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1.
J Zhejiang Univ Sci B ; 22(1): 1-20, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33448183

RESUMO

Proteins are major functional units that are tightly connected to form complex and dynamic networks. These networks enable cells and organisms to operate properly and respond efficiently to environmental cues. Over the past decades, many biochemical methods have been developed to search for protein-binding partners in order to understand how protein networks are constructed and connected. At the same time, rapid development in proteomics and mass spectrometry (MS) techniques makes it possible to identify interacting proteins and build comprehensive protein‒protein interaction networks. The resulting interactomes and networks have proven informative in the investigation of biological functions, such as in the field of DNA damage repair. In recent years, a number of proteins involved in DNA damage response and DNA repair pathways have been uncovered with MS-based protein‒protein interaction studies. As the technologies for enriching associated proteins and MS become more sophisticated, the studies of protein‒protein interactions are entering a new era. In this review, we summarize the strategies and recent developments for exploring protein‒protein interaction. In addition, we discuss the application of these tools in the investigation of protein‒protein interaction networks involved in DNA damage response and DNA repair.

2.
Ann Plast Surg ; 86(2): 175-181, 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-32756249

RESUMO

BACKGROUND: Weak alar cartilage and lack of soft tissue on the cleft side are considered to be the main critical factors leading to the asymmetry of bilateral nostrils. The costal cartilage can provide strong structural support and can be used to maintain long-term stability of nostril shape after surgical correction. With the advancement in rhinoplasty techniques, the application and understanding of costal cartilage in cleft lip nasal deformity is still on going. Herein, we present our technique of applying costal cartilage to provide nostril support and correct asymmetry in Asian patients with unilateral secondary cleft lip nasal deformity. METHODS: Ninety-seven patients who underwent nostril asymmetry correction from January 1, 2013, to October 31, 2018, were analyzed retrospectively. Modified integrative alar cartilage strut and diced nostril augmentation with costal cartilage were implemented to improve the collapsed and flat cleft-side nostril. The release and restoration of muscle and bone were also performed when required. Surgical outcomes were analyzed based on the comparison of nostril parameters, the shape and contour, and symmetry of bilateral nostrils after surgery. During postoperative follow-up, the patients' satisfactions with the corrective outcomes were also investigated. RESULTS: All patients received the corrective operations with complete survival of all implanted cartilages. The nostril width was narrower in postoperative group (P < 0.05). The nostril height and long axis angle were higher postoperatively (P < 0.05). After correction, the proportion of moderate type increased from 13.4% to 80.4%, whereas the proportion of horizontal type decreased from 86.6% to 17.5%. The symmetry score on the nostril parameters manifested the rate of high score (AS >3) in postoperative groups were 84.5%, 93.8%, and 87.6% for width, height, and angle of the long axis, respectively. They were higher compared with those of preoperative group (0%). More than 95% of the patients were satisfied with the overall aesthetic outcome of the surgery. CONCLUSIONS: Through ameliorating its constructive technology and optimizing its filling form, the modified use of costal cartilage displayed excellent correction effects in the width, height, and long axis angle asymmetry of Asian patients' nostril. Precise and comprehensive rhinoplasty technique is the cornerstone for achieving satisfactory long-term aesthetic outcomes, especially in severe cases, such as secondary cleft lip nasal deformity.

4.
J Proteome Res ; 20(1): 858-866, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33289385

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest cancers. Dissecting the tumor cell proteome from that of the non-tumor cells in the PDAC tumor bulk is critical for tumorigenesis studies, biomarker discovery, and development of therapeutics. However, investigating the tumor cell proteome has proven evasive due to the tumor's extremely complex cellular composition. To circumvent this technical barrier, we have combined bioorthogonal noncanonical amino acid tagging (BONCAT) and data-independent acquisition mass spectrometry (DIA-MS) in an orthotopic PDAC model to specifically identify the tumor cell proteome in vivo. Utilizing the tumor cell-specific expression of a mutant tRNA synthetase transgene, this approach provides tumor cells with the exclusive ability to incorporate an azide-bearing methionine analogue into newly synthesized proteins. The azide-tagged tumor cell proteome is subsequently enriched and purified via a bioorthogonal reaction and then identified and quantified using DIA-MS. Applying this workflow to the orthotopic PDAC model, we have identified thousands of proteins expressed by the tumor cells. Furthermore, by comparing the tumor cell and tumor bulk proteomes, we showed that the approach can distinctly differentiate proteins produced by tumor cells from those of non-tumor cells within the tumor microenvironment. Our study, for the first time, reveals the tumor cell proteome of PDAC under physiological conditions, providing broad applications for tumorigenesis, therapeutics, and biomarker studies in various human cancers.

5.
Mol Cell ; 80(6): 1013-1024.e6, 2020 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-33338401

RESUMO

Impaired DNA crosslink repair leads to Fanconi anemia (FA), characterized by a unique manifestation of bone marrow failure and pancytopenia among diseases caused by DNA damage response defects. As a germline disorder, why the hematopoietic hierarchy is specifically affected is not fully understood. We find that reprogramming transcription during hematopoietic differentiation results in an overload of genotoxic stress, which causes aborted differentiation and depletion of FA mutant progenitor cells. DNA damage onset most likely arises from formaldehyde, an obligate by-product of oxidative protein demethylation during transcription regulation. Our results demonstrate that rapid and extensive transcription reprogramming associated with hematopoietic differentiation poses a major threat to genome stability and cell viability in the absence of the FA pathway. The connection between differentiation and DNA damage accumulation reveals a novel mechanism of genome scarring and is critical to exploring therapies to counteract the aplastic anemia for the treatment of FA patients.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Reprogramação Celular/genética , Anemia de Fanconi/genética , Formaldeído/toxicidade , Dano ao DNA/efeitos dos fármacos , Reparo do DNA/genética , Anemia de Fanconi/sangue , Anemia de Fanconi/patologia , Formaldeído/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Regulação da Expressão Gênica no Desenvolvimento/genética , Instabilidade Genômica/genética , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/efeitos dos fármacos , Humanos , Células K562 , Transcrição Genética
6.
Bioorg Chem ; 107: 104578, 2020 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-33383323

RESUMO

Hyperelodione D (1), an undescribed polyprenylated phloroglucinol derivative possessing 6/6/5/5 fused tetracyclic core, together with hyperelodiones E-F (2-3), two unreported analogues bearing 6/5/5 fused tricyclic structure, were isolated from Hypericum elodeoides Choisy. Their planar structures were elucidated by spectroscopic analysis (HRESIMS, 1D and 2D NMR) and their absolute configurations were determined by comparison of experimental and calculated ECD data. The cytotoxicity and retinoid X receptor-α (RXRα) related activities of the isolates were evaluated and the plausible biogenetic pathways of 1-3 were proposed.

7.
Proc Natl Acad Sci U S A ; 117(52): 33436-33445, 2020 Dec 29.
Artigo em Inglês | MEDLINE | ID: mdl-33376220

RESUMO

Fanconi anemia (FA) is caused by defects in cellular responses to DNA crosslinking damage and replication stress. Given the constant occurrence of endogenous DNA damage and replication fork stress, it is unclear why complete deletion of FA genes does not have a major impact on cell proliferation and germ-line FA patients are able to progress through development well into their adulthood. To identify potential cellular mechanisms that compensate for the FA deficiency, we performed dropout screens in FA mutant cells with a whole genome guide RNA library. This uncovered a comprehensive genome-wide profile of FA pathway synthetic lethality, including POLI and CDK4 As little is known of the cellular function of DNA polymerase iota (Pol ι), we focused on its role in the loss-of-function FA knockout mutants. Loss of both FA pathway function and Pol ι leads to synthetic defects in cell proliferation and cell survival, and an increase in DNA damage accumulation. Furthermore, FA-deficient cells depend on the function of Pol ι to resume replication upon replication fork stalling. Our results reveal a critical role for Pol ι in DNA repair and replication fork restart and suggest Pol ι as a target for therapeutic intervention in malignancies carrying an FA gene mutation.

8.
Biomed Chromatogr ; : e5044, 2020 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-33283298

RESUMO

Hemorrhagic shock (HS) is a medical emergency during trauma. Significant loss of tissue perfusion may result in cellular hypoxia, organ damage and death. The primary treatment of HS is control of the source of bleeding as soon as possible and fluid replacement (crystalloid solutions and blood transfusion). Metabolomics can identify novel biomarkers for various functional and organic diseases. Therefore, systematic exploration of the biological mechanisms of HS and blood transfusion enables the optimization of treatments for HS to reduce the occurrence of organ damage. In this study, a global metabolic profiling strategy is applied to evaluate metabolic changes in the HS rat model. A serum metabolic network with 58 significant metabolites was constructed for HS and resuscitation. Our investigation will offer insights into the pathogenesis.

9.
Cancer Biol Med ; 17(4): 864-878, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-33299640

RESUMO

Cancer-related diseases represent the second overall cause of death worldwide. Human papilloma virus (HPV) is an infectious agent which is mainly sexually transmitted and may lead to HPV-associated cancers in both men and women. Almost all cervical cancers are HPV-associated, however, an increasing number of head and neck cancers (HNCs), especially oropharyngeal cancer, can be linked to HPV infection. Moreover, anogenital cancers, including vaginal, vulvar, penial, and anal cancers, represent a subset of HPV-related cancers. Whereas testing and prevention of cervical cancer have significantly improved over past decades, anogenital cancers remain more difficult to confirm. Current clinical trials including patients with HPV-related cancers focus on finding proper testing for all HPV-associated cancers as well as improve the currently applied treatments. The HPV viral oncoproteins, E6 and E7, lead to degradation of, respectively, p53 and pRb resulting in entering the S phase without G1 arrest. These high-risk HPV viral oncogenes alter numerous cellular processes, including DNA repair, angiogenesis, and/or apoptosis, which eventually result in carcinogenesis. Additionally, a comprehensive analysis of gene expression and alteration among a panel of DNA double strand breaks (DSB) repair genes in HPV-negative and HPV-positive HNC cancers reveals differences pointing to HPV-dependent modifications of DNA repair processes in these cancers. In this review, we discuss the current knowledge regarding HPV-related cancers, current screening, and treatment options as well as DNA damage response-related biological aspects of the HPV infection and clinical trials.

10.
Bioengineered ; 11(1): 1313-1324, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33251971

RESUMO

Instantaneous blood coagulation after bioengineered liver transplantation is a major issue, and the key process in its prevention is the construction of the endothelial vascular bed on biomimetic scaffolds. However, the specific molecules involved in the regulation of the vascular bed formation remain unclear. Syndecan-4 is a type I transmembrane glycoprotein commonly expressed in the human body; its receptor has been reported as critical for optimal cell adhesion and initiation of intracellular signaling, indicating its promising application in vascular bed formation. In the current study, bioinformatics analysis and in vitro experiments were performed to evaluate whether syndecan-4 promoted endothelial cell migration and functional activation. Exogenous syndecan-4-overexpressing endothelial cells were perfused into the decellularized liver scaffold, which was assessed by Masson's trichrome staining. Western blotting and qRT-PCR were used to evaluate the effects of syndecan-4 on the thrombospondin 1 (THBS1) stability. We found that syndecan-4 promoted the adhesion of vascular endothelial cells and facilitated cell migration and angiogenesis. Furthermore, syndecan-4 overexpression resulted in a well-aligned endothelium on the decellularized liver scaffolds. Mechanistically, syndecan-4 destabilized THBS1 at the protein level. Therefore, our data revealed that syndecan-4 promoted the biological activity of endothelial cells on the bionic liver vascular bed through THBS1. These findings provide scientific evidences for solving transient blood coagulation after bionic liver transplantation.

11.
Org Lett ; 22(23): 9169-9173, 2020 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-33186036

RESUMO

We report herein the Pd-catalyzed oxazoline-directed C-H olefination of the N-arylindole skeleton, affording two diastereomers of axially chiral olefin-oxazoline ligands in a one-step procedure. Modifications at the 3- and 3'-positions were facilely achieved via electrophilic substitution of the indole fragment and subsequent oxazoline-directed C-H amidation or olefination of the arene fragment.

12.
Org Biomol Chem ; 18(43): 8850-8853, 2020 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-33119022

RESUMO

A palladium(ii)-catalyzed cyclization of 2-ethynylaniline tethered cinnamyl acetate involving aminopalladation/alkene insertion/ß-acetoxy elimination cascade processes was established. The new protocol provides efficient access to indenoindoles in moderate to good yields under mild conditions.

13.
Biomed Res Int ; 2020: 9786428, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33102601

RESUMO

Background: Colorectal cancer (CRC) is an underlying deadly malignancy with poor prognosis, lacking effective therapies currently available to improve the prognosis. C18H17NO6 (AUCAN), a kind of dibenzofuran extracted from a special plant in Yunnan Province (China), is identified as a natural anticancer agent exerting strong inhibitory activities on various cancers. Our study was committed to investigating the potency of AUCAN against colorectal cancers and further exploring the potential mechanisms via proteomic analysis. Methods: Cell Counting Kit-8 assay and immunofluorescence staining were used to investigate the effect of AUCAN on the viability and proliferation of HCT-116 cells and RKO cells. The apoptosis of HCT-116 and RKO cells after AUCAN administration was determined by the flow cytometry test. The effects of AUCAN on invasion and migration of tumor cells were investigated by the colony formation assay, wound healing test, and Transwell invasion test. Meanwhile, the energy metabolism and growth of tumor tissues after AUCAN administration with 10 mg/kg and 20 mg/kg were examined by PET-CT in vivo. The side effects of AUCAN treatment were also evaluated through blood routine and liver function examination. RKO cell proliferation and apoptosis in vivo were further determined by hematoxylin and eosin staining, TUNEL staining, and immunohistochemistry. Furthermore, the differentially expressed proteins (DEPs) involved in AUCAN treatment were determined by proteomic analysis followed by functional clustering analysis. Results: The results showed that AUCAN suppressed the migratory abilities and enhanced apoptosis of HCT-116 and RKO cell lines. Meanwhile, AUCAN treatment dramatically depressed the growth and volume of colorectal tumors in nude mice and suppressed the survival of RKO cells in tumor tissues without any side effects on the blood routine and liver function. In addition, twenty-four upregulated and forty-two downregulated proteins were identified. Additionally, functional clustering analysis concealed enriched biological processes, cellular components, molecular functions, and related pathways of these proteins involved in cellular metabolic. Finally, the protein-protein interaction analysis revealed the regulatory connection among these DEPs. Conclusions: Taken together, AUCAN exerted its significant antitumor effect without side effects in the blood routine and liver function and the underlying mechanisms were preliminarily investigated by proteomic analysis.

14.
Mol Cell Proteomics ; 19(12): 2015-2029, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32958691

RESUMO

Specific E3 ligases target tumor suppressors for degradation. Inhibition of such E3 ligases may be an important approach to cancer treatment. RNF146 is a RING domain and PARylation-dependent E3 ligase that functions as an activator of the ß-catenin/Wnt and YAP/Hippo pathways by targeting the degradation of several tumor suppressors. Tankyrases 1 and 2 (TNKS1/2) are the only known poly-ADP-ribosyltransferases that require RNF146 to degrade their substrates. However, systematic identification of RNF146 substrates have not yet been performed. To uncover substrates of RNF146 that are targeted for degradation, we generated RNF146 knockout cells and TNKS1/2-double knockout cells and performed proteome profiling with label-free quantification as well as transcriptome analysis. We identified 160 potential substrates of RNF146, which included many known substrates of RNF146 and TNKS1/2 and 122 potential TNKS-independent substrates of RNF146. In addition, we validated OTU domain-containing protein 5 and Protein mono-ADP-ribosyltransferase PARP10 as TNKS1/2-independent substrates of RNF146 and SARDH as a novel substrate of TNKS1/2 and RNF146. Our study is the first proteome-wide analysis of potential RNF146 substrates. Together, these findings not only demonstrate that proteome profiling can be a useful general approach for the systemic identification of substrates of E3 ligases but also reveal new substrates of RNF146, which provides a resource for further functional studies.

15.
Sensors (Basel) ; 20(18)2020 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-32933186

RESUMO

Unmanned aerial vehicles (UAVs), equipped with a variety of sensors, are being used to provide actionable information to augment first responders' situational awareness in disaster areas for urban search and rescue (SaR) operations. However, existing aerial robots are unable to sense the occluded spaces in collapsed structures, and voids buried in disaster rubble that may contain victims. In this study, we developed a framework, AiRobSim, to simulate an aerial robot to acquire both aboveground and underground information for post-disaster SaR. The integration of UAV, ground-penetrating radar (GPR), and other sensors, such as global navigation satellite system (GNSS), inertial measurement unit (IMU), and cameras, enables the aerial robot to provide a holistic view of the complex urban disaster areas. The robot-collected data can help locate critical spaces under the rubble to save trapped victims. The simulation framework can serve as a virtual training platform for novice users to control and operate the robot before actual deployment. Data streams provided by the platform, which include maneuver commands, robot states and environmental information, have potential to facilitate the understanding of the decision-making process in urban SaR and the training of future intelligent SaR robots.

16.
Molecules ; 25(18)2020 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-32916811

RESUMO

Aflatoxin (AF) contamination is a major concern in the food and feed industry because of its prevalence and toxicity. Improved aflatoxin detection methods are still needed. Immunoassays are an important method for total aflatoxin (TAF) analysis in food due to its technical advantages such as high specificity, sensitivity, and simplicity, but require high-quality antibodies. Here, we first review the three ways to prepare high-quality antibodies for TAF immunoassay, second, compare the advantages and disadvantages of antigen synthesis methods for B-group and G-group aflatoxins, and third, describe the status of novel genetic engineering antibodies. This review can provide new methods and ideas for the development of TAF immunoassays.

17.
DNA Repair (Amst) ; 95: 102946, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32853826

RESUMO

Ataxia Telangiectasia and Rad3-Related kinase (ATR) is a master regulator of genome maintenance, and participates in DNA replication and various DNA repair pathways. In a genome-wide screen for ATR-dependent fitness genes, we identified a previously uncharacterized gene, C17orf53, whose loss led to hypersensitivity to ATR inhibition. C17orf53 is conserved in vertebrates and is required for efficient cell proliferation. Loss of C17orf53 slowed down DNA replication and led to pronounced interstrand crosslink (ICL) repair defect. We showed that C17orf53 is a ssDNA- and RPA-binding protein and both characteristics are important for its functions in the cell. In addition, using multiple omics methods, we found that C17orf53 works with MCM8/9 to promote cell survival in response to ICL lesions. Taken together, our data suggest that C17orf53 is a novel component involved in ICL repair pathway.

18.
Breast ; 53: 189-200, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32858404

RESUMO

BACKGROUND: The axillary reverse mapping (ARM) technique, identify and preserve arm nodes during sentinel lymph node biopsy (SLNB) or axillary lymph node dissection (ALND), was developed to prevent breast-cancer related lymphedema (BCRL) remains controversial. METHODS: A comprehensive search of Medline Ovid, Pubmed, Web of Science and the Cochrane CENTRAL databases was conducted from the inception till January 2020. The key word including "breast cancer", "axillary reverse mapping", and "lymphedema". Stata 15.1 software was used for the meta-analysis. RESULTS: As a result, twenty-nine related studies involving 4954 patients met our inclusion criteria. The pooled overall estimate lymphedema incidence was 7% (95% CI 4%-11%, I2 = 90.35%, P < 0.05), with SLNB showed a relatively lower pooled incidence of lymphedema (2%, 95% CI 1%-3%), I2 = 26.06%, P = 0.23) than that of ALND (14%, 95% CI 5%-26%, I2 = 93.28%, P < 0.05) or SLNB and ALND combined (11%, 95% CI 1%-30%). The ARM preservation during ALND procedure could significantly reduce upper extremity lymphedema in contrast with ARM resection (OR = 0.27, 95% CI 0.20-0.36, I2 = 31%, P = 0.161). Intriguingly, the result favored ALND-ARM over standard-ALND in preventing lymphedema occurrence (OR = 0.21, 95% CI 0.14-0.31, I2 = 43%, P = 0.153). The risk of metastases in the ARM-nodes was not significantly lower in the patients who had received neoadjuvant chemotherapy, as compared to those without neoadjuvant treatment (OR = 1.20, 95% CI 0.74-1.94, I2 = 49.4%, P = 0.095). CONCLUSIONS: ARM was found to significantly reduce the incidence of BCRL. The selection of patients for this procedure should be based on their axillary nodal status. Preoperative neoadjuvant chemotherapy has no significant impact on the ARM lymph node metastasis rate.

19.
Biochem Biophys Res Commun ; 530(1): 160-166, 2020 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-32828280

RESUMO

Rosiglitazone is a ligand of peroxisome proliferation-activated receptor gamma (PPARγ). However, it exerts biological activities and therapeutic effects through both PPARγ-dependent and independent mechanisms. In this study, we defined that rosiglitazone was also a ligand of retinoid X receptor alpha (RXRα) and displayed RXRα-dependent activities. We found that rosiglitazone directly bound to the ligand binding domain (LBD) of RXRα and induced RXRα/LBD tetramerization. Rosiglitazone inhibited the agonist-induced transcriptional activity of RXRα homodimers and heterodimers likely through inhibiting RXRα homo- and hetero-dimerization. In acute promyelocytic leukemia (APL) NB4 cells, rosiglitazone inhibited cell proliferation and induced cell differentiation, resulting from inhibiting RXRα/PML-RARα complex formation and down-regulating PML-RARα. Together, our study identified RXRα as a novel target of rosiglitazone and RXRα mediating the anti-APL activity of rosiglitazone.

20.
J Biomech Eng ; 2020 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-32803227

RESUMO

Cells sense the biophysical cues in the microenvironment and respond to the cues biochemically and biophysically. Proper responses from the cells are critical to maintain the homeostasis in the body. The abnormal biophysical cues will cause pathological development in the cells; the pathological or aging cells, on the other hand, can alter the microenvironment to become abnormal. In this mini-review, we discuss four important biophysical cues of the microenvironment - stiffness, curvature, ECM architecture and viscosity - in terms of their roles in health, aging and diseases.

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