The Chinese initiative of constructing the 21st Century Maritime Silk Road could be identified as a new chance to promote the protection of underwater cultural heritage (UCH) in the South China Sea. ...However, uncertainties concerning the jurisdictional issue over the UCH in the exclusive economic zone (EEZ) or on the continental shelf constitute an obstacle. The Convention on the Protection of Underwater Cultural Heritage has, to some extent, enlarged the coastal state's jurisdiction. State practice differs on this issue. This article focuses on the domestic legislations of states bordering the South China Sea related to the jurisdiction over UCH found in their EEZ or on their continental shelf.
Alternative splicing (AS) generates extensive transcriptomic and proteomic complexity. However, the functions of species- and lineage-specific splice variants are largely unknown. Here we show that ...mammalian-specific skipping of polypyrimidine tract–binding protein 1 (PTBP1) exon 9 alters the splicing regulatory activities of PTBP1 and affects the inclusion levels of numerous exons. During neurogenesis, skipping of exon 9 reduces PTBP1 repressive activity so as to facilitate activation of a brain-specific AS program. Engineered skipping of the orthologous exon in chicken cells induces a large number of mammalian-like AS changes in PTBP1 target exons. These results thus reveal that a single exon-skipping event in an RNA binding regulator directs numerous AS changes between species. Our results further suggest that these changes contributed to evolutionary differences in the formation of vertebrate nervous systems.
Chaperones are abundant cellular proteins that promote the folding and function of their substrate proteins (clients). In vivo, chaperones also associate with a large and diverse set of cofactors ...(cochaperones) that regulate their specificity and function. However, how these cochaperones regulate protein folding and whether they have chaperone-independent biological functions is largely unknown. We combined mass spectrometry and quantitative high-throughput LUMIER assays to systematically characterize the chaperone-cochaperone-client interaction network in human cells. We uncover hundreds of chaperone clients, delineate their participation in specific cochaperone complexes, and establish a surprisingly distinct network of protein-protein interactions for cochaperones. As a salient example of the power of such analysis, we establish that NUDC family cochaperones specifically associate with structurally related but evolutionarily distinct β-propeller folds. We provide a framework for deciphering the proteostasis network and its regulation in development and disease and expand the use of chaperones as sensors for drug-target engagement.
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•Client interactions for >60 chaperones and cochaperones mapped by AP-MS and LUMIER•Characterization of cellular roles of cochaperones and their client specificities•NUDC family cochaperones associate with β-propeller domains (Kelch, WD40, and RCC1)•Cochaperones may promote the evolutionary diversification of client folds
Mass spectrometry and quantitative LUMIER assays map the proteostasis network in human cells, revealing hundreds of new client proteins, their integration into the network, and the client specificity of most cochaperones.
Introduction
Osteogenesis imperfecta (OI) is a well-known heritable disorder of connective tissue characterized by skeletal fragility and low bone mass. Nearly 90% of patients with OI have disease ...variants in
COL1A1
and
COL1A2
that encode for the α1 and α2 chains of type I collagen.
Materials and methods
A retrospective analysis of 185 probands who were diagnosed with OI in Shanghai Jiao Tong University Affiliated Sixth People’s Hospital from March 2005 to December 2019 was performed.
Results
A total of 140 mutations in
COL1A1
and 45 mutations in
COL1A2
were identified, of which 18 variations were novel. In the phenotype analysis, there were more sporadic cases than familial OI cases in China (54.6% vs. 45.4%,
P
< 0.001). A total of 98.9% of patients presented with a fracture history. The most common fracture sites were extremity long bones (femur, tibia-fibula and radius-ulna accounted for 36.6%, 17.1% and 11.7%, respectively). Patients with OI types III and IV, especially type III, had a higher proportion of dentinogenesis imperfecta (DI) than patients with OI type I (55% vs. 28%,
P
< 0.001). Interestingly, G767S and D1219N in
COL1A1
and G337S in
COL1A2
were the most frequent (3.52%, 2.11% and 8.89%, respectively), which seem to be hotspot mutations in the
COL1A1
and
COL1A2
genes in Chinese patients.
Conclusions
This study describes the mutations in the main pathogenic genes,
COL1A1
and
COL1A2
, and the clinical characteristics of osteogenesis imperfecta in China. Furthermore, these findings help reveal the genetic basis of Asian OI patients and contribute to genetic counselling.
Recent studies have shown that chlorogenic acid (CGA), which is present in coffee, has protective effects on the nervous system. However, its role in neonatal hypoxic-ischemic brain injury remains ...unclear. In this study, we established a newborn mouse model of hypoxic-ischemic brain injury using a modified Rice-Vannucci method and performed intraperitoneal injection of CGA. We found that CGA intervention effectively reduced the volume of cerebral infarct, alleviated cerebral edema, restored brain tissue structure after injury, and promoted axon growth in injured brain tissue. Moreover, CGA pretreatment alleviated oxygen-glucose deprivation damage of primary neurons and promoted neuron survival. In addition, changes in ferroptosis-related proteins caused by hypoxic-ischemic brain injury were partially reversed by CGA. Furthermore, CGA intervention upregulated the expression of the key ferroptosis factor glutathione peroxidase 4 and its upstream glutamate/cystine antiporter related factors SLC7A11 and SLC3A2. In summary, our findings reveal that CGA alleviates hypoxic-ischemic brain injury in neonatal mice by reducing ferroptosis, providing new ideas for the treatment of neonatal hypoxic-ischemic brain injury.
As an opportunistic pathogen, Bacillus cereus (B. cereus) has caused increasing emetic and diarrheal food poisoning, even fulminant hepatic failure and death case. Herein, a mimetic oxidase-mediated ...ratiometric fluorescence enzyme-linked immunosorbent assay (ELISA) was developed to detect B. cereus. In this system, 3D MnO2-Au nanoflowers with layered crystalline structure can oxidize o-phenylenediamine (OPD) to generate a fluorescence peak at 570 nm (I570, response signal), while blue carbon quantum dots (bCDs) display a fluorescence peak at 455 nm (I455, reference signal). Under the effect of fluorescence resonance energy transfer (FRET), the response signal increased while the reference signal was weakened. By using MnO2-Au as the mimetic oxidase to replace the horseradish peroxidase and associate with antibody in traditional ELISA, a linear relationship was established between the ratiometric fluorescence signal (I570/I455) and the logarithm of B. cereus concentrations in the range from 1.7 × 102 to 3.3 × 106 CFU/mL. Comparing with conventional sandwich ELISA, the detection time was shortened by 43 min and the sensitivity was improved by 5-folds, indicating that the proposed ratiometric immunoassay holds great potential as a rapid and convenient tool for sensitive screening of B. cereus.
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•A ratiometric fluorescent immunoassay based on FRET was developed to detect B. cereus.•MnO2-Au nanoflowers was used as mimic oxidase to anchor antibody.•A linear range from 1.7 × 102 to 3.3 × 106 CFU/mL B. cereus was realized.•Bacillus cereus in milk was successfully detected with satisfactory recoveries.
The interactions of protein kinases and phosphatases with their regulatory subunits and substrates underpin cellular regulation. We identified a kinase and phosphatase interaction (KPI) network of ...1844 interactions in budding yeast by mass spectrometric analysis of protein complexes. The KPI network contained many dense local regions of interactions that suggested new functions. Notably, the cell cycle phosphatase Cdc14 associated with multiple kinases that revealed roles for Cdc14 in mitogen-activated protein kinase signaling, the DNA damage response, and metabolism, whereas interactions of the target of rapamycin complex 1 (TORC1) uncovered new effector kinases in nitrogen and carbon metabolism. An extensive backbone of kinase-kinase interactions cross-connects the proteome and may serve to coordinate diverse cellular responses.
ABSTRACT
Vitamin D deficiency has been recognized as a major public health issue worldwide. Recent studies have indicated that genetic factors might play an important role in determining serum ...25‐hydroxyvitamin D 25(OH)D levels in Caucasians and African Americans. However, the genes that contribute to the variation in serum 25(OH)D levels in Chinese are unknown. In this study, we screened 15 key genes within the vitamin D metabolic pathway using 96 single‐nucleotide polymorphism (SNP) markers in a group of 2897 unrelated healthy Chinese subjects. Significant confounding factors that may influence the variability in serum 25(OH)D levels were used as covariates for association analyses. An association test for quantitative traits was performed to evaluate the association between candidate genes and serum 25(OH)D levels. In the present study, variants and/or haplotypes in GC, CYP2R1, and DHCR7/NADSYN1 were identified as being associated with 25(OH)D levels. Participants with three or four risk alleles of the two variants (GC‐rs4588 and CYP2R1‐rs10766197) had an increased chance of presenting with a 25(OH)D concentration lower than 20 ng/mL (odds ratio 2.121, 95% confidence interval 1.586–2.836, p = 6.1 × 10−8) compared with those lacking the risk alleles. Each additional copy of a risk allele was significantly associated with a 0.12‐fold decrease in the log‐25(OH)D concentration (p = 3.7 × 10−12). Haplotype TGA of GC rs705117‐rs2282679‐rs1491710, haplotype GAGTAC of GC rs842999‐rs705120‐rs222040‐rs4588‐rs7041‐rs10488854, haplotype CA of GC rs1155563‐rs222029, and haplotype AAGA of CYP2R1 rs7936142‐rs12794714‐rs2060793‐rs16930609 were genetic risk factors toward a lower 25(OH)D concentration. In contrast, haplotype TGGGCCC of DHCR7/NADSYN1 rs1790349‐rs7122671‐rs1790329‐rs11606033‐rs2276360‐rs1629220‐rs2282618 were genetic protective factors. The results suggest that the GC, CYP2R1, and DHCR7/NADSYN1 genes might contribute to variability in the serum 25(OH)D levels in a healthy Chinese population in Shanghai. These markers could be used as tools in Mendelian randomization analyses of vitamin D, and they could potentially be drug targets in the Chinese population in Shanghai.
In view of the lack of effective information fusion model for heterogeneous multi-sensor, an improved Dempster/Shafer (DS) evidence theory algorithm is designed to fuse heterogeneous multi-sensor ...information. The algorithm first introduces the compatibility coefficient to characterize the compatibility between the evidence, obtains the weight matrix of each proposition, and then redistributes the basic probability distribution of each focal element to obtain a new evidence source. Then the concept of credibility is introduced, and the average support of evidence credibility and evidence focal element is used to improve the synthesis rule, so as to obtain the fusion result. Compared with other algorithms, the proposed algorithm can solve the problems existing in DS evidence theory when dealing with highly conflicting evidence to a certain extent, and the fusion results are more reasonable and the convergence speed is faster.
Guanine nucleotide exchange factors (RhoGEFs) and GTPase-activating proteins (RhoGAPs) coordinate the activation state of the Rho family of GTPases for binding to effectors. Here, we exploited ...proximity-dependent biotinylation to systematically define the Rho family proximity interaction network from 28 baits to produce 9,939 high-confidence proximity interactions in two cell lines. Exploiting the nucleotide states of Rho GTPases, we revealed the landscape of interactions with RhoGEFs and RhoGAPs. We systematically defined effectors of Rho proteins to reveal candidates for classical and atypical Rho proteins. We used optogenetics to demonstrate that KIAA0355 (termed GARRE here) is a RAC1 interactor. A functional screen of RHOG candidate effectors identified PLEKHG3 as a promoter of Rac-mediated membrane ruffling downstream of RHOG. We identified that active RHOA binds the kinase SLK in Drosophila and mammalian cells to promote Ezrin-Radixin-Moesin phosphorylation. Our proximity interactions data pave the way for dissecting additional Rho signalling pathways, and the approaches described here are applicable to the Ras family.
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