Miracle-dz/UniFAR-FTUs huggingface dataset:
KvLQT1 Modulates the Distribution and Biophysical Properties of HERG

Cardiac repolarization is under joint control of the slow (IKs) and rapid (IKr) delayed rectifier currents. Experimental and clinical evidence indicates important functional interactions between these components. We hypothesized that there might be more direct interactions between the KvLQT1 and HERG α-subunits of IKs and IKr and tested this notion with a combination of biophysical and biochemical techniques. Co-expression of KvLQT1 with HERG in a mammalian expression system significantly accelerated HERG current deactivation at physiologically relevant potentials by increasing the contribution of the fast component (e.g. upon repolarization from +20 mV to -50 mV: from 20 ± 3 to 32 ± 5%, p < 0.05), making HERG current more like native IKr. In addition, HERG current density was approximately doubled (e.g. tail current after a step to +10 mV: 18 ± 3 versus 39 ± 7 pA/picofarad, p < 0.01) by co-expression with KvLQT1. KvLQT1 co-expression also increased the membrane immunolocalization of HERG by ∼2-fold (p < 0.05). HERG and KvLQT1 co-immunolocalized in canine ventricular myocytes and co-immunoprecipitated in cultured Chinese hamster ovary cells as well as in native cardiac tissue, indicating physical interactions between HERG and KvLQT1 proteins in vitro and in vivo. Protein interaction assays also demonstrated binding of KvLQT1 (but not another K+ channel α-subunit, Kv3.4) to a C-terminal HERG glutathione S-transferase fusion protein. Co-expression with HERG did not affect the membrane localization or ionic current properties of KvLQT1. This study shows that the α-subunit of IKs can interact with and modify the localization and current-carrying properties of the α-subunit of IKr, providing potentially novel insights into the molecular function of the delayed rectifier current system.
Factors associated with serum antibodies to reticulin, endomysium, and gliadin in an adult population.

BACKGROUND: Gluten sensitivity is thought to be significantly under-diagnosed in the population. AIMS: The aims of this study were to investigate the prevalence of antibodies associated with coeliac disease in a large representative sample of the adult population and to determine factors that are associated with their presence. PATIENTS: Serum samples from 5420 subjects with approximately equal numbers in each five year group from ages 15 to 65 years were obtained from the Belfast MONICA project and Change of Heart surveys, set up to monitor and assess risk factors associated with coronary heart disease in the population. METHODS: Using immunofluorescence and enzyme linked immunosorbent assay (ELISA) techniques autoantibodies, including those to reticulin, endomysium, and gliadin were determined. RESULTS: The results establish that IgA antigliadin antibody prevalence is high at 5.7%. Antiendomysial antibody was present in 1.2% of samples and gliadin and endomysial antibodies in 0.4%. No significant differences were found between men and women, area of residence in Northern Ireland or the year of sampling over the eight year period. However, there was a significant increase in the prevalence of IgA gliadin antibody, and to a lesser extent IgA endomysial antibody, with increasing age. CONCLUSION: The high prevalence of these positive antibodies suggests that coeliac disease may be relatively common in Northern Ireland.
HIV/AIDS stigma in a South African community

Abstract HIV/AIDS-related stigma threatens to undermine interventions to prevent and treat HIV/AIDS. To address stigma in a South African community, a thorough understanding of the nature of stigma in the specific cultural context is needed. The goals of this research were to assess the level of stigmatising attitudes among members of a community, compare this to the level of stigma that is perceived to exist within the community and determine to what extent stigmatising attitudes are affected by socio-demographic characteristics, HIV-related experience and cultural beliefs. A questionnaire was completed by 1077 respondents in key areas in two communities in Tshwane, South Africa. The questionnaire included an assessment of HIV-related experience, HIV-knowledge, personal stigma and perceptions of stigma within the community. The findings indicate that the level of personal stigma was significantly lower than that perceived to be present in the community. Respondents who were more stigmatising were older, male, less educated and less knowledgeable about HIV. They were less likely to know someone with HIV and had more traditional cultural viewpoints. While socio-demographic and cultural factors are difficult to change, efforts aimed at increasing people's knowledge and experience of the epidemic occurring in their community could change the level of stigmatising attitudes within their community. Such efforts could have potential benefits in addressing the epidemic and providing greater support for those with HIV.
Polyproline‐type helical‐structured low‐molecular weight heparin (LMWH)‐taurocholate conjugate as a new angiogenesis inhibitor

Although heparin can regulate angiogenesis, tumor growth and metastasis, its clinical application, as well as that of low‐molecular heparin (LMWH), for treating cancer are limited because of heparin's anticoagulant activity and risk of hemorrhages. LMWH‐taurocholate conjugates (LHT7), which have low anticoagulant activity, were synthesized. The structural property of LHT was evaluated by circular dichroism and the binding affinity of LHT7 to vascular endothelial growth factor 165 (VEGF165) was measured by isothermal titration calorimetry. The inhibitory effect of LHT7 on VEGF‐mediated KDR (VEGF‐receptor 2) phosphorylation in Human umbilical vein endothelial cells was evaluated. The VEGF165 dependent Matrigel plug assay was performed to verify the antiangiogenic potential of LHT7 on a VEGF165 inhibitor. Finally, tumor growth inhibition effects of LHT7 on SCC7 and the survival rate of animal models were investigated. Moreover, MDA‐MB231 xenograft mouse model was additionally used to confirm the therapeutic effect of LHT7 on human breast cancer cell line. As a result, LHT7 which has 12.7% of anticoagulant activity of the original LMWH showed a peculiar polyproline‐type helical structure. LHT7 binds to VEGF strongly and inhibits VEGF dependent KDR phosphorylation. The results of Matrigel plug assay proved LHT7 as a strong antiangiogenic agent inhibiting VEGF165. Remarkably, LHT7 showed a significant tumor growth inhibition potential on SCC7 with an increased survival rate. LHT7 also delayed tumor growth in MDA‐MB231 human breast cancer cell lines. © 2008 UICC
Parameter determination for singlet oxygen modeling of BPD-mediated PDT

Photodynamic therapy (PDT) offers a cancer treatment modality capable of providing minimally invasive localized tumor necrosis. To accurately predict PDT treatment outcome based on pre-treatment patient specific parameters, an explicit dosimetry model is used to calculate apparent reacted 1O2 concentration ([1O2]rx) at varied radial distances from the activating light source inserted into tumor tissue and apparent singlet oxygen threshold concentration for necrosis ([1O2]rx, sd) for type-II PDT photosensitizers. Inputs into the model include a number of photosensitizer independent parameters as well as photosensitizer specific photochemical parameters ξ σ, and β. To determine the specific photochemical parameters of benzoporphyrin derivative monoacid A (BPD), mice were treated with BPDPDT with varied light source strengths and treatment times. All photosensitizer independent inputs were assessed pre-treatment and average necrotic radius in treated tissue was determined post-treatment. Using the explicit dosimetry model, BPD specific ξ σ, and β photochemical parameters were determined which estimated necrotic radii similar to those observed in initial BPD-PDT treated mice using an optimization algorithm that minimizes the difference between the model and that of the measurements. Photochemical parameters for BPD are compared with those of other known photosensitizers, such as Photofrin. The determination of these BPD specific photochemical parameters provides necessary data for predictive treatment outcome in clinical BPD-PDT using the explicit dosimetry model.
Side effects of methylphenidate in children with attention deficit hyperactivity disorder: a systemic, placebo-controlled evaluation.

The frequency and severity of 17 side effects presumably associated with stimulant medication were assessed during a rigorous, triple-blind, placebo-controlled, crossover evaluation of methylphenidate, 0.3 and 0.5 mg/kg twice a day, in 83 children with attention deficit hyperactivity disorder. Side effects were rated by parents and teachers at the end of each weekly drug condition. Three children (3.6%) had side effects that were sufficiently serious to warrant immediate discontinuation of medication. Parent ratings indicated that only the side effects of decreased appetite, insomnia, stomachaches, and headaches increased significantly in frequency and severity during the two active medication doses as compared with the placebo condition. Fewer than half of the children experienced these side effects and among those who did, ratings of mean severity remained in the mild range. Teacher ratings showed little change over drug conditions, except on ratings of staring, sadness, and anxiety, which declined with increasing dose of medication. Parent ratings indicated that only the side effects of decreased appetite, insomnia, stomachaches, and headaches increased significantly in frequency and severity during the two active medication doses as compared with the placebo condition. Fewer than half of the children experienced these side effects and among those who did, ratings of mean severity remained in the mild range. Teacher ratings showed little change over drug conditions, except on ratings of staring, sadness, and anxiety, which declined with increasing dose of medication. Surprisingly, a high frequency of these behavior side effects were reported during the placebo condition. Stimulant medication within this therapeutic range, therefore, results in few, generally mild side effects. (ABSTRACT TRUNCATED AT 250 WORDS)
Efavirenz Intoxication Due to a New Cyp2B6 Constellation

Here, we describe severe neuropsychiatric symptoms in an HIV-positive Asian man with extremely high efavirenz plasma levels while receiving standard treatment with efavirenz/tenofovir/emtricitabine fixed-dose regimen. Genetic examination revealed compound homozygosity for loss-of-function alleles of CYP2B6, including coding for a rare truncated protein. Neuropsychiatric symptoms resolved completely after efavirenz discontinuation.
Redox Regulation of PTEN by S-Nitrosothiols

PTEN (phosphatase with sequence homology to tensin) is a phosphatidylinositol 3,4,5-trisphosphate phosphatase that regulates many cellular processes. Activity of the enzyme is dependent on the redox state of the active site cysteine such that oxidation by H2O2 leads to inhibition. Because S-nitrosothiols are known to modify enzymes containing reactive cysteines, we hypothesized that S-nitrosothiols would oxidize PTEN and inhibit its phosphatase activity. In the present study, we show that S-nitrosocysteine (CSNO), S-nitrosoglutathione (GSNO), and S-nitroso-N-acetylpenicillamine (SNAP) reversibly oxidized recombinant PTEN. In addition, CSNO led to concentration- and time-dependent oxidation of endogenous cellular PTEN. However, in contrast, GSNO and SNAP were effective only when coincubated with cysteine, suggesting that these nitrosothiols must react with cysteine to form CSNO, which can be transferred across cell membranes. Oxidation of cellular PTEN resulted from thiol modification and led to reversible inhibition of phosphatase activity. Although oxidation of PTEN by H2O2 led to formation of an intramolecular disulfide, oxidation of PTEN by CSNO seemed to lead to formation of a mixed disulfide. Glutathionylation of cellular proteins by incubating cells with diamide or incubating cellular extracts with GSSG oxidized PTEN in a manner similar to that of CSNO. Overall, these data demonstrate for the first time that S-nitrosothiols oxidatively modify PTEN, leading to reversible inhibition of its phosphatase activity, and suggest that the oxidized species is a mixed disulfide.
Analysis of the host-specific haemagglutination of influenza A(H1N1) viruses isolated in the 1995/6 season

Two phenotypes of human influenza A(H1N1) virus are currently circulating in Japan. One (group 1) agglutinates both chicken and goose red blood cells (CRBC and GRBC), the other (group 2) agglutinates GRBC but not CRBC. In the 1995/6 season, group 2 viruses accounted for 70% of the H1N1 viruses isolated in MDCK cells. The 1995/6 viruses were located on two branches of the genetic tree. One branch contained both group 1 and group 2 viruses and the other branch contained only group 2 viruses. Group 2 viruses had aspartic acid at residue 225 in the haemagglutinin (HA) protein, the key amino acid residue for group 2 phenotype. The HA protein of group 1 viruses had a change from aspartic acid to asparagine at residue 225 and the expressed HA protein of these viruses adsorbed CRBC. Serial passage of group 2 viruses in MDCK cells or embryonated chicken eggs caused these viruses to gain the ability to agglutinate CRBC. MDCK-adapted viruses had the same amino acid sequences of HA polypeptide as the original ones, but egg-adapted viruses had changed amino acid sequences. The expressed HA protein from one egg-adapted virus that originally belonged to group 2 adsorbed CRBC.
Apparent ‘sympatric’ speciation in ecologically similar herbivorous beetles facilitated by multiple colonizations of an island

Coexistence of recently diverged and ecologically similar sister species in complete sympatry represents a particularly compelling case for sympatric speciation. This study investigates the possible sympatric origin of two coexisting bark beetle taxa that utilize the same host plant on the island of La Palma in the Canary Islands. Aphanarthrum subglabrum and Aphanarthrum glabrum ssp. nudum breed inside dead twigs of Euphorbia lamarckii plants and are closely related to the allopatric A. glabrum ssp. glabrum in Tenerife, El Hierro and La Gomera. We tested the various speciation hypotheses in a genealogical context, using mitochondrial gene fragments from Cytochrome Oxidase I and 16S, and nuclear gene fragments from Enolase, Elongation Factor 1α and Histone H3. Phylogenetic analyses of the combined nuclear DNA data strongly supported a sister relationship between two sympatric and reproductively isolated taxa in La Palma. However, network analyses of subdivided nonrecombinant segments of the Enolase locus indicated a closer relationship between the two allopatric A. glabrum subspecies, suggesting multiple colonizations of this island. A bimodal distribution of mtDNA haplotypes in La Palma further documented the independent colonization of this island, with asymmetric introgression of mtDNA between two lineages. Consequently, the sympatric origin of the La Palma species is concluded to have involved allopatric phases before the parallel colonization of this island and subsequent introgression at some loci. The clear genetic and morphological evidence for reproductive isolation between these species suggests that the sympatric completion of divergence was either due to initial genetic incompatibility, morphological character displacement in male genitalia, or a combination of these factors.
Ca2+‐independent insulin exocytosis induced by α‐latrotoxin requires latrophilin, a G protein‐coupled receptor

α‐Latrotoxin (α‐LTX) induces exocytosis of small synaptic vesicles (SSVs) in neuronal cells both by a calcium‐independent mechanism and by opening cation‐permeable pores. Since the basic molecular events regulating exocytosis in neurons and endocrine cells may be similar, we have used the exocytosis of insulin‐containing large dense core vesicles (LDCVs) as a model system. In primary pancreatic β‐cells and in the derived cell lines INS‐1 and MIN6, α‐LTX increased insulin release in the absence of extracellular calcium, but the insulin‐secreting cell lines HIT‐T15 and RINm5F were unresponsive. α‐LTX did not alter membrane potential or cytosolic calcium, and its stimulatory effect on exocytosis was still observed in pre‐permeabilized INS‐1 cells kept at 0.1 μM Ca2+. Consequently, pore formation or ion fluxes induced by α‐LTX could be excluded. The Ca2+‐independent α‐LTX‐binding protein, latrophilin, is a novel member of the secretin family of G protein‐coupled receptors (GPCR). Sensitivity to α‐LTX correlated with expression of latrophilin, but not with synaptotagmin I or neurexin Iα expression. Moreover, transient expression of latrophilin in HIT‐T15 cells conferred α‐LTX‐induced exocytosis. Our results indicate that direct stimulation of exocytosis by a GPCR mediates the Ca2+‐independent effects of α‐LTX in the absence of altered ion fluxes. Therefore, direct regulation by receptor‐activated heterotrimeric G proteins constitutes an important feature of the endocrine exocytosis of insulin‐containing LDCVs and may also apply to SSV exocytosis in neurons.
Variable expression of Epstein–Barr virus‐induced gene 3 during normal B‐cell differentiation and among B‐cell lymphomas

Epstein–Barr virus (EBV)‐induced gene 3 (EBI3) is expressed by tumour cells in several EBV‐associated malignancies. EBI3 was recently found to associate with a novel peptide, p28, to form a new heterodimeric cytokine, called interleukin‐27. In this study, we investigated EBI3 and p28 expression in normal human B lymphocytes and in non‐EBV‐associated B‐cell lymphomas. Low levels of EBI3 were detected in purified tonsillar B cells and expression was upregulated upon anti‐CD40 or anti‐µ stimulation via NF‐κB activation. In non‐neoplastic tissues, EBI3 expression by lymphocytes was largely restricted to a subset of germinal centre (GC) B cells located at the margin of the light zone, in close contact with CD3+ T lymphocytes. Over 50% of EBI3+ GC B cells were engaged in cell proliferation as assessed by Ki67 expression, and 10–30% expressed MUM1, an early marker of plasma cell differentiation expressed by late centrocytes. Many EBI3+ GC B cells had downregulated bcl‐6 expression, which further suggests that these cells correspond to late CD40‐activated centrocytes. Immunohistochemical analysis of 64 B‐cell lymphomas showed that the highest EBI3 levels were detected in follicular lymphomas and in diffuse large B‐cell lymphomas of both GC B‐cell‐like or non‐GC B‐cell‐like types. No or rare p28 expression was detected in normal or tumour B cells. This constitutive expression of EBI3 by neoplastic B cells may be involved in lymphomagenesis, and may be a useful marker for lymphoma diagnosis. Copyright © 2006 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Recent developments in novel freezing and thawing technologies applied to foods

ABSTRACT This article reviews the recent developments in novel freezing and thawing technologies applied to foods. These novel technologies improve the quality of frozen and thawed foods and are energy efficient. The novel technologies applied to freezing include pulsed electric field pre-treatment, ultra-low temperature, ultra-rapid freezing, ultra-high pressure and ultrasound. The novel technologies applied to thawing include ultra-high pressure, ultrasound, high voltage electrostatic field (HVEF), and radio frequency. Ultra-low temperature and ultra-rapid freezing promote the formation and uniform distribution of small ice crystals throughout frozen foods. Ultra-high pressure and ultrasound assisted freezing are non-thermal methods and shorten the freezing time and improve product quality. Ultra-high pressure and HVEF thawing generate high heat transfer rates and accelerate the thawing process. Ultrasound and radio frequency thawing can facilitate thawing process by volumetrically generating heat within frozen foods. It is anticipated that these novel technologies will be increasingly used in food industries in the future.
Diminished HIV-1 Sensitivity to Stavudine in Patients on Prolonged Therapy Occurs Only at Low Levels and Cannot be Attributed to Any Single Amino Acid Substitution in Reverse Transcriptase

To study the extent to which phenotypic resistance to stavudine occurs under therapy, we studied 18 pairs of human immunodeficiency virus type 1 (HIV-1) isolates from patients both prior to and following 24–48 weeks of treatment with stavudine monotherapy or stavudine in combination with either didanosine or lamivudine. We also used a nested polymerase chain reaction (PCR) assay to probe for the presence of specific mutations associated in culture with stavudine resistance. The results showed that resistance to stavudine (≍3–10 fold) was observed in nine of ten cases of monotherapy, in three of four cases of therapy involving both stavudine and didanosine, and in two of four cases involving stavudine and lamivudine. Viruses from the four patients receiving stavudine plus didanosine became resistant to didanosine in only one instance while the use of lamivudine plus stavudine yielded resistance to lamivudine each time. Whereas changes in the reverse transcriptase (RT) genes of resistant isolates were frequently observed, two mutations, previously identified with stavudine resistance in tissue culture (i.e. V75T and I50T), could not be identified in the clinical samples by either direct sequencing of the RT gene or by PCR amplification. Thus, resistance to stavudine can occur, albeit at low levels, in the context of prolonged therapy with this drug but is not associated with specific mutations in HIV RT at either codons 75 or 50 in clinical samples.
Acute ethanol administration and reinforcer magnitude reduction both reduce responding and increase response latency in a go/no-go task.

BACKGROUND Ethanol (EtOH) administration decreases behavioral inhibition in human subjects, assessed using cued Go/No-Go tasks, in which an unreliable cue suggests whether participants will be required to respond or not when a signal occurs. Few studies have examined EtOH's effects on behavioral inhibition in animals, and those that have done so have used Go/No-Go tasks in which no warning cue was provided. METHODS Two cohorts of male Long-Evans rats were trained and tested on 2 different Go/No-Go procedures with differing ratios of Go to No-Go trials (25 to 75 and 50 to 50). Using a within-subjects design, each rat was administered 0.0, 0.63, 0.95, and 1.27 g/kg of EtOH (i.p.) on 3 separate occasions according to an incomplete Latin square. An additional experiment examined the effects of reducing the amount of sucrose given for correct responses to either the Go or the No-Go signal in the absence of EtOH administration. RESULTS Acute intraperitoneal EtOH administration dose-dependently decreased responding during the No-Go signal (false alarms), the Go signal (hits), and responding prior to the occurrence of either signal (precue response rate). These effects were more pronounced in rats with the 50 to 50 ratio. Reducing the amount of sucrose presented generally led to a decrease in responding, although this effect was also moderated by the Go to No-Go ratio employed and the contingency relationship (reduced sucrose for correct Go trial responding or for correct No-Go trial response withholding). CONCLUSIONS Acute EtOH administration does not decrease behavioral inhibition in rats in this task. Rather EtOH appears to dose-dependently decrease behavior in general, possibly by reducing the efficacy of the sucrose reinforcer, as both EtOH administration and sucrose reduction for Go trials yielded similar patterns of behavioral responding in this task in rats.