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.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract
The Muon
g
-2 Experiment at Fermilab uses a gaseous straw
tracking detector to make detailed measurements of the stored muon
beam profile, which are essential for the experiment to achieve ...its
uncertainty goals. Positrons from muon decays spiral inward and pass
through the tracking detector before striking an electromagnetic
calorimeter. The tracking detector is therefore located inside the
vacuum chamber in a region where the magnetic field is large and
non-uniform. As such, the tracking detector must have a low leak
rate to maintain a high-quality vacuum, must be non-magnetic so as
not to perturb the magnetic field and, to minimize energy loss, must
have a low radiation length. The performance of the tracking
detector has met or surpassed the design requirements, with adequate
electronic noise levels, an average straw hit resolution of
(110 ± 20) μm, a detection efficiency of 97% or higher,
and no performance degradation or signs of aging. The tracking
detector's measurements result in an otherwise unachievable
understanding of the muon's beam motion, particularly at early times
in the experiment's measurement period when there are a
significantly greater number of muons decaying. This is vital to the
statistical power of the experiment, as well as facilitating the
precise extraction of several systematic corrections and
uncertainties. This paper describes the design, construction,
testing, commissioning, and performance of the tracking detector.
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.
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BFBNIB, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The parameters of the electroweak theory are determined in a combined electroweak and QCD analysis using all deep-inelastic
e
+
p
and
e
-
p
neutral current and charged current scattering cross ...sections published by the H1 Collaboration, including data with longitudinally polarised lepton beams. Various fits to Standard Model parameters in the on-shell scheme are performed. The mass of the
W
boson is determined as
m
W
=
80.520
±
0.115
GeV
. The axial-vector and vector couplings of the light quarks to the
Z
boson are also determined. Both results improve the precision of previous H1 determinations based on HERA-I data by about a factor of two. Possible scale dependence of the weak coupling parameters in both neutral and charged current interactions beyond the Standard Model is also studied. All results are found to be consistent with the Standard Model expectations.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The H1 Forward Track Detector at HERA II Laycock, P J; Henderson, R C W; Maxfield, S J ...
Journal of instrumentation,
08/2012, Volume:
7, Issue:
8
Journal Article
Peer reviewed
Open access
In order to maintain efficient tracking in the forward region of H1 after the luminosity upgrade of the HERA machine, the H1 Forward Track Detector was also upgraded. While much of the original ...software and techniques used for the HERA I phase could be reused, the software for pattern recognition was completely rewritten. This, along with several other improvements in hit finding and high-level track reconstruction, are described in detail together with a summary of the performance of the detector.
The authors set out to evaluate the quality of life (QOL), social-emotional functioning, and behavioral functioning of children treated surgically for craniopharyngiomas.
Twelve girls and 17 boys ...with a mean age at diagnosis of 8 +/- 3.8 years were surgically treated between 1985 and 1998 at the New York University Medical Center. After a mean follow-up period of 6.8 +/- 3.5 years, these 29 patients were administered either the 36-item Short Form Health Survey version 2 or the Child Health Questionnaire-Parent Form to assess QOL, as well as the Achenbach Child Behavior Checklist or Young Adult Checklist to measure social-emotional and behavioral functioning. Patients older than 19 years of age and parents of patients younger than 19 years of age reported low average overall physical QOL, with overall psychosocial QOL in the average range. Behavioral difficulties were noted, including internalizing, attention, somatic, and social difficulties. Further analyses indicated that retrochiasmatic tumor location, recurrence, and additional surgery were associated with poorer outcomes. In contrast, hydrocephalus, tumor size, and sex were not prognostic variables, and patients significantly improved as post-operative time increased.
Attention toward late effects arising after the treatment of pediatric craniopharyngioma, including decreased postoperative physical health and behavioral functioning, is warranted. Future approaches to treatment should consider the documented effects of either gross-total resection or limited surgery followed by cranial irradiation on QOL, with specific evaluation for those with retrochiasmatic tumors, a recurrent tumor, or the need for additional surgery. Psychosocial QOL and social-emotional functioning should be maintained through ongoing counseling and education.
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