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PubMed2006

Identification and characterization of two mature isoforms of retinoschisin in murine retina.

Retinoschisin (RS) is a 24 kDa secreted protein expressed in retina and is required for the structural and functional integrity of the retina. RS has been predicted to serve as an adhesive protein but the precise molecular mechanism by which it functions in retina is not yet known. During investigations on structural and functional aspects of RS in murine retina using proteomic tools, we identified two isoforms of RS that differed in mass by 200 Da with no apparent change in charge. Mass spectra and amino acid sequence analysis of the tryptic peptides revealed that these isoforms differed by two amino acids at the N-terminus which suggested processing of RS signal sequence at two cleavage sites by signal peptidase as the basic mechanism underlying the occurrence of two mature RS isoforms in retina. Bioinformatic analysis identified two potential cleavage sites (between amino acids 21-22 and 23-24) in RS signal sequence. The flexibility of the signal peptidase to cleave at two sites is correlated to the amino acid composition of the RS signal sequence. This finding represents a rare example of a naturally occurring signal sequence cleavage at more than one site in vivo.

Amino Acid Sequence↗

PubMed2006

Integration of feeding and spontaneous physical activity: role for orexin.

Spontaneous physical activity is activity that is non-volitional, or subconscious, such as fidgeting and shifting in one's seat, and time spent moving (standing and ambulating). Recent evidence indicates that spontaneous physical activity, and the resulting thermogenesis (non-exercise activity thermogenesis) may be regulated by brain systems. A large number of brain areas, with their associated neurotransmitter populations and connectivity, participate in the regulation of feeding behavior by acting as energy sensing and modulating centers. Although less well characterized, it is likely that a multitude of neurotransmitters and brain areas act to mediate spontaneous physical activity. These two behaviors, feeding and spontaneous physical activity, affect energy intake and expenditure and thus are important to body weight. Interestingly, often the two behaviors are affected simultaneously; when feeding is affected, so too is spontaneous physical activity, and both food intake and physical activity (whether spontaneous or volitional) influence activity of brain areas important to both. Several brain areas and neuropeptides are important to feeding and spontaneous physical activity. The lateral hypothalamus is one area that appears important to both behaviors, as stimulation or lesion of this region produces alterations in feeding behavior and spontaneous physical activity. Orexin neurons, with their central location in the lateral hypothalamus, widespread projections and connectivity to other brain areas important to energy homeostasis, are well situated to perform an integrative function. This review focuses on how hypothalamic orexins participate in both feeding and spontaneous physical activity, and provides potential models for the integration of signals important to both.

Animals↗

PubMed2004

Assaying gene function by growth competition experiment.

High-throughput screening and analysis is one of the emerging paradigms in biotechnology. In particular, high-throughput methods are essential in the field of functional genomics because of the vast amount of data generated in recent and ongoing genome sequencing efforts. In this report we discuss integrated functional analysis methodologies which incorporate both a growth competition component and a highly parallel assay used to quantify results of the growth competition. Several applications of the two most widely used technologies in the field, i.e., transposon mutagenesis and deletion strain library growth competition, and individual applications of several developing or less widely reported technologies are presented.

Animals↗

PubMed2000

Effect of different baculovirus inactivation procedures on the integrity and immunogenicity of porcine parvovirus-like particles.

We have demonstrated earlier the usefulness of recombinant porcine parvovirus (PPV) virus-like particles (VLPs) as an efficient recombinant vaccine for PPV. Here, we have demonstrated that preparations of PPV VLPs could be contaminated by recombinant baculoviruses. Since these baculoviruses can be a problem for the registration and safety requirements of the recombinant vaccine, we have tested different baculovirus inactivation strategies, studying simultaneously the integrity and immunogenicity of the VLPs. These methods were pasteurization, treatment with detergents and alkylation with binary ethylenimine (BEI). The structural and functional integrity of the PPV VLPs after the inactivation treatments were analyzed by electron microscopy, hemagglutination, double antibody sandwich (DAS)-ELISA and immunogenicity studies. Binary ethylenimine and Triton X-100 inactivated particles maintained all the original structural and antigenic properties. In addition, PPV VLPs were subjected to size-exclusion chromatography to analyze the presence of VP2 monomers or any other contaminant. The resulting highly purified material was used as the standard of reference to quantify PPV VLPs in order to determine the dose of vaccine by DAS-ELISA. After immunization experiments in guinea pigs, the antibody titers obtained with all the inactivation procedures were very similar. Triton X-100 treatment was selected for further testing in animals because of the speed, simplicity and safety of the overall procedure.

Animals↗

PubMed2025

Analytical Considerations for the Development of Plate-Based Proteomics Platforms Using Isobaric Labeling.

Mass spectrometer-based proteomics platforms have great potential to rapidly advance our systematic understanding of complex biological problems, enable drug discovery, decipher drug mechanisms of action, and discover novel biomarkers. As the demand for processing large sets of samples in an automatic manner is constantly increasing, the integration of automation platforms (nanoliter dispensers, liquid handlers, etc.) has become a routinary configuration paired with liquid chromatography-mass spectrometers. The functional integration of all of those instruments into a single unit is what we call a plate-based high-throughput proteomics platform (HT proteomics). The readout of the platform is the quantitative proteome data at the protein or peptide level. In this work, we developed a plate-based HT proteomics standard that we called the HT-sKO. The HT-sKO allows the evaluation of accuracy and the estimation of the relative limit of quantification when the target proteins vary up to 60-fold in abundance. The HT-sKO utilizes nonhuman recombinant proteins that can be spiked into the samples, allowing for sample acquisition and HT proteomics platform evaluation at the same time. We also showed the foundational role of a robust acquisition strategy for developing a stable HT proteomics platform and the value of using a tube-based method as an informant assay on data quality expectations for the platform. Using this new standard, we demonstrated that the intra- and inter-plate variance is around 4-6% for the protein level or around 10% for the peptide-level readout. We also showed that the HT-sKO standard is compatible with whole-proteome, phospho-proteome, and reactive cysteine profiling platforms.

Proteomics↗

PubMed2002

Onychomycosis of toenails: orthopaedic and podiatric considerations.

Onychomycosis is common, affecting approximately 5% of the population, and is the most resistant form of superficial fungal infection. Dermatologists often view the nail apparatus in static terms and unfortunately give little consideration to the functional aspects of the digit. In the case of toenails, it is important to consider the toes and foot as a closely integrated functional unit. It is essential that in any case of onychomycosis or onychodystrophy that, as clinicians, we have an understanding of foot dynamics, of structure/function relationships and of the implications of orthopaedic/podiatric factors when evaluating cases of nail dystrophy. When confronted with cases of possible onychomycosis, we must adopt a systematic and sometimes multidisciplinary approach in the evaluation and management of these patients to improve patient outcomes.

Foot Dermatoses↗

PubMed2000

Attentional modulation of effective connectivity from V2 to V5/MT in humans.

The nonlinear nature of integration among cortical brain areas renders the effective connectivity between them inherently dynamic and context-sensitive. One emerging architectural principle of functional brain organization, which rests explicitly on these nonlinear interactions, is that neuronal responses expressed at any level in a sensory hierarchy reflect an interaction between (i) bottom up "driving" afferents from lower cortical areas and (ii) backwards "modulatory" inputs from higher areas that mediate top-down contextual effects. A compelling example is attentional modulation of responses in functionally specialized sensory areas. The aim of this work was to demonstrate that parietal regions may mediate selective attention to motion by modulating the effective connectivity from early visual cortex to the motion-sensitive area V5/MT. Using functional magnetic resonance imaging, and an analysis of effective connectivity based on nonlinear system identification, we found that backwards modulatory influences from the posterior parietal cortex are sufficient to account for a significant component of attentional modulation of V5/MT responses to "driving" inputs from V2. By explicitly modeling interactions among inputs to V5/MT, we were able to make inferences about the influences of V2 inputs and their concomitant activity-dependent modulation by parietal afferents. The latter effects embody dynamic changes in effective connectivity that may underlie attentional mechanisms. These results speak to the context-sensitive nature of functional integration in the brain and provide empirical evidence that attentional effects may be mediated by backwards connections, of a modulatory sort, in humans.

Attention↗

PubMed1982

Selective chemical hepatic sympathectomy in the dog.

Intraportal injection of 6-hydroxydopamine (6-OHDA) was used to produce selective hepatic sympathectomy in the dog. Previously reported techniques for 6-OHDA induced hepatic sympathectomy in rats and cats were modified considerably using alpha and beta adrenergic blocking agents to prevent the otherwise intense and fatal sympathomimetic response which has prevented adaptation of the intraportal 6-OHDA injection for dogs. After 6-OHDA injection, histofluorescent staining demonstrated loss of hepatic adrenergic nerves with preservation of normal adrenergic innervation in the heart and pancreas. Tyramine iv was used to further document functional integrity of peripheral sympathetic mechanisms. This technique provides a useful model for evaluation of sympathetic nervous system mediated changes in hepatic metabolic function associated with the neuroendocrine response to hemorrhage in the classic dog model.

Animals↗

PubMed1994

Congenital hypertrophy of the retinal pigment epithelium associated with familial adenomatous polyposis.

PURPOSE: Multiple, bilateral areas of congenital hypertrophy of the retinal pigment epithelium (CHRPE) have been described in association with familial adenomatous polyposis (FAP). Histopathologic findings have suggested a generalized effect of the FAP gene on the RPE, which could impair the functional integrity of the RPE. The clinical, psychophysical, electrophysiologic, and fluorescein angiographic findings in CHRPE in subjects with FAP were assessed. METHODS: RPE function was assessed in 7 subjects with CHRPE and a family history of FAP. Four had documented FAP (mean age = 22.25 years) and the other three were siblings of affected subjects, with a 50% risk of developing FAP (mean age = 6.33 years). All subjects underwent comprehensive ophthalmologic examination. RESULTS: All subjects showed mild hyperopia (mean, +1.13 D; best corrected visual acuity, 20/20 or better). On perimetry, there were scotomas corresponding to some lesions. ERG showed normal rod, maximal, single-flash cone, and flicker responses. Light-dark ratio was within the normal range on EOG. Fluorescein angiography demonstrated normal retinal vasculature overlying the CHRPE lesions, which blocked background choroidal fluorescence. A normal choriocapillaris was observed through some hypopigmented lacuna. CONCLUSION: CHRPE has been related to generalized expression of an abnormal gene in RPE, but its functional abnormalities tend to be localized.

Adenomatous Polyposis Coli↗

PubMed1997

The pathologic physiology of chronic Bright's disease. An exposition of the "intact nephron hypothesis".

Clinical and experimental data relating to the functional capacity of the surviving nephrons of the chronically diseased kidney for the most part support the thesis that these nephrons retain their essential functional integrity regardless of the nature of the underlying form of chronic Bright's disease. There are instances in which specific alterations of function correlate with pathologic involvement of a particular site of the nephron but these appear to represent the exceptions, and in general the more advanced the disease becomes, the less evident are the differentiating features. Studies on dogs with unilateral renal disease indicate that the functional capacity of the nephrons of the diseased kidney parallels that of the nephrons of the contralateral normal kidney. These data tend to exclude widespread intrinsic damage to the functioning nephrons by the underlying pathologic processes. From these observations, as well as from certain supporting clinical and experimental observations, it is suggested that the majority of surviving nephrons in the patient with bilateral renal disease similarly are functionally intact. Concepts of the pathologic physiology of the kidney, based on the "intact nephron hypothesis", are presented. Within the framework of this hypothesis it is concluded that (1) the diseased kidney consists of a diminished number of nephrons, most of which retain essentially normal functional abilities; (2) certain of the apparent abnormalities in function in bilateral renal disease may relate to adaptive changes imposed by the decreased nephron population and the attendant derangements in body fluids rather than to structural distortion of nephrons; (3) the over-all flexibility of the diseased kidney decreases as the number of constituent nephrons decreases; but (4) there is an orderly and predictable pattern of excretion for all substances.

Animals↗

PubMed2005

EEG correlates of G-induced loss of consciousness.

INTRODUCTION: Electroencephalographic (EEG) correlates of Gz-induced loss of consciousness (G-LOC) were examined to better understand the mechanisms of G-LOC. METHODS: There were 10 subjects (4 women) who provided 35 G-LOC episodes during which 13 channels of EEG and eye activity were recorded. Subjects simultaneously performed tracking and mathematical tasks prior to and following G-LOC. The performance data and cerebral regional oxygen saturation (rSO2), as measured using near infrared spectroscopy, were correlated with the EEG changes. RESULTS: Across all subjects, seven EEG events were identified and measured. The two most significant were found over widespread scalp sites. They were a 1-2 Hz waveform just prior to G-LOC and a very large, approximately 1 Hz waveform just prior to regaining consciousness. These were associated with a drop of rSO2 levels to approximately 90% of the pre-G-LOC baseline levels. rSO2 levels returned to pre-G-LOC levels within approximately 15 s following G-LOC while EEG and performance measures took approximately 60 s. DISCUSSION: There were two unique EEG waveforms found, one preceding unconsciousness and the other preceding the return to consciousness during G-LOC episodes. Further, the supply of oxygen to the brain was rapidly restored, within approximately 15 s, while the EEG and performance data showed that approximately 60 s were required for the brain to regain functional integrity. The delay in performance and EEG recovery following G-LOC demonstrates that the recovery of brain activity to support cognitive function requires more than just the restoration of normal oxygen levels.

Adult↗

PubMed1986

[Mechanism of the transmission of the causative agents of infectious diseases].

Another interpretation, differing from the commonly acknowledged one, of the transfer mechanism is presented. The factors transporting pathogens in the body are the integral part of the transfer mechanism. They ensure the interrelation of the infectious and epidemic processes. In typical contact infections these factors function integrally as the transfer mechanism consisting of two components. This is the sum total of environment and internal factors, specific for a given pathogenic species. These factors ensure the travel of the pathogens from an infected body to a new one. From this viewpoint, the source of infection cannot be an independent element of the infectious process. It is only a transfer factor. The localization of the pathogen, constituting just one of the stages of its travel route in the body, cannot determine the specificity of the transfer mechanism. Its specificity depends on the properties of the pathogen.

Bacteria↗

PubMed2001

Innovative approaches to the preservation of the peritoneal membrane: from bench to bedside.

The functional integrity of the peritoneal membrane is of critical importance for the long-term success of peritoneal dialysis therapy. In addition to water and solute transport properties, the function of the membrane encompasses complex interactions with immune cells, invading microorganisms, and dialysis fluid components. During chronic peritoneal dialysis, intraperitoneal homeostasis is threatened by the repeated exposure to an unphysiologic environment that is created by the instilled solutions. Whereas their acidic pH and hyperosmolality were shown to primarily induce alterations of acute cell function, long-term peritoneal function might be affected by the repeated exposure to high concentrations of glucose and glucose degradation products. In addition to their intrinsic toxicity, these might induce or accelerate glycation processes, such as formation and deposition of advanced glycation end products in the peritoneal membrane. Presently, a new generation of dual-chambered peritoneal dialysis solutions combining the advantages of neutral pH and reduced glucose degradation products content is being introduced into clinical practice. In addition to an improved in vitro biocompatibility profile, emerging clinical trials of these novel solutions indicate that they might also improve the host defense status, membrane transport characteristics, ultrafiltration capacity, and effluent markers of peritoneal membrane integrity, while being safe and effective in correcting uremic acidosis and providing relief of inflow pain. Overall, these findings suggest that these new dialysis solutions might constitute an important step toward better preservation of long-term peritoneal membrane function during peritoneal dialysis.

Dialysis Solutions↗

PubMed2007

Microdamage and altered vascularity at the enthesis-bone interface provides an anatomic explanation for bone involvement in the HLA-B27-associated spondylarthritides and allied disorders.

OBJECTIVE: To describe the basis for entheseal-associated bone disease in the spondylarthritides, by analyzing microanatomic and histopathologic relationships between soft tissue, bone cortex, and adjacent trabeculae. METHODS: Serial sections from 52 entheses were examined; these entheses encompassed small and large insertions in the upper limb (n = 21), lower limb (n = 27), and spine (n = 4) from 60 cadavers. Enthesis microdamage (fissuring) as well as vascular and reparative changes were evaluated. Contact radiographs were used to ascertain the relationship between entheses and the trabecular network. RESULTS: At virtually all fibrocartilaginous entheses, the deep cortical boundary was extremely thin (typically 50-600 microm) or indistinguishable, and 96% of entheses had small holes in the cortical shell (typically 100-400 microm wide). Such regions were frequent sites of bone formation and renewal (96%) and microdamage (31%); these changes were more common in the lower limb. The presence of blood vessels near holes in the cortical shell was common; in 85% of attachments, blood vessels were present on the soft tissue side of the enthesis. Highly orientated trabeculae were more obvious in the lower limb than the upper limb (59% versus 29%). CONCLUSION: The trabecular network supporting the cortical shell is an integral part of the enthesis, transferring load to an extensive skeletal region. In many cases, tendons/ligaments are anchored directly to such networks. This functional integration is associated with microdamage and repair at the hard tissue-soft tissue interface. These findings have implications for understanding bone involvement in SpA and for the SpA concept in general, especially the hypothesis that enthesis-bone architecture may be important in disease initiation.

Aged↗

PubMed1990

Heterogeneity of polyoma tumors in hamsters: analysis of cytoskeletal proteins and viral gene expression.

Murine polyomavirus-induced hamster tumors revealed an unexpected heterogeneity with respect to patterns of cytoskeletal proteins expressed in different visceral and subcutaneous tumors and with respect to viral gene expression early during tumor outgrowth. All tumors analyzed expressed vimentin. Desmin was found in all heart tumors, to variable degrees in kidney tumors and in trace amounts only in 1 out of 4 s.c. tumors. The alpha-smooth-muscle actin isoform was observed in heart tumors only and was restricted to structures that we interpret as being proliferating pericytes or proliferating smooth-muscle cells of the media. In kidneys of infected newborn animals and before the appearance of macroscopic tumors, viral early mRNAs were transcribed from free viral genomes. In tumor tissue the size of the viral transcripts was altered, suggesting that they were transcribed from integrated viral DNA. Since in each tumor discrete bands of viral RNAs were detected, individual tumors arose presumably from single cells and one functional integration event. In contrast, in situ hybridizations of kidney tissue and tumors showed large quantitative differences in viral gene expression not only between different tumors but also between individual cells of the same tumor.

Animals↗

PubMed1992

Cardiac fibroblasts: function, regulation of gene expression, and phenotypic modulation.

Cardiac fibroblasts constitute the majority of the non-myocyte cell population in the ventricular myocardium. These cells are located in the interstitium, in areas between and surrounding cardiac myocytes. Cardiac fibroblasts are responsible for the synthesis of extracellular matrix proteins such as fibrillar collagen types I and III, basement membrane type IV collagen, fibronectin, and laminin. In addition to its role in muscle development and myoblast differentiations, extracellular matrix consisting primarily of fibrillar collagen is an intricate and highly organized structure that serves to support cardiac myocytes and to maintain functional integrity of the myocardium. Balanced synthesis and degradation of this matrix is the key to normal development of cardiac muscle and perfect myocardial function. Collagen remodeling and accumulation has been demonstrated in several experimental models of cardiac hypertrophy. To gain insights into molecular and cellular mechanisms that affect cardiac fibroblast behavior, cardiac fibroblasts from rat and rabbit ventricular myocardium were cultured and the impact of neurotransmitters and growth factors such as norepinephrine and transforming growth factor--beta (TGF-beta 1), to which cardiac fibroblasts are exposed in vivo, was studied. Results of these studies, with regards to gene expression, proliferation and differentiation of cardiac fibroblasts in culture, and their biological implications are discussed.

Animals↗

PubMed2006

Isolation of mutations synthetic-lethal to prohibitin 2 null mutants of Saccharomyces cerevisiae.

Prohibitins are ubiquitous, abundant proteins found in a wide range of organisms and that have a high degree of sequence conservation. In yeast it has previously been demonstrated that prohibitin proteins form a complex and are involved in maintaining the morphological and functional integrity of mitochondria. We have used a colony-sectoring assay as a screen for mutants that are dependent upon the presence of functional Phb2p in the cell. Two classes of prohibitin dependent mutation (pbd1 and pbd2) were isolated and characterised. The effect of these mutations on replicative lifespan was determined, demonstrating that the pbd1 mutant slightly extended lifespan, whereas in contrast, the pbd2 mutation resulted in a shortening in both the mean- and the maximum-lifespan. The pbd1 mutation was also found to reduce chronological lifespan. Reducing the expression of the PHB2 gene in the pbd mutants was found to retard the rate of growth and to affect replicative lifespan. As the two mutants behave in a different manner they probably affect different aspects of prohibitin function.

Cell Division↗

PubMed1992

Validation of the antral mucosal/submucosal sleeve preparation: studies of gastrin and acetylcholine release in response to luminal stimulation.

In the present study we developed an experimental model for direct assessment of antral endocrine cell and cholinergic neural responses to luminal stimulation. A sleeve of antral mucosal/submucosal tissue was prepared from rat antrum, mounted in perfusion chamber, and perfused in both luminal and submucosal compartments. Morphological and functional integrity of the antral sleeve were confirmed by histological examination and measurement of protein synthesis. Antral gastrin release was assessed in response to luminal stimulation with acid, peptone and distension. Luminal acid (pH3) inhibited basal gastrin release by -70.4% and luminal peptone stimulated gastrin release to 210% above control (p < 0.02). Distention of the antral sleeve by hydrostatic pressure (3-25cm H2O) caused stepwise and significant increase in gastrin release that was reversible. 3H-acetylcholine was stimulated significantly by KCl (56mM) to values twice control. In summary, these results establish the integrity and responsiveness of the antral sleeve to pharmacological and luminal stimulation. The antral sleeve may be a useful model in assessing antral function in response to luminal stimulation.

Acetylcholine↗