Hypospadias is the displacement of the urethral meatus from the tip of the glans to the ventral side of the phallus. During fetal development, SRY, SOX9, WT1, SRD5A2 and AR are important at different stages in the differentiation and development of the male genital system. Mutations in these genes impair masculinization and may be associated with hypospadias. In order to explore these possibilities, we employed polymerase chain reaction and direct sequencing to analyze the coding regions of these five genes in 90 Chinese hypospadias patients. We found a total of 16 different mutations in SRD5A2, AR and WT1 in 24 of these 90 patients. Seven mutations are novel. No mutation was found in SRY or SOX9. SNP V89L found in SRD5A2 was statistically significant between patients and controls. Our results indicated that mutations in SRD5A2, AR and WT1 were associated with hypospadias. In conclusion, mutations are frequently found in genes that control androgen action and metabolism, but are seldom found in genes active in the early phase of sex determination and differentiation. Mutations in AR, SRD5A2 or WT1 seem to be associated not only with hypospadias but also with micropenis.
Bruton’s
tyrosine kinase (BTK), a non-receptor tyrosine
kinase, is a member of the Tec family of kinases and is essential
for B cell receptor (BCR) mediated signaling. BTK also plays a critical
role in the downstream signaling pathways for the Fcγ receptor
in monocytes, the Fcε receptor in granulocytes, and the RANK
receptor in osteoclasts. As a result, pharmacological inhibition of
BTK is anticipated to provide an effective strategy for the clinical
treatment of autoimmune diseases such as rheumatoid arthritis and
lupus. This article will outline the evolution of our strategy to
identify a covalent, irreversible inhibitor of BTK that has the intrinsic
potency, selectivity, and pharmacokinetic properties necessary to
provide a rapid rate of inactivation systemically following a very
low dose. With excellent in vivo efficacy and a very desirable tolerability
profile, 5a (branebrutinib, BMS-986195) has advanced
into clinical studies.
Bruton's tyrosine kinase (BTK), a nonreceptor tyrosine kinase, is a member of the Tec family of kinases. BTK plays an essential role in B cell receptor (BCR)-mediated signaling as well as Fcγ receptor signaling in monocytes and Fcε receptor signaling in mast cells and basophils, all of which have been implicated in the pathophysiology of autoimmune disease. As a result, inhibition of BTK is anticipated to provide an effective strategy for the clinical treatment of autoimmune diseases such as lupus and rheumatoid arthritis. This article details the structure-activity relationships (SAR) leading to a novel series of highly potent and selective carbazole and tetrahydrocarbazole based, reversible inhibitors of BTK. Of particular interest is that two atropisomeric centers were rotationally locked to provide a single, stable atropisomer, resulting in enhanced potency and selectivity as well as a reduction in safety liabilities. With significantly enhanced potency and selectivity, excellent in vivo properties and efficacy, and a very desirable tolerability and safety profile, 14f (BMS-986142) was advanced into clinical studies.
Remote sensing image fusion (also known as pan-sharpening) aims at generating high resolution multi-spectral (MS) image from inputs of a high spatial resolution single band panchromatic (PAN) image and a low spatial resolution multi-spectral image. Inspired by the astounding achievements of convolutional neural networks (CNNs) in a variety of computer vision tasks, in this paper, we propose a two-stream fusion network (TFNet) to address the problem of pan-sharpening. Unlike previous CNN based methods that consider pan-sharpening as a super resolution problem and perform pan-sharpening in pixel level, the proposed TFNet aims to fuse PAN and MS images in feature level and reconstruct the pan-sharpened image from the fused features. The TFNet mainly consists of three parts. The first part is comprised of two networks extracting features from PAN and MS images, respectively. The subsequent network fuses them together to form compact features that represent both spatial and spectral information of PAN and MS images, simultaneously. Finally, the desired high spatial resolution MS image is recovered from the fused features through an image reconstruction network. Experiments on Quickbird and GaoFen-1 satellite images demonstrate that the proposed TFNet can fuse PAN and MS images, effectively, and produce pan-sharpened images competitive with even superior to state of the arts.
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