Leftward Shift Research Articles

ETHOLOGICAL AND VEGETATIVE CORRELATES OF EXPERIMENTAL NEUROGENIC STRESS

The study aimed to comprehensively investigate the ethological and vegetative mechanisms involved in the development of experimental emotional stress, establish the relationship between these correlates, and identify an indicator or group of indicators with prognostic value for the occurrence of cardiac dysfunction under neurogenic stress conditions. Materials and Methods. The study presents the results of research on the ethological and autonomic correlates of emotional stress in 254 sexually mature male Wistar rats, using the "afferent excitation conflict" model. Results. Heart rhythm was studied electrocardiographically as an autonomic correlate of emotional stress. The results of the research have shown that ethological and vegetative reactions that perform regulatory and adaptive functions are constant and natural correlates of emotional stress states. The data obtained allow us to note that animals of all three typological groups responded to the onset of stress with a tendency to increase heart rate. Prolonged exposure to the conflict situation was associated with a return of heart rate to baseline values in animals of groups I and II, and a significant decrease in heart rate in animals of group III. Qualitative analysis of the variation curves showed that vagotonic (right position of the variation curve – right graph) prevailed in animals of group I before stress exposure, and sympathotonic (left graph) regulatory influences on the sinus node prevailed in the animals of group III. The onset of stress exposure led to a leftward shift of the variation curves in animals of all groups. However, in animals of group I, this shift was accompanied by a widening of the variation curves (83%), and in animals of group III – by a narrowing (67%). Conclusion. As a result of the studies, four types of heart rate changes were identified during prolonged (3-hour) exposure to stress. A correlation was established between the ethological and typological characteristics of the animals and the occurrence of cardiac rhythm disorders. In animals with a high frequency of cardiac arrhythmias under stress, there was also an increased influence of the sympathetic nervous system on the sinus node, accompanied by a decrease in heart rate variability. Animals with a high frequency of cardiac arrhythmias under stress also showed an increase in the influence of the sympathetic nervous system on the sinus node but with a decrease in heart rate variability.

Long-term hypoxia modulates depolarization activation of BKCa currents in fetal sheep middle cerebral arterial myocytes

IntroductionPrevious evidence indicates that gestational hypoxia disrupts cerebrovascular development, increasing the risk of intracranial hemorrhage and stroke in the newborn. Due to the role of cytosolic Ca2+ in regulating vascular smooth muscle (VSM) tone and fetal cerebrovascular blood flow, understanding Ca2+ signals can offer insight into the pathophysiological disruptions taking place in hypoxia-related perinatal cerebrovascular disease. This study aimed to determine the extent to which gestational hypoxia disrupts local Ca2+ sparks and whole-cell Ca2+ signals and coupling with BKCa channel activity.MethodsConfocal imaging of cytosolic Ca2+ and recording BKCa currents of fetal sheep middle cerebral arterial (MCA) myocytes was performed. MCAs were isolated from term fetal sheep (∼140 days of gestation) from ewes held at low- (700 m) and high-altitude (3,801 m) hypoxia (LTH) for 100+ days of gestation. Arteries were depolarized with 30 mM KCl (30K), in the presence or absence of 10 μM ryanodine (Ry), to block RyR mediated Ca2+ release.ResultsMembrane depolarization increased Ry-sensitive Ca2+ spark frequency in normoxic and LTH groups along with BKCa activity. LTH reduced Ca2+ spark and whole-cell Ca2+ activity and induced a large leftward shift in the voltage-dependence of BKCa current activation. The influence of LTH on the spatial and temporal aspects of Ca2+ sparks and whole-cell Ca2+ responses varied.DiscussionOverall, LTH attenuates Ca2+ signaling while increasing the coupling of Ca2+ sparks to BKCa activity; a process that potentially helps maintain oxygen delivery to the developing brain.

Invasive hemodynamic response to exercise in hemodynamically significant aortic stenosis with preserved left ventricular ejection fraction

Abstract Background Guidelines acknowledge that discordant low-gradient (LG) aortic stenosis (AS) may be severe, but verifying this can be challenging. Right heart catheterization during exercise is considered the gold standard evaluating ventricular hemodynamics. No invasive studies have compared the hemodynamic response of discordant LG and severe AS during exercise. Purpose To describe exercise hemodynamics in patients with asymptomatic discordant AS and left ventricular ejection fraction ≥50%, and to identify the variables associated with the steepness of the pulmonary capillary wedge pressure (PCWP)/cardiac output (CO) slope defined as (peak exercise PCWP-rest PCWP)/(peak exercise CO-rest CO). Methods Patients with aortic valve area (AVA) ≤1.5 cm² underwent right heart catheterization at rest and during maximal exercise measuring pulmonary artery pressures, PCWP, CO and PCWP/CO slope. Patients were stratified in three groups: 1) discordant LG AS (AVA ≤1.0 cm² and mean gradient <40 mmHg); 2) moderate AS (AVA >1.0 cm²) and 3) high-gradient severe AS (AVA ≤1.0 cm² and mean gradient ≥40 mmHg). Results Among 86 patients, 17 (20%) had discordant LG, 49 (57%) moderate, and 20 (23%) high-gradient severe AS. The PCWP/CO slope was significantly steeper in discordant LG: median 3.3 mmHg/L/min (interquartile range: 2.2 mmHg/L/min) and high-gradient severe AS: 2.7 mmHg/L/min (1.5 mmHg/L/min) compared to moderate AS: 1.9 mmHg/L/min (2.0 mmHg/L/min), p=0.004. In a linear regression model adjusted for age, sex and rest PCWP, systemic arterial compliance and AS severity were significantly associated with the PCWP/CO slope. Furthermore, patients with discordant LG AS had a leftward and upward shift in the PCWP/CO slope. Conclusions Discordant LG and high-gradient severe AS had similar hemodynamic response to exercise with steeper PCWP/CO slope than in moderate AS, suggesting that discordant LG AS is a severe form of AS. In addition, the left-upward shift in PCWP/CO slope for discordant LG compared to high-gradient severe AS indicates that, this group also has latent heart failure with preserved ejection fraction physiology.

Ventricular interaction and clinical outcomes in patients undergoing transcatheter tricuspid valve repair

Abstract Background Excessive volume overload of the right ventricle (RV) due to tricuspid regurgitation (TR) can cause a leftward shift of the interventricular septum and changes left ventricular (LV) geometry, which leads to decreases LV distensibility and results in cardiac output. This unfavorable ventricular interaction might have prognostic impacts of patients undergoing transcatheter tricuspid valve repair (TTVr). Purpose We investigated the association between the ventricular interaction and clinical outcomes in patients undergoing TTVr. Methods We retrospectively assessed 304 patients who underwent TTVr. The ventricular interaction was assessed using LV eccentricity index which was defined as LV antero-posterior dimension / LV septo-lateral dimension at end-diastole in the parasternal short-axis view (Figure 1). Increased ventricular interaction was defined as LV eccentricity index ≥1.2. The primary outcome was a composite of all-cause mortality and heart failure hospitalization within one year after TTVr. Results The mean LV eccentricity index at baseline was 1.23 ± 0.20, and 168 of 304 patients (55.3%) had increased ventricular interaction. Patients with increased ventricular interaction were more likely to have massive or torrential TR, reduced RV function, larger RV areas, and lower cardiac index. Increased ventricular interaction at baseline was associated with an increased risk of the composite outcome (HR 2.14; 95%CI 1.36–3.37; p=0.001; Figure 2A), which was consistent after adjusting for age, male sex, renal function, LV ejection fraction, RV function, and residual TR. Echocardiography at baseline showed that 83 of 168 patients (49.4%) with increased ventricular interaction at baseline had an improvement in the ventricular interaction (i.e., LV eccentricity index ≥1.2 at baseline but <1.2 at discharge), which was associated with a lower risk of the composite outcome than persisted ventricular interaction (i.e., LV eccentricity index ≥1.2 at both baseline and discharge) (Figure 2B), irrespectively of baseline characteristics and residual TR. Smaller RV area and residual TR ≤2+ were related to the improved ventricular interaction. Conclusion Ventricular interaction, defined as LV eccentricity index ≥1.2, is associated with an increased risk of clinical outcomes after TTVr. However, the post-procedural improvement in ventricular interaction after TTVr may be linked to better prognosis.Figure 1Figure 2

Dopamine D1-Like Receptor-Mediated Insurmountable Blockade of the Reinforcing Effects of Cocaine in Rats.

Previous studies indicated differing effects of dopamine D1-like and D2-like receptor (D1R and D2R, respectively) agonists on cocaine self-administration. Leftward shifts by D2R agonists in the cocaine self-administration dose-effect function contrast with decreases by D1R agonists in maximal cocaine self-administration without rightward or leftward displacement. Whether the effects of the D1R agonists are due to actions at D1Rs has not been determined possibly due to the difficulty in separating the blockade by a D1R antagonist of the effects of the D1R agonists and those of cocaine. In the present study, pretreatment with the D1R agonists R(+)-SKF-81297 (0.1-1.0 mg/kg) and ({plus minus})-SKF-82958 (0.032-0.32 mg/kg) dose-dependently decreased maximal cocaine self-administration at doses below those affecting food-reinforced responding. In contrast, pretreatment with the D2R agonists R(-)-NPA (0.001-0.01 mg/kg) and (-)-quinpirole (0.01-0.1 mg/kg) dose-dependently left shifted the cocaine self-administration dose-effect function. The decreases by D1R agonists in maximal cocaine self-administration were dose-dependently antagonized by the D1R antagonist SCH-39166 at doses that alone had no effects on cocaine self-administration. Doses of SCH-39166 that blocked the effects of the D1R agonists on cocaine self-administration were like those that shifted self-administration of D1R agonists to the right but had no effects on self-administration of D2R agonists. Self-administration of the D2R agonists was dose-dependently shifted to the right by the preferential D2R antagonist, L-741,626, but not by SCH-39166. These results demonstrate that the decreases by the D1R agonists in cocaine self-administration are selectively D1R-mediated, and support findings suggesting fundamentally distinct roles of the D1Rs and D2Rs in cocaine reinforcement. Significance Statement Dopamine D1-like (D1R) agonists decrease maximal cocaine self-administration, whereas D2-like (D2R) agonists shift the cocaine self-administration dose-effect function leftward with mechanisms for those different effects unclear. The present study demonstrates blockade by the selective D1R antagonist SCH-39166 of decreases in maximal cocaine self-administration at doses that blocked other D1R-mediated effects but not effects of cocaine, suggesting fundamentally distinct roles of the dopamine D1-like and D2-like receptors in cocaine reinforcement and development of D1R agonists as potential treatments for cocaine-use disorder.

MMP-8 causes leftward shift in end-diastolic pressure-volume relationship and may explain the development of diastolic dysfunction in septic cardiomyopathy.

Septic cardiomyopathy (SCM) with diastolic dysfunction carries a poor prognosis, and the mechanisms underlying the development of diastolic dysfunction remain unclear. Matrix metalloproteinase-8 (MMP-8) is released from neutrophils and degrades collagen I. MMP-8 levels correlate with SCM severity. We scrutinized, for the first time, the direct impact of MMP-8 on cardiac systolic and diastolic functions. Isolated rat hearts were perfused with Krebs-Henseleit solution in a Langendorff setup with computer-controlled filling pressures of both ventricles in an isovolumetric regime. The end-diastolic pressure (EDP) varied periodically between 3 and 20 mmHg. After baseline recordings, MMP-8 (100 µg/mL) was added to the perfusion. Short-axis views of both ventricles were continuously acquired by echocardiography. MMP-8 perfusion resulted in a progressive decline in peak systolic pressures (Psys) in both ventricles, but without significant changes in their end-systolic pressure-area relationships (ESPARs). Counterintuitively, conspicuous leftward shifts of the end-diastolic pressure-area relationships (EDPARs) were observed in both ventricles. The left ventricle (LV) end-diastolic area (EDA) decreased by 32.8 ± 5.7% (P = 0.008) at an EDP of 10.5 ± 0.4 mmHg, when LV Psys dropped by 20%. The decline of Psys was primarily due to the decrease in EDA, and restoring the baseline EDA by increasing EDP recovered 81.33 ± 5.87% of the pressure drop. Collagen I generates tensile (eccentric) stress, and its degradation by MMP-8 causes end-diastolic pressure-volume relationship (EDPVR) leftward shift, resulting in diastolic and systolic dysfunctions. The diastolic dysfunction explains the clinically observed fluid unresponsiveness, whereas the decrease in end-diastolic volume (EDV) diminishes the systolic functions. MMP-8 can explain the development of SCM with diastolic dysfunction.NEW & NOTEWORTHY MMP-8, released from activated neutrophils and macrophages, is markedly elevated in sepsis, correlating with sepsis severity and mortality. MMP-8 targets collagen I of the cardiac ECM and induces diastolic dysfunction with fluid unresponsiveness, associated with decreased EDV, reduced sarcomere length, and diminished systolic function. Unlike other MMPs that predominantly cleave collagen-III and contribute to cardiac dilatation, thereby increasing sarcomere length, MMP-8 leads to a leftward shift in the EDPVR, resulting in diastolic and systolic dysfunctions.

Unraveling the dynamics of firing patterns for neurons with impairment of sodium channels.

Various factors such as mechanical trauma, chemical trauma, local ischemia, and inflammation can impair voltage-gated sodium channels (Nav) in neurons. These impairments lead to a distinctive leftward shift in the activation and inactivation curves of voltage-gated sodium channels. The resulting sodium channel impairments in neurons are known to affect firing patterns, which play a significant role in neuronal activities within the nervous system. However, the underlying dynamic mechanism for the emergence of these firing patterns remains unclear. In this study, we systematically investigated the effects of sodium channel dysfunction on individual neuronal dynamics and firing patterns. By employing codimension-1 bifurcation analysis, we revealed the underlying dynamical mechanism responsible for the generation of different firing patterns. Additionally, through codimension-2 bifurcation analysis, we theoretically determined the distribution of firing patterns on different parameter planes. Our results indicate that the firing patterns of impaired neurons are regulated by multiple parameters, with firing pattern transitions caused by the degree of sodium channel impairment being more diverse than those caused by the ratio of impaired sodium channel and current. Furthermore, we observed that the firing pattern of tonic firing is more likely to be the norm in impaired sodium channel neurons, providing valuable insights into the signaling of impaired neurons. Overall, our findings highlight the intricate relationships among sodium channel impairments, neuronal dynamics, and firing patterns, shedding light on the impact of disruptions in ion concentration gradients on neuronal function.

A venom peptide-induced NaV channel modulation mechanism involving the interplay between fixed channel charges and ionic gradients

Venoms are used by arthropods either to immobilise prey or as defence against predators. Our study focuses on the venom peptide, Ta3a, from the African ant species, Tetramorium africanum and its effects on voltage-gated sodium (NaV) channels, which are ion channels responsible for the generation of electrical signals in electrically excitable cells, such as neurons. Using the NaV1.7 isoform as our model NaV channel we show that Ta3a prolongs single channel active periods with increased open probability and induces non-inactivating whole-cell currents. Ta3a-affected NaV1.7 channels exhibit a leftward (hyperpolarising) shift in activation threshold, constitutive activity even in the absence of an activating voltage stimulus, and at cell membrane voltages where channels are normally silent. Current-voltage experiments show that Ta3a shifts the voltage at which NaV current changes direction (reversal potential) by altering the local ionic concentration of permeant ions (Na+) rather than changing the channel’s preference for ionic species. We propose a model where Ta3a maintains the positively charged voltage-sensing (S4) domains of the channel in the activated configuration where their electric field is exposed to the extracellular membrane surface to create an ionic bilayer comprising S4 domains and mobile anions (Cl−). This bilayer has a depolarising effect on the cell membrane, thus reducing the amount of externally applied voltage required for channel activation.

TRPV1 corneal neuralgia mutation: Enhanced pH response, bradykinin sensitization, and capsaicin desensitization

The factors that contribute to pain after nerve injury remain incompletely understood. Laser-assisted in situ keratomileusis (LASIK) and photorefractive keratectomy (PRK) are common surgical techniques to correct refractive errors. After LASIK or PRK, a subset of patients suffers intense and persistent pain, of unknown origin, described by patients as feeling like shards of glass in their eye. Here, we evaluated a TRPV1 variant, p.V527M, found in a 49-y-old woman who developed corneal pain after LASIK and subsequent PRK enhancement, reporting an Ocular Surface Disease Index score of 100. Using patch-clamp and Ca2+ imaging, we found that the V527M mutation enhances the response to acidic pH. Increasing proton concentration induced a stronger leftward shift in the activation curve of V527M compared to WT, resulting in channel activity of the mutant in acidic pH at more physiological membrane potentials. Finally, comparing the responses to consecutive applications of different agonists, we found in V527M channels a reduced capsaicin-induced desensitization and increased sensitization by the arachidonic acid metabolite 12-hydroxyeicosatetraenoic acid (12-HETE). We hypothesize that the increased response in V527M channels to protons and enhanced sensitization by 12-HETE, two inflammatory mediators released in the cornea after tissue damage, may contribute to the pathogenesis of corneal neuralgia after refractive surgery.

Low‐field nuclear magnetic resonance relaxometry: a new approach for monosaccharide identification in sugar solutions

SummaryMonosaccharides such as glucose, fructose, and galactose are the building blocks of oligosaccharides and act as the major energy sources in our body. These three monosaccharides are the most prominent in food processing and widely consumed analytes, found in fruits or milk. Although several analytical methods are available to identify and quantify sugar solutions, their drawbacks urge the search for better possible alternatives. A simple, rapid, and efficient method for identifying monosaccharides (ᴅ‐fructose, ᴅ‐galactose, and ᴅ‐glucose) was investigated using low‐field nuclear magnetic resonance (LF‐NMR), exploring the applicability and reliability of this machine. The transverse (T2) relaxation curve was analysed to distinguish monosaccharides from each other. The increasing monosaccharide concentration in the sugar solution causes leftward shifts in signals, indicating a gradual reduction in the mobility of water molecules. The addition of sugar generated a secondary peak, which assisted in identifying monosaccharides. Notably, fructose exhibited distinct behaviour from that of glucose and galactose. The regression coefficient consistently exceeded 0.98, indicating the reliability of this experiment. LF‐NMR encountered challenges in differentiating stereo‐isomeric glucose and galactose. However, quantification of monosaccharides from known binary mixtures (water and one monosaccharide) is possible by preparing standard curves of different concentrations of sugars. These standard curves can be either T2 or the total surface area of the peaks as a function of sugar concentration. The study concludes that LF‐NMR has potential for the qualitative and quantitative analysis of monosaccharides in pure solutions or powdered samples. It is hoped that the rapid and easy way of monosaccharide identification by simple analysis of peaks obtained from NMR spectra will enhance its accessibility for users. However, it also acknowledges limitations in applying this method to complex systems (mixtures of different sugars in a solution).

Abstract P228: Kdm6a Regulates Extracellular Matrix Genes During Arterial Stiffening and High Blood Pressure in Female Mice

Arterial stiffness measured by pulse wave velocity (PWV) increases steeply during menopause due to estradiol decline. Longitudinal studies show higher PWV in postmenopausal women compared to age-matched men. Previously, we have demonstrated increased PWV in ovariectomized (OVX) and middle-aged female mice. However, the impact of sex chromosomes on PWV is unknown in female mice. We hypothesize that a decline in estradiol unleashes the female sex chromosomes effect that promotes arterial stiffening. This study used four core genotype mice (n=6-10/group) of XX or XY sex chromosomes left intact or OVX for 8 weeks. Arterial stiffening was assessed with pulse wave Doppler and 24-hour blood pressure by radiotelemetry. Carotid artery passive myography and vascular reactivity of 2 nd order mesenteric artery were assessed by pressure myography. To induce hypertension, XX and XY mice were treated with deoxycorticosterone acetate (DOCA; 50 mg/pellet) for 21 days and 1% saline. In vitro, isolated aortic vascular smooth muscle cells (VSMC) were stretched on collagen matrix or treated with Kdm6a inhibitor GSKJ-1. PWV was significantly increased in OVX than in gonadal intact XX and XY mice (P<0.001). However, an interaction effect was indicated with higher PWV in XX than XY OVX mice (4.9±0.1 vs. 4.2±0.2 m/s; P<0.001), indicating a sex chromosome effect. Carotid artery stress-strain curves showed a leftward shift of XX than XY mice, suggesting increased structural stiffness. Masson’s trichrome staining of the aorta showed increased collagen in the adventitia of XX than XY (30% vs. 26%; P=0.005) mice. Higher systolic blood pressure (SBP) was indicated in XX than in XY mice (Baseline; 123±3 vs. 116±4 mmHg; P=0.02). Aortic RNAseq showed increased X-linked genes, including Kdm6a, in XX compared to XY mice. Stretched aortic VSMC showed increased Col1a1 and decreased Itga4 and Lama2 genes reversed by GSKJ-1. DOCA-induced hypertension blunted the PWV difference between XX and XY mice; however, SBP was higher in XX than in XY mice (Week 1: 135±13 vs.127±3 mmHg; P=0.03), but not weeks 2 and 3. We observed impaired acetylcholine-mediated relaxation in hypertensive XX than XY mice (47% vs. 24%; P=0.03). Our data suggested that OVX mice with XX sex chromosomes promote arterial stiffening and high blood pressure, and Kdm6a regulates extracellular matrix genes in XX female VSMC. DOCA-induced hypertension promotes endothelial dysfunction and blunts PWV in ovariectomized XX and XY mice.

The Quantum Cyclic Rotation Gate

A circular shift operator (or cyclic rotation gate) ROTk\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${{\\,\\mathrm{\ exttt {ROT}}\\,}}_k$$\\end{document} applies a rightward (or leftward) shift to an input register of n qubits o by as many positions as encoded by an additional input k∈N\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$k \\in \\mathbb N$$\\end{document}. Specifically, the qubit at position x is moved to position (x+k)modn\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$(x+k) \\mod n$$\\end{document}. While it is known that there exists a quantum rotation operator that can be implemented in O(log(n))\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${{\\,\\mathrm{\\mathcal {O}}\\,}}(\\log (n))$$\\end{document}-time, through the repeated parallel application of the elementary Swap\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${{\\,\\mathrm{\ exttt {Swap}}\\,}}$$\\end{document} operators, there is no systematic procedure that concretely constructs the quantum operator ROT\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${{\\,\\mathrm{\ exttt {ROT}}\\,}}$$\\end{document} for variable size n of the quantum register and a variable parameter k. We fill the gap, providing a systematic implementation of the cyclic rotation operator (denoted ROT\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${{\\,\\mathrm{\ exttt {ROT}}\\,}}$$\\end{document}) in a quantum circuit model of computation whose depth is O(log(n))\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${{\\,\\mathrm{\\mathcal {O}}\\,}}(\\log (n))$$\\end{document}. We show how the circular shift operator can be utilized in quantum approaches to text processing, focusing on the problem of getting all possible cyclic rotations of a string in O(log2(n))\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${{\\,\\mathrm{\\mathcal {O}}\\,}}(\\log ^2(n))$$\\end{document} depth.

Improved Low-field NMR porosity characterization of cementitious materials containing water-soluble organic admixtures

Water-soluble organic admixtures (WSOAs) are widely used in cementitious materials, and may affect the porosity, but their effects on low-field nuclear magnetic resonance (LF-NMR) measurement are often overlooked. Using viscosity modifying admixture (VMA) as an example, this study demonstrates the presence of WSOAs would lead to an overestimation of porosity and a leftward shift of pore size distribution using LF-NMR. This is attributed to the formation of hydrogen bonds between polymer and water molecules, and the decreased distance between nuclear spins, respectively. A strategy is proposed to improve the accuracy of the porosity characterization by eliminating the additional effects of WSOAs in LF-NMR testing. The results show that the addition of small molecular mass non-ionic VMAs replacing mixing water (within a 20 % replacing rate) does not alter the porosity of the paste. This method can be extended to characterize the porosity of various porous materials containing WSOAs.

Identification of a new retigabine derivative with improved photostability for selective activation of neuronal Kv7 channels and antiseizure activity.

Pharmacological activation of neuronal Kv7 channels by the antiepileptic drug retigabine (RTG; ezogabine) has been proven effective in treating partial epilepsy. However, RTG was withdrawn from the market due to the toxicity caused by its phenazinium dimer metabolites, leading to peripheral skin discoloration and retinal abnormalities. To address the undesirable metabolic properties of RTG and prevent the formation of phenazinium dimers, we made chemical modifications to RTG, resulting in a new RTG derivative, 1025c, N,N'-{4-[(4-fluorobenzyl) (prop-2-yn-1-yl)amino]-1,2-phenylene}bis(3,3-dimethylbutanamide). Whole-cell recordings were used to evaluate Kv7 channel openers. Site-directed mutagenesis and molecular docking were adopted to investigate the molecular mechanism underlying 1025c and Kv7.2 interactions. Mouse seizure models of maximal electroshock (MES), subcutaneous pentylenetetrazol (scPTZ), and PTZ-induced kindling were utilized to test compound antiepileptic activity. The novel compound 1025c selectively activates whole-cell Kv7.2/7.3 currents in a concentration-dependent manner, with half-maximal effective concentration of .91 ± .17 μmol·L-1. The 1025c compound also causes a leftward shift in Kv7.2/7.3 current activation toward a more hyperpolarized membrane potential, with a shift of the half voltage of maximal activation (ΔV1/2) of -18.6 ± 3.0 mV. Intraperitoneal administration of 1025c demonstrates dose-dependent antiseizure activities in assays of MES, scPTZ, and PTZ-induced kindling models. Moreover, through site-directed mutagenesis combined with molecular docking, a key residue Trp236 has been identified as critical for 1025c-mediated activation of Kv7.2 channels. Photostability experiments further reveal that 1025c is more photostable than RTG and is unable to dimerize. Our findings demonstrate that 1025c exhibits potent and selective activation of neuronal Kv7 channels without being metabolized to phenazinium dimers, suggesting its developmental potential as an antiseizure agent for therapy.

Assessment of silent reading ability among glaucoma patients using an eye tracking system with horizontally scrolling text.

There have been many reports suggesting that glaucoma patients with visual field defects may have decreased silent reading ability compared with individuals without glaucoma. This study used an eye tracking system to assess the ability of glaucoma patients to silently read horizontally scrolling text. Glaucoma patients who met the following criteria were recruited: age of ≤ 70 years, at least one eye with a 10 - 2 threshold on standard automated perimetry, a mean deviation value of n 4.0 dB or less, and corrected decimal visual acuity of 0.7 or better in both eyes. Using heat map images created from data from an eye tracking system operating during presentation of a video in which a sentence scrolled horizontally from right to left, reading time, average gaze position, and average fixation time (AFT) were compared between normal eyes (23 individuals, 46 eyes) and glaucomatous eyes (25 patients, 45 eyes). Four styles of sentences (large slow, large fast, small slow, and small fast) were scrolled in the top or bottom sections of the screen. Primary open-angle glaucoma was the most common type of glaucoma in 34 eyes (75.6%), followed by secondary glaucoma in six eyes (13.3%). In comparison with normal eyes, the reading time among right eyes was significantly longer in glaucomatous eyes when reading large fast text that was shown in the bottom area and left glaucomatous eyes showed a leftward shift in gaze position in the top, bottom, or both sections with all four sentence types. There was no significant difference in AFT between glaucomatous and normal eyes across the four sentence styles. In the left eye with inferior visual field loss, text presented at the top consistently showed a correlation with leftward shift of the gaze position across all scenarios. Glaucoma patients with central visual field defects in their left eyes may experience greater difficulty reading horizontally scrolling text than individuals with normal eyes.

The Mitragyna speciosa (kratom) alkaloid mitragynine: Analysis of adrenergic α2 receptor activity in vitro and in vivo

Mitragynine, an alkaloid present in the leaves of Mitragyna speciosa (kratom), has a complex pharmacology that includes low efficacy agonism at μ-opioid receptors (MORs). This study examined the activity of mitragynine at adrenergic α2 receptors (Aα2Rs) in vitro and in vivo. Mitragynine displaced a radiolabeled Aα2R antagonist ([3H]RX821002) from human Aα2ARs in vitro with lower affinity (Ki = 1260 nM) than the agonists (−)-epinephrine (Ki = 263 nM) or lofexidine (Ki = 7.42 nM). Mitragynine did not significantly stimulate [35S]GTPγS binding at Aα2ARs in vitro, but in rats trained to discriminate 32 mg/kg mitragynine from vehicle (intraperitoneally administered; i.p.), mitragynine exerted an Aα2R agonist-like effect. Both α2R antagonists (atipamezole and yohimbine) and MOR antagonists (naloxone and naltrexone) produced rightward shifts in mitragynine discrimination dose-effect function and Aα2R agonists lofexidine and clonidine produced leftward shifts. In the mitragynine trained rats, Aα2R agonists also produced leftward shifts in discrimination dose-effect functions for morphine and fentanyl. In a separate rat cohort trained to discriminate 3.2 mg/kg i.p. morphine from vehicle, naltrexone produced a rightward shift, but neither an Aα2R agonist or antagonist affected morphine discrimination. In a hypothermia assay, both lofexidine and clonidine produced marked effects antagonized by yohimbine. Mitragynine did not produce hypothermia. Together, these data demonstrate that mitragynine acts in vivo like an Aα2R agonist, although its failure to induce hypothermia or stimulate [35S]GTPγS binding in vitro, suggests that mitragynine maybe a low efficacy Aα2R agonist.

Sex differences in heat stress vulnerability among middle-aged and older adults (PSU HEAT Project).

Individuals over the age of 65 yr are the most vulnerable population during severe environmental heat events, experiencing worse health outcomes than any other age cohort. The risk is greater in older women than in age-matched men; however, whether that reflects a greater susceptibility to heat in women, or simply population sex proportionality, is unclear. Seventy-two participants (29 M/43 F) aged 40-92 yr were exposed to progressive heat stress at a metabolic rate designed to reflect activities of daily living. Experiments were conducted in both hot-dry (HD; up to 53°C; ≤25% rh) and warm-humid (WH; ∼35°C; ≥50% rh) environments. After critical limits were determined for each condition, forward stepwise multiple linear regression analyses were conducted with net metabolic rate (Mnet) and age entered into the model first, followed by sex, body mass (mb), maximal oxygen consumption (V̇o2max), body surface area, and LDL cholesterol. After accounting for Mnet and age, sex further improved the regression model in the HD environment ([Formula: see text] = 0.34, P < 0.001) and the WH environment ([Formula: see text] = 0.36, P < 0.005). Sex explained ∼15% of the variance in critical environmental limits in HD conditions and 12% in WH conditions. Heat compensability curves were shifted leftward for older women, indicating age- and sex-dependent heat vulnerability compared with middle-aged women and older men in WH (P = 0.007, P = 0.03) and HD (P = 0.001, P = 0.01) environments. This reflects the heterogeneity of thermal-balance thresholds associated with aging relative to those seen in young adults and suggests that older females are more vulnerable than their age-matched male counterparts.NEW & NOTEWORTHY In contrast to young adults, there are sex differences in critical environmental limits in middle-aged and older adults. Older women exhibit lower critical environmental limits in both humid and dry extreme environments demonstrated by a leftward shift in heat compensability curves. These data confirm a true sex difference in heat vulnerability of older adults and support the epidemiological mortality data from environmental heat waves.

Basal release of 6-cyanodopamine from rat isolated vas deferens and its role on the tissue contractility.

6-Cyanodopamine is a novel catecholamine released from rabbit isolated heart. However, it is not known whether this catecholamine presents any biological activity. Here, it was evaluated whether 6-cyanodopamine (6-CYD) is released from rat vas deferens and its effect on this tissue contractility. Basal release of 6-CYD, 6-nitrodopamine (6-ND), 6-bromodopamine, 6-nitrodopa, and 6-nitroadrenaline from vas deferens were quantified by LC-MS/MS. Electric-field stimulation (EFS) and concentration-response curves to noradrenaline, adrenaline, and dopamine of the rat isolated epididymal vas deferens (RIEVD) were performed in the absence and presence of 6-CYD and /or 6-ND. Expression of tyrosine hydroxylase was assessed by immunohistochemistry. The rat isolated vas deferens released significant amounts of both 6-CYD and 6-ND. The voltage-gated sodium channel blocker tetrodotoxin had no effect on the release of 6-CYD, but it virtually abolished 6-ND release. 6-CYD alone exhibited a negligible RIEVD contractile activity; however, at 10 nM, 6-CYD significantly potentiated the noradrenaline- and EFS-induced RIEVD contractions, whereas at 10 and 100 nM, it also significantly potentiated the adrenaline- and dopamine-induced contractions. The potentiation of noradrenaline- and adrenaline-induced contractions by 6-CYD was unaffected by tetrodotoxin. Co-incubation of 6-CYD (100 pM) with 6-ND (10 pM) caused a significant leftward shift and increased the maximal contractile responses to noradrenaline, even in the presence of tetrodotoxin. Immunohistochemistry revealed the presence of tyrosine hydroxylase in both epithelial cell cytoplasm of the mucosae and nerve fibers of RIEVD. The identification of epithelium-derived 6-CYD and its remarkable synergism with catecholamines indicate that epithelial cells may regulate vas deferens smooth muscle contractility.

Sleep restriction reduces voluntary isometric quadriceps strength through reduced neuromuscular efficiency, not impaired contractile performance.

To determine how SR affects quadriceps contractile function and recruitment. Eighteen healthy subjects (9M, 9F, age 23.8 ± 2.8y) underwent isometric (maximal and submaximal), isokinetic (300-60°·s-1), and interpolated twitch (ITT) assessment of knee extensors following 3d of adequate sleep (SA; 7-9h·night-1), 3d of SR (5h·night-1), and 7d of washout (WO; 7-9h·night-1). Compared to SA (227.9 ± 76.6Nm) and WO (228.19 ± 62.9Nm), MVIC was lesser following SR (209.9 ± 73.9Nm; p = 0.006) and this effect was greater for males (-9.8 v. -4.8%). There was no significant effect of sleep or sleep x speed interaction on peak isokinetic torque. Peak twitch torque was greater in the potentiated state, but no significant effect of sleep was noted. Males displayed greater potentiation of peak twitch torque (12 v. 7.5%) and rate of torque development (16.7 v. 8.2%) than females but this was not affected by sleep condition. ITT-assessed voluntary activation did not vary among sleep conditions (SA: 81.8 ± 13.1% v. SR: 84.4 ± 12.6% v. WO 84.9 ± 12.6%; p = 0.093). SR induced a leftward shift in Torque-EMG relationship at high torque output in both sexes. Compared to SA, females displayed greater y-intercept and lesser slope with SR and WO and males displayed lesser y-intercept and greater slope with SR and WO. Three nights of SR decreases voluntary isometric knee extensor strength, but not twitch contractile properties. Sex-specific differences in neuromuscular efficiency may explain the greater MVIC reduction in males following SR.

Experiment study on particle pulverization-assisted convective air drying of sewage sludge

Sewage sludge drying is a pivotal step in sludge reduction, harmlessness, and resource utilization. Pulverizing sewage sludge can significantly increase the surface area of sludge particles available for contact with the air medium, consequently strengthening the convective drying process of the sludge. In this paper, the adopted deep drying system mainly combined sewage sludge pulverization and sewage sludge drying functions. Parametric studies were carried out to investigate the effects on the drying process. The moisture content of the sewage sludge decreased from 50.3% to 26.8% when the linear speed of the rotating blade tip of the pulverizing dryer and induced draft fan reached 28.3 m·s−1, 62.8 m−1, and air velocity reached 9.5 m·s−1, respectively. Furthermore, this work also preliminarily reveals the mechanism of the pulverizing dryer. The pores on the sludge particle surfaces are destroyed during the drying process. As the linear speed of the rotating blade tip in the pulverizing dryer increased, the hydrophilicity and the average particle size of the sewage sludge particles decreased, with the particle size representing the highest volume fraction being reduced by 62% in the particle size distribution. The pulverizing dryer not only breaks up the sludge to increase the surface area of the sludge in contact with the air but may also have a centrifugal effect. As the intensity of the pulverizing dryer increases, Nuclear Magnetic Resonance (NMR) measurements show a leftward shift in the peak of the weakly bound water in the sludge and a noticeable shortening of the transverse relaxation time. Overall, the results suggested that pulverizing is a suitable assistive method to improve the drying effect of the sewage sludge.