Gabriela Sánchez-Mejorada

Signal transduction by immunoglobulin Fc receptors.

Receptors for the Fc portion of immunoglobulin molecules (FcR) present on leukocyte cell membranes mediate a large number of cellular responses that are very important in host defense. Cross‐linking of FcR by immune complexes leads to functions such as phagocytosis, cell cytotoxicity, production and secretion of inflammatory mediators, and modulation of the immune response. Molecular characterization of FcRs indicates the existence of several types of these receptors, which seem to be redundant in their cell distribution and function. There is a great deal of interest in understanding how these various receptors signal the cell to respond in different ways during inflammation and the immune response. Previous studies indicate that FcR signaling shares elements with the T and B cell antigen receptors. Signaling is initiated in all of them by activation of tyrosine kinases of the Src and ZAP‐70 families. Subsequent events, which vary depending on the cell type and receptor involved, include activation of other enzymes such as phospholipase Cγ1, phosphatidylinositol‐3‐kinase, and mitogen‐activated protein kinase. Several recent lines of research, including studies of phagocytosis by FcR‐transfected cells, antibody‐dependent cytotoxicity by natural killer cells, mast cell degranulation, and FcR‐deficient mice, have given us new insights on the signal transduction pathways activated by FcRs. This review describes the advances in these areas and presents a general model for FcR‐mediated signaling. J. Leukoc. Biol. 63: 521–533; 1998.

FCGAMMA RECEPTOR-MEDIATED MITOGEN-ACTIVATED PROTEIN KINASE ACTIVATION IN MONOCYTES IS INDEPENDENT OF RAS

Receptors for the Fc portion of immunoglobulin molecules (FcR) present on leukocyte cell membranes mediate a large number of cellular responses that are very important in host defense, including phagocytosis, cell cytotoxicity, production and secretion of inflammatory mediators, and modulation of the immune response. Cross-linking of FcR with immune complexes leads, first to activation of protein-tyrosine kinases. The molecular events that follow and that transduce signals from these receptors to the nucleus are still poorly defined. We have investigated the signal transduction pathway from Fc receptors that leads to gene activation and production of cytokines in monocytes. Cross-linking of FcR, on the THP-1 monocytic cell line, by immune complexes resulted in both activation of the transcription factor NF-κB and interleukin 1 production. These responses were completely blocked by tyrosine kinase inhibitors. In contrast, expression of dominant negative mutants of Ras and Raf-1, in these cells, did not have any effect on FcR-mediated nuclear factor activation, suggesting that the mitogen-activated protein kinase (MAPK) signaling pathway was not used by these receptors. However, MAPK activation was easily detected by in vitro kinase assays, after FcR cross-linking with immune complexes. Using the specific MAPK/extracellular signal-regulated kinase kinase (MAPK kinase) inhibitor PD98059, we found that MAPK activation is necessary for FcR-dependent activation of the nuclear factor NF-κB. These results strongly suggest that the signaling pathway from Fc receptors leading to expression of different genes important to leukocyte biology, initiates with tyrosine kinases and requires MAPK activation; but in contrast to other tyrosine kinase receptors, FcR-mediated MAPK activation does not involve Ras and Raf.

Phosphatidylinositol 3‐kinase and ERK are required for NF‐κB activation but not for phagocytosis

The molecular events that transduce signals from Fc receptors to the various cellular responses are still poorly defined. We have investigated the role of phosphatidylinositol 3‐kinase (PI 3‐K) and extracellular signal‐regulated kinase (ERK) in gene activation and phagocytosis in monocytes. In the THP‐1 monocytic cell line, cross‐linking of Fc receptors by immune complexes results in activation of the transcription factor NF‐κB, via activation of ERK. Activation of both ERK and NF‐κB was blocked by wortmannin and LY294002, specific inhibitors of PI 3‐K. Wortmannin also inhibited the Fc receptor‐mediated increase in the cytosolic calcium concentration, but it did not block immunoglobulin G (IgG)‐mediated phagocytosis. In addition, the ERK inhibitor PD98059 did not block phagocytosis of IgG‐coated erythrocytes. Both the increase in the cytosolic calcium concentration and phagocytosis depend on an active actin cytoskeleton, as indicated by the total lack of both responses after treatment with cytochalasin B. In contrast, cytochalasin B did not affect Fc receptor‐mediated activation of NF‐κB. These results identify PI 3‐K and ERK as important signaling molecules in the Fc receptor signal transduction pathway of monocytes, which leads to the nucleus for gene activation. These results also suggest that, in contrast to other cell types, unstimulated monocytes do not require PI 3‐K and ERK for phagocytosis.

Discriminant function analysis for sex assessment in pelvic girdle bones: sample from the contemporary Mexican population.

Abstract:  Sex assessment of skeletal remains plays an important role in forensic anthropology. The pelvic bones are the most studied part of the postcranial skeleton for the assessment of sex. It is evident that a population‐specific approach improves rates of accuracy within the group. The present study proposes a discriminant function method for the sex assessment of skeletal remains from a contemporary Mexican population. A total of 146 adult human pelvic bones (61 females and 85 males) from the skeletal series pertaining to the National Autonomous University of Mexico were evaluated. Twenty‐four direct metrical parameters of coxal and sacral bones were measured and subsequently, sides and sex differences were evaluated, applying a stepwise discriminant function analysis. Coxal and sacra functions achieved accuracies of 99% and 87%, respectively. These analyses follow a population‐specific approach; nevertheless, we consider that our results are applicable to any other Hispanic samples for purposes of forensic human identification.

Comparison of methods to determine sex by evaluating the greater sciatic notch: Visual, angular and geometric morphometrics

Sex estimation is the first step for biological profile reconstruction of an unknown skeleton (archaeological or contemporary) and consequently for positive identification of skeletal remains recovered from forensic settings. Several tools have been developed using different osseous structures. With the intention to provide an objective method comparison, we reported the analysis of three different methods (visual, metric and geometric morphometrics) for sex assessment of the greater sciatic notch. One hundred and thirty pelvic bones (45.4% females and 54.6% males) from the National Autonomous University of Mexico Skeletal Collection pertaining to the contemporary Mexican population were analyzed. We used the ROC-analysis to test between desired false positive thresholds (1-specificity) and expected true positive rates (sensitivity) in order to predict the best approach to sex assessment. The comparison of the area under the ROC-curves shows significant differences among visual and metric methods. At the same time, the analysis suggested that higher morphological variation among the sexes is independent of the methodological approach. The results indicate that the metric (angle), with a high percent of indeterminate cases (34.6%), and visual, with 26.2% of the cases allocated as intermediate cases, were poorly accurate; we cannot recommend these techniques for sexing an unknown specimen. On the other hand, the geometric morphometrics approach improves sex estimation in 82.3% of correctly classified individuals with more than 95% of posterior probability. In addition to the method comparison, the major sexual variation of the greater sciatic notch was determined to be located on its posterior border.

Technical Note: Geometric Morphometrics and Sexual Dimorphism of the Greater Sciatic Notch in Adults From Two Skeletal Collections: The Accuracy and Reliability of Sex Classification

The greater sciatic notch (GSN) is one of the most important and frequently used characteristics for determining the sex of skeletons, but objective assessment of this characteristic is not without its difficulties. We tested the robustness of GSN sex classification on the basis of geometric morphometrics (GM) and support vector machines (SVM), using two different population samples. Using photographs, the shape of the GSN in 229 samples from two assemblages (documented collections of a Euroamerican population from the Maxwell Museum, University of New Mexico, and a Hispanic population from Universidad Nacional Autónoma de México, Mexico City) was segmented automatically and evaluated using six curve representations. The optimal dimensionality for each representation was determined by finding the best sex classification. The classification accuracy of the six curve representations in our study was similar but the highest and concurrently homologous cross-validated accuracy of 92% was achieved for a pooled sample using Fourier coefficient and Legendre polynomial methods. The success rate of our classification was influenced by the number of semilandmarks or coefficients and was only slightly affected by GSN marginal point positions. The intrapopulation variability of the female GSN shape was significantly lower compared with the male variability, possibly as a consequence of the intense selection pressure associated with reproduction. Males were misclassified more often than females. Our results show that by using a suitable GSN curve representation, a GM approach, and SVM analysis, it is possible to obtain a robust separation between the sexes that is stable for a multipopulation sample.

Age- and gender-related variations in morphometric characteristics of thoracic spine pedicle: A study of 4,800 pedicles.

Transpedicular spinal fusion is the most commonly used fixation technique for the surgical treatment of vertebral disorders. However, the instrumentation of the thoracic spine using this technique continues to be controversial. The objective of the present study was to determine the morphometric characteristics of the thoracic pedicle and to establish how these characteristics vary with gender and age. Two hundred thoracic spines (4800 thoracic pedicles) from individuals of known gender and age were analyzed (in accordance with the order of vertebrae). The spines were divided into six groups according to age and gender. The horizontal and vertical diameters of the thoracic pedicle were determined for each piece. The mean and standard deviation of each variable were determined, and differences between age groups for each gender were evaluated using parametric correlation tests. The pedicle diameters of men and women differed significantly for most groups (P < 0.05). The horizontal diameters decreased from T1 to T5 and increased up to T12. The vertical diameter followed a cephalocaudal pattern of development from T1‐T12. The pedicle diameters decreased with increasing age in women, while the opposite trend was observed in men. In men, the dimensions of the thoracic spine pedicle increase with increasing age; in women, they decrease. These differences should be taken into account when selecting the appropriate pedicle screw. Clin. Anat. 27:441–450, 2014.

FGFR1 signaling is associated with the magnitude of morphological integration in human head shape

The head can be used as a model to study complex phenotypes controlled simultaneously by morphological integration (MI) due to common factors, and modular patterns caused by local factors affecting the development and functional demands of specific structures. The fibroblast growth factor and receptor system (FGF/FGFR) participates in cell communication and pattern formation in osseous tissues, among others, and there is compelling evidence from mouse model studies suggesting a role of the FGF/FGFR pathway as a covariance‐generating signaling process in head development. Here we use human data to test if specific genetic variants of another gene of this pathway, the FGFR1 gene, can be associated with differences in the integration of the head.

Fibroblast Growth Factor Receptor 1 (FGFR1) Variants and Craniofacial Variation in Amerindians and Related Populations

The polymorphic site rs4647905 of the FGFR1 gene was previously associated with a decrease in cephalic index (CI). Here, we evaluate the relationships between genotypes and cephalometric measurements and indices in one Mexican Native and two mestizo Mexican populations using two haplotype‐tag SNPs (rs4647905 and rs3213849) that represent >85% of the FGFR1 variability, plus three other SNPs (rs2293971, rs2304000, and rs930828) situated nearby. In addition, we genotyped five South American natives, two European, one African, and one Siberian populations to evaluate their intra and intercontinental population diversity.

A new Morphological Classification of the Anterior Inferior Iliac Spine: Relevance in Subspine Hip Impingement

El Sindrome de Pinzamiento Femoroacetabular (PFA) es una entidad clinica reconocida en los ultimos anos como una causa de dolor y desarrollo de artrosis temprana de cadera. El pinzamiento subespinoso de la cadera se caracteriza por una espina iliaca anteroinferior (EIAI) prominente o con una morfologia anormal, lo que contribuye al desarrollo de un cuadro clinico similar al PFA. El objetivo fue proponer una nueva clasificacion morfologica de la EIAI y determinar las prevalencias de las distintas morfologias de la EIAI en base a la misma y correlacionarla con los distintos sexos y grupos de edad. La muestra consistio en un total de 458 hemipelvis, de sexo y edad conocidos (264 hombres y 194 mujeres). Cada pieza fue analizada para determinar la prevalencia de variaciones morfologicas de la EIAI en base a la clasificacion propuesta. Tipo 1: presencia de una superficie concava entre la EIAI y reborde acetabular, Tipo 2A: presencia de una superficie plana entre la EIAI y el reborde acetabular, Tipo 2B: presencia de una superficie convexa entre la EIAI y el reborde acetabular y Tipo 3: la EIAI protruye hacia el acetabulo anterior o inferiormente. Se determino una prevalencia de 69,87% para la EIAI Tipo 1 (320/458). En cuanto a las morfologias anormales, se determino una prevalencia de 17,90% (82/458), 3,71% (17/458) y 8,52% (39/459) para los Tipos 2A, 2B y 3, respectivamente. La prevalencia de una morfologia anormal en las EIAI de especimenes del sexo masculino fue de 30,30% (80/264) y en el sexo femenino 29,90% (58/194). Se evidencia la prevalencia de las diferentes morfologias que puede tener la EIAI; esta informacion sera de ayuda para determinar el papel de la EIAI en la aparicion del pinzamiento subespinoso de la cadera.