BCL11B regulates arterial stiffness and related target organ damage

RATIONALE: BCL11B (B-cell leukemia 11b) is a transcription factor known as an essential regulator of T lymphocytes and neuronal development during embryogenesis. A genome-wide association study showed that a gene desert region downstream of BCL11B, known to function as a BCL11B enhancer, harbors single nucleotide polymorphisms associated with increased arterial stiffness. However, a role for BCL11B in the adult cardiovascular system is unknown. OBJECTIVE: Based on these human findings, we sought to examine the relation between BCL11B and arterial function. METHODS AND RESULTS: Here we report that BCL11B is expressed in the vascular smooth muscle where it regulates vascular stiffness. RNA sequencing of aortas from wild-type and Bcl11b null mice (BSMKO) identified the cGMP (cyclic guanosine monophosphate)-cGMP-dependent protein kinase G (PKG) as the most significant differentially regulated signaling pathway in BSMKO compared with wild-type mice. BSMKO aortas showed decreased levels of PKG1, increased levels of Ca++-calmodulin-dependent serine/threonine phosphatase calcineurin (PP2B) and decreased levels of their common phosphorylation target, phosphorylated vasodilator-stimulated phosphoprotein (pVASPS239), a regulator of cytoskelatal actin rearrangements. Decreased pVASPS239 in BSMKO aortas was associated with increased actin polymerization (filamentous/globular actin ratio). Functionally, aortic force, stress, wall tension, and stiffness, measured ex vivo in organ baths, were increased in BSMKO aortas, and BSMKO mice had increased pulse wave velocity, the in vivo index of arterial stiffness. Despite having no effect on blood pressure or microalbuminuria, increased arterial stiffness in BSMKO mice was associated with increased incidence of cerebral microbleeds compared with age-matched wild-type littermates. CONCLUSIONS: We have identified vascular smooth muscle BCL11B as a crucial regulator of aortic smooth muscle function and a potential therapeutic target for vascular stiffness.R01 HL136311 - NHLBI NIH HHS; R01 AG053274 - NIA NIH HHS; R01 HL107385 - NHLBI NIH HHS; T32 HL007224 - NHLBI NIH HHS; P30 DK046200 - NIDDK NIH HHS; R01 HL105287 - NHLBI NIH HHS; R01 HL070100 - NHLBI NIH HHS; R01 HL126136 - NHLBI NIH HHS; R21 AG050599 - NIA NIH HHS; R01 HL080124 - NHLBI NIH HHS; R01 AI067846 - NIAID NIH HHSPublished versio

TRY plant trait database – enhanced coverage and open access

Plant traits - the morphological, anatomical, physiological, biochemical and phenological characteristics of plants - determine how plants respond to environmental factors, affect other trophic levels, and influence ecosystem properties and their benefits and detriments to people. Plant trait data thus represent the basis for a vast area of research spanning from evolutionary biology, community and functional ecology, to biodiversity conservation, ecosystem and landscape management, restoration, biogeography and earth system modelling. Since its foundation in 2007, the TRY database of plant traits has grown continuously. It now provides unprecedented data coverage under an open access data policy and is the main plant trait database used by the research community worldwide. Increasingly, the TRY database also supports new frontiers of trait‐based plant research, including the identification of data gaps and the subsequent mobilization or measurement of new data. To support this development, in this article we evaluate the extent of the trait data compiled in TRY and analyse emerging patterns of data coverage and representativeness. Best species coverage is achieved for categorical traits - almost complete coverage for ‘plant growth form’. However, most traits relevant for ecology and vegetation modelling are characterized by continuous intraspecific variation and trait–environmental relationships. These traits have to be measured on individual plants in their respective environment. Despite unprecedented data coverage, we observe a humbling lack of completeness and representativeness of these continuous traits in many aspects. We, therefore, conclude that reducing data gaps and biases in the TRY database remains a key challenge and requires a coordinated approach to data mobilization and trait measurements. This can only be achieved in collaboration with other initiatives

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

The aryl hydrocarbon receptor cell intrinsically promotes resident memory CD8+ T cell differentiation and function

Summary: The Aryl hydrocarbon receptor (Ahr) regulates the differentiation and function of CD4+ T cells; however, its cell-intrinsic role in CD8+ T cells remains elusive. Herein we show that Ahr acts as a promoter of resident memory CD8+ T cell (TRM) differentiation and function. Genetic ablation of Ahr in mouse CD8+ T cells leads to increased CD127–KLRG1+ short-lived effector cells and CD44+CD62L+ T central memory cells but reduced granzyme-B-producing CD69+CD103+ TRM cells. Genome-wide analyses reveal that Ahr suppresses the circulating while promoting the resident memory core gene program. A tumor resident polyfunctional CD8+ T cell population, revealed by single-cell RNA-seq, is diminished upon Ahr deletion, compromising anti-tumor immunity. Human intestinal intraepithelial CD8+ T cells also highly express AHR that regulates in vitro TRM differentiation and granzyme B production. Collectively, these data suggest that Ahr is an important cell-intrinsic factor for CD8+ T cell immunity

Identification and Occurrence of Analogues of Dechlorane 604 in Lake Ontario Sediment and their Accumulation in Fish

The dechlorane family of flame retardants, which includes Mirex (also known as Dechlorane), Dechlorane Plus (DP), and Dechloranes (Dec) 602, 603, and 604, were manufactured at a facility along the Niagara River, upstream of Lake Ontario. Some of these compounds remain in use. In a previous study, we found Mirex and Dec602 to have greater bioaccumulation potentials than Dec604 and DP based on calculated biota-sediment accumulation factors (BSAFs). In this study, analogues of Dec604, containing fewer bromines and mixed substitutions of bromine and chlorine, were identified in Lake Ontario sediment and fish using high and ultrahigh resolution mass spectrometric techniques. The tribromo-Dec604 (Br₃Dec604) analogue, known as Dechlorane 604 Component B (Dec604 CB), was present in lake trout and whitefish at concentrations of 10–60 ng/g lipid weight, approximately 50–200 times greater than concentrations measured for Dec604. In addition, BrDec604 and Br₂Dec604 analogues, and mixed Br₂Cl₂Dec604, Br₃ClDec604, Br₂ClDec604, and BrCl₂Dec604 analogues were also present. We have shown that solutions of Dec604 and Dec604 CB exposed to UV-light undergo photodebromination and give rise to the analogues found in sediment and fish. Dec604 CB and other lesser halogenated analogues of Dec604 show greater bioaccumulation potentials than Dec604, Dec602 and DP, based on BSAFs, which highlight the need to consider likely impurities and degradation products in the assessment of persistent, bioaccumulative, and toxic compounds

Stabilization of Nickel Complexes with Ni⁰···H–N Bonding Interactions Using Sterically Demanding Cyclic Diphosphine Ligands

The series of complexes Ni­(P^<i>t</i>Bu₂N^R₂)₂, [Ni­(P^<i>t</i>Bu₂N^R₂)₂]­BF₄, [HNi­(P^<i>t</i>Bu₂N^R₂)₂]­BF₄, and [Co­(P^<i>t</i>Bu₂N^Ph₂)₂]­BF₄ (P^<i>t</i>Bu₂N^R₂ = 1,5-dialkyl-3,7-<i>tert</i>-butyl-1,5-diaza-3,7-diphosphacyclooctane; alkyl = phenyl, benzyl) have been synthesized and characterized. Spectroscopic, electrochemical, and X-ray diffraction studies indicate these complexes are stable as a result of the tetrahedral arrangement of the two diphosphine ligands. Electrochemical oxidation of [HNi­(P^<i>t</i>Bu₂N^Ph₂)₂]­BF₄ results in rapid proton transfer from nickel at a rate faster than can be observed on the CV time scale. Double protonation of Ni­(P^<i>t</i>Bu₂N^Bn₂)₂ forms the endo-endo, endo-exo, and exo-exo isomers of [Ni­(P^<i>t</i>Bu₂N^BnHN^Bn)₂]­(BF₄)₂, which were found to be more stable toward loss of H₂ than previously observed for similar complexes. The presence of Ni⁰···HN hydrogen bonds at the endo protonation sites of [Ni­(P^<i>t</i>Bu₂N^BnHN^Bn)₂]­(BF₄)₂ results in significant differences in the Ni­(I/0) oxidation potentials of each of the isomers. The differences in <i>E</i>_1/2(I/0) values correspond to bond free energies of 7.4 and 3.7 kcal/mol for the first and second Ni⁰···HN hydrogen bonds of the endo-exo and endo-endo isomers, respectively. Computational studies give bond dissociation energies of the Ni⁰···HN bonds that are within 1–2 kcal/mol of the experimentally determined values

Stabilization of Nickel Complexes with Ni⁰···H–N Bonding Interactions Using Sterically Demanding Cyclic Diphosphine Ligands

The series of complexes Ni­(P^<i>t</i>Bu₂N^R₂)₂, [Ni­(P^<i>t</i>Bu₂N^R₂)₂]­BF₄, [HNi­(P^<i>t</i>Bu₂N^R₂)₂]­BF₄, and [Co­(P^<i>t</i>Bu₂N^Ph₂)₂]­BF₄ (P^<i>t</i>Bu₂N^R₂ = 1,5-dialkyl-3,7-<i>tert</i>-butyl-1,5-diaza-3,7-diphosphacyclooctane; alkyl = phenyl, benzyl) have been synthesized and characterized. Spectroscopic, electrochemical, and X-ray diffraction studies indicate these complexes are stable as a result of the tetrahedral arrangement of the two diphosphine ligands. Electrochemical oxidation of [HNi­(P^<i>t</i>Bu₂N^Ph₂)₂]­BF₄ results in rapid proton transfer from nickel at a rate faster than can be observed on the CV time scale. Double protonation of Ni­(P^<i>t</i>Bu₂N^Bn₂)₂ forms the endo-endo, endo-exo, and exo-exo isomers of [Ni­(P^<i>t</i>Bu₂N^BnHN^Bn)₂]­(BF₄)₂, which were found to be more stable toward loss of H₂ than previously observed for similar complexes. The presence of Ni⁰···HN hydrogen bonds at the endo protonation sites of [Ni­(P^<i>t</i>Bu₂N^BnHN^Bn)₂]­(BF₄)₂ results in significant differences in the Ni­(I/0) oxidation potentials of each of the isomers. The differences in <i>E</i>_1/2(I/0) values correspond to bond free energies of 7.4 and 3.7 kcal/mol for the first and second Ni⁰···HN hydrogen bonds of the endo-exo and endo-endo isomers, respectively. Computational studies give bond dissociation energies of the Ni⁰···HN bonds that are within 1–2 kcal/mol of the experimentally determined values

Hectd3 promotes pathogenic Th17 lineage through Stat3 activation and Malt1 signaling in neuroinflammation

Ubiquitination may control protein stability or function. Here the authors show that an ubiquitination enzyme, Hectd3, ubiquitinates Stat3 and Malt1 to modulate their function but not degradation in T cells, and thereby promoting the differentiation of pathogenic Th17 cells and susceptibility to a mouse model of multiple sclerosis