Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 35
Filter
1.
Blood Cancer Discov ; 2024 May 07.
Article in English | MEDLINE | ID: mdl-38713018

ABSTRACT

Despite advances in understanding the genetic abnormalities in myeloproliferative neoplasms (MPNs) and the development of JAK2 inhibitors, there is an urgent need to devise new treatment strategies, particularly for triple negative myelofibrosis (MF) patients who lack mutations in the JAK2 kinase pathway and have very poor clinical outcomes. Here we report that MYC copy number gain and increased MYC expression frequently occur in triple negative MF, and that MYC-directed activation of S100A9, an alarmin protein that plays pivotal roles in inflammation and innate immunity, is necessary and sufficient to drive development and progression of MF. Notably, the MYC-S100A9 circuit provokes a complex network of inflammatory signaling that involves numerous hematopoietic cell types in the bone marrow microenvironment. Accordingly, genetic ablation of S100A9 or treatment with small molecules targeting the MYC-S100A9 pathway effectively ameliorates MF phenotypes, highlighting the MYC-alarmin axis as a novel therapeutic vulnerability for this subgroup of MPNs.

2.
Behav Sci (Basel) ; 13(6)2023 Jun 09.
Article in English | MEDLINE | ID: mdl-37366740

ABSTRACT

Cardiovascular diseases (CVD) are highly prevalent and strongly associated with the risk of falls in the elderly. Falls are associated with impairments in cognition and functional or gait performance; however, little is known about these associations in the elderly population with CVD. In this study, we aimed to clarify the possible associations of physical capacity and functional and cognitive outcomes with the incidence of falls in older adults with CVD. In this comparative study, 72 elderly patients were divided into fallers (n = 24 cases) and non-fallers (n = 48 controls) according to the occurrence of falls within one year. Machine learning techniques were adopted to formulate a classification model and identify the most important variables associated with the risk of falls. Participants with the worst cardiac health classification, older age, the worst cognitive and functional performance, balance and aerobic capacity were prevalent in the case group. The variables of most importance for the machine learning model were VO2max, dual-task in seconds and the Berg Scale. There was a significant association between cognitive-motor performance and the incidence of falls. Dual-task performance, balance, and aerobic capacity levels were associated with an increased risk of falls, in older adults with CVD, during a year of observation.

3.
Nat Chem Biol ; 19(11): 1309-1319, 2023 Nov.
Article in English | MEDLINE | ID: mdl-37248412

ABSTRACT

With an eye toward expanding chemistries used for covalent ligand discovery, we elaborated an umpolung strategy that exploits the 'polarity reversal' of sulfur when cysteine is oxidized to sulfenic acid, a widespread post-translational modification, for selective bioconjugation with C-nucleophiles. Here we present a global map of a human sulfenome that is susceptible to covalent modification by members of a nucleophilic fragment library. More than 500 liganded sulfenic acids were identified on proteins across diverse functional classes, and, of these, more than 80% were not targeted by electrophilic fragment analogs. We further show that members of our nucleophilic fragment library can impair functional protein-protein interactions involved in nuclear oncoprotein transport and DNA damage repair. Our findings reveal a vast expanse of ligandable sulfenic acids in the human proteome and highlight the utility of nucleophilic small molecules in the fragment-based covalent ligand discovery pipeline, presaging further opportunities using non-traditional chemistries for targeting proteins.


Subject(s)
Cysteine , Sulfenic Acids , Humans , Cysteine/metabolism , Ligands , Proteome/metabolism , Protein Processing, Post-Translational
4.
J Thromb Haemost ; 21(8): 2137-2150, 2023 08.
Article in English | MEDLINE | ID: mdl-37037379

ABSTRACT

BACKGROUND: Oxidative stress contributes to thrombosis in atherosclerosis, inflammation, infection, aging, and malignancy. Oxidant-induced cysteine modifications, including sulfenylation, can act as a redox-sensitive switch that controls protein function. Protein disulfide isomerase (PDI) is a prothrombotic enzyme with exquisitely redox-sensitive active-site cysteines. OBJECTIVES: We hypothesized that PDI is sulfenylated during oxidative stress, contributing to the prothrombotic potential of PDI. METHODS: Biochemical and enzymatic assays using purified proteins, platelet and endothelial cell assays, and in vivo murine thrombosis studies were used to evaluate the role of oxidative stress in PDI sulfenylation and prothrombotic activity. RESULTS: PDI exposure to oxidants resulted in the loss of PDI reductase activity and simultaneously promoted sulfenylated PDI generation. Following exposure to oxidants, sulfenylated PDI spontaneously converted to disulfided PDI. PDI oxidized in this manner was able to transfer disulfides to protein substrates. Inhibition of sulfenylation impaired disulfide formation by oxidants, indicating that sulfenylation is an intermediate during PDI oxidation. Agonist-induced activation of platelets and endothelium resulted in the release of sulfenylated PDI. PDI was also sulfenylated by oxidized low-density lipoprotein (oxLDL). In an in vivo model of thrombus formation, oxLDL markedly promoted platelet accumulation following an arteriolar injury. PDI oxidoreductase inhibition blocked oxLDL-mediated augmentation of thrombosis. CONCLUSION: PDI sulfenylation is a critical posttranslational modification that is an intermediate during disulfide PDI formation in the setting of oxidative stress. Oxidants generated by vascular cells during activation promote PDI sulfenylation, and interference with PDI during oxidative stress impairs thrombus formation.


Subject(s)
Protein Disulfide-Isomerases , Thrombosis , Animals , Mice , Cysteine/metabolism , Disulfides , Oxidants , Oxidative Stress , Oxidoreductases/metabolism , Protein Disulfide-Isomerases/metabolism , Thrombosis/metabolism
5.
Biota Neotrop. (Online, Ed. ingl.) ; 23(4): e20231551, 2023. tab, graf
Article in English | LILACS-Express | LILACS | ID: biblio-1527946

ABSTRACT

Abstract The Brazilian state of Acre is located in the southwestern Amazon and it is characterized by a humid tropical forest vegetation that covers plains and mountains. Up to this point, the composition of termite species in the state is not known. The aim of this study was to provide a checklist of termite species or recognizable taxonomic units for the state of Acre. Sampling was conducted through field expeditions at the Serra do Divisor National Park, Chandless State Park, Humaitá Forest Reserve, and Chico Mendes Environmental Park using a standardized rapid termite inventory protocol in the first two areas and active searching collections in the others, without a specific protocol. This study also included occurrence records published in the scientific literature. A total of 128 species and morphospecies of termites were found in Acre, distributed across 59 genera and four families. The most frequently occurring species in Acre was Heterotermes tenuis (Hagen, 1858). The study also identified six new species records for Brazil. The predominant feeding groups were soil-feeders and wood-feeders, as expected from data obtained from surveys in humid tropical forests. Despite the significant number of new records for Acre (112), it is concluded that a larger sampling effort is still required, as many areas of the state have not yet been studied for termites.


Resumen O estado brasileiro do Acre está localizado no sudoeste da Amazônia e é caracterizado por uma vegetação de floresta tropical úmida que cobre planícies e montanhas. Até então, a composição de espécies de térmitas no estado não é conhecida. O objetivo desse estudo foi construir um checklist de espécies ou unidades taxonômicas reconhecíveis de térmitas para o estado do Acre. A amostragem foi conduzida através de expedições de campo no Parque Nacional da Serra do Divisor, no Parque Estadual Chandless, na Reserva Florestal Humaitá, e no Parque Ambiental Chico Mendes utilizando o protocolo rápido de diversidade de térmitas nas duas primeiras áreas e coletas avulsas nas demais, sem um protocolo específico. Este estudo também incluiu registros de ocorrência publicados na literature científica. Um total de 128 espécies e morfoespécies de térmitas foram encontradas no Acre, distribuídas em 59 gêneros e quatro famílias. A espécie de ocorrência mais frequente no Acre foi Heterotermes tenuis (Hagen, 1858). O estudo também identificou seis novos registros de espécies para o Brasil. Os grupos alimentares predominantes foram os humívoros e xilófagos, como esperado a partir de dados obtidos de pesquisas em florestas tropicais úmidas. Apesar do número significativo de novos registros para o Acre (112), conclui-se que ainda é necessário um esforço amostral maior, uma vez que muitas áreas do estado ainda não foram estudadas para térmitas.

7.
Nat Commun ; 13(1): 5522, 2022 09 21.
Article in English | MEDLINE | ID: mdl-36130931

ABSTRACT

'Turn-on' fluorescence probes for detecting H2O2 in cells are established, but equivalent tools to monitor the products of its reaction with protein cysteines have not been reported. Here we describe fluorogenic probes for detecting sulfenic acid, a redox modification inextricably linked to H2O2 signaling and oxidative stress. The reagents exhibit excellent cell permeability, rapid reactivity, and high selectivity with minimal cytotoxicity. We develop a high-throughput assay for measuring S-sulfenation in cells and use it to screen a curated kinase inhibitor library. We reveal a positive association between S-sulfenation and inhibition of TK, AGC, and CMGC kinase group members including GSK3, a promising target for neurological disorders. Proteomic mapping of GSK3 inhibitor-treated cells shows that S-sulfenation sites localize to the regulatory cysteines of antioxidant enzymes. Our studies highlight the ability of kinase inhibitors to modulate the cysteine sulfenome and should find broad application in the rapidly growing field of redox medicine.


Subject(s)
Cysteine , Sulfenic Acids , Antioxidants/metabolism , Cysteine/metabolism , Glycogen Synthase Kinase 3/metabolism , Hydrogen Peroxide/metabolism , Oxidation-Reduction , Proteomics
8.
ChemMedChem ; 17(14): e202200165, 2022 07 19.
Article in English | MEDLINE | ID: mdl-35491396

ABSTRACT

Reported are structure-property-function relationships associated with a class of cyclic thiosulfonate molecules-disulfide-bond disrupting agents (DDAs)-with the ability to downregulate the Epidermal Growth Factor Receptor (HER) family in parallel and selectively induce apoptosis of EGFR+ or HER2+ breast cancer cells. Recent findings have revealed that the DDA mechanism of action involves covalent binding to the thiol(ate) from the active site cysteine residue of members of the protein disulfide isomerase (PDI) family. Reported is how structural modifications to the pharmacophore can alter the anticancer activity of cyclic thiosulfonates by tuning the dynamics of thiol-thiosulfonate exchange reactions, and the studies reveal a correlation between the biological potency and thiol-reactivity. Specificity of the cyclic thiosulfonate ring-opening reaction by a nucleophilic attack can be modulated by substituent addition to a parent scaffold. Lead compound optimization efforts are also reported, and have resulted in a considerable decrease of the IC50 /IC90 values toward HER-family overexpressing breast cancer cells.


Subject(s)
Antineoplastic Agents , Antineoplastic Agents/pharmacology , Cysteine , Protein Disulfide-Isomerases , Structure-Activity Relationship , Sulfhydryl Compounds/chemistry
9.
Cancer Lett ; 534: 215604, 2022 05 28.
Article in English | MEDLINE | ID: mdl-35247515

ABSTRACT

Breast cancer mortality remains unacceptably high, indicating a need for safer and more effective therapeutic agents. Disulfide bond Disrupting Agents (DDAs) were previously identified as a novel class of anticancer compounds that selectively kill cancers that overexpress the Epidermal Growth Factor Receptor (EGFR) or its family member HER2. DDAs kill EGFR+ and HER2+ cancer cells via the parallel downregulation of EGFR, HER2, and HER3 and activation/oligomerization of Death Receptors 4 and 5 (DR4/5). However, the mechanisms by which DDAs mediate these effects are unknown. Affinity purification analyses employing biotinylated-DDAs reveal that the Protein Disulfide Isomerase (PDI) family members AGR2, PDIA1, and ERp44 are DDA target proteins. Further analyses demonstrate that shRNA-mediated knockdown of AGR2 and ERp44, or expression of ERp44 mutants, enhance basal DR5 oligomerization. DDA treatment of breast cancer cells disrupts PDIA1 and ERp44 mixed disulfide bonds with their client proteins. Together, the results herein reveal DDAs as the first small molecule, active site inhibitors of AGR2 and ERp44, and demonstrate roles for AGR2 and ERp44 in regulating the activity, stability, and localization of DR4 and DR5, and activation of Caspase 8.


Subject(s)
Breast Neoplasms , Disulfides , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Cell Death , Disulfides/metabolism , Disulfides/therapeutic use , ErbB Receptors/metabolism , Female , Humans , Membrane Proteins , Molecular Chaperones/metabolism , Mucoproteins , Oncogene Proteins/genetics , Protein Disulfide-Isomerases/genetics , Protein Disulfide-Isomerases/metabolism , Proteins , Receptors, Death Domain
10.
IEEE Trans Image Process ; 31: 1994-2003, 2022.
Article in English | MEDLINE | ID: mdl-35104220

ABSTRACT

Point cloud compression has been studied in standard bodies and we are here concerned with the Moving Picture Experts Group video-based point cloud compression (V-PCC) solution. Plenoptic point clouds (PPC) is a novel volumetric data representation wherein points are associated with colors in all viewing directions to improve realism. It is sampled as a number ( Nc ) of attribute colors per point. We propose a new method for the efficient video-based compression of PPC that is backwards compatible with the existing single-color V-PCC decoder. V-PCC generates three image atlases which are encoded using an image/video encoder. We assume there may be a reference color which is to be encoded as the main payload. We generate Nc+3 atlases and we produce Nc differential images against the reference color image. Those difference images are pixel-wise transformed using an Nc -point discrete cosine transform, generating Nc transformed atlases which are encoded, forming the secondary payload. Such secondary information is the plenoptic enhancement to the point cloud. If there is no reference attribute, we skip the differences and use the lowest frequency of the transformed atlases as the main payload. Results are presented that show an unrivaled performance of the proposed method.

11.
J Aging Phys Act ; 30(5): 872-879, 2022 10 01.
Article in English | MEDLINE | ID: mdl-35045391

ABSTRACT

This study aimed to investigate the relationship between physical ability and spatial navigation in older adults with mild cognitive impairment and healthy controls, using the floor maze test. Study participants (n = 58) were subjected to the following tests: floor maze test, sit-to-stand, 8-foot up-and-go, and aerobic steps. Factorial analyses showed that performance of the physical tests combined explained approximately 87% of the sample variability. Mobility (R2 = .22, p ≤ .001) and aerobic capacity (R2 = .27, p ≤ .001) were both associated with delayed maze time in the floor maze test. Low levels of aerobic capacity were also associated with an increased odds to perform poorly in the delayed maze time after controlling for age, sex, and mild cognitive impairment diagnosis (odds ratio = 3.1; 95% confidence interval [1.0, 9.5]; p = .04). Aerobic capacity and mobility are associated with spatial navigation in patients with mild cognitive impairment and healthy older adults.


Subject(s)
Cognitive Dysfunction , Spatial Navigation , Aged , Cognitive Dysfunction/diagnosis , Cognitive Dysfunction/psychology , Cross-Sectional Studies , Health Status , Humans
12.
J Alzheimers Dis ; 81(3): 1243-1252, 2021.
Article in English | MEDLINE | ID: mdl-33935093

ABSTRACT

BACKGROUND: Spatial navigation and dual-task (DT) performance may represent a low-cost approach to the identification of the cognitive decline in older adults and may support the clinical diagnosis of mild cognitive impairment (MCI) and Alzheimer's disease (AD). OBJECTIVE: To assess the accuracy of different types of motor tasks in differentiating older persons with MCI and AD from healthy peers. METHODS: Older adults aged 60 years or over (n = 105; healthy = 39; MCI = 23; AD = 43) were evaluated by the floor maze test (FMT), the senior fitness test, and DT performance. Receiver operating characteristic curve (ROC) analysis was used to evaluate the accuracy of the tests. We also performed principal component analysis (PCA) and logistic regression analysis to explore the variance and possible associations of the variables within the sample. RESULTS: FMT (AUC = 0.84, sensitivity = 75.7%, specificity = 76.1%, p < 0.001) and DT (AUC = 0.87, sensitivity = 80.4%, specificity = 86.9%, p < 0.001) showed the highest performance for distinguishing MCI from AD individuals. Moreover, FMT presented better sensitivity in distinguishing AD patients from their healthy peers (AUC = 0.93, sensitivity = 94%, specificity = 85.6%, p < 0.001) when compared to the Mini-Mental State Examination. PCA revealed that the motor test performance explains a total of 73.9% of the variance of the sample. Additionally, the results of the motor tests were not influenced by age and education. CONCLUSION: Spatial navigation tests showed better accuracy than usual cognitive screening tests in distinguishing patients with neurocognitive disorders.


Subject(s)
Alzheimer Disease/diagnosis , Cognitive Dysfunction/diagnosis , Neuropsychological Tests , Spatial Navigation , Aged , Aged, 80 and over , Alzheimer Disease/psychology , Cognitive Dysfunction/psychology , Female , Humans , Male , Mass Screening
13.
Nat Commun ; 12(1): 1415, 2021 03 03.
Article in English | MEDLINE | ID: mdl-33658510

ABSTRACT

Post-translational changes in the redox state of cysteine residues can rapidly and reversibly alter protein functions, thereby modulating biological processes. The nematode C. elegans is an ideal model organism for studying cysteine-mediated redox signaling at a network level. Here we present a comprehensive, quantitative, and site-specific profile of the intrinsic reactivity of the cysteinome in wild-type C. elegans. We also describe a global characterization of the C. elegans redoxome in which we measured changes in three major cysteine redox forms after H2O2 treatment. Our data revealed redox-sensitive events in translation, growth signaling, and stress response pathways, and identified redox-regulated cysteines that are important for signaling through the p38 MAP kinase (MAPK) pathway. Our in-depth proteomic dataset provides a molecular basis for understanding redox signaling in vivo, and will serve as a valuable and rich resource for the field of redox biology.


Subject(s)
Caenorhabditis elegans Proteins/metabolism , Caenorhabditis elegans/metabolism , Cysteine/metabolism , Animals , Antioxidants/metabolism , Caenorhabditis elegans/drug effects , Caenorhabditis elegans/microbiology , Caenorhabditis elegans Proteins/genetics , Hydrogen Peroxide/pharmacology , MAP Kinase Kinase 4/metabolism , Mitogen-Activated Protein Kinases/genetics , Mitogen-Activated Protein Kinases/metabolism , Mutation , Oxidation-Reduction , Proteomics/methods , Signal Transduction , Transcription Factors/metabolism , p38 Mitogen-Activated Protein Kinases/metabolism
14.
Redox Biol ; 41: 101898, 2021 05.
Article in English | MEDLINE | ID: mdl-33647858

ABSTRACT

Sulfur dioxide (SO2) has emerged as a physiological relevant signaling molecule that plays a prominent role in regulating vascular functions. However, molecular mechanisms whereby SO2 influences its upper-stream targets have been elusive. Here we show that SO2 may mediate conversion of hydrogen peroxide (H2O2) to a more potent oxidant, peroxymonosulfite, providing a pathway for activation of H2O2 to convert the thiol group of protein cysteine residues to a sulfenic acid group, aka cysteine sulfenylation. By using site-centric chemoproteomics, we quantified >1000 sulfenylation events in vascular smooth muscle cells in response to exogenous SO2. Notably, ~42% of these sulfenylated cysteines are dynamically regulated by SO2, among which is cysteine-64 of Smad3 (Mothers against decapentaplegic homolog 3), a key transcriptional modulator of transforming growth factor ß signaling. Sulfenylation of Smad3 at cysteine-64 inhibits its DNA binding activity, while mutation of this site attenuates the protective effects of SO2 on angiotensin II-induced vascular remodeling and hypertension. Taken together, our findings highlight the important role of SO2 in vascular pathophysiology through a redox-dependent mechanism.


Subject(s)
Hydrogen Peroxide , Vascular Remodeling , Humans , Oxidation-Reduction , Signal Transduction , Smad3 Protein , Sulfenic Acids
15.
J Environ Manage ; 280: 111713, 2021 Feb 15.
Article in English | MEDLINE | ID: mdl-33257181

ABSTRACT

This study aims to assess different machine learning approaches for streamflow regionalization in a tropical watershed, analyzing their advantages and limitations, and to point the benefits of using them for water resources management. The algorithms applied were: Random Forest, Earth and linear model. The response variables were the three types of minimum streamflow (Q7.10, Q95 and Q90), besides the long-term average streamflow (Qmld). The database involved 76 environmental covariates related to morphometry, topography, climate, land use and cover, and surface conditions. The elimination of covariates was performed using two processes: Pearson's correlation analysis and importance analysis by Recursive Feature Elimination (RFE). To validate the models, the following statistical metrics were used: Nash-Sutcliffe coefficient (NSE), percent bias (PBIAS), Willmott's index of agreement (d), coefficient of determination (R2), root mean square error (RMSE), mean absolute error (MAE) and relative error (RE). The linear model was unsatisfactory for all response variables. The results show that nonlinear models performed well, and their covariate of greatest predictive importance was flow equivalent to the precipitated volume, considering the subtraction of an abstraction factor of 750 mm (Peq750). Generally, the Random Forest and Earth models showed similar performances and great ability to predict the minimum streamflow and long-term average streamflow assessed, constituting powerful and promising alternatives for the streamflow regionalization in support to the management and integrated planning of water resources at the level of river basins.


Subject(s)
Models, Theoretical , Rivers , Climate , Machine Learning , Water Movements
16.
J Refract Surg ; 36(12): 796-803, 2020 Dec 01.
Article in English | MEDLINE | ID: mdl-33295991

ABSTRACT

PURPOSE: To evaluate the visual outcomes and patient satisfaction after blended implantation of rotationally asymmetric multifocal intraocular lenses (IOLs) (LENTIS Mplus LS-313 +3.00 and +1.50 diopters [D], Oculentis GmbH). METHODS: This was an interventional prospective study that included 40 eyes of 20 patients who underwent uneventful refractive lens exchange. Patients were implanted with the LENTIS Mplus LS-313 +3.00 D IOL in the non-dominant eye and the +1.50 D IOL in the dominant eye. Twelve months after surgery, binocular and monocular uncorrected and corrected near, intermediate, and distance visual acuity, defocus curve, contrast sensitivity, and light distortion analysis (LDA) were evaluated. Monocular total ocular aberrometry with a pyramidal wavefront sensor (Osiris; CSO) and patient satisfaction was evaluated with the 10-item Near Activity Vision Questionnaire (NAVQ-10). RESULTS: There was a statistically significant improvement in the uncorrected distance visual acuity in both eyes after surgery (P < .001), with good uncorrected near and intermediate distance visual acuity (0.18 and 0.38 logMAR, respectively). The binocular defocus curve showed good levels of visual acuity for the most important ranges of vision. Contrast sensitivity and LDA had significantly better results when measured binocularly than monocularly. Higher order aberrations were significantly higher in the +3.00 D eye (P < .001). The mean Rasch score for the NAVQ-10 questionnaire was 26.9 ± 27.66. CONCLUSIONS: Visual outcomes, defocus curve, LDA, and contrast sensitivity were significantly better binocularly than monocularly. The implantation of a blended IOL combination with different near addition complements the advantages of each IOL, improving binocular visual outcomes and providing good patient satisfaction. [J Refract Surg. 2020;36(12):796-803.].


Subject(s)
Lenses, Intraocular , Multifocal Intraocular Lenses , Phacoemulsification , Humans , Patient Satisfaction , Prospective Studies , Prosthesis Design , Pseudophakia , Refraction, Ocular
17.
Blood Adv ; 4(18): 4494-4507, 2020 09 22.
Article in English | MEDLINE | ID: mdl-32946569

ABSTRACT

Arterial thrombosis in the setting of dyslipidemia promotes clinically significant events, including myocardial infarction and stroke. Oxidized lipids in low-density lipoproteins (oxLDL) are a risk factor for athero-thrombosis and are recognized by platelet scavenger receptor CD36. oxLDL binding to CD36 promotes platelet activation and thrombosis by promoting generation of reactive oxygen species. The downstream signaling events initiated by reactive oxygen species in this setting are poorly understood. In this study, we report that CD36 signaling promotes hydrogen peroxide flux in platelets. Using carbon nucleophiles that selectively and covalently modify cysteine sulfenic acids, we found that hydrogen peroxide generated through CD36 signaling promotes cysteine sulfenylation of platelet proteins. Specifically, cysteines were sulfenylated on Src family kinases, which are signaling transducers that are recruited to CD36 upon recognition of its ligands. Cysteine sulfenylation promoted activation of Src family kinases and was prevented by using a blocking antibody to CD36 or by enzymatic degradation of hydrogen peroxide. CD36-mediated platelet aggregation and procoagulant phosphatidylserine externalization were inhibited in a concentration-dependent manner by a panel of sulfenic acid-selective carbon nucleophiles. At the same concentrations, these probes did not inhibit platelet aggregation induced by the purinergic receptor agonist adenosine diphosphate or the collagen receptor glycoprotein VI agonist collagen-related peptide. Selective modification of cysteine sulfenylation in vivo with a benzothiazine-based nucleophile rescued the enhanced arterial thrombosis seen in dyslipidemic mice back to control levels. These findings suggest that CD36 signaling generates hydrogen peroxide to oxidize cysteines within platelet proteins, including Src family kinases, and lowers the threshold for platelet activation in dyslipidemia.


Subject(s)
Dyslipidemias , Thrombosis , Animals , CD36 Antigens , Cysteine , Mice , Platelet Activation
18.
Cell Death Discov ; 5: 153, 2019.
Article in English | MEDLINE | ID: mdl-31839995

ABSTRACT

Disulfide bond-disrupting agents (DDAs) are a new chemical class of agents recently shown to have activity against breast tumors in animal models. Blockade of tumor growth is associated with downregulation of EGFR, HER2, and HER3 and reduced Akt phosphorylation, as well as the induction of endoplasmic reticulum stress. However, it is not known how DDAs trigger cancer cell death without affecting nontransformed cells. As demonstrated here, DDAs are the first compounds identified that upregulate the TRAIL receptor DR5 through transcriptional and post-transcriptional mechanisms to activate the extrinsic cell death pathway. At the protein level, DDAs alter DR5 disulfide bonding to increase steady-state DR5 levels and oligomerization, leading to downstream caspase 8 and 3 activation. DDAs and TRAIL synergize to kill cancer cells and are cytotoxic to HER2+ cancer cells with acquired resistance to the EGFR/HER2 tyrosine kinase inhibitor Lapatinib. Investigation of the mechanisms responsible for DDA selectivity for cancer cells reveals that DDA-induced upregulation of DR5 is enhanced in the context of EGFR overexpression. DDA-induced cytotoxicity is strongly amplified by MYC overexpression. This is consistent with the known potentiation of TRAIL-mediated cell death by MYC. Together, the results demonstrate selective DDA lethality against oncogene-transformed cells, DDA-mediated DR5 upregulation, and protein stabilization, and that DDAs have activity against drug-resistant cancer cells. Our results indicate that DDAs are unique in causing DR5 accumulation and oligomerization and inducing downstream caspase activation and cancer cell death through mechanisms involving altered DR5 disulfide bonding. DDAs thus represent a new therapeutic approach to cancer therapy.

19.
Proc Natl Acad Sci U S A ; 116(42): 21256-21261, 2019 10 15.
Article in English | MEDLINE | ID: mdl-31578252

ABSTRACT

Hydrogen peroxide (H2O2) is an important messenger molecule for diverse cellular processes. H2O2 oxidizes proteinaceous cysteinyl thiols to sulfenic acid, also known as S-sulfenylation, thereby affecting the protein conformation and functionality. Although many proteins have been identified as S-sulfenylation targets in plants, site-specific mapping and quantification remain largely unexplored. By means of a peptide-centric chemoproteomics approach, we mapped 1,537 S-sulfenylated sites on more than 1,000 proteins in Arabidopsis thaliana cells. Proteins involved in RNA homeostasis and metabolism were identified as hotspots for S-sulfenylation. Moreover, S-sulfenylation frequently occurred on cysteines located at catalytic sites of enzymes or on cysteines involved in metal binding, hinting at a direct mode of action for redox regulation. Comparison of human and Arabidopsis S-sulfenylation datasets provided 155 conserved S-sulfenylated cysteines, including Cys181 of the Arabidopsis MITOGEN-ACTIVATED PROTEIN KINASE4 (AtMAPK4) that corresponds to Cys161 in the human MAPK1, which has been identified previously as being S-sulfenylated. We show that, by replacing Cys181 of recombinant AtMAPK4 by a redox-insensitive serine residue, the kinase activity decreased, indicating the importance of this noncatalytic cysteine for the kinase mechanism. Altogether, we quantitatively mapped the S-sulfenylated cysteines in Arabidopsis cells under H2O2 stress and thereby generated a comprehensive view on the S-sulfenylation landscape that will facilitate downstream plant redox studies.


Subject(s)
Arabidopsis/metabolism , Proteins/metabolism , Sulfhydryl Compounds/metabolism , Catalytic Domain/physiology , Cysteine/metabolism , Humans , Hydrogen Peroxide/metabolism , Mitogen-Activated Protein Kinase 1/metabolism , Oxidation-Reduction , RNA/metabolism , Serine/metabolism , Signal Transduction/physiology , Sulfenic Acids/metabolism
20.
Article in English | MEDLINE | ID: mdl-31395547

ABSTRACT

We present a method to compress geometry information of point clouds that explores redundancies across consecutive frames of a sequence. It uses octrees and works by progressively increasing resolution of the octree. At each branch of the tree, we generate an approximation of the child nodes by a number of methods which are used as contexts to drive an arithmetic coder. The best approximation, i.e. the context that yields the least amount of encoding bits, is selected and the chosen method is indicated as side information for replication at the decoder. The core of our method is a context-based arithmetic coder in which a reference octree is used as reference to encode the current octree, thus providing 255 contexts for each output octet. The 255×255 frequency histogram is viewed as a discrete 3D surface and is conveyed to the decoder using another octree. We present two methods to generate the predictions (contexts) which use adjacent frames in the sequence (inter-frame) and one method that works purely intra-frame. The encoder continuously switches the best mode among the three and conveys such information to the decoder. Since an intra-frame prediction is present, our coder can also work in purely intra-frame mode, as well. Extensive results are presented to show the method's potential against many compression alternatives for the geometry information in dynamic voxelized point clouds.

SELECTION OF CITATIONS
SEARCH DETAIL
...