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Biomedical subjects

S Coutinho

Publications and source records attributed to S Coutinho.

14 recordsLinked to original sources
PubMed2001

Dynamics of HIV infection: a cellular automata approach.

We use a cellular automata model to study the evolution of human immunodeficiency virus (HIV) infection and the onset of acquired immunodeficiency syndrome (AIDS). The model takes into account the global features of the immune response to any pathogen, the fast mutation rate of the HIV, and a fair amount of spatial localization, which may occur in the lymph nodes. Our results reproduce the three-phase pattern observed in T cell and virus counts of infected patients, namely, the primary response, the clinical latency period, and the onset of AIDS. The dynamics of real experimental data is related to the transient behavior of our model and not to its steady state. We have also found that the infected cells organize themselves into spatial structures, which are responsible for the decrease on the concentration of uninfected cells, leading to AIDS.

Cell Death↗
PubMed2001

Grb4/Nckbeta acts as a nuclear repressor of v-Abl-induced transcription from c-jun/c-fos promoter elements.

Grb4 is an adaptor protein consisting of three src homology (SH) 3 domains and a single SH2 domain. We previously cloned Grb4 as a direct interacting partner of Bcr-Abl and v-Abl via the Grb4 SH2 domain. We now show that overexpression of Grb4 results in significant inhibition of v-Abl-induced transcriptional activation from promitogenic enhancer elements such as activator protein 1 (AP-1) and serum-responsive element (SRE). We demonstrate that the inhibitory activity of Grb4 is independent of the direct interaction of v-Abl and Grb4: a Grb4 mutant that lacks a functional SH2 domain shows an even more pronounced inhibition of AP-1/SRE. Further mutational analysis revealed that the first two SH3 domains primarily mediate the inhibitory function. The inhibitory activity of Grb4 is specific for c-jun/c-fos-regulated promoter elements and is located downstream of MEKK1 and JNK because co-expression of Grb4 resulted in down-regulation of MEKK1-induced AP-1 activity without affecting JNK activity. Thus, the nuclear pool of Grb4 is likely to mediate this inhibition. Indeed, cell fractionation and fluorescence microscopy studies revealed that the stronger inhibitory potential of the Grb4 SH2 mutant occurred in conjunction with increased nuclear localization of this mutant. Our results suggest a novel role for Grb4 in the inhibition of promitogenic enhancer elements such as 12-O-tetradecanoylphorbol-13-acetate-responsive element and SRE.

3T3 Cells↗
PubMed2000

Characterization of Ggrb4, an adapter protein interacting with Bcr-Abl.

We report here the characterization of an adapter protein identified in a yeast 2-hybrid screen with the use of Bcr-Abl as the bait. Grb4 bound to Bcr-Abl in a variety of systems, both in vitro and in vivo, and is an excellent substrate of the Bcr-Abl tyrosine kinase. The association of Grb4 and Bcr-Abl in intact cells was mediated by an src homology (SH)2-mediated phosphotyrosine-dependent interaction as well as an SH3-mediated phosphotyrosine-independent interaction. Grb4 has 68% homology to the adapter protein Nck and has similar but distinct binding specificities in K562 lysates. Subcellular localization studies indicate that Grb4 localizes to both the nucleus and the cytoplasm. Coexpression of kinase-active Bcr-Abl with Grb4 resulted in the translocation of Grb4 from the cytoplasm and the nucleus to the cytoskeleton to colocalize with Bcr-Abl. In addition, expression of Grb4 with kinase-active Bcr-Abl resulted in a redistribution of actin-associated Bcr-Abl. Finally, coexpression of Grb4 and oncogenic v-Abl strongly inhibited v-Abl-induced AP-1 activation. Together, these data indicate that Grb4 in conjunction with Bcr-Abl may be capable of modulating the cytoskeletal structure and negatively interfering with the signaling of oncogenic Abl kinases. Grb4 may therefore play a role in the molecular pathogenesis of chronic myelogenous leukemia. (Blood. 2000;96:618-624) (Blood. 2000;96:618-624)

Adaptor Proteins, Signal Transducing↗
PubMed1999

Ground-state degeneracies of Ising spin glasses on diamond hierarchical lattices.

The total number of ground states for short-range Ising spin glasses, defined on diamond hierarchical lattices of fractal dimensions d=2, 3, 4, 5, and 2.58, is estimated by means of analytic calculations (three last hierarchy levels of the d=2 lattice) and numerical simulations (lower hierarchies for d=2 and all remaining cases). It is shown that in the case of continuous probability distributions for the couplings, the number of ground states is finite in the thermodynamic limit. However, for a bimodal probability distribution (+/-J with probabilities p and 1-p, respectively), the average number of ground states is maximum for a wide range of values of p around p=1 / 2 and depends on the total number of sites at hierarchy level n, Nn. In this case, for all lattices investigated, it is shown that the ground-state degeneracy behaves like exp[h(d)Nn], in the limit Nn large, where h(d) is a positive number which depends on the lattice fractal dimension. The probability of finding frustrated cells at a given hierarchy level n, Fn(p), is calculated analytically (three last hierarchy levels for d=2 and the last hierarchy of the d=3 lattice, with 0 >1, only the last hierarchies contribute significantly to the ground-state degeneracy; such a dominant behavior becomes stronger for high fractal dimensions. The exponential increase of the number of ground states with the total number of sites is in agreement with the mean-field picture of spin glasses.

Journal Article↗
PubMed1998

[Radiotherapy-induced pemphigus].

The authors report the clinical case of a woman exposed to ionizing radiotherapy, for the treatment of breast carcinoma, in whom a pemphigus lesion developed within the area of irradiation. This is, to the authors' knowledge, the 14th case of ionizing radiation-induced pemphigus.

Aged↗
PubMed1997

Infection of human marrow stroma by human immunodeficiency virus-1 (HIV-1) is both required and sufficient for HIV-1-induced hematopoietic suppression in vitro: demonstration by gene modification of primary human stroma.

Patients with human immunodeficiency virus-1 (HIV-1) infection often present with bone marrow (BM) failure that may affect all hematopoietic lineages. It is presently unclear whether this failure reflects a direct viral impairment of the CD34+ hematopoietic progenitor cells or whether the virus affects the BM microenvironment. To study the effects of HIV-1 on the BM microenvironment, we examined the stromal cell monolayers in long-term BM culture (LTBMC), which are the in vitro equivalent of the hematopoietic microenvironment. We assessed the hematopoietic support function (HSF) of human stromal layers by determining the cellular proliferation and colony-forming ability of hematopoietic progenitors from BM cells grown on the stromal layers. We show that the HSF is reduced by in vitro infection of the human stromal cell layer by a monocytotropic isolate of HIV-1 (JR-FL). There is no loss of HSF when the stromal cell layer is resistant to HIV-1 replication, either using murine stromal cell layers that are innately resistant to HIV-1 infection or using human stromal cells genetically modified to express a gene that inhibits HIV-1 replication (an RRE decoy). Decreased HSF was seen using either human or murine hematopoietic cells, if the stromal cells were human cells that were susceptible to HIV-1 infection. These in vitro studies implicate HIV-1 replication in the stroma as the essential component causing decreased hematopoietic cell production in HIV-1 infection.

Bone Marrow↗
PubMed1993

Relationships between mandibular canine calcification stages and skeletal maturity.

Hand wrist radiographs and dental panoramic radiographs of 200 boys and 215 girls were assessed to determine the relationship between the developmental stages of the mandibular canine and skeletal maturity indicators of the pubertal growth spurt. Chi-square and Kendall's tau statistics demonstrated significant (P < 0.001) relationships between skeletal maturity indicators. Associations between canine development and skeletal maturity ranged from 0.53 to 0.85. Most children having attained canine stage G showed the presence of the adductor sesamoid (81%), capping of the diaphysis of the third middle phalanx (77%), and capping of the fifth proximal phalanx (87%). Growth reference data for American children suggest that stage G occurred approximately 0.4 years and 1.3 years before peak height velocity for girls and boys, respectively. It is indicated that canine calcification could serve as a useful tool for evaluating childrens' skeletal maturation and, by association, somatic maturity.

Adolescent↗
PubMed1984

Inhibitory effects of salicylate on contractility in skeletal muscle.

Salicylate (1-5 mM) had no effect on the peak amplitude (Pt) of twitches elicited at 0.05 to 0.05 Hz, but depressed the Pt in frog and toad "toe" muscles stimulated at 5 to 10 Hz. The maximal tetanic tension (Po) was not reduced significantly by salicylate, but the time to reach Po was increased to several seconds. K-induced contractures were reduced by ca 40 and 50%, respectively, in the presence of 5 and 10 mM salicylate. Pretreatment with salicylate (5 mM) reduced the twitch potentiation by quinine, shortened the duration of twitches in caffeine-treated muscles and inhibited the caffeine- and the quinine-induced contractures. Muscles in contracture because of a previous exposure to quinine relaxed promptly upon addition of salicylate to the bathing medium. The inhibitory effects of salicylate on Pt, on Po and on K- or drug-induced contractures were reversible and were not affected by changes in pH between 7.5 and 6.5. Salicylate depressed the caffeine-rapid cooling contractures (RCC). In toad muscles, this effect was affected markedly by the order in which caffeine and salicylate were applied. Blockade of the caffeine-RCC by salicylate was enhanced by lowering the pH of the medium. Salicylamide (1-5 mM) reproduced the effects of salicylate on the caffeine- and the quinine-induced contractures and the caffeine-RCC. In addition, salicylamide reduced the twitch tension. It is proposed that salicylate and salicylamide affect Casequestration by the sarcoplasmic reticulum.

Animals↗
PubMed1982

Effects of hypertonicity on frog muscle contractures induced by quinine.

1. Frog sartorius and extensor longus digiti ("toe") muscles were used to investigate the effects of solutions of two (2T) and three (3T) times normal tonicity on the contractures elicited by quinine or by high-[K]O media, and on twitch and tetanic tension. 2. Solution 2T had no effect on the peak amplitude of quinine-induced contractures (PQ) of toe muscle but increased the PQ of sartorius muscle. Toe muscle PQ was significantly reduced by 3T. The quinine-induced contractures of sartorii bathed in 3T were slower than, but reached peak values not significantly different from, those obtained with control Ringer solution (1T). 3. The twitch and tetanic contractions of both sartorius and toe muscles were partially or totally blocked by 2T and were always abolished by solution 3T. 4. The maximal amplitude of K+-induced contractures (PK) of toe muscle was significantly reduced, but not abolished, by solutions 2T and 3T. The PK of sartorius muscle was greater at 2T than at 1T, but, in contrast to the transient tension recorded for 1T, the K+-induced contracture in solution 2T had a prolonged plateau. 5. The results suggest that hypertonicity affects the contractile apparatus as well as the excitation-contraction coupling process. The enhancement of quinine- and K+-induced contractures is ascribed to inhibitory effects of hypertonicity on Ca2+-sequestration by the sarcoplasmic reticulum.

Action Potentials↗