Niemann-Pick type C1 (NPC1) disease is a lysosomal lipid storage disorder caused by mutations of the NPC1 gene. More than 300 disease-associated mutations are reported in patients, resulting in ...abnormal accumulation of unesterified cholesterol, glycosphingolipids, and other lipids in late endosomes and lysosomes (LE/Ly) of many cell types. Previously, we showed that treatment of many different NPC1 mutant fibroblasts with histone deacetylase inhibitors resulted in reduction of cholesterol storage, and we found that this was associated with enhanced exit of the NPC1 protein from the endoplasmic reticulum and delivery to LE/Ly. This suggested that histone deacetylase inhibitors may work through changes in protein chaperones to enhance the folding of NPC1 mutants, allowing them to be delivered to LE/Ly. In this study, we evaluated the effect of several HSP90 inhibitors on NPC1I1061T skin fibroblasts. We found that HSP90 inhibition resulted in clearance of cholesterol from LE/Ly, and this was associated with enhanced delivery of the mutant NPC1I1061T protein to LE/Ly. We also observed that inhibition of HSP90 increased the expression of HSP70, and overexpression of HSP70 also reduced cholesterol storage in NPC1I1061T fibroblasts. However, we did not see correction of cholesterol storage by arimoclomol, a drug that is reported to increase HSP70 expression, at doses up to 0.5 mM. The increase in other chaperones as a consequence of HSP90 improves folding of NPC1 protein and relieves cholesterol accumulation in NPC1 mutant fibroblasts.
We report for the first time the adoptive transfer of donor HLA‐specific allosensitization in two recipients following kidney transplantation from a highly sensitized donor. Kidneys from a donation ...after circulatory death donor were transplanted into two nontransfused, HLA‐specific antibody negative males receiving their first transplant. Antibody screening 7 days after transplant showed high level de novo IgG HLA class I‐ and class II‐specific antibodies in both recipients, with largely overlapping antibody profiles but no antibodies to donor HLA. The unusually rapid appearance of de novo alloantibodies in immunosuppressed nonsensitized recipients and absence of donor HLA‐specific antibody prompted testing of stored donor serum that revealed high antibody levels with specificities very similar to those seen in both recipients, but in addition the presence of strong antibodies to each recipient HLA. Alloantibody levels gradually declined but were still detectable at 3 months. These findings suggest that alloreactive passenger B cells/plasma cells within the kidneys of highly sensitized donors may give rise to rapid development of posttransplant de novo HLA‐specific alloantibodies. While the clinical significance of this phenomenon is uncertain it provides one explanation for the appearance of de novo HLA‐specific antibodies directed against third party but not donor HLA.
Two cases described in this report suggest that adoptive transfer of alloreactive passenger B cells/plasma cells present within the kidneys of a highly sensitized donor may give rise to the rapid development of posttransplant de novo HLA‐specific alloantibodies in recipient sera, directed against third‐party HLA.
Phenotypic alterations in keratinocyte behavior are essential for maintaining epidermal integrity during growth and wound repair and rely on co-ordinated cell signaling events. Numerous growth ...factors and cytokines have been shown to be instrumental in guiding such changes in keratinocyte activity; here we provide evidence which proposes a novel epidermal signaling pathway mediated by the excitatory amino acid glutamate. Glutamate is the major excitatory neurotransmitter at synaptic junctions within the central nervous system; however, we have identified expression in vivo of several regulatory molecules associated with glutamate signaling in keratinocytes. In resting rat skin epidermis, different classes of glutamate receptors, transporters, and a recently described clustering protein were shown to display distinct distribution patterns, supportive of a multifunctional cellular communication pathway. Immunoreactive N-methyl-D-aspartate-type, α-amino-3-hydroxy-5-methyl-4-isoxazole propionate-type, and metabotropic-type glutamate receptors were colocalized with the specific glutamate transporter EAAC1 in basal layer keratinocytes, and GLT-1, a related transporter, was expressed suprabasally. In full-thickness rat skin wounds, marked modifications in the distribution of N-methyl-D-aspartate receptors and EAAC1 were observed during re-epithelialization, and alterations in N-methyl-D-aspartate receptor expression accompanied embryonic epidermal development, implicating glutamate signaling in these important biologic events. Furthermore, we provide evidence that these receptors are functional in vitro. These data provide strong evidence to support a role for glutamate in the control of epidermal renewal, and therefore suggest potentially novel therapeutic targets for the treatment of skin disease and enhancement of wound healing.
A suite of 10 autonomous ozone monitoring units, each powered using renewable energy, was developed and built to study surface ozone in Antarctica during the International Polar Year (2007–2009). The ...monitoring systems were deployed in a network around the Weddell Sea sector of coastal Antarctica with a transect up onto the Antarctic Plateau. The aim was to measure for a full year, thus gaining a much-improved broader view of boundary layer ozone seasonality at different locations as well as of factors affecting the budget of surface ozone in Antarctica. Ozone mixing ratios were measured based on UV photometry using a modified version of the commercial 2B Technologies Inc. Model 202 instrument. All but one of the autonomous units measured successfully within its predefined duty cycle throughout the year, with some differences in performance dependent on power availability and ambient temperature. Mean data recovery after removal of outliers was on average 70% (range 44–83%) and precision varied between 1.5 and 8 ppbv, thus was sufficiently good to resolve year-round the main ozone features of scientific interest. We conclude that, with adequate power, and noting a minor communication problem, our units would be able to operate successfully at ambient temperatures down to −60 °C. Systems such as the one described in this paper, or derivatives of it, could therefore be deployed either as local or regional networks elsewhere in the Arctic or Antarctic. Here we present technical information and first results from the experiment.
A precision measurement of jet cross sections in neutral current deep-inelastic scattering for photon virtualities
5.5
<
Q
2
<
80
GeV
2
and inelasticities
0.2
<
y
<
0.6
is presented, using data taken ...with the H1 detector at HERA, corresponding to an integrated luminosity of
290
pb
-
1
. Double-differential inclusive jet, dijet and trijet cross sections are measured simultaneously and are presented as a function of jet transverse momentum observables and as a function of
Q
2
. Jet cross sections normalised to the inclusive neutral current DIS cross section in the respective
Q
2
-interval are also determined. Previous results of inclusive jet cross sections in the range
150
<
Q
2
<
15
,
000
GeV
2
are extended to low transverse jet momenta
5
<
P
T
jet
<
7
GeV
. The data are compared to predictions from perturbative QCD in next-to-leading order in the strong coupling, in approximate next-to-next-to-leading order and in full next-to-next-to-leading order. Using also the recently published H1 jet data at high values of
Q
2
, the strong coupling constant
α
s
(
M
Z
)
is determined in next-to-leading order.
The H1 Collaboration reports the first measurement of the 1-jettiness event shape observable
τ
1
b
in neutral-current deep-inelastic electron-proton scattering (DIS). The observable
τ
1
b
is ...equivalent to a thrust observable defined in the Breit frame. The data sample was collected at the HERA
ep
collider in the years 2003–2007 with center-of-mass energy of
s
=
319
GeV
, corresponding to an integrated luminosity of 351.1
pb
-
1
. Triple differential cross sections are provided as a function of
τ
1
b
, event virtuality
Q
2
, and inelasticity
y
, in the kinematic region
Q
2
>
150
GeV
2
. Single differential cross sections are provided as a function of
τ
1
b
in a limited kinematic range. Double differential cross sections are measured, in contrast, integrated over
τ
1
b
and represent the inclusive neutral-current DIS cross section measured as a function of
Q
2
and
y
. The data are compared to a variety of predictions and include long-standing and more recent Monte Carlo event generators, predictions in fixed-order perturbative QCD where calculations up to
O
(
α
s
3
)
are available for
τ
1
b
or inclusive DIS, and resummed predictions at next-to-leading logarithmic accuracy matched to fixed order predictions at
O
(
α
s
2
)
. These comparisons reveal sensitivity of the 1-jettiness observable to QCD parton shower and resummation effects, as well as the modeling of hadronization and fragmentation. Within their range of validity, the fixed-order predictions provide a good description of the data. Monte Carlo event generators are predictive over the full measured range and hence their underlying models and parameters can be constrained by comparing to the presented data.
The H1 Collaboration at HERA reports the first measurement of groomed event shape observables in deep inelastic electron-proton scattering (DIS) at
s
=
319
GeV, using data recorded between the years ...2003 and 2007 with an integrated luminosity of 351
pb
-
1
. Event shapes provide incisive probes of perturbative and non-perturbative QCD. Grooming techniques have been used for jet measurements in hadronic collisions; this paper presents the first application of grooming to DIS data. The analysis is carried out in the Breit frame, utilizing the novel Centauro jet clustering algorithm that is designed for DIS event topologies. Events are required to have squared momentum-transfer
Q
2
>
150
GeV
2
and inelasticity
0.2
<
y
<
0.7
. We report measurements of the production cross section of groomed event 1-jettiness and groomed invariant mass for several choices of grooming parameter. Monte Carlo model calculations and analytic calculations based on Soft Collinear Effective Theory are compared to the measurements.
The Breit frame provides a natural frame to analyze lepton–proton scattering events. In this reference frame, the parton model hard interactions between a quark and an exchanged boson defines the ...coordinate system such that the struck quark is back-scattered along the virtual photon momentum direction. In Quantum Chromodynamics (QCD), higher order perturbative or non-perturbative effects can change this picture drastically. As Bjorken-
x
decreases below one half, a rather peculiar event signature is predicted with increasing probability, where no radiation is present in one of the two Breit-frame hemispheres and all emissions are to be found in the other hemisphere. At higher orders in
α
s
or in the presence of soft QCD effects, predictions of the rate of these events are far from trivial, and that motivates measurements with real data. We report on the first observation of the empty current hemisphere events in electron–proton collisions at the HERA collider using data recorded with the H1 detector at a center-of-mass energy of 319 GeV. The fraction of inclusive neutral-current DIS events with an empty hemisphere is found to be
0.0112
±
3.9
%
stat
±
4.5
%
syst
±
1.6
%
mod
in the selected kinematic region of
150
<
Q
2
<
1500
GeV
2
and inelasticity
0.14
<
y
<
0.7
. The data sample corresponds to an integrated luminosity of 351.1 pb
-
1
, sufficient to enable differential cross section measurements of these events. The results show an enhanced discriminating power at lower Bjorken-
x
among different Monte Carlo event generator predictions.
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