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PubMed1994

Functional integrity of metallothionein genes in testicular cell lines.

The presence and inducibility of the major cadmium (Cd) chelating protein metallothionein (MT) in testicular cells has been controversial. In this study, the induction and production of MT in testicular cells were studied using mouse Leydig and Sertoli cell lines. Metal accumulation was studied by subjecting the cells to increasing levels of Cd. The presence of transcription factors for MT synthesis was analyzed by transfecting the cells with a reporter gene under the control of the MT promoter. The dose- and time-dependent induction of MT were conducted by Northern analyses. Expression of MT genes occurred in both Leydig and Sertoli cells. To avoid cross hybridization of the MT probe with mRNAs encoding testicular metal binding proteins and to investigate the integrity of MT mRNA, isoMT mRNA identification and primer extension experiments were performed. Those studies show that the induced mRNA indeed encodes MT. The biosynthesis of MT was confirmed by following 35S-cysteine incorporation into the protein. Finally, cadmium tolerance of testicular cells is compared with that of fibroblast cells. By these studies, we conclude that the MT genes are functional and inducible in testicular cells.

Animals↗

PubMed2004

Functional integration of the histone acetyltransferase MOF into the dosage compensation complex.

Dosage compensation in flies involves doubling the transcription of genes on the single male X chromosome to match the combined expression level of the two female X chromosomes. Crucial for this activation is the acetylation of histone H4 by the histone acetyltransferase (HAT) MOF. In male cells, MOF resides in a complex (dosage compensation complex, DCC) with MSL proteins and noncoding roX RNA. Previous studies suggested that MOF's localization to the X chromosome was largely RNA-mediated. We now found that contact of the MOF chromo-related domain with roX RNA plays only a minor role in correct targeting to the X chromosome in vivo. Instead, a strong, direct interaction between a conserved MSL1 domain and a zinc finger within MOF's HAT domain is crucial. The functional consequences of this interaction were studied in vitro. Simultaneous contact of MOF with MSL1 and MSL3 led to its recruitment to chromatin, a dramatic stimulation of HAT activity and to improved substrate specificity. Activation of MOF's HAT activity upon integration into the DCC may serve to restrict the critical histone modification to the male X chromosome.

Acetylation↗

PubMed1996

The renal adenosine triphosphatases: functional integration and clinical significance.

The ion-transporting ATPases determine the chemical composition of cells both directly and through their secondary effects. The Na,K-ATPase generates the transmembrane sodium gradient which provides the primary energy for uptake and extrusion of a wide variety of solutes by renal tubular epithelia. The H-ATPase and the H,K-ATPase acidify the urine, and also generates bicarbonate for excretion by the cortical collecting duct. Calcium ATPase regulates the intracellular calcium, which in turn impacts on the myriad of cellular functions for which calcium serves as an intracellular messenger. If one considers the impact of potential pump dysfunction in a purely speculative mode, the list of disorders which might be potentially ascribed to 'pump disease' would be enormous. This article reviews those disorders of renal transport already considered to be 'pump diseases'.

Acidosis, Renal Tubular↗

PubMed2003

DNA repair gene Ercc1 is essential for normal spermatogenesis and oogenesis and for functional integrity of germ cell DNA in the mouse.

Ercc1 is essential for nucleotide excision repair (NER) but, unlike other NER proteins, Ercc1 and Xpf are also involved in recombination repair pathways. Ercc1 knockout mice have profound cell cycle abnormalities in the liver and die before weaning. Subsequently Xpa and Xpc knockouts have proved to be good models for the human NER deficiency disease, xeroderma pigmentosum, leading to speculation that the recombination, rather than the NER deficit is the key to the Ercc1 knockout phenotype. To investigate the importance of the recombination repair functions of Ercc1 we studied spermatogenesis and oogenesis in Ercc1-deficient mice. Male and female Ercc1-deficient mice were both infertile. Ercc1 was expressed at a high level in the testis and the highest levels of Ercc1 protein occurred in germ cells following meiotic crossing over. However, in Ercc1 null males some germ cell loss occurred prior to meiotic entry and there was no evidence that Ercc1 was essential for meiotic crossing over. An increased level of DNA strand breaks and oxidative DNA damage was found in Ercc1-deficient testis and increased apoptosis was noted in male germ cells. We conclude that the repair functions of Ercc1 are required in both male and female germ cells at all stages of their maturation. The role of endogenous oxidative DNA damage and the reason for the sensitivity of the germ cells to Ercc1 deficiency are discussed.

Animals↗

PubMed2006

Functional integration of hepatocytes derived from human mesenchymal stem cells into mouse livers.

AIMS: At present, clinical success of hepatocyte transplantation as an alternative to whole liver transplantation is hampered by the limited availability of suitable donor organs for the isolation of transplantable hepatocytes. Hence, novel cell sources are required to deliver hepatocytes of adequate quality for clinical use. Mesenchymal stem cells (MSCs) from human bone marrow may have the potential to differentiate into hepatocytes in vitro and in vivo. METHODS: Isolated MSCs were selected by density gradient centrifugation and plastic adherence, differentiated in the presence of human hepatocyte growth medium and transplanted in immunodeficient Pfp/Rag2 mice. RESULTS: Here, we demonstrate that human MSCs gain in vitro the characteristic morphology and function of hepatocytes in response to specified growth factors. Specifically, preconditioned MSCs store glycogen, synthesise urea and feature the active hepatocyte-specific gene promoter of phosphoenolpyruvate carboxykinase (PCK1). After transplantation into livers of immunodeficient mice, preconditioned MSCs engraft predominantly in the periportal portion of the liver lobule. In situ, the cells continue to store glycogen and express PCK1, connexin32, albumin and the human hepatocyte-specific antigen HepPar1, indicating that the transplanted cells retain prominent qualities of hepatocytes after their regional integration. CONCLUSION: MSCs derived from human bone marrow may serve as a novel source for the propagation of hepatocyte-like cells suitable for cell therapy in liver diseases.

Animals↗

PubMed1988

Mini organ culture of thyroid tissue: a new technique for maintaining the structural and functional integrity of thyroid tissue in vitro.

We have developed a culture technique by which the normal configuration of follicles and most other structural characteristics of the thyroid gland are well preserved. Small tissue fragments (diameter 0.5 to 0.9 mm) from various mammalian species were prepared and kept in hydrophobic culture dishes to prevent their attachment. It was essential to raise the oxygen concentration in the incubator to 50% and the D-glucose concentration to 5.6 mM. Under these conditions, mini organs were formed by the outgrowth of epithelial cells from follicles located on the fragment surface and opened during tissue preparation. After 2 to 3 days, the mini organs were enclosed by a confluent and tight monolayer of follicle cells and [3H]thymidine incorporation returned to background levels. The structural integrity of follicles underneath the monolayer and in the center of the mini organs could be maintained for at least several weeks. Light microscope autoradiographs of mini organs incubated with iodide, sulfate, or phosphate revealed that the vectorial transport and the posttranslational modifications of thyroglobulin were maintained. An assay for the precise quantitation of biosynthetic activities in individual mini organs was developed. The observations indicate that thyroid-specific functions in mini organs can be preserved for prolonged periods of time.

Animals↗

PubMed2006

Esp-independent functional integration of the translocated intimin receptor (Tir) of enteropathogenic Escherichia coli (EPEC) into host cell membranes.

The pathogenesis of enteropathogenic Escherichia coli (EPEC) is characterized by the type III secretion system-dependent exploitation of target cells that results in attaching and effacing (A/E) lesions, actin rearrangements and pedestal formation. This pathology is mediated by effector proteins which are translocated by the type III secretion system into the host cell such as the translocated intimin receptor (Tir) and several E. coli secreted proteins (Esp). Secretion of virulence proteins of EPEC is tightly regulated. In response to Ca(2+), Esp secretion is drastically reduced, whereas secretion of Tir is increased. Membrane insertion of Tir, secreted under low Ca(2+) conditions, is therefore independent of Esp. Furthermore, espB and espD mutant strains of EPEC, unable to form the translocation pore, still translocate Tir into host cells membranes. This autointegrated Tir is functional, as it is able to complement a tir mutant strain in recruiting actin to bacterial contact sites. The uptake of Tir into the host cell appears to depend on the C-terminal part of the protein, as deletion of this part of Tir prevents autointegration. Together, our results demonstrate that under conditions of limited Ca(2+) an alternative mechanism for Tir integration can trigger the induction of A/E lesions.

Actins↗

PubMed2005

Adjacent tissues (cartilage, bone) affect the functional integration of engineered calf cartilage in vitro.

OBJECTIVE: An in vitro model was used to test the hypothesis that culture time and adjacent tissue structure and composition affected chondrogenesis and integrative repair in engineered cartilage. METHOD: Engineered constructs made of bovine calf chondrocytes and hyaluronan benzyl ester non-woven mesh were press-fitted into adjacent tissue rings made of articular cartilage (AC), devitalized bone (DB), or vital bone (VB) and cultured in rotating bioreactors for up to 8 weeks. Structure (light and electron microscopy), biomechanical properties (interfacial adhesive strength, construct compressive modulus), biochemical composition (construct glycosaminoglycans (GAG), collagen, and cells), and adjacent tissue diffusivity were assessed. RESULTS: Engineered constructs were comprised predominately of hyaline cartilage, and appeared either closely apposed to adjacent cartilage or functionally interdigitated with adjacent bone due to interfacial deposition of extracellular matrix. An increase in culture time significantly improved construct adhesive strength (P<0.001), modulus (P=0.02), GAG (P=0.04) and cellularity (P<0.001). The type of adjacent tissue significantly affected construct adhesion (P<0.001), modulus (P<0.001), GAG (P<0.001) and collagen (P<0.001). For constructs cultured in rings of cartilage, negative correlations were observed between ring GAG content (log transformed) and construct adhesion (R2=0.66, P<0.005), modulus (R2=0.49, P<0.05) and GAG (R2=0.44, P<0.05). Integrative repair was better for constructs cultured adjacent to bone than cartilage, in association with its solid architectural structure and high GAG content, and best for constructs cultured adjacent to DB, in association with its high diffusivity. CONCLUSIONS: Chondrogenesis and integrative repair in engineered cartilage improved with time and depended on adjacent tissue architecture, composition, and transport properties.

Animals↗

PubMedDate not supplied

Ultrapure polymerized bovine hemoglobin improves structural and functional integrity of the isolated perfused rat kidney.

Since it became evident that organ dysfunctions after acute hemolysis are not induced by hemoglobin per se, but by stroma-contaminated hemoglobin, solutions of ultrapure stroma-free hemoglobins were regarded to be possible substitutes for blood in transfusion medicine. We tested one of the recently developed modified bovine hemoglobins (Ultrapure polymerized bovine hemoglobin 1; UPPBHb1) in the isolated perfused rat kidney (IPRK) model, using a recirculating system. Control kidneys were perfused with a substrate-enriched Ringer solution containing hydroxyethyl starch (HES) to produce isoncotic conditions. In the experimental group HES was substituted in part by UPPBHb1 (34 g/l). For determination of functional parameters, the kidneys were perfused for 180 min. A separate set of kidneys of both groups was perfusion fixed after 80 min of perfusion which is the period of optimal function. Light and electron microscopic analysis revealed major alterations only for the outer medulla of HES kidneys. Only these suffered from a considerable extent of proximal tubular S3 damage, exhibiting condensed tubular epithelia. In the inner stripe of the outer medulla, which is the zone of greatest sensitivity to damage in the isolated perfused kidney, severe hydropic degeneration, cell detachment, and necrotic destruction of the medullary thick ascending limb were seen in the HES-perfused group, too. In the UPPBHb1 group, the medullary thick ascending limb was well preserved, and S3 showed only a minor degree of damage. UPPBHB1 kidneys were further characterized by the occurrence of intracapillary and interstitial precipitates of UPPBHb1 in inner stripe of the outer medulla and inner medulla. The glomerular filtration rate was significantly higher in UPPBHb1-perfused kidneys (870 +/- 80 vs. 630 +/- 55 microliters/min/g kidney weight for HES). Absolute reabsorption of sodium paralleled the behavior of the glomerular filtration rate. The values for renal perfusate flow and urinary flow rate did not differ significantly between both groups. Renal autoregulation was better preserved in UPPBHb1-perfused kidneys (74 +/- 6% of full autoregulatory response) than in HES-perfused controls (42 +/- 4%). Our results suggest that perfusion of isolated rat kidneys with UPPBHb1 improves kidney function and morphology, providing better oxygenation than in control kidneys. UPPBHb1 does not exert additional nephrotoxic effects on the IPRK that will exceed the noxious potential of the method itself. Thus, it must be concluded that UPPBHb1 may be an oxyphoretic blood substitute with nephroprotective characteristics when compared with nonoxyphoretic substitutes. At least, UPPBHb1 seems to be a promising candidate as oxyphoretic additive to perfusates for the IPRK model.

Animals↗

PubMed1985

Functional integrity of cytokineplasts: specific chemotactic and capping responses.

Cytokineplasts (CKP) are motile, membrane-bound, anucleate, granule-poor cytoplasmic fragments that are induced from human blood polymorphonuclear leukocytes (PMN) by the brief application of heat. We examined CKP with respect to specific chemotactic and capping responses, the presence of the N-formyl-peptide chemotactide receptor, and evidence of respiratory burst activity and compared them with CB-cytoplasts, which are fragments created by the centrifugation of cytochalasin B (CB)-treated PMN at high speeds. Under agarose, CKP responded chemotactically to both N-formyl-methionyl-leucyl-phenylalanine (fmlp) and zymosan-activated serum; CB-cytoplasts responded to neither chemoattractant. Despite the functional differences, both fragments retained N-formyl-peptide receptors as measured by affinity labeling with N-formyl-norleu-leu-phe-norleu-125I-tyr-lys and autoradiography of dried SDS-PAGE gels. For studies of capping we used a murine monoclonal antibody, PMN7C3, which binds a specific, widely distributed membrane component of intact PMN, and on warming, promptly induces capping of ligand-receptor complexes. Rhodamine-conjugated PMN7C3 at 4 degrees C labeled the surface of CKP homogeneously. As the CKP warmed to 37 degrees C, label became concentrated in small fluorescent caps at the rear of migrating fragments. Although CB-cytoplasts also bound the fluorochromed antibody homogeneously in the cold, on warming they were unable to concentrate the label normally. With respect to respiratory burst activity, the situation in the two fragments was reversed: CKP did not generate superoxide anion when stimulated either with phorbol myristate acetate or with fmlp after pretreatment with CB; CB-cytoplasts, as noted earlier by other investigators, did. These two types of cytoplasts with markedly different capabilities have complementary roles in the analysis of PMN function.

Chemotactic Factors↗

PubMed1983

Functional integrity of desensitized beta-adrenergic receptors.

The adenylate cyclase-coupled beta 2-adrenergic receptor of the frog erythrocyte has served as a useful model system for elucidating the mechanisms of catecholamine-induced densensitization. In this system, it has been previously demonstrated that agonist-induced refractoriness is associated with sequestration of the beta-adrenergic receptors in vesicles away from the cell surface and from their effector unit, the adenylate cyclase system (Stadel, J.M., Strulovici, B., Nambi, P., Lavin, T.N., Briggs, M.M., Caron, M.G., and Lefkowitz, R.J. (1983) J. Biol. Chem. 258, 3032-3038). These internalized beta-adrenergic receptors appear to be structurally intact as assessed by photoaffinity labeling, but their functional status has previously been unknown. In the present studies, we sought to assess the functionality of the sequestered vesicular receptors by fusing them to Xenopus laevis erythrocytes. This cell is suitable for such studies, since it has almost no detectable beta-adrenergic receptor or catecholamine-sensitive adenylate cyclase, but contains prostaglandin E1-stimulable adenylate cyclase. Fusion of beta-adrenergic receptor-containing vesicles from desensitized frog erythrocytes with X. laevis erythrocytes results in a 30-fold stimulation of the hybrid adenylate cyclase by the beta-adrenergic agonist isoproterenol. This effect was entirely blocked by the beta-antagonist propranolol. The catecholamine-sensitive adenylate cyclase activity established in the vesicle-Xenopus hybrids showed the characteristic agonist potency series of the donor frog erythrocyte beta 2-adrenergic receptor. Fusion of vesicles from desensitized frog erythrocytes in which the beta-adrenergic receptors had been inactivated with the group specific reagent dicyclohexylcarbodiimide, or of vesicles derived from control frog erythrocytes, which contain low amounts of beta-adrenergic receptor, did not establish catecholamine-sensitive adenylate cyclase activity in the hybrids. These data demonstrate that beta-adrenergic receptors internalized during desensitization retain their functionality when recoupled to an adenylate cyclase system from a different source. The functional uncoupling of these receptors during desensitization is thus more likely due to their sequestration away from the other components of the adenylate cyclase than to any alterations in the receptors themselves.

Adenylyl Cyclases↗

PubMed1994

Nuclear but not mitochondrial genome involvement in human age-related mitochondrial dysfunction. Functional integrity of mitochondrial DNA from aged subjects.

The role of mtDNA and nuclear genome in human aging was examined by their intercellular transfer using skin fibroblasts and mtDNA-less HeLa cells (rho o-HeLa cells). We found in vivo age-related reductions in the activity of cytochrome c oxidase in human skin fibroblasts obtained from 16 donors of various ages (0-97 years). The abnormality in mitochondria of the aged donors was not attributable to either decrease in the copy number of mtDNA molecules or increase in the copy number of deletion mutant mtDNA molecules, but to significant decrease in overall polypeptide synthesis in the mitochondria. However, intercellular mtDNA transfer experiments showed that fibroblast mtDNA from elderly donors is functionally intact. By contrast, intercellular transfer of HeLa nuclei to fibroblasts from aged donors restored cytochrome c oxidase activity, suggesting that the age-related phenotype was nuclear recessive. However, during subsequent cultivation of these hybrids, the activity gradually reduced again, associated with gradual chromosome loss. These observations support the idea that accumulation of nuclear recessive somatic mutations, but not mtDNA mutations, is responsible for the in vivo age-related mitochondrial dysfunction observed in human skin fibroblasts.

Aged↗

PubMed2026

Integrated functional, metabolomic, and biotransformation profiling of mycotoxin hepatotoxicity in 2D and 3D human hepatic models.

Mycotoxins pose a major risk to food safety and human health, yet their hepatotoxic mechanisms remain incompletely characterized due to limitations in conventional in vitro models. In this study, we systematically compared mycotoxin-induced hepatotoxicity and metabolomic profiling across two human hepatic models cultured under 2D monolayer and 3D spheroid conditions. The various mycotoxins (Aflatoxin B1, Citrinin, Deoxynivalenol, Ochratoxin A, Patulin, and Zearalenone) exhibit distinct metabolic signatures, thereby serving as an appropriate panel for comprehensively evaluating diverse hepatotoxic mechanisms. Mycotoxin exposure induced concentration-dependent hepatotoxicity accompanied by functional impairment and structural disruption in hepatic models. Metabolomic profiling revealed distinctive regulatory patterns between 2D and 3D hepatic models, with 3D spheroids showing consistent down-regulation across multiple intracellular metabolic pathways and altered extracellular metabolite release, whereas 2D monolayers predominantly exhibited global metabolic activation. In silico-assisted MS/MS analysis further demonstrated that Phase I biotransformation was largely conserved across models, whereas Phase II conjugation reactions were more frequently detected and exhibited greater model specificity in 3D spheroids. Overall, these findings indicate that 3D hepatic spheroids capture more integrated and coordinated hepatotoxic and metabolic responses to mycotoxins compared with 2D monolayer systems. These distinctive regulatory dynamics support their value as a physiologically relevant platform for toxicity assessment and mechanistic investigation.

3D hepatic spheroids↗

PubMed2006

Comparative and integrative functional genomics of HCC.

Global gene expression profiling of hepatocellular carcinoma (HCC) is a promising new technology that has already refined the diagnosis and prognostic predictions of HCC patients. This has been accomplished by identifying genes whose expression pattern is associated with clinicopathological features of HCC tumors. Molecular characterization of HCC from gene expression profiling studies will undoubtedly improve the prediction of treatment responses, selection of treatments for specific molecular subtypes of HCC and ultimately the clinical outcome of HCC patients. The research focus is now shifting toward the identification of genetic determinants that are components of the specific regulatory pathways altered in cancers, and that may constitute novel therapeutic targets. Here we review the recent advances in gene expression profiling of HCC and discuss the future strategies for analysing large and complicated data sets from microarray studies and how to integrate these with diverse genomic data.

Animals↗

PubMed1999

Functional integrity of green fluorescent protein conjugated glycine receptor channels.

The alpha subunit (alphaZ1) of the zebrafish glycine receptor (GlyR) has been N-terminus fused with green fluorescent protein (GFP). We found that both pharmacological and electrophysiological properties of this chimeric alphaZ1-GFP are indistinguishable from those of the wild-type receptor when expressed in Xenopus oocytes and cell lines. The apparent affinities of this receptor for agonists (glycine, taurine and GABA), and the antagonist (strychnine) are unchanged, and single channel kinetics are not altered. In the same expression systems, alphaZ1-GFP was visualized using fluorescence microscopy. Fluorescence was distributed anisotropically across cellular membranes. In addition to the Golgi apparatus and endoplasmic reticulum, its presence was also detected on the plasmalemma, localized at discrete hot-spots which were identified as sites of high membrane turnover. Overall, the preservation in alphaZ1-GFPs of the wild type receptor functional properties makes it a promising new tool for further in situ investigations of GlyR expression, distribution and function.

Animals↗

PubMed2005

High-throughput metabolic state analysis: the missing link in integrated functional genomics of yeasts.

The lack of comparable metabolic state assays severely limits understanding the metabolic changes caused by genetic or environmental perturbations. The present study reports the application of a novel derivatization method for metabolome analysis of yeast, coupled to data-mining software that achieve comparable throughput, effort and cost compared with DNA arrays. Our sample workup method enables simultaneous metabolite measurements throughout central carbon metabolism and amino acid biosynthesis, using a standard GC-MS platform that was optimized for this purpose. As an implementation proof-of-concept, we assayed metabolite levels in two yeast strains and two different environmental conditions in the context of metabolic pathway reconstruction. We demonstrate that these differential metabolite level data distinguish among sample types, such as typical metabolic fingerprinting or footprinting. More importantly, we demonstrate that this differential metabolite level data provides insight into specific metabolic pathways and lays the groundwork for integrated transcription-metabolism studies of yeasts.

Aerobiosis↗

PubMed2004

Plant responses to precipitation in desert ecosystems: integrating functional types, pulses, thresholds, and delays.

The 'two-layer' and 'pulse-reserve' hypotheses were developed 30 years ago and continue to serve as the standard for many experiments and modeling studies that examine relationships between primary productivity and rainfall variability in aridlands. The two-layer hypothesis considers two important plant functional types (FTs) and predicts that woody and herbaceous plants are able to co-exist in savannas because they utilize water from different soil layers (or depths). The pulse-reserve model addresses the response of individual plants to precipitation and predicts that there are 'biologically important' rain events that stimulate plant growth and reproduction. These pulses of precipitation may play a key role in long-term plant function and survival (as compared to seasonal or annual rainfall totals as per the two-layer model). In this paper, we re-evaluate these paradigms in terms of their generality, strengths, and limitations. We suggest that while seasonality and resource partitioning (key to the two-layer model) and biologically important precipitation events (key to the pulse-reserve model) are critical to understanding plant responses to precipitation in aridlands, both paradigms have significant limitations. Neither account for plasticity in rooting habits of woody plants, potential delayed responses of plants to rainfall, explicit precipitation thresholds, or vagaries in plant phenology. To address these limitations, we integrate the ideas of precipitation thresholds and plant delays, resource partitioning, and plant FT strategies into a simple 'threshold-delay' model. The model contains six basic parameters that capture the nonlinear nature of plant responses to pulse precipitation. We review the literature within the context of our threshold-delay model to: (i) develop testable hypotheses about how different plant FTs respond to pulses; (ii) identify weaknesses in the current state-of-knowledge; and (iii) suggest future research directions that will provide insight into how the timing, frequency, and magnitude of rainfall in deserts affect plants, plant communities, and ecosystems.

Age Factors↗

PubMedDate not supplied

[Effect of inhibitors of protein biosynthesis on integrative functions of the cerebral cortex during elaboration and consolidation of defensive conditioned reactions].

A conditioned defensive reaction was elaborated in non-anaesthetized non-immobilized rabbits and a study was made of the dynamics of background and evoked impulse activity of neurones in the somatosensory cortex under conditions of microionophoretic administration of puromycin and cycloheximide inhibitors of the translation stage of protein biosynthesis. It was found that the blockaders produce selective and reversible changes in the pattern of nerve cells responses to conditioned and reinforcing stimuli, in the frequency of background impulse activity and spikes amplitude. Direction and dynamics of the changes may not correlate. Effects of the inhibitors are frequently observed in a few seconds, being most pronounced in five to ten min. after their administration. Restoration of initial reactions takes usually place during 30 and more minutes. The data obtained are discussed in the light of "chemical" hypothesis of neurone integrative activity.

Animals↗