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PubMed2004

Autocrine/paracrine regulation of pituitary function by activin, inhibin and follistatin.

The precise regulation of the anterior pituitary is achieved by the cell-specific and combined actions of central, peripheral and local factors. Activins, inhibins, and follistatins were first discovered as gonadal factors with actions on FSH production from pituitary gonadotropes. With the realization that these factors are expressed in a wide array of tissues, including the pituitary, it became apparent that the functional importance of activins, inhibins, and follistatins extends beyond the reproductive axis and that they often exert their effects by autocrine/paracrine mechanisms. As members of the TGF-beta superfamily, activins and inhibins control and orchestrate many physiological processes and are vital for the development, the growth, and the functional integrity of most tissues, including the pituitary. Activins exert effects on multiple pituitary cell types but the best-characterized pituitary targets of the autocrine/paracrine function of activins are the gonadotropes. The autocrine/paracrine function of the activin-binding proteins, follistatins, constitutes an important local mechanism to modulate activin bioactivity while the restricted actions of gonadal inhibins to betaglycan-expressing gonadotropes provides a secondary mode of regulation of cell-specific actions of activins. The aim of this review is to highlight and evaluate experimental evidence that supports the roles of activins, inhibins, and follistatins as autocrine, paracrine, and/or endocrine modulators of the pituitary.

Activins↗

PubMed1994

Properties of recombinant chimeric human protein C and activated protein C containing the gamma-carboxyglutamic acid and trailing helical stack domains of protein C replaced by those of human coagulation factor IX.

The properties of a recombinant (r) chimeric human protein C (PC) containing replacement of its gamma-carboxyglutamic acid (Gla) and helical stack (HS) domains by those of human coagulation factor IX (fIX) have been examined. Titration with Ca2+ of the divalent cation-induced intrinsic fluorescence quenching of this chimera (r-GDIX/PC) allowed determination of the [Ca2+], of 1.8 mM, required to produce this alteration in 50% of the protein molecules. These values were 0.41 and 0.61 mM for wtr-PC and fIX, respectively. The chimera did not react with a Ca(2+)-dependent, Gla domain-directed conformational monoclonal antibody (MAb) to r-PC but did interact with a similar MAb (H5B7) to fIX. The [Ca2+] required to induced H5B7 binding to 50% of the r-GDIX/PC molecules was 6.6 mM, while this same value for fIX was a nearly identical 7.2 mM. The [Ca2+] needed for binding of 50% of r-GDIX/PC to acidic phospholipid (PL) vesicles was 0.58 mM, while that for wtr-PC and fIX were 1.2 and 0.55 mM, respectively. The [protein] required for 50% binding of r-GDIX/PC to PL at 20 mM Ca2+ was 0.29 microM. These same values for r-PC and fIX were 0.38 and 1.8 microM, respectively. The Ca(2+)-mediated inhibition of the thrombin-catalyzed activation of r-GDIX/PC was characterized by a Ki of 118 microM, a value similar to that of 125 microM obtained for this same inhibition of wtr-PC activation. The thrombin-catalyzed activation of both r-GDIX/PC and wtr-PC was stimulated by soluble r-thrombomodulin. Similar to the case of wtr-PC, Ca2+ initially enhanced and, at higher concentrations, inhibited the activation of r-GDIX/PC. The Km and kcat values for this latter activation at optimal [Ca2+] (100 microM) were 4.1 microM and 2.5 s-1, respectively. These same kinetic constants for activation of wtr-PC were 4.3 microM and 2.9 s-1, respectively. These results show that many of the features needed for functional integrity of the Ca2+-bound Gla/HS domains of PC are also present in those same modules of fIX, a finding that points to a generalized functional role for the Ca2+-induced conformation of the structural unit consisting of the Gla and HS domains. The data also suggest that the Ca2+-bound form of the Gla/HS region is an independently folded unit in PC and perhaps in fIX.(ABSTRACT TRUNCATED AT 400 WORDS)

1-Carboxyglutamic Acid↗

PubMed1997

Molecular determinants of selectivity in 5-hydroxytryptamine1B receptor-G protein interactions.

The recognition between G protein and cognate receptor plays a key role in specific cellular responses to environmental stimuli. Here we explore specificity in receptor-G protein coupling by taking advantage of the ability of the 5-hydroxytryptamine1B (5-HT1B) receptor to discriminate between G protein heterotrimers containing Galphai1 or Galphat. Gi1 can interact with the 5-HT1B receptor and stabilize a high affinity agonist binding state of this receptor, but Gt cannot. A series of Galphat/Galphai1 chimeric proteins have been generated in Escherichia coli, and their functional integrity has been reported previously (Skiba, N. P., Bae, H., and Hamm, H. E. (1996) J. Biol. Chem. 271, 413-424). We have tested the functional coupling abilities of the Galphat/Galphai1 chimeras to 5-HT1B receptors using high affinity agonist binding and receptor-stimulated guanosine 5'-3-O-(thio)triphosphate (GTPgammaS) binding. In the presence of betagamma subunits, amino acid residues 299-318 of Galphai1 increase agonist binding to the 5-HT1B receptor and receptor stimulation of GTPgammaS binding. Moreover, Galphai1 containing only Galphat amino acid sequences from this region does not show any coupling ability to 5-HT1B receptors. Our studies suggest that the alpha4 helix and alpha4-beta6 loop region of Galphas are an important region for specific recognition between receptors and Gi family members.

Amino Acid Sequence↗

PubMed1978

A multi-systems theory of the structure and dynamics of motor functions.

A theoretical analysis of the structure and dynamics of human motor functioning is presented from the perspective of a general theory of individuality. Within multifactor-systems theory, the structural units of the six systems of integrative personality (i.e., sensory, motor, cognitive, affect, style, and value) are hierarchical factor structures. Integrative functioning, both within and among systems, is described via the principles of general systems and information-processing theory. Our theoretical synthesis of the structure and dynamics of human motor functioning involves conceptualizing the hierarchy of motor factors as: (a) the basic dimensions of individual differences in the motor domain, (b) classes of decomposable motor programs that specify the spatio-temporal organization of behavior, and (c) decomposable classes of processing components entailed by motor programs. Some of the implications for understanding the role of affect in motor functioning and some research suggestions were presented.

Journal Article↗

PubMedDate not supplied

Sperm DNA integrity: correlation with sperm plasma membrane integrity in semen evaluated for male infertility.

Previous independent studies have indicated that abnormally low parameters of sperm DNA integrity and sperm membrane integrity correlate to reduced fertility due in part to implantation disorders. The purpose of our study was to evaluate the relationship between sperm plasma membrane functional integrity assessed by the hypo-osmotic swelling test (HOST) and sperm DNA integriy test assesed by DNA fragmentation index (DFI). Semen samples from 102 random patients were evaluated in terms of standard semen parameters and assessed by DFI and HOST. Both tests showed a significant correlation to standard semen parameters (p < .05). In addition, patients with abnormal HOST results had a higher likehood of a subnormal or abnormal DFI result (p < .001). Our results suggest that a common sublethal insult may manifest as abnormalities in both the nucleus and the plasma membrane that act at the implantation and/or subsequent levels of development rather than at the fertilization stage.

Adult↗

PubMed2004

Induction of Hsp90 protein expression in malignant melanomas and melanoma metastases.

The heat-shock protein Hsp90 has been shown to be essential for the functional integrity of the telomerase complex. The telomerase activity is enhanced in melanoma and stabilizes the chromosomal integrity in proliferating cells. Furthermore, overexpression of Hsp90 induces silencing of point mutations in transcription factors which, otherwise, would result in a loss-of-function phenotype. In melanocytic lesions there is a higher risk of mutations caused by the enhanced proliferation in melanocytic cells. By analyzing microdissected melanocytic tumors by semiquantitative PCR, we demonstrate an overexpression of Hsp90 mRNA in malignant melanomas (10/14) and in melanoma metastases (6/6) as well as in melanoma cell lines (9/9) when compared with melanocytic nevi (2/9). These results could be confirmed on protein level by immunohistochemistry. While melanocytic nevi show discrete Hsp90 expression only in a minor fraction (2/9), malignant melanomas and metastases show a positive Hsp90 immunohistochemistry in the majority of cases; (7/9) and (13/14), respectively. In addition, by analyzing melanoma metastases by flow cytometry we show that Hsp90 is expressed on the surface of tumor cells (7/8). From these data we conclude that Hsp90 is present in advanced malignant melanomas and may have a stabilizing effect on the cellular functions in proliferating cells of melanocytic lesions and could thereby be a prerequisite for the tumor progression. As Hsp90 is expressed on the cell surface, it might also be a potential immunorelevant target structure for immunotherapy of melanoma.

Biopsy↗

PubMed1999

Eye movement deficits following ibotenic acid lesions of the nucleus prepositus hypoglossi in monkeys II. Pursuit, vestibular, and optokinetic responses.

The eyes are moved by a combination of neural commands that code eye velocity and eye position. The eye position signal is supposed to be derived from velocity-coded command signals by mathematical integration via a single oculomotor neural integrator. For horizontal eye movements, the neural integrator is thought to reside in the rostral nucleus prepositus hypoglossi (nph) and project directly to the abducens nuclei. In a previous study, permanent, serial ibotenic acid lesions of the nph in three rhesus macaques compromised the neural integrator for fixation but saccades were not affected. In the present study, to determine further whether the nph is the neural substrate for a single oculomotor neural integrator, the effects of those lesions on smooth pursuit, the vestibulo-ocular reflex (VOR), vestibular nystagmus (VN), and optokinetic nystagmus (OKN) are documented. The lesions were correlated with long-lasting deficits in eye movements, indicated most clearly by the animals' inability to maintain steady gaze in the dark. However, smooth pursuit and sinusoidal VOR in the dark, like the saccades in the previous study, were affected minimally. The gain of horizontal smooth pursuit (eye movement/target movement) decreased slightly (<25%) and phase lead increased slightly for all frequencies (0.3-1.0 Hz, +/-10 degrees target tracking), most noticeably for higher frequencies (0.8-0.7 and approximately 20 degrees for 1.0-Hz tracking). Vertical smooth pursuit was not affected significantly. Surprisingly, horizontal sinusoidal VOR gain and phase also were not affected significantly. Lesions had complex effects on both VN and OKN. The plateau of per- and postrotatory VN was shortened substantially ( approximately 50%), whereas the initial response and the time constant of decay decreased slightly. The initial OKN response also decreased slightly, and the charging phase was prolonged transiently then recovered to below normal levels like the VN time constant. Maximum steady-state, slow eye velocity of OKN decreased progressively by approximately 30% over the course of the lesions. These results support the previous conclusion that the oculomotor neural integrator is not a single neural entity and that the mathematical integrative function for different oculomotor subsystems is most likely distributed among a number of nuclei. They also show that the nph apparently is not involved in integrating smooth pursuit signals and that lesions of the nph can fractionate the VOR and nystagmic responses to adequate stimuli.

Animals↗

PubMed2003

Glucotoxicity and beta-cell failure in type 2 diabetes mellitus.

Type 2 diabetes mellitus is increasing worldwide with a trend of declining age of onset. It is characterized by insulin resistance and a progressive loss of beta-cell function. The ability to secrete adequate amounts of insulin is determined by the functional integrity of beta-cells and their overall mass. Glucose, the main regulator of insulin secretion and production, exerts negative effects on beta-cell function when present in excessive amounts over a prolonged period. The multiple metabolic aberrations induced by chronic hyperglycemia in the beta-cell include increased sensitivity to glucose, increased basal insulin release, reduced response to stimulus to secrete insulin, and a gradual depletion of insulin stores. Inadequate insulin production during chronic hyperglycemia results from decreased insulin gene transcription due to hyperglycemia-induced changes in the activity of beta-cell specific transcription factors. Hyperglycemia may negatively affect beta-cell mass by inducing apoptosis without a compensatory increase in beta-cell proliferation and neogenesis. The detrimental effect of excessive glucose concentrations is referred to as 'glucotoxicity'. The present review discusses the role of glucotoxicity in beta-cell dysfunction in type 2 diabetes mellitus.

Animals↗

PubMed2006

Pituitary actions of ligands of the TGF-beta family: activins and inhibins.

Activins, as members of the transforming growth factor-beta superfamily, control and orchestrate many physiological processes and are vital for the development, growth and functional integrity of most tissues, including the pituitary. Activins produced by pituitary cells work in conjunction with central, peripheral, and other local factors to influence the function of gonadotropes and maintain a normal reproductive axis. Follistatin, also produced by the pituitary, acts as a local buffer to bind activin and modulate its bioactivity. On the other hand, inhibins of gonadal origin provide an endocrine feedback signal to antagonize activin signaling in cells that express the inhibin co-receptor, betaglycan, such as gonadotropes. This review highlights the pituitary roles of activin and the mechanisms through which these actions are modulated by inhibin and follistatin.

Activins↗

PubMed2000

Occlusal considerations in determining treatment prognosis.

To function in occlusal harmony, the masticatory apparatus--composed of the teeth and its supporting structures, temporomandibular joints, and associated neuromusculoskeletal structures--must operate in an integrated and dynamic manner. Loss of integrated function, or of homeostasis in response to functional demand, may generate problems in occlusion. In health, adaptive changes occur with the teeth and periodontium in response to functional occlusal forces. With periodontal and endodontic disease, this adaptive capacity diminishes. The ability to foresee how these changes may influence dental treatment is important in the art of determining treatment prognosis.

Adaptation, Physiological↗

PubMedDate not supplied

[Banks of vascular homografts].

We define as Banking of the tissues all the procedures that include the finding, preparation, conservation and distribution of the homograft. The vascular homografts are taken and put into a solution of transportation at +4 degrees C and kept at this temperature till their arrival at the Bank. The following step is the dissection of the homograft which will have to be performed as quickly as possible at most 24 hours after the taking in conditions of maximum sterility. At the Italian Homograft Bank at Centro Cardiologico, the vascular homografts are kept at +4 degrees C for 96 hours on average with antibiotics. After a phase of sterilization at +4 degrees C the tissue is frozen according to a homogeneous and controlled thermic decrease and stored at -150 degrees C/-180 degrees C in fumes of liquid nitrogen till the moment of their employment allowing a long term conservation. The aim of all these procedures of cryopreservation is to keep the structural and functional integrity of cells and tissues. The thermic decrease of the tissues must occur so that to avoid all the damages of the cellular vitality and functionality and especially of the tissue structure in toto. In order to limitate these events some cryoprotector agents are employed because they reduce the concentration of the solutes, the cellular dehydration, the formation of micro-macro crystals. Another step to establish if the homograft is proper is the study of bacteriological and viral aspects. The viral screenings are performed on the donor's blood and the bacteriological tests are performed on the tissue and on the liquids. For each phase of the banking a series of information about the donor and about the tissues are recorded and filed both on paper and database so that to grant always a right conduct of the material.

Blood Vessels↗

PubMed1992

[Electromyography findings of pelvic floor muscles in patients with anorectal incontinence].

In the presented study the electromyographical signs of the sphincter muscle of 14 patients with incontinence of the faeces are described and compared with those of a group of continent controls. We found significant differences in the duration of the action potential, the average amplitude, the frequency of polarity turns and the integral of the curves. The application of automatic EMG-analysers allows exact differentiation between neurogenic and myogenic disturbances as well as conclusions about the functional integrity of the m. sphincter ani externus and m. puborectalis. The electromyography as a dynamic diagnostic method is a valuable enrichment of the equipment for diagnostic evaluation of the diseases of the pelvic floor. It will be of increasing importance in the differential diagnosis of the incontinence of the faeces and of pudendus nerve lesions as well as in any disease in which a denervation of the parietal or visceral muscles of the pelvic floor is involved.

Adult↗

PubMed1988

Role of the plasma contact system in the pathogenesis of experimental anti-GBM glomerulonephritis.

To study the participation of the Hageman factor-related contact system of plasma in the pathogenesis of glomerulonephritis (GN), an anti-BM GN was induced in a group of 10 normal Brown Norway rats and another of seven Brown Norway BN/Mai Pfd f rats. The latter strain is characterized by a congenital deficiency of plasma prekallikrein and of high-molecular weight kininogen, with lengthening of the activated partial thromboplastin time. In the deficient group, one animal developed crescents in less than 25% of glomeruli, five in 25-50% and one in 50-75%. In the group of normal rats, extracapillary proliferation was of greater severity: one animal showed crescents in less than 25% of glomeruli, two in 50-75% and five in more than 75% of glomeruli. Although in both groups intense glomerular fibrin deposition was documented, the intensity of these deposits was less severe in the deficient animals. These data suggest, in the first place, that functional integrity of the contact system is not a necessary requirement for glomerular fibrinogenesis, other mechanisms being implicated in this phenomenon. On the other hand, this functional deficit has exerted a protective effect on crescent formation, which suggests that the contact system can play a role as a mediator of injury in glomerulonephritis, perhaps through the release of contact system-dependent mediators of inflammation.

Animals↗

PubMed1996

Abundance of surfactant-like particles reflects mucosal integrity in patients with peptic ulcer disease.

BACKGROUND: Surfactant-like particles, normal products of the human enterocyte, are released into the lumen and secreted into blood. AIMS: To assess their role as markers for mucosal functional integrity, this study examined their content in biopsy specimens and serum of patients with duodenal ulcer disease, compared with non-diseased control subjects. PATIENTS: Endoscopic biopsy specimens were taken 1-2 cm from areas of active inflammation or ulcer (peptic ulcer patients) or just beyond the duodenal bulb (normals) in 35 consecutive subjects. METHODS: After staining for phospholipid, extracellular and intracellular particles were counted on transmission electron micrographs of coded specimens. Serum was obtained from 24 patients, and densitometry of the 59 kDa band detected on western blot by antiserum against human jejunal particle was measured. RESULTS: Normal duodenum (n = 15) contained more particles (44 (4.7)) particles/block, mean (SD) than active duodenal ulcer (n = 13, 17 (3.9)) or gastritis/duodenitis patients (n = 4, 9 (2.7)). Three patients examined after healing of duodenal ulcers showed abundant particles (n = 3, 67 (2.2)). Similarly, the 59 kDa band was decreased in serum of patients with active peptic ulcer disease (n = 11, 0.25 (0.04) absorbance units) compared with normal patients (n = 10, 0.40 (0.03)) or healed ulcers (n = 3, 0.62 (0.04)). There was good correlation between morphological mucosal particle abundance and particle protein content of serum assayed from the same patients (r = 0.831). These changes were independent of Helicobacter pylori status. CONCLUSION: The mucosal and serum content of surfactant-like particles may reflect general mucosal integrity of the enterocytes from which they are derived.

Adult↗

PubMed2004

Adsorption of a novel recombinant glycoprotein from HIV (Env gp120dV2 SF162) to anionic PLG microparticles retains the structural integrity of the protein, whereas encapsulation in PLG microparticles does not.

PURPOSE: To evaluate the delivery of a novel HIV-1 antigen (gp120dV2 SF162) by surface adsorption or encapsulation within polylactide-co-glycolide microparticles and to compare both the formulations for their ability to preserve functional activity as measured by binding to soluble CD4. METHODS: Poly(lactide-co-glycolide) microparticles were synthesized by a water-in-oil-in-water (w/o/w) emulsification method in the presence of the anionic surfactant dioctylsulfosuccinate (DSS) or polyvinyl alcohol. The HIV envelope glyocoprotein was adsorbed and encapsulated in the PLG particles. Binding efficiency and burst release measured to determine adsorption characteristics. The ability to bind CD4 was assayed to measure the functional integrity of gp120dV2 following different formulation processes. RESULTS: Protein (antigen) binding to PLG microparticles was influenced by both electrostatic interaction and other mechanisms such as hydrophobic attraction and structural accommodation of the polymer and biomolecule. The functional activity as measured by the ability of gp120dV2 to bind CD4 was maintained by adsorption onto anionic microparticles but drastically reduced by encapsulation. CONCLUSIONS: The antigen on the adsorbed PLG formulation maintained its binding ability to soluble CD4 in comparison to encapsulation, demonstrating the feasibility of using these novel anionic microparticles as a potential vaccine delivery system.

Adsorption↗

PubMed2026

Tackling non-canonical splicing in arrhythmogenic cardiomyopathy to reduce the uncertain significance variants burden.

BACKGROUND: Splice-altering variants (SAVs), particularly those outside canonical splice sites, are an underappreciated contributor to inherited cardiovascular diseases. In arrhythmogenic cardiomyopathy (ACM), these variants frequently remain classified as of uncertain significance (VUS) due to limited predictive power and lack of transcript-level evidence, constraining genetic yield and clinical management. Our study aimed to determine the functional impact of SAVs in ACM genes and refine their classification using ACMG/AMP and ClinGen SVI criteria. METHODS: SAVs identified in 200 ACM probands underwent SpliceAI prediction, GTEx cardiac exon-usage annotation, and functional assessment using pSPL3-based minigene assays. Aberrant transcripts were quantified using Percent Splicing Alteration (PSA). Segregation data and ACMG/AMP criteria refined by ClinGen SVI were applied to integrate functional and clinical evidence for classification. RESULTS: Aberrant splicing was confirmed in 9/20 variants (45%), including synonymous, missense, and non-canonical intronic changes. SpliceAI scores correlated strongly with PSA values (R²=0.86). Case-control burden testing revealed significant enrichment of splice-altering variants in DSP, DSG2, DSC2 and FLNC. Integrating predictive algorithms with experimental validation and segregation analysis markedly enhances reclassification of 16/20 variants (80%). CONCLUSION: Splicing defects beyond canonical sites significantly shape ACM genetic landscape. Integrating predictive models with experimental validation clarifies uncertain variants bridging the gap between genomic uncertainty and clinical decision-making.

Humans↗

PubMed2005

Psychoanalytic psychotherapy for severely disturbed borderline patients: observations on the supervision group of psychotherapists.

The authors describe the role of a supervision group of psychotherapists within a wider therapeutic field for severely disturbed borderline patients. The group concentrates on the transference and countertransference, seen according to Racker's distinction between concordant and complementary identifications. The implications of the prevalence of the complementary identifications over the concordant identifications of the therapists to their patients and the resulting regression to primitive defense mechanisms can be counterbalanced by the group's integrative functioning as receiver (1) of a variety of information about the patient, (2) of the therapist's attempt to understand and synthesize, and (3) of the therapist's countertransference reactions to his patient. The major discrepancies between the various conceptions of the borderline patients' psychic world and the appropriate therapeutic technique to be applied are also discussed, as well as the way the group filters the information and integrates the therapeutic thought. It might be said, therefore, that, in the "inpatient" phase of the individual psychotherapy, the group of psychotherapists functions, for the patient and the treatment, in a synthesizing context, as it provides the therapist with a space of integration for his split-off part of self and object representations, which the therapist makes use of for his patient.

Borderline Personality Disorder↗

PubMed1993

Taxonomy of subjective phenomena: a neuropsychological basis of functional assessment of ischemic or traumatic brain lesions.

A proper evaluation of functional competence after central lesions has to be based on a classification of functions that one can agree upon. It is a sad fact in neuropsychology that such a classification is not available. An attempt will be made to discuss such a classification (or taxonomy) that might be useful. The basic idea is that elementary psychological functions are evolutionary products whose availability is dependent on the functional integrity of neuronal modules. Such modules are embedded neuronal mechanisms that are linked to localized structures or distributed neuronal algorithms. Constancy of interindividual loss of psychological functions associated with lesions of modules can be used to define a catalogue of functions. Using this principle one can differentiate four areas of psychological functions that are represented in a modular fashion. These areas are stimulus representations ("perception"), processing of information ("learning and memory"), evaluation of information (for instance by emotions), and finally action or reaction. Functional competence is, however, not only described by the potential availability of elementary psychological functions, but also by formal aspects, i.e. how functions are made available. Such formal aspects refer to activation and in particular to temporal problems of neuronal processing. A particular "time machine" will be discussed which is essential for functional competence. Central lesions may either effect the what of functions or the how of functions. A differentiation between these material and formal aspects of functional competence are essential with respect to recovery or restitution of function.

Algorithms↗