Miracle-dz/UniFAR-FTUs huggingface dataset:
Nuclear-delimited Angiotensin Receptor-mediated Signaling Regulates Cardiomyocyte Gene Expression*

Angiotensin-II (Ang-II) from extracardiac sources and intracardiac synthesis regulates cardiac homeostasis, with mitogenic and growth-promoting effects largely due to altered gene expression. Here, we assessed the possibility that angiotensin-1 (AT1R) or angiotensin-2 (AT2R) receptors on the nuclear envelope mediate effects on cardiomyocyte gene expression. Immunoblots of nucleus-enriched fractions from isolated cardiomyocytes indicated the presence of AT1R and AT2R proteins that copurified with the nuclear membrane marker nucleoporin-62 and histone-3, but not markers of plasma (calpactin-I), Golgi (GRP-78), or endoplasmic reticulum (GM130) membranes. Confocal microscopy revealed AT1R and AT2R proteins on nuclear membranes. Microinjected Ang-II preferentially bound to nuclear sites of isolated cardiomyocytes. AT1R and AT2R ligands enhanced de novo RNA synthesis in isolated cardiomyocyte nuclei incubated with [α-32P]UTP (e.g. 36.0 ± 6.0 cpm/ng of DNA control versus 246.4 ± 15.4 cpm/ng of DNA Ang-II, 390.1 ± 15.5 cpm/ng of DNA L-162313 (AT1), 180.9 ± 7.2 cpm/ng of DNA CGP42112A (AT2), p < 0.001). Ang-II application to cardiomyocyte nuclei enhanced NFκB mRNA expression, a response that was suppressed by co-administration of AT1R (valsartan) and/or AT2R (PD123177) blockers. Dose-response experiments with Ang-II applied to purified cardiomyocyte nuclei versus intact cardiomyocytes showed greater increases in NFκB mRNA levels at saturating concentrations with ∼2-fold greater affinity upon nuclear application, suggesting preferential nuclear signaling. AT1R, but not AT2R, stimulation increased [Ca2+] in isolated cardiomyocyte nuclei. Inositol 1,4,5-trisphosphate receptor blockade by 2-aminoethoxydiphenyl borate prevented AT1R-mediated Ca2+ release and attenuated AT1R-mediated transcription initiation responses. We conclude that cardiomyocyte nuclear membranes possess angiotensin receptors that couple to nuclear signaling pathways and regulate transcription. Signaling within the nuclear envelope (e.g. from intracellularly synthesized Ang-II) may play a role in Ang-II-mediated changes in cardiac gene expression, with potentially important mechanistic and therapeutic implications.
Bupivacaine Suppresses [Ca2+]i Oscillations in Neonatal Rat Cardiomyocytes with Increased Extracellular K+ and Is Reversed with Increased Extracellular Mg2+

Lidocaine is used to treat cardiac arrhythmias, whereas bupivacaine is noted for its cardiotoxicity. A precise mechanism for these differences is unclear, and there is no well defined antidote for local anesthetic cardiotoxicity. Our study compares the effect of lidocaine and bupivacaine on oscillations of intracellular Ca2+ coupled with contractions in neonatal rat cardiomyocytes by using digital imaging. In medium containing 5.6 mM K+, both 42 &mgr;M lidocaine and 5.5 &mgr;M bupivacaine significantly reduced the oscillation rate. The oscillatory patterns were highly irregular, and the rates were increased in the presence of bupivacaine in 7.6 mM K+ medium, eventually degenerating into a loss of oscillations after several minutes of bupivacaine exposure. Irregular oscillations did not occur with lidocaine until the K+ concentration was increased to 10 mM. Increasing the Mg2+ and Ca2+ concentrations by 2 mM each recovered oscillation that had been suppressed by bupivacaine in high K+ buffer. Evaluation of intracellular Ca2+ oscillations in neonatal rat suggests that increased extracellular K+ may be an important component of bupivacaine cardiotoxicity. Implications Evaluation of intracellular Ca2+ oscillations in neonatal rat myocytes suggests that increased extracellular K+ may be an important component of bupivacaine cardiotoxicity.
Prenatal stress in the rat results in increased blood pressure responsiveness to stress and enhanced arterial reactivity to neuropeptide Y in adulthood

We have shown previously that stress in the pregnant rat leads to a heightened cardiovascular response to restraint in adult offspring. The present study was undertaken to explore further the persistent cardiovascular effects of prenatal stress, with a focus on peripheral vascular function. Sprague–Dawley female rats were exposed to restraint/bright light three times daily in the last week of pregnancy. Litters from stressed and control females were cross‐fostered to control dams to eliminate possible effects of maternal stress on nursing behaviour. At 120 days, offspring cardiovascular variables were measured by radiotelemetry. Reactivity of mesenteric small arteries was assessed by myography, and responses to electrical field stimulation determined. Resting cardiovascular parameters in prenatally stressed (PS) offspring were similar to controls but PS rats showed a greater increase in systolic blood pressure following restraint stress (P < 0.05). Recovery was also prolonged in PS animals compared with controls and was of longer duration in PS females than in PS males (P < 0.05). Adult PS females, but not males, also had elevated basal plasma corticosterone levels in comparison with controls (P < 0.05). Vascular reactivity to neuropeptide Y (P < 0.05) and electrical field stimulation (P < 0.05) in mesenteric arteries was also significantly increased in PS animals. Vascular responses to adrenergic agonists as well as endothelial dilator function did not differ between PS and controls. We conclude that prenatal stress during late gestation has long‐lasting effects on cardiovascular responsiveness and vascular reactivity to neuropeptide Y in the offspring.
Disparity in regional and systemic circulatory capacities: do they affect the regulation of the circulation?

In this review we integrate ideas about regional and systemic circulatory capacities and the balance between skeletal muscle blood flow and cardiac output during heavy exercise in humans. In the first part of the review we discuss issues related to the pumping capacity of the heart and the vasodilator capacity of skeletal muscle. The issue is that skeletal muscle has a vast capacity to vasodilate during exercise [∼300 mL (100 g)−1 min−1], but the pumping capacity of the human heart is limited to 20–25 L min−1 in untrained subjects and ∼35 L min−1 in elite endurance athletes. This means that when more than 7–10 kg of muscle is active during heavy exercise, perfusion of the contracting muscles must be limited or mean arterial pressure will fall. In the second part of the review we emphasize that there is an interplay between sympathetic vasoconstriction and metabolic vasodilation that limits blood flow to contracting muscles to maintain mean arterial pressure. Vasoconstriction in larger vessels continues while constriction in smaller vessels is blunted permitting total muscle blood flow to be limited but distributed more optimally. This interplay between sympathetic constriction and metabolic dilation during heavy whole‐body exercise is likely responsible for the very high levels of oxygen extraction seen in contracting skeletal muscle. It also explains why infusing vasodilators in the contracting muscles does not increase oxygen uptake in the muscle. Finally, when ∼80% of cardiac output is directed towards contracting skeletal muscle modest vasoconstriction in the active muscles can evoke marked changes in arterial pressure.
Auditory Masking Effects on Speech Fluency in Apraxia of Speech and Aphasia: Comparison to Altered Auditory Feedback.

PURPOSE To study the effects of masked auditory feedback (MAF) on speech fluency in adults with aphasia and/or apraxia of speech (APH/AOS). We hypothesized that adults with AOS would increase speech fluency when speaking with noise. Altered auditory feedback (AAF; i.e., delayed/frequency-shifted feedback) was included as a control condition not expected to improve speech fluency. METHOD Ten participants with APH/AOS and 10 neurologically healthy (NH) participants were studied under both feedback conditions. To allow examination of individual responses, we used an ABACA design. Effects were examined on syllable rate, disfluency duration, and vocal intensity. RESULTS Seven of 10 APH/AOS participants increased fluency with masking by increasing rate, decreasing disfluency duration, or both. In contrast, none of the NH participants increased speaking rate with MAF. In the AAF condition, only 1 APH/AOS participant increased fluency. Four APH/AOS participants and 8 NH participants slowed their rate with AAF. CONCLUSIONS Speaking with MAF appears to increase fluency in a subset of individuals with APH/AOS, indicating that overreliance on auditory feedback monitoring may contribute to their disorder presentation. The distinction between responders and nonresponders was not linked to AOS diagnosis, so additional work is needed to develop hypotheses for candidacy and underlying control mechanisms.
Photophysical and Photodynamical Study of Fluoroquinolone Drug Molecule in Bile Salt Aggregates

Photophysical properties of two widely used antibiotic fluoroquinolone drugs, namely Norfloxacin (NOR) and Ofloxacin (OFL) have been investigated in biomimicking environments formed by bile salts. Experimental results demonstrate that photophysical enhancement and fall of a particular prototropic species are sensitive to the excitation wavelength in bile salt aggregates. Excitation at shorter wavelengths reveals quenching of fluorescence of these fluoroquinolone with addition of sodium deoxycholate (NaDC), sodium taurocholate (NaTC) and sodium glycodeoxycholate (NaGDC). On the contrary, we observe a steady increase in the fluorescence intensity with a continuous redshift upon excitation at longer wavelength. The experimental results were rationalized in terms of the fact that, neutral and zwitterionic species of fluoroquinolone molecules in bile salt aggregates are selectively excited at shorter wavelength while the cationic form of fluoroquinolone molecules are excited at longer wavelength. The excess hydronium ions in the hydrophilic surface of bile salt aggregates convert the neutral species of NOR and OFL into cationic species causing an enhancement in the emission intensity. We found that NaGDC and NaTC because of the conjugate head group are more effective in converting the neutral species of fluoroquinolones into a cationic species than NaDC. The quenching order is in accordance with hydrophobicity indices of bile salt.
Who works in the sex industry? A profile of female prostitutes in Victoria

Abstract: A large‐scale survey was conducted to obtain a comprehensive picture of the range of women involved in prostitution in ‘Victoria and to document their concerns about health in relation to sex work’. There was considerable diversity in the ages, education levels, family situations and attitudes to sex work among women working mainly in the legal brothels in Victoria. While their practices in client‐worker interactions were low‐risk for human immunodeficiency virus and other sexually transmitted diseases, many of the women were more at risk from unprotected sex with private partners and some were more at risk from injecting drug use. Most women reported economic reasons for entering the sex industry and cited problems associated with male clients as the worst aspects. Effective health interventions should be devised and aimed at specific sub‐populations of these (and other) sex workers.
NF‐κB involvement in the induction of high affinity CAT‐2 in lipopolysaccharide‐stimulated rat lungs

Background: Endotoxemia stimulates nitric oxide (NO) biosynthesis through induction of inducible NO synthase (iNOS). Cellular uptake of l‐arginine, the sole substrate for iNOS, is an important mechanism regulating NO biosynthesis by iNOS. The isozymes of type‐2 cationic amino acid transporters, including CAT‐2, CAT‐2A, and CAT‐2B, constitute the most important pathways responsible for trans‐membrane l‐arginine transportation. Therefore, regulation of CAT‐2 isozymes expression may constitute one of the downstream regulatory pathways that control iNOS activity. We investigated the time course of enzyme induction and the role of nuclear factor‐κB (NF‐κB) in CAT‐2 isozymes expression in lipopolysaccharide‐(LPS) treated rat lungs.
Multiple independent lineages of HIV-1 persist in breast milk and plasma

Design:The origin and evolution of HIV-1 in breast milk is unclear, despite the continuing significance of this tissue as a transmitting compartment. To elucidate the evolutionary trajectory of viral populations in a transient mucosal compartment, longitudinal sequences of the envelope glycoprotein (gp120) region from plasma and breast milk spanning the first year after delivery were analyzed in six women infected by HIV-1 subtype C. Methods:Multiple phylogenetic algorithms were used to elucidate the evolutionary history and spatial structure of virus populations between tissues. Results:Overall persistent mixing of viral sequences between plasma and breast milk indicated that breast milk is not a distinct genetic viral compartment. Unexpectedly, longitudinal phylogenies showed multiple lineages defined by long branches that included virus from both the breast milk and the plasma. Plasma was unlikely the anatomical origin of the most recent common ancestor (MRCA) in at least three of the patients, although in other women, the temporal origin of the MRCA of the viral populations following delivery occurred well before the onset of breast milk production. Conclusions:These findings suggest that during pregnancy/lactation, a viral variant distinct from the plasma virus initially seeds the breast milk, followed by subsequent gene flow between the plasma and breast milk tissues. This study indicates the potential for reactivation or reintroduction of distinct lineages during major immunological disruptions during the course of natural infection.
Getting the run around: accessing services for children with developmental co-ordination disorder.

BACKGROUND Accessing services for children with developmental co-ordination disorder (DCD) is frequently difficult for parents who have to navigate both health and education systems to find a diagnosis and appropriate interventions. METHOD A qualitative study design incorporating a phenomenological perspective was utilized to understand the nature of the experiences of these parents in attempting to access support for their children with DCD. Twelve parents, whose children attended the Kids Skills Clinic at the University of Western Ontario and were identified as having DCD, were interviewed by the second author. Interviews were transcribed verbatim and analysed using constant comparative method. Member checking, peer checking and code-recoding were carried out to enhance rigour in data analysis. RESULTS A number of themes emerged focusing on the common problems experienced leading to occupational therapy referral. Parents' journeys to seek and access services for their children with DCD were characterized by a sense of maternal knowing, experience of frustration, trivialization of the problem, a sense of 'going it alone', and 'getting the run around'. CONCLUSIONS Implications for health and educational professionals working with children, in terms of recognition of DCD and referral for services, are described.
Body temperature regulation and thermoneutrality in rats.

Various concepts of thermoneutrality were considered for a proposed study of the role of hypothalamic amines in temperature regulation of rats. The classic definition, the ambient temperature over which metabolic rate is minimum and constant, gave a range of approximately 28 to 32 degrees C. However, within this temperature range rats were inactive, the inactivity apparently representing a behavioural response to heat stress and itself responsible for the reduced metabolic rate; certain thermoregulatory effectors were also activated to increase heat loss. Therefore an alternative range, 18.0 +/- 1.9 (mean +/- S.D.) to 28.1 +/- 1.0 degrees C, was defined in which rats displayed normal activity, behavioural thermoregulations being absent.
Contact hypersensitivity: the mechanism of immune responses and T cell balance.

The skin is the largest organ in the human body. It acts not only as an important structural barrier against injury but also as a peripheral arm of the immune system. Elucidating the characteristics of this latter function has taken on renewed importance in recent years. Exposure to chemicals in everyday life has increased exponentially over the past decades. This has been accompanied by an increased incidence of contact hypersensitivity (CHS), a dendritic cell-dependent, T cell-derived, cytokine-mediated skin inflammation. Cytokines derived from Langerhans cells (i.e., interleukin-12 [IL-12]) and from T cell (i.e., interferon-gamma [IFN-gamma], IL-4, and IL-10) play a pivotal role in the induction and initiation of CHS. Developments in immunology and molecular biology have improved our understanding of the molecular mechanisms underlying this immune response. However, the conflicting opinions that continue to characterize discussions of CHS supply clear testimony that our knowledge is as yet incomplete.
An Arf-Egr-C/EBPβ Pathway Linked to Ras-Induced Senescence and Cancer

ABSTRACT Oncogene-induced senescence (OIS) protects normal cells from transformation by Ras, whereas cells lacking p14/p19Arf or other tumor suppressors can be transformed. The transcription factor C/EBPβ is required for OIS in primary fibroblasts but is downregulated by H-RasV12 in immortalized NIH 3T3 cells through a mechanism involving p19Arf loss. Here, we report that members of the serum-induced early growth response (Egr) protein family are also downregulated in 3T3Ras cells and directly and redundantly control Cebpb gene transcription. Egr1, Egr2, and Egr3 recognize three sites in the Cebpb promoter and associate transiently with this region after serum stimulation, coincident with Cebpb induction. Codepletion of all three Egrs prevented Cebpb expression, and serum induction of Egrs was significantly blunted in 3T3Ras cells. Egr2 and Egr3 levels were also reduced in RasV12-expressing p19Arf null mouse embryonic fibroblasts (MEFs), and overall Egr DNA-binding activity was suppressed in Arf-deficient but not wild-type (WT) MEFs, leading to Cebpb downregulation. Analysis of human cancers revealed a strong correlation between EGR levels and CEBPB expression, regardless of whether CEBPB was increased or decreased in tumors. Moreover, overexpression of Egrs in tumor cell lines induced CEBPB and inhibited proliferation. Thus, our findings identify the Arf-Egr-C/EBPβ axis as an important determinant of cellular responses (senescence or transformation) to oncogenic Ras signaling.
Applying burden of disease methods in developing countries: a case study from Pakistan.

OBJECTIVES Disability-adjusted life-year (DALY) and healthy life-year (HeaLY) are composite indicators of disease burden that combine mortality and morbidity into a single measurement. This study examined the application of these methods in a developing country to assess the loss of healthy life from prevalent conditions and their use in resource-poor national contexts. METHODS A data set for Pakistan was constructed on the basis of 180 sources for population and disease parameters. The HeaLY approach was used to generate data on loss of healthy life from premature mortality and disability in 1990, categorized by 58 conditions. RESULTS Childhood and infectious diseases were responsible for two thirds of the burden of disease in Pakistan. Condition-specific analysis revealed that chronic diseases and injuries were among the top 10 causes of HeaLY loss. Comparison with regional estimates demonstrates consistency of disease trends in both communicable and chronic diseases. CONCLUSIONS The burden of disease in countries such as Pakistan can be assessed by using composite indicators. The HeaLY method provides an explicit framework for national health information assessment. Obtaining disease- and population-based data of good quality is the main challenge for any method in the developing world.
Age‐specific interval breast cancers in Japan: estimation of the proper sensitivity of screening using a population‐based cancer registry

The age‐specific sensitivity of a screening program was investigated using a population‐based cancer registry as a source of false‐negative cancer cases. A population‐based screening program for breast cancer was run using either clinical breast examinations (CBE) alone or mammography combined with CBE in the Miyagi Prefecture from 1997 to 2002. Interval cancers were newly identified by linking the screening records to the population‐based cancer registry to estimate the number of false‐negative cases of screening program. Among 112 071 women screened by mammography combined with CBE, the number of detected cancers, false‐negative cases and the sensitivity were 289, 22 and 92.9%, respectively, based on the reports from participating municipalities. The number of newly found false‐negative cases and corrected sensitivity when using the registry were 34 and 83.8%, respectively. In detected cancers, the sensitivity of screening by mammography combined with CBE in women ranging from 40 to 49 years of age based on a population‐based cancer registry was much lower than that in women 50–59 and 60–69 years of age (40–49: 18, 71.4%, 50–59: 19, 85.8%, 60–69: 19, 87.2%). These data suggest that the accurate outcome of an evaluation of breast cancer screening must include the use of a population‐based cancer registry for detecting false‐negative cases. Screening by mammography combined with CBE may therefore not be sufficiently sensitive for women ranging from 40 to 49 years of age. (Cancer Sci 2008; 99: 2264–2267)
Impaired elastic matrix development in the great arteries after ablation of the cardiac neural crest

The cells that form the aorticopulmonary septum in the avian embryo have been shown to be similar to the cells that form the walls of the great vessels in two ways: both are derived from the cardiac neural crest and both are able to synthesize an elastogenic matrix in the early embryo. Because of these similarities, and because ablation of the cardiac neural crest causes congenital defects of the outflow tract that are related to failure of proper septation, it was hypothesized that such an ablation also would cause the walls of the great vessels to be defective. The purpose of this study was to compare the elastic matrix in the mediae of the great vessels of normal embryos with those from which the cardiac neural crest had been ablated.