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PubMed2004

Characterizing function-structure relationships in the human visual system with functional MRI and diffusion tensor imaging.

A key objective in neuroscience is to improve our understanding of the relationship between brain function and structure. We investigated this in the posterior visual pathways of healthy volunteers by applying functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) with tractography. The optic radiations were segmented using the Probabilistic Index of Connectivity (PICo) tractography algorithm and extracted at several thresholds of connection confidence. The mean fractional anisotropy (FA) of the estimated tracts was found to correlate significantly with fMRI measures of visual cortex activity (induced by a photic stimulation paradigm). The results support the hypothesis that the visual cortical fMRI response is constrained by the external anatomical connections of the subserving optic radiations.

Adult↗
PubMed2004

Functional interaction among opioid receptor types: up-regulation of mu- and delta-opioid receptor functions after repeated stimulation of kappa-opioid receptors.

It has been widely accepted that repeated administration of kappa-opioid receptor agonists leads to the development of antinociceptive tolerance. The present study was designed to investigate the effect of repeated administration of a selective kappa-opioid receptor agonist (1S-trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-benzeneacetamide hydrochloride ((-)U-50,488H) on the mu- and delta-opioid receptor agonist-induced antinociception and G-protein activation in mice. The mice were injected either subcutaneously (s.c.) or intracerebroventricularly (i.c.v.) pretreated with saline or (-)U-50,488H once a day for seven consecutive days. Two hours after the last injection, the mice were challenged by either mu- or delta-opioid receptor agonist for the antinociceptive assay. Repeated treatment with (-)U-50,488H (s.c. or i.c.v.) significantly enhanced antinociceptive effect of both mu-opioid receptor agonist (morphine) and delta-opioid receptor agonists ([d-Ala2]deltorphin (DELT) and (+)-4-[(alphaR)-alpha-((2S,5R)-4-allyl-2,5-dime thyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC-80) compared to saline-treated groups. Under these conditions, repeated s.c. injection of (-)U-50,488H significantly enhanced both mu- and delta-opioid receptor agonist-stimulated [35S]GTPgammaS binding in the membrane of the thalamus. On the contrary, either repeated administration of morphine (s.c. or i.c.v.) or SNC-80 failed to affect the kappa-opioid receptor agonist-induced antinociception and G-protein activation. Taken together, these results suggest that repeated stimulation of kappa-opioid receptor markedly increases the functional mu- and delta-opioid receptors, whereas repeated stimulation of either mu- or delta-opioid receptor had no direct effect on kappa-opioidergic function in mice.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed2006

Is it possible to improve elderly male bladder function by having them drink more water? A randomized trial of effects of increased fluid intake/urine output on male lower urinary tract function.

OBJECTIVES: Several animal studies have shown that bladder performance improves as a result of diuresis. Whether increased urine output also has beneficial effects on elderly male bladder function and lower urinary tract symptoms is unknown. METHODS: We performed a randomized placebo-controlled trial of 141 men, 55 to 75 years of age, with moderate lower urinary tract symptoms. The experimental group drank 1.5 L of extra water daily. The control group consumed one tablespoon of placebo syrup daily. After 6 months, we evaluated bladder contractility, voided volumes, and the severity of lower urinary tract symptoms. The actual increase in water consumption was measured using the deuterium urine dilution method. RESULTS: Water consumption in the intervention group increased by 359 mL (95% confidence interval [CI] 171 to 548) per 24 hours compared with the control group. At 6 months, no statistically significant effect was found in the maximal flow rate (0.9 mL/s, 95% CI -0.4 to 2.2) compared with placebo. A statistically significant effect was found for bladder pressure (20 cm H2O, 95% CI 6 to 34) and bladder wall stress (1.9 N/cm2, 95% CI 0.3 to 3.5). In addition, it showed that the experimental group had greater maximal (44 mL, 95% CI -1 to 90) and average (26 mL, 95% CI 1 to 51) voided volumes per urination. The subjective effect parameters improved in both groups, but no statistically significant differences were found between the two groups. CONCLUSIONS: It seems possible to improve some aspects of male bladder function by drinking more water. However, the effects are too small to be clinically relevant.

Aged↗
PubMed2005

Human papillomavirus 16 L2 inhibits the transcriptional activation function, but not the DNA replication function, of HPV-16 E2.

In this study we analysed the outcome of the interaction between HPV-16 L2 and E2 on the transactivation and DNA replication functions of E2. When E2 was expressed on its own, it transactivated a number of E2-responsive promoters but co-expression of L2 led to the down-regulation of the transcription transactivation activity of the E2 protein. This repression is not mediated by an increased degradation of the E2 protein. In contrast, the expression of L2 had no effect on the ability of E2 to activate DNA replication in association with the viral replication factor E1. Deletion mutagenesis identified L2 domains responsible for binding to E2 (first 50 N-terminus amino acid residues) and down-regulating its transactivation function (residues 301-400). The results demonstrate that L2 selectively inhibits the transcriptional activation property of E2 and that there is a direct interaction between the two proteins, although this is not sufficient to mediate the transcriptional repression. The consequences of the L2-E2 interaction for the viral life cycle are discussed.

Capsid Proteins↗
PubMed2006

Cortical visual function in the rd12 mouse model of Leber Congenital Amarousis (LCA) after gene replacement therapy to restore retinal function.

One eye of rd12 mice received a sub-retinal injection of a vector carrying normal human RPE65 cDNA at post-natal day 18, and at 6- and 13-months of age. Electroretinograms (ERGs) and visual-evoked potentials (VEPs) were recorded to luminance, and to spatially and temporally modulated stimuli to assess the consequences of delayed treatment on visual pathway function. Early treatment resulted in better overall retinal rescue and better rescue of cone-mediated function. VEPs to low temporal frequency luminance modulation were well preserved at all but the oldest treatment age and corresponded to predictions based on the amount of retinal rescue. In contrast, VEPs to high frequency spatially and temporally modulated stimuli were impaired even at the earliest age. These results provide further support that early treatment in human LCA will have the most hope for optimal visual performance.

Animals↗
PubMed1997

Endothelial function as a determinant of vascular function and structure: a new therapeutic target.

Recent insights into the pathogenesis of vascular disease have opened up a new frontier that has implications for future therapies. The vasculature has been redefined as a vital organ that can regulate its own tone and structure via numerous cellular mechanisms. The endothelium plays the role of gatekeeper in this process, sensing and responding to stimuli and activating various vasoactive systems that function as mediators. Locally generated vasoactive substances such as angiotensin II and nitric oxide appear to be important determinants of vessel function and structure. Vasoactive substances generated within the endothelium influence cell proliferation and cell death in a complex interplay that, when disturbed, can result in structural alteration known as vascular remodeling. Normal vascular homeostasis is maintained by a balance between vasoconstrictors such as angiotensin II and vasodilators such as nitric oxide. Endothelial dysfunction involves an imbalance between vasoactive substances such that perturbations in the regulation of tone, hemostasis, and vessel structure result in the development of cardiovascular diseases, such as hypertension, atherosclerosis, and heart failure.

Animals↗
PubMed1999

Human Na(+)-dependent vitamin C transporter 1 (hSVCT1): primary structure, functional characteristics and evidence for a non-functional splice variant.

We report here on the cloning and functional characterization of human Na(+)-dependent vitamin C transporter 1 (SVCT1). The human SVCT1 cDNA, obtained from a Caco2 cell cDNA library, encodes a protein of 598 amino acids with 12 putative transmembrane domains. The SVCT1-specific transcript, 2.4 kb in size, is expressed in kidney, liver, small intestine, thymus and prostate. When expressed heterologously in HRPE cells, SVCT1 mediates the transport of ascorbate, the reduced form of vitamin C, in a Na(+)-dependent manner. The transporter is specific for ascorbate with a K(t) of approximately 75 microM. The relationship between the cDNA-specific uptake rate of ascorbate and Na(+) concentration is sigmoidal with a Na(+):ascorbate stoichiometry of 2:1, indicating that the transport process is electrogenic. In Caco2 cells and in normal human intestine, SVCT1 also exists as a non-functional splice variant with a four amino acid sequence inserted between E-155 and V-156. The splice variant results from the use of a donor site 12 bp downstream of the normal donor site.

Amino Acid Sequence↗
PubMed2003

A novel function of connexin 32: marked enhancement of liver function in a hepatoma cell line.

Connexin 32 (Cx32) is the main gap junction protein in hepatocytes and plays an important role in the regulation of signal transfer and growth control in the liver by constructing gap junction channels and gap junctional intercellular communication (GJIC). In this study, the human Cx32 gene was transfected into a hepatoma cell line (HepG2) that showed aberrant expression of Cx32 and was deficient in GJIC. Cx32-transfected HepG2 not only expressed a higher level of Cx32 mRNA, but also showed increased GJIC compared with HepG2 and vector-transfected HepG2. Furthermore, the liver functions of ammonia removal and albumin secretion of HepG2 were markedly enhanced with Cx32 gene transfection. It may be expected to improve the cellular functions of the hepatoma cell line by Cx32 gene transfection and serve to develop an efficacious bioartificial liver.

Albumins↗
PubMed1993

Structure-dynamics-function relationships in Asian elephant (Elephas maximus) myoglobin. An optical spectroscopy and flash photolysis study on functionally important motions.

In this work we report the thermal behavior (10-300 K) of the Soret band lineshape of deoxy and carbonmonoxy derivatives of Asian elephant (Elephas maximus) and horse myoglobins together with their carbon monoxide recombination kinetics after flash photolysis; the results are compared to analogous data relative to sperm whale myoglobin. The Soret band profile is modeled as a Voigt function that accounts for the coupling with high and low frequency vibrational modes, while inhomogeneous broadening is taken into account with suitable distributions of purely electronic transition frequencies. This analysis makes it possible to isolate the various contributions to the overall lineshape that; in turn, give information on structural and dynamic properties of the systems studied. The optical spectroscopy data point out sizable differences between elephant myoglobin on one hand and horse and sperm whale myoglobins on the other. These differences, more pronounced in deoxy derivatives, involve both the structure and dynamics of the heme pocket; in particular, elephant myoglobin appears to be characterized by larger anharmonic contributions to soft modes than the other two proteins. Flash photolysis data are analyzed as sums of kinetic processes with temperature-dependent fractional amplitudes, characterized by discrete pre-exponentials and either discrete or distributed activation enthalpies. In the whole temperature range investigated the behavior of elephant myoglobin appears to be more complex than that of horse and sperm whale myoglobins, which is in agreement with the increased anharmonic contributions to soft modes found in the former protein. Thus, to satisfactorily fit the time courses for CO recombination to elephant myoglobin five distinct processes are needed, only one of which is populated over the whole temperature range investigated. The remarkable convergence and complementarity between optical spectroscopy and flash photolysis data confirms the utility of combining these two experimental techniques in order to gain new and deeper insights into the functional relevance of protein fluctuations.

Animals↗
PubMed2001

Functional alterations in gap junction channels formed by mutant forms of connexin 32: evidence for loss of function as a pathogenic mechanism in the X-linked form of Charcot-Marie-Tooth disease.

CMTX, the X-linked form of Charcot-Marie-Tooth disease, is an inherited peripheral neuropathy arising in patients with mutations in the gene encoding the gap junction protein connexin 32 (Cx32). In this communication, we describe the expression levels and biophysical parameters of seven mutant forms of Cx32 associated with CMTX, when expressed in paired Xenopus oocytes. Paired oocytes expressing the R15Q and H94Q mutants show junctional conductances not statistically different from that determined for Cx32WT, though both show a trend toward reduced levels. The S85C and G12S mutants induce reduced levels of junctional conductance. Three other mutants (R15W, H94Y and V139M) induce no conductance above baseline when expressed in paired oocytes. Analysis of the conductance voltage relations for these mutants shows that the reduced levels of conductance are entirely (H94Y and V139M) or partly (S85C and R15W) explicable by a reduced open probability of the mutant hemichannels. The R15Q and H94Q mutations also show alterations in the conductance voltage relations that would be expected to minimally (H94Q) or moderately (R15Q) reduce the available gap junction communication pathway. The reduction in G12S induced conductance cannot be explained by alterations in hemichannel open probability and are more likely due to reduced junction formation. These results demonstrate that many CMTX mutations lead to loss of function of Cx32. For these mutations, the loss of function model is likely to explain the pathogenesis of CMTX.

Amino Acid Substitution↗
PubMed1997

Functional mapping reveals the importance of yeast cytochrome b C-terminal region in assembly and function of the bc1 complex.

Genetic and molecular analyses have been undertaken for four respiratory deficient mutants (mit-). The four mutations affect the C-terminal region of apocytochrome b. The frameshift (L263STOP) and non-sense (Q338STOP) mutations give rise to a truncated apocytochrome b. The mutant G337R conserves only 32% of its NADH oxidase activity which suggests that the presence of a positively charged amino acid in the transmembranous helix 7 of cytochrome b alters, either directly or indirectly, the bc1 function, without affecting its assembly. The mutation G352V has a 65% loss of cytochrome b spectral content and prevents all of the mitochondrial respiratory activity. This leads us to believe that the glycine, conserved in position 352, may play a crucial role in bc1 complex function.

Amino Acid Sequence↗
PubMed1998

Mutations at position 1122 in the catalytic domain of the mouse ras-specific guanine nucleotide exchange factor CDC25Mm originate both loss-of-function and gain-of-function proteins.

The role of two residues within the catalytic domain of CDC25Mm, a mouse ras-specific guanine nucleotide exchange factor (GEF), was investigated by site-directed mutagenesis. The function of the mutant proteins was tested in vivo in both a Saccharomyces cerevisiae cdc25 complementation assay and in a mammalian fos-luciferase assay, and in in vitro assays on human and yeast Ras proteins. Mutants CDC25Mm(E1048K) and CDC25Mm(S1122V) were shown to be (partly) inactive proteins, similar to their yeast homologs. Mutant CDC25Mm(S1122A) showed higher nucleotide exchange activity than the wild type protein on the basis of both in vitro and in vivo assays. Thus, alanine and valine substitutions at position 1122 within the GEF catalytic domain originate mutations with opposite biological properties, indicating an important role for position 1122 in GEF function.

3T3 Cells↗
PubMed1999

The ALSFRS-R: a revised ALS functional rating scale that incorporates assessments of respiratory function. BDNF ALS Study Group (Phase III).

The ALS Functional Rating Scale (ALSFRS) is a validated rating instrument for monitoring the progression of disability in patients with amyotrophic lateral sclerosis (ALS). One weakness of the ALSFRS as originally designed was that it granted disproportionate weighting to limb and bulbar, as compared to respiratory, dysfunction. We have now validated a revised version of the ALSFRS, which incorporates additional assessments of dyspnea, orthopnea, and the need for ventilatory support. The Revised ALSFRS (ALSFRS-R) retains the properties of the original scale and shows strong internal consistency and construct validity. ALSFRS-R scores correlate significantly with quality of life as measured by the Sickness Impact Profile, indicating that the quality of function is a strong determinant of quality of life in ALS.

Activities of Daily Living↗
PubMed2001

A loss-of-function mutation of c-kit results in depletion of mast cells and interstitial cells of Cajal, while its gain-of-function mutation results in their oncogenesis.

Loss-of-function mutations of the c-kit receptor tyrosine kinase (KIT) result in depletion of mast cells and interstitial cells of Cajal (ICCs). In contrast, gain-of-function mutations of KIT induce neoplasms of mast cells and ICCs. In humans, the sites of mutations are different between mast cell neoplasms and those of ICCs. The former were found in the juxtamembrane domain between the transmembrane and tyrosine kinase domains, and the latter in the tyrosine kinase domain. Moreover, the mechanism of constitutive activation is different. Point mutations and/or deletions in the juxtamembrane domain induced the KIT dimerization, and the dimerized KIT was activated. A point mutation at the particular aspartic acid in the tyrosine kinase domain induced spontaneous activation without forming dimers. Mutations of the c-kit gene are a good model for understanding the relationship between mutations and diseases in both humans and mice.

Animals↗
PubMed2002

Functionally rodless mice: transgenic models for the investigation of cone function in retinal disease and therapy.

Two genetically engineered strains of mice were used to characterize murine cone function electroretinographically, without interference of rod-driven responses: (1) mice with a deletion of the gene for the rod transducin alpha-subunit (transducin alpha-/-), and (2) mice with rod arrestin deleted (arrestin -/-). In the first three months of age, both strains have a normal complement of rods and normal rod structure, but transducin alpha-/- mice have no rod-driven responses to light, while rod-driven activity of arrestin -/- mice can be suppressed by a single intense flash for hours. In response to intense flashes the electroretinograms of these strains of mice showed a readily identifiable, pure-cone a-wave of approximately 10 microV saturating amplitude. A 530 nm background that saturates rod responses of wild type mice was found to desensitize the b-wave responses of mice of both transgenic lines, whether the b-waves were driven by photons captured by M- or UV-cone pigments. The desensitizing effect of the 530 nm background on UV-pigment driven responses provides new evidence in support of the hypothesis of functional co-expression of the M-pigment in cones expressing primarily the UV-pigment.

Animals↗
PubMed1999

Diagnostic evaluation of the erectile function domain of the International Index of Erectile Function.

OBJECTIVES: To evaluate the erectile function (EF) domain of the International Index of Erectile Function (IIEF) as a diagnostic tool to discriminate between men with and without erectile dysfunction (ED) and to develop a clinically meaningful gradient of severity for ED. METHODS: One thousand one hundred fifty-one men (1035 with and 116 without ED) who reported attempting sexual activity were evaluated using data from four clinical trials of sildenafil citrate (Viagra) and two control samples. The statistical program Classification and Regression Trees was used to determine optimal cutoff scores on the EF domain (range 6 to 30) to distinguish between men with and without ED and to determine levels of ED severity on the EF domain using the IIEF item on sexual intercourse satisfaction. RESULTS: For a 0.5 prevalence rate of ED, the optimal cutoff score was 25, with men scoring less than or equal to 25 classified as having ED and those scoring above 25 as not having ED (sensitivity 0.97, specificity 0.88). Sensitivity analyses revealed a robust statistical solution that was well supported with different assumed prevalence rates and several cross-validations. The severity of ED was classified into five categories: no ED (EF score 26 to 30), mild (EF score 22 to 25), mild to moderate (EF score 17 to 21), moderate (EF score 11 to 16), and severe (EF score 6 to 10). Substantial agreement was shown between these predicted and "true" classes (weighted kappa 0.80). CONCLUSIONS: The EF domain possesses favorable statistical properties as a diagnostic tool, not only in distinguishing between men with and without ED, but also in classifying levels of ED severity. Clinical validation with self-rated assessments of ED severity is warranted.

Erectile Dysfunction↗
PubMed1998

Immune function alterations in mice tolerant to delta9-tetrahydrocannabinol: functional and biochemical parameters.

We studied the effect of acute (1 h) or chronic exposure (7 and 14 days) to delta9-tetrahydrocannabinol (delta9-THC) on immune parameters in male Swiss mice. One hour after a dose of 10 mg/kg s.c., the splenocyte proliferative response to ConA and NK activity were not inhibited, but there was a significant decrease in the production of IL-2. After 7 days of treatment, when mice were tolerant to delta9-THC-induced analgesia, these functional parameters were strongly inhibited and there was a persistent reduction in IL-2 and IFNgamma. With 14 days exposure to the drug, splenocyte proliferation was significantly reduced only with 5 microg/ml ConA, and NK activity was still significantly depressed (about 37%). IL-2 had returned to the control value, whereas IFNgamma was still 40% down. Flow cytometry analysis of spleen cell composition indicated no changes after the acute and 7 day treatments, but at 14 days there was a 20% decrease in the number of T lymphocytes, mirrored by a 26% increase of B lymphocytes. In conclusion, in vivo exposure to psychoactive doses of delta9-THC has profound effects on immune function. This implies some important questions in relation to the liberalization of marijuana and its therapeutic uses.

Animals↗