Germinal centres (GCs) promote humoral immunity and vaccine efficacy. In GCs, antigen-activated B cells proliferate, express high-affinity antibodies, promote antibody class switching, and yield B ...cell memory. Whereas the cytokine milieu has long been known to regulate effector functions that include the choice of immunoglobulin class, both cell-autonomous and extrinsic metabolic programming have emerged as modulators of T-cell-mediated immunity. Here we show in mice that GC light zones are hypoxic, and that low oxygen tension () alters B cell physiology and function. In addition to reduced proliferation and increased B cell death, low impairs antibody class switching to the pro-inflammatory IgG2c antibody isotype by limiting the expression of activation-induced cytosine deaminase (AID). Hypoxia induces HIF transcription factors by restricting the activity of prolyl hydroxyl dioxygenase enzymes, which hydroxylate HIF-1α and HIF-2α to destabilize HIF by binding the von Hippel-Landau tumour suppressor protein (pVHL). B-cell-specific depletion of pVHL leads to constitutive HIF stabilization, decreases antigen-specific GC B cells and undermines the generation of high-affinity IgG, switching to IgG2c, early memory B cells, and recall antibody responses. HIF induction can reprogram metabolic and growth factor gene expression. Sustained hypoxia or HIF induction by pVHL deficiency inhibits mTOR complex 1 (mTORC1) activity in B lymphoblasts, and mTORC1-haploinsufficient B cells have reduced clonal expansion, AID expression, and capacities to yield IgG2c and high-affinity antibodies. Thus, the normal physiology of GCs involves regional variegation of hypoxia, and HIF-dependent oxygen sensing regulates vital functions of B cells. We propose that the restriction of oxygen in lymphoid organs, which can be altered in pathophysiological states, modulates humoral immunity.
The Single-cloud Star Formation Relation Pokhrel, Riwaj; Gutermuth, Robert A.; Krumholz, Mark R. ...
Astrophysical journal. Letters,
05/2021, Letnik:
912, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Abstract
One of the most important and well-established empirical results in astronomy is the Kennicutt–Schmidt relation between the density of interstellar gas and the rate at which that gas forms ...stars. A tight correlation between these quantities has long been measured at galactic scales. More recently, using surveys of YSOs, a KS relationship has been found within molecular clouds relating the surface density of star formation to the surface density of gas; however, the scaling of these laws varies significantly from cloud to cloud. In this Letter, we use a recently developed, high-accuracy catalog of young stellar objects from Spitzer combined with high-dynamic-range gas column density maps of 12 nearby (<1.5 kpc) molecular clouds from Herschel to re-examine the KS relation within individual molecular clouds. We find a tight, linear correlation between clouds’ star formation rate per unit area and their gas surface density normalized by the gas freefall time. The measured intracloud KS relation, which relates star formation rate to the volume density, extends over more than two orders of magnitude within each cloud and is nearly identical in each of the 12 clouds, implying a constant star formation efficiency per freefall time
ϵ
ff
≈ 0.026. The finding of a universal correlation within individual molecular clouds, including clouds that contain no massive stars or massive stellar feedback, favors models in which star formation is regulated by local processes such as turbulence or stellar feedback such as protostellar outflows, and disfavors models in which star formation is regulated only by galaxy properties or supernova feedback on galactic scales.
A key legacy of the recently launched the Transiting Exoplanet Survey Satellite (TESS) mission will be to provide the astronomical community with many of the best transiting exoplanet targets for ...atmospheric characterization. However, time is of the essence to take full advantage of this opportunity. The James Webb Space Telescope (JWST), although delayed, will still complete its nominal five year mission on a timeline that motivates rapid identification, confirmation, and mass measurement of the top atmospheric characterization targets from TESS. Beyond JWST, future dedicated missions for atmospheric studies such as the Atmospheric Remote-sensing Infrared Exoplanet Large-survey (ARIEL) require the discovery and confirmation of several hundred additional sub-Jovian size planets (Rp < 10 R⊕) orbiting bright stars, beyond those known today, to ensure a successful statistical census of exoplanet atmospheres. Ground-based extremely large telescopes (ELTs) will also contribute to surveying the atmospheres of the transiting planets discovered by TESS. Here we present a set of two straightforward analytic metrics, quantifying the expected signal-to-noise in transmission and thermal emission spectroscopy for a given planet, that will allow the top atmospheric characterization targets to be readily identified among the TESS planet candidates. Targets that meet our proposed threshold values for these metrics would be encouraged for rapid follow-up and confirmation via radial velocity mass measurements. Based on the catalog of simulated TESS detections by Sullivan et al., we determine appropriate cutoff values of the metrics, such that the TESS mission will ultimately yield a sample of ∼300 high-quality atmospheric characterization targets across a range of planet size bins, extending down to Earth-size, potentially habitable worlds.
Redox-Active Ligands in Catalysis Praneeth, Vijayendran K. K.; Ringenberg, Mark R.; Ward, Thomas R.
Angewandte Chemie (International ed.),
October 8, 2012, Letnik:
51, Številka:
41
Journal Article
Recenzirano
Nature’s use of redox‐active moieties combined with 3d transition‐metal ions is a powerful strategy to promote multi‐electron catalytic reactions. The ability of these moieties to store redox ...equivalents aids metalloenzymes in promoting multi‐electron reactions, avoiding high‐energy intermediates. In a biomimetic spirit, chemists have recently developed approaches relying on redox‐active moieties in the vicinity of metal centers to catalyze challenging transformations. This approach enables chemists to impart noble‐metal character to less toxic, and cost effective 3d transitional metals, such as Fe or Cu, in multi‐electron catalytic reactions.
Juggling with both hands: For sustainable energy, mastering multi‐electron catalytic processes is the key feature. To address this challenge, nature combines redox‐active metals with redox‐active mediators or ligands. The resulting catalytic transformations (e.g. water splitting, CO2 reduction, CH activation) proceed with low kinetic barriers. This Minireview highlights recent examples of homogeneous catalysis involving redox‐active ligands.
A rich body of literature exists that has demonstrated adverse human health effects following exposure to ambient air particulate matter (PM), and there is strong support for an important role of ...ultrafine (nanosized) particles. At present, relatively few human health or epidemiology data exist for engineered nanomaterials (NMs) despite clear parallels in their physicochemical properties and biological actions in
models.
NMs are available with a range of physicochemical characteristics, which allows a more systematic toxicological analysis. Therefore, the study of ultrafine particles (UFP, <100 nm in diameter) provides an opportunity to identify plausible health effects for NMs, and the study of NMs provides an opportunity to facilitate the understanding of the mechanism of toxicity of UFP.
A workshop of experts systematically analyzed the available information and identified 19 key lessons that can facilitate knowledge exchange between these discipline areas.
Key lessons range from the availability of specific techniques and standard protocols for physicochemical characterization and toxicology assessment to understanding and defining dose and the molecular mechanisms of toxicity. This review identifies a number of key areas in which additional research prioritization would facilitate both research fields simultaneously.
There is now an opportunity to apply knowledge from NM toxicology and use it to better inform PM health risk research and vice versa. https://doi.org/10.1289/EHP424.
Neuroligins (NLs) are a family of neural cell-adhesion molecules that are involved in excitatory/inhibitory synapse specification. Multiple members of the NL family (including NL1) and their binding ...partners have been linked to cases of human autism and mental retardation. We have now characterized NL1-deficient mice in autism- and mental retardation-relevant behavioral tasks. NL1 knock-out (KO) mice display deficits in spatial learning and memory that correlate with impaired hippocampal long-term potentiation. In addition, NL1 KO mice exhibit a dramatic increase in repetitive, stereotyped grooming behavior, a potential autism-relevant abnormality. This repetitive grooming abnormality in NL1 KO mice is associated with a reduced NMDA/AMPA ratio at corticostriatal synapses. Interestingly, we further demonstrate that the increased repetitive grooming phenotype can be rescued in adult mice by administration of the NMDA receptor partial coagonist d-cycloserine. Broadly, these data are consistent with a role of synaptic cell-adhesion molecules in general, and NL1 in particular, in autism and implicate reduced excitatory synaptic transmission as a potential mechanism and treatment target for repetitive behavioral abnormalities.
Berzosertib (formerly M6620, VX-970) is a highly potent and selective, first-in-class inhibitor of ataxia telangiectasia and Rad3-related protein kinase (ATR). We assessed multiple ascending doses of ...berzosertib + gemcitabine ± cisplatin in patients with resistant/refractory advanced solid tumours.
We evaluated the safety, tolerability, pharmacokinetics (PK) and preliminary efficacy of intravenous berzosertib + gemcitabine ± cisplatin using a standard 3 + 3 dose-escalation design. The starting doses were berzosertib 18 mg/m
, gemcitabine 875 mg/m
and cisplatin 60 mg/m
.
Fifty-two patients received berzosertib + gemcitabine and eight received berzosertib + gemcitabine + cisplatin. Four patients receiving berzosertib + gemcitabine had a total of seven dose-limiting toxicities (DLTs) and three receiving berzosertib + gemcitabine + cisplatin had a total of three DLTs. Berzosertib 210 mg/m
(days 2 and 9) + gemcitabine 1000 mg/m
(days 1 and 8) Q3W was established as the recommended Phase 2 dose (RP2D); no RP2D was determined for berzosertib + gemcitabine + cisplatin. Neither gemcitabine nor cisplatin affected berzosertib PK. Most patients in both arms achieved a best response of either partial response or stable disease.
Berzosertib + gemcitabine was well tolerated in patients with advanced solid tumours and showed preliminary efficacy signs.
NCT02157792.
The genomic resources that are available to the grapevine research community have increased enormously during the past five years, in parallel with a renewed interest in grapevine (
Vitis vinifera ...L.) germplasm resources and analysis of genetic diversity in grapes. Genetic variation, either natural or induced, is invaluable for crop improvement and understanding gene function, and the same is true for the grapevine. The history and vineyard cultural practices have largely determined the genetic diversity that exists today in grapevines. In this article, we provide a synopsis of what is known about the origin and genetics of grapes and how molecular genetics is helping us understand more about this plant: its evolution, historical development, genetic diversity and potential for genetic improvement.
The cell of origin and the tumor microenvironment's role remain elusive for the most common peripheral T-cell lymphomas (PTCLs). As macrophages promote the growth and survival of malignant T cells ...and are abundant constituents of the tumor microenvironment, their functional polarization was examined in T-cell lymphoproliferative disorders. Cytokines that are abundant within the tumor microenvironment, particularly interleukin (IL)-10, were observed to promote alternative macrophage polarization. Macrophage polarization was signal transducer and activator of transcription 3 dependent and was impaired by the Janus kinase inhibitor ruxolitinib. In conventional T cells, the production of T helper (Th)2-associated cytokines and IL-10, both of which promote alternative macrophage polarization, is regulated by the T-cell transcription factor GATA-binding protein 3 (GATA-3). Therefore, its role in the T-cell lymphomas was examined. GATA-3 expression was observed in 45% of PTCLs, not otherwise specified (PTCL, NOS) and was associated with distinct molecular features, including the production of Th2-associated cytokines. In addition, GATA-3 expression identified a subset of PTCL, NOS with distinct clinical features, including inferior progression-free and overall survival. Collectively, these data suggest that further understanding the cell of origin and lymphocyte ontogeny among the T-cell lymphomas may improve our understanding of the tumor microenvironment's pathogenic role in these aggressive lymphomas.
•Alternatively polarized macrophages are abundant constituents of the tumor microenvironment in T-cell lymphoproliferative disorders.•GATA-3 expression identifies a subset of PTCL, NOS with a distinct cytokine profile and inferior survival.
Deletions in the neurexin-1α gene were identified in large-scale unbiased screens for copy-number variations in patients with autism or schizophrenia. To explore the underlying biology, we studied ...the electrophysiological and behavioral phenotype of mice lacking neurexin-1α. Hippocampal slice physiology uncovered a defect in excitatory synaptic strength in neurexin-1α deficient mice, as revealed by a decrease in miniature excitatory postsynaptic current (EPSC) frequency and in the input-output relation of evoked postsynaptic potentials. This defect was specific for excitatory synaptic transmission, because no change in inhibitory synaptic transmission was observed in the hippocampus. Behavioral studies revealed that, compared with littermate control mice, neurexin-1α deficient mice displayed a decrease in prepulse inhibition, an increase in grooming behaviors, an impairment in nest-building activity, and an improvement in motor learning. However, neurexin-1α deficient mice did not exhibit any obvious changes in social behaviors or in spatial learning. Together, these data indicate that the neurexin-1α deficiency induces a discrete neural phenotype whose extent correlates, at least in part, with impairments observed in human patients.
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