Miracle-dz/UniFAR-FTUs huggingface dataset:
Influence of rabeprazole and lansoprazole on the pharmacokinetics of tacrolimus in relation to CYP2C19, CYP3A5 and MDR1 polymorphisms in renal transplant recipients

The objective of this study was to evaluate whether genetic polymorphisms of CYP2C19, CYP3A5 and MDR1 significantly impact the interaction between tacrolimus and rabeprazole or lansoprazole. Seventy‐three recipients were randomly assigned after renal transplantation to receive repeated doses of tacrolimus for 28 days with a regimen of either 20 mg of rabeprazole or 30 mg of lansoprazole. Blood concentrations of tacrolimus were measured by microparticle enzyme immunoassay. The mean daily dose and the dose‐adjusted area under the plasma concentration‐time curves from 0 to 12 h (AUC0–12) of tacrolimus coadministered with rabeprazole or lansoprazole were the lowest and highest, respectively, in CYP2C19 poor metabolizers (PMs) having the CYP3A5*3/*3 genotype (0.084 and 0.112 mg/kg/day and 1.269 and 1.033 ng·h/ml/mg/kg, respectively). On the other hand, the mean dose‐adjusted AUC0−12 of tacrolimus coadministered with rabeprazole or lansoprazole were the highest in CYP2C19 PMs having the MDR13435CC+CT genotype, but not significantly.
Steady state analysis of the CLMS and augmented CLMS algorithms for noncircular complex signals

The recently introduced augmented complex least mean square (ACLMS) algorithm is shown to be suitable for the processing of both second order circular (proper) and noncircular (improper) signals, by virtue of the underlying widely linear model. In theory, both the linear CLMS and widely linear ACLMS achieve the same mean square error for propers signals, whereas the ACLMS exhibits lower mean square error for improper signals. However, improperness can arise due to the system noise, input, or channel model and to shed more light on the convergence and steady state properties of ACLMS and CLMS in these cases we here employ the energy conservation principle. Simulations in adaptive prediction and system identification settings for signals with different probability distributions and degrees of noncircularity support the the analysis.
Intermolecular energy transfer in the bioluminescent system of Aequorea.

The jellyfish Aequoreci emits green light whereas the photoprotein aequorin extracted from the same organism emits blue light when Ca2+ is added. Because the photogenic cells contain a green fluorescent protein (GFP) in addition to aequorin, an energy transfer from the light emitter of aequorin to GFP has been postulated. In the present study, GFP has been purified, crystallized, and partially characterized and an energy transfer in citro from aequorin to this protein has been demonstrated. GFP was found to consist of several kinds of isomeric proteins, of which two kinds predominated. After separation, both kinds evinced the same absorption maxima T he bioluminescent jellyfish Aequorea emits "green light" in cico, whereas the pure photoprotein aequorin extracted from the same organism emits "blue" light on addition of Ca? -. This difference, along with some of the properties of the purified aequorin and also the occurrence of a green fluores- cent protein in the luminescent extract, was first reported over 10 years ago (Shimomura et al., 1962). The blue light (A,,,,, 470 nm) of aequorin (mol wt ca. 30,000; Shimomura and Johnson, 1969; Kohama et a/., 1971) results from an intramolecular reaction when Ca2+ is added, yielding a reaction product "BFP" ("blue fluorescent protein") which shows a fluorescence spectrum corresponding exactly to the bioluminescence spectrum (Shimomura and Johnson, 1970a). The chemical structure of the light emitting chromophore has been recently determined to be 2-(p-hydroxyphenylacetyl)- atnino-3-benzyl-5-(p-hydroxyphenyl)pyrazine (Shimomura
The gating effect of calmodulin and calcium on the connexin50 hemichannel

Abstract Gap junction channels formed by connexin50 (Cx50) are critical for the maintenance of eye lens transparency, which is sensitive to pH and external Ca2+ concentration, but the mechanism is still not clear. In this study we performed dye uptake-leakage assays, patch clamping and confocal co-localization experiments to confirm the function of calmodulin (CaM) and Ca2+ in the Cx50 hemichannel. Below pH 7.4, lucifer yellow (LY)-preloaded Cx50-HeLa cells allow dye to leak out when washed with Ca2+-free solution or incubated in solution containing 50 μg/ml W7 (CaM inhibitor) first, then washed in solution containing 2 mM Ca2+, whereas little or no dye leakage was observed when LY-preloaded Cx50-HeLa cells were incubated in solution containing 2 mM Ca2+. Moreover, in the absence of Ca2+, polarizing pulses applied to Cx50-HeLa activated outward transmembrane currents, which were inhibited by 2 mM external Ca2+. When Cx50-HeLa cells were incubated with 2 mM Ca2+and 50 μg/ml W7, the transmembrane currents were activated again. This indicates that Ca2+ and CaM play a gating role in Cx50 hemichannels. Either the chelation of Ca2+ or the inhibition of CaM increased the permeability of Cx50 hemichannels. The same phenomena were observed below pH 6.5. Furthermore, CaM could be localized in gap junctions formed by Cx50 below pH 6.5. Our results demonstrate that CaM and Ca2+ can cooperate in the gating control of Cx50 hemichannels.
Functional reorganization in adult monkey thalamus after peripheral nerve injury

LARGE changes in somatotopic organization can be induced in adult primate somatosensory cortex by cutting peripheral afferents. The role, if any, of the thalamus in these changes has not been investigated previously. In the present experiments, electrophysiological recording in the ventroposterior lateral nucleus (VPL) has revealed that not only can reorganization occur in the thalamus, but it may be as extensive as that revealed in the cortex of the same monkeys. Thus, for at least some types of deafferentation, the reorganization revealed in the cortex may depend largely on subcortical changes.
MIDTERM OUTCOME AFTER MICROENDOSCOPIC DECOMPRESSIVE LAMINOTOMY FOR LUMBAR SPINAL STENOSIS: 4‐YEAR PROSPECTIVE STUDY

OBJECTIVETo evaluate the efficacy of radicular decompression in lumbar spinal stenosis using a microendoscopic technique. METHODSThis was a longitudinal prospective study of 50 patients with a diagnosis of lumbar spinal stenosis who were treated by microendoscopic decompression using an 18-mm METRx tubular retractor according to the METRx technique (Medtronic Sofamor Danek, Memphis, TN). Twenty of the patients had an additional disc prolapse, and a microendoscopic discectomy was associated with decompressive laminectomy. The results were evaluated using the visual analog scale pain score, Oswestry Disability Index score, patient satisfaction questionnaire, and modified Macnab classification. RESULTSThe average age of the patients was 56 years; 29 (58%) were men and 21 (42%) were women. The most commonly affected level was L4–L5 (64%). The mean surgical intervention time was 94.3 (± 14.3) minutes. Mean postoperative hospital stay was 3.16 (± 2.3) days. The follow-up time after surgery was 4 years (48 ± 6.6 months; range, 24–72 months). We obtained good or excellent results in 72% of patients, achieving good subjective satisfaction in 68% of the patients. The mean decrease in the Oswestry Disability Index score was 30.23 (± 24.29), the mean decrease in the leg pain visual analog scale score was 6.02 (± 2.57), and the mean decrease in the lumbar pain visual analog scale score was 0.84 (± 2.06). Adjusted mean differences were in all cases statistically significant (P < 0.05). CONCLUSIONData indicate that, in our experience, on midterm follow-up, microendoscopic laminectomy decompression is an effective technique for the treatment of lumbar spinal stenosis.
Brucellosis: a study of five calves from reactor dams

Five calves from Brucella abortus reactor cows bought after they had been on infected farms for two to six weeks, were reared in isolation and examined serologically for approximately six months prior to cultural and biological examination post mertem. One calf which had been serologically negative to the Rose-Bengal, serum agglutination and complement fixation tests for the last eight weeks of its life yielded a culture of Br abortus biotype 1. This serotype had also been isolated from its dam at parturition.
Prevalence, incidence and types of mild anemia in the elderly: the “Health and Anemia” population-based study

Background Hemoglobin concentrations slightly below the lower limit of normal are a common laboratory finding in the elderly, but scant evidence is available on the actual occurrence of mild anemia despite its potential effect on health. The objectives of this study were to estimate the prevalence and incidence of mild grade anemia and to assess the frequency of anemia types in the elderly. Design and Methods This was a prospective, population-based study in all residents 65 years or older in Biella, Italy. Results Blood test results were available for analysis from 8,744 elderly. Hemoglobin concentration decreased and mild anemia increased steadily with increasing age. Mild anemia (defined as a hemoglobin concentration of 10.0–11.9 g/dL in women and 10.0–12.9 g/dL in men) affected 11.8% of the elderly included in the analysis, while the estimated prevalence in the entire population was 11.1%. Before hemoglobin determination, most mildly anemic individuals perceived themselves as non-anemic. Chronic disease anemia, thalassemia trait, and renal insufficiency were the most frequent types of mild anemia. The underlying cause of mild anemia remained unexplained in 26.4% of the cases, almost one third of which might be accounted for by myelodysplastic syndromes. In a random sample of non-anemic elderly at baseline (n=529), after about 2 years, the annual incidence rate of mild anemia was 22.5 per 1000 person-years and increased with increasing age. Conclusions The prevalence and incidence of mild anemia increase with age and mild anemia affects more than one out of ten elderly individuals. Unexplained anemia is common and may be due to myelodysplastic syndromes in some cases.
CACNA1H Mutations in Autism Spectrum Disorders*

Autism spectrum disorders (ASD) are neurodevelopmental conditions characterized by impaired social interaction, communication skills, and restricted and repetitive behavior. The genetic causes for autism are largely unknown. Previous studies implicate CACNA1C (L-type CaV1.2) calcium channel mutations in a disorder associated with autism (Timothy syndrome). Here, we identify missense mutations in the calcium channel gene CACNA1H (T-type CaV3.2) in 6 of 461 individuals with ASD. These mutations are located in conserved and functionally relevant domains and are absent in 480 ethnically matched controls (p = 0.014, Fisher's exact test). Non-segregation within the pedigrees between the mutations and the ASD phenotype clearly suggest that the mutations alone are not responsible for the condition. However, functional analysis shows that all these mutations significantly reduce CaV3.2 channel activity and thus could affect neuronal function and potentially brain development. We conclude that the identified mutations could contribute to the development of the ASD phenotype.
Aquaporins contribute to diarrhoea caused by attaching and effacing bacterial pathogens

Attaching and effacing (A/E) pathogens such as enterohemorrhagic Escherichia coli (EHEC) and enteropathogenic E. coli (EPEC) cause serious global health problems. These bacteria colonize the gastrointestinal system, attach to intestinal epithelial cells, efface (collapse) infected cell microvilli and cause overt diarrhoea that may ultimately result in death of the host. Although pathogenically induced diarrhoea is a significant global health issue, the molecular mechanisms that underlie this disease remain largely unknown. A natural murine infection model, employing the A/E pathogen Citrobacter rodentium, has been helpful in studying the diseases in vivo. C. rodentium colonize the colon at high levels, attach to colonocytes, efface microvilli and cause hyperplasia and inflammation in infected mice. As the disease progresses, the mice develop a diarrhoea‐like phenotype. Aquaporin (AQP) water channels have been proposed to play a role in the normal dehydration of faecal contents. Here we examine whether C. rodentium infection may alter AQP localization in colonocytes. We demonstrate that during infection, AQP2 and AQP3 are mislocalized from their normal location along cell membranes to the cell cytoplasm. The change in localization of these proteins correlates with the diarrhoea‐like phenotype present in infected mice. Mice that recover from the infection at 28–35 days post inoculum regain their normal membrane AQP localization. The altered localization of AQPs is partially dependent on the bacterial type III effector proteins EspF and EspG. We conclude that altered AQP localization may be a contributing factor to diarrhoea during bacterial infection.
A novel non‐CB1/TRPV1 endocannabinoid‐mediated mechanism depresses excitatory synapses on hippocampal CA1 interneurons

Endocannabinoids (eCBs) mediate various forms of synaptic plasticity at excitatory and inhibitory synapses in the brain. The eCB anandamide binds to several receptors including the transient receptor potential vanilloid 1 (TRPV1) and cannabinoid receptor 1 (CB1). We recently identified that TRPV1 is required for long‐term depression at excitatory synapses on CA1 hippocampal stratum radiatum interneurons. Here we performed whole‐cell patch clamp recordings from CA1 stratum radiatum interneurons in rat brain slices to investigate the effect of the eCB anandamide on excitatory synapses as well as the involvement of Group I metabotropic glutamate receptors (mGluRs), which have been reported to produce eCBs endogenously. Application of the nonhydrolysable anandamide analog R‐methanandamide depressed excitatory transmission to CA1 stratum radiatum interneurons by ∼50%. The Group I mGluR agonist DHPG also depressed excitatory glutamatergic transmission onto interneurons to a similar degree, and this depression was blocked by the mGluR5 antagonist MPEP (10 μM) but not by the mGluR1 antagonist CPCCOEt (50 μM). Interestingly, however, neither DHPG‐mediated nor R‐methanandamide‐mediated depression was blocked by the TRPV1 antagonist capsazepine (10 μM), the CB1 antagonist AM‐251 (2 μM) or a combination of both, suggesting the presence of a novel eCB receptor or anandamide target at excitatory hippocampal synapses. DHPG also occluded R‐methanandamide depression, suggesting the possibility that the two drugs elicit synaptic depression via a shared signaling mechanism. Collectively, this study illustrates a novel CB1/TRPV1‐independent eCB pathway present in the hippocampus that mediates depression at excitatory synapses on CA1 stratum radiatum interneurons. © 2010 Wiley Periodicals, Inc.
Effects of Aspirin and Other Nonsteroidal Anti-Inflammatory Drugs on Biofilms and Planktonic Cells of Candida albicans

ABSTRACT Prostaglandins are now known to be produced by Candida albicans and may play an important role in fungal colonization. Their synthesis in mammalian cells is decreased by inhibitors of the cyclooxygenase isoenzymes required for prostaglandin formation. In the present study, a catheter disk model system was used to investigate the effects of nonsteroidal anti-inflammatory drugs (all cyclooxygenase inhibitors) on biofilm formation by three strains of C. albicans. Seven of nine drugs tested at a concentration of 1 mM inhibited biofilm formation. Aspirin, etodolac, and diclofenac produced the greatest effects, with aspirin causing up to 95% inhibition. Celecoxib, nimesulide, ibuprofen, and meloxicam also inhibited biofilm formation, but to a lesser extent. Aspirin was active against growing and fully mature (48-h) biofilms; its effect was dose related, and it produced significant inhibition (20 to 80%) at pharmacological concentrations. Simultaneous addition of prostaglandin E2 abolished the inhibitory effect of 25 or 50 μM aspirin. At 1 mM, aspirin reduced the viability of biofilm organisms to 1.9% of that of controls. Surviving cells had a wrinkled appearance, as judged by scanning electron microscopy, and consisted of both yeasts and hyphae. Treatment with other cyclooxygenase inhibitors, such as etodolac, resulted in biofilms that consisted almost entirely of yeast cells. In conventional assays for germ tube formation, these drugs produced significant inhibition, whereas aspirin had little effect. Our findings suggest that cyclooxygenase-dependent synthesis of fungal prostaglandin(s) is important for both biofilm development and morphogenesis in C. albicans and may act as a regulator in these physiological processes. Our results also demonstrate that aspirin possesses potent antibiofilm activity in vitro and could be useful in combined therapy with conventional antifungal agents in the management of some biofilm-associated Candida infections.
Development of a New Model for the Induction of Chronic Kidney Disease via Intraperitoneal Adenine Administration, and the Effect of Treatment with Gum Acacia thereon

Oral adenine (0.75% w/w in feed), is an established model for chronic kidney disease (CKD). Gum acacia (GA) has been shown to be a nephroprotective agent in this model. Here we aimed at developing an adenine‐induced CKD model in rats via a systemic route (intraperitoneal, i.p.) to test it with GA to obviate the possibility of a physical interaction between GA and adenine in the gut. Adenine was injected i.p. (50/100 mg/Kg for four weeks) and GA was given concomitantly in drinking water (15%, w/v). Several plasma and urinary biomarkers of oxidative stress were measured and renal damage was assessed histopathologically. Adenine, at the two given i.p. doses, significantly reduced body weight, and increased relative kidney weight, water intake and urine output. It dose‐dependently increased inflammatory and oxidative stress biomarkers, and caused morphological and histological damage resembling that which has been reported with oral adenine. Concomitant treatment with GA significantly mitigated almost all the above measured indices. Administration of adenine i.p. induced CKD signs very similar to those induced by oral adenine. Therefore, this model is quicker, more practical and accurate than the original (oral) model. GA ameliorates the CKD effects caused by adenine given i.p. suggesting that the antioxidant and anti‐inflammatory properties possessed by oral GA are the main mechanism for its salutary action in adenine‐induced CKD, an action that is independent of its possible interaction with adenine in the gut.
Odorant–Receptor Interactions and Odor Percept: A Chemical Perspective

Receptor–ligand interaction models are generally based on a ‘lock and key’ concept. How far this holds true for olfactory receptors and odor molecules is currently uncertain. Here, we have investigated the response of a human olfactory receptor, OR1D2, to a broad array of odorants and found that there is no simple, direct correlation between a molecule's ability to activate this receptor and the odor impression elicited in the brain. In a parallel study on specific anosmia, we have found no evidence for odor‐specific anosmia to either musk or amber, but rather to specific molecules within these categories. Cluster analysis confirmed that there is no simple correlation between molecular structure and impaired perception in either odor type. There are some differences in patterns of impairment between the two odor types and some evidence to suggest that subjects with specific anosmia to a given substance can identify its presence in a mixture. Taken together, our results show that simplistic ‘lock and key’ models of olfaction based on a concept of odor‐quality‐tuned receptors are inadequate, irrespective of the nature of the lock–key interaction. Receptor activation is only one step in a long chain of events leading from inhalation of odorants to perception of odor in the higher brain, and, therefore, although structure–odor correlations are useful tools for the design of novel odorants, caution should be exercised when extrapolating them to models of olfactory perception. Those seeking to understand the odorant–receptor interaction should use receptor activation rather than odor as input data.
Holistic differential analysis of embryo‐induced alterations in the proteome of bovine endometrium in the preattachment period

During the peri‐implantation period, molecular signaling between embryo and endometrium (layer of tissue lining the uterus lumen) is supposed to be crucial for the maintenance of pregnancy. To investigate embryo‐induced alterations in the proteome of bovine endometrium in the preattachment period (day 18), we used monozygotic cattle twins (generated by embryo splitting) as a model eliminating genetic variability as a source for proteome differences. One of the twins was pregnant after the transfer of two in vitro produced blastocysts, while the corresponding twin received a sham‐transfer and served as a nonpregnant control. The two‐dimensional fluorescence difference gel electrophoresis (2‐D DIGE) analysis of the endometrium samples of three twin pairs (pregnant/nonpregnant) revealed four proteins with significantly higher abundance (p < 10−9) in each sample derived from the pregnant animals: Rho GDP dissociation inhibitor beta; 20 alpha‐hydroxysteroid dehydrogenase (20 alpha‐HSD); soluble NADP+‐dependent isocitrate dehydrogenase 1; and acyl‐CoA‐binding protein. To verify the accuracy of the 2‐D DIGE quantification, the abundances of 20 alpha‐HSD were quantified by a targeted cleavable isotope‐coded affinity tag (ICAT) approach. The mass spectrometry‐based ICAT quantification matched perfectly the results obtained by 2‐D DIGE quantification, demonstrating the accuracy of our data. These results demonstrate that our model (monozygotic twins) in combination with the appropriate analytical tools is particularly suitable for the detection of the proteins involved in the embryo–maternal interactions.