Miracle-dz/UniFAR-FTUs huggingface dataset:
Late Sodium Current Contributes to the Reverse Rate-Dependent Effect of IKr Inhibition on Ventricular Repolarization

Background— The reverse rate dependence (RRD) of actions of IKr-blocking drugs to increase the action potential duration (APD) and beat-to-beat variability of repolarization (BVR) of APD is proarrhythmic. We determined whether inhibition of endogenous, physiological late Na+ current (late INa) attenuates the RRD and proarrhythmic effect of IKr inhibition. Methods and Results— Duration of the monophasic APD (MAPD) was measured from female rabbit hearts paced at cycle lengths from 400 to 2000 milliseconds, and BVR was calculated. In the absence of a drug, duration of monophasic action potential at 90% completion of repolarization (MAPD90) and BVR increased as the cycle length was increased from 400 to 2000 milliseconds (n=36 and 26; P<0.01). Both E-4031 (20 nmol/L) and d-sotalol (10 &mgr;mol/L) increased MAPD90 and BVR at all stimulation rates, and the increase was greater at slower than at faster pacing rates (n=19, 11, 12 and 7, respectively; P<0.01). Tetrodotoxin (1 &mgr;mol/L) and ranolazine significantly attenuated the RRD of MAPD90, reduced BVR (P<0.01), and abolished torsade de pointes in hearts treated with either 20 nmol/L E-4031 or 10 &mgr;mol/L d-sotalol. Endogenous late INa in cardiomyocytes stimulated at cycle lengths from 500 to 4000 milliseconds was greater at slower than at faster stimulation rates, and rapidly decreased during the first several beats at faster but not at slower rates (n=8; P<0.01). In a computational model, simulated RRD of APD caused by E-4031 and d-sotalol was attenuated when late INa was inhibited. Conclusion— Endogenous late INa contributes to the RRD of IKr inhibitor–induced increases in APD and BVR and to bradycardia-related ventricular arrhythmias.
Many-Layered Learning

We explore incremental assimilation of new knowledge by sequential learning. Of particular interest is how a network of many knowledge layers can be constructed in an on-line manner, such that the learned units represent building blocks of knowledge that serve to compress the overall representation and facilitate transfer. We motivate the need for many layers of knowledge, and we advocate sequential learning as an avenue for promoting the construction of layered knowledge structures. Finally, our novel STL algorithm demonstrates a method for simultaneously acquiring and organizing a collection of concepts and functions as a network from a stream of unstructured information.
Vascular Smooth Muscle Contractile Elements Cellular Regulation

For many years the simple view was held that contractile force in smooth muscle was proportional to cytosolic Ca2+ concentrations ([Ca2+],). With the discovery that phosphorylation of myosin light chain by Ca2+/calmodulin-dependent myosin light chain kinase initiated contraction, regulation of the contractile elements developed more complex properties. Molecular and biochemical investigations have identified important domains of myosin light chain kinase: light chain binding sites, catalytic core, pseudosubstrate prototope, and calmodulin- binding domain. New protein phosphatase inhibitors such as okadaic acid and calyculin A should help in the identification of the physiologically important phosphatase and potential modes of regulation. The proposal of an attached, dephosphorylated myosin cross bridge (latch bridge) that can maintain force has evoked considerable controversy about the detailed functions of the myosin phosphorylation system. The latch bridge has been defined by a model based on physiological properties but has not been identified biochemically. Thin-filament proteins have been proposed as secondary sites of regulation of contractile elements, but additional studies are needed to establish physiological roles. Changes in the Ca2+ sensitivity of smooth muscle contractile elements with different modes of cellular stimulation may be related to inactivation of myosin light chain kinase or activation of protein phosphatase activities. Thus, contractile elements in smooth muscle cells are not dependent solely on [Ca2+], but use additional regulatory mechanisms. The immediate challenge is to define their relative importance and to describe molecular-biochemical properties that provide insights into proposed physiological functions.
Influence of the Cyp3a5 genotype on tacrolimus pharmacokinetics and pharmacodynamics in young kidney transplant recipients

Abstract: CYP3A enzyme plays a pivotal role in TAC metabolism. The aim of this study was to analyze retrospectively the influence of CYP3A5 gene polymorphism on TAC pharmacokinetics and pharmacodynamics in 30 teenage kidney transplant recipients. TAC dose, trough blood levels, apparent volume of distribution, as well as blood pressure and antihypertensive therapy obtained at different post‐transplant periods, were correlated with the corresponding genotype. Despite a therapeutic monitoring strategy, heterozygotes (CYP3A5*1/*3) displayed a lower TAC blood concentration compared with homozygotes (CYP3A5*3/*3). Therefore, a two‐fold increase of the daily TAC dose was required in the heterozygotes to reach the desired therapeutic target level. A significant group by time interaction effect was present for both variables (repeated measures anova: p = 0.002) meaning a significant different pharmacokinetic response in these two cohorts. Mean blood pressure was also elevated in CYP3A5*1/*3 recipients despite similar antihypertensive treatment. This was parallel with an elevated apparent volume of distribution of TAC in this group. Thus, the allele‐effect was correlated with one of the most common TAC side‐effects suggesting a possible influence of CYP3A5 polymorphism on TAC pharmacodynamics. The authors concluded that a pre‐emptive CYP3A5 pharmacogenetic screening could contribute to better individualization of TAC therapy.
The syndrome of the wrist cutter.

Many hospitals are experiencing an influx of patients who have made several suicide attempts through wrist slashing. A study was undertaken to learn the possible causes of such behavior. It suggested that the wrist slashers have a common behavior pattern stemming from early maternal deprivation and imbedded in inability to give and receive meaningful verbal communications. Therapy is directed at fostering more mature methods of giving and receiving love.
Atmospheric amines and ammonia measured with a chemical ionization mass spectrometer (CIMS)

Abstract. We report measurements of ambient amines and ammonia with a fast response chemical ionization mass spectrometer (CIMS) in a southeastern US forest and a moderately polluted midwestern site during the summer. At the forest site, mostly C3-amines (from pptv to tens of pptv) and ammonia (up to 2 ppbv) were detected, and they both showed temperature dependencies. Aerosol-phase amines measured thermal-desorption chemical ionization mass spectrometer (TDCIMS) showed a higher mass fraction in the evening with cooler temperatures and lower in the afternoon with warmer temperatures, a trend opposite to the gas-phase amines. Concentrations of aerosol-phase primary amines measured with Fourier transform infrared spectroscopy (FTIR) from micron and submicron particles were 2 orders of magnitude higher than the gas-phase amines. These results indicate that gas to particle conversion is one of the major processes that control the ambient amine concentrations at this forest site. Temperature dependencies of C3-amines and ammonia also imply reversible processes of evaporation of these nitrogen-containing compounds from soil surfaces in daytime and deposition to soil surfaces at nighttime. During the transported biomass burning plume events, various amines (C1–C6) appeared at the pptv level, indicating that biomass burning is a substantial source of amines in the southeastern US. At the moderately polluted Kent site, there were higher concentrations of C1- to C6-amines (pptv to tens of pptv) and ammonia (up to 6 ppbv). C1- to C3-amines and ammonia were well correlated with the ambient temperature. C4- to C6-amines showed frequent spikes during the nighttime, suggesting that they were emitted from local sources. These abundant amines and ammonia may in part explain the frequent new particle formation events reported from Kent. Higher amine concentrations measured at the polluted site than at the rural forested site highlight the importance of constraining anthropogenic emission sources of amines.
The Role of High-Level Processes for Oscillatory Phase Entrainment to Speech Sound

Constantly bombarded with input, the brain has the need to filter out relevant information while ignoring the irrelevant rest. A powerful tool may be represented by neural oscillations which entrain their high-excitability phase to important input while their low-excitability phase attenuates irrelevant information. Indeed, the alignment between brain oscillations and speech improves intelligibility and helps dissociating speakers during a “cocktail party”. Although well-investigated, the contribution of low- and high-level processes to phase entrainment to speech sound has only recently begun to be understood. Here, we review those findings, and concentrate on three main results: (1) Phase entrainment to speech sound is modulated by attention or predictions, likely supported by top-down signals and indicating higher-level processes involved in the brain’s adjustment to speech. (2) As phase entrainment to speech can be observed without systematic fluctuations in sound amplitude or spectral content, it does not only reflect a passive steady-state “ringing” of the cochlea, but entails a higher-level process. (3) The role of intelligibility for phase entrainment is debated. Recent results suggest that intelligibility modulates the behavioral consequences of entrainment, rather than directly affecting the strength of entrainment in auditory regions. We conclude that phase entrainment to speech reflects a sophisticated mechanism: several high-level processes interact to optimally align neural oscillations with predicted events of high relevance, even when they are hidden in a continuous stream of background noise.
High Prevalence of Abnormal Glucose Metabolism and Poor Sensitivity of Fasting Plasma Glucose in the Chronic Phase of Stroke

Background: Cardiovascular disease is the leading cause of death in long-term stroke survivors, and whole-body glucose metabolism is strongly linked to cardiovascular disease risk. This study provides important preliminary information on the prevalence of abnormal glucose metabolism in chronic stroke patients (mean 3 years after stroke) and reports on the utility of screening for abnormalities using fasting plasma glucose (FPG) in this population. Methods: Two hundred and sixteen chronic hemiparetic stroke patients were screened for diabetes status by medical history and FPG. A subset (n = 80) was evaluated by oral glucose tolerance test to assess the utility of screening for abnormalities using FPG alone. Results: Seventy-five of the 216 (35%) had type 2 diabetes by medical history. Another 70 were either diabetic (n = 11) or had impaired fasting glucose (n = 59) based on a single blood draw at the time of screening. FPG among non-diabetic stroke patients had a sensitivity of 49% for predicting abnormalities in the 2-hour glucose level during oral glucose tolerance test. Cumulative results identify 77% as abnormal (impaired or diabetic) on the basis of medical history, fasting plasma glucose, and/or 2-hour glucose level. Conclusions: The prevalence of abnormal glucose metabolism is extremely high in chronic stroke and is underestimated on the basis of FPG.
Therapeutic Drug Monitoring and Pharmacogenetic Study of HIV-Infected Ethnic Chinese Receiving Efavirenz-Containing Antiretroviral Therapy with or without Rifampicin-Based Anti-Tuberculous Therapy

Objectives Plasma efavirenz concentrations in HIV-infected patients with tuberculosis (TB) may be affected by cytochrome P450 (CYP) 2B6 single-nucleotide polymorphisms and concurrent rifampicin use. We aimed to investigate the effects of CYP2B6 G516T polymorphisms and concomitant rifampicin use on the plasma efavirenz concentrations in HIV-infected Taiwanese. Methods HIV-infected patients with or without TB who had received combination antiretroviral therapy containing efavirenz (600 mg daily) for two weeks or greater were enrolled for determinations of CYP2B6 G516T polymorphism and plasma efavirenz concentrations with the use of polymerase-chain-reaction restriction fragment-length polymorphism and high-performance liquid chromatography, respectively. Results From October 2009 to August 2012, 171 HIV-infected patients, including 18 with TB, were enrolled 113 (66.1%) with CYP2B6 G516G, 55 (32.2%) GT, and 3 (1.8%) TT genotype. Patients receiving rifampicin had a significantly lower median plasma efavirenz concentration than the control group (2.16 vs 2.92 mg/L, P = 0.003); however, all patients achieved target plasma concentration (>1 mg/L). Patients with GT or TT genotype had a significantly higher plasma concentration than those with GG genotype (2.50 vs 3.47 mg/L for GT genotype and 8.78 mg/L for TT genotype, P<0.001). Plasma efavirenz concentration >4 mg/L was noted in 38 (22.2%) patients, which was associated with a lower weight (per 10-kg increase, odds ratio, 0.52; 95% confidence interval, 0.33–0.83) and GT or TT genotype (odds ratio, 4.35; 95% confidence interval, 1.97–9.59) in multivariate analysis. Conclusions Despite combination with rifampicin, sufficient plasma efavirenz concentrations can be achieved in HIV-infected Taiwanese with TB who receive efavirenz 600 mg daily. Carriage of CYP2B6 516 GT and TT genotypes and a lower weight are associated with higher plasma efavirenz concentrations.
Personal values and moral motivation 1 Personal values and moral motivation : disentangling moral integrity and moral hypocrisy

Positioning moral motivations within the framework provided by Schwartz’ (1992) values theory, we ran three dictator game studies (total N = 256) investigating moral integrity and moral hypocrisy. We adapted Batson’s (et al., 1997; et al., 1999; et al., 2002) landmark research design into the experimental economics laboratory (Study 1), and showed that the behavioral inconsistency – out of 64 dictators, all 26 who chose to flip a coin to determine the allocation of money ended up with the self-favoring outcome – revealed in such a design is indeed indicative of dishonest claims to morality (arguably the core of moral hypocrisy), and not overpowered moral integrity. Supporting this interpretation, dictators who masked their selfishness behind the coin flip were motivated by high Conformity values (Study 1), and thereby similar to participants who made more obviously disingenuous claims to morality (Study 2). Further, dictators did generally not select the coin flip in case the result could not be rigged (only four out of 32 dictators did this; Study 3). Universalism and Benevolence values were predictive of moral integrity (Studies 1 and 3). Morality ratings of behavior generally showed both self-serving and outcome bias.
Negative Signaling Pathways of the Killer Cell Inhibitory Receptor and FcγRIIb1 Require Distinct Phosphatases

Inhibition of natural killer (NK) cells by the killer cell inhibitory receptor (KIR) involves recruitment of the tyrosine phosphatase SHP-1 by KIR and is prevented by expression of a dominant negative SHP-1 mutant. Another inhibitory receptor, the low affinity Fc receptor for immunoglobulin G (IgG) (FcγRIIb1), has been shown to bind SHP-1 when cocross-linked with the antigen receptor on B cells (BCR). However, coligation of FcγRIIb1 with BCR and with FcεRI on mast cells leads to recruitment of the inositol 5′ phosphatase SHIP and to inhibition of mast cells from SHP-1–deficient mice. In this study, we evaluated the ability of these two inhibitory receptors to block target cell lysis by NK cells, and the contribution of SHP-1 and SHIP to inhibition. Recombinant vaccinia viruses encoding chimeric receptors and dominant negative mutants of SHP-1 and SHIP were used for expression in mouse and human NK cells. When the KIR cytoplasmic tail was replaced by that of FcγRIIb1, recognition of HLA class I on target cells by the extracellular domain resulted in inhibition. A dominant negative mutant of SHP-1 reverted the inhibition mediated by the KIR cytoplasmic tail but not that mediated by FcγRIIb1. In contrast, a dominant negative mutant of SHIP reverted only the inhibition mediated by the FcγRIIb1 tail, providing functional evidence that SHIP plays a role in the FcγRIIb1-mediated negative signal. These data demonstrate that inhibition of NK cells by KIR involves primarily the tyrosine phosphatase SHP-1, whereas inhibition mediated by FcγRIIb1 requires the inositol phosphatase SHIP.
Baby friendly hospital practices: cesarean section is a persistent barrier to early initiation of breastfeeding.

BACKGROUND Documented barriers to the implementation of Step 4 of the Baby Friendly Hospital Initiative, which relates to early initiation of breastfeeding, have not considered the impact of operative intervention in delivery on achievement of the goal. This study was designed to test the hypothesis that hospital practices in the immediate postpartum period that are associated with operative intervention in delivery can affect first mother-infant contact and initiation of breastfeeding. METHODS In a prospective, longitudinal study, a sociodemographically representative sample of 203 primiparous women was recruited. Participants were interviewed at 2 days postpartum in metropolitan hospitals in Melbourne, Australia, and medical records were inspected. At 8 months postpartum 81 percent of participants completed a postal questionnaire. Three mode-of-delivery groups (spontaneous vaginal delivery, instrumentally assisted vaginal delivery and cesarean section) and 4 hospital-of-delivery groups (including one accredited Baby Friendly Hospital) were compared. RESULTS Two way ANOVA revealed that women who had a cesarean section experienced a significant delay in initiating breastfeeding compared with women giving birth vaginally, with or without instrumental assistance (p < 0.001). Significant differences in this aspect of care were also observed among hospitals, with the Baby-Friendly hospital performing significantly better than the other three hospitals (p < 0.001). An effect due to mode of delivery alone was demonstrated that could not be abolished by differences in hospital practices (p = 0.231). Nevertheless, shorter elapsed time between birth and initiation of breastfeeding was not significantly associated with continuation of breastfeeding at 8 months postpartum (p = 0.642). CONCLUSIONS The findings confirmed that cesarean section was a significant barrier to the implementation of Baby Friendly Hospital Initiative Step 4 and that hospital practices were amenable to changes that enabled its implementation regardless of the mode of delivery.
Spring-Loaded Heptad Repeat Residues Regulate the Expression and Activation of Paramyxovirus Fusion Protein

ABSTRACT During viral entry, the paramyxovirus fusion (F) protein fuses the viral envelope to a cellular membrane. Similar to other class I viral fusion glycoproteins, the F protein has two heptad repeat regions (HRA and HRB) that are important in membrane fusion and can be targeted by antiviral inhibitors. Upon activation of the F protein, HRA refolds from a spring-loaded, crumpled structure into a coiled coil that inserts a hydrophobic fusion peptide into the target membrane and binds to the HRB helices to form a fusogenic hairpin. To investigate how F protein conformational changes are regulated, we mutated in the Sendai virus F protein a highly conserved 10-residue sequence in HRA that undergoes major structural changes during protein refolding. Nine of the 15 mutations studied caused significant defects in F protein expression, processing, and fusogenicity. Conversely, the remaining six mutations enhanced the fusogenicity of the F protein, most likely by helping spring the HRA coil. Two of the residues that were neither located at “a” or “d” positions in the heptad repeat nor conserved among the paramyxoviruses were key regulators of the folding and fusion activity of the F protein, showing that residues not expected to be important in coiled-coil formation may play important roles in regulating membrane fusion. Overall, the data support the hypothesis that regions in the F protein that undergo dramatic changes in secondary and tertiary structure between the prefusion and hairpin conformations regulate F protein expression and activation.
Neurohormonal Profile Before and After β‐Blockade in Patients with Neurocardiogenic Syncope

Our objective was to evaluate the effects of β‐blockers on the neurohormonal profile, particularly vasopressin (VP) release, in vasovagal syncope and to gain further insight on the pathophysiology of this syndrome. Patients (≤75 years) with no cardiovascular, neurological disorders, or contraindications to the use of isoproterenol or β‐blockers and being explored for unexplained syncope were included. An 80± HUT was performed under identical conditions. After a 25‐min period of passive tilt, isoproterenol was infused at a rate of 1–5 μg/mn if required. Two groups matched for age and sex were considered: a HUT‐positive and a HUT‐negative group. The HUT‐positive group was then given β‐blockers, subsequently reassessed, and divided into two subgroups: a β‐blocker nonresponder group and a β‐blocker responder group. Blood samples for assays of norepinephrine (NE), epinephrine (E), and VP were taken at baseline and the end of the procedure. In all, 44 subjects entered the study, 22 in each group. The HUT‐positive group exhibited an obvious lesser increase in plasma NE and a clear‐cut rise in plasma E and VP compared to the HUT‐negative group (P < 0.05). Even though no patient in the HUT‐positive group reported recurrent symptoms under treatment, the second HUT could distinguish two subgroups: a β‐blocker nonresponder group (n = 12) whose HUT remained positive and a β‐blocker responder group (n = 10) whose HUT was normalized. The time course of plasma E and VP during the second HUT was similar to that for the HUT‐positive and HUT‐negative groups. In conclusion, the efficacy of β‐blockers is associated not only with a reduction of the sympathoadrenal stimulation seen in vasovagal syncope but also with a lower release of VP suggesting that low‐pressure baroreceptors might be involved in VP release.
Rapid fluctuations in the deep North Atlantic heat budget during the last glacial period

[1] Our understanding of past ocean-climate interactions has been hampered by a paucity of proxy reconstructions of physical ocean circulation parameters. Here we present the first detailed record of deepwater temperature variability that resolves Dansgaard-Oeschger climate fluctuations during the last glaciation. Results indicate a positive coupling between abrupt temperature changes over Greenland and in the deep North Atlantic that was mediated by perturbations to the Atlantic overturning circulation. The occurrence of sharp warming events at the center of the “Heinrich” stadials 4 and 5 further indicates that the response of the ocean interior was less static across these major climate events than has been previously apparent.