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Inflammation and thrombosis occur together in many diseases. The leukocyte integrin Mac-1 (also known as integrin α M β 2 , or CD11b/CD18) is crucial for leukocyte recruitment to the endothelium, and Mac-1 engagement of platelet GPIbα is required for injury responses in diverse disease models. However, the role of Mac-1 in thrombosis is undefined. Here we report that mice with Mac-1 deficiency ( Mac-1 −/− ) or mutation of the Mac-1-binding site for GPIbα have delayed thrombosis after carotid artery and cremaster microvascular injury without affecting parameters of haemostasis. Adoptive wild-type leukocyte transfer rescues the thrombosis defect in Mac-1 −/− mice, and Mac-1-dependent regulation of the transcription factor Foxp1 contributes to thrombosis as evidenced by delayed thrombosis in mice with monocyte-/macrophage-specific overexpression of Foxp1. Antibody and small-molecule targeting of Mac-1:GPIbα inhibits thrombosis. Our data identify a new pathway of thrombosis involving leukocyte Mac-1 and platelet GPIbα, and suggest that targeting this interaction has anti-thrombotic therapeutic potential with reduced bleeding risk. The binding of the leukocyte integrin Mac1 to the platelet receptor GPIbα is important for the physiological response to tissue injury. Here the authors show that this interaction also regulates thrombosis, without influencing bleeding time, which may provide clues for the development of new anti-thrombotic drugs.

This corrects the article DOI: 10.1038/ncomms15559.

The leukocyte integrin alpha(M)beta(2)/Mac-1 appears to support the inflammatory response through multiple ligands, but local engagement of fibrin(ogen) may be particularly important for leukocyte function. To define the biological significance of fibrin(ogen)-alpha(M)beta(2) interaction in vivo, gene-targeted mice were generated in which the alpha(M)beta(2)-binding motif within the fibrinogen gamma chain (N(390)RLSIGE(396)) was converted to a series of alanine residues. Mice carrying the Fibgamma(390-396A) allele maintained normal levels of fibrinogen, retained normal clotting function, supported platelet aggregation, and never developed spontaneous hemorrhagic events. However, the mutant fibrinogen failed to support alpha(M)beta(2)-mediated adhesion of primary neutrophils, macrophages, and alpha(M)beta(2)-expressing cell lines. The elimination of the alpha(M)beta(2)-binding motif on fibrin(ogen) severely compromised the inflammatory response in vivo as evidenced by a dramatic impediment in leukocyte clearance of Staphylococcus aureus inoculated into the peritoneal cavity. This defect in bacterial clearance was due not to diminished leukocyte trafficking but rather to a failure to fully implement antimicrobial functions. These studies definitively demonstrate that fibrin(ogen) is a physiologically relevant ligand for alpha(M)beta(2), integrin engagement of fibrin(ogen) is critical to leukocyte function and innate immunity in vivo, and the biological importance of fibrinogen in regulating the inflammatory response can be appreciated outside of any alteration in clotting function.

Nature Communications 8: Article number:15559 (2017); Published 30 May 2017; Updated 4 July 2017 The original version of this Article contained an error in the email address of the corresponding author Daniel I. Simon. The correct email is Daniel.Simon@UHHospitals.org. The error has been corrected in the HTML and PDF versions of the article.

This corrects the article DOI: 10.1038/ncomms15559

Inflammation and thrombosis occur together in many diseases. The leukocyte integrin Mac-1 (also known as integrin αM β2 , or CD11b/CD18) is crucial for leukocyte recruitment to the endothelium, and Mac-1 engagement of platelet GPIbα is required for injury responses in diverse disease models. However, the role of Mac-1 in thrombosis is undefined. Here we report that mice with Mac-1 deficiency (Mac-1-/- ) or mutation of the Mac-1-binding site for GPIbα have delayed thrombosis after carotid artery and cremaster microvascular injury without affecting parameters of haemostasis. Adoptive wild-type leukocyte transfer rescues the thrombosis defect in Mac-1-/- mice, and Mac-1-dependent regulation of the transcription factor Foxp1 contributes to thrombosis as evidenced by delayed thrombosis in mice with monocyte-/macrophage-specific overexpression of Foxp1. Antibody and small-molecule targeting of Mac-1:GPIbα inhibits thrombosis. Our data identify a new pathway of thrombosis involving leukocyte Mac-1 and platelet GPIbα, and suggest that targeting this interaction has anti-thrombotic therapeutic potential with reduced bleeding risk.

The leukocyte integrin αMβ2/Mac-1 appears to support the inflammatory response through multiple ligands, but local engagement of fibrin(ogen) may be particularly important for leukocyte function. To define the biological significance of fibrin(ogen)-αMβ2 interaction in vivo, gene-targeted mice were generated in which the αMβ2-binding motif within the fibrinogen γ chain (N390RLSIGE396) was converted to a series of alanine residues. Mice carrying the Fibγ390–396A allele maintained normal levels of fibrinogen, retained normal clotting function, supported platelet aggregation, and never developed spontaneous hemorrhagic events. However, the mutant fibrinogen failed to support αMβ2-mediated adhesion of primary neutrophils, macrophages, and αMβ2-expressing cell lines. The elimination of the αMβ2-binding motif on fibrin(ogen) severely compromised the inflammatory response in vivo as evidenced by a dramatic impediment in leukocyte clearance of Staphylococcus aureus inoculated into the peritoneal cavity. This defect in bacterial clearance was due not to diminished leukocyte trafficking but rather to a failure to fully implement antimicrobial functions. These studies definitively demonstrate that fibrin(ogen) is a physiologically relevant ligand for αMβ2, integrin engagement of fibrin(ogen) is critical to leukocyte function and innate immunity in vivo, and the biological importance of fibrinogen in regulating the inflammatory response can be appreciated outside of any alteration in clotting function.

The paper describes the new principle of passive NPP safety systems designing, in which the natural circulation of working fluid or gas is replaced by forced circulation in order to increase it’s capacity. The energy required by the system is converted from the emergency process itself, which this system resists when performing a given safety function. The goal is to expand the variety and capacity of passive NPP safety systems in order to optimize and reduce costs of NPP power units with various types of reactors while increasing the safety level. The proposed technical solutions are based on the use of direct non-mechanical conversion of the energy, comprised in emergency process, to electricity, and then to mechanical energy of hydraulic machine for working medium moving in a forced circulation mode. To demonstrate the proposed principles, the following technical solutions have been considered: • new passive electrochemical hydrogen recombiner for NPPs with light water reactors. Application of new techniques allowed increasing the performance by weight of the recommended hydrogen simultaneously with increasing the hydrogen torch threshold, as well as other important characteristics; • passive emergency core cooling system for heavy liquid metal cooled reactors. Application of new techniques allowed increasing the core remove heat capacity in order to scale down the main equipment; • passive system for in-vessel core melt retention of Pressurized Water Reactors of high thermal capacity (more than 3000 MWe). Application of new techniques allowed increasing the system thermal capacity in order to be able to apply to high thermal power reactors like VVER-1000 and more.

We present multi-sensor measurements from satellites, unmanned aerial vehicle, marine radar, thermal profilers, and repeated conductivity–temperature–depth casts made in the Kara Gates strait connecting the Barents and the Kara Seas during spring tide in August 2021. Analysis of the field data during an 18-h period from four stations provides evidence that a complex sill in the Kara Gates is the site of regular production of intense large-amplitude nonlinear internal waves. Satellite data show a presence of a relatively warm northeastward surface current from the Barents Sea toward the Kara Sea attaining 0.8–0.9 m/s. Triangle-shaped measurements using three thermal profilers revealed pronounced vertical thermocline oscillations up to 40 m associated with propagation of short-period nonlinear internal waves of depression generated by stratified flow passing a system of shallow sills in the strait. The most intense waves were recorded during the ebb tide slackening and reversal when the background flow was predominantly supercritical. Observed internal waves had wavelengths of ~100 m and traveled northeastward with phase speeds of 0.8–0.9 m/s. The total internal wave energy per unit crest length for the largest waves was estimated to be equal to 1.0–1.8 MJ/m.