Rightward Shift Research Articles

A registered re-examination of the effects of leftward prism adaptation on landmark judgements in healthy people.

It has long been known that active adaptation to a shift of the visual field, caused by laterally-displacing prisms, induces short-term sensorimotor aftereffects. More recent evidence suggests that prism adaptation may also stimulate higher-level changes in spatial cognition, which can modify the spatial biases of healthy people. The first reported, and most replicated, higher-level aftereffect is a rightward shift in the point of subjective equality (PSE) for a perceptual bisection task (the landmark task), following adaptation to leftward prisms. A recent meta-analysis suggests that this visuospatial aftereffect should be robustly induced by an extended period of adaptation to strong leftward prisms (15°, ∼26.8 prism dioptres). However, we have been unable to replicate this effect, suggesting that the effect size estimated from prior literature might be over-optimistic. This Registered Report compared visuospatial aftereffects on the landmark task for a 15° leftward prism adaptation group (n=102) against a sham-adaptation control group (n=102). The effect size for the comparison was Cohen's d=.27, 95% CI [-.01, .55], which did not pass the criterion set for significance. A Bayesian analysis indicated that the data were more than 4.1 times as likely under the null than under an informed experimental hypothesis. Exploratory analyses showed no evidence for a rightward shift of landmark judgements in the prism group considered alone, and no relationship between sensorimotor and visuospatial aftereffects. We further found no support for previous suggestions that visuospatial aftereffects are modulated by a person's baseline bias (leftward or rightward) for the landmark task. Null findings are also presented for a preliminary group of 62 participants adapted to 15° leftward prisms, and an additional group of 29 participants adapted to 10° leftward prisms. We do not rule out the possibility that leftward prisms might induce higher-level visuospatial aftereffects in healthy people, but we should be more sceptical about this claim.

Effects of sprint versus strength training on risk factors for hamstring injury in football players.

This study aimed to compare the effects of in-season sprint training vs. Nordic hamstring exercise (NHE) training on risk factors for hamstring strain injuries (HSI). Eighteen male university football players (20.9±2.5 years; 181±7 cm; 75.8±9.1 kg; 15.2±3.5% of body fat) were randomly allocated to a sprint group or NHE group. They completed baseline isokinetic strength and sprint mechanics assessments prior to their assigned intervention performed twice weekly for 4-weeks, before post-testing. A mixed design ANOVA with repeated measures assessed time, group and interaction effects for all risk factors. There were significant increases in hamstring eccentric peak torque at 60°·s-1 (+8% - 9.9%), the torque produced at 20° (+15%) and 10° (+21% - 31%), as well as a rightward shift in angle of peak torque towards knee extension (-27% - -36%) in both groups (P<0.05). We also observed a significant increase (+24.5%) in hamstring eccentric peak torque at 180°·s-1 in the strength group only and significant improvements (+29.4%) in the rate of torque development of the dominant leg at 60°·s-1 in the sprint group only (P<0.05). No significant effect was noted on sprint performance or sprint mechanics (P>0.05). These findings suggest that both training programs can be effective to mitigate the risk of HSI, but through different mechanisms.

Investigations of plausible pharmacodynamics supporting the antispasmodic, bronchodilator, and antidiarrheal activities of Berberis lycium Royle. Via in silico, in vitro, and in vivo studies

Ethnopharmacological relevanceBerberis lycium Royle, a member of the Berberidaceae family, is a high-value medicinal plant with a documented history of usage in traditional medicine and has demonstrated significant therapeutic results among local populations throughout the globe. It is used traditionally in many parts of Pakistan to treat diarrhea, abdominal spasms, coughs, and chest problems. Aim of the studyTo investigate the antispasmodic, bronchodilator, and antidiarrheal effects of B. lycium and its possible underlying mechanisms through in silico, in vitro, and in vivo studies. Materials and methodsLC ESI–MS/MS analysis was used to identify bioactive components within the hydromethanolic extract of B. lycium. In silico studies, including network pharmacology and molecular docking, were utilized to investigate the antispasmodic and bronchodilator properties of the extract's bioactive components. In vitro pharmacological studies were conducted using isolated rabbit jejunum, trachea, urinary bladder, and rat ileum preparations. In vivo antidiarrheal activities were conducted in mice, including castor oil-induced diarrhea, intestinal transit, and castor oil-induced enteropooling. ResultsThe LC ESI–MS/MS analysis of the hydromethanolic extract of B. lycium identified 38 bioactive compounds. Network pharmacology study demonstrated that the mechanism of BLR for the treatment of diarrhea might involve IL1B, TLR4, PIK3R1, TNF, PTPRC, IL2, PIK3CD, and ABCB1, whereas, for respiratory ailments, it may involve PIK3CG, TRPV1, STAT3, ICAM1, ACE, PTGER2, PTGS2, TNF, MMP9, NOS2, IL2, CCR5, HRH1, and VDR. Molecular docking research revealed that chlorogenic acid, epigallocatechin, isorhamnetin, quinic acid, gallic acid, camptothecin, formononetin-7-O-glucoside, velutin, caffeic acid, and (S)-luteanine exhibited a higher docking score than dicyclomine with validated proteins of smooth muscle contractions such as CACB2_HUMAN, ACM3_HUMAN, MYLK_HUMAN, and PLCG1_HUMAN. In vitro investigations demonstrated that Blr.Cr, Blr.EtOAc, and Blr.Aq relaxed spontaneously contracting jejunum preparations; carbachol (1 μM)-induced and K+ (80 mM)-induced jejunum, trachea, and urinary bladder contractions in a concentration-dependent manner, similar to dicyclomine. Moreover, Blr.Cr, Blr.EtOAc, and Blr.Aq exhibited a rightward shift in Ca+2 and carbachol cumulative response curves, similar to dicyclomine, demonstrating the coexistence of antimuscarinic and Ca+2 antagonistic mechanisms due to the presence of alkaloids and flavonoids. In vivo antidiarrheal activities showed that the hydromethanolic extract was significantly effective against castor oil-induced diarrhea and castor oil-induced enteropooling, similar to loperamide, and charcoal meal intestinal transit, similar to atropine, in mice at doses of 50, 100, and 200 mg/kg body weight, which supports its traditional use in diarrhea. ConclusionThe dual blocking mechanism of muscarinic receptors and Ca+2 channels behind the smooth muscle relaxing activity reveals the therapeutic relevance of B. lycium in diarrhea, abdominal spasms, coughs, and chest problems.

Attenuation of the Positive-Reinforcing Effects of Ultra-Potent Fentanyl Analogs, Along with Those of Fentanyl and Heroin, During Daily Treatment with Methocinnamox in Rhesus Monkeys.

Without substantial intervention, the opioid crisis is projected to continue, underscoring the need to develop new treatments for opioid use disorder (OUD). One drug under development is the µ opioid receptor antagonist methocinnamox (MCAM), which appears to offer advantages over currently available medications; however, some questions remain about its potential utility, including its ability to block the effects of ultra-potent fentanyl analogs. The goal of this study was to examine its effectiveness in attenuating the abuse-related effects of the fentanyl analogs carfentanil and 3-methylfentanyl in monkeys responding for food or intravenous infusions under a choice procedure. These drugs were compared with fentanyl, heroin, methamphetamine, and cocaine. Food was preferred over saline, and there was a dose-dependent increase in responding for drug over food with no marked decrease in response rates or number of choice trials completed for any of the six drugs studied. Naltrexone (0.032 mg/kg) antagonized choice of µ opioid receptor agonists, producing rightward shifts in dose-effect curves ranging from 27-fold (carfentanil) to 71-fold (heroin). In contrast, naltrexone was less effective in attenuating choice of methamphetamine or cocaine with curves obtained in the presence of naltrexone shifted <3-fold. Daily treatment with 0.032 mg/kg MCAM also antagonized the effects of opioids, shifting curves 20-fold (fentanyl) to 72-fold (heroin) rightward; MCAM did not significantly change dose-effect curves for methamphetamine or cocaine. Thus, antagonism by MCAM is similar across a variety of µ opioid receptor agonists, including ultra-potent fentanyl analogs, further supporting its potential utility as a treatment for OUD. SIGNIFICANCE STATEMENT: Treatments for opioid use disorder (OUD) should attenuate the effects of a variety of opioids, including emerging threats like the ultra-potent fentanyl analogs. The novel µ opioid receptor antagonist MCAM is being developed to treat OUD because it provides long-lasting blockade of the reinforcing effects of heroin and fentanyl. The current study shows that MCAM attenuates the abuse-related effects of the fentanyl analogs carfentanil and 3-methylfentanyl, further supporting the utility of MCAM as a treatment for OUD.

Virtual occlusion effects on the perception of self-initiated visual stimuli

Virtual reality (VR) has established itself as a useful tool in the study of human perception in the laboratory. A recent study introduced a new approach to examine visual sensory attenuation (SA) effects in VR. Hand movements triggered the appearance of Gabor stimuli, which were either presented behind the participant’s hand – not rendered in VR (“virtual occlusion”) - or elsewhere on the display. Virtual occlusion led to a rightward shift of the psychometric curve, suggesting that self-generated hand movements reduced the perceived contrast of the stimulus. Since such attenuation effects might provide a window into the predictive processing of the sensory and cognitive apparatus, we sought to better understand the nature of the virtual occlusion effects. In our study, the presentation of test stimuli was either self-initiated, self-initiated with a variable delay, or triggered externally; the test stimuli were occluded or not. In conflict with our hypothesis, we found moderate to strong evidence for an absence of any horizontal shifts between the psychometric curves. However, virtual occlusion was associated with a decrease in the slope of the psychometric function. Our results suggest that virtual occlusion attenuated the relative perceptual sensitivity, so that participants had more difficulty discriminating contrast differences when the test stimulus was presented behind the hand. We tentatively conclude that, in the visual domain, the discriminability of stimulus intensity is modified by internal predictive cues (i.e., proprioception), possibly linked to shifts in covert spatial attention.

A KCNB1 gain of function variant causes developmental delay and speech apraxia but not seizures.

Objective: Numerous pathogenic variants in KCNB1, which encodes the voltage-gated potassium channel, KV2.1, are linked to developmental and epileptic encephalopathies and associated with loss-of-function, -regulation, and -expression of the channel. Here we describe a novel de novo variant (P17T) occurring in the KV2.1 channel that is associated with a gain-of-function (GoF), with altered steady-state inactivation and reduced sensitivity to the selective toxin, guanxitoxin-1E and is clinically associated with neurodevelopmental disorders, without seizures. Methods: The autosomal dominant variant was identified using whole exome sequencing (WES). The functional effects of the KCNB1 variant on the encoded KV2.1 channel were investigated using whole-cell patch-clamp recordings. Results: We identified a de novo missense variant in the coding region of the KCNB1 gene, c.49C>A which encodes a p.P17T mutation in the N-terminus of the voltage-gated, KV2.1 potassium channel. Electrophysiological studies measuring the impact of the variant on the functional properties of the channel, identified a gain of current, rightward shifts in the steady-state inactivation curve and reduced sensitivity to the blocker, guanxitoxin-1E. Interpretation: The clinical evaluation of this KCNB1 mutation describes a novel variant that is associated with global developmental delays, mild hypotonia and joint laxity, but without seizures. Most of the phenotypic features described are reported for other variants of the KCNB1 gene. However, the absence of early-onset epileptic disorders is a much less common occurrence. This lack of seizure activity may be because other variants reported have resulted in loss-of-function of the encoded KV2.1 potassium channel, whereas this variant causes a gain-of-function.

Anatomical Distribution of Colon Cancer: A Retrospective 10-Year Study to Evaluate Rightward Shift in Two Referral Hospitals in Iran

Background: In Iran, the incidence of colorectal cancer has been increasing over the last 25 years. Although left-sided colon cancers are still more common, several studies in recent years have shown a shift toward right colon. This rightward shift could have important clinical and healthcare consequences, as right-sided tumors generally have poorer prognoses compared to left-sided tumors and besides, are more likely to be missed in screening colonoscopy. Objectives: This retrospective study aimed at describing the demographic and clinicopathologic characteristics of patients with colon cancer based on tumor sidedness in two referral hospitals in Tehran. Methods: Data of the patients with colon cancer who had been treated from 2010 to 2020 in two referral hospitals in Tehran, Iran were retrospectively reviewed. Collected data included patients’ demographics, tumor histology and differentiation, tumor location, stage, and disease-free survival (DFS). Results: A total of 1535 cases entered the study including 849 (55.3%) males and 686 (44.7%) females with a mean age of 58.22 years (range: 22 - 89). Regarding the sidedness, 800 (52.1%) had left-sided and 735 (47.9%) had right-sided tumors. Although there were more cases of left-sided tumors compared to right-sided ones in total, there existed a trend toward shifting to the right side, which was statistically significant. There existed more cases of poorly differentiated tumors in the right side and besides, right-sided tumors had poorer DFS compared to the left-sided tumors (68.3% vs 78.3%). Conclusions: Left and right colon tumors differ in molecular mechanisms involved in tumorigenesis. These differences in epidemiological, molecular and histological parameters can have clinical implications. Tumor-sidedness should be acknowledged as an important epidemiological parameter with significant impacts on screening, tumorgenesis, response to treatment, and prognosis.

Regulation of Papillary Muscle Contractility by NAD and Ammonia Interplay: Contribution of Ion Channels and Exchangers.

Various models, including stem cells derived and isolated cardiomyocytes with overexpressed channels, are utilized to analyze the functional interplay of diverse ion currents involved in cardiac automaticity and excitation-contraction coupling control. Here, we used β-NAD and ammonia, known hyperpolarizing and depolarizing agents, respectively, and applied inhibitory analysis to reveal the interplay of several ion channels implicated in rat papillary muscle contractility control. We demonstrated that: 4 mM β-NAD, having no strong impact on resting membrane potential (RMP) and action potential duration (APD90) of ventricular cardiomyocytes, evoked significant suppression of isometric force (F) of paced papillary muscle. Reactive blue 2 restored F to control values, suggesting the involvement of P2Y-receptor-dependent signaling in β-NAD effects. Meantime, 5 mM NH4Cl did not show any effect on F of papillary muscle but resulted in significant RMP depolarization, APD90 shortening, and a rightward shift of I-V relationship for total steady state currents in cardiomyocytes. Paradoxically, NH4Cl, being added after β-NAD and having no effect on RMP, APD, and I-V curve, recovered F to the control values, indicating β-NAD/ammonia antagonism. Blocking of HCN, Kir2.x, and L-type calcium channels, Ca2+-activated K+ channels (SK, IK, and BK), or NCX exchanger reverse mode prevented this effect, indicating consistent cooperation of all currents mediated by these channels and NCX. We suggest that the activation of Kir2.x and HCN channels by extracellular K+, that creates positive and negative feedback, and known ammonia and K+ resemblance, may provide conditions required for the activation of all the chain of channels involved in the interplay. Here, we present a mechanistic model describing an interplay of channels and second messengers, which may explain discovered antagonism of β-NAD and ammonia on rat papillary muscle contractile activity.

Bidirectional sensitivity of CALHM1 channel to protons from both sides of plasma membrane.

Calcium homeostasis modulator 1 (CALHM1), a newly discovered voltage-dependent nonselective ion channel, has drawn attention for its role in neuronal activity and taste sensation. Its sluggish voltage-dependent activation is facilitated by lowering extracellular Ca2+ concentration ([Ca2+]e). Here, we investigated the effects of extracellular and intracellular pH (pHe and pHi) on human CALHM1. When normalized to the amplitude of the CALHM1 current (ICALHM1) under whole cell patch clamp at symmetrical pH 7.4, ICALHM1 decreased at acidic pHe or pHi, whereas it sharply increased at alkaline pHe or pHi. The effects of pH were preserved in the inside-out configuration. The voltage dependence of ICALHM1 showed leftward and rightward shifts at alkaline and acidic pHe and pHi, respectively. Site-directed mutagenesis of the water-accessible charged residues of the pore and nearby domains revealed that E17, K229, E233, D257, and E259 are nonadditively responsible for facilitation at alkaline pHi. Identification of the pHe-sensing residue was not possible because mutation of putative residues impaired membrane expression, resulting in undetectable ICALHM1. Alkaline pHe-dependent facilitation appeared gradually with depolarization, suggesting that the sensitivity to pHe might be due to H+ diffusion through the open-state CALHM1. At pHe 6.2, decreased [Ca2+]e could not recover the inhibited ICALHM1 but further augmented the increased ICALHM1 at pHe 8.6, suggesting that unidentified common residues might contribute to the [Ca2+]e and acidic pHe. This study is the first, to our knowledge, to demonstrate the remarkable pH sensitivity of CALHM1, which might contribute to the pH-dependent modulation of neuronal excitability or taste sensation.

Functional consequences of short-term exposure to opioids versus cannabinoids in nonhuman primates

Opioids provide pain relief but are associated with several adverse effects. Researchers are exploring cannabis-based medicine as an alternative. However, little is known about the tendency for physical dependence on cannabinoids in comparison with that on opioids in primates. The aim of this study was to compare the potency of heroin and delta-9-tetrahydrocannabinol (THC) in eliciting analgesic effects and the development of physical dependence between opioids and cannabinoids in both male and female rhesus monkeys. Systemic administration of either heroin (0.03–0.18 mg/kg) or THC (0.3–1.8 mg/kg) in a dose-dependent manner produced antinociceptive effects against an acute thermal nociceptive stimulus. The μ-opioid receptor antagonist naltrexone (0.01 mg/kg) and the cannabinoid receptor antagonist SR141716A (0.3 mg/kg) produced the same degree of rightward shift in the dose-response curves for heroin- and THC-induced antinociception, respectively. Monkeys implanted with telemetry devices were subjected to short-term repeated administrations (two injections per day for 1–3 days) of either heroin (0.18 mg/kg), morphine (1.8 mg/kg), THC (1.8 mg/kg), or CP 55,940 (0.032 mg/kg). Administration of naltrexone (0.01 mg/kg) increased respiration, heart rate, and blood pressure in heroin- or morphine-treated monkeys. In contrast, administration of SR141716A (0.3 mg/kg) did not cause a significant change in these physiological parameters in THC- or CP 55,940-treated monkeys. Additionally, morphine, but not CP 55,940, enhanced the monkeys’ hypersensitivity to the algogen capsaicin. Collectively, these results demonstrate that in nonhuman primates, both opioids and cannabinoids exert comparable antinociception; however, physical dependence on opioids, but not cannabinoids, at their antinociceptive doses, occurs following short-term exposures.

Eight weeks of inorganic nitrate/nitrite supplementation improves aerobic exercise capacity and the gas exchange threshold in patients with type 2 diabetes.

Patients with type 2 diabetes mellitus (T2DM) have reduced exercise capacity, indexed by lower maximal oxygen consumption (V̇o2max) and achievement of the gas exchange threshold (GET) at a lower % V̇o2max. The ubiquitous signaling molecule nitric oxide (NO) plays a multifaceted role during exercise and, as patients with T2DM have poor endogenous NO production, we investigated if inorganic nitrate/nitrite supplementation (an exogenous source of NO) improves exercise capacity in patients with T2DM. Thirty-six patients with T2DM (10F, 59 ± 9 yr, 32.0 ± 5.1 kg/m2, HbA1c = 7.4 ± 1.4%) consumed beetroot juice containing either inorganic nitrate/nitrite (4.03 mmol/0.29 mmol) or a placebo (0.8 mmol/0.00 mmol) for 8 wk. A maximal exercise test was completed before and after both interventions. V̇o2max was determined by averaging 15-s data, whereas the GET was identified using the V-slope method and breath-by-breath data. Inorganic nitrate/nitrite increased both absolute (1.96 ± 0.67 to 2.07 ± 0.75 L/min) and relative (20.7 ± 7.0 to 21.9 ± 7.4 mL/kg/min, P < 0.05 for both) V̇o2max, whereas no changes were observed following placebo (1.94 ± 0.40 to 1.90 ± 0.39 L/min, P = 0.33; 20.0 ± 4.2 to 19.7 ± 4.6 mL/kg/min, P = 0.39). Maximal workload was also increased following inorganic nitrate/nitrite supplementation (134 ± 47 to 140 ± 51 W, P < 0.05) but not placebo (138 ± 32 to 138 ± 32 W, P = 0.98). V̇o2 at the GET (1.11 ± 0.27 to 1.27 ± 0.38L/min) and the %V̇o2max in which GET occurred (56 ± 8 to 61 ± 7%, P < 0.05 for both) increased following inorganic nitrate/nitrite supplementation but not placebo (1.10 ± 0.23 to 1.08 ± 0.21 L/min, P = 0.60; 57 ± 9 to 57 ± 8%, P = 0.90) although the workload at GET did not achieve statistical significance (group-by-time P = 0.06). Combined inorganic nitrate/nitrite consumption improves exercise capacity, maximal workload, and promotes a rightward shift in the GET in patients with T2DM. This manuscript reports data from a registered Clinical Trial at ClinicalTrials.gov ID: NCT02804932.NEW & NOTEWORTHY We report that increasing nitric oxide bioavailability via 8 wk of inorganic nitrate/nitrite supplementation improves maximal aerobic exercise capacity in patients with type 2 diabetes mellitus. Similarly, we observed a rightward shift in the gas exchange threshold. Taken together, these data indicate inorganic nitrate/nitrite may serve as a means to improve fitness in patients with type 2 diabetes mellitus.

ODP470 Compressive Goiter with COVID-19: An Unusual Etiology of Respiratory Distress Requiring Endotracheal Intubation with Surgical Resection

Abstract Introduction Gradual enlargement of multinodular goiter (MNG) may compress surrounding structures which may progressively cause complications of tracheal stenosis and airway compromise. Surgical resection remains the gold standard treatment in MNG patients presenting with respiratory distress. In the current global COVID -19 pandemic, compressive goiter should be a differential diagnosis in patients with stable benign thyroid goiter presenting with dyspnea. We present a case of MNG with life threatening airway obstruction during an active COVID-19 infection. Case presentation A 74-year-old female with a history of hyperthyroidism with multi-nodular goiter and recurrent atrial fibrillation status-post ablation, was transferred to the intensive care unit for treatment after being intubated for respiratory distress at a nearby hospital. She was diagnosed with hyperthyroidism about 40 years ago and managed with methimazole. Over the last two years, thyroid ultrasound and prior imaging showed MNG with patent but moderate tracheal narrowing; fine-needle aspiration (FNA) confirmed benign colloid nodules with cystic degeneration. She was pending cardiac clearance for surgery when symptoms acutely worsened two days before admission. On initial assessment, she was hemodynamically stable, afebrile, with oxygen saturation of 86% on room air. She was alert and able to follow commands. On physical examination, she had stridor and thyromegaly was evident with mild tenderness on palpation. Cardiopulmonary examination was remarkable for coarse breath sounds. Labs showed TSH 4.82 (Normal 0.3 - 4.5 ulU/mL), FT4 0.64 (Normal 0.5- 1.26 ng/dL). Respiratory panel test came back positive for SARS-CoV-2. Racemic epinephrine and albuterol nebulizers were administered to help with her symptoms. CT scan of the neck revealed a severe narrowing and mild rightward shift of the trachea by a large multinodular goiter, prompting the decision to intubate for airway protection. CT scan of the chest with contrast demonstrated the large MNG with tracheal stenosis. Her methimazole dose was adjusted. After cardiac clearance, she underwent thyroidectomy through a transcervical approach. Levothyroxine and calcium supplementation were started post-surgery. She was extubated two days after her thyroidectomy. Pathology results showed no evidence of malignancy. Discussion Acute airway obstruction by large MNG requiring emergent airway protection is rare. Typically airway compromise from large otherwise stable benign goiters results from sudden hemorrhage into a cyst, upper respiratory tract infection leading to tracheal edema, or worseningcomorbid conditions. During the COVID-19 pandemic, acute respiratory failure and shortness of breath is typical of worsening disease course. This case highlights the importance of maintaining wider differentials of respiratory failure even and we need to consider worsening of tracheal narrowing with a large goiter due to tracheal edema from SARS- CoV-2 Infection. Thyroidectomy before SARS-CoV-2 infection may have reduced her need for emergent intubation for acute respiratory failure by improving pre existing airway compression. Presentation: No date and time listed

Poststroke action slowing: Motor and attentional impairments and their imaging determinants. Evidence from lesion-symptom mapping, disconnection and fMRI activation studies

Background and objectivesAlthough action slowing is the main cognitive impairment in stroke survivors, its mechanisms and determinants are still poorly understood. The objectives of the present study were to determine the mechanisms of post-stroke action slowing (using validated, highly specific simple reaction time (SRT) and tapping tests) and identify its imaging determinants (using multivariate lesion-symptom mapping (mLSM)). MethodsAction speed in the GRECogVASC cohort was assessed using finger tapping and SRT tests performed with both hands and analyzed using previously validated indices. Imaging determinants were identified using validated mLSM analyses and disconnection analysis and compared to those of an fMRI activation meta-analytic database. ResultsBoth the tapping time and SRT were 10.7% slower for the 394 patients (p = 0.0001) than for the 786 controls, without a group × test interaction (p = 0.2). The intra-individual distribution curve was characterized by a rightward shift with an unaltered attentional peak. The mLSM analyses showed tapping to be associated with lesions in the frontostriatal tract (p = 0.0007). The SRT was associated with lesions in the frontostriatal tract (p = 0.04) and the orbital part of F3 (p = 0.0001). The SRT-tapping index was associated with lesions in the orbital part of F3 (p = 0.0001). All lesions were located in the right hemisphere only and were responsible for the disconnection of several structures involved in motor preparation, initiation, and speed. A comparison with fMRI activation meta-analytic data highlighted mostly the same regions, including the orbital part of F3, the ventral and dorsal parts of F1, and the premotor and cingulate regions in the right hemisphere. DiscussionOur results confirm the marked impairment of action speed in stroke and show that the primary mechanism is motor slowing and that it is related to lesions in the right frontostriatal tract. A deficit in sustained alertness accounted for action slowing in the subgroup with lesions in the right orbital part of F3. Our SRT and mLSM results were in accordance with the fMRI activation data. Thus, stroke induces slowing in the broad network associated with SRT tasks by disrupting the frontostriatal tract and, to a lesser extent, other sites involved in attention.

Characterization of chronic lung allograft dysfunction phenotypes using spectral and intrabreath oscillometry.

Background: Chronic lung allograft dysfunction (CLAD) is the major cause of death beyond 2 years after lung transplantation and develops in 50% of all patients by 5 years post-transplant. CLAD is diagnosed on the basis of a sustained drop of 20% for at least 3 months in the forced expiratory volume (FEV1), compared to the best baseline value achieved post-transplant. CLAD presents as two main phenotypes: bronchiolitis obliterans syndrome (BOS) is more common and has better prognosis than restrictive allograft syndrome (RAS). Respiratory oscillometry is a different modality of lung function testing that is highly sensitive to lung mechanics. The current study investigated whether spectral and intrabreath oscillometry can differentiate between CLAD-free, BOS- and RAS-CLAD at CLAD onset, i.e., at the time of the initial 20% drop in the FEV1. Methods: A retrospective, cross-sectional analysis of 263 double lung transplant recipients who underwent paired testing with oscillometry and spirometry at the Toronto General Pulmonary Function Laboratory from 2017 to 2022 was conducted. All pulmonary function testing and CLAD diagnostics were performed following international guidelines. Statistical analysis was conducted using multiple comparisons. Findings: The RAS (n = 6) spectral oscillometry pattern differs from CLAD-free (n = 225) by right-ward shift of reactance curve similar to idiopathic pulmonary fibrosis whereas BOS (n = 32) has a pattern similar to obstructive lung disease. Significant differences were found in most spectral and intrabreath parameters between BOS, RAS, and time-matched CLAD-free patients. Post-hoc analysis revealed these differences were primarily driven by BOS instead of RAS. While no differences were found between CLAD-free and RAS patients with regards to spectral oscillometry, the intrabreath metric of reactance at end-inspiration (XeI) was significantly different (p < 0.05). BOS and RAS were differentiated by spectral oscillometry measure R5, and intrabreath resistance at end expiration, ReE (p < 0.05 for both). Conclusion: Both spectral and intrabreath oscillometry can differentiate BOS-CLAD from CLAD-free states while intrabreath oscillometry, specifically XeI, can uniquely distinguish RAS-CLAD from CLAD-free. Spectral and intrabreath oscillometry offer complementary information regarding lung mechanics in CLAD patients to help distinguish the two phenotypes and could prove useful in prognostication.

Polling, Partisanship, and Promoting Violence: New Developments in Impression Management From Candidate and Super PAC Advertisements

Super PACs have become a pivotal force in U.S. elections, often working in tandem with political campaigns to create cohesive messages in advertisements that serve as a tool for impression management. In previous research, I outlined a series of performance types, impression management techniques used by candidates and Super PACS in the 2012 Republican Primary. Since then, a second Republican Primary occurred, and a more expansive dataset on 2012 was released. In this paper I replicate my past work with the new dataset and compare performance types in advertisements from the 2012 and 2016 primaries. When comparing datasets, the findings were overwhelmingly consistent. At the same time, there were fundamental changes between 2012 and 2016. Notably, the inclusion of a new performance type, “the warrior,” which promotes an eagerness to use physical violence toward non-Americans. This change further indicates the rightward shift in Republican messaging that leans into fascism.

Functional analysis of novel SCN5A mutations related to Brugada syndrome

Abstract Brugada syndrome (BrS) is an arrhythmogenic disorder that has been linked to mutations in SCN5A, the gene encoding for the pore-forming α-subunit of the cardiac Na+ channel. Recently, novel SCN5A missense mutations (A385T and R504T) were identified in a BrS patient. Since the mutations are in the loop connecting transmembrane segments 5 and 6 in domain 1 (S5-S6 in DI) and segments 6 and 1 between domain 1 and 2 (DI-DII linker), it can lead to dysfunctional property of the Na+ channel. Here we aimed to characterize the electrophysiological properties of A385T and R504T. The wild-type (WT) and mutant SCN5A were transiently transfected in HEK293 cells, and the Na+ channel was analyzed using the whole-cell patch-clamp technique. WT, A385T, R504T, and double mutant (A385T/R504T) showed no significant differences in the current density and the voltage-dependent activation. Unexpectedly, a rightward shift of the voltage-dependent inactivation was identified in the three groups of mutation. Besides, the recovery from inactivation of double mutant was faster than that of WT. These results suggest that, contrary to the expected mechanism of BrS, the mutations cause a gain-of-function of NaV1.5. However, the current densities of R504T and double mutant transfected with β-subunit SCN1B were significantly suppressed but A385T was not different from WT. The voltage dependent activation and inactivation of all mutants were not significantly different from WT. The recovery from inactivation of all mutants were slower than that of WT. These results suggest that R504T mutation of α-subunit SCN5A interacting with β-subunit SCN1B is responsible to pathophysiological function of novel BrS. Funding Acknowledgement Type of funding sources: None.

Competitive Interactions Between Propofol and Diazepam: Studies in GABAA Receptors and Zebrafish.

Although propofol is among the most commonly administered general anesthetics, its mechanism of action is not fully understood. It has been hypothesized that propofol acts via a similar mechanism as (R)-ethyl 1-(1-phenylethyl)-1H-imidazole-5-carboxylate (etomidate) by binding within the GABAA receptor transmembrane receptor domain at the two β +/α - subunit interfaces with resultant positive allosteric modulation. To test this hypothesis, we leveraged the ability of diazepam to bind to those sites and act as a competitive antagonist. We used oocyte-expressed α 1 β 3 γ 2L GABAA receptors to define the actions of diazepam (± flumazenil) on currents activated or potentiated by propofol and a zebrafish activity assay to define the impact of diazepam and flumazenil on propofol-induced anesthesia. We found that diazepam increased the amplitudes of GABAA receptor-mediated currents at nanomolar concentrations but reduced them at micromolar concentrations. The current amplitude changes produced by nanomolar diazepam concentrations were inhibited by flumazenil whereas those produced by micromolar diazepam concentrations were not. Studies of agonist potentiation showed that the micromolar inhibitory action of diazepam was surmountable by high concentrations of propofol and produced a rightward shift in the propofol concentration-response curve characterized by a Schild slope not statistically significantly different from 1, consistent with competition between diazepam and propofol. Although micromolar concentrations of diazepam (plus flumazenil) similarly reduced GABAA receptor currents modulated by propofol and etomidate, it only reduced the anesthetic actions of etomidate. We conclude that while both propofol and etomidate can modulate GABAA receptors by binding to the β +/α - subunit interfacial sites, propofol-induced anesthesia likely involves additional target sites. SIGNIFICANCE STATEMENT: Although the drug combination of diazepam and flumazenil reverses the GABAA receptor positive modulatory actions of both propofol and (R)-ethyl 1-(1-phenylethyl)-1H-imidazole-5-carboxylate (etomidate), it only reverses the in vivo anesthetic actions of etomidate. These results strongly suggest that distinct mechanisms of action account for the anesthetic actions of these two commonly administered anesthetic agents.

Self-Administration of Fentanyl-Alprazolam Combinations by Rhesus Monkeys Responding under a Progressive-Ratio Schedule.

This study evaluated the reinforcing effects of fentanyl, alone or in combination with the benzodiazepine alprazolam, in rhesus monkeys (3 females, 3 males). Subjects were trained to self-administer the opioid remifentanil (0.3 µg/kg/injection) under a progressive-ratio schedule of reinforcement. The reinforcing effects of fentanyl (0.1-10 µg/kg/injection) or alprazolam (1.0-100 µg/kg/injection) alone, or in combinations of fixed proportions (1:1, 1:3, and 3:1 fentanyl:alprazolam, with 1:1 based on the potencies of drugs alone) were evaluated in single-day test sessions (with double determinations). Dose-equivalence analysis was used to determine the extent to which fentanyl and alprazolam combinations differed from additivity. Fentanyl functioned as a positive reinforcer in all monkeys, while alprazolam was a reinforcer in 3 of 6 monkeys only. Therefore, drug combination data were grouped as "alprazolam-taking" and "non-alprazolam-taking" monkeys. For alprazolam-taking monkeys, we observed additive effects for the 3:1 and 1:3 combinations, and a significant supra-additive interaction for the 1:1 combination of fentanyl and alprazolam. For 2 of the 3 non-alprazolam-taking monkeys, the combination of fentanyl and alprazolam resulted in enhanced reinforcing effects relative to either drug alone. However, the one monkey showed primarily inhibitory, or suppressive effects, with the 3:1 dose combination resulting in a relatively modest rightward shift in the fentanyl dose-response function. In summary, our findings show that combining fentanyl and alprazolam generally result in proportion-dependent additive or supra-additive enhancements. These data raise the possibility that the prevalence of opioid-benzodiazepine polydrug abuse may reflect a unique enhancement of these drugs' reinforcing effects, although individual differences may exist. SIGNIFICANCE STATEMENT: Addressing the critical question of the degree to which benzodiazepines can modulate the abuse-related effects of opioids may provide improved pathways to treatment of this common form of polydrug addiction. In the present study, we show that combinations of the opioid fentanyl and the benzodiazepine alprazolam can be more reinforcing than either drug alone in a rhesus monkey model, suggesting that enhancement of reinforcement processes may underlie this prevalent form of polydrug use disorder.

Release of 6-nitrodopamine modulates vascular reactivity of Pantherophis guttatus aortic rings

6-Nitrodopamine (6-ND) is a novel catecholamine that is released from human umbilical cord vessels and Chelonoidis carbonaria aortic rings. The synthesis/release of 6-ND is inhibited by either pre-incubation of the vessels with the nitric oxide (NO) synthase inhibitor L-NAME or by mechanical removal of the endothelium. 6-ND causes powerful vasorelaxation, acting as a potent and selective dopamine D2-like receptor antagonist.Basal release of 6-ND from Panterophis guttatus endothelium intact and denuded aortic rings was quantified by LC-MS/MS. In order to evaluate the interaction of 6-ND with other catecholamines, aortic rings were suspended vertically between two metal hooks in 10-mL organ baths containing Krebs-Henseleit's solution and attached to isometric transducers.Endothelium intact aortic rings presented basal release of 6-ND, which was significantly reduced by previous incubation with L-NAME (100 μM). In endothelin-1 (3 nM) pre-contracted endothelium intact aortic rings, 6-ND (10pM-1 μM) and the dopamine D2-receptor antagonist L-761,626 (10 pM–1 μM) induced concentration-dependent relaxations, which were not affected by incubation with L-NAME but greatly reduced in endothelium-removed aortic rings.6-ND (0.1–1 μM) produced significant rightward shifts of the concentration-response curves to dopamine in L-NAME pre-treated endothelium-intact (pA2 7.01) rings. Contractions induced by noradrenaline and adrenaline were not affected by pre-incubation with 6-ND (1 μM). The EFS-induced contractions of L-NAME pre-treated endothelium-intact aortic rings were significantly inhibited by incubation with 6-ND (1 μM).The results indicate that 6-ND released from Pantherophis guttatus aortic rings is coupled to NO release and represents a new mechanism by which NO can modulate vascular reactivity independently of cGMP production.

Experimental Characterization of Hydrodynamic Properties of a Deformable Rock Fracture

Characterization of stress-dependent single-phase and multiphase fluid transport in fractured geo-materials is essential for a wide range of applications, including CO2 sequestration, energy storage, and geo-energy extraction. However, pivotal studies on capillarity and multiphase fluid flow in deformable rock fractures are surprisingly sparse. In this study, we initially investigated the hydro-mechanical properties of an intact mixed-wet Calumet carbonate from the Waterways formation (Alberta) under isothermal conditions (40 °C). Then, we conducted core-flooding experiments using water and N2 to assess changes in the aperture, absolute permeability, relative permeability, and capillary pressure of an artificially fractured Calumet core in response to changes in effective confining stress during loading (0–10 MPa) and unloading (10–3 MPa). We quantified the fracture’s non-linear closure and hysteresis effect during the cyclic loading–unloading processes. We found that porosity and absolute permeability of the fracture decreased from 1.5% and 19.8 D to 1.18% and 0.22 D, respectively, during the loading. We revealed a systematic rightward shift in the relative permeability and a significant upward shift in the dynamic capillary pressure curves as the fracture deformed. This fundamental study demonstrates the critical role of fracture deformation on fluid flow in fractured rocks, which paves the way for future research in geoscience and engineering.