Adeno-associated virus (AAV) vectors are currently the leading candidates for virus-based gene therapies because of their broad tissue tropism, non-pathogenic nature and low immunogenicity. They have ...been successfully used in clinical trials to treat hereditary diseases such as haemophilia B (ref. 2), and have been approved for treatment of lipoprotein lipase deficiency in Europe. Considerable efforts have been made to engineer AAV variants with novel and biomedically valuable cell tropisms to allow efficacious systemic administration, yet basic aspects of AAV cellular entry are still poorly understood. In particular, the protein receptor(s) required for AAV entry after cell attachment remains unknown. Here we use an unbiased genetic screen to identify proteins essential for AAV serotype 2 (AAV2) infection in a haploid human cell line. The most significantly enriched gene of the screen encodes a previously uncharacterized type I transmembrane protein, KIAA0319L (denoted hereafter as AAV receptor (AAVR)). We characterize AAVR as a protein capable of rapid endocytosis from the plasma membrane and trafficking to the trans-Golgi network. We show that AAVR directly binds to AAV2 particles, and that anti-AAVR antibodies efficiently block AAV2 infection. Moreover, genetic ablation of AAVR renders a wide range of mammalian cell types highly resistant to AAV2 infection. Notably, AAVR serves as a critical host factor for all tested AAV serotypes. The importance of AAVR for in vivo gene delivery is further highlighted by the robust resistance of Aavr(-/-) (also known as Au040320(-/-) and Kiaa0319l(-/-)) mice to AAV infection. Collectively, our data indicate that AAVR is a universal receptor involved in AAV infection.
Synchrotron monochromatic-beam x-ray topography observation has been performed on high-quality ammonothermal gallium nitride single crystal to evaluate threading dislocations (TD) in a nondestructive ...manner. Asymmetric diffractions with six equivalent
g
-vectors of 11–26, in addition to a symmetric diffraction with
g
= 0008, were applied to determine the Burgers vectors (
b
) of dislocations. It was found that pure edge-type TDs with
b
=
11
-
20
/
3
did not exist in the sample. A dominant proportion of TDs were of mixed type with
b
=
11
-
20
/
3
+
0001
, i.e., so-called
c
+
a
dislocations. Pure 1
c
screw dislocations with
b
=
0001
and TDs with
c
-component larger than 1
c
were also observed.
Abstract
To extend the search for quasars in the epoch of reionization beyond the tip of the luminosity function, we explore point-source candidates at redshift
z
∼ 8 in SuperBoRG, a compilation of ...∼0.4 deg
2
archival medium-deep (
m
F160
W
∼ 26.5 ABmag, 5
σ
) parallel infrared (IR) images taken with the Hubble Space Telescope (HST). Initial candidates are selected by using the Lyman-break technique. We then carefully analyze source morphology, and robustly identify three point sources at
z
∼ 8. Photometric redshift analysis reveals that they are preferentially fit by extragalactic templates, and we conclude that they are unlikely to be low-
z
interlopers, including brown dwarfs. A clear IRAC ch2 flux excess is seen in one of the point sources, which is expected if the source has strong H
β
+O
iii
emission with a rest-frame equivalent width of ∼3000 Å. Deep spectroscopic data taken with Keck/MOSFIRE, however, do not reveal Ly
α
emission from the object. In combination with the estimated H
β
+O
iii
equivalent width, we place an upper limit on its Ly
α
escape fraction of
. We estimate the number density of these point sources as ∼1 × 10
−6
Mpc
−3
mag
−1
at
M
UV
∼ −23 mag. The final interpretation of our results remains inconclusive: extrapolation from low-
z
studies of
faint
quasars suggests that ≳100× survey volume may be required to find one of this luminosity. The James Webb Space Telescope will be able to conclusively determine the nature of our luminous point-source candidates, while the Roman Space Telescope will probe ∼200 times the area of the sky with the same observing time considered in this HST study.
Transforming growth factor (TGF)-beta is known to promote tumor invasion and metastasis. Although bone morphogenetic proteins (BMPs), members of the TGF-beta family, are expressed in a variety of ...human carcinoma cell lines, their roles in tumor progression have not been fully clarified. In this study, we sought to determine the roles of BMPs in the progression of breast cancer bone metastasis using human breast cancer samples and a mouse xenograft model. Immunohistochemical analysis of samples from breast cancer patients as well as a mouse xenograft model of MDA-231-D, highly metastatic human breast cancer cells, revealed phospho-Smad2 and phospho-Smad1/5/8 staining in the nuclei of cancer cells in primary tumor and/or bone metastasis. Using a functional in vivo bioluminescence imaging system, we showed that TGF-beta- and BMP-induced transcriptional pathways are active in bone metastatic lesions in vivo. In addition, both TGF-beta3 and BMP-2 promoted the motility and invasiveness of the MDA-231-D cells in vitro. Moreover, expression of dominant-negative receptors for TGF-beta and/or BMPs in the MDA-231-D cells inhibited invasiveness in vitro and bone metastasis in the xenograft model. These results suggest that BMPs as well as TGF-beta promote invasion and bone metastasis of breast cancer.
Summary
This study compared spinal alignment, muscular strength, and quality of life (QOL) between women with postmenopausal osteoporosis and healthy volunteers. The results indicated that lower QOL ...in osteoporosis patients may be associated with increased thoracic kyphosis, reduced lean muscle mass, and generalized muscle weakness.
Introduction
Increased spinal kyphosis is common in patients with osteoporosis and negatively impacts quality of life (QOL). Muscular strength is also important for QOL in patients with osteoporosis. However, spinal kyphosis and muscle weakness also occur in healthy individuals with advancing age. The purposes of this study were thus to compare spinal alignment, muscular strength, and QOL between women with postmenopausal osteoporosis and healthy volunteers.
Methods
Participants comprised 236 female patients with postmenopausal osteoporosis (mean age, 68.7 years) and 93 healthy volunteer women (mean age, 71.0 years). Body mass index (BMI), angles of spinal kyphosis, back extensor strength, grip strength, and QOL were compared between groups.
Results
BMI, back extensor strength, and grip strength were significantly higher in the volunteer group than in the osteoporosis group (
p
< 0.01). Both thoracic kyphosis and lumbar lordosis were significantly greater in the osteoporosis group than in the volunteer group (
p
< 0.01). With regard to QOL, the 36-Item Short-Form Health Survey (SF-36) subscale scores of role physical, bodily pain, general health, and role emotional were all significantly lower in the osteoporosis group than in the volunteer group (
p
< 0.05 each). SF-36 physical component summary (PCS) score was significantly lower in the osteoporosis group than in the volunteer group (
p
< 0.001). SF-36 PCS score correlated positively with thoracic kyphosis and negatively with BMI only in the osteoporosis group (
p
< 0.05 each).
Conclusions
These results indicated that lower QOL in osteoporosis patients may be associated with increased thoracic kyphosis, reduced lean muscle mass, and generalized muscle weakness.
Unlike crystalline materials, metallic glasses usually have a uniform structure without long-range periodicity and characteristic structural constituents. It has long been believed that no interfaces ...associated with separate grains can be found in metallic glasses. Here, we report on the successful synthesis of a gold-based nanograined metallic glass (NGMG) exhibiting a heterogeneously granular structure but possessing a glassy nature. The smallest particle size of the NGMG can be less than 10nm. Having the advantage of the high surface area typical for nanostructures, the Au-based NGMG shows significantly enhanced catalytic activity. In addition, this NGMG sustains the good mechanical properties of metallic glasses, showing a high hardness of ∼5.3GPa. This work provides new insights into glass formation, offers the opportunity for further studies of the physical and chemical properties of this new type of non-crystalline solid, and promotes the applications of metallic glasses as catalysts, which may trigger intensive research in materials science.
Background and aim
Sessile serrated adenoma/polyps (SSAPs) are suspected to have a high malignant potential, although few reports have evaluated the incidence of carcinomas derived from SSAPs using ...the new classification for serrated polyps (SPs). The aim of study was to compare the frequency of cancer coexisting with the various SP subtypes including mixed polyps (MIXs) and conventional adenomas (CADs).
Methods
A total of 18,667 CADs were identified between April 2005 and December 2011, and 1858 SPs (re-classified as SSAP, hyperplastic polyp (HP), traditional serrated adenoma (TSA), or MIX) were removed via snare polypectomy, endoscopic mucosal resection, or endoscopic sub-mucosal dissection.
Results
Among 1160 HP lesions, 1 (0.1 %) coexisting sub-mucosal invasive carcinoma (T1) was detected. Among 430 SSAP lesions, 3 (0.7 %) high-grade dysplasia (HGD/Tis) and 1 (0.2 %) T1 were detected. All of the lesions were detected in the proximal colon, with a mean tumor diameter of 18 mm (SD 9 mm). Among 212 TSA lesions, 3 (1 %) HGD/Tis were detected but no T1 cancer. Among 56 MIX lesions, 9 (16 %) HGD/Tis and 1 (2 %) T1 cancers were detected, and among 18,677 CAD lesions, 964 (5 %) HGD/Tis and 166 (1 %) T1 cancers were identified.
Conclusions
Among the resected lesions that were detected during endoscopic examination, a smaller proportion (1 %) of SSAPs harbored HGD or coexisting cancer, compared to CAD or MIX lesions. Therefore, more attention should be paid to accurately identifying lesions endoscopically for intentional resection and the surveillance of each SP subtype.
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