JAM-L–mediated leukocyte adhesion to endothelial cells is regulated in cis by α4β1 integrin activation

Junctional adhesion molecules (JAMs) are endothelial and epithelial adhesion molecules involved in the recruitment of circulating leukocytes to inflammatory sites. We show here that JAM-L, a protein related to the JAM family, is restricted to leukocytes and promotes their adhesion to endothelial cells. Cis dimerization of JAM-L is required to engage in heterophilic interactions with its cognate counter-receptor CAR (coxsackie and adenovirus receptor). Interestingly, JAM-L expressed on neutrophils binds CAR independently of integrin activation. However, on resting monocytes and T lymphocytes, which express the integrin VLA-4, JAM-L molecules engage in complexes with VLA-4 and mainly accumulate in their monomeric form. Integrin activation is required for the dissociation of JAM-L–VLA-4 complexes and the accumulation of functional JAM-L dimers, which indicates that the leukocyte integrin VLA-4 controls JAM-L function in cis by controlling its dimerization state. This provides a mechanism through which VLA-4 and JAM-L functions are coordinately regulated, allowing JAM-L to strengthen integrin-dependent adhesion of leukocytes to endothelial cells

JAM-L–mediated leukocyte adhesion to endothelial cells is regulated in cis by α4β1 integrin activation

Junctional adhesion molecules (JAMs) are endothelial and epithelial adhesion molecules involved in the recruitment of circulating leukocytes to inflammatory sites. We show here that JAM-L, a protein related to the JAM family, is restricted to leukocytes and promotes their adhesion to endothelial cells. Cis dimerization of JAM-L is required to engage in heterophilic interactions with its cognate counter-receptor CAR (coxsackie and adenovirus receptor). Interestingly, JAM-L expressed on neutrophils binds CAR independently of integrin activation. However, on resting monocytes and T lymphocytes, which express the integrin VLA-4, JAM-L molecules engage in complexes with VLA-4 and mainly accumulate in their monomeric form. Integrin activation is required for the dissociation of JAM-L–VLA-4 complexes and the accumulation of functional JAM-L dimers, which indicates that the leukocyte integrin VLA-4 controls JAM-L function in cis by controlling its dimerization state. This provides a mechanism through which VLA-4 and JAM-L functions are coordinately regulated, allowing JAM-L to strengthen integrin-dependent adhesion of leukocytes to endothelial cells

Spin relaxation in a complex environment

We report the study of a model of a two-level system interacting in a non-diagonal way with a complex environment described by Gaussian orthogonal random matrices (GORM). The effect of the interaction on the total spectrum and its consequences on the dynamics of the two-level system are analyzed. We show the existence of a critical value of the interaction, depending on the mean level spacing of the environment, above which the dynamics is self-averaging and closely obey a master equation for the time evolution of the observables of the two-level system. Analytic results are also obtained in the strong coupling regimes. We finally study the equilibrium values of the two-level system population and show under which condition it thermalizes to the environment temperature.Comment: 45 pages, 49 figure

Quantum master equation for a system influencing its environment

A perturbative quantum master equation is derived for a system interacting with its environment, which is more general than the ones derived before. Our master equation takes into account the effect of the energy exchanges between the system and the environment and the conservation of energy in a finite total system. This master quantum describes relaxation mechanisms in isolated nanoscopic quantum systems. In its most general form, this equation is non-Markovian and a Markovian version of it rules the long-time relaxation. We show that our equation reduces to the Redfield equation in the limit where the energy of the system does not affect the density of state of its environment. This master equation and the Redfield one are applied to a spin-environment model defined in terms of random matrices and compared with the solutions of the exact von Neumann equation. The comparison proves the necessity to allow energy exchange between the subsystem and the environment in order to correctly describe the relaxation in isolated nanoscopic total system.Comment: 39 pages, 10 figure

The Human and Mouse Islet Peptidome: Effects of Obesity and Type 2 Diabetes, and Assessment of Intraislet Production of Glucagon-like Peptide-1.

To characterize the impact of metabolic disease on the peptidome of human and mouse pancreatic islets, LC-MS was used to analyze extracts of human and mouse islets, purified mouse alpha, beta, and delta cells, supernatants from mouse islet incubations, and plasma from patients with type 2 diabetes. Islets were obtained from healthy and type 2 diabetic human donors, and mice on chow or high fat diet. All major islet hormones were detected in lysed islets as well as numerous peptides from vesicular proteins including granins and processing enzymes. Glucose-dependent insulinotropic peptide (GIP) was not detectable. High fat diet modestly increased islet content of proinsulin-derived peptides in mice. Human diabetic islets contained increased content of proglucagon-derived peptides at the expense of insulin, but no evident prohormone processing defects. Diabetic plasma, however, contained increased ratios of proinsulin and des-31,32-proinsulin to insulin. Active GLP-1 was detectable in human and mouse islets but 100-1000-fold less abundant than glucagon. LC-MS offers advantages over antibody-based approaches for identifying exact peptide sequences, and revealed a shift toward islet insulin production in high fat fed mice, and toward proglucagon production in type 2 diabetes, with no evidence of systematic defective prohormone processing

ASB2 is an Elongin BC-interacting protein that can assemble with Cullin 5 and Rbx1 to reconstitute an E3 ubiquitin ligase complex.

International audience; The ankyrin repeat-containing protein with a suppressor of cytokine signaling box-2 (ASB2) gene was identified as a retinoic acid-response gene and a target of the promyelocytic leukemia-retinoic acid receptor-alpha oncogenic protein characteristic of acute promyelocytic leukemia. Expression of ASB2 in myeloid leukemia cells inhibits growth and promotes commitment, recapitulating an early step known to be critical for differentiation. Here we show that ASB2, by interacting with the Elongin BC complex, can assemble with Cullin5.Rbx1 to form an E3 ubiquitin ligase complex that stimulates polyubiquitination by the E2 ubiquitin-conjugating enzyme Ubc5. This is a first indication that a member of the ASB protein family, ASB2, is a subunit of an ECS (Elongin C-Cullin-SOCS box)-type E3 ubiquitin ligase complex. Altogether, our results strongly suggest that ASB2 targets specific proteins to destruction by the proteasome in leukemia cells that have been induced to differentiate

Increased functional coupling of the mu opioid receptor in the anterior insula of depressed individuals

The mu opioid receptor (MOR) is a G protein-coupled receptor that plays an essential role in reward and hedonic processes, and that has been implicated in disorders such as depression and addiction. Over the last decade, several brain imaging studies in depressed patients have consistently found that dysregulation of MOR function occurs in particular in the anterior insular cortex, an important brain site for the perception of internal states and emotional regulation. To investigate molecular mechanisms that may underlie these effects, here we assessed genetic polymorphisms, expression, and functional G-protein coupling of MOR in a large post-mortem cohort (N = 95) composed of depressed individuals who died by suicide, and healthy controls. Results indicated that depression, but not comorbid substance use disorder or acute opiate consumption, was associated with increased MOR activity. This effect was partly explained by a specific increase in expression of the inhibitory alpha G-protein subunit GNAI2. Consistent with previous neuroimaging studies, our findings support the notion that enhanced endogenous opioidergic tone in the anterior insula may buffer negative affective states in depressed individuals, a mechanism that could potentially contribute to the antidepressant efficacy of emerging opioid-based medications.journal articleresearch support, non-u.s. gov't2021 042021 02 02importe

Spatially Resolved Millimeter Interferometry of SMMJ02399-0136: a Very Massive Galaxy at z=2.8

We report high-resolution millimeter mapping with the IRAM Plateau de Bure interferometer of rest-frame 335 micron continuum and CO(3-2) line emission from the z=2.8 submillimeter galaxy SMMJ02399-0136. The continuum emission comes from a ~3" diameter structure whose elongation is approximately east-west and whose centroid is coincident within the astrometric errors with the brightest X-ray and rest-UV peak (L1). The line data show that this structure is most likely a rapidly rotating disk. Its rotation velocity of >420 km/s implies a total dynamical mass of >3x10^11 solar masses within an intrinsic radius of 8 kpc, most of which is plausibly in the form of stars and gas. SMMJ02399-0136 is thus a very massive system, whose formation at z~3 is not easy to understand in current CDM hierarchical merger cosmogonies.Comment: 19 pages, 6 figures (5 PS + 1 GIF), accepted by ApJ; added color versions of Figures 1, 5, &

Discovery of a bright quasar without a massive host galaxy

Quasars are thought to be powered by the infall of matter onto a supermassive black hole at the centre of massive galaxies. As the optical luminosity of quasars exceeds that of their host galaxy, disentangling the two components can be difficult. This led in the 1990's to the controversial claim of the discovery of 'naked' quasars. Since then, the connection between quasars and galaxies has been well established. Here we report on the observation of a quasar lying at the edge of a gas cloud, whose size is comparable to that of a small galaxy, but whose spectrum shows no evidence for stars. The gas cloud is excited by the quasar itself. If a host galaxy is present, it is at least six times fainter than would normally be expected for such a bright quasar. The quasar is interacting dynamically with a neighbouring galaxy - which matter might be feeding the black hole.Comment: 5 figures, published in Natur

Measurement and Interpretation of Fermion-Pair Production at LEP energies above the Z Resonance

This paper presents DELPHI measurements and interpretations of cross-sections, forward-backward asymmetries, and angular distributions, for the e+e- -> ffbar process for centre-of-mass energies above the Z resonance, from sqrt(s) ~ 130 - 207 GeV at the LEP collider. The measurements are consistent with the predictions of the Standard Model and are used to study a variety of models including the S-Matrix ansatz for e+e- -> ffbar scattering and several models which include physics beyond the Standard Model: the exchange of Z' bosons, contact interactions between fermions, the exchange of gravitons in large extra dimensions and the exchange of sneutrino in R-parity violating supersymmetry.Comment: 79 pages, 16 figures, Accepted by Eur. Phys. J.