxidant-based therapeutic interventions in redox-related diseases