Structural and functional analysis of crossveinless 2 / BMP-2 /Chordin interaction

No abstract availabl

Comparative Phosphoproteomic Profiling of Type III Adenylyl Cyclase Knockout and Control, Male, and Female Mice

Type III adenylyl cyclase (AC3, ADCY3) is predominantly enriched in neuronal primary cilia throughout the central nervous system (CNS). Genome-wide association studies in humans have associated ADCY3 with major depressive disorder and autistic spectrum disorder, both of which exhibit sexual dimorphism. To date, it is unclear how AC3 affects protein phosphorylation and signal networks in central neurons, and what causes the sexual dimorphism of autism. We employed a mass spectrometry (MS)-based phosphoproteomic approach to quantitatively profile differences in phosphorylation between inducible AC3 knockout (KO) and wild type (WT), male and female mice. In total, we identified 4,655 phosphopeptides from 1,756 proteins, among which 565 phosphopeptides from 322 proteins were repetitively detected in all samples. Over 46% phosphopeptides were identified in at least three out of eight biological replicas. Comparison of AC3 KO and WT datasets revealed that phosphopeptides with motifs matching proline-directed kinases' recognition sites had a lower abundance in the KO dataset than in WTs. We detected 14 phosphopeptides restricted to WT dataset (i.e., Rabl6, Spast and Ppp1r14a) and 35 exclusively in KOs (i.e., Sptan1, Arhgap20, Arhgap44, and Pde1b). Moreover, 95 phosphopeptides (out of 90 proteins) were identified only in female dataset and 26 only in males. Label-free MS spectrum quantification using Skyline further identified phosphopeptides that had higher abundance in each sample group. In total, 204 proteins had sex-biased phosphorylation and 167 of them had increased expression in females relative to males. Interestingly, among the 204 gender-biased phosphoproteins, 31% were found to be associated with autism, including Dlg1, Dlgap2, Syn1, Syngap1, Ctnna1, Ctnnd1, Ctnnd2, Pkp4, and Arvcf. Therefore, this study also provides the first phosphoproteomics evidence suggesting that gender-biased post-translational phosphorylation may be implicated in the sexual dimorphism of autism

The antioxidant activity of polysaccharides from Armillaria gallica

The purpose of this study was to investigate the antioxidant activity of Armillaria gallica polysaccharides. It explored whether Armillaria gallica polysaccharides (AgP) could prevent HepG2 cells from H2O2-induced oxidative damage. The results demonstrated that HepG2 cells were significantly protected by AgP, and efficiently suppressed the production of reactive oxygen species (ROS) in HepG2 cells. Additionally, AgP significantly decreased the abnormal leakage of alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) caused by H2O2, protecting cell membrane integrity. It was discovered that AgP was also found to regulate the activities of antioxidant enzymes, superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-PX), while reducing malondialdehyde (MDA), thus protecting cells from oxidative damage. According to the flow cytometry analysis and measurement of caspase-3, caspase-8, and caspase-9 activities, AgP could modulate apoptosis-related proteins and attenuate ROS-mediated cell apoptosis

Oligomeric Structure of the MALT1 Tandem Ig-Like Domains

Mucosa-associated lymphoid tissue 1 (MALT1) plays an important role in the adaptive immune program. During TCR- or BCR-induced NF-κB activation, MALT1 serves to mediate the activation of the IKK (IκB kinase) complex, which subsequently regulates the activation of NF-κB. Aggregation of MALT1 is important for E3 ligase activation and NF-κB signaling.Unlike the isolated CARD or paracaspase domains, which behave as monomers, the tandem Ig-like domains of MALT1 exists as a mixture of dimer and tetramer in solution. High-resolution structures reveals a protein-protein interface that is stabilized by a buried surface area of 1256 Å(2) and contains numerous hydrogen and salt bonds. In conjunction with a second interface, these interactions may represent the basis of MALT1 oligomerization.The crystal structure of the tandem Ig-like domains reveals the oligomerization potential of MALT1 and a potential intermediate in the activation of the adaptive inflammatory pathway.This article can also be viewed as an enhanced version in which the text of the article is integrated with interactive 3D representations and animated transitions. Please note that a web plugin is required to access this enhanced functionality. Instructions for the installation and use of the web plugin are available in Text S1

Genome-Wide Screening for Genetic Alterations in Esophageal Cancer by aCGH Identifies 11q13 Amplification Oncogenes Associated with Nodal Metastasis

Esophageal squamous cell carcinoma (ESCC) is highly prevalent in China and other Asian countries, as a major cause of cancer-related mortality. ESCC displays complex chromosomal abnormalities, including multiple structural and numerical aberrations. Chromosomal abnormalities, such as recurrent amplifications and homozygous deletions, directly contribute to tumorigenesis through altering the expression of key oncogenes and tumor suppressor genes.To understand the role of genetic alterations in ESCC pathogenesis and identify critical amplification/deletion targets, we performed genome-wide 1-Mb array comparative genomic hybridization (aCGH) analysis for 10 commonly used ESCC cell lines. Recurrent chromosomal gains were frequently detected on 3q26-27, 5p15-14, 8p12, 8p22-24, 11q13, 13q21-31, 18p11 and 20q11-13, with frequent losses also found on 8p23-22, 11q22, 14q32 and 18q11-23. Gain of 11q13.3-13.4 was the most frequent alteration in ESCC. Within this region, CCND1 oncogene was identified with high level of amplification and overexpression in ESCC, while FGF19 and SHANK2 was also remarkably over-expressed. Moreover, a high concordance (91.5%) of gene amplification and protein overexpression of CCND1 was observed in primary ESCC tumors. CCND1 amplification/overexpression was also significantly correlated with the lymph node metastasis of ESCC.These findings suggest that genomic gain of 11q13 is the major mechanism contributing to the amplification. Novel oncogenes identified within the 11q13 amplicon including FGF19 and SHANK2 may play important roles in ESCC tumorigenesis

South China Sea Rifted Margin Testing hypotheses for lithosphere thinning during continental breakup: Drilling at the South China Sea rifted margin

International Ocean Discovery Program Expedition 368 is the second of two consecutive cruises that form the South China Sea Rifted Margin program. Expeditions 367 and 368 share the common key objectives of testing scientific hypotheses of breakup of the northern South China Sea (SCS) margin and comparing its rifting style and history to other nonvolcanic or magma-poor rifted margins. Four primary sites were selected for the overall program: one in the outer margin high (OMH) and three seaward of the OMH on distinct, margin-parallel basement ridges. These three ridges are informally labeled A, B, and C. They are located within the continent-ocean transition (COT) zone ranging from the OMH to the interpreted steady-state oceanic crust (Ridge C) of the SCS. The main scientific objectives include 1. Determining the nature of the basement within crustal units across the COT of the SCS that are critical to constrain style of rifting, 2. Constraining the time interval from initial crustal extension and plate rupture to the initial generation of igneous ocean crust, 3. Constraining vertical crustal movements during breakup, and 4. Examining the nature of igneous activity from rifting to seafloor spreading. In addition, the sediment cores from the drill sites targeting primarily tectonic and basement objectives will provide information on the Cenozoic regional environmental development of the Southeast Asia margin. Expedition 368 was planned to drill at two primary sites (U1501 and U1503) at the OMH and Ridge C, respectively. However, based on drilling results from Expedition 367, Expedition 368 chose to insert an alternate site on Ridge A (Site U1502). In total, the expedition completed operations at four sites (U1501, U1502, U1504, and U1505). Site U1503, however, was not completed beyond casing to 990 m because of mechanical problems with the drilling equipment that limited the expedition from 25 May 2017 to the end of the expedition to operate with a drill string not longer than 3400 m. New alternate Site U1504 proposed during Expedition 367 met this condition. Site U1505 also met the operational constraints of the 3400 m drill string (total) and was an alternate site for the already drilled Site U1501. At Site U1501, we cored to 697.1 m in 9.4 days, with 78.5% recovery. We also drilled ahead for 433.5 m in Hole U1501D and then logged downhole data from 78.3 to 399.3 m. In 19.3 days at Site U1502, we penetrated 1679.0 m, set 723.7 m of casing and cored a total of 576.3 m with 53.5% recovery, and collected downhole log data from 785.3 to 875.3 m and seismic data through the 10¾ inch casing. At Site U1503, we penetrated 995.1 m, setting 991.5 m of 10¾ inch casing, but no cores were taken. At Site U1504, we took 40 rotary core barrel (RCB) cores over two holes. The cored interval between both holes was 277.3 m with 26.8% recovery. An 88.2 m interval was drilled in Hole U1504B. At Site U1505, we cored 668.0 m with 101.1% recovery. Logging data was collected from 80.1 to 341.2 m. Operations at this site covered 6.1 days. Except for Site U1505, we drilled to acoustic basement, which prior to the expedition, except for Site U1501, had been interpreted to be crystalline basement. A total of 6.65 days were lost due to mechanical breakdown or waiting on spare supplies for repair of drilling equipment. At Site U1501 on the OMH, coring ~45 m into the acoustic basement sampled highly lithified sandstone to conglomerate of presumed Mesozoic age overlain by siliciclastic Eocene pre- to synrift sediments of Oligocene age and topped by primarily carbonaceous postrift sediments of early Miocene to Pleistocene age. Site U1502 on Ridge A was cased to 723.7 m. At this site, we recovered 180 m of hydrothermally altered brecciated basalts comprising sheet and pillow lavas below deep-marine sediments of Oligocene to late Miocene age. Coring was not performed within the upper 380 m (~Pliocene-Pleistocene) at Site U1502. At Site U1503 on Ridge C, 991.5 m of casing was installed in preparation for the planned deep drilling to ~1800 m, but no coring was performed due to mechanical failures, and the site was abandoned without further activity. Coring at Site U1504 on the OMH ~45 km east of Site U1501 recovered metamorphic schist to gneiss (greenschist facies) below late Eocene (?) carbonate rocks (partly reef debris) and early Miocene to Pleistocene sediments. At Site U1505, we cored to 480.15 m through Pleistocene to late Oligocene mainly carbonaceous ooze followed at depth by early Oligocene to late Eocene siliciclastic sediments. Efforts were made at every drill site to correlate the core with the seismic data and seismic stratigraphic unconformities interpreted within the Eocene to Plio-Pleistocene sedimentary sequence prior to drilling. The predrilling interpretation of ages of these unconformities was in general confirmed by drilling results. As a result of the constraints on the length of drill string that could be deployed during the later part of Expedition 368, the secondary expedition objectives addressing the environmental history of the SCS and Southeast Asia received more focus than planned because these sites are located in shallower water depths and required less penetration depth. This forced change in emphasis, however, was without fatal consequences for the primary tectonic objectives. The two expeditions together provided solid evidence for a process of breakup that included vigorous synrift magmatism as opposed to the often-favored interpretation of the SCS margin as a magma-starved margin

Doxorubicin hydrochloride and L-arginine co-loaded nanovesicle for drug resistance reversal stimulated by near-infrared light

Drug resistance is accountable for the inadequate outcome of chemotherapy in clinics. The newly emerging role of nitric oxide (NO) to conquer drug resistance has been recognized as a potential strategy. However, it remains a great challenge to realize targeted delivery as well as accurate release of NO at desired sites. Herein, we developed a PEGylated indocyanine green (mPEG-ICG) integrated nanovesicle system (PIDA) to simultaneously load doxorubicin hydrochloride (DOX⋅HCl) and the NO donor L-arginine (L-Arg), which can produce NO triggered by NIR light irradiation and exert multimodal therapy to sensitize drug-resistant cancers. Upon 808 nm irradiation, the NO released from PIDA led to a decrease in mitochondrial membrane potential, an increase in ROS and significant ATP depletion in K562/ADR cells, thus inhibiting cell growth and resolving the problem of drug resistance. Consequently, the in vivo experiment on K562/ADR-bearing nude mice indicated that PIDA nanovesicles achieved significant anticancer efficacy with a tumor inhibition rate of 80.8%. Above all, PIDA nanovesicles offer guidance for designing nanoplatforms for drug-resistant cancer treatment

Optimizing Hydrophobic Groups in Amphiphiles to Induce Gold Nanoparticle Complex Vesicles for Stability Regulation

Polymeric graft polyphosphazene containing 4-aminobenzoic acid diethylaminoethyl ester (DEAAB) as hydrophobic side groups was rationally designed and named PDEP. PDEP can self-assemble into a nanovesicle in water. More importantly, when compared with the amphiphile poly­[(methoxy-poly­(ethylene glycol))­(ethyl p-amino­benzoate)]­phosphazene (PEP) copolymer containing benzene rings and the amphiphile poly­[(methoxy-poly­(ethylene glycol)­(N,N-diisopropyl­ethylenedi­amine)]­phosphazene (PDP) copolymer containing tertiary amino groups, the coexistence of benzene and tertiary amino groups in PDEP enabled it to effectively load water-soluble small-molecule doxorubicin hydrochloride (DOX·HCl) into the vesicle and efficiently induce in situ transformation of gold tetrachloroaurate (HAuCl₄) to gold nanoparticles (AuNPs) as both a reductant and a stabilizer. By optimizing the reduction conditions, such as the temperature, reaction time, and hydrophobic group in polymer/HAuCl₄ molar ratio, the AuNP complex PDEP vesicles significantly inhibited the DOX·HCl burst release at pH 7.4 while displaying a fast release responsive to pH 5.5