Antisense oligonucleotides (ASOs) and small interfering RNA (siRNA) promise specific correction of disease-causing gene expression. Therapeutic implementation, however, has been forestalled by poor ...delivery to the appropriate tissue, cell type, and subcellular compartment. Topical administration is considered to circumvent these issues. The availability of inhalation devices and unmet medical need in lung disease has focused efforts in this tissue. We report the development of a novel cell sorting method for quantitative, cell type-specific analysis of siRNA, and locked nucleic acid (LNA) ASO uptake and efficacy after intratracheal (i.t.) administration in mice. Through fluorescent dye labeling, we compare the utility of this approach to whole animal and whole tissue analysis, and examine the extent of tissue distribution. We detail rapid systemic access and renal clearance for both therapeutic classes and lack of efficacy at the protein level in lung macrophages, epithelia, or other cell types. We nevertheless observe efficient redirection of i.t. administered phosphorothioate (PS) LNA ASO to the liver and kidney leading to targeted gene knockdown. These data suggest delivery remains a key obstacle to topically administered, naked oligonucleotide efficacy in the lung and introduce inhalation as a potentially viable alternative to injection for antisense administration to the liver and kidneys.
Many daily behaviors rely critically on estimates of our body motion. Such estimates must be computed by combining neck proprioceptive signals with vestibular signals that have been transformed from ...a head- to a body-centered reference frame. Recent studies showed that deep cerebellar neurons in the rostral fastigial nucleus (rFN) reflect these computations, but whether they explicitly encode estimates of body motion remains unclear. A key limitation in addressing this question is that, to date, cell tuning properties have only been characterized for a restricted set of motions across head-re-body orientations in the horizontal plane. Here we examined, for the first time, how 3D spatiotemporal tuning for translational motion varies with head-re-body orientation in both horizontal and vertical planes in the rFN of male macaques. While vestibular coding was profoundly influenced by head-re-body position in both planes, neurons typically reflected at most a partial transformation. However, their tuning shifts were not random but followed the specific spatial trajectories predicted for a 3D transformation. We show that these properties facilitate the linear decoding of fully body-centered motion representations in 3D with a broad range of temporal characteristics from small groups of 5-7 cells. These results demonstrate that the vestibular reference frame transformation required to compute body motion is indeed encoded by cerebellar neurons. We propose that maintaining partially transformed rFN responses with different spatiotemporal properties facilitates the creation of downstream body motion representations with a range of dynamic characteristics, consistent with the functional requirements for tasks such as postural control and reaching.
Estimates of body motion are essential for many daily activities. Vestibular signals are important contributors to such estimates but must be transformed from a head- to a body-centered reference frame. Here, we provide the first direct demonstration that the cerebellum computes this transformation fully in 3D. We show that the output of these computations is reflected in the tuning properties of deep cerebellar rostral fastigial nucleus neurons in a specific distributed fashion that facilitates the efficient creation of body-centered translation estimates with a broad range of temporal properties (i.e., from acceleration to position). These findings support an important role for the rostral fastigial nucleus as a source of body translation estimates functionally relevant for behaviors ranging from postural control to perception.
We present new limits on exotic keV-scale physics based on 478 kg d of Majorana Demonstrator commissioning data. Constraints at the 90% confidence level are derived on bosonic dark matter (DM) and ...solar axion couplings, Pauli exclusion principle violating (PEPV) decay, and electron decay using monoenergetic peak signal limits above our background. Our most stringent DM constraints are set for 11.8 keV mass particles, limiting g_{Ae}<4.5×10^{-13} for pseudoscalars and (α^{'}/α)<9.7×10^{-28} for vectors. We also report a 14.4 keV solar axion coupling limit of g_{AN}^{eff}×g_{Ae}<3.8×10^{-17}, a 1/2β^{2}<8.5×10^{-48} limit on the strength of PEPV electron transitions, and a lower limit on the electron lifetime of τ_{e}>1.2×10^{24} yr for e^{-}→ invisible.
Planck 2018 results Aghanim, N.; Akrami, Y.; Ashdown, M. ...
Astronomy and astrophysics (Berlin),
09/2020, Letnik:
641
Journal Article
Recenzirano
Odprti dostop
Observations of the submillimetre emission from Galactic dust, in both total intensity
I
and polarization, have received tremendous interest thanks to the
Planck
full-sky maps. In this paper we make ...use of such full-sky maps of dust polarized emission produced from the third public release of
Planck
data. As the basis for expanding on astrophysical studies of the polarized thermal emission from Galactic dust, we present full-sky maps of the dust polarization fraction
p
, polarization angle
ψ
, and dispersion function of polarization angles . The joint distribution (one-point statistics) of
p
and
N
H
confirms that the mean and maximum polarization fractions decrease with increasing
N
H
. The uncertainty on the maximum observed polarization fraction,
p
max
= 22.0
−1.4
+3.5
% at 353 GHz and 80′ resolution, is dominated by the uncertainty on the Galactic emission zero level in total intensity, in particular towards diffuse lines of sight at high Galactic latitudes. Furthermore, the inverse behaviour between
p
and found earlier is seen to be present at high latitudes. This follows the ∝
p
−1
relationship expected from models of the polarized sky (including numerical simulations of magnetohydrodynamical turbulence) that include effects from only the topology of the turbulent magnetic field, but otherwise have uniform alignment and dust properties. Thus, the statistical properties of
p
,
ψ
, and for the most part reflect the structure of the Galactic magnetic field. Nevertheless, we search for potential signatures of varying grain alignment and dust properties. First, we analyse the product map ×
p
, looking for residual trends. While the polarization fraction
p
decreases by a factor of 3−4 between
N
H
= 10
20
cm
−2
and
N
H
= 2 × 10
22
cm
−2
, out of the Galactic plane, this product ×
p
only decreases by about 25%. Because is independent of the grain alignment efficiency, this demonstrates that the systematic decrease in
p
with
N
H
is determined mostly by the magnetic-field structure and not by a drop in grain alignment. This systematic trend is observed both in the diffuse interstellar medium (ISM) and in molecular clouds of the Gould Belt. Second, we look for a dependence of polarization properties on the dust temperature, as we would expect from the radiative alignment torque (RAT) theory. We find no systematic trend of ×
p
with the dust temperature
T
d
, whether in the diffuse ISM or in the molecular clouds of the Gould Belt. In the diffuse ISM, lines of sight with high polarization fraction
p
and low polarization angle dispersion tend, on the contrary, to have colder dust than lines of sight with low
p
and high . We also compare the
Planck
thermal dust polarization with starlight polarization data in the visible at high Galactic latitudes. The agreement in polarization angles is remarkable, and is consistent with what we expect from the noise and the observed dispersion of polarization angles in the visible on the scale of the
Planck
beam. The two polarization emission-to-extinction ratios,
R
P
/
p
and
R
S/V
, which primarily characterize dust optical properties, have only a weak dependence on the column density, and converge towards the values previously determined for translucent lines of sight. We also determine an upper limit for the polarization fraction in extinction,
p
V
/
E
(
B
−
V
), of 13% at high Galactic latitude, compatible with the polarization fraction
p
≈ 20% observed at 353 GHz. Taken together, these results provide strong constraints for models of Galactic dust in diffuse gas.
Predicting clinically significant drug interactions during drug development is a challenge for the pharmaceutical industry and regulatory agencies. Since the publication of the US Food and Drug ...Administration's (FDA's) first in vitro and in vivo drug interaction guidance documents in 1997 and 1999, researchers and clinicians have gained a better understanding of drug interactions. This knowledge has enabled the FDA and the industry to progress and begin to overcome these challenges. The FDA has continued its efforts to evaluate methodologies to study drug interactions and communicate recommendations regarding the conduct of drug interaction studies, particularly for CYP‐based and transporter‐based drug interactions, to the pharmaceutical industry. A drug interaction Web site was established to document the FDA's current understanding of drug interactions (http:www.fda.govcderdrugdrugInteractionsdefault.htm). This report provides an overview of the evolution of the drug interaction guidances, includes a synopsis of the steps taken by the FDA to revise the original drug interaction guidance documents, and summarizes and highlights updated sections in the current guidance document, Drug Interaction Studies—Study Design, Data Analysis, and Implications for Dosing and Labeling.
Toll-like receptor 9 (TLR9) agonists are being developed for treatment of colorectal and other cancers, yet the impact of these drugs on human intestines remains unknown. This, together with the fact ...that there are additional potential indications for TLR9 agonist therapy (e.g., autoimmune and infectious diseases), led us to investigate the impact of MGN1703 (Lefitolimod) on intestinal homeostasis and viral persistence in HIV-positive individuals. Colonic sigmoid biopsies were collected (baseline and week four) from 11 HIV+ individuals on suppressive antiretroviral therapy, who received MGN1703 (60 mg s.c.) twice weekly for 4 weeks in a single-arm, phase 1b/2a study. Within sigmoid mucosa, global transcriptomic analyses revealed 248 modulated genes (false discovery rate<0.05) including many type I interferon (IFN)-stimulated genes. MGN1703 increased the frequencies of cells exhibiting MX1 (P=0.001) and ISG15 (P=0.014) protein expression. No changes were observed in neutrophil infiltration (myeloperoxidase; P=0.97). No systematic effect on fecal microbiota structure was observed (analysis of similarity Global R=-0.105; P=0.929). TLR9 expression at baseline was inversely proportional to the change in integrated HIV DNA during MGN1703 treatment (P=0.020). In conclusion, MGN1703 induced a potent type I IFN response, without a concomitant general inflammatory response, in the intestines.
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