Therapeutic agents that block the calcitonin gene-related peptide (CGRP) signaling pathway are a highly anticipated and promising new drug class for migraine therapy, especially after reports that ...small-molecule CGRP-receptor antagonists are efficacious for both acute migraine treatment and migraine prevention. Using XenoMouse technology, we successfully generated AMG 334, a fully human monoclonal antibody against the CGRP receptor. Here we show that AMG 334 competes with (125)I-CGRP binding to the human CGRP receptor, with a Ki of 0.02 nM. AMG 334 fully inhibited CGRP-stimulated cAMP production with an IC50 of 2.3 nM in cell-based functional assays (human CGRP receptor) and was 5000-fold more selective for the CGRP receptor than other human calcitonin family receptors, including adrenomedullin, calcitonin, and amylin receptors. The potency of AMG 334 at the cynomolgus monkey (cyno) CGRP receptor was similar to that at the human receptor, with an IC50 of 5.7 nM, but its potency at dog, rabbit, and rat receptors was significantly reduced (>5000-fold). Therefore, in vivo target coverage of AMG 334 was assessed in cynos using the capsaicin-induced increase in dermal blood flow model. AMG 334 dose-dependently prevented capsaicin-induced increases in dermal blood flow on days 2 and 4 postdosing. These results indicate AMG 334 is a potent, selective, full antagonist of the CGRP receptor and show in vivo dose-dependent target coverage in cynos. AMG 334 is currently in clinical development for the prevention of migraine.
Abstract
Research studies based on tractography have revealed a prominent reduction of asymmetry in some key white-matter tracts in schizophrenia (SCZ). However, we know little about the influence of ...common genetic risk factors for SCZ on the efficiency of routing on structural brain networks (SBNs). Here, we use a novel recall-by-genotype approach, where we sample young adults from a population-based cohort (ALSPAC:N genotyped = 8,365) based on their burden of common SCZ risk alleles as defined by polygenic risk score (PRS). We compared 181 individuals at extremes of low (N = 91) or high (N = 90) SCZ-PRS under a robust diffusion MRI-based graph theoretical SBN framework. We applied a semi-metric analysis revealing higher SMR values for the high SCZ-PRS group compared with the low SCZ-PRS group in the left hemisphere. Furthermore, a hemispheric asymmetry index showed a higher leftward preponderance of indirect connections for the high SCZ-PRS group compared with the low SCZ-PRS group (PFDR < 0.05). These findings might indicate less efficient structural connectivity in the higher genetic risk group. This is the first study in a population-based sample that reveals differences in the efficiency of SBNs associated with common genetic risk variants for SCZ.
Kisspeptins are products of the KiSS-1 gene, which bind to a G protein-coupled receptor known as GPR54. Mutations or targeted disruptions in the GPR54 gene cause hypogonadotropic hypogonadism in ...humans and mice, suggesting that kisspeptin signaling may be important for the regulation of gonadotropin secretion. To examine the effects of kisspeptin-54 (metastin) and kisspeptin-10 (the biologically active C-terminal decapeptide) on gonadotropin secretion in the mouse, we administered the kisspeptins directly into the lateral cerebral ventricle of the brain and demonstrated that both peptides stimulate LH secretion. Further characterization of kisspeptin-54 demonstrated that it stimulated both LH and FSH secretion, at doses as low as 1 fmol; moreover, this effect was shown to be blocked by pretreatment with acyline, a potent GnRH antagonist. To learn more about the functional anatomy of kisspeptins, we mapped the distribution of KiSS-1 mRNA in the hypothalamus. We observed that KiSS-1 mRNA is expressed in areas of the hypothalamus implicated in the neuroendocrine regulation of gonadotropin secretion, including the anteroventral periventricular nucleus, the periventricular nucleus, and the arcuate nucleus. We conclude that kisspeptin-GPR54 signaling may be part of the hypothalamic circuitry that governs the hypothalamic secretion of GnRH.
The ultraviolet-to-radio continuum spectral energy distributions are presented for all 75 galaxies in the Spitzer Infrared Nearby Galaxies Survey (SINGS). A principal component analysis of the sample ...shows that most of the sample's spectral variations stem from two underlying components one representative of a galaxy with a low infrared-to-ultraviolet ratio and one representative of a galaxy with a high infrared-to-ultraviolet ratio. The influence of several parameters on the infrared-to-ultraviolet ratio is studied (e.g., optical morphology, disk inclination, far-infrared color, ultraviolet spectral slope, and star formation history). Consistent with our understanding of normal star-forming galaxies, the SINGS sample of galaxies in comparison to more actively star-forming galaxies exhibits a larger dispersion in the infrared-to-ultraviolet versus ultraviolet spectral slope correlation. Early-type galaxies, exhibiting low star formation rates and high optical surface brightnesses, have the most discrepant infrared-to-ultraviolet correlation. These results suggest that the star formation history may be the dominant regulator of the broadband spectral variations between galaxies. Finally, a new discovery shows that the 24 km morphology can be a useful tool for parameterizing the global dust temperature and ultraviolet extinction in nearby galaxies. The dust emission in dwarf/irregular galaxies is clumpy and warm accompanied by low ultraviolet extinction, while in spiral galaxies there is typically a much larger diffuse component of cooler dust and average ultraviolet extinction. For galaxies with nuclear 24 km emission, the dust temperature and ultraviolet extinction are relatively high compared to disk galaxies.
ABSTRACT
At 66 Mpc, AT2019qiz is the closest optical tidal disruption event (TDE) to date, with a luminosity intermediate between the bulk of the population and the faint-and-fast event iPTF16fnl. ...Its proximity allowed a very early detection and triggering of multiwavelength and spectroscopic follow-up well before maximum light. The velocity dispersion of the host galaxy and fits to the TDE light curve indicate a black hole mass ≈106 M⊙, disrupting a star of ≈1 M⊙. By analysing our comprehensive UV, optical, and X-ray data, we show that the early optical emission is dominated by an outflow, with a luminosity evolution L ∝ t2, consistent with a photosphere expanding at constant velocity (≳2000 km s−1), and a line-forming region producing initially blueshifted H and He ii profiles with v = 3000–10 000 km s−1. The fastest optical ejecta approach the velocity inferred from radio detections (modelled in a forthcoming companion paper from K. D. Alexander et al.), thus the same outflow may be responsible for both the fast optical rise and the radio emission – the first time this connection has been observed in a TDE. The light-curve rise begins 29 ± 2 d before maximum light, peaking when the photosphere reaches the radius where optical photons can escape. The photosphere then undergoes a sudden transition, first cooling at constant radius then contracting at constant temperature. At the same time, the blueshifts disappear from the spectrum and Bowen fluorescence lines (N iii) become prominent, implying a source of far-UV photons, while the X-ray light curve peaks at ≈1041 erg s−1. Assuming that these X-rays are from prompt accretion, the size and mass of the outflow are consistent with the reprocessing layer needed to explain the large optical to X-ray ratio in this and other optical TDEs, possibly favouring accretion-powered over collision-powered outflow models.
Abstract
We present reverberation mapping results from the first year of combined spectroscopic and photometric observations of the Sloan Digital Sky Survey Reverberation Mapping Project. We ...successfully recover reverberation time delays between the
g
+
i
band emission and the broad H
β
emission line for a total of 44 quasars, and for the broad H
α
emission line in 18 quasars. Time delays are computed using the
JAVELIN
and
CREAM
software and the traditional interpolated cross-correlation function (ICCF): using well-defined criteria, we report measurements of 32 H
β
and 13 H
α
lags with
JAVELIN
, 42 H
β
and 17 H
α
lags with
CREAM
, and 16 H
β
and eight H
α
lags with the ICCF. Lag values are generally consistent among the three methods, though we typically measure smaller uncertainties with
JAVELIN
and
CREAM
than with the ICCF, given the more physically motivated light curve interpolation and more robust statistical modeling of the former two methods. The median redshift of our H
β
-detected sample of quasars is 0.53, significantly higher than that of the previous reverberation mapping sample. We find that in most objects, the time delay of the H
α
emission is consistent with or slightly longer than that of H
β
. We measure black hole masses using our measured time delays and line widths for these quasars. These black hole mass measurements are mostly consistent with expectations based on the local
–
relationship, and are also consistent with single-epoch black hole mass measurements. This work increases the current sample size of reverberation-mapped active galaxies by about two-thirds and represents the first large sample of reverberation mapping observations beyond the local universe (
z
< 0.3).
In his Rerum vulgarium fragmenta, Francesco Petrarch introduced a new poetic strategy of deliberate and beneficial failure as a central requirement of literary love and a means of unifying a newly ...complex and fragmented literary subjectivity. In his rendering of Petrarch, Thomas Wyatt carries this celebration of necessary failure into the sixteenth century. By making Petrarchan failure central to his own concerns, Wyatt changes its fundamental nature. This is more than simply transferring the same narrative strategies into a new historical context. In lifting poetic love out of the realm of the spiritual, and rooting it firmly in the context of a purely secular striving, Wyatt effectively raises the stakes and alters the meaning of the poetic dynamic he embraces. What was, in Petrarch, a narrative strategy—an important part of the fictional construct—becomes for Wyatt, and the English Petrarchists who followed him, a structural element of the lyric form and a new basis for the construction of the literary self—I fail, therefore I am.
Purpose
Benefit from convalescent plasma therapy for coronavirus disease 2019 (COVID-19) has been inconsistent in randomized clinical trials (RCTs) involving critically ill patients. As COVID-19 ...patients are immunologically heterogeneous, we hypothesized that immunologically similar COVID-19 subphenotypes may differ in their treatment responses to convalescent plasma and explain inconsistent findings between RCTs .
Methods
We tested this hypothesis in a substudy involving 1239 patients, by measuring 26 biomarkers (cytokines, chemokines, endothelial biomarkers) within the randomized, embedded, multifactorial, adaptive platform trial for community-acquired pneumonia (REMAP-CAP) that assigned 2097 critically ill COVID-19 patients to either high-titer convalescent plasma or usual care. Primary outcome was organ support free days at 21 days (OSFD-21) .
Results
Unsupervised analyses identified three subphenotypes/endotypes. In contrast to the more homogeneous subphenotype-2 (
N
= 128 patients, 10.3%; with elevated type i and type ii effector immune responses) and subphenotype-3 (
N
= 241, 19.5%; with exaggerated inflammation), the subphenotype-1 had variable biomarker patterns (
N
= 870 patients, 70.2%). Subphenotypes-2, and -3 had worse outcomes, and subphenotype-1 had better outcomes with convalescent plasma therapy compared with usual care (median (IQR). OSFD-21 in convalescent plasma vs usual care was 0 (− 1, 21) vs 10 (− 1, to 21) in subphenotype-2; 1.5 (− 1, 21) vs 12 (− 1, to 21) in suphenotype-3, and 0 (− 1, 21) vs 0 (− 1, to 21) in subphenotype-1 (test for between-subphenotype differences in treatment effects
p
= 0.008).
Conclusions
We reported three COVID-19 subphenotypes, among critically ill adults, with differential treatment effects to ABO-compatible convalescent plasma therapy. Differences in subphenotype prevalence between RCT populations probably explain inconsistent results with COVID-19 immunotherapies.
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