Miracle-dz/UniFAR-FTUs huggingface dataset:
Pharmacokinetic Modeling of Plasma and Intracellular Concentrations of Raltegravir in Healthy Volunteers

ABSTRACT Raltegravir is a potent inhibitor of HIV integrase. Persistently high intracellular concentrations of raltegravir may explain sustained efficacy despite high pharmacokinetic variability. We performed a pharmacokinetic study of healthy volunteers. Paired blood samples for plasma and peripheral blood mononuclear cells (PBMCs) were collected predose and 4, 8, 12, 24, and 48 h after a single 400-mg dose of raltegravir. Samples of plasma only were collected more frequently. Raltegravir concentrations were determined using liquid chromatography-mass spectrometry. The lower limits of quantitation for plasma and PBMC lysate raltegravir were 2 nmol/liter and 0.225 nmol/liter, respectively. Noncompartmental analyses were performed using WinNonLin. Population pharmacokinetic analysis was performed using NONMEM. Six male subjects were included in the study; their median weight was 67.4 kg, and their median age was 33.5 years. The geometric mean (GM) (95% confidence interval shown in parentheses) maximum concentration of drug (Cmax), area under the concentration-time curve from 0 to 12 h (AUC0–12), and area under the concentration-time curve from 0 h to infinity (AUC0–∞) for raltegravir in plasma were 2,246 (1,175 to 4,294) nM, 10,776 (5,770 to 20,126) nM · h, and 13,119 (7,235 to 23,788) nM · h, respectively. The apparent plasma raltegravir half-life was 7.8 (5.5 to 11.3) h. GM intracellular raltegravir Cmax, AUC0–12, and AUC0–∞ were 383 (114 to 1,281) nM, 2,073 (683 to 6,290) nM · h, and 2,435 (808 to 7,337) nM · h (95% confidence interval shown in parentheses). The apparent intracellular raltegravir half-life was 4.5 (3.3 to 6.0) h. Intracellular/plasma ratios were stable for each patient without significant time-related trends over 48 h. Population pharmacokinetic modeling yielded an intracellular-to-plasma partitioning ratio of 11.2% with a relative standard error of 35%. The results suggest that there is no intracellular accumulation or persistence of raltegravir in PBMCs.
Long-term outcome of Chinese patients with membranous lupus nephropathy

A retrospective analysis of the long-term outcome of patients with membranous lupus nephropathy (MLN) was conducted. One hundred Chinese patients, 90 females and 10 males with a mean age of 32 ± 9 years, with systemic lupus erythematosus and biopsy-proven MLN (ISN/RPS2003 classification criteria) were enrolled in this study. The patient and renal survivals were estimated by the Kaplan—Meier method and the risk factors associated with end-stage renal failure (ESRF) were assessed by the Cox proportional hazards regression analysis. The mean follow-up of all patients was 77.6 ± 56 months. During follow-up, two patients died. Patient survival at 5 and 10 years was 98%. Renal survival at 5 and 10 years was 96.1% and 92.7%, respectively. Severe tubular-intersticial lesion (HR 66.514), nephrotic range proteinuria (HR 19.159) and refractoriness to treatments (HR 9.834) were independent risk factors for developing ESRF. Three of the six patients with ESRF had severe tubular-interstitial lesions on initial biopsy. Twenty-one patients underwent a repeat biopsy after 33months' (median time) follow-up, eight (38.1%) of these (class V superimposed class IV in 5, class V superimposed class III in 2 and class VI in 1) had transformed and three (37.5%) of them progressed to ESRF. Complications included infection (13%), thrombosis (3%), avascular necrosis (3%), diabetes mellitus (4%) and skin cancer (1%). The rate of patient and renal survival was high in this group of patients with MLN.
Unconventional metaphors and emotional-cognitive regulation in a metacognitive interpersonal therapy

Abstract This study investigates the relationship between unconventional (i.e., creative) metaphors and emotional-cognitive regulation in a metacognitive interpersonal therapy (MIT). The occurrence of unconventional metaphor was identified using the Metaphor Analysis in Psychotherapy (MAP) model, and emotional-cognitive regulation was assessed by the Therapeutic Cycles Model (TCM). The results showed that the dyad's frequency of unconventional metaphors is significantly related to emotional-cognitive integration, reflective processes and moments of therapeutic engagement based on the quality of such regulation. More specifically, client metaphors were associated with emotional-cognitive integration and moments of therapeutic engagement, while therapist metaphors were associated with reflective processes. The results suggest that unconventional metaphors may be considered markers for different cognitive-emotional regulatory processes and moments of heightened therapeutic work and change in MIT.
Power Consumption in Direct Interface Circuits

This paper analyzes theoretically and experimentally the current consumption in direct interface circuits, i.e., circuits in which the sensor is directly connected to a microcontroller ( μC) without using either a signal conditioning circuit or an analog-to-digital converter. The theoretical analysis, which takes into account the current consumed by both the internal electronics of the μC and the external components, proposes formulas to estimate the average current consumption in active mode. The estimated values fairly agree with those obtained in the experimental tests carried out by an AVR ATtiny2313 μC at different operating conditions. For example, the current consumption in active mode at 3 V-4 MHz was about 1.5 mA for the measurement of a 1-kΩ resistive sensor and 0.6 mA for the measurement of a 177-pF capacitive sensor. The results reported herein are expected to be useful for the design of direct interface circuits intended for battery-powered measurement systems.
Lactose Biosensor Based on Lactase and Galactose Oxidase Immobilized in Polyvinyl Formal

A lactose biosensor was developed by immobilizing lactase and galactose oxidase in a polyvinyl formal membrane and was attached to the oxygen electrode of a dissolved oxygen analyzer for estimation of lactose in milk and food products. The enzyme immobilized polyvinyl formal membrane was characterized by atomic force microscopy. The biosensor showed the linearity for 1–7 g dl−1 of lactose and can be reused for up to 20 measurements. The effects of pH, temperature and the stability of the immobilized lactase and galactose oxidase in PVF membrane were also studied. The enzyme membrane was found stable up to 35°C and had a shelf-life of more than three months at 4°C.
Neurotoxicity associated with suspected Southern Pacific rattlesnake (Crotalus viridis helleri) envenomation

An 18-year-old man was bitten on the hand by a snake he believed to be a Southern Pacific rattlesnake (Crotalus viridis helleri). Within minutes he developed generalized weakness, difficulty breathing, diplopia, dysphagia, and dysphonia. Neurological examination revealed ptosis and decreased motor strength. These symptoms partially improved after administration of Antivenin (Crotalidae) Polyvalent, but the patient continued to have difficulty walking for several days due to weakness. In addition to neurological symptoms, the patient also experienced pain immediately after the bite occurred and rapid swelling of the entire extremity, which extended beyond the shoulder. He complained of a metallic taste in his mouth and developed intense muscle fasciculations of the face, tongue, and upper extremities, which lasted for 2 days and did not improve with antivenin treatment. He exhibited laboratory evidence of coagulopathy and rhabdomyolysis. Although neurotoxins are known to occur in the venom of certain populations of rattlesnakes, only a few clinical reports describing severe neurological symptoms appear in the literature. To our knowledge, this is the first reported case of neurotoxicity associated with a suspected Southern Pacific rattlesnake envenomation.
Pre-vaccination incidence of genital warts in 15–23-year-old women and men attending youth clinics in Stockholm, Sweden

Abstract Background: Human papillomavirus (HPV) vaccines were introduced to the market in 2006 and 2007. The present pilot study was designed to examine the incidence of genital warts in the population up to 23 y of age in the county of Stockholm before the start of mass HPV vaccination. Methods: Data from the electronic health records of 9 youth clinics in the county of Stockholm were collected retrospectively for the y 2006–2008. Results: In total, 49,985 patients visited the study youth clinics during 2006–2008. Of these, 1817 were denoted genital warts patients. An extrapolation of the study data was done in an attempt to estimate the annual number of genital warts cases in the full Stockholm County population aged 15–23 y. Results showed that there were approximately 1792 genital warts patients in the age group 15–23 y each year in Stockholm County. Female cases represented approximately 62% of all cases in the age group 15–23 y. The peak incidence was at around 20 y of age for females, while males had a more flattened peak incidence around 19–23 y of age. Conclusion: This pilot study demonstrates that, compared to other reported data, genital warts are at least as common in Sweden as in other countries among 15–23 y old females and males.
Cytochrome c Biogenesis: Mechanisms for Covalent Modifications and Trafficking of Heme and for Heme-Iron Redox Control

SUMMARY Heme is the prosthetic group for cytochromes, which are directly involved in oxidation/reduction reactions inside and outside the cell. Many cytochromes contain heme with covalent additions at one or both vinyl groups. These include farnesylation at one vinyl in hemes o and a and thioether linkages to each vinyl in cytochrome c (at CXXCH of the protein). Here we review the mechanisms for these covalent attachments, with emphasis on the three unique cytochrome c assembly pathways called systems I, II, and III. All proteins in system I (called Ccm proteins) and system II (Ccs proteins) are integral membrane proteins. Recent biochemical analyses suggest mechanisms for heme channeling to the outside, heme-iron redox control, and attachment to the CXXCH. For system II, the CcsB and CcsA proteins form a cytochrome c synthetase complex which specifically channels heme to an external heme binding domain; in this conserved tryptophan-rich “WWD domain” (in CcsA), the heme is maintained in the reduced state by two external histidines and then ligated to the CXXCH motif. In system I, a two-step process is described. Step 1 is the CcmABCD-mediated synthesis and release of oxidized holoCcmE (heme in the Fe+3 state). We describe how external histidines in CcmC are involved in heme attachment to CcmE, and the chemical mechanism to form oxidized holoCcmE is discussed. Step 2 includes the CcmFH-mediated reduction (to Fe+2) of holoCcmE and ligation of the heme to CXXCH. The evolutionary and ecological advantages for each system are discussed with respect to iron limitation and oxidizing environments.
Continuous arteriovenous haemofiltration in patients with hepatic encephalopathy and renal failure.

Une observation d'encephalopathie hepatique et d'insuffisance renale apres intoxication volontaire (100 comprimes de paracetamol). Traitement par hemofiltration selon 2 methodes differentes. Pendant l'hemofiltration par machine Gambro FH77, la pression intracrânienne est augmentee pendant la premiere heure, puis diminuee. Lors de l'hemofiltration arterioveineuse continue la pression intracrânienne est inchangee. Apres 5 j de ces traitements alternes la diurese se retablit et la malade se retablit rapidement sans sequelles
Proenkephalin B Messenger RNA in Porcine Tissues: Characterization, Quantification, and Correlation with Opioid Peptides

Abstract: Concentrations of proenkephalin B (PENK B) mRNA in porcine brain, pituitary, spinal cord, and peripheral tissues were measured using RNA blotting and solution hybridization. A single hybridizing species of ∼2,800 bases in size was present in the CNS, with the highest concentration in the caudate nucleus, followed by hypothalamus and hippocampus. The abundance of PENK B mRNA ranged from 22 pg/μg of poly(A)‐rich RNA in caudate nucleus to <0.1 pg/μg in cerebellum. Concentrations of immunoreac‐tive PENK B‐derived peptides showed a similar distribution, with the exception of the hypothalamus, which had lower PENK B mRNA levels than expected from peptide concentrations. PENK B mRNA of the same size as in the brain was also found in the anterior lobe of the pituitary and in the heart ventricle, whereas in intestine, lung, and kidney, smaller mRNA species of 1,800 bases became apparent by RNA blot analysis. An intermediate size of 2,200 bases was found in heart atrium. As revealed by S1 mapping, however, these smaller mRNAs are not completely homologous with PENK B mRNA, but rather may represent closely related mRNAs from a different gene(s).
Approaches to catheter ablation for persistent atrial fibrillation.

BACKGROUND Catheter ablation is less successful for persistent atrial fibrillation than for paroxysmal atrial fibrillation. Guidelines suggest that adjuvant substrate modification in addition to pulmonary-vein isolation is required in persistent atrial fibrillation. METHODS We randomly assigned 589 patients with persistent atrial fibrillation in a 1:4:4 ratio to ablation with pulmonary-vein isolation alone (67 patients), pulmonary-vein isolation plus ablation of electrograms showing complex fractionated activity (263 patients), or pulmonary-vein isolation plus additional linear ablation across the left atrial roof and mitral valve isthmus (259 patients). The duration of follow-up was 18 months. The primary end point was freedom from any documented recurrence of atrial fibrillation lasting longer than 30 seconds after a single ablation procedure. RESULTS Procedure time was significantly shorter for pulmonary-vein isolation alone than for the other two procedures (P<0.001). After 18 months, 59% of patients assigned to pulmonary-vein isolation alone were free from recurrent atrial fibrillation, as compared with 49% of patients assigned to pulmonary-vein isolation plus complex electrogram ablation and 46% of patients assigned to pulmonary-vein isolation plus linear ablation (P=0.15). There were also no significant differences among the three groups for the secondary end points, including freedom from atrial fibrillation after two ablation procedures and freedom from any atrial arrhythmia. Complications included tamponade (three patients), stroke or transient ischemic attack (three patients), and atrioesophageal fistula (one patient). CONCLUSIONS Among patients with persistent atrial fibrillation, we found no reduction in the rate of recurrent atrial fibrillation when either linear ablation or ablation of complex fractionated electrograms was performed in addition to pulmonary-vein isolation. (Funded by St. Jude Medical; ClinicalTrials.gov number, NCT01203748.).
Two mutations which affect the barrier function of the Escherichia coli K-12 outer membrane

Two genetically distinct classes of novobiocin-supersensitive mutants were isolated from Escherichia coli K-12. One class, given the phenotypic name NbsA, lies at 10 min on the E. coli chromosome. The order of the genes in this region, based on transductional analyses, is proC NbsA plsA purE. The second, NbsB, lies at 80 min. The order of the genes in this region, based on transduction analyses, is xyl cysE NbsB pyrE. Both classes of mutants show increased sensitivity to hydrophobic drugs but are different: NbsA cells tend to be more sensitive to cationic agents, whereas NbsB cells show the opposite tendency. The sole detectable biochemical alteration in NbsA strain is greater than 90% reduction in the phosphate content of the lipid A region of the lipopolysaccharide. The NbsB mutation results in lipopolysaccharide that contains primarily the stereoisomer D-glycero-D-mannoheptose, rather than L-glycero-D-mannoheptose, and which contains very little of the distal sugars. Since NbsA strains have apparently normal outer membrane proteins and total cellular phospholipids, changes solely in lipopolysaccharide can increase permeability to certain hydrophobic antibiotics. Complementation studies indicate that the NbsA marker is probably allelic with acrA. In addition, the NbsB marker is genetically and phenotypically similar to the rfaD locus of Salmonella typhimurium. For this reason, the phenotypic designations NbsA and NbsB have been changed to the genotypic designations acrA and rfaD, respectively.
Changing range genetic algorithm for multimodal function optimisation

The performance of a sequential changing range genetic algorithm SCRGA is described. This algorithm enables the transformation of an unconstrained numerical optimisation problem to a constrained problem by implementing constraints which convert the area near previously found optima to an infeasible region. This SCRGA feature is used for locating all optima of unconstrained and constrained numerical optimisation problems. Several test cases, related to unconstrained and constrained numerical optimisation problems, demonstrate the ability of this approach to reduce the computational costs, significantly improving success rates, accurately and precisely locating all optimal solutions.
The Localization of HCV and the Expression of Fas Antigen in the Liver of HCV-related Chronic Liver Disease

We have investigated the localization of HCV in the liver and the expression of Fas antigen, involved in hepatocellular death through apoptosis, to examine the relation between HCV infection and Fas antigen cellular expression. The localization of HCV was investigated by in situ hybridization (ISH), and the expression of Fas antigen was determined by immunohistochemistry using an anti-Fas monoclonal antibody, in 20 surgically-resected liver specimens from anti-HCV positive patients. The Methylgreen/Pyronin Y technique clearly showed well-preserved tissue RNA in 8 of 20 livers. ISH determined the co-localization of signals for plus and minus strands of HCV-RNA in the cytoplasm of hepatocytes. Fas antigen was more strongly expressed on the plasma membrane of the periportal hepatocytes than on the plasma membrane of the centrilobular hepatocytes, even when HCV-RNA was found to be widely distributed in the hepatocytes throughout the liver lobule. Furthermore, Fas antigen positive hepatocytes were frequently observed close to the area of piecemeal necrosis associated with a high incidence of apoptosis. The results suggested that the expression of Fas antigen does not occur by HCV infection alone, but probably requires several other factors.
Role of the aminotransferase domain in Bacillus subtilis GabR, a pyridoxal 5′‐phosphate‐dependent transcriptional regulator

MocR/GabR family proteins are widely distributed prokaryotic transcriptional regulators containing pyridoxal 5′‐phosphate (PLP), a coenzyme form of vitamin B6. The Bacillus subtilis GabR, probably the most extensively studied MocR/GabR family protein, consists of an N‐terminal DNA‐binding domain and a PLP‐binding C‐terminal domain that has a structure homologous to aminotransferases. GabR suppresses transcription of gabR and activates transcription of gabT and gabD, which encode γ‐aminobutyrate (GΑΒΑ) aminotransferase and succinate semialdehyde dehydrogenase, respectively, in the presence of PLP and GABA. In this study, we examined the mechanism underlying GabR‐mediated gabTD transcription with spectroscopic, crystallographic and thermodynamic studies, focusing on the function of the aminotransferase domain. Spectroscopic studies revealed that GABA forms an external aldimine with the PLP in the aminotransferase domain. Isothermal calorimetry demonstrated that two GabR molecules bind to the 51‐bp DNA fragment that contains the GabR‐binding region. GABA minimally affected ΔGbinding upon binding of GabR to the DNA fragment but greatly affected the contributions of ΔH and ΔS to ΔGbinding. GABA forms an external aldimine with PLP and causes a conformational change in the aminotransferase domain, and this change likely rearranges GabR binding to the promoter and thus activates gabTD transcription.
Cerebellar networks in individuals at ultra high‐risk of psychosis: Impact on postural sway and symptom severity

Despite known deficits in postural control in patients with schizophrenia, this domain has not been investigated in youth at ultra high‐risk (UHR) for psychosis. This is particularly relevant as postural control implicates dysfunction in the cerebellum‐a region implicated in cognitive dysmetria conceptions of schizophrenia but poorly understood in the prodrome. Here, we extended our understanding of movement abnormalities in UHR individuals to include postural control, and have linked these deficits to both symptom severity and cerebello‐cortical network connectivity. UHR and healthy control participants completed an instrumentally based balance task to quantify postural control along with a resting state brain imaging scan to investigate cerebellar networks. We also quantified positive and negative symptom severity with structured clinical interviews. The UHR group showed overall increased postural sway and decreased cerebello‐cortical resting state connectivity, relative to controls. The decreased cerebello‐cortical connectivity was seen across multiple networks. Postural sway was also correlated with cerebellar connectivity in this population and uniquely positively correlated with the severity of negative symptoms. Finally, symptom severity was also associated with cerebellar connectivity. Together, our results point to a potential deficit in sensory integration as an underlying contributor to the increased postural sway, and provide evidence of cerebellar abnormalities in UHR individuals. These results extend our understanding of the motor abnormalities of UHR individuals beyond striatum‐based dyskinesias to include postural control and sensory integration deficits, and implicate the cerebellum as a distinct neural substrate preceding the onset of psychosis. Taken together, our results extend the cognitive dysmetria framework to UHR populations. Hum Brain Mapp 35:4064–4078, 2014. © 2014 Wiley Periodicals, Inc.
A 72 Gb/s 2/sup 31/-1 PRBS generator in SiGe BiCMOS technology

A 2/sup 31/-1 72 Gb/s PRBS generator is reported in a 0.13 /spl mu/m SiGe BiCMOS technology with 150 GHz-f/sub T/ HBTs. Variable delays are introduced along the 36 GHz clock path to increase timing margins. A true BiCMOS logic family using NMOS FETs in the clock path is employed throughout the circuit, which dissipates 9.28 W from a 3.3 V supply to provide a single-ended output swing of 300 mV at 72 Gb/s.