208 results on '"Mok, A."'
Search Results
2. Interaction of the Hsp90 Cochaperone Cyclophilin 40 with Hsc70
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Carrello, Amerigo, Allan, Rudi K., Morgan, Sarah L., Mok, Danny, Ward, Bryan K., Minchin, Rodney F., Toft, David O., and Ratajczak, Thomas
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- 2004
3. A Maize Cytokinin Gene Encoding an O-Glucosyltransferase Specific to cis-Zeatin
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Martin, Ruth C., Mok, Machteld C., and Habben, Jeffrey E.
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- 2001
4. Microfibril-associated protein 5 and the regulation of skin scar formation.
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Han, Chen, Leonardo, Trevor R., Romana-Souza, Bruna, Shi, Junhe, Keiser, Shalyn, Yuan, Heidi, Altakriti, Mohamad, Ranzer, Matthew J., Ferri-Borgogno, Sammy, Mok, Samuel C., Koh, Timothy J., Hong, Seok Jong, Chen, Lin, and DiPietro, Luisa A.
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WOUND healing ,SCARS ,EXTRACELLULAR matrix ,SKIN injuries ,PROTEINS ,NEOVASCULARIZATION - Abstract
Many factors regulate scar formation, which yields a modified extracellular matrix (ECM). Among ECM components, microfibril-associated proteins have been minimally explored in the context of skin wound repair. Microfibril-associated protein 5 (MFAP5), a small 25 kD serine and threonine rich microfibril-associated protein, influences microfibril function and modulates major extracellular signaling pathways. Though known to be associated with fibrosis and angiogenesis in certain pathologies, MFAP5's role in wound healing is unknown. Using a murine model of skin wound repair, we found that MFAP5 is significantly expressed during the proliferative and remodeling phases of healing. Analysis of existing single-cell RNA-sequencing data from mouse skin wounds identified two fibroblast subpopulations as the main expressors of MFAP5 during wound healing. Furthermore, neutralization of MFAP5 in healing mouse wounds decreased collagen deposition and refined angiogenesis without altering wound closure. In vitro, recombinant MFAP5 significantly enhanced dermal fibroblast migration, collagen contractility, and expression of pro-fibrotic genes. Additionally, TGF-ß1 increased MFAP5 expression and production in dermal fibroblasts. Our findings suggest that MFAP5 regulates fibroblast function and influences scar formation in healing wounds. Our work demonstrates a previously undescribed role for MFAP5 and suggests that microfibril-associated proteins may be significant modulators of wound healing outcomes and scarring. [ABSTRACT FROM AUTHOR]
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- 2023
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5. Mutant PfCRT Can Mediate Piperaquine Resistance in African Plasmodium falciparum With Reduced Fitness and Increased Susceptibility to Other Antimalarials.
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Wicht, Kathryn J, Small-Saunders, Jennifer L, Hagenah, Laura M, Mok, Sachel, and Fidock, David A
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PLASMODIUM falciparum ,ANTIMALARIALS ,MALARIA ,CHLOROQUINE ,QUININE ,DRUG therapy for malaria ,QUINOLINE ,PROTEINS ,PROTOZOA ,DRUG resistance ,PARASITES ,ANIMALS ,PHARMACODYNAMICS - Abstract
Background: Additional therapeutic strategies could benefit efforts to reverse the recent increase in malaria cases in sub-Saharan Africa, which mostly affects young children. A primary candidate is dihydroartemisinin + piperaquine (DHA + PPQ), which is effective for uncomplicated malaria treatment, seasonal malaria chemoprevention, and intermittent preventive treatment. In Southeast Asia, Plasmodium falciparum parasites acquired PPQ resistance, mediated primarily by mutations in the P falciparum chloroquine resistance transporter PfCRT. The recent emergence in Africa of DHA-resistant parasites creates an imperative to assess whether PPQ resistance could emerge in African parasites with distinct PfCRT isoforms.Methods: We edited 2 PfCRT mutations known to mediate high-grade PPQ resistance in Southeast Asia into GB4 parasites from Gabon. Gene-edited clones were profiled in antimalarial concentration-response and fitness assays.Results: The PfCRT F145I mutation mediated moderate PPQ resistance in GB4 parasites but with a substantial fitness cost. No resistance was observed with the PfCRT G353V mutant. Both edited clones became significantly more susceptible to amodiaquine, chloroquine, and quinine.Conclusions: A single PfCRT mutation can mediate PPQ resistance in GB4 parasites, but with a growth defect that may preclude its spread without further genetic adaptations. Our findings support regional use of drug combinations that exert opposing selective pressures on PfCRT. [ABSTRACT FROM AUTHOR]- Published
- 2022
- Full Text
- View/download PDF
6. Domain structure of the DEMETER 5-methylcytosine DNA glycosylase
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Mok, Young Geun, Uzawa, Rie, Lee, Jiyoon, Weiner, Gregory M., Eichman, Brandt F., Fischer, Robert L., and Huh, Jin Hoe
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- 2010
7. Heteromeric complexes of heat shock protein 70 (HSP70) family members, including Hsp70B', in differentiated human neuronal cells
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Chow, Ari M., Mok, Philip, Xiao, Dawn, Khalouei, Sam, and Brown, Ian R.
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- 2010
8. N-terminal methionine excision of proteins creates tertiary destabilizing N-degrons of the Arg/N-end rule pathway
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Kha The Nguyen, Jeong-Mok Kim, Sang-Eun Park, and Cheol-Sang Hwang
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0301 basic medicine ,Protein subunit ,N-end rule ,Saccharomyces cerevisiae ,Protein degradation ,Arginine ,Biochemistry ,03 medical and health sciences ,chemistry.chemical_compound ,Methionine ,Protein biosynthesis ,Humans ,Molecular Biology ,030102 biochemistry & molecular biology ,biology ,Proteins ,Cell Biology ,Ubiquitin ligase ,N-terminus ,030104 developmental biology ,chemistry ,Protein Synthesis and Degradation ,Acetylation ,Protein Biosynthesis ,Proteolysis ,biology.protein - Abstract
All organisms begin protein synthesis with methionine (Met). The resulting initiator Met of nascent proteins is irreversibly processed by Met aminopeptidases (MetAPs). N-terminal (Nt) Met excision (NME) is an evolutionarily conserved and essential process operating on up to two-thirds of proteins. However, the universal function of NME remains largely unknown. MetAPs have a well-known processing preference for Nt-Met with Ala, Ser, Gly, Thr, Cys, Pro, or Val at position 2, but using CHX-chase assays to assess protein degradation in yeast cells, as well as protein-binding and RT-qPCR assays, we demonstrate here that NME also occurs on nascent proteins bearing Met–Asn or Met–Gln at their N termini. We found that the NME at these termini exposes the tertiary destabilizing Nt residues (Asn or Gln) of the Arg/N-end rule pathway, which degrades proteins according to the composition of their Nt residues. We also identified a yeast DNA repair protein, MQ-Rad16, bearing a Met–Gln N terminus, as well as a human tropomyosin–receptor kinase–fused gene (TFG) protein, MN-TFG, bearing a Met–Asn N terminus as physiological, MetAP-processed Arg/N-end rule substrates. Furthermore, we show that the loss of the components of the Arg/N-end rule pathway substantially suppresses the growth defects of naa20Δ yeast cells lacking the catalytic subunit of NatB Nt acetylase at 37 °C. Collectively, the results of our study reveal that NME is a key upstream step for the creation of the Arg/N-end rule substrates bearing tertiary destabilizing residues in vivo.
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- 2019
9. Seroprevalence of SARS-CoV-2 antibodies in people with an acute loss in their sense of smell and/or taste in a community-based population in London, UK: An observational cohort study
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Cormac Magee, Alisia Carnemolla, Janine M. Makaronidis, Rachel L. Batterham, Jessica Mok, Rumana Z Omar, and N Balogun
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RNA viruses ,Male ,Taste ,Viral Diseases ,Coronaviruses ,Physiology ,Social Sciences ,030204 cardiovascular system & hematology ,Antibodies, Viral ,Biochemistry ,Olfaction Disorders ,Taste Disorders ,0302 clinical medicine ,Medical Conditions ,COVID-19 Testing ,Seroepidemiologic Studies ,Immune Physiology ,London ,Coughing ,Psychology ,030212 general & internal medicine ,Pathology and laboratory medicine ,Virus Testing ,education.field_of_study ,Immune System Proteins ,biology ,General Medicine ,Medical microbiology ,Middle Aged ,Smell ,Infectious Diseases ,Point-of-Care Testing ,Seroconversion ,Viruses ,Medicine ,Sensory Perception ,Female ,SARS CoV 2 ,Pathogens ,Coronavirus Infections ,Cohort study ,Research Article ,Adult ,medicine.medical_specialty ,SARS coronavirus ,Population ,Immunology ,Pneumonia, Viral ,Olfaction ,Microbiology ,Antibodies ,03 medical and health sciences ,Betacoronavirus ,Signs and Symptoms ,Diagnostic Medicine ,Internal medicine ,medicine ,Seroprevalence ,Humans ,education ,Pandemics ,Medicine and health sciences ,Text Messaging ,business.industry ,Clinical Laboratory Techniques ,SARS-CoV-2 ,fungi ,Cognitive Psychology ,Organisms ,Viral pathogens ,Biology and Life Sciences ,Proteins ,COVID-19 ,Covid 19 ,Microbial pathogens ,Immunoglobulin M ,Immunoglobulin G ,biology.protein ,Cognitive Science ,Perception ,Clinical Medicine ,business ,Physiological Processes ,Neuroscience - Abstract
Background Loss of smell and taste are commonly reported symptoms associated with coronavirus disease 2019 (COVID-19); however, the seroprevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies in people with acute loss of smell and/or taste is unknown. The study aimed to determine the seroprevalence of SARS-CoV-2 antibodies in a community-based population with acute loss of smell and/or taste and to compare the frequency of COVID-19 associated symptoms in participants with and without SARS-CoV-2 antibodies. It also evaluated whether smell or taste loss are indicative of COVID-19 infection. Methods and findings Text messages, sent via primary care centers in London, United Kingdom, invited people with loss of smell and/or taste in the preceding month, to participate. Recruitment took place between 23 April 2020 and 14 May 2020. A total of 590 participants enrolled via a web-based platform and responded to questions about loss of smell and taste and other COVID-19–related symptoms. Mean age was 39.4 years (SD ± 12.0) and 69.1% (n = 392) of participants were female. A total of 567 (96.1%) had a telemedicine consultation during which their COVID-19–related symptoms were verified and a lateral flow immunoassay test that detected SARS-CoV-2 immunoglobulin G (IgG) and immunoglobulin M (IgM) antibodies was undertaken under medical supervision. A total of 77.6% of 567 participants with acute smell and/or taste loss had SARS-CoV-2 antibodies; of these, 39.8% (n = 175) had neither cough nor fever. New loss of smell was more prevalent in participants with SARS-CoV-2 antibodies, compared with those without antibodies (93.4% versus 78.7%, p < 0.001), whereas taste loss was equally prevalent (90.2% versus 89.0%, p = 0.738). Seropositivity for SARS-CoV-2 was 3 times more likely in participants with smell loss (OR 2.86; 95% CI 1.27–6.36; p < 0.001) compared with those with taste loss. The limitations of this study are the lack of a general population control group, the self-reported nature of the smell and taste changes, and the fact our methodology does not take into account the possibility that a population subset may not seroconvert to develop SARS-CoV-2 antibodies post-COVID-19. Conclusions Our findings suggest that recent loss of smell is a highly specific COVID-19 symptom and should be considered more generally in guiding case isolation, testing, and treatment of COVID-19. Trials registration ClinicalTrials.gov NCT04377815, In a UK-based cohort, Janine Makaronidis and colleagues investigate COVID-19 seropositivity in individuals with loss of smell and/or taste., Author summary Why was this study done? Coronavirus disease 2019 (COVID-19), an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, was declared a pandemic in March 2020. COVID-19 can cause loss or reduced ability to smell (anosmia) or taste, without cough or fever, but few countries recommend self-isolation and testing on the basis of smell or taste changes alone. This study aimed to find out the proportion of people who have developed SARS-CoV-2 antibodies in a community-based population with a newly developed loss in their sense of smell and/or taste in London, UK. What did the researchers do and find? Text messages were sent out to people registered with a number of primary care centers in London inviting people with a new loss in their sense of smell and/or taste to participate. Recruited participants completed online questionnaires regarding demographics, their loss of smell and/or taste, and other COVID-19 symptoms, before they had a telemedicine consultation with a healthcare professional who confirmed the history of their symptoms and supervised a test to find out if they had SARS-CoV-2 antibodies. A total of 78% of 567 people with smell and/or taste loss had SARS-CoV-2 antibodies; of these, 40% had neither cough nor fever, and participants with loss of smell were 3 times more to have SARS-CoV-2 antibodies, compared with those with loss of taste. What do these findings mean? Loss of smell is a highly specific symptom of COVID-19. COVID-19 can present with loss of smell and/or taste without cough or fever. Loss of smell should be take into consideration in case isolation, testing, and treatment strategies for COVID-19.
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- 2020
10. SARS-CoV-2 accessory proteins reveal distinct serological signatures in children.
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Hachim, Asmaa, Gu, Haogao, Kavian, Otared, Mori, Masashi, Kwan, Mike Y. W., Chan, Wai Hung, Yau, Yat Sun, Chiu, Susan S., Tsang, Owen T. Y., Hui, David S. C., Mok, Chris K. P., Ma, Fionn N. L., Lau, Eric H. Y., Amarasinghe, Gaya K., Qavi, Abraham J., Cheng, Samuel M. S., Poon, Leo L. M., Peiris, J. S. Malik, Valkenburg, Sophie A., and Kavian, Niloufar
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CYTOSKELETAL proteins ,SARS-CoV-2 ,ANTIBODY formation ,IMMUNOGLOBULINS ,PRINCIPAL components analysis ,PROTEINS - Abstract
The antibody response magnitude and kinetics may impact clinical severity, serological diagnosis and long-term protection of COVID-19, which may play a role in why children experience lower morbidity. We therefore tested samples from 122 children in Hong Kong with symptomatic (n = 78) and asymptomatic (n = 44) SARS-CoV-2 infections up to 200 days post infection, relative to 71 infected adults (symptomatic n = 61, and asymptomatic n = 10), and negative controls (n = 48). We assessed serum IgG antibodies to a 14-wide antigen panel of structural and accessory proteins by Luciferase Immuno-Precipitation System (LIPS) assay and circulating cytokines. Infected children have lower levels of Spike, Membrane, ORF3a, ORF7a, ORF7b antibodies, comparable ORF8 and elevated E-specific antibodies than adults. Combination of two unique antibody targets, ORF3d and ORF8, can accurately discriminate SARS-CoV-2 infection in children. Principal component analysis reveals distinct pediatric serological signatures, and the highest contribution to variance from adults are antibody responses to non-structural proteins ORF3d, NSP1, ORF3a and ORF8. From a diverse panel of cytokines that can modulate immune priming and relative inflammation, IL-8, MCP-1 and IL-6 correlate with the magnitude of pediatric antibody specificity and severity. Antibodies to SARS-CoV-2 internal proteins may become an important sero surveillance tool of infection with the roll-out of vaccines in the pediatric population. The antibody response of children to SARS-CoV-2 is less well studied than in adults. Here Hachim et al. show that children have reduced antibody levels to structural proteins and suggest that the predominance of antibody responses to non-structural proteins can be used to discriminate infection and vaccination. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
11. Proteomic Profiling of
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Goyeun, Yun, Jong-Moon, Park, Van-An, Duong, Jeong-Hun, Mok, Jongho, Jeon, Onyou, Nam, Joonwon, Lee, EonSeon, Jin, and Hookeun, Lee
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Proteomics ,Chromatography, Reverse-Phase ,photosynthesis ,Proteome ,fungi ,proteomic profiling ,Haptophyta ,Proteins ,Emiliania huxleyi ,Article ,Workflow ,Gene Ontology ,Tandem Mass Spectrometry ,Peptides ,three-dimensional (3D-LC) separation - Abstract
Emiliania huxleyi is one of the most abundant marine planktons, and it has a crucial feature in the carbon cycle. However, proteomic analyses of Emiliania huxleyi have not been done extensively. In this study, a three-dimensional liquid chromatography (3D-LC) system consisting of strong cation exchange, high- and low-pH reversed-phase liquid chromatography was established for in-depth proteomic profiling of Emiliania huxleyi. From tryptic proteome digest, 70 fractions were generated and analyzed using liquid chromatography-tandem mass spectrometry. In total, more than 84,000 unique peptides and 10,000 proteins groups were identified with a false discovery rate of ≤0.01. The physicochemical properties of the identified peptides were evaluated. Using ClueGO, approximately 700 gene ontology terms and 15 pathways were defined from the identified protein groups with p-value ≤0.05, covering a wide range of biological processes, cellular components, and molecular functions. Many biological processes associated with CO2 fixation, photosynthesis, biosynthesis, and metabolic process were identified. Various molecular functions relating to protein binding and enzyme activities were also found. The 3D-LC strategy is a powerful approach for comparative proteomic studies on Emiliania huxleyi to reveal changes in its protein level and related mechanism.
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- 2020
12. Can a semi-quantitative method replace the current quantitative method for the annual screening of microalbuminuria in patients with diabetes? Diagnostic accuracy and cost-saving analysis considering the potential health burden
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Kwon Wook Joo, Seokwoo Park, Seungyeup Han, Jung Pyo Lee, Hye Soon Kim, Seung Seok Han, Myung Hee Kim, Dong Ki Kim, Yong Chul Kim, Sang Hoon Song, Yon Su Kim, Yaerim Kim, Chun Soo Lim, Hajeong Lee, Won Mok Lee, and Kyubok Jin
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Physiology ,Economics ,030232 urology & nephrology ,Social Sciences ,Urine ,Cardiovascular Medicine ,Biochemistry ,Cohort Studies ,0302 clinical medicine ,Endocrinology ,Mathematical and Statistical Techniques ,Chronic Kidney Disease ,Medicine and Health Sciences ,Mass Screening ,Diabetic Nephropathies ,030212 general & internal medicine ,health care economics and organizations ,Multidisciplinary ,Hazard ratio ,Statistics ,Metaanalysis ,Body Fluids ,Nephrology ,Cardiovascular Diseases ,Meta-analysis ,Creatinine ,Cohort ,Physical Sciences ,Medicine ,medicine.symptom ,Anatomy ,Cohort study ,Research Article ,medicine.medical_specialty ,Endocrine Disorders ,Science ,Urinalysis ,Research and Analysis Methods ,03 medical and health sciences ,Health Economics ,Cost Savings ,Diabetes mellitus ,Albumins ,Republic of Korea ,medicine ,Diabetes Mellitus ,Albuminuria ,Humans ,Statistical Methods ,business.industry ,Biology and Life Sciences ,Proteins ,Reproducibility of Results ,medicine.disease ,Annual Screening ,Health Care ,Metabolic Disorders ,Emergency medicine ,Microalbuminuria ,business ,Biomarkers ,Mathematics - Abstract
Objectives Diabetes is a global epidemic, and the high cost of annually and quantitatively measuring urine albumin excretion using the turbidimetric immunoassay is challenging. We aimed to determine whether a semi-quantitative urinary albumin-creatinine ratio test could be used as a screening tool for microalbuminuria in diabetic patients. Methods We assessed the diagnostic accuracy of the semi-quantitative method. The costs of false results in the semi-quantitative method were calculated based on the annual probability of disease progression analyzed through a systematic literature review and meta-analysis. The pooled long-term cost-saving effect of the semi-quantitative method compared with the quantitative test was assessed using a Markov model simulating a long-term clinical setting. Diagnostic accuracy and the cost-saving effect were also validated in an independent external cohort. Results Compared with the quantitative test, the semi-quantitative method had sensitivities of 93.5% and 81.3% and specificities of 61.4% and 63.1% in the overall sample of diabetic patients (n = 1,881) and in diabetic patients with eGFR ≥60 ml/min/1.73 m2 and a negative dipstick test (n = 1,110), respectively. After adjusting for direct and indirect medical costs, including the risk of disease progression, which was adjusted by the meta-analyzed hazard ratio for clinical outcomes, it was determined that using the semi-quantitative method could save 439.4 USD per person for 10 years. Even after adjusting the result to the external validation cohort, 339.6 USD could be saved for one diabetic patient for 10 years. Conclusions The semi-quantitative method could be an appropriate screening tool for albuminuria in diabetic patients. Moreover, it can minimize the testing time and inconvenience and significantly reduce national health costs.
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- 2020
13. Super-enhancers for RUNX3 are required for cell proliferation in EBV-infected B cell lines
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Takashi Sonoki, Giselle Sek Suan Nah, Avinash Govind Bahirvani, Alan Prem Kumar, Yoshiaki Ito, Daniel G. Tenen, Hiroki Hosoi, Michelle Meng Huang Mok, Akiko Niibori-Nambu, Takaomi Sanda, and Motomi Osato
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0301 basic medicine ,Herpesvirus 4, Human ,Genes, myc ,Biology ,medicine.disease_cause ,Article ,Cell Line ,03 medical and health sciences ,0302 clinical medicine ,Super-enhancer ,Protein Domains ,Cell Line, Tumor ,Genetics ,medicine ,Humans ,Enhancer ,Gene ,Transcription factor ,B cell ,Cell Proliferation ,B-Lymphocytes ,Cell growth ,G1 Phase ,Proteins ,Azepines ,General Medicine ,Triazoles ,Burkitt Lymphoma ,Epstein–Barr virus ,digestive system diseases ,Bromodomain ,Cell biology ,Core Binding Factor Alpha 3 Subunit ,Enhancer Elements, Genetic ,030104 developmental biology ,medicine.anatomical_structure ,Gene Expression Regulation ,030220 oncology & carcinogenesis ,CRISPR-Cas Systems - Abstract
Epstein-Barr virus nuclear antigens 2 (EBNA2) mediated super-enhancers, defined by in silico data, localize near genes associated with B cell transcription factors including RUNX3. However, the biological function of super-enhancer for RUNX3 gene (seR3) remains unclear. Here, we show that two seR3s, tandemly-located at 59- and 70-kb upstream of RUNX3 transcription start site, named seR3 –59h and seR3 –70h, are required for RUNX3 expression and cell proliferation in Epstein-Barr virus (EBV)-positive malignant B cells. A BET bromodomain inhibitor, JQ1, potently suppressed EBV-positive B cell growth through the reduction of RUNX3 and MYC expression. Excision of either or both seR3s by employing CRISPR/Cas9 system resulted in the decrease in RUNX3 expression and the subsequent suppression of cell proliferation and colony forming capability. The expression of MYC was also reduced when seR3s were deleted, probably due to the loss of trans effect of seR3s on the super-enhancers for MYC. These findings suggest that seR3s play a pivotal role in expression and biological function of both RUNX3 and MYC. seR3s would serve as a potential therapeutic target in EBV-related widespread tumors.
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- 2021
14. Size Determination of Protein Oligomers/Aggregates Using Diffusion NMR Spectroscopy
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Pancham S, Kandiyal, Ji Yoon, Kim, Daniel L, Fortunati, and K H, Mok
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Diffusion ,Kinetics ,Protein Aggregates ,Magnetic Resonance Spectroscopy ,Hydrodynamics ,Proteins - Abstract
Diffusion-ordered spectroscopy (DOSY) is a widely used NMR technique for the identification of different chemical moieties/compounds contained in mixtures and has been successfully employed for the separation of small molecules based on hydrodynamic radii. Herein we show that DOSY can also be applied for the size determination of larger biomolecules such as proteins and protein oligomers/aggregates. Proof-of-principle is first shown with a cross-linked oligomeric protein mixture where the hydrodynamic volumes of each component are estimated and subsequently verified with size-exclusion HPLC and SDS polyacrylamide gel electrophoresis. We then determine the sizes of protein oligomers contained in a protein solution subjected under amyloid fibrillogenesis conditions. These studies aim to provide insight into the kinetics behind protein aggregation involved in amyloidosis as well as to determine the hydrodynamic radii of proteins within the mixture.
- Published
- 2019
15. N-terminal formylmethionine as a novel initiator and N-degron of eukaryotic proteins
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Jeong-Mok Kim
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Hydroxymethyl and Formyl Transferases ,Formyltransferase ,Saccharomyces cerevisiae Proteins ,Ubiquitin-Protein Ligases ,Saccharomyces cerevisiae ,Mitochondrion ,Biochemistry ,Psh1 ,03 medical and health sciences ,Cytosol ,Methionine ,Ubiquitin ,Amino Acids ,Molecular Biology ,0303 health sciences ,biology ,Chemistry ,030302 biochemistry & molecular biology ,Proteins ,General Medicine ,biology.organism_classification ,Yeast ,Ubiquitin ligase ,Mitochondria ,Up-Regulation ,Eukaryotic Cells ,Protein Biosynthesis ,Proteolysis ,Perspective ,biology.protein ,Eukaryote ,Gcn2 ,Degron - Abstract
The ribosomal synthesis of proteins in the eukaryotic cytosol has always been thought to start from the unformylated N-terminal (Nt) methionine (Met). In contrast, in virtually all nascent proteins in bacteria and eukaryotic organelles, such as mitochondria and chloroplasts, Nt-formyl-methionine (fMet) is the first building block of ribosomal synthesis. Through extensive approaches, including mass spectrometric analyses of the N-termini of proteins and molecular genetic techniques with an affinity-purified antibody for Nt-formylation, we investigated whether Nt-formylated proteins could also be produced and have their own metabolic fate in the cytosol of a eukaryote, such as yeast Saccharomyces cerevisiae. We discovered that Nt-formylated proteins could be generated in the cytosol by yeast mitochondrial formyltransferase (Fmt1). These Nt-formylated proteins were massively upregulated in the stationary phase or upon starvation for specific amino acids and were crucial for the adaptation to specific stresses. The stress-activated kinase Gcn2 was strictly required for the upregulation of Nt-formylated proteins by regulating the activity of Fmt1 and its retention in the cytosol. We also found that the Nt-fMet residues of Nt-formylated proteins could be distinct N-terminal degradation signals, termed fMet/N-degrons, and that Psh1 E3 ubiquitin ligase mediated the selective destruction of Nt-formylated proteins as the recognition component of a novel eukaryotic fMet/N-end rule pathway, termed fMet/N-recognin. [BMB Reports 2019; 52(3): 163-164].
- Published
- 2019
16. Lactate normalization within 6 hours of bundle therapy and 24 hours of delayed achievement were associated with 28-day mortality in septic shock patients
- Author
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Seung Mok Ryoo, Ryeok Ahn, Tae Gun Shin, You Hwan Jo, Sung Phil Chung, Jin Ho Beom, Sung-Hyuk Choi, Young-Hoon Yoon, Byuk Sung Ko, Hui Jai Lee, Gil Joon Suh, Won Young Kim, and Korean Shock Society (KoSS) Investigators
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Male ,Resuscitation ,Time Factors ,Critical Care and Emergency Medicine ,030204 cardiovascular system & hematology ,Pathology and Laboratory Medicine ,Biochemistry ,Endocrinology ,0302 clinical medicine ,Medicine and Health Sciences ,030212 general & internal medicine ,Multidisciplinary ,Mortality rate ,C-Reactive Proteins ,Shock, Septic ,Chemistry ,Creatinine ,Physical Sciences ,Lactates ,Cardiology ,Medicine ,Female ,Research Article ,Adult ,Normalization (statistics) ,medicine.medical_specialty ,Death Rates ,Endocrine Disorders ,Science ,Sepsis ,03 medical and health sciences ,Signs and Symptoms ,Population Metrics ,Diagnostic Medicine ,Internal medicine ,Diabetes Mellitus ,medicine ,Humans ,Lactic Acid ,Hemoglobin ,Aged ,Population Biology ,business.industry ,Septic shock ,Chemical Compounds ,Biology and Life Sciences ,Proteins ,Odds ratio ,medicine.disease ,Confidence interval ,Blood pressure ,Metabolic Disorders ,Multivariate Analysis ,business ,Biomarkers - Abstract
This study evaluated the prognostic ability of lactate normalization achieved within 6 and 24 h from septic shock recognition. Data from a septic shock registry from October 2015 to February 2017 were reviewed. The study included 2,102 eligible septic shock patients to analyze the prognostic ability of lactate normalization, defined as a follow-up lactate level
- Published
- 2019
17. N-Terminal Acetylation-Targeted N-End Rule Proteolytic System: The Ac/N-End Rule Pathway
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Ji-Eun Heo, Cheol-Sang Hwang, Jeong-Mok Kim, and Kang-Eun Lee
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0301 basic medicine ,Specific protein ,proteolysis ,Proteolysis ,N-end rule ,Bioinformatics ,03 medical and health sciences ,Ubiquitin ,ubiquitin ,medicine ,Humans ,Molecular Biology ,030102 biochemistry & molecular biology ,biology ,medicine.diagnostic_test ,N-terminal acetylation ,Proteins ,Acetylation ,Cell Biology ,General Medicine ,degron ,Cell biology ,Crosstalk (biology) ,030104 developmental biology ,biology.protein ,Posttranslational modification ,Minireview ,Degron ,Protein Processing, Post-Translational ,Signal Transduction - Abstract
Although Nα-terminal acetylation (Nt-acetylation) is a pervasive protein modification in eukaryotes, its general functions in a majority of proteins are poorly understood. In 2010, it was discovered that Nt-acetylation creates a specific protein degradation signal that is targeted by a new class of the N-end rule proteolytic system, called the Ac/N-end rule pathway. Here, we review recent advances in our understanding of the mechanism and biological functions of the Ac/N-end rule pathway, and its crosstalk with the Arg/N-end rule pathway (the classical N-end rule pathway).
- Published
- 2016
18. Author Correction: Comprehensive aptamer-based screening identifies a spectrum of urinary biomarkers of lupus nephritis across ethnicities
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Deena Habazi, Hemant Suryawanshi, Chaim Putterman, Jill P. Buyon, Evan Der, Claudia Pedroza, Thomas Tuschl, Michelle Petri, Samantha Stanley, Ramesh Saxena, Shree Mohan, Chandra Mohan, Samar Soliman, Kamala Vanarsa, Chi Chiu Mok, Gabriel Gidley, and Ting Zhang
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Oncology ,Adult ,Proteomics ,medicine.medical_specialty ,Science ,Aptamer ,Lupus nephritis ,MEDLINE ,General Physics and Astronomy ,Vascular Cell Adhesion Molecule-1 ,Sensitivity and Specificity ,General Biochemistry, Genetics and Molecular Biology ,White People ,Article ,Young Adult ,Population screening ,Asian People ,Internal medicine ,Activated-Leukocyte Cell Adhesion Molecule ,Medicine ,Humans ,Author Correction ,lcsh:Science ,Multidisciplinary ,Properdin ,business.industry ,Proteins ,Diagnostic markers ,General Chemistry ,medicine.disease ,Urinary biomarkers ,Black or African American ,Female ,lcsh:Q ,business ,E-Selectin ,Aptamers, Peptide ,Biomarkers - Abstract
Emerging urinary biomarkers continue to show promise in evaluating lupus nephritis (LN). Here, we screen urine from active LN patients for 1129 proteins using an aptamer-based platform, followed by ELISA validation in two independent cohorts comprised of 127 inactive lupus, 107 active LN, 67 active non-renal lupus patients and 74 healthy controls, of three different ethnicities. Urine proteins that best distinguish active LN from inactive disease are ALCAM, PF-4, properdin, and VCAM-1 among African-Americans, sE-selectin, VCAM-1, BFL-1 and Hemopexin among Caucasians, and ALCAM, VCAM-1, TFPI and PF-4 among Asians. Most of these correlate significantly with disease activity indices in the respective ethnic groups, and surpass conventional metrics in identifying active LN, with better sensitivity, and negative/positive predictive values. Several elevated urinary molecules are also expressed within the kidneys in LN, based on single-cell RNAseq analysis. Longitudinal studies are warranted to assess the utility of these biomarkers in tracking lupus nephritis., Developing noninvasive diagnostic biomarkers for lupus nephritis (LN) diagnosis is an important clinical goal. Here the authors identify urinary proteins correlated with active LN and disease severity, which differ across ethnicities but collectively outperform the current clinical method.
- Published
- 2020
19. Insights into the intracellular localization, protein associations and artemisinin resistance properties of Plasmodium falciparum K13
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Kim C. Heimsch, Gavreel Kalantarov, Marcus C. S. Lee, Sachel Mok, Michal Kuderjavy, Judith Straimer, Barbara H. Stokes, Audrey R. Odom John, Katja Becker, Ilya Trakht, David A. Fidock, Rachel L. Edwards, Nina F. Gnädig, and Audrey Crane
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Plasmodium ,medicine.medical_treatment ,Cell Membranes ,Mutant ,Drug Resistance ,Protozoan Proteins ,Vacuole ,Endoplasmic Reticulum ,Biochemistry ,Parasite hosting ,Biology (General) ,Malaria, Falciparum ,Energy-Producing Organelles ,0303 health sciences ,Secretory Pathway ,biology ,030302 biochemistry & molecular biology ,Artemisinins ,Mitochondria ,Cell biology ,Cell Processes ,Cellular Structures and Organelles ,Research Article ,QH301-705.5 ,Plasmodium falciparum ,Immunology ,Dihydroartemisinin ,Bioenergetics ,Microbiology ,Antimalarials ,03 medical and health sciences ,Virology ,DNA-binding proteins ,Parasite Groups ,parasitic diseases ,Genetics ,medicine ,Humans ,Trophozoites ,Hemoglobin ,Vesicles ,Molecular Biology ,030304 developmental biology ,Endoplasmic reticulum ,Biology and Life Sciences ,Proteins ,Membrane Proteins ,Cell Biology ,RC581-607 ,biology.organism_classification ,Membrane protein ,Mutation ,Parasitology ,Rab ,Immunologic diseases. Allergy ,Apicomplexa - Abstract
The emergence of artemisinin (ART) resistance in Plasmodium falciparum intra-erythrocytic parasites has led to increasing treatment failure rates with first-line ART-based combination therapies in Southeast Asia. Decreased parasite susceptibility is caused by K13 mutations, which are associated clinically with delayed parasite clearance in patients and in vitro with an enhanced ability of ring-stage parasites to survive brief exposure to the active ART metabolite dihydroartemisinin. Herein, we describe a panel of K13-specific monoclonal antibodies and gene-edited parasite lines co-expressing epitope-tagged versions of K13 in trans. By applying an analytical quantitative imaging pipeline, we localize K13 to the parasite endoplasmic reticulum, Rab-positive vesicles, and sites adjacent to cytostomes. These latter structures form at the parasite plasma membrane and traffic hemoglobin to the digestive vacuole wherein artemisinin-activating heme moieties are released. We also provide evidence of K13 partially localizing near the parasite mitochondria upon treatment with dihydroartemisinin. Immunoprecipitation data generated with K13-specific monoclonal antibodies identify multiple putative K13-associated proteins, including endoplasmic reticulum-resident molecules, mitochondrial proteins, and Rab GTPases, in both K13 mutant and wild-type isogenic lines. We also find that mutant K13-mediated resistance is reversed upon co-expression of wild-type or mutant K13. These data help define the biological properties of K13 and its role in mediating P. falciparum resistance to ART treatment., Author summary The development of drug resistance in Plasmodium falciparum parasites presents a significant impediment to the global fight against malaria. Partial resistance to artemisinin (ART), the core component of current first-line drugs, has swept across Southeast Asia. In P. falciparum-infected patients, ART-resistant parasites show slow rates of clearance following treatment with an ART derivative or ART-based combination therapy. Resistance to partner drugs has also emerged in Southeast Asia, leading to frequent treatment failures. Single amino acid mutations in the P. falciparum K13 protein constitute the primary genetic cause of ART resistance and predict an increased risk of treatment failure. By generating monoclonal antibodies, we have investigated the subcellular localization of K13 in dihydroartemisinin-treated or untreated parasites. Analytical microscopy data localize K13 to or near the endoplasmic reticulum and vesicles that mediate intracellular trafficking, including plasma membrane-associated cytostomes that import host hemoglobin into the parasite. Co-immunoprecipitation experiments with K13-specific monoclonal antibodies identified multiple proteins associated with the endoplasmic reticulum, vesicular trafficking, the cytosol, or the mitochondria, with no apparent differences between K13 mutant and wild-type parasites. We also observed that overexpression of mutant or wild-type K13 in K13 mutant parasites could restore susceptibility, supporting the hypothesis that K13 mutations cause loss of function.
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- 2020
20. Oxidative stress and protein damage responses mediate artemisinin resistance in malaria parasites
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Zbynek Bozdech, Kek-Yee Liong, Sachel Mok, Olivo Miotto, Arjen M. Dondorp, Lei Zhu, Frances Rocamora, Cooper, Roland, and School of Biological Sciences
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0301 basic medicine ,Plasmodium ,Drug Resistance ,Protozoan Proteins ,Gene Expression ,Drug resistance ,Biochemistry ,Transcriptome ,Medicine and Health Sciences ,Artemisinin ,Malaria, Falciparum ,Biology (General) ,Genetics ,Protozoans ,Artemisinin Resistance ,Malarial Parasites ,Eukaryota ,Genomics ,Phenotype ,Artemisinins ,3. Good health ,Transcriptome Analysis ,medicine.drug ,Research Article ,Genetic Markers ,QH301-705.5 ,030106 microbiology ,Immunology ,Plasmodium falciparum ,Biology ,Microbiology ,03 medical and health sciences ,Antimalarials ,Antibiotic resistance ,Virology ,Microbial Control ,Parasite Groups ,DNA-binding proteins ,parasitic diseases ,medicine ,Parasitic Diseases ,Humans ,Gene Regulation ,Parasites ,Molecular Biology ,Pharmacology ,Polymorphism, Genetic ,Gene Expression Profiling ,Organisms ,Biology and Life Sciences ,Computational Biology ,Proteins ,RC581-607 ,medicine.disease ,biology.organism_classification ,Genome Analysis ,Parasitic Protozoans ,Regulatory Proteins ,Oxidative Stress ,030104 developmental biology ,Genetic marker ,Parasitology ,Antimicrobial Resistance ,Immunologic diseases. Allergy ,Apicomplexa ,Malaria ,Transcription Factors - Abstract
Due to their remarkable parasitocidal activity, artemisinins represent the key components of first-line therapies against Plasmodium falciparum malaria. However, the decline in efficacy of artemisinin-based drugs jeopardizes global efforts to control and ultimately eradicate the disease. To better understand the resistance phenotype, artemisinin-resistant parasite lines were derived from two clones of the 3D7 strain of P. falciparum using a selection regimen that mimics how parasites interact with the drug within patients. This long term in vitro selection induced profound stage-specific resistance to artemisinin and its relative compounds. Chemosensitivity and transcriptional profiling of artemisinin-resistant parasites indicate that enhanced adaptive responses against oxidative stress and protein damage are associated with decreased artemisinin susceptibility. This corroborates our previous findings implicating these cellular functions in artemisinin resistance in natural infections. Genomic characterization of the two derived parasite lines revealed a spectrum of sequence and copy number polymorphisms that could play a role in regulating artemisinin response, but did not include mutations in pfk13, the main marker of artemisinin resistance in Southeast Asia. Taken together, here we present a functional in vitro model of artemisinin resistance that is underlined by a new set of genetic polymorphisms as potential genetic markers., Author summary The emergence of artemisinin resistance within and beyond Southeast Asia is a looming threat that needs to be promptly addressed. With this in mind, we derived several artemisinin-resistant parasite lines in vitro in order to fully characterize the resistance phenotype at the cellular and molecular levels. In addition to reinforcing the role of stress responses in mediating artemisinin resistance, we also identified novel genetic alterations that could also be responsible for causing artemisinin resistance. Collectively, this work provides additional insight in relation to, and beyond the paradigm of pfk13-driven artemisinin resistance and artemisinin response in P. falciparum. Understanding the processes that govern the acquisition of artemisinin resistance could aid in the development of strategies to prevent and contain it.
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- 2018
21. The wtf4 meiotic driver utilizes controlled protein aggregation to generate selective cell death.
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Nuckolls, Nicole L., Mok, Anthony C., Lange, Jeffrey J., Kexi Yi, Kandola, Tejbir S., Hunn, Andrew M., McCroskey, Scott, Snyder, Julia L., Bravo Núñez, María Angélica, McClain, Melainia, McKinney, Sean A., Wood, Christopher, Halfmann, Randal, and Zanders, Sarah E.
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CELL death , *SCHIZOSACCHAROMYCES pombe , *PROTEINS , *SACCHAROMYCES cerevisiae , *GAMETOGENESIS - Abstract
Meiotic drivers are parasitic loci that force their own transmission into greater than half of the offspring of a heterozygote. Many drivers have been identified, but their molecular mechanisms are largely unknown. The wtf4 gene is a meiotic driver in Schizosaccharomyces pombe that uses a poison-antidote mechanism to selectively kill meiotic products (spores) that do not inherit wtf4. Here, we show that the Wtf4 proteins can function outside of gametogenesis and in a distantly related species, Saccharomyces cerevisiae. The Wtf4poison protein forms dispersed, toxic aggregates. The Wtf4antidote can co-assemble with the Wtf4poison and promote its trafficking to vacuoles. We show that neutralization of the Wtf4poison requires both co-assembly with the Wtf4antidote and aggregate trafficking, as mutations that disrupt either of these processes result in cell death in the presence of the Wtf4 proteins. This work reveals that wtf parasites can exploit protein aggregate management pathways to selectively destroy spores. [ABSTRACT FROM AUTHOR]
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- 2020
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22. Genome-Wide DNA Methylation Analysis of Chinese Patients with Systemic Lupus Erythematosus Identified Hypomethylation in Genes Related to the Type I Interferon Pathway
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Pamela Pui Wah Lee, Wilfred Hing Sang Wong, Yu-Lung Lau, Wanling Yang, Chak Sing Lau, Yi-an Chen, Mo Yin Mok, Daniel Tak Mao Chan, Kit San Yeung, Daria Grafodatskaya, Wai Lap Wong, Rosanna Weksberg, Christopher C.Y. Mak, Brian H.Y. Chung, Raymond Woon Sing Wong, and Sanaa Choufani
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0301 basic medicine ,Microarray ,Microarrays ,lcsh:Medicine ,Biochemistry ,Epigenesis, Genetic ,White Blood Cells ,chemistry.chemical_compound ,Animal Cells ,Medicine and Health Sciences ,Ethnicities ,Lupus Erythematosus, Systemic ,Gene Regulatory Networks ,lcsh:Science ,Oligonucleotide Array Sequence Analysis ,Genetics ,DNA methylation ,Multidisciplinary ,T Cells ,Methylation ,Middle Aged ,Chromatin ,Nucleic acids ,Bioassays and Physiological Analysis ,CpG site ,Interferon Type I ,Epigenetics ,Female ,Cellular Types ,DNA microarray ,DNA modification ,Chromatin modification ,Research Article ,Chromosome biology ,Adult ,Cell biology ,China ,Adolescent ,Immune Cells ,Immunology ,Biology ,Research and Analysis Methods ,Systemic Lupus Erythematosus ,Autoimmune Diseases ,Young Adult ,03 medical and health sciences ,Rheumatology ,Humans ,Gene ,Aged ,Treatment Guidelines ,Health Care Policy ,Blood Cells ,Biology and life sciences ,Lupus Erythematosus ,Genome, Human ,lcsh:R ,Proteins ,DNA ,Health Care ,030104 developmental biology ,chemistry ,Case-Control Studies ,People and Places ,Clinical Immunology ,Population Groupings ,lcsh:Q ,Gene expression ,Interferons ,Clinical Medicine ,Chinese People ,Biomarkers ,Genome-Wide Association Study - Abstract
Background Epigenetic variants have been shown in recent studies to be important contributors to the pathogenesis of systemic lupus erythematosus (SLE). Here, we report a 2-step study of discovery followed by replication to identify DNA methylation alterations associated with SLE in a Chinese population. Using a genome-wide DNA methylation microarray, the Illumina Infinium HumanMethylation450 BeadChip, we compared the methylation levels of CpG sites in DNA extracted from white blood cells from 12 female Chinese SLE patients and 10 healthy female controls. Results We identified 36 CpG sites with differential loss of DNA methylation and 8 CpG sites with differential gain of DNA methylation, representing 25 genes and 7 genes, respectively. Surprisingly, 42% of the hypomethylated CpG sites were located in CpG shores, which indicated the functional importance of the loss of DNA methylation. Microarray results were replicated in another cohort of 100 SLE patients and 100 healthy controls by performing bisulfite pyrosequencing of four hypomethylated genes, MX1, IFI44L, NLRC5 and PLSCR1. In addition, loss of DNA methylation in these genes was associated with an increase in mRNA expression. Gene ontology analysis revealed that the hypomethylated genes identified in the microarray study were overrepresented in the type I interferon pathway, which has long been implicated in the pathogenesis of SLE. Conclusion Our epigenetic findings further support the importance of the type I interferon pathway in SLE pathogenesis. Moreover, we showed that the DNA methylation signatures of SLE can be defined in unfractionated white blood cells.
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- 2017
23. Single dose primaquine to reduce gametocyte carriage and Plasmodium falciparum transmission in Cambodia: An open-label randomized trial
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Soklyda Chann, David L. Saunders, Worachet Kuntawunginn, Rifat Rahman, Michele D. Spring, Steven R. Meshnick, Mengchuor Char, Kheangheng Thay, Mali Ittiverakul, Panita Gosi, Charlotte A. Lanteri, Sujata Balasubramanian, Somethy Sok, Ratawan Ubalee, Mok My, Chanthap Lon, and Jessica T. Lin
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Male ,0301 basic medicine ,Primaquine ,Drug Resistance ,lcsh:Medicine ,Artificial Gene Amplification and Extension ,Drug resistance ,Disease Vectors ,Gametocytes ,Mosquitoes ,Biochemistry ,Polymerase Chain Reaction ,0302 clinical medicine ,Animal Cells ,Medicine and Health Sciences ,Malaria, Falciparum ,Artemisinin ,lcsh:Science ,Glucose-6-Phosphate Dehydrogenase Deficiency ,Multidisciplinary ,Drugs ,Anemia ,Hematology ,Artemisinins ,3. Good health ,Insects ,Drug Combinations ,Infectious Diseases ,Female ,Cellular Types ,Research Article ,medicine.drug ,Adult ,medicine.medical_specialty ,Arthropoda ,Adolescent ,Combination therapy ,Plasmodium falciparum ,030231 tropical medicine ,030106 microbiology ,Biology ,Research and Analysis Methods ,Antimalarials ,03 medical and health sciences ,Internal medicine ,Parasite Groups ,Anopheles ,parasitic diseases ,Parasitic Diseases ,medicine ,Gametocyte ,Animals ,Humans ,Hemoglobin ,Molecular Biology Techniques ,Molecular Biology ,Pharmacology ,Dose-Response Relationship, Drug ,lcsh:R ,Organisms ,Oocysts ,Hemolytic Anemia ,Biology and Life Sciences ,Proteins ,Cell Biology ,Reverse Transcriptase-Polymerase Chain Reaction ,Tropical Diseases ,medicine.disease ,biology.organism_classification ,Invertebrates ,Virology ,Insect Vectors ,Malaria ,Species Interactions ,Germ Cells ,Parasitology ,lcsh:Q ,Apicomplexa ,Glucose-6-phosphate dehydrogenase deficiency - Abstract
Background Single low dose primaquine (SLD PQ, 0.25mg/kg) is recommended in combination with artemisinin-based combination therapy (ACT) as a gametocytocide to prevent Plasmodium falciparum transmission in areas threatened by artemisinin resistance. To date, no randomized controlled trials have measured primaquine’s effect on infectiousness to Anopheline mosquitoes in Southeast Asia. Methods Cambodian adults with uncomplicated falciparum malaria were randomized to receive a single 45mg dose of primaquine (equivalent to three SLD PQ) or no primaquine after the third dose of dihydroartemisin-piperaquine (DHP) therapy. A membrane-feeding assay measured infectiousness to Anopheles dirus on days 0, 3, 7, and 14 of blood-stage therapy. Gametocytemia was evaluated by microscopy and reverse-transcriptase PCR. Results Prior to trial halt for poor DHP treatment efficacy, 101 participants were randomized and 50 received primaquine. Overall microscopic gametocyte prevalence was low (9%), but gametocytemic subjects given primaquine were gametocyte-free by day 14, and significantly less likely to harbor gametocytes by day 7 compared to those treated with DHP-alone, who remained gametocytemic for a median of two weeks. Only one infectious subject was randomized to the primaquine group, precluding assessment of transmission-blocking efficacy. However, he showed a two-fold reduction in oocyst density of infected mosquitoes less than 24 hours after primaquine dosing. In the DHP-alone group, four subjects remained infectious through day 14, infecting roughly the same number of mosquitoes pre and post-treatment. Overall, microscopic gametocytemia was an excellent predictor of infectiousness, and performed better than submicroscopic gametocytemia post-treatment, with none of 474 mosquitoes infected post-treatment arising from submicroscopic gametocytes. Conclusions In a setting of established ACT resistance, a single dose of 45mg primaquine added to DHP rapidly and significantly reduced gametocytemia, while DHP-alone failed to reduce gametocytemia and prevent malaria transmission to mosquitoes. Continued efforts to make single dose primaquine widely available are needed to help achieve malaria elimination.
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- 2017
24. The impact of anti-drug antibodies on drug concentrations and clinical outcomes in rheumatoid arthritis patients treated with adalimumab, etanercept, or infliximab: Results from a multinational, real-world clinical practice, non-interventional study
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Joan M. Korth-Bradley, Sameer Kotak, Mustafa Al-Maini, Bonnie Vlahos, Qi Shen, Ricardo Machado Xavier, Linda Mele, Ron Pedersen, Robert J. Moots, Ehab Mahgoub, Wen-Chan Tsai, Mahboob Rahman, Chi Chiu Mok, and Karel Pavelka
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0301 basic medicine ,Physiology ,Cancer Treatment ,Arthritis ,lcsh:Medicine ,Vascular Medicine ,Biochemistry ,Etanercept ,0302 clinical medicine ,Animal Cells ,Materials Physics ,Red Blood Cells ,Immune Physiology ,Medicine and Health Sciences ,lcsh:Science ,Immune System Proteins ,Multidisciplinary ,medicine.diagnostic_test ,Pharmaceutics ,Physics ,Incidence (epidemiology) ,Oncology ,Research Design ,Erythrocyte sedimentation rate ,Rheumatoid arthritis ,Physical Sciences ,Cellular Types ,Sedimentation ,Research Article ,medicine.drug ,medicine.medical_specialty ,Clinical Research Design ,Immunology ,Materials Science ,Rheumatoid Arthritis ,Research and Analysis Methods ,Autoimmune Diseases ,03 medical and health sciences ,Pharmacotherapy ,Drug Therapy ,Rheumatology ,Thromboembolism ,Internal medicine ,medicine ,Adalimumab ,Antigens ,030203 arthritis & rheumatology ,Blood Cells ,business.industry ,lcsh:R ,Biology and Life Sciences ,Proteins ,Cell Biology ,medicine.disease ,Infliximab ,Surgery ,030104 developmental biology ,Clinical Immunology ,lcsh:Q ,Adverse Events ,Clinical Medicine ,business - Abstract
Objective To assess the incidence of anti-drug antibodies (ADA) in patients with rheumatoid arthritis (RA) treated with the TNF inhibitors etanercept (ETN), adalimumab (ADL), or infliximab (IFX), and determine the potential relationship with trough drug concentration, efficacy, and patient-reported outcomes. Methods This multi-national, non-interventional, cross-sectional study (NCT01981473) enrolled adult patients with RA treated continuously for 6–24 months with ETN, ADL, or IFX. ADA and trough drug concentrations were measured by independent assays ≤2 days before the next scheduled dose. Efficacy measurements included Disease Activity Score 28-joint count (DAS28), low disease activity (LDA), remission, and erythrocyte sedimentation rate (ESR). Targeted medical histories of injection site/infusion reactions, serum sickness, and thromboembolic events were collected. Results Baseline demographics of the 595 patients (ETN: n = 200; ADL: n = 199; IFX: n = 196) were similar across groups. The mean duration of treatment was 14.6, 13.5, and 13.1 months for ETN, ADL, and IFX, respectively. All ETN-treated patients tested negative for ADA, whereas 31.2% and 17.4% patients treated with ADL and IFX, respectively, tested positive. In ADL- or IFX-treated patients, those with ADA had significantly lower trough drug concentrations. There were negative correlations between trough drug levels and both CRP and ESR in ADL- and IFX-treated patients. DAS28-ESR LDA and remission rates were higher in patients without ADA. The rate of targeted medical events reported was low. Conclusion ADA were detected in ADL- and IFX-treated but not ETN-treated patients. Patients without ADA generally showed numerically better clinical outcomes than those with ADA. Trial registration This study was registered on www.ClinicalTrials.gov (NCT01981473).
- Published
- 2017
25. The P4-ATPase ATP9A is a novel determinant of exosome release
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Lysbeth ten Bloemendaal, H.E. de Vries, Jyoti Naik, Chi M. Hau, Coen C. Paulusma, Sander Meisner, Ann M. Wehman, Vanesa Muncan, Nanne J. Paauw, K. S. Mok, Rienk Nieuwland, Piter J. Bosma, Najat Hajji, Molecular cell biology and Immunology, Amsterdam Neuroscience - Neuroinfection & -inflammation, ACS - Microcirculation, Graduate School, AGEM - Inborn errors of metabolism, AGEM - Endocrinology, metabolism and nutrition, CCA - Cancer biology and immunology, Laboratory Specialized Diagnostics & Research, Tytgat Institute for Liver and Intestinal Research, Gastroenterology and Hepatology, AGEM - Digestive immunity, and AGEM - Re-generation and cancer of the digestive system
- Subjects
Cell Membranes ,Apoptosis ,Cell Communication ,Exosomes ,Biochemistry ,Contractile Proteins ,Cell-Derived Microparticles ,Phospholipids ,Adenosine Triphosphatases ,0303 health sciences ,Multidisciplinary ,Cell Death ,Caspase 3 ,Chemistry ,Vesicle ,030302 biochemistry & molecular biology ,Intracellular vesicle ,Hep G2 Cells ,Lipids ,Endocytosis ,Cell biology ,Protein Transport ,Cell Processes ,Medicine ,Cellular Structures and Organelles ,Intracellular ,Research Article ,Science ,Exosome ,Extracellular Vesicles ,03 medical and health sciences ,Animals ,Humans ,Vesicles ,Caenorhabditis elegans ,Caenorhabditis elegans Proteins ,030304 developmental biology ,Cell Membrane ,Biology and Life Sciences ,Membrane Proteins ,Proteins ,Membrane Transport Proteins ,Biological membrane ,Cell Biology ,Intracellular Membranes ,Actins ,Microvesicles ,Cytoskeletal Proteins ,Cytosol ,Gene Expression Regulation ,Biogenesis - Abstract
Extracellular vesicles (EVs) released by cells have a role in intercellular communication to regulate a wide range of biological processes. Two types of EVs can be recognized. Exosomes, which are released from multi-vesicular bodies upon fusion with the plasma membrane, and ectosomes, which directly bud from the plasma membrane. How cells regulate the quantity of EV release is largely unknown. One of the initiating events in vesicle biogenesis is the regulated transport of phospholipids from the exoplasmic to the cytosolic leaflet of biological membranes. This process is catalyzed by P4-ATPases. The role of these phospholipid transporters in intracellular vesicle transport has been established in lower eukary-otes and is slowly emerging in mammalian cells. In Caenorhabditis elegans (C. elegans), deficiency of the P4-ATPase member TAT-5 resulted in enhanced EV shedding, indicating a role in the regulation of EV release. In this study, we investigated whether the mammalian ortholog of TAT-5, ATP9A, has a similar function in mammalian cells. We show that knockdown of ATP9A expression in human hepatoma cells resulted in a significant increase in EV release that was independent of caspase-3 activation. Pharmacological blocking of exosome release in ATP9A knockdown cells did significantly reduce the total number of EVs. Our data support a role for ATP9A in the regulation of exosome release from human cells.
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- 2019
26. Symptomatic Female Spastic Paraplegia Patient with a Novel Heterozygous Variant of the PLP1 Gene.
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Ae Ryoung Kim, Yun-Jeong Lee, Mi Hee Kwack, and Jong-Mok Lee
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DNA analysis ,PROTEINS ,X-linked genetic disorders ,SEQUENCE analysis ,GENETIC mutation ,GENETIC variation ,FAMILIAL spastic paraplegia ,GENETIC carriers ,GENE expression ,GENOTYPES ,POLYNEUROPATHIES ,NEUROGLIA ,PHENOTYPES - Abstract
A case study of a 47‑year‑old unmarried female presented with gait disturbance and voiding difficulty with a novel heterozygous variant of the PLP1 gene. Topics include somatosensory evoked potential tests showed a central conduction defect in the left median and bilateral tibial nerve stimulations; and using whole‑exome sequencing (WES), we identified a novel heterozygous duplication mutation in PLP1, causing the condition.
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- 2021
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27. A scientific journey from discovery to validation of efficacy in cancer patients: HAMLET and alpha1-oleate.
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Ho, James C.S., Ambite, Ines, Mok, K. H., Babjuk, Marek, and Svanborg, Catharina
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CANCER patients ,PROTEINS ,TUMORS ,PLACEBOS ,PEPTIDES ,BLADDER cancer - Abstract
The protein-lipid complex alpha1-oleate, derived from HAMLET (Human Alpha-lactalbumin Made LEthal to Tumor cells), is identified as a molecular entity with significant therapeutic potential. Structural characterization of the complex and results of a successful placebo-controlled clinical trial are presented. [ABSTRACT FROM AUTHOR]
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- 2021
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28. Profiling and semiquantitative analysis of the cell surface proteome in human mesenchymal stem cells
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Sang Kwang Lee, Nam Hyun Park, Kyung-Hoon Kwon, Kun Cho, Taewook Kang, Sung-Soo Kim, Zee Won Lee, Young Mok Park, Hyun Joo An, Ji Young Han, Haeyoung Suh-Kim, Jong Shin Yoo, Su Yeoung Yun, Jae Ho Kim, and Sang Sook Lee
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Proteomics ,Spectrometry, Mass, Electrospray Ionization ,Cell signaling ,Proteome ,Cellular differentiation ,Biochemistry ,Mass Spectrometry ,Analytical Chemistry ,Receptors, Laminin ,Tandem Mass Spectrometry ,Humans ,Cells, Cultured ,Gel electrophoresis ,Chemistry ,Multipotent Stem Cells ,Mesenchymal stem cell ,Proteins ,Reproducibility of Results ,Cell Differentiation ,Mesenchymal Stem Cells ,Molecular biology ,Cell biology ,Blot ,14-3-3 Proteins ,Electrophoresis, Polyacrylamide Gel ,Fibroblast Growth Factor 2 ,Rab - Abstract
Mulitpotent mesenchymal stem cells (MSCs) derived from human bone marrow are promising candidates for the development of cell therapeutic strategies. MSC surface protein profiles provide novel biological knowledge concerning the proliferation and differentiation of these cells, including the potential for identifying therapeutic targets. Basic fibroblast growth factor (bFGF) affects cell surface proteins, which are associated with increased growth rate, differentiation potential, as well as morphological changes of MSCs in vitro. Cell surface proteins were isolated using a biotinylation-mediated method and identified using a combination of one-dimensional sodium dodecyl sulfate-polyacrylamide gel electrophoresis and mass spectrometry. The resulting gel lines were cut into 20 bands and digested with trypsin. Each tryptic fragment was analyzed by liquid chromatography-electrospray ionization tandem mass spectrometry. Proteins were identified using the Mascot search program and the International Protein Index human database. Noble MSC surface proteins (n = 1,001) were identified from cells cultured either with (n = 857) or without (n = 667) bFGF-containing medium in three independent experiments. The proteins were classified using FatiGO to elucidate their function. We also confirmed the proteomics results using Western blotting and immunofluorescence microscopic analysis. The nature of the proteins identified makes it clear that MSCs express a wide variety of signaling molecules, including those related to cell differentiation. Among the latter proteins, four Ras-related Rab proteins, laminin-R, and three 14-3-3 proteins that were fractionated from MSCs cultured on bFGF-containing medium are implicated in bFGF-induced signal transduction of MSCs. Consequently, these finding provide insight into the understanding of the surface proteome of human MSCs.
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- 2013
29. Gene–Gene Interactions ofCFHandLOC387715/ARMS2with Korean Exudative Age-related Macular Degeneration Patients
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Yeong Hoon Kim, Jee Won Mok, Choun-Ki Joo, and Hyun-Seok Kim
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Male ,medicine.medical_specialty ,Genotype ,Single-nucleotide polymorphism ,Polymerase Chain Reaction ,Polymorphism, Single Nucleotide ,Gastroenterology ,Gene Frequency ,Internal medicine ,Humans ,Medicine ,Gene ,Allele frequency ,Genetics (clinical) ,Aged ,Aged, 80 and over ,Genetics ,Korea ,business.industry ,Haplotype ,Proteins ,Epistasis, Genetic ,Middle Aged ,Macular degeneration ,medicine.disease ,eye diseases ,Genotype frequency ,Ophthalmology ,Haplotypes ,Complement Factor H ,Factor H ,Pediatrics, Perinatology and Child Health ,Wet Macular Degeneration ,Female ,sense organs ,business ,Biomarkers - Abstract
To evaluate the association and interaction of single nucleotide polymorphisms in CFH and LOC387715/ARMS2 with age-related macular degeneration (AMD) in a Korean population.A total of 114 exudative AMD patients and 240 normal subjects participated in the study. PCR and direct sequencing were used to screen SNPs in the CFH and in the LOC387715/ARMS2. Genotype and haplotype analyses were performed. Two-locus gene-gene interactions were evaluated by the data mining approach multifactor-dimensionality reduction method.The *C/*T genotype frequency of rs1061170 in CFH showed a significant difference (OR = 1.79). Genotype and allele frequencies of rs551397 (*C/*C, OR = 2.84; *C, OR = 1.67) and rs800292 (*G/*G, OR = 2.198; *G, OR = 1.676) in CFH, and rs10490924 (T/*T, OR = 12.45; *T, OR = 4.45) and rs2736911 (*C/*C, OR = 3.21; *C, OR = 2.71) in LOC387715/ARMS2 were significantly higher in patients. In the haplotype analysis, C-T of rs2736911-rs10490924 in LOC387715/ARMS2 (OR = 4.85) and C-G of rs551397-rs800292 in CFH (OR = 2.22) predisposed significantly to AMD. After cross-validation consistency (CVC) and permutation tests, we identified the 1 marker model (rs10490924), which has a prediction accuracy of 73.5%, and the two locus model, rs10490924_ rs800292, with 75.3% balanced accuracy in predicting AMD disease risk.Korean individuals with the LOC387715/ARMS2 rs10490924, and to a lesser extent, CFH rs800292 variants might be at a greater risk for the development of exudative AMD. Furthermore, the risk of exudative AMD may increase significantly if these variants are both present in the two genes.
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- 2013
30. Chromosome 11-Centric Human Proteome Analysis of Human Brain Hippocampus Tissue
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Jin Young Kim, Kyung Hoon Kwon, Se-Young Kim, Bonghee Lee, Hyoung Joo Lee, Hyun Joo An, Hye Kyeong Min, William S. Hancock, Isidro Ferrer, Chun Kee Chung, Young Ki Paik, Taewook Kang, Rivka Ravid, Gun Wook Park, Jong Shin Yoo, Young Mok Park, and In Jung Ji
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Adult ,Proteome ,Gene Expression ,Biology ,Hippocampus ,Biochemistry ,GeneCards ,Chromosome (genetic algorithm) ,Alzheimer Disease ,Gene expression ,medicine ,Human proteome project ,Humans ,Databases, Protein ,Gene ,Aged ,Aged, 80 and over ,Genetics ,Epilepsy ,Olfactory receptor ,Chromosomes, Human, Pair 11 ,Proteins ,General Chemistry ,Human brain ,Middle Aged ,medicine.anatomical_structure - Abstract
Human chromosome 11 is the third gene-rich chromosome having 1304 protein-coding genes. According to the GeneCards, this chromosome contains 240 genes related to diseases, as it is well known as a disease-rich chromosome. Although there are many protein-coding genes, the proteomic identification ratio is rather low. As a model study, human hippocampal tissues from patients suffering from Alzheimer's disease and epilepsy were prepared to evaluate the gene-centric statistics related to the gene expression and disorders of chromosome 11. A total of 8828 protein coding genes from brain tissues were extensively off-gel fractionated and profiled by a high resolution mass spectrometer with collision induced dissociation and electron transfer dissociation. Five-hundred twenty-three of the proteins from brain tissues were determined to belong to chromosome 11, representing 37% of the proteins reported in the Global Proteome Machine Database. We extracted gene clusters from a specific biological process or molecular function in gene ontology, among which the olfactory receptor genes showed the largest cluster on chromosome 11. Analysis of the proteome data set from the hippocampus provides a significant network associated with genes and proteins and leads to new insights into the biological and genetic mechanisms of chromosome 11-specific diseases such as Alzheimer's disease.
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- 2013
31. GenomewidePDB, a Proteomic Database Exploring the Comprehensive Protein Parts List and Transcriptome Landscape in Human Chromosomes
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Hoguen Kim, Keun Na, Jin Young Cho, Jong Shin Yoo, William S. Hancock, Young Ki Paik, Seul Ki Jeong, Young Mok Park, Ja Young Kwon, Min Jung Lee, and Hyoung Joo Lee
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Proteome ,Placenta ,Human Protein Atlas ,Gene Expression ,Biology ,Proteomics ,computer.software_genre ,Biochemistry ,Mass Spectrometry ,Pregnancy ,Human proteome project ,Humans ,Ensembl ,Databases, Protein ,Chromosome 13 ,Genetics ,Chromosomes, Human, Pair 13 ,Database ,NeXtProt ,Genome, Human ,Proteins ,General Chemistry ,Female ,PeptideAtlas ,Transcriptome ,computer - Abstract
In an effort to map the human proteome, the Chromosome-centric Human Proteome Project (C-HPP) was recently initiated. As a member of the international consortium working on this project, our laboratory developed a gene-centric proteomic database called GenomewidePDB, which integrates proteomic data for proteins encoded by chromosomes with transcriptomic data and other information from public databases. As an example case, we chose chromosome 13, which is the largest acrocentric human chromosome with the lowest gene density and contains 326 predicted proteins. All proteins stored in GenomewidePDB are linked to other resources, including neXtProt and Ensembl for protein and gene information, respectively. The Global Proteome Machine database (GPMdb) and the PeptideAtlas are also accessed for observed mass spectrometry (MS) information, while Human Protein Atlas is used for information regarding antibody availability and tissue expression, respectively. Gene ontology disease information is also included. As a pilot work, we constructed this GenomewidePDB with the identified 3615 proteins including 53 chromosome 13-origin proteins that are present in normal human placenta tissue. Thus, developing a comprehensive database containing actual experimental proteomics data will provide a valuable resource for cross chromosomal comparison in the C-HPP community.
- Published
- 2012
32. Development of Electrochemiluminescent Serology Assays to Measure the Humoral Response to Antigens of Respiratory Syncytial Virus
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Marla Chu, Fengrong Zuo, Bodrey Ro, Sarah V. Maifeld, Ryan Yamagata, Shushil Machhi, Bandita Parhy, Mark T. Esser, Nancy Ulbrandt, Ann R. Falsey, Edward E. Walsh, Vera Chio, Marcia Carlson, Hoyin Mok, C. Kathy Wang, Li Yu, Samuel Park, and Tansy Leonardson
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0301 basic medicine ,Physiology ,lcsh:Medicine ,Artificial Gene Amplification and Extension ,Antibodies, Viral ,Pathology and Laboratory Medicine ,Biochemistry ,Polymerase Chain Reaction ,Serology ,0302 clinical medicine ,Elderly ,Viral Envelope Proteins ,Immune Physiology ,Medicine and Health Sciences ,Medicine ,030212 general & internal medicine ,Enzyme-Linked Immunoassays ,lcsh:Science ,Antigens, Viral ,Multidisciplinary ,Immune System Proteins ,biology ,Nucleocapsid Proteins ,3. Good health ,Vaccination ,Bioassays and Physiological Analysis ,Child, Preschool ,Monoclonal ,Antibody ,Research Article ,endocrine system ,Immunology ,Enzyme-Linked Immunosorbent Assay ,Respiratory Syncytial Virus Infections ,Antibodies, Monoclonal, Humanized ,Research and Analysis Methods ,Virus ,Antibodies ,03 medical and health sciences ,Antigen ,Neutralization Tests ,Diagnostic Medicine ,Microneutralization Assay ,Humans ,Serologic Tests ,Immunoassays ,Molecular Biology Techniques ,Colorimetric Assays ,Molecular Biology ,Aged ,business.industry ,lcsh:R ,Infant ,Biology and Life Sciences ,Proteins ,Gold standard (test) ,Reverse Transcriptase-Polymerase Chain Reaction ,Virology ,Antibodies, Neutralizing ,Immunity, Humoral ,030104 developmental biology ,Age Groups ,Geriatrics ,Respiratory Syncytial Virus, Human ,Luminescent Measurements ,People and Places ,biology.protein ,Immunologic Techniques ,lcsh:Q ,Population Groupings ,business ,Biochemical Analysis ,Viral Fusion Proteins - Abstract
Sensitive and precise serology assays are needed to measure the humoral response to antigens of respiratory syncytial virus (RSV) following natural infection or vaccination. We developed and evaluated a collection of electrochemiluminescent (ECL) serology assays using four RSV antigens (F, N, Ga and Gb). To assess the merits of ECL technology, the four ECL serology assays were evaluated using a well-characterized "gold standard" panel of acute and convalescent serum samples from fifty-nine RSV-positive and thirty RSV-negative elderly subjects (≥65 years old). The combined results from the four ECL assays demonstrated good concordance to the "gold standard" diagnosis, reaching 95% diagnostic sensitivity and 100% diagnostic specificity. Additionally, a combination of ECL assays provided higher diagnostic sensitivity than a commercially available diagnostic ELISA or cell-based microneutralization assay. In summary, these data demonstrate the advantages of using ECL-based serology assays and highlight their use as a sensitive diagnostic approach to detect recent RSV infection in an elderly population.
- Published
- 2016
33. Methylsulfonylmethane Inhibits RANKL-Induced Osteoclastogenesis in BMMs by Suppressing NF-κB and STAT3 Activities
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Pramod Darvin, Dong Young Kang, Chi Ho Lee, Hyo Joo Byun, Nipin Sp, Hak Kyo Lee, Youn Hee Joung, and Young Mok Yang
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0301 basic medicine ,Cell signaling ,Physiology ,Cellular differentiation ,Gene Expression ,Osteoclasts ,lcsh:Medicine ,Signal transduction ,Biochemistry ,chemistry.chemical_compound ,Mice ,Animal Cells ,Medicine and Health Sciences ,Sulfones ,Post-Translational Modification ,Phosphorylation ,lcsh:Science ,Connective Tissue Cells ,Gene knockdown ,Multidisciplinary ,biology ,NF-kappa B ,Cell Differentiation ,Osteoblast Differentiation ,STAT signaling ,medicine.anatomical_structure ,RANKL ,Connective Tissue ,Bone Remodeling ,Anatomy ,Cellular Types ,Research Article ,STAT3 Transcription Factor ,musculoskeletal diseases ,Research and Analysis Methods ,Bone resorption ,03 medical and health sciences ,Osteoclast ,DNA-binding proteins ,medicine ,Genetics ,Animals ,Dimethyl Sulfoxide ,Bone Resorption ,Bone ,Molecular Biology Techniques ,Molecular Biology ,Tartrate-Resistant Acid Phosphatase ,Macrophages ,RANK Ligand ,lcsh:R ,Biology and Life Sciences ,Proteins ,NF-κB ,Marker Genes ,Cell Biology ,030104 developmental biology ,Biological Tissue ,chemistry ,Cancer research ,biology.protein ,lcsh:Q ,Physiological Processes ,Biomarkers ,Developmental Biology - Abstract
Osteoclast differentiation is dependent on the activities of receptor activator NF-kB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF). Given that RANKL plays a critical role in osteoclast formation and bone resorption, any new compounds found to alter its activity would be predicted to have therapeutic potential for disorders associated with bone loss. Methylsulfonylmethane (MSM) is a naturally occurring sulfur compound with well-documented anti-oxidant and anti-inflammatory properties; currently its effects on osteoclast differentiation are unknown. We sought to investigate whether MSM could regulate osteoclastogenesis, and if so, its mechanism of action. In this study, we investigated the effects of MSM on RANKL-induced osteoclast differentiation, together with STAT3's involvement in the expression of osteoclastic gene markers. These experiments were conducted using bone marrow derived macrophages (BMMs) and cell line material, together with analyses that interrogated both protein and mRNA levels, as well as signaling pathway activity. Although MSM was not toxic to osteoclast precursors, MSM markedly inhibited RANKL-induced TRAP activity, multinucleated osteoclast formation, and bone resorptive activity. Additionally, the expression of several osteoclastogenesis-related marker genes, including TRAF6, c-Fos, NFATc1, cathepsin K, and OSCAR were suppressed by MSM. MSM mediated suppression of RANKL-induced osteoclastogenesis involved inhibition of ITAM signaling effectors such as PLCγ and Syk, with a blockade of NF-kB rather than MAPK activity. Furthermore, MSM inhibited RANKL-induced phosphorylation of STAT3 Ser727. Knockdown of STAT3 using shRNAs resulted in reduced RANKL-mediated phosphorylation of Ser727 STAT3, and TRAF6 in cells for which depletion of STAT3 was confirmed. Additionally, the expression of RANKL-induced osteoclastogenic marker genes were significantly decreased by MSM and STAT3 knockdown. Taken together, these results indicate that STAT3 plays a pivotal role in RANKL-induced osteoclast formation, and that MSM can attenuate RANKL-induced osteoclastogenesis by blocking both NF-kB and STAT3 activity.
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- 2016
34. PB2-Q591K Mutation Determines the Pathogenicity of Avian H9N2 Influenza Viruses for Mammalian Species
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Zi Feng Yang, Chris Ka Pun Mok, Horace Hok Yeung Lee, Congrong Wang, and Zhi Zhang
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RNA viruses ,0301 basic medicine ,Physiology ,animal diseases ,viruses ,lcsh:Medicine ,Pathogenesis ,Pathology and Laboratory Medicine ,medicine.disease_cause ,Biochemistry ,Polymerases ,Immune Physiology ,Zoonoses ,Pandemic ,Medicine and Health Sciences ,lcsh:Science ,Genetics ,Innate Immune System ,Multidisciplinary ,Microbial Mutation ,virus diseases ,H5N1 ,Medical microbiology ,Infectious Diseases ,Influenza A virus ,Viruses ,Mutation (genetic algorithm) ,Cytokines ,Pathogens ,Research Article ,Highly pathogenic ,Immunology ,Biology ,Microbiology ,H7N9 ,03 medical and health sciences ,Virology ,DNA-binding proteins ,medicine ,Influenza viruses ,Gene ,lcsh:R ,Organisms ,Viral pathogens ,Biology and Life Sciences ,Proteins ,Molecular Development ,biochemical phenomena, metabolism, and nutrition ,Pathogenicity ,Viral Replication ,Influenza A virus subtype H5N1 ,Microbial pathogens ,respiratory tract diseases ,030104 developmental biology ,Viral replication ,Immune System ,lcsh:Q ,Adaptation ,Developmental Biology ,Orthomyxoviruses - Abstract
Background Influenza A subtype H9N2 is widespread and prevalent in poultry. It has repeatedly transmitted zoonotically to cause mild influenza-like illness in humans and is regarded as a potential pandemic candidate. In additon, the six internal genes of H7N9 and H10N8 viruses which caused infection in human in China as well as some of the highly pathogenic H5N1 strains are origined from H9N2. Previous studies have shown that the mammalian adaptation PB2-Q591K contributes to the pathogenicity of H5N1 and H7N9 viruses. However, the role of the PB2-Q591K mutation in H9N2 subtype is still not well understood. Methods To define and compare the individual role of PB2-Q591K substitution in the PB2 gene segment of H9N2 in relation to polymerase activity, replication competence and the pathogenicity using in vitro and in vivo models. Results The PB2-Q591K mutation in H9N2 virus enhanced the polymerase activity and virus replication in human NHBE cells when compared to the wild type strain. Mice infected with the PB2 mutant showed significant weight loss, higher virus replication and immune responses in the lungs. Conclusions Our evidences suggest that the PB2-Q591K, in addition to the -E627K mutation in H9N2 enhanced the pathogenicity in mammalian host.
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- 2016
35. Temperature and Mg2+ Sensing by a Novel PhoP-PhoQ Two-component System for Regulation of Virulence in Edwardsiella tarda
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Smarajit Chakraborty, Mo Li, Yu-Keung Mok, J. Sivaraman, Ka Yin Leung, and Chiradip Chatterjee
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Conformational change ,Transcription, Genetic ,Virulence ,Biology ,Microbiology ,Biochemistry ,Protein structure ,Bacterial Proteins ,Genes, Reporter ,Magnesium ,Secretion ,Cloning, Molecular ,Edwardsiella tarda ,Molecular Biology ,Protein secondary structure ,Circular Dichroism ,Genetic Complementation Test ,Temperature ,Proteins ,Cell Biology ,biology.organism_classification ,Two-component regulatory system ,Protein tertiary structure ,Protein Structure, Tertiary ,Kinetics ,Biophysics ,Signal Transduction - Abstract
The PhoP-PhoQ two-component system is commonly used by bacteria to sense environmental factors. Here we show that the PhoP-PhoQ system of Edwardsiella tarda detects changes in environmental temperature and Mg(2+) concentration as well as regulates the type III and VI secretion systems through direct activation of esrB. Protein secretion is activated from 23 to 35 °C or at low Mg(2+) concentrations, but it is suppressed at or below 20 °C, at or above 37 °C, or at high Mg(2+) concentrations. The effects of temperature and Mg(2+) concentration are additive. The PhoQ sensor domain has a low T(m) of 37.9 °C, and it detects temperatures through a conformational change of its secondary structure. Mutation of specific Pro or Thr residues increased the stability of the PhoQ sensor drastically, altering its temperature-sensing ability. The PhoQ sensor detects Mg(2+) concentration through the direct binding of Mg(2+) to a cluster of acidic residues (DDDSAD) and through changes that likely affect its tertiary structure. Here, we describe for the first time the use of PhoP-PhoQ as a temperature sensor for bacterial virulence control.
- Published
- 2010
36. Human Infection with Highly Pathogenic Avian Influenza A(H7N9) Virus, China.
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Changwen Ke, Ka Pun Mok, Chris, Wenfei Zhu, Haibo Zhou, Jianfeng He, Wenda Guan, Jie Wu, Wenjun Song, Dayan Wang, Jiexiong Liu, Qinhan Lin, Ka Wing Chu, Daniel, Lei Yang, Nanshan Zhong, Zifeng Yang, Yuelong Shu, Malik Peiris, Joseph Sriyal, Ke, Changwen, Mok, Chris Ka Pun, and Zhu, Wenfei
- Subjects
- *
AVIAN influenza A virus , *VIRUS diseases , *AMINO acid sequence , *NEURAMINIDASE , *PUBLIC health , *INFLUENZA complications , *INFLUENZA transmission , *AMINO acids , *ANIMAL experimentation , *AVIAN influenza , *COMPARATIVE studies , *CYTOMEGALOVIRUS diseases , *DISEASE complications , *INFLUENZA , *RESEARCH methodology , *MEAT , *MEDICAL cooperation , *POULTRY , *PROTEINS , *RESEARCH , *RESEARCH funding , *EVALUATION research , *INFLUENZA A virus , *TREATMENT effectiveness , *INFECTIOUS disease transmission - Abstract
The recent increase in zoonotic avian influenza A(H7N9) disease in China is a cause of public health concern. Most of the A(H7N9) viruses previously reported have been of low pathogenicity. We report the fatal case of a patient in China who was infected with an A(H7N9) virus having a polybasic amino acid sequence at its hemagglutinin cleavage site (PEVPKRKRTAR/GL), a sequence suggestive of high pathogenicity in birds. Its neuraminidase also had R292K, an amino acid change known to be associated with neuraminidase inhibitor resistance. Both of these molecular features might have contributed to the patient's adverse clinical outcome. The patient had a history of exposure to sick and dying poultry, and his close contacts had no evidence of A(H7N9) disease, suggesting human-to-human transmission did not occur. Enhanced surveillance is needed to determine whether this highly pathogenic avian influenza A(H7N9) virus will continue to spread. [ABSTRACT FROM AUTHOR]
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- 2017
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37. Folding of a dimeric β-barrel: Residual structure in the urea denatured state of the human papillomavirus E2 DNA binding domain
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L.M.T.R. Lima, Mark Bycroft, Leonardo G. Alonso, G. De Prat-Gay, and Y.K. Mok
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Protein Denaturation ,Protein Folding ,Magnetic Resonance Spectroscopy ,PROTEINS ,Molecular Sequence Data ,HUMAN PAPILLOMAVIRUS ,Phi value analysis ,Nuclear Overhauser effect ,Biochemistry ,Humans ,Urea ,Amino Acid Sequence ,Papillomaviridae ,Molecular Biology ,Binding Sites ,Chemistry ,Otras Ciencias Químicas ,Ciencias Químicas ,Oncogene Proteins, Viral ,DNA-binding domain ,Contact order ,Random coil ,DNA-Binding Proteins ,Folding (chemistry) ,Kinetics ,Crystallography ,FOLDING PROTEIN ,Protein folding ,Dimerization ,CIENCIAS NATURALES Y EXACTAS ,Heteronuclear single quantum coherence spectroscopy ,Research Article - Abstract
The dimeric beta-barrel is a characteristic topology initially found in the transcriptional regulatory domain of the E2 DNA binding domain from papillomaviruses. We have previously described the kinetic folding mechanism of the human HPV-16 domain, and, as part of these studies, we present a structural characterization of the urea-denatured state of the protein. We have obtained a set of chemical shift assignments for the C-terminal domain in urea using heteronuclear NMR methods and found regions with persistent residual structure. Based on chemical shift deviations from random coil values, 3'J(NHN alpha) coupling constants, heteronuclear single quantum coherence peak intensities, and nuclear Overhauser effect data, we have determined clusters of residual structure in regions corresponding to the DNA binding helix and the second beta-strand in the folded conformation. Most of the structures found are of nonnative nature, including turn-like conformations. Urea denaturation at equilibrium displayed a loss in protein concentration dependence, in absolute parallel to a similar deviation observed in the folding rate constant from kinetic experiments. These results strongly suggest an alternative folding pathway in which a dimeric intermediate is formed and the rate-limiting step becomes first order at high protein concentrations. The structural elements found in the denatured state would collide to yield productive interactions, establishing an intermolecular folding nucleus at high protein concentrations. We discuss our results in terms of the folding mechanism of this particular topology in an attempt to contribute to a better understanding of the folding of dimers in general and intertwined dimeric proteins such as transcription factors in particular. Fil: Mok, Yu Keung. University of Cambridge; Reino Unido Fil: Alonso, Leonardo Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina Fil: Lima, L. Mauricio T.R.. Universidade Federal do Rio de Janeiro; Brasil Fil: Bycroft, Mark. University of Cambridge; Reino Unido Fil: de Prat Gay, Gonzalo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina
- Published
- 2008
38. Water-free microencapsulation of proteins within PLGA microparticles by spray drying using PEG-assisted protein solubilization technique in organic solvent
- Author
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Hyejung Mok and Tae Gwan Park
- Subjects
Surface Properties ,Chemistry, Pharmaceutical ,Drug Compounding ,Pharmaceutical Science ,Polyethylene glycol ,Dosage form ,Polyethylene Glycols ,chemistry.chemical_compound ,Polylactic Acid-Polyglycolic Acid Copolymer ,Polymer chemistry ,PEG ratio ,Animals ,Humans ,Technology, Pharmaceutical ,Lactic Acid ,Desiccation ,Particle Size ,Bovine serum albumin ,Microparticle ,Drug Carriers ,Methylene Chloride ,Chromatography ,biology ,Human Growth Hormone ,technology, industry, and agriculture ,Proteins ,Water ,Serum Albumin, Bovine ,General Medicine ,Recombinant Proteins ,Kinetics ,PLGA ,Solubility ,chemistry ,Delayed-Action Preparations ,Spray drying ,Solvents ,biology.protein ,Cattle ,Drug carrier ,Polyglycolic Acid ,Biotechnology - Abstract
Poly(d,l-lactic-co-glycolic acid) (PLGA) microparticles encapsulating therapeutic proteins were prepared under a water-free formulation condition. Bovine serum albumin (BSA) and recombinant human growth hormone (rhGH) were homogeneously solubilized as nano-scale complexes in methylene chloride phase by using polyethylene glycol (PEG) as a complex-forming agent. The organic phase containing dissolved PLGA and PEG/protein complexes was directly spray dried to obtain PLGA microparticles encapsulating proteins. They exhibited sustained release profiles of BSA and rhGH up to 30 days with reduced initial bursts. The released protein molecules from the microparticles maintained structural integrity without aggregation, suggesting that the current single-step protein microencapsulation method without using water could be potentially applied for sustained delivery of a wide range of therapeutic protein drugs that are not soluble in organic solvents.
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- 2008
39. Identification of potential protein interactors of Lrrk2
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Matthew J. Farrer, Rachel M. Bailey, Leonard Petrucelli, Jennifer Szutu, Justus C. Dachsel, Jacob H. Hines, Su San Mok, Owen A. Ross, Benjamin J. Madden, Julie P. Taylor, and Kelly M. Hinkle
- Subjects
Protein Serine-Threonine Kinases ,Biology ,Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 ,Tandem mass spectrometry ,Mass Spectrometry ,Article ,medicine ,Humans ,Immunoprecipitation ,Kinase activity ,Cytoskeleton ,Cell Line, Transformed ,Genetics ,Parkinsonism ,Neurodegeneration ,Proteins ,medicine.disease ,LRRK2 ,nervous system diseases ,Cell biology ,Molecular Weight ,Neurology ,Phosphorylation ,Identification (biology) ,Neurology (clinical) ,Geriatrics and Gerontology - Abstract
Pathogenic substitutions in the Lrrk2 protein have been shown to be an important cause of both familial and sporadic parkinsonism. The molecular pathway involved in Lrrk2 dopaminergic neuron degeneration remains elusive. Employing a combination of Lrrk2-mediated protein precipitation and tandem mass spectrometry, we identified 14 potential Lrrk2 binding partners. The majority of these interactions may be subgrouped into three functional cellular pathways: (i) chaperone-mediated response, (ii) proteins associated with the cytoskeleton and trafficking and (iii) phosphorylation and kinase activity. Future investigation of these candidates is now warranted and may help resolve the pathomechanism behind Lrrk2 neurodegeneration.
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- 2007
40. Meta-analysis Followed by Replication Identifies Loci in or near CDKN1B, TET3, CD80, DRAM1, and ARID5B as Associated with Systemic Lupus Erythematosus in Asians
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Change Zhang, Mo Yin Mok, Chun Yin Chong, Raymond Woon Sing Wong, Hongzhou Cui, Paul K.H. Tam, Stacey S. Cherny, Lu Zhang, Huayang Tang, Nan Shen, Hong Fang, Yujun Sheng, Hai-Feng Pan, Shirley King Yee Ying, Yong Cui, Xuejun Zhang, Xiao-Jing Kang, Jinping Gao, Fei Hao, Bingjun Shi, Zhifang Zhai, Wanling Yang, Fei Gao, Thavatchai Deekajorndej, Xianfa Tang, Fusheng Zhou, Pak C. Sham, Qingchun Diao, Qing Guo, Chun-Ming Wong, Xiong-Ming Pu, Li Juan Zhang, Xianbo Zuo, Yang Li, Qianjin Lu, Xiang Chen, Xianyong Yin, Brian H.Y. Chung, Yonghu Sun, Chak Sing Lau, Jing Yang, Tak Mao Chan, Kwok Lung Tong, KW Lee, Hui Cheng, Liangdan Sun, Yu-Lung Lau, Wilfred Hing Sang Wong, Yan Zhang, Xiaoguang Zhang, Kanya Suphapeetiporn, Maria-Mercè Garcia-Barceló, Vorasuk Shotelersuk, Yingyos Avihingsanon, Irene Oi-Lin Ng, Nattiya Hirankarn, Samuel Ka Shun Fung, Sik Nin Wong, Niko Kei Chiu Tse, Jing Zhang, Yan Hui, Qiji Liu, Sen Yang, Dingxian Zhu, Dingge Ying, Wai Ming Lai, Bo Liang, Fanqin Zeng, Dong-Qing Ye, Alexander Moon Ho Leung, Chi Chiu Mok, Pornpimol Rianthavorn, Marco Ho, Hongfu Xie, Tsz Leung Lee, Pamela Pui Wah Lee, and Xiang-Pei Li
- Subjects
Single-nucleotide polymorphism ,Genome-wide association study ,Disease ,Biology ,Polymorphism, Single Nucleotide ,Article ,Dioxygenases ,Asian People ,Missing heritability problem ,medicine ,Genetics ,Humans ,Lupus Erythematosus, Systemic ,Genetics(clinical) ,Genetic Predisposition to Disease ,skin and connective tissue diseases ,Genetics (clinical) ,Genetic association ,Autoimmune disease ,Membrane Proteins ,Proteins ,Heritability ,medicine.disease ,DNA-Binding Proteins ,DNA demethylation ,Immunology ,B7-1 Antigen ,Cyclin-Dependent Kinase Inhibitor p27 ,Genome-Wide Association Study ,Transcription Factors - Abstract
Systemic lupus erythematosus (SLE) is a prototype autoimmune disease with a strong genetic involvement and ethnic differences. Susceptibility genes identified so far only explain a small portion of the genetic heritability of SLE, suggesting that many more loci are yet to be uncovered for this disease. In this study, we performed a meta-analysis of genome-wide association studies on SLE in Chinese Han populations and followed up the findings by replication in four additional Asian cohorts with a total of 5,365 cases and 10,054 corresponding controls. We identified genetic variants in or near CDKN1B, TET3, CD80, DRAM1, and ARID5B as associated with the disease. These findings point to potential roles of cell-cycle regulation, autophagy, and DNA demethylation in SLE pathogenesis. For the region involving TET3 and that involving CDKN1B, multiple independent SNPs were identified, highlighting a phenomenon that might partially explain the missing heritability of complex diseases.
- Published
- 2013
41. Lactate normalization within 6 hours of bundle therapy and 24 hours of delayed achievement were associated with 28-day mortality in septic shock patients.
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Ryoo, Seung Mok, Ahn, Ryeok, Shin, Tae Gun, Jo, You Hwan, Chung, Sung Phil, Beom, Jin Ho, Choi, Sung-Hyuk, Yoon, Young -Hoon, Ko, Byuk Sung, Lee, Hui Jai, Suh, Gil Joon, Kim, Won Young, and null, null
- Subjects
- *
SEPTIC shock , *LOGISTIC regression analysis , *LACTATES , *MORTALITY - Abstract
This study evaluated the prognostic ability of lactate normalization achieved within 6 and 24 h from septic shock recognition. Data from a septic shock registry from October 2015 to February 2017 were reviewed. The study included 2,102 eligible septic shock patients to analyze the prognostic ability of lactate normalization, defined as a follow-up lactate level <2 mmol/L within six hours of bundle therapy and within 24 hours of delayed normalization. The primary outcome was 28-day mortality. The overall 28-day mortality rate was 21.4%. The rates of lactate normalization within 6 and 24 h were significantly higher in the survivor groups than in the non-survivor group (42.4% vs. 23.4% and 60.2% vs. 31.2%; P<0.001, respectively). Multivariate logistic regression analysis showed that both 6- and 24-h lactate normalization were independent predictors (odds ratio [OR] 0.58, 95% confidence interval [CI] 0.45–0.75, p<0.001 and OR 0.42, 95% CI 0.33–0.54, p<0.001, respectively). When we could not achieve the lactate normalization, the sensitivity, specificity, positive, and negative predictive value to predict mortality were 76.6%, 42.4%, 26.5% and 87.0% respectively for 6-h normalization, and 68.8%, 60.2%, 32.0% and 87.7% respectively for 24-h normalization. Besides 6-h lactate normalization, 24-h delayed lactate normalization was associated with decreasing mortality in septic shock patients. Lactate normalization may have a role in early risk stratification and as a therapeutic target. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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42. The P4-ATPase ATP9A is a novel determinant of exosome release.
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Naik, Jyoti, Hau, Chi M., ten Bloemendaal, Lysbeth, Mok, Kam S., Hajji, Najat, Wehman, Ann M., Meisner, Sander, Muncan, Vanesa, Paauw, Nanne J., de Vries, H. E., Nieuwland, Rienk, Paulusma, Coen C., and Bosma, Piter J.
- Subjects
EXOSOMES ,BIOLOGICAL membranes ,CELL communication ,CELL membranes ,MEMBRANE fusion ,CAENORHABDITIS elegans - Abstract
Extracellular vesicles (EVs) released by cells have a role in intercellular communication to regulate a wide range of biological processes. Two types of EVs can be recognized. Exosomes, which are released from multi-vesicular bodies upon fusion with the plasma membrane, and ectosomes, which directly bud from the plasma membrane. How cells regulate the quantity of EV release is largely unknown. One of the initiating events in vesicle biogenesis is the regulated transport of phospholipids from the exoplasmic to the cytosolic leaflet of biological membranes. This process is catalyzed by P4-ATPases. The role of these phospholipid transporters in intracellular vesicle transport has been established in lower eukaryotes and is slowly emerging in mammalian cells. In Caenorhabditis elegans (C. elegans), deficiency of the P4-ATPase member TAT-5 resulted in enhanced EV shedding, indicating a role in the regulation of EV release. In this study, we investigated whether the mammalian ortholog of TAT-5, ATP9A, has a similar function in mammalian cells. We show that knockdown of ATP9A expression in human hepatoma cells resulted in a significant increase in EV release that was independent of caspase-3 activation. Pharmacological blocking of exosome release in ATP9A knockdown cells did significantly reduce the total number of EVs. Our data support a role for ATP9A in the regulation of exosome release from human cells. [ABSTRACT FROM AUTHOR]
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- 2019
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43. A Review of Complementary and Alternative Medicine Therapies on Muscular Atrophy: A Literature Review of In Vivo/In Vitro Studies.
- Author
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Jeong, Seong-Mok, Seo, Byung-Kwan, Park, Yeon-Cheol, and Baek, Yong-Hyeon
- Subjects
- *
MUSCULAR atrophy , *AUTOPHAGY , *ALTERNATIVE medicine , *APOPTOSIS , *INFORMATION storage & retrieval systems , *MEDICAL databases , *MEDLINE , *ONLINE information services , *PROTEINS , *SYSTEMATIC reviews , *IN vitro studies , *IN vivo studies , *PREVENTION - Abstract
Objective. The objective of this review is to evaluate the recent treatment and study trends of complementary and alternative medicine (CAM) treatments on muscular atrophy by reviewing in vivo/in vitro studies. Materials and Methods. The searches were conducted via electronic databases including PubMed, the Cochrane Library, China National Knowledge Infrastructure (CNKI), Wanfang MED, and five Korean databases. Only in vivo and in vitro studies were included in this study. Results. A total of 44 studies (27 in vivo studies, 8 in vitro studies, and 9 in vivo with in vitro) were included. No serious maternal or fetal complications occurred. There were various animal models induced with muscular atrophy through “hindlimb suspension”, “nerve damage”, ‘alcohol or dexamethasone treatment’, “diabetes”, “CKD”, “stroke”, “cancer”, “genetic modification”, etc. In 28 of 36 articles measuring muscle mass, CAM significantly increased the mass. Additionally, 10 of them showed significant improvement in muscle function. In most in vitro studies, significant increases in both the diameter of myotubes and muscle cell numbers were reported. The mechanisms of action of protein synthesis, degradation, autophagy, and apoptotic markers were also investigated. Conclusions. These results demonstrate that CAM could prevent muscular atrophy. Further studies about CAM on muscular atrophy are needed. [ABSTRACT FROM AUTHOR]
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- 2018
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44. Urinary Biomarkers in Lupus Nephritis: Are We There Yet?
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Mok, Chi Chiu and Mohan, Chandra
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- *
BIOMARKERS , *PROTEINS , *SERIAL publications , *URINALYSIS , *LUPUS nephritis - Abstract
An introduction is presented in which the editor discusses articles in the issue on topics including investigated the association of urinary matrix metalloproteinase 7, and urinary epidermal growth factor (EGF) level and progression of chronic kidney disease in several cohorts of patients.
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- 2021
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45. Prostate carcinoma tissue proteomics for biomarker discovery
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Bin Ye, Yaxin Zheng, Michael P. O'Leary, Junyi Lei, Jerome P. Richie, Brian C.-S. Liu, Michael H. Weinstein, Samuel C. Mok, and Ye Xu
- Subjects
Adult ,Male ,Proteomics ,PCA3 ,Cancer Research ,Pathology ,medicine.medical_specialty ,Prostatic Hyperplasia ,Protein Array Analysis ,Sensitivity and Specificity ,Prostate ,Biomarkers, Tumor ,Carcinoma ,Humans ,Medicine ,Biomarker discovery ,Aged ,Laser capture microdissection ,business.industry ,Lasers ,Prostatic Neoplasms ,Proteins ,Cancer ,Middle Aged ,Prostate-Specific Antigen ,medicine.disease ,Neoplasm Proteins ,Prostate-specific antigen ,medicine.anatomical_structure ,Oncology ,Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization ,business - Abstract
BACKGROUND The advent of the prostate-specific antigen (PSA) test has had a profound impact on the diagnosis and treatment of prostate carcinoma. However, the use of PSA levels alone for screening for prostate carcinoma was compromised by the variations in the amount of PSA produced by the benign prostatic tissue specimens. Proteins were involved in various pathways that determine the behavior of a cell. Therefore, information regarding proteins may reveal drug targets and/or markers for early detection. METHODS The authors used surface-enhanced laser desorption/ionization time-of-flight mass spectrometry to determine the protein profiles from fresh tissues of the prostate. Laser capture microdissection was performed to isolate pure populations of cells. RESULTS The authors identified a protein with an average m/Z of 24,782.56 ± 107.27 that was correlated with the presence of prostate carcinoma. Furthermore, using laser capture microdissection, they demonstrated that the origin of this protein, which the authors designated PCa-24, was derived from the epithelial cells of the prostate. PCa-24 expression was detected in 16 of 17 (94%) prostate carcinoma specimens but not in paired normal cells. In addition, this protein was not expressed in any of the 12 benign prostatic hyperplasia specimens that were assayed. CONCLUSIONS PCa-24 may be useful a marker for prostate carcinoma. Cancer 2003;98:2576–82. © 2003 American Cancer Society.
- Published
- 2003
46. Screening a UK amyotrophic lateral sclerosis cohort provides evidence of multiple origins of the C9orf72 expansion
- Author
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Fratta, Pietro, Polke, James M., Newcombe, Jia, Mizielinska, Sarah, Lashley, Tammaryn, Poulter, Mark, Beck, Jon, Preza, Elisavet, Devoy, Anny, Sidle, Katie, Howard, Robin, Malaspina, Andrea, Orrell, Richard W., Clarke, Jan, Lu, Ching-Hua, Mok, Kin, Collins, Toby, Shoaii, Maryam, Nanji, Tina, Wray, Selina, Adamson, Gary, Pittman, Alan, Renton, Alan E., Traynor, Bryan J., Sweeney, Mary G., Revesz, Tamas, Houlden, Henry, Mead, Simon, Isaacs, Adrian M., and Fisher, Elizabeth M.C.
- Subjects
DNA Repeat Expansion ,C9orf72 Protein ,Neuroscience(all) ,Amyotrophic Lateral Sclerosis ,Clinical Neurology ,Proteins ,United Kingdom ,Cohort Studies ,Ageing ,Frontotemporal Dementia ,Somatic instability ,Humans ,Genetic Report Abstract ,Geriatrics and Gerontology ,Developmental Biology - Abstract
An expanded hexanucleotide repeat in the C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS/FTD). Although 0–30 hexanucleotide repeats are present in the general population, expansions >500 repeats are associated with C9ALS/FTD. Large C9ALS/FTD expansions share a common haplotype and whether these expansions derive from a single founder or occur more frequently on a predisposing haplotype is yet to be determined and is relevant to disease pathomechanisms. Furthermore, although cases carrying 50–200 repeats have been described, their role and the pathogenic threshold of the expansions remain to be identified and carry importance for diagnostics and genetic counseling. We present clinical and genetic data from a UK ALS cohort and report the detailed molecular study of an atypical somatically unstable expansion of 90 repeats. Our results across different tissues provide evidence for the pathogenicity of this repeat number by showing they can somatically expand in the central nervous system to the well characterized pathogenic range. Our results support the occurrence of multiple expansion events for C9ALS/FTD.
- Published
- 2014
47. A disordered region in the EvpP protein from the type VI secretion system of Edwardsiella tarda is essential for EvpC binding
- Author
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J. Sivaraman, Wentao Hu, Ka Yin Leung, Ganesh S. Anand, and Yu-Keung Mok
- Subjects
Protein Structure ,Protein Folding ,Recombinant Fusion Proteins ,Molecular Sequence Data ,lcsh:Medicine ,Virulence ,Secretion Systems ,Plasma protein binding ,Biology ,Biochemistry ,Microbiology ,03 medical and health sciences ,Bacterial Proteins ,Macromolecular Structure Analysis ,Secretion ,Amino Acid Sequence ,Bacterial Physiology ,lcsh:Science ,Peptide sequence ,Bacterial Secretion Systems ,Edwardsiella tarda ,Nuclear Magnetic Resonance, Biomolecular ,Molecular Biology ,030304 developmental biology ,Type VI secretion system ,0303 health sciences ,Multidisciplinary ,Effector ,lcsh:R ,030302 biochemistry & molecular biology ,Biology and Life Sciences ,Proteins ,Bacteriology ,biology.organism_classification ,Solutions ,Chaperone (protein) ,Mutation ,biology.protein ,lcsh:Q ,Protein Multimerization ,Protein Structure Networks ,Protein Binding ,Research Article - Abstract
The type VI secretion system (T6SS) of pathogenic bacteria plays important roles in both virulence and inter-bacterial competitions. The effectors of T6SS are presumed to be transported either by attaching to the tip protein or by interacting with HcpI (haemolysin corregulated protein 1). In Edwardsiella tarda PPD130/91, the T6SS secreted protein EvpP (E. tarda virulent protein P) is found to be essential for virulence and directly interacts with EvpC (Hcp-like), suggesting that it could be a potential effector. Using limited protease digestion, nuclear magnetic resonance heteronuclear Nuclear Overhauser Effects, and hydrogen-deuterium exchange mass spectrometry, we confirmed that the dimeric EvpP (40 kDa) contains a substantial proportion (40%) of disordered regions but still maintains an ordered and folded core domain. We show that an N-terminal, 10-kDa, protease-resistant fragment in EvpP connects to a shorter, 4-kDa protease-resistant fragment through a highly flexible region, which is followed by another disordered region at the C-terminus. Within this C-terminal disordered region, residues Pro143 to Ile168 are essential for its interaction with EvpC. Unlike the highly unfolded T3SS effector, which has a lower molecular weight and is maintained in an unfolded conformation with a dedicated chaperone, the T6SS effector seems to be relatively larger, folded but partially disordered and uses HcpI as a chaperone.
- Published
- 2014
48. Human temporal lobe epilepsy analyses by tissue proteomics
- Author
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Céline, Mériaux, Julien, Franck, Dan Bi, Park, Jusal, Quanico, Young Hye, Kim, Chun Kee, Chung, Young Mok, Park, Harry, Steinbusch, Michel, Salzet, and Isabelle, Fournier
- Subjects
Adult ,Male ,Proteomics ,Sex Characteristics ,Intracellular Signaling Peptides and Proteins ,Proteins ,Middle Aged ,Hippocampus ,Young Adult ,Epilepsy, Temporal Lobe ,Tandem Mass Spectrometry ,Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization ,Dentate Gyrus ,Humans ,Female - Abstract
Although there are many types of epilepsy, temporal lobe epilepsy (TLE) is probably in humans the most common and most often studied. TLE represents 40% of the total epilepsy form of the disease and is difficult to treat. Despite a wealth of descriptive data obtained from the disease history of patients, the EEG recording, imaging techniques, and histological studies, the epileptogenic process remains poorly understood. However, it is unlikely that a single factor or a single mechanism can cause many changes associated with this neuropathological phenomenon. MALDI mass spectrometry imaging (MSI) coupled to protein identification, because of its ability to study a wide range of molecules, appears to be suitable for the preparation of molecular profiles in TLE. Seven neuropeptides have been have been identified in Dental gyrus regions of the hippocampus in relation with TLE pathology. Shot-gun studies taking into account gender influence have been performed. Tissue microextraction from control (10) toward 10 TLE patients have been analyzed after trypsin digestion followed by separation on nanoLC coupled to LTQ orbitrap. From the shot-gun analyses, results confirmed the presence of specific neuropeptides precursors and receptors in TLE patients as well as proteins involved in axons regeneration including neurotrophins, ECM proteins, cell surface proteins, membrane proteins, G-proteins, cytoskeleton proteins and tumor suppressors. Among the tumor suppressors identified, the Leucine-rich glioma inactivated 1 (LGI1) protein was found. LGI1 gene recently been demonstrated being implicated in heritability of TLE. We have also demonstrate the presence a complete profile of tumor suppressors in TLE patients, 7 have been identified. Refining this analysis taken into account the gender influence in both control and in TLE reflected the presence of specific proteins between male and female and thus mechanisms in pathology development could be completely different.
- Published
- 2014
49. Differential expression of NF1 type I and type II isoforms in sporadic borderline and invasive epithelial ovarian tumors
- Author
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William R. Welch, Shu Wing Ng, Debra A. Bell, Samuel C. Mok, Ross S. Berkowitz, Tara D. Iyengar, and Ching C. Lau
- Subjects
Cancer Research ,medicine.medical_specialty ,Tumor suppressor gene ,Cellular differentiation ,Tretinoin ,Adenocarcinoma ,Biology ,Ovarian tumor ,Internal medicine ,Tumor Cells, Cultured ,Genetics ,medicine ,Humans ,Protein Isoforms ,Neoplasm Invasiveness ,Neuroectodermal tumor ,Molecular Biology ,Ovarian Neoplasms ,Neurofibromin 1 ,Oncogene ,Proteins ,Cancer ,Epithelial Cells ,medicine.disease ,Gene Expression Regulation, Neoplastic ,Endocrinology ,Tumor progression ,Protein Biosynthesis ,Cancer research ,Female ,Ovarian cancer ,Cell Division - Abstract
The NF1 gene, a putative tumor suppressor gene, contains a GAP related domain (GRD) which accelerates hydrolysis of ras-bound GTP to GDP, thereby converting the ras oncogene from its active to inactive form. Two forms of the NF1 GRD transcript (Type I and Type II) are differentially expressed in neuroectodermal tumor tissue relative to differentiated neural cells, and in gastric cancer cell lines relative to normal stomach mucosa. We measured relative expression of NF1 Type II and Type I isoforms in cultured normal and malignant human ovarian surface epithelial cells(HOSE) and in invasive and borderline ovarian tumor tissue. We demonstrated an 11-fold increase in Type II: Type I ratio in 7 HOSE cultures relative to eight ovarian cancer cell lines. Our findings indicate a significant decrease in Type II isoform expression and increase in Type I expression in ovarian cancer cells and tumor tissue relative to HOSE cells. We also demonstrate an increase in Type II: Type I ratio, and a decrease in cell proliferation rate in three ovarian cancer cell lines on treatment with retinoic acid. We propose that differential expression of the NF1 Type I and Type II isoforms is related to cellular differentiation in ovarian epithelial cancer and strategies based on alteration in NF1 isoform expression may have thera-peutic potential in ovarian malignancies.
- Published
- 1999
50. Hepatic bile versus gallbladder bile: A comparison of protein and lipid concentration and composition in cholesterol gallstone patients
- Author
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Albert K. Groen, Yolande C.A. Keulemans, Dirk J. Gouma, Laurens Th de Wit, K. S. Mok, and Other departments
- Subjects
Male ,medicine.medical_specialty ,Absorption (skin) ,Gastroenterology ,Epithelium ,chemistry.chemical_compound ,Cholelithiasis ,Internal medicine ,medicine ,Bile ,Humans ,Serum Albumin ,chemistry.chemical_classification ,Hepatology ,biology ,Cholesterol ,Gallbladder ,Osmolar Concentration ,Mucin ,Haptoglobin ,Mucins ,Albumin ,Proteins ,Middle Aged ,Lipids ,Endocrinology ,medicine.anatomical_structure ,Liver ,chemistry ,Immunoglobulin G ,biology.protein ,Female ,Antibody ,Glycoprotein - Abstract
Many studies have demonstrated that gallbladder bile (but not hepatic bile) of animals or patients with cholesterol gallstones contains higher protein concentrations than does gallbladder bile of control patients without stones or with pigment stones. The underlying defect has not been elucidated. To establish whether there is net production or net absorption/degradation of protein by gallbladder epithelium for different classes of protein, paired samples of hepatic and gallbladder bile were obtained from fourteen patients with cholesterol gallstones during elective cholecystectomy. In these paired samples, lipid and protein composition were determined. To obtain the concentration ratio (CR) of protein and lipid, its concentration in the gallbladder was divided by the concentration determined in the paired hepatic bile sample. The CR of bile salts was used as a parameter for water absorption in the gallbladder. Of the biliary proteins that were determined only mucin, albumin, immunoglobulin (Ig) G, and aminopeptidase N appeared to increase in the gallbladder from another cause than water absorption. A strong correlation was found between mucin, albumin, and IgG. Haptoglobin, alpha1-acid glycoprotein, IgM, and IgA appeared to be absorbed by gallbladder epithelium in the majority of patients. In cholesterol gallstone patients, total protein concentration in gallbladder bile of cholesterol gallstone patients is increased when compared with hepatic bile. The increase in protein concentration cannot be explained for all bile samples solely by water absorption. In this study we show that the defect is largely caused by a selective increase in albumin, mucin, and IgG. All other proteins which were investigated are taken up by the gallbladder.
- Published
- 1998
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