To date, the mRNA delivery field has been heavily dominated by lipid‐based systems. Reports on the use of nonlipid carriers for mRNA delivery in contrast are rare in the context of mRNA vaccination. ...This paper describes the potential of a cell‐penetrating peptide containing the amphipathic RALA motif to deliver antigen‐encoding mRNA to the immune system. RALA condenses mRNA into nanocomplexes that display acidic pH‐dependent membrane disruptive properties. RALA mRNA nanocomplexes enable mRNA escape from endosomes and thereby allow expression of mRNA inside the dendritic cell cytosol. Strikingly, RALA mRNA nanocomplexes containing pseudouridine and 5‐methylcytidine modified mRNA elicit potent cytolytic T cell responses against the antigenic mRNA cargo and show superior efficacy in doing so when compared to RALA mRNA nanocomplexes containing unmodified mRNA. RALA's unique sequence and structural organization are vital to act as mRNA vaccine vehicle, as arginine‐rich peptide variants that lack the RALA motif show reduced mRNA complexation, impaired cellular uptake and lose the ability to transfect dendritic cells in vitro and to evoke T cell immunity in vivo.
T‐cell immunity elicited by mRNA vaccines is heavily influenced by the delivery system. Cell penetrating peptide containing amphipathic RALA motifs condenses mRNA into nanocomplexes that efficiently translocate their mRNA cargo from endocytic vesicles to the cytosol. Through unique immune activation and enhanced expression, nucleoside modified mRNA complexed with RALA peptide induces potent antigen specific cytolytic T cells in vivo.
R-spondin1 is a secreted regulator of WNT signaling, involved in both embryonic development and homeostasis of adult organs. It can have a dual role, acting either as a mitogen or as a tumor ...suppressor. During ovarian development, Rspo1 is a key factor required for sex determination and differentiation of the follicular cell progenitors, but is downregulated after birth. In human, increased RSPO1 expression is associated with ovarian carcinomas, but it is not clear whether it is a cause or a consequence of the tumorigenic process. To address the role of Rspo1 expression in adult ovaries, we generated an Rspo1 gain-of-function mouse model. Females were hypofertile and exhibited various ovarian defects, ranging from cysts to ovarian tumors. Detailed phenotypical characterization showed anomalies in the ovulation process. Although follicles responded to initial follicle-stimulating hormone stimulation and developed normally until the pre-ovulatory stage, they did not progress any further. Although non-ovulated oocytes degenerated, the surrounding follicular cells did not begin atresia. RSPO1-induced expression not only promotes canonical WNT signaling but also alters granulosa cell fate decisions by maintaining epithelial-like traits in these cells. This prevents follicle cells from undergoing apoptosis, leading to the accumulation of granulosa cell tumors that reactivates the epithelial program from their progenitors. Taken together, our data demonstrate that activation of RSPO1 is sufficient in promoting ovarian tumors and thus supports a direct involvement of this gene in the commencement of ovarian cancers.
A
bstract
We propose an approach for measuring the moments of the hadronic invariant mass distribution in semileptonic
B
s
0
meson decays using a sum-of-exclusive technique. Using the present and ...foreseen knowledge about exclusive semileptonic
B
s
0
decays, we estimate the uncertainties on moments of the kinematic distribution. Semileptonic
B
s
0
decays can be described, as their
B
0
counterpart, using the Heavy Quark Expansion (HQE), with the only difference between the
B
s
0
and
B
0
mesons being the SU(3)
F
breaking effects that change the numerical values of the non-perturbative HQE parameters. We extract the HQE parameters for the
B
s
0
decays from our estimates of the moments, showing the potential of the proposed method. We identify a set of required measurements for a future precision measurement.
A bstract We propose an approach for measuring the moments of the hadronic invariant mass distribution in semileptonic $$ {B}_s^0 $$ B s 0 meson decays using a sum-of-exclusive technique. Using the ...present and foreseen knowledge about exclusive semileptonic $$ {B}_s^0 $$ B s 0 decays, we estimate the uncertainties on moments of the kinematic distribution. Semileptonic $$ {B}_s^0 $$ B s 0 decays can be described, as their B 0 counterpart, using the Heavy Quark Expansion (HQE), with the only difference between the $$ {B}_s^0 $$ B s 0 and B 0 mesons being the SU(3) F breaking effects that change the numerical values of the non-perturbative HQE parameters. We extract the HQE parameters for the $$ {B}_s^0 $$ B s 0 decays from our estimates of the moments, showing the potential of the proposed method. We identify a set of required measurements for a future precision measurement.
Expression of heat shock proteins (hsp) is a homeostatic mechanism induced in both prokaryotic and eukaryotic cells in response to metabolic and environmental insults. A growing body of evidence ...suggests that in mammals, the hsp response is integrated with physiological responses through neuroendocrine signaling. In the present study, we have examined the effect of noradrenaline (NA) on the hsp70 response in mollusc immune cells. Oyster and abalone hemocytes transfected with a gene construct containing a gastropod hsp70 gene promoter linked to the luciferase reporter-gene were exposed to physiological concentrations of NA, or to various alpha- and beta-adrenoceptor agonists and antagonists. Results show that NA and alpha-adrenergic stimulations induced the expression of luciferase in transfected mollusc immunocytes. Furthermore, exposure of hemocytes to NA or to the alpha-adrenoceptor agonist phenylephrine (PE) resulted in the expression of the inducible isoform of the hsp70 protein. Pertussis toxin (PTX), the phospholipase C (PLC) inhibitor U73122, the protein kinase C (PKC) inhibitor calphostin C, the Ca(2+)-dependent PKC inhibitor Gö 6976 and the phosphatidylinositol 3-kinase (PI 3-kinase) inhibitor LY294002 blocked the PE-mediated induction of the hsp70 gene promoter. These results suggest that alpha-adrenergic signaling induces the transcriptionnal upregulation of hsp70 in mollusc hemocytes through a PTX-sensitive G-protein, PLC, Ca(2+)-dependent PKC and PI 3-kinase. Thus, a functional link exists between neuroendocrine signaling and the hsp70 response in mollusc immune cells.
We present an alternative implementation of the Kalman filter employed for track fitting within the LHCb experiment. It uses simple parametrizations for the extrapolation of particle trajectories in ...the field of the LHCb dipole magnet and for the effects of multiple scattering in the detector material. A speedup of more than a factor of four is achieved while maintaining the quality of the estimated track quantities. This Kalman filter implementation could be used in the purely software-based trigger of the LHCb upgrade.
In the Standard Model of particle physics, the strength of the couplings of the b quark to the u and c quarks, |Vub| and |Vcb|, are governed by the coupling of the quarks to the Higgs boson. Using ...data from the LHCb experiment at the Large Hadron Collider, the probability for the Λb0 baryon to decay into the p final state relative to the final state is measured. Combined with theoretical calculations of the strong interaction and a previously measured value of |Vcb|, the first |Vub| measurement to use a baryonic decay is performed. This measurement is consistent with previous determinations of |Vub| using B meson decays to specific final states and confirms the existing incompatibility with those using an inclusive sample of final states.
The production of the
η
c
(
1
S
)
state in proton-proton collisions is probed via its decay to the
p
p
¯
final state with the LHCb detector, in the rapidity range
2.0
<
y
<
4.5
and in the meson ...transverse-momentum range
p
T
>
6.5
GeV
/
c
. The cross-section for prompt production of
η
c
(
1
S
)
mesons relative to the prompt
J
/
ψ
cross-section is measured, for the first time, to be
σ
η
c
(
1
S
)
/
σ
J
/
ψ
=
1.74
±
0.29
±
0.28
±
0
.
18
B
at a centre-of-mass energy
s
=
7
TeV
using data corresponding to an integrated luminosity of 0.7 fb
-
1
, and
σ
η
c
(
1
S
)
/
σ
J
/
ψ
=
1.60
±
0.29
±
0.25
±
0
.
17
B
at
s
=
8
TeV
using 2.0 fb
-
1
. The uncertainties quoted are, in order, statistical, systematic, and that on the ratio of branching fractions of the
η
c
(
1
S
)
and
J
/
ψ
decays to the
p
p
¯
final state. In addition, the inclusive branching fraction of
b
-hadron decays into
η
c
(
1
S
)
mesons is measured, for the first time, to be
B
(
b
→
η
c
X
)
=
(
4.88
±
0.64
±
0.29
±
0
.
67
B
)
×
10
-
3
, where the third uncertainty includes also the uncertainty on the
J
/
ψ
inclusive branching fraction from
b
-hadron decays. The difference between the
J
/
ψ
and
η
c
(
1
S
)
meson masses is determined to be
114.7
±
1.5
±
0.1
MeV
/
c
2
.
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