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"Fathers" and "sons" of theories in cell physiology: the membrane theory.

The last 50 years in the history of life sciences are remarkable for a new important feature that looks as a great threat for their future. A profound specialization dominating in quickly developing fields of science causes a crisis of the scientific method. The essence of the method is a unity of two elements, the experimental data and the theory that explains them. To us, "fathers" of science, classically, were the creators of new ideas and theories. They were the true experts of their own theories. It is only they who have the right to say: "I am the theory". In other words, they were carriers of theories, of the theoretical knowledge. The fathers provided the necessary logical integrity to their theories, since theories in biology have still to be based on strict mathematical proofs. It is not true for sons. As a result of massive specialization, modern experts operate in very confined close spaces. They formulate particular rules far from the level of theory. The main theories of science are known to them only at the textbook level. Nowadays, nobody can say: "I am the theory". With whom, then is it possible to discuss today on a broader theoretical level? How can a classical theory--for example, the membrane one--be changed or even disproved under these conditions? How can the "sons" with their narrow education catch sight of membrane theory defects? As a result, "global" theories have few critics and control. Due to specialization, we have lost the ability to work at the experimental level of biology within the correct or appropriate theoretical context. The scientific method in its classic form is now being rapidly eroded. A good case can be made for "Membrane Theory", to which we will largely refer throughout this article.

Animals↗

A 10-year follow-up of sons of alcoholics: preliminary results.

Since 1977, 237 sons of alcoholic fathers and 237 controls (474 men) have been studied in our laboratory. At the time of initial evaluation, and at an average age of approximately 21 years, the sons of alcoholics demonstrated a diminished response to alcohol as measured by their subjective feelings, levels of body sway, electrophysiological functioning, and changes in 3 hormones. This paper presents the preliminary findings of a 10-year follow-up carried out in an attempt to determine whether the combination of family history status and the intensity of reaction to alcohol at age 21 predicted the likelihood of developing severe and repetitive alcohol life problems over the subsequent decade.

Adult↗

[Analysis of dysanapsis in healthy twins and sons of patients with chronic obstructive lung disease].

Pulmonary function tests and tracheal cross-sectional area (X-SA) measured on chest roentgenograms were analyzed in 72 healthy pairs of twins and in 34 healthy sons of patients with chronic obstructive lung disease. In the twin study, genetic influence was positive on most pulmonary function tests, including VC, FEV1/FVC, V25, but not so on X-SA. The ratio of X-SA to VC, which represents dysanapsis, had no relation to sex nor height. However, the ratio of X-SA/VC showed marked sex-associated differences, when expressed as a function of VC, and had a negative correlation with VC both in men and women. The ratio of X-SA/VC was significantly lower in sons of patients with COPD than in normal controls, which was caused by significantly larger VC in the former group. The relatively low ratio of tracheal size to lung size may partly explain the susceptibility to the possible future development of COPD in those subjects.

Adolescent↗

Evaluation of EEG alpha activity in sons of alcoholics.

The results of computer-analyzed electroencephalographic (EEG) data from 24 sons of alcoholics (family history positive [FHP]) and their matched controls (family history negative [FHN]) were compared before and 90 minutes following alcohol and placebo challenge. Blind analysis of the data revealed that FHP men had more energy in the fast-frequency alpha range (9 to 12 Hz) of their EEG than did FHN subjects at baseline. EEG response to ethanol was also found to differ between the two groups. FHN but not FHP subjects evidenced a decrease in fast-frequency alpha energy following ethanol challenge. These data support other evidence of a less intense reaction to ethanol in FHPs as measured by subjective response, body sway, and hormone levels. In addition, these findings suggest that certain normal alpha wave variants may be more common in sons of alcoholics.

Adult↗

[HIV infection caused by nursing care? HIV infection in the mother of a son with AIDS].

The case of a 78-year-old woman with a 2-year history of chronic persistent oral candidiasis, in whom an HIV infection (stage III, Frankfurt Classification according to Brodt, stage 6 Walter Reed Staging Classification, stage IV WHO Classification, manifest AIDS according to the new 1988 Classification) was diagnosed, is reported. The 44-year-old son (since deceased) of the patient was known to have had the acquired immune deficiency syndrome since December, 1986. Transmission of HIV from son to mother seems likely.

Acquired Immunodeficiency Syndrome↗

[Tetralogy of Fallot in a father and son].

A family is reported on, in which the tetralogy of Fallot is present in the father and the eldest son. In both the patients a total correction took place. The mother and the second son are healthy.

Adolescent↗

Preference for sons, family size, and sex ratio: an empirical study in Korea.

This study investigates the effects of son preference on sex ratio and fertility at the family level, utilizing World Fertility Survey data for Korea, whose population is known to have a strong preference for sons and a fairly high level of contraceptive use. The sex ratio (number of males per 100 females) of siblings in small families is considerably higher than in large families. The sex ratio of last-born children in families of any size is markedly higher than that of the previous children. The sex distribution of children for a given family size, if less than five, deviates significantly from the Bernoulli sequence. The observed frequency of all-girl families is especially small in comparison with the expected value. The sex of the last child strongly influences couples' decision making regarding additional births in all steps of family building except for bearing a second child. In increasing their families to moderate size, parents appear to take into consideration the sex distribution of all earlier births.

Adult↗

A contextual model of stress among parent caregivers of gay sons with AIDS.

This paper examines the impact of AIDS on the parent/adult child relationship among parent caregivers of gay sons with AIDS. Drawing on literature on family caregiving of older people and research on parents of gay sons with AIDS, the theoretical concepts of family ethos of affection/obligation, attitudes toward homosexuality, and stress are reviewed. Based on these key theoretical concepts and linkages, a model is developed that suggests the family characteristics that differentiate low-stressed parent caregivers and high-stressed parent caregivers. A case study is presented to illustrate the model. Recommendations for research and implications for professionals are discussed.

Acquired Immunodeficiency Syndrome↗

Oxytocin neurones in the supraoptic nucleus (SON) are inhibited by endogenous opioids in late pregnant rats.

Late pregnant rats exhibit endogenous opioid restraint of oxytocin cells since i.v. naloxone (NLX opioid antagonist) increases oxytocin (OXT) secretion but OXT nerve terminals become desensitised to opioids. We have studied central opioid inhibition of OXT neurones in late pregnancy by measuring SON OXT neurones firing rate, immediate early gene (Fos) expression and dendritic OXT release under the influence of NLX On day 21 of pregnancy NLX strongly potentiated cholecystokinin (CCK) excitation of OXT neurones increased Fos protein expression and increased intranuclear release of OXT in the SON; NLX was ineffective in virgin rats. The data indicate central endogenous opioid inhibition of OXT neurone activity in late pregnancy which may restrain premature OXT release.

Animals↗

Craniofrontonasal dysplasia: more severe expression in the mother than in her son.

Craniofrontonasal dysplasia: more severe expression in the mother than in her son: We report a family with craniofrontonasal dysplasia in a mother and her son. In addition to the typical clinical features, the present case report further illustrates two sofar unexplained observations in craniofrontonasal dysplasia: a more severe clinical expression in females and an increased incidence of miscarriages.

Abnormalities, Multiple↗

Economic hardship, family relationships, and adolescent distress: an evaluation of a stress-distress mediation model in mother-daughter and mother-son dyads.

This study evaluated a stress-distress mediation model of the relationships among economic hardship, maternal financial strain, maternal marital happiness, the parent-child relationships, and adolescent distress in a group of 188 sixth and 210 eighth graders and their mothers. The model predicted that economic hardship would increase maternal financial strain which was predicted to lead to more distress in the adolescent children by decreasing the mothers' marital happiness and the quality of the mother-child relationship. Separate latent variable path analyses with partial least squares (LVPLS) were conducted for the mother-daughter and the mother-son dyads. The results supported the hypothesized paths between economic hardship, mothers' financial strain, the mother-child relationship, and adolescent distress in both the mother-daughter and mother-son dyads.

Adolescent↗

Familial neuronal migration disorder: subcortical laminar heterotopia in a mother and pachygyria in the son.

We describe clinical manifestations and magnetic resonance imaging (MRI) findings in a man and his mother who were diagnosed as having a neuronal migration disorder. The son had severe psychomotor retardation and the mother had intractable seizures and mild psychomotor retardation. MRI demonstrated moderate pachygyria in the son and subcortical heterotopia in the mother. In both patients, the frontal parts of the brain were characteristically more affected than any other areas. A dominant pattern of inheritance in the family suggests a genetic role in the underlying cause of the migration disorder. The difference in severity between the two patients also suggests an X-linked dominant inheritance. Our family fits the condition of X-linked lissencephaly.

Adult↗

New class of Son-of-sevenless (Sos) alleles highlights the complexities of Sos function.

The guanine nucleotide exchange factor (GEF) Son-of-sevenless (Sos) encodes a complex multidomain protein best known for its role in activating the small GTPase RAS in response to receptor tyrosine kinase (RTK) stimulation. Much less well understood is SOS's role in modulating RAC activity via a separate GEF domain. In the course of a genetic modifier screen designed to investigate the complexities of RTK/RAS signal transduction, a complementation group of 11 alleles was isolated and mapped to the Sos locus. Molecular characterization of these alleles indicates that they specifically affect individual domains of the protein. One of these alleles, SosM98, which contains a single amino acid substitution in the RacGEF motif, functions as a dominant negative in vivo to downregulate RTK signaling. These alleles provide new tools for future investigations of SOS-mediated activation of both RAS and RAC and how these dual roles are coordinated and coregulated during development.

Alleles↗

Structural analysis of autoinhibition in the Ras activator Son of sevenless.

The classical model for the activation of the nucleotide exchange factor Son of sevenless (SOS) involves its recruitment to the membrane, where it engages Ras. The recent discovery that Ras*GTP is an allosteric activator of SOS indicated that the regulation of SOS is more complex than originally envisaged. We now present crystallographic and biochemical analyses of a construct of SOS that contains the Dbl homology-pleckstrin homology (DH-PH) and catalytic domains and show that the DH-PH unit blocks the allosteric binding site for Ras and suppresses the activity of SOS. SOS is dependent on Ras binding to the allosteric site for both a lower level of activity, which is a result of Ras*GDP binding, and maximal activity, which requires Ras*GTP. The action of the DH-PH unit gates a reciprocal interaction between Ras and SOS, in which Ras converts SOS from low to high activity forms as Ras*GDP is converted to Ras*GTP by SOS.

Allosteric Site↗

Son of sevenless directly links the Robo receptor to rac activation to control axon repulsion at the midline.

Son of sevenless (Sos) is a dual specificity guanine nucleotide exchange factor (GEF) that regulates both Ras and Rho family GTPases and thus is uniquely poised to integrate signals that affect both gene expression and cytoskeletal reorganization. Here, using genetics, biochemistry, and cell biology, we demonstrate that Sos is recruited to the plasma membrane, where it forms a ternary complex with the Roundabout receptor and the SH3-SH2 adaptor protein Dreadlocks (Dock) to regulate Rac-dependent cytoskeletal rearrangement in response to the Slit ligand. Intriguingly, the Ras and Rac-GEF activities of Sos can be uncoupled during Robo-mediated axon repulsion; Sos axon guidance function depends on its Rac-GEF activity, but not its Ras-GEF activity. These results provide in vivo evidence that the Ras and RhoGEF domains of Sos are separable signaling modules and support a model in which Robo recruits Sos to the membrane via Dock to activate Rac during midline repulsion.

Adaptor Proteins, Signal Transducing↗

Tandem histone folds in the structure of the N-terminal segment of the ras activator Son of Sevenless.

The Ras activator Son of Sevenless (Sos) contains a Cdc25 homology domain, responsible for nucleotide exchange, as well as Dbl/Pleckstrin homology (DH/PH) domains. We have determined the crystal structure of the N-terminal segment of human Sos1 (residues 1-191) and show that it contains two tandem histone folds. While the N-terminal domain is monomeric in solution, its structure is surprisingly similar to that of histone dimers, with both subunits of the histone "dimer" being part of the same peptide chain. One histone fold corresponds to the region of Sos that is clearly similar in sequence to histones (residues 91-191), whereas the other is formed by residues in Sos (1-90) that are unrelated in sequence to histones. Residues that form a contiguous patch on the surface of the histone domain of Sos are conserved from C. elegans to humans, suggesting a potential role for this domain in protein-protein interactions.

Amino Acid Sequence↗

Activation of Ras and its downstream extracellular signal-regulated protein kinases by the CDC25 homology domain of mouse Son-of-sevenless 1 (mSos1).

A fragment consisting of residues 584-1071 of the mouse Son-of-sevenless 1 (mSos1) protein was found to be sufficient for stimulation of the guanine nucleotide exchange of Ras in vitro, which defines the CDC25 homology (CDC25H) domain of mSos1. Furthermore, we found that the CDC25H-domain fragment activated the extracellular signal-regulated protein kinases (ERKs), and was mainly membrane localized, when expressed in unstimulated human embryonic kidney 293 cells. Then, we examined the roles of other mSos1 domains in autoinhibition of the CDC25H-domain functions in unstimulated cellular environments. First, longer fragments that have the CDC25H domain and the following proline-rich Grb2-binding domain exhibited negligible membrane localization, and accordingly much lower ERK-activation activities, under serum-starved conditions. On the other hand, the preceding Pleckstrin-homology (PH) domain affects neither the ERK-activation activity nor the membrane-localization activity of the CDC25H domain. By contrast, the cells expressing a fragment containing the Dbl homology (DH) domain in addition to the PH and CDC25H domains exhibited remarkably low ERK activities under serum-starved conditions. This autoinhibitory effect of the DH domain on the CDC25H-domain function was shown to be relieved when cells were stimulated with epidermal growth factor. The DH-domain extension affected neither the in vitro guanine nucleotide exchange activity nor the membrane-localization activity of the CDC25H domain. Therefore, one of the roles of the DH domain is to exert an autoinhibition over the CDC25H-domain function on the cell membrane, in the absence, but not in the presence, of extracellular stimuli.

Animals↗