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1.
Nat Rev Mol Cell Biol ; 17(9): 597-604, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27381243

RESUMO

The development of the CRISPR-Cas9 system triggered a revolution in the field of genome engineering. Initially, the use of this system was focused on the study of protein-coding genes but, recently, a number of CRISPR-Cas9-based tools have been developed to study non-coding transcriptional regulatory elements. These technological advances offer unprecedented opportunities for elucidating the functions of enhancers in their endogenous context. Here, we discuss the application, current limitations and future development of CRISPR-Cas9 systems to identify and characterize enhancer elements in a high-throughput manner.


Assuntos
Sistemas CRISPR-Cas , Edição de Genes/métodos , Elementos Facilitadores Genéticos , Epigênese Genética , Epigenômica/métodos
2.
J Biomed Inform ; 137: 104272, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36563828

RESUMO

BACKGROUND: Secondary use of health data is a valuable source of knowledge that boosts observational studies, leading to important discoveries in the medical and biomedical sciences. The fundamental guiding principle for performing a successful observational study is the research question and the approach in advance of executing a study. However, in multi-centre studies, finding suitable datasets to support the study is challenging, time-consuming, and sometimes impossible without a deep understanding of each dataset. METHODS: We propose a strategy for retrieving biomedical datasets of interest that were semantically annotated, using an interface built by applying a methodology for transforming natural language questions into formal language queries. The advantages of creating biomedical semantic data are enhanced by using natural language interfaces to issue complex queries without manipulating a logical query language. RESULTS: Our methodology was validated using Alzheimer's disease datasets published in a European platform for sharing and reusing biomedical data. We converted data to semantic information format using biomedical ontologies in everyday use in the biomedical community and published it as a FAIR endpoint. We have considered natural language questions of three types: single-concept questions, questions with exclusion criteria, and multi-concept questions. Finally, we analysed the performance of the question-answering module we used and its limitations. The source code is publicly available at https://bioinformatics-ua.github.io/BioKBQA/. CONCLUSION: We propose a strategy for using information extracted from biomedical data and transformed into a semantic format using open biomedical ontologies. Our method uses natural language to formulate questions to be answered by this semantic data without the direct use of formal query languages.


Assuntos
Processamento de Linguagem Natural , Semântica , Software , Idioma , Bases de Dados Factuais
3.
Zygote ; 31(5): 483-490, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37449710

RESUMO

The influence of the method of evaluating developmentally competent oocytes on their viability after cryopreservation still needs to be better understood. The objective of this study was to determine the cleavage and embryo developmental rates after parthenogenetic activation of cumulus-oocyte complexes (COCs) selected by different concentrations of brilliant cresyl blue (BCB) and cryopreservation. In the first experiment, COCs were separated into groups and incubated for 1 h in medium containing BCB (13 µM, 16 µM, or 20 µM). The control group was not exposed to BCB staining. In the second experiment, COCs were divided into four groups: 13 µM BCB(+), 13 µM BCB(-), fresh control (selected by morphologic observation and immediately in vitro matured) and vitrified control (selected by morphologic evaluation, vitrified, and in vitro matured). In the first experiment, the 13 µM BCB group displayed greater development rates at the morula stage (65.45%, 36/55) when compared with the other groups. In the second experiment, cleavage (47.05%, 72/153) and morula development (33.55%, 51/153) of the control group of fresh COCs were increased compared with the other groups. However, when comparing morula rates between vitrified COC control and BCB(+) groups, the BCB(+) group had better results (19.23%, 5/26 and 64.7%, 11/17, respectively). Our best result in rat COC selection by BCB staining was obtained using a concentration of 13 µM. This selection could be a valuable tool to improve vitrification outcomes, as observed by the BCB(+) group that demonstrated better results compared with the vitrified COC control.


Assuntos
Técnicas de Maturação in Vitro de Oócitos , Vitrificação , Ratos , Animais , Técnicas de Maturação in Vitro de Oócitos/métodos , Oócitos/fisiologia , Oxazinas/farmacologia
4.
Nature ; 530(7591): 490-4, 2016 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-26878238

RESUMO

Tumour growth and metabolic adaptation may restrict the availability of certain amino acids for protein synthesis. It has recently been shown that certain types of cancer cells depend on glycine, glutamine, leucine and serine metabolism to proliferate and survive. In addition, successful therapies using L-asparaginase-induced asparagine deprivation have been developed for acute lymphoblastic leukaemia. However, a tailored detection system for measuring restrictive amino acids in each tumour is currently not available. Here we harness ribosome profiling for sensing restrictive amino acids, and develop diricore, a procedure for differential ribosome measurements of codon reading. We first demonstrate the functionality and constraints of diricore using metabolic inhibitors and nutrient deprivation assays. Notably, treatment with L-asparaginase elicited both specific diricore signals at asparagine codons and high levels of asparagine synthetase (ASNS). We then applied diricore to kidney cancer and discover signals indicating restrictive proline. As for asparagine, this observation was linked to high levels of PYCR1, a key enzyme in proline production, suggesting a compensatory mechanism allowing tumour expansion. Indeed, PYCR1 is induced by shortage of proline precursors, and its suppression attenuated kidney cancer cell proliferation when proline was limiting. High PYCR1 is frequently observed in invasive breast carcinoma. In an in vivo model system of this tumour, we also uncover signals indicating restrictive proline. We further show that CRISPR-mediated knockout of PYCR1 impedes tumorigenic growth in this system. Thus, diricore has the potential to reveal unknown amino acid deficiencies, vulnerabilities that can be used to target key metabolic pathways for cancer treatment.


Assuntos
Neoplasias da Mama/metabolismo , Códon/genética , Neoplasias Renais/metabolismo , Prolina/metabolismo , Biossíntese de Proteínas , Ribossomos/metabolismo , Animais , Asparaginase/metabolismo , Asparagina/genética , Asparagina/metabolismo , Aspartato-Amônia Ligase/metabolismo , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Técnicas de Inativação de Genes , Humanos , Neoplasias Renais/patologia , Camundongos , Prolina/biossíntese , Prolina/deficiência , Biossíntese de Proteínas/genética , Pirrolina Carboxilato Redutases/deficiência , Pirrolina Carboxilato Redutases/genética , Pirrolina Carboxilato Redutases/metabolismo , delta-1-Pirrolina-5-Carboxilato Redutase
5.
Sensors (Basel) ; 23(1)2022 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-36616871

RESUMO

Football performance behaviour relies on the individual and collective perceptual attunement to the opportunities for action (affordances) available in a given competitive environment. Such perception-action coupling is constrained by players' spatial dominance. Aiming to understand the influence of team formation and players' roles in their dynamic interaction (interpersonal linkages), Voronoi diagrams were used to assess the differences in players' spatial dominance resulting from their interactions according to ball-possession status in high-performance football. Notational (i.e., team formation, players' role, and ball-possession status) and positional data (from optical sensors) from ten matches of the men's French main football league were analysed. Voronoi diagrams were computed from players' positional data for both teams. Probability density functions of the players' Voronoi cell areas were then computed and compared, using the Kolmogorov-Smirnov test, for the different variables (i.e., team formation, player role, and ball-possession status) and their classes. For these variables, the players' Voronoi cell areas presented statistical differences, which were sensitive to team formation classes (i.e., defenders, midfielders, and forwards) and relative pitch location (interior or exterior in the effective play space). Differences were also found between players with similar roles when in different team formations. Our results showed that team formation and players' roles constrain their interpersonal linkages, resulting in different spatial dominance patterns. Using positional data captured by optical sensors, Voronoi diagrams can be computed into compound variables, which are meaningful for understanding the match and thus offer information to the design representative training tasks.


Assuntos
Desempenho Atlético , Futebol Americano , Futebol , Masculino , Humanos , Futebol Americano/fisiologia , Desempenho Atlético/fisiologia , Futebol/fisiologia , Desempenho Psicomotor
6.
Behav Res Methods ; 2022 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-36509942

RESUMO

The existence of crime-related racial stereotypes has been well documented. People tend to associate certain groups with specific crimes, which, in turn, impacts criminal-sentencing decisions through the perceptions of crime severity. This evidence calls for regular updating of rating norms combining these variables. With this objective, and given that most of the normative studies provide norms for a small number of crimes and/or with an insufficient number of participants, a new norming study was conducted. Furthermore, norms from European countries are absent, and the existing ones (mostly with USA-based populations) do not simultaneously examine crime stereotypicality and crime severity. The Crime Stereotypicality and Severity Database (CriSSD) presents normative ratings for a set of 63 crimes on three dimensions: White stereotypicality, Black stereotypicality, and crime severity. The crimes were selected according to a comprehensive procedure. A total of 340 Portuguese participants (72.6% female; Mage = 26.86, SD = 7.65) answered an online survey. Each crime was evaluated by a range of 46-60 participants. Data allowed us to identify a crime typology with three clusters. We present descriptive data (means, standard deviations, and 95% confidence intervals) for each crime. Crime evaluations were associated with sociodemographic characteristics. Additionally, this study gives input regarding the understudied link between crime stereotypes and crime severity, showing that crime severity is predicted by ratings of both Black and White stereotypicality. The CriSSD (available at osf.io/gkbrm ) provides a valuable resource for researchers in the field of social psychology to conduct studies with controlled materials on potential disparities in criminal-sentencing decisions.

7.
Nucleic Acids Res ; 47(18): 9557-9572, 2019 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-31372638

RESUMO

Estrogen receptor α (ERα) is an enhancer activating transcription factor, a key driver of breast cancer and a main target for cancer therapy. ERα-mediated gene regulation requires proper chromatin-conformation to facilitate interactions between ERα-bound enhancers and their target promoters. A major determinant of chromatin structure is the CCCTC-binding factor (CTCF), that dimerizes and together with cohesin stabilizes chromatin loops and forms the boundaries of topologically associated domains. However, whether CTCF-binding elements (CBEs) are essential for ERα-driven cell proliferation is unknown. To address this question in a global manner, we implemented a CRISPR-based functional genetic screen targeting CBEs located in the vicinity of ERα-bound enhancers. We identified four functional CBEs and demonstrated the role of one of them in inducing chromatin conformation changes in favor of activation of PREX1, a key ERα target gene in breast cancer. Indeed, high PREX1 expression is a bona-fide marker of ERα-dependency in cell lines, and is associated with good outcome after anti-hormonal treatment. Altogether, our data show that distinct CTCF-mediated chromatin structures are required for ERα- driven breast cancer cell proliferation.


Assuntos
Neoplasias da Mama/genética , Fator de Ligação a CCCTC/genética , Proliferação de Células/genética , Receptor alfa de Estrogênio/genética , Sítios de Ligação/genética , Neoplasias da Mama/patologia , Sistemas CRISPR-Cas/genética , Cromatina/genética , Elementos Facilitadores Genéticos/genética , Feminino , Humanos , Células MCF-7 , Ligação Proteica/genética
8.
Sensors (Basel) ; 21(8)2021 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-33918912

RESUMO

Adequate conditions are critical to avoiding damage or degradation of products during transportation, especially in the case of delicate goods like food products, live animals, precision machinery or art items, among others. The damages are not always readily identified: sometimes they are only detected several days or weeks after the merchandise has been delivered. Moreover, it may be hard to assess if the problems resulted from the transport conditions, and it may be even harder to prove it, making it difficult to determine and assign responsibilities. Also, transport is a global business, typically involving different companies and means (truck, train, plane, ship, …). Usually, customers hire the service to a single commercial entity, but the service is performed by several companies, like transporters, stockists and dispatchers. To know whether the transport requirements are fulfilled or not is thus essential to assessing responsibilities and encouraging compliance by all the players in the process. In this paper, the authors propose an architecture that allows certifying, in an exempt manner, the conditions under which the transport of sensitive goods are carried out. In case of compliance, it protects the entities of the transport chain and ensures the customer that the merchandise has not been subject to conditions that may have affected its integrity or quality. If problems are detected, it allows to identify the non-compliant players and to assign responsibilities. The solution is based on ultra-low-power, low-cost devices (equipped with several sensors, a real-time clock, and Bluetooth Low Energy services), a mobile application and several cloud services (including a Coordinated Universal Time service).

9.
Nucleic Acids Res ; 46(8): 4213-4227, 2018 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-29481642

RESUMO

Oncogene-induced senescence (OIS), provoked in response to oncogenic activation, is considered an important tumor suppressor mechanism. Long non-coding RNAs (lncRNAs) are transcripts longer than 200 nt without a protein-coding capacity. Functional studies showed that deregulated lncRNA expression promote tumorigenesis and metastasis and that lncRNAs may exhibit tumor-suppressive and oncogenic function. Here, we first identified lncRNAs that were differentially expressed between senescent and non-senescent human fibroblast cells. Using RNA interference, we performed a loss-function screen targeting the differentially expressed lncRNAs, and identified lncRNA-OIS1 (lncRNA#32, AC008063.3 or ENSG00000233397) as a lncRNA required for OIS. Knockdown of lncRNA-OIS1 triggered bypass of senescence, higher proliferation rate, lower abundance of the cell-cycle inhibitor CDKN1A and high expression of cell-cycle-associated genes. Subcellular inspection of lncRNA-OIS1 indicated nuclear and cytosolic localization in both normal culture conditions as well as following oncogene induction. Interestingly, silencing lncRNA-OIS1 diminished the senescent-associated induction of a nearby gene (Dipeptidyl Peptidase 4, DPP4) with established role in tumor suppression. Intriguingly, similar to lncRNA-OIS1, silencing DPP4 caused senescence bypass, and ectopic expression of DPP4 in lncRNA-OIS1 knockdown cells restored the senescent phenotype. Thus, our data indicate that lncRNA-OIS1 links oncogenic induction and senescence with the activation of the tumor suppressor DPP4.


Assuntos
Senescência Celular/genética , Dipeptidil Peptidase 4/genética , RNA Longo não Codificante/metabolismo , Dipeptidil Peptidase 4/metabolismo , Expressão Gênica , Genes ras , Genoma , Células HEK293 , Humanos , Neoplasias/genética , Neoplasias/metabolismo
10.
J Sports Sci ; 38(5): 494-502, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31876443

RESUMO

Understanding team behaviours in sports performance requires understanding the interdependencies established between their levels of complexity (micro-meso-macro). Previously, most studies examined interactions emerging at micro- and macro-levels, thus neglecting those emerging at a meso-level (reveals connections between player and team levels, depicted by the emergence of coordination in specific sub-groups of players-simplices during performance). We addressed this issue using the multilevel hypernetworks approach, adopting a cluster-phase method, to record player-simplice synchronies in two performance conditions where the number, size and location of goals were manipulated (first-condition: 6 × 6 + 4 mini-goals; second-condition: Gk + 6 × 6 + Gk). We investigated meso-level coordination tendencies, as a function of ball-possession (attacking/defending), field-direction (longitudinal/lateral) and teams (Team A/Team B). Generally, large synergistic relations and more stable patterns were observed in the longitudinal direction of the field than the lateral direction for both teams, and for both game phases in the first condition. The second condition displayed higher synchronies and more stable patterns in the lateral direction than the longitudinal plane for both teams, and for both game phases. Results suggest: (i) usefulness of hypernetworks in assessing synchronisation of teams at a meso-level; (ii) coaches may consider manipulating these task constraints to develop levels of local synchronies within teams.


Assuntos
Desempenho Atlético/psicologia , Processos Grupais , Desempenho Psicomotor , Futebol , Adolescente , Sistemas de Informação Geográfica , Humanos , Masculino
11.
Sensors (Basel) ; 20(17)2020 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-32899219

RESUMO

The ecological dynamics approach to interpersonal relationships provides theoretical support to the use of kinematic data, obtained with sensor-based systems, in which players of a team are linked mainly by information from the performance environment. Our goal was to capture the properties of synergic behavior in football, using spatiotemporal data from one match of the 2018 FIFA WORLD CUP RUSSIA, to explore the application of player-ball-goal angles in cluster phase analysis. Linear mixed effects models were used to test the statistical significance of different effects, such as: team, half(-time), role and pitch zones. Results showed that the cluster phase values (synchronization) for the home team, had a 3.812×10-2±0.536×10-2 increase with respect to the away team (X2(41)=259.8, p<0.001) and that changing the role from with ball to without ball increased synchronization by 16.715×10-2±0.283×10-2 (X2(41)=12227.0, p<0.001). The interaction between effects was also significant. The player-team relative phase, the player-ball-goal angles relative frequency and the team configurations, showed that variations of synchronization might indicate critical performance changes (ball possession changes, goals scored, etc.). This study captured the ongoing player-environment link and the properties of team synergic behavior, supporting the use of sensor-based data computations in the development of relevant indicators for tactical analysis in sports.


Assuntos
Desempenho Atlético , Processos Grupais , Futebol , Atletas , Fenômenos Biomecânicos , Humanos
12.
Arch Orthop Trauma Surg ; 140(8): 1133-1141, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32448930

RESUMO

INTRODUCTION: Fracture-dislocation and pilon injuries of the proximal interphalangeal joints (PIPJ) continue to pose significant management challenges. Stable fracture configurations can be treated with extension block splinting or pinning. Unstable fractures usually require open or closed reduction and fixation either directly/internally onto the fracture using Kirschner wires, cerclage wires, screws or miniplates or indirectly/externally by ligamentotaxis using external fixators which can be dynamic or static. Dynamic external fixators, such as Suzuki's pins and rubber traction system, S-Quattro and Hynes/Giddins frame, appear intuitive as they provide axial distraction, which reduces the fracture whilst obviating the need to open the fracture. They also allow immediate active movement whilst maintaining reduction. The Ligamentotaxor® (Arex, Pallaiseau Cedex, France) is a commercially-available dynamic external fixator which has been used at our institution since 2013. MATERIALS AND METHODS: This retrospective study assessed the outcomes (interphalangeal joint active range of movement (AROM), QuickDASH score and complications) in 19 patients [mean age of 48.6 (SD 16.2)] whose proximal interphalangeal joint (PIPJ) fracture-dislocations and/or pilon fractures were treated with the Ligamentotaxor®. Injuries were classified according to Seno i.e. (1) volar lip fracture ± dorsal dislocation (2) dorsal lip fracture ± volar dislocation (3) pilon fracture. RESULTS: There were fifteen (79%) pilon/Seno 3, three (16%) Seno 1 and one (5%) Seno 2 fractures. The mean PIPJ AROM was 70.6° (SD 4.48°) for all Seno classes and 70° (SD 5.6°) for the pilon subgroup. The QuickDASH score averaged to 2.65 (SD 0.88). There were two pin-site infections, three pin-site inflammations, one osteomyelitis and two complex regional pain syndrome diagnoses. One patient required arthroplasty after missing several appointments. CONCLUSIONS: These results, considering the predominance of pilon fractures, compare favourably the published Ligamentotaxor® and other dynamic external fixator systems.


Assuntos
Fraturas do Tornozelo/cirurgia , Traumatismos dos Dedos/cirurgia , Fixação Interna de Fraturas , Fixadores Internos , Fraturas Intra-Articulares/cirurgia , Adulto , Fixação Interna de Fraturas/instrumentação , Fixação Interna de Fraturas/métodos , Humanos , Luxações Articulares/cirurgia , Pessoa de Meia-Idade , Amplitude de Movimento Articular
13.
Eat Weight Disord ; 25(1): 163-167, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30168031

RESUMO

Orthorexia nervosa (ON) is a recently proposed eating disordered behaviour characterized by an obsessional or exaggerated fixation on healthy eating. The published literature is scarce regarding its classification, clinical presentation, management and long-term outcomes. Herein, we present the clinical and follow-up findings of an 18-year-old woman with ON comorbid with depression, successfully treated with mirtazapine. The patient had a 12-month history of obsessional behaviours for "healthy food", characterized by suppression of sugar and fat from her diet, tightly counted meal calorie content, eating only self-made meals, avoidance of eating in public, unacceptance of other person's opinions on diet, social isolation and a weight loss of 15 kg (body mass index of 16.2 kg/m2). A score of 19-points was initially obtained on the ORTO-15 questionnaire, suggesting the presence of orthorexic tendencies and behaviours. The patient also reported a 1-month history of depressed mood, anxiety, anhedonia, fatigue, insomnia with early morning waking, leading to the presumptive diagnosis of ON with comorbid depression. Treatment with mirtazapine for 11 months resulted in the remission of the disordered eating behaviour, a sustained regain of weight, a score of 41-points on the ORTO-15, and to the resolution of depressive symptomatology (including insomnia). To our knowledge, this is the first description of ON with comorbid depression successfully treated with mirtazapine. This case highlights the possible usefulness of mirtazapine as a treatment option for patients with ON. However, randomized controlled studies are warranted to confirm the current findings.


Assuntos
Antidepressivos/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Transtornos da Alimentação e da Ingestão de Alimentos/tratamento farmacológico , Mirtazapina/uso terapêutico , Adolescente , Transtorno Depressivo Maior/complicações , Transtorno Depressivo Maior/psicologia , Transtornos da Alimentação e da Ingestão de Alimentos/complicações , Transtornos da Alimentação e da Ingestão de Alimentos/psicologia , Feminino , Humanos
14.
Psychol Sci ; 30(11): 1625-1637, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31566081

RESUMO

Societal inequality has been found to harm the mental and physical health of its members and undermine overall social cohesion. Here, we tested the hypothesis that economic inequality is associated with a wish for a strong leader in a study involving 28 countries from five continents (Study 1, N = 6,112), a study involving an Australian community sample (Study 2, N = 515), and two experiments (Study 3a, N = 96; Study 3b, N = 296). We found correlational (Studies 1 and 2) and experimental (Studies 3a and 3b) evidence for our prediction that higher inequality enhances the wish for a strong leader. We also found that this relationship is mediated by perceptions of anomie, except in the case of objective inequality in Study 1. This suggests that societal inequality enhances the perception that society is breaking down (anomie) and that a strong leader is needed to restore order (even when that leader is willing to challenge democratic values).


Assuntos
Relações Interpessoais , Liderança , Sistemas Políticos , Fatores Socioeconômicos , Adolescente , Adulto , Anomia (Social) , Austrália , Feminino , Nível de Saúde , Humanos , Masculino , Adulto Jovem
15.
EMBO Rep ; 18(4): 549-557, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28274951

RESUMO

Cancer cells modulate their metabolic networks to support cell proliferation and a higher demand of building blocks. These changes may restrict the availability of certain amino acids for protein synthesis, which can be utilized for cancer therapy. However, little is known about the amino acid demand changes occurring during aggressive and invasive stages of cancer. Recently, we developed diricore, an approach based on ribosome profiling that can uncover amino acid limitations. Here, we applied diricore to a cellular model in which epithelial breast cells respond rapidly to TGFß1, a cytokine essential for cancer progression and metastasis, and uncovered shortage of leucine. Further analyses indicated that TGFß1 treatment of human breast epithelial cells reduces the expression of SLC3A2, a subunit of the leucine transporter, which diminishes leucine uptake and inhibits cell proliferation. Thus, we identified a specific amino acid limitation associated with the TGFß1 response, a vulnerability that might be associated with aggressiveness in cancer.


Assuntos
Códon , Leucina/genética , Leucina/metabolismo , Biossíntese de Proteínas , Ribossomos/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Feminino , Cadeia Pesada da Proteína-1 Reguladora de Fusão/genética , Cadeia Pesada da Proteína-1 Reguladora de Fusão/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Biossíntese de Proteínas/efeitos dos fármacos , Transdução de Sinais , Fator de Crescimento Transformador beta1/farmacologia
16.
EMBO Rep ; 16(12): 1723-36, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26538417

RESUMO

c-Myc is one of the major human proto-oncogenes and is often associated with tumor aggression and poor clinical outcome. Paradoxically, Myc was also reported as a suppressor of cell motility, invasiveness, and metastasis. Among the direct targets of Myc are many components of the protein synthesis machinery whose induction results in an overall increase in protein synthesis that empowers tumor cell growth. At present, it is largely unknown whether beyond the global enhancement of protein synthesis, Myc activation results in translation modulation of specific genes. Here, we measured Myc-induced global changes in gene expression at the transcription, translation, and protein levels and uncovered extensive transcript-specific regulation of protein translation. Particularly, we detected a broad coordination between regulation of transcription and translation upon modulation of Myc activity and showed the connection of these responses to mTOR signaling to enhance oncogenic transformation and to the TGFß pathway to modulate cell migration and invasiveness. Our results elucidate novel facets of Myc-induced cellular responses and provide a more comprehensive view of the consequences of its activation in cancer cells.


Assuntos
Transformação Celular Neoplásica/genética , Regulação Neoplásica da Expressão Gênica , Invasividade Neoplásica , Metástase Neoplásica/genética , Neoplasias/genética , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Apoptose , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células , Perfilação da Expressão Gênica , Genes myc , Humanos , Biossíntese de Proteínas , Transdução de Sinais , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo
17.
Pharm Res ; 32(1): 91-102, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25037861

RESUMO

PURPOSE: A strategy not usually used to improve carrier-mediated delivery of therapeutic enzymes is the attachment of the enzymes to the outer surface of liposomes. The aim of our work was to design a new type of enzymosomes with a sufficient surface-exposed enzyme load while preserving the structural integrity of the liposomal particles and activity of the enzyme. METHODS: The therapeutic antioxidant enzyme superoxide dismutase (SOD) was covalently attached to the distal terminus of polyethylene glycol (PEG) polymer chains, located at the surface of lipid vesicles, to obtain SOD-enzymosomes. RESULTS: The in vivo fate of the optimized SOD-enzymosomes showed that SOD attachment at the end of the activated PEG slightly reduced the residence time of the liposome particles in the bloodstream after IV administration. The biodistribution studies showed that SOD-enzymosomes had a similar organ distribution profile to liposomes with SOD encapsulated in their aqueous interior (SOD-liposomes). SOD-enzymosomes showed earlier therapeutic activity than both SOD-liposomes and free SOD in rat adjuvant arthritis. SOD-enzymosomes, unlike SOD-liposomes, have a therapeutic effect, decreasing liver damage in a rat liver ischemia/reperfusion model. CONCLUSIONS: SOD-enzymosomes were shown to be a new and successful therapeutic approach to oxidative stress-associated inflammatory situations/diseases.


Assuntos
Portadores de Fármacos/química , Polietilenoglicóis/química , Superóxido Dismutase/administração & dosagem , Superóxido Dismutase/uso terapêutico , Animais , Artrite Experimental/tratamento farmacológico , Artrite Experimental/metabolismo , Composição de Medicamentos , Liberação Controlada de Fármacos , Lipossomos , Fígado/irrigação sanguínea , Masculino , Estresse Oxidativo/efeitos dos fármacos , Tamanho da Partícula , Ratos Wistar , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/metabolismo , Superóxido Dismutase/farmacocinética , Propriedades de Superfície , Distribuição Tecidual , Resultado do Tratamento
18.
Biochemistry ; 53(24): 3867-78, 2014 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-24866928

RESUMO

The small GTPase Ras is an essential component of signal transduction pathways within the cell, controlling proliferation, differentiation, and apoptosis. Only in the GTP-bound form does Ras interact strongly with effector molecules such as Raf-kinase, thus acting as a molecular switch. In the GTP-bound form, Ras exists in a dynamic equilibrium between at least two distinct conformational states, 1(T) and 2(T), offering different functional properties of the protein. Zn2+-cyclen is a typical state 1(T) inhibitor; i.e., it interacts selectively with Ras in conformational state 1(T), a weak effector binding state. Here we report that active K-Ras4B, which is prominently found to be mutated in human tumors, exhibits a dynamic equilibrium like H-Ras, which can be modulated by Zn2+-cyclen. The titration experiments of Ras with Zn2+-cyclen indicate a cooperatively coupled binding of the ligands to the two interaction sites on Ras that could be identified for H-Ras previously. Our data further indicate that as in state 2(T) where induced fit produces the substate 2(T)* after effector binding, a corresponding substate 1(T)* can be detected at the state 1(T) mutant Ras(T35A). The interaction of Zn2+-cyclen with Ras not only shifts the equilibrium toward the weak effector binding state 1(T) but also perturbs the formation of substate 1(T)*, thus enhancing the inhibitory effect. Although Zn2+-cyclen shows an affinity for Ras in only the millimolar range, its potency of inhibition corresponds to a competitive state 2 inhibitor with micromolar binding affinity. Thus, the results demonstrate the mode of action and potency of this class of allosteric Ras inhibitors.


Assuntos
Complexos de Coordenação/farmacologia , Compostos Heterocíclicos com 1 Anel/farmacologia , Proteínas ras/antagonistas & inibidores , Ciclamos , Guanosina Trifosfato/metabolismo , Compostos Heterocíclicos/farmacologia , Humanos , Ligantes , Modelos Moleculares , Ressonância Magnética Nuclear Biomolecular , Ligação Proteica , Conformação Proteica , Quinases raf/metabolismo , Proteínas ras/química , Proteínas ras/genética , Proteínas ras/metabolismo
19.
Eat Weight Disord ; 19(1): 125-31, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23888402

RESUMO

Choking phobia, also known as phagophobia or swallowing phobia is an uncommon clinical entity that has been underappreciated and is included in the new DSM-5 and upcoming ICD-11 diagnostic category of avoidant/restrictive food intake disorder. Phenomenologically distinct from other eating disorders, it is characterized by the phobic stimulus of swallowing that results in the avoidance of food or drinks, and ultimately to low weight, social withdrawal, anxiety and depression states. Its prevalence and long-term course on the general population still needs to be determined, probably reflecting years of indefiniteness regarding its nosology and by the absence of a clear set of diagnostic criteria. We present a clinical case of choking phobia in a 32-year-old male patient after an episode of choke when eating chicken. An early diagnosis and distinction from other eating disorders is important for proper treatment and fundamental for prognosis. We also make a thorough revision on literature in clinical features, differential diagnosis and treatment approaches, suggesting a conceptual approach for choking phobia as a clinical spectrum settled by different degrees of phobic subtypes, which may depend on a varied number of clinical variables.


Assuntos
Obstrução das Vias Respiratórias/psicologia , Transtornos Fóbicos/terapia , Adulto , Ansiolíticos/uso terapêutico , Ansiedade/tratamento farmacológico , Terapia Cognitivo-Comportamental , Humanos , Masculino , Transtornos Fóbicos/tratamento farmacológico
20.
Int J Psychol ; 49(6): 508-12, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25355674

RESUMO

The current work sought to test the moderating role of a multicultural ideology on the relationship between categorisation salience and ingroup bias. Accordingly, in one experimental study, we manipulated categorisation salience and the accessibility of a multicultural ideology, and measured intergroup attitudes. Results show that categorisation salience only leads to ingroup bias when a multiculturalism (MC) ideology is not made salient. Thus, MC ideology attenuates the negative effects of categorisation salience on ingroup bias. These results pertain to social psychology in general showing that the cognitive processes should be construed within the framework of ideological contexts.


Assuntos
Atitude , Diversidade Cultural , Adulto , Feminino , Processos Grupais , Humanos , Masculino , Preconceito , Inquéritos e Questionários
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