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Theories of embodied cognition postulate that perceptual, sensorimotor, and affective properties of concepts support language learning and processing. In this paper, we argue that language acquisition, as well as processing, is situated in addition to being embodied. In particular, first, it is the situated nature of initial language development that affords for the developing system to become embodied. Second, the situated nature of language use changes across development and adulthood. We provide evidence from empirical studies for embodied effects of perception, action, and valence as they apply to both embodied cognition and situated cognition across developmental stages. Although the evidence is limited, we urge researchers to consider differentiating embodied cognition within situated context, in order to better understand how these separate mechanisms interact for learning to occur. This delineation also provides further clarity to the study of classroom-based applications and the role of embodied and situated cognition in the study of developmental disorders. We argue that theories of language acquisition need to address for the complex situated context of real-world learning by completing a "circular notion": observing experimental paradigms in real-world settings and taking these observations to later refine lab-based experiments., Competing Interests: The authors have no competing interests to declare., (Copyright: © 2023 The Author(s).)

In adults, grip force has reliably been used to investigate motor simulation evoked by linguistic action, suggesting that motor phenomena are linked to semantic action. The parietal and frontal lobes and their connexions are essential neural structures for pragmatic aspects of hand semantic action. In this perspective, the aim of the study was to determine the extent to which two groups of children and adolescents, classically characterized by degree of axonal myelination in fronto-parietal circuits, monitored the occurrence of nouns and manual action verbs presented auditorily while holding a grip force sensor. Differential effects of grip force were seen only in the adolescents when monitoring action verbs. Interestingly, weaker effects of grip force were modulated by noun targets only in the younger children, revealing that the ability to profit from a full semantic representation of verbs is not clearly established in the younger children. Grip force modulation was observed as early as 300 ms post target onset and peaked at the 500-750 ms window of observation for both groups. These group differences are in line with the motor simulation difficulties seen in younger children. The results may also indicate that degree of grip force in response to specific linguistic categories parallels the maturation of the parietal-frontal circuits, including the anterior intra-parietal area which plays a determining role in semantic aspects of hand action., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the least deadly but most infectious coronavirus strain transmitted from wild animals. It may affect many organ systems. Aim of the current guideline is to delineate the effects of SARS-CoV-2 on the liver. Asymptomatic aminotransferase elevations are common in coronavirus disease 2019 (COVID-19) disease. Its pathogenesis may be multifactorial. It may involve primary liver injury and indirect effects such as "bystander hepatitis," myositis, toxic liver injury, hypoxia, and preexisting liver disease. Higher aminotransferase elevations, lower albumin, and platelets have been reported in severe compared with mild COVID-19. Despite the dominance of respiratory disease, acute on chronic liver disease/acute hepatic decompensation have been reported in patients with COVID-19 and preexisting liver disease, in particular cirrhosis. Metabolic dysfunction-associated fatty liver disease (MAFLD) has a higher risk of respiratory disease progression than those without MAFLD. Alcohol-associated liver disease may be severely affected by COVID-19-such patients frequently have comorbidities including metabolic syndrome and smoking-induced chronic lung disease. World Gastroenterology Organization (WGO) recommends that interventional procedures such as endoscopy and endoscopic retrograde cholangiopancreatography should be performed in emergency cases or when they are considered strictly necessary such as high risk varices or cholangitis. Hepatocellular cancer surveillance may be postponed by 2 to 3 months. A short delay in treatment initiation and non-surgical approaches should be considered. Liver transplantation should be restricted to patients with high MELD scores, acute liver failure and hepatocellular cancer within Milan criteria. Donors and recipients should be tested for SARS-CoV-2 and if found positive donors should be excluded and liver transplantation postponed until recovery from infection.

The link between language processing and motor systems has been the focus of increasing interest to Cognitive Neuroscience. Some classical papers studying Event Related Potentials (ERPs) induced by linguistic stimuli have found differences in electrophysiological activity when comparing action and non-action words; more specifically, a bigger p200 for action words. On the other hand, a series of studies have validated the use of a grip force sensor (GFS) to measure language-induced motor activity during both isolated words and sentence listening, finding that action words induce an augmentation in the grip force around 250-300 ms after the onset of the stimulus. The purpose of the present study is to combine both techniques to assess if the p200 is related to the augmentation of the grip force measured by a GFS. We measured ERP and GFS changes elicited by listening to action and non-action words while maintaining an active grasping task. Our results show that both the p200 and the grip force around 300 ms are bigger for action words, compared to non-action. We also report a statistical correlation between these measures. To our knowledge, this is the first study where the electrophysiological activity and the changes in the grip force induced by auditory language processing are put together, opening new venues of interpretation for the sensorimotor interaction in language processing., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Manual action verbs modulate the right-hand grip force in right-handed subjects. However, to our knowledge, no studies demonstrate the ability to accomplish this modulation during bimanual tasks nor describe their effect on left-hand behavior in unimanual and bimanual tasks. Using load cells and word playlists, we evaluated the occurrence of grip force modulation by manual action verbs in unimanual and symmetrical bimanual tasks across the three auditory processing phases. We found a significant grip force increase for all conditions compared to baseline, indicating the occurrence of modulation. When compared to each other, the grip force variation from baseline for the three phases of both hands in the symmetrical bimanual task was not different from the right-hand in the unimanual task. The left-hand grip force showed a lower amplitude for auditory phases 1 and 2 when compared to the other conditions. The right-hand grip force modulation became significant from baseline at 220 ms after the word onset in the unimanual task. This moment occurred earlier for both hands in bimanual task (160 ms for the right-hand and 180 for the left-hand). It occurred later for the left-hand in unimanual task (320 ms). We discuss the hypothesis that Broca's area and Broca's homologue area likely control the left-hand modulation in a unilateral or a bilateral fashion. These results provide new evidence for understanding the linguistic function processing in both hemispheres.

Objectives: Although effective, direct acting antiviral (DAA) therapies for genotype 1 (GT 1) hepatitis C virus (HCV) have been associated with compliance challenges. Additionally, treatment at predominantly community-based centers has been associated with low retention of patients on treatment and higher dropout rates. The OPTIMAL Phase IV interventional trial (ClinicalTrials.gov Identifier: NCT01405027) was designed to evaluate the impact of an education program for community investigator (CI) sites participating in a Chronic Liver Disease Foundation study treating chronic GT 1 HCV patients., Methods: This physician educational program was administered by 22 Hepatology Centers of Educational Expertise (HCEE) academic sites to 33 CI sites asked to participate from December 2011 to July 2012. The HCEE mentors from DAA-experienced academic sites educated those at CI sites on therapeutic management, practice, and patient outcomes through a series of four standardized educational sequence visits regarding the use of first generation HCV protease inhibitors and the overall treatment of HCV., Results: Treatment duration compliance rates for patients treated at CI sites versus those treated at HCEE academic sites were evaluable in 77 of 84 HCEE academic site patients, 102 of 113 patients treated at CI sites, and 179 of 197 overall patients. The treatment duration compliance rates for patients treated at HCEE academic sites, CI sites and overall were 85.4 ± 25.39%, 83.8 ± 27.37%, and 84.5 ± 26.48%, respectively, and did not differ statistically between the groups (p = 0.49). Almost half (47%) of the patients in the study achieved a sustained virological response for 24 weeks (SVR24) regardless of the type of site (p = 0.64). Safety profiles were similar at both HCEE and CI sites., Conclusions: These results demonstrated that education of CI sites unfamiliar with DAAs resulted in patient outcomes consistent with those observed at DAA-experienced academic sites.

A new series of potent and selective histamine-3 receptor (H3R) antagonists was identified on the basis of an azaspiro[2.5]octane carboxamide scaffold. Many scaffold modifications were largely tolerated, resulting in nanomolar-potent compounds in the H3R functional assay. Exemplar compound 6s demonstrated a selective profile against a panel of 144 secondary pharmacological receptors, with activity at only σ2 (62% at 10 μM). Compound 6s demonstrated free-plasma exposures above the IC50 (∼50×) with a brain-to-plasma ratio of ∼3 following intravenous dosing in mice. At three doses tested in the mouse novel object recognition model (1, 3, and 10 mg/kg s.c.), 6s demonstrated a statistically significant response compared with the control group. This series represents a new scaffold of H3 receptor antagonists that demonstrates in vivo exposure and efficacy in an animal model of cognition.

Rationale: Low-mass cut-off restrictions for injecting ions from external ion sources into high magnetic fields impose limitations for wide mass range analyses with Fourier transform ion cyclotron resonance (FTICR) instruments. Radio-frequency (RF)-only quadrupole ion guides (QIGs) with higher frequencies can be used to overcome low-mass cut-off in FTICR instruments., Methods: RF signals (1.0 MHz to 10.0 MHz) were applied to QIGs to transfer externally generated ions from either electron ionization (EI) or electrospray ionization (ESI) sources into ICR cells of 9.4 T FTICR mass spectrometers. Efficiencies of QIGs were evaluated using externally generated ions from: EI of acetone, air, and perfluorotributylamine mixture, EI of gas chromatography (GC)-separated components of a standard sample mixture, and ESI of complex mixtures such as petroleum and fulvic acid samples., Results: We were able to transfer ions with m/z as low as 26 from an external EI source into the ICR cell of a 9.4 T FTICR mass spectrometer and extend the operational low-mass range for ESI-FTICR analyses. High mass resolving power and mass measurement accuracy of GC/FTICR mass spectrometry were utilized to discriminate between oxygenated and non-oxygenated compounds in a 'Grob' sample. Ion losses based on SIMION ion trajectory predictions were consistent with experimental findings., Conclusions: We demonstrated that the use of high-frequency QIGs can extend the operational lower m/z range for both external EI- and ESI-FTICR mass spectrometers. By considering both ICR and Mathieu equations of motions to describe ion trajectories, theoretical ion ejection thresholds (consistent with our experimental findings) could be predicted., (Copyright © 2013 John Wiley & Sons, Ltd.)

Benzothiazole amides were identified as TRPV1 antagonists from high throughput screening using recombinant human TRPV1 receptor and structure-activity relationships were explored to pinpoint key pharmacophore interactions. By increasing aqueous solubility, through the attachment of polar groups to the benzothiazole core, and enhancing metabolic stability, by blocking metabolic sites, the drug-like properties and pharmokinetic profiles of benzothiazole compounds were sufficiently optimized such that their therapeutic potential could be verified in rat pharmacological models of pain., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Calcium carbonate is a secondary mineral precipitate influencing zero valent iron (ZVI) barrier reactivity and hydraulic performance. We conducted column experiments to investigate electrical signatures resulting from concurrent CaCO(3) and iron oxides precipitation under simulated field geochemical conditions. We identified CaCO(3) as a major mineral phase throughout the columns, with magnetite present primarily close to the influent based on XRD analysis. Electrical measurements revealed decreases in conductivity and polarization of both columns, suggesting that electrically insulating CaCO(3) dominates the electrical response despite the presence of electrically conductive iron oxides. SEM/EDX imaging suggests that the electrical signal reflects the geometrical arrangement of the mineral phases. CaCO(3) forms insulating films on ZVI/magnetite surfaces, restricting charge transfer between the pore electrolyte and ZVI particles, as well as across interconnected ZVI particles. As surface reactivity also depends on the ability of the surface to engage in redox reactions via charge transfer, electrical measurements may provide a minimally invasive technology for monitoring reactivity loss due to CaCO(3) precipitation. Comparison between laboratory and field data shows consistent changes in electrical signatures due to iron corrosion and secondary mineral precipitation.

Geophysical methods have been proposed as technologies for non-invasively monitoring geochemical alteration in permeable reactive barriers (PRBs). We conducted column experiments to investigate the effect of mineralogy on the electrical signatures resulting from iron corrosion and mineral precipitation in Fe0 columns using (a) Na2SO4, and (b) NaHCO3 plus CaCl2 mixture, solutions. At the influent interface where the reactions were most severe, a contrasting time-lapse electrical response was observed between the two columns. Solid phase analysis confirmed the formation of corrosion halos and increased mineralogical complexity in the corroded sections of the columns compared to the minimal/non-corroded sections. We attribute the contrasting time-lapse signatures to the differences in the electrical properties of the mineral phases formed within the two columns. While newly precipitated/transformed polarizable and semi-conductive iron oxides (mostly magnetite and green rust) increase the polarization and conductivity of the sulfate column, the decrease of both parameters in the bicarbonate column is attributed to the precipitation of non-polarizable and non-conductive calcite. Our results show that precipitate mineralogy is an important factor influencing the electrical properties of the corroded iron cores and must be considered if electrical geophysical methods are to be developed to monitor PRB barrier corrosion processes in situ.

As a continuation of our efforts to discover and develop apoptosis inducing 4-aryl-4H-chromenes as novel anticancer agents, we explored modifications at the 2- and 3-positions. It was found that replacement of the 3-cyano group by an ester, including methyl and ethyl ester, resulted in >200-fold reduction of activity. Conversion of the 2-amino group into an amide or urea resulted in 4- to 10-fold drop of activity. Similarly, converting the 2-amino group into a hydrogen resulted in 4- to 10-fold reduction of activity. Compound 3d was highly active with an EC(50) value of 29 nM and a GI(50) value of 6 nM in T47D cells. Importantly, the 2-H analog 3d was found to be much more stable under acidic conditions compared to the 2-NH(2) analog 3b, suggesting that 2-H analogs might have better bioavailability than the 2-NH(2) analogs.

Unlabelled: Rapid recurrence of severe hepatitis C (HCV) after liver transplantation is a major barrier to survival of the transplanted liver. While cyclosporine (CsA) in vitro has been shown to suppress HCV replication, an effect is not seen with tacrolimus (Tac). Evidence is inconsistent whether or how this translates to clinical practice. To expand the evidence on this issue, we analyzed graft survival and histological outcomes after liver transplantation for HCV hepatitis., Methods: Using our longitudinal database (1991 onward) graft outcomes for all liver transplant recipients with HCV were evaluated (105 grafts in 97 patients). Severe activity, severe fibrosis, and graft survival were analyzed. All liver biopsies were scored (blinded) according to the Ludwig scale. Immunosuppression was based on prednisone and a calcineurin inhibitor (Tac n = 89, 85%; CsA n = 15, 14%). Comparisons of outcomes using CsA versus Tac therapy were done using survival analysis via the log-rank test., Results: Graft survival was significantly better in the CsA group. Although there was no apparent difference in severe activity (grade 2), there was a statistically significant difference in graft survival without fibrosing cholestatic hepatitis (P = .01) and a trend toward a difference in fibrosis-free survival (P = 0.1). The rate of sustained response to antiviral therapy was twice as high in the CsA group, 50% versus 22% (P = 0.16; NS)., Conclusions: Graft survival in liver transplant recipients with HCV may be greater with CsA-based immunosuppression. There may also be a lower rate of fibrosing cholestatic hepatitis in this group.

As a continuation of our efforts to discover and develop the apoptosis inducing 4-aryl-4H-chromenes as novel anticancer agents, we explored the SAR of 4-aryl-4H-chromenes with modifications at the 7- and 5-, 6-, 8-positions. It was found that a small hydrophobic group, such as NMe2, NH2, NHEt, and OMe, is preferred at the 7-position. Di-substitution at either the 5,7-positions or the 6,7-positions generally led to a large decrease in potency. Di-substitution at the 7,8-positions, in general, was found to result in potent compounds. 7-NMe2, 7-NHEt, 7-OMe, and 7,8-di-NH2 analogs were found to have similar SAR for the 4-aryl group, and several 7-substituted and 7,8-di-substituted analogs were found to have similar potencies as the lead compound MX58151 (2a) both as caspase activators and inhibitors of cell proliferation.

This work seeks to identify factors that facilitate or diminish care-providers' propensity to improve continence care in long-term care (LTC) settings. We conducted a cross-sectional qualitative study using focus group methodology in four long-term care institutions in Montreal, QC. Forty-two nurses, nursing assistants, and orderlies caring for incontinent elderly residents were asked how they perceived urinary incontinence (UI), how it was being managed, and what factors enabled or hindered continence care in their institution. Content analysis was used. Facilitating and inhibiting elements of three individual/internal factors (beliefs about UI, attitudes towards the elderly, and knowledge about UI) and five institutional/external factors (workload demands, type of patient, environmental support, co-worker support, and attributes of UI interventions) emerged as important determinants of care-providers' propensity to manage UI. To be successful, continence programs must target multidimensional elements that take into account personal, systems, and organizational level factors.

We report on the heterobimetallic system, Eu[Ag(x)Au(1-x)(CN)(2)](3) (x = 0-1) in which sensitization of europium luminescence occurs by energy transfer from [Ag(x)Au(1-x)(CN)(2)](-) donor excited states. The donor states have energies which are tunable and dependent on the Ag/Au stoichiometric ratio. These layered systems exhibit interesting properties, one of which is their emission energy tunability when excited at different excitation wavelengths. In this paper, we report on their use as donor systems with Eu(III) ions as acceptor ions in energy transfer studies. Luminescence results show that the mixed metal dicyanides with the higher silver loading have a better energy transfer efficiency than the pure Ag(CN)(2)(-) and Au(CN)(2)(-) donors. The better energy transfer efficiency is due to the greater overlap between the donor emission and acceptor excitation. Additionally, more acceptor states are available in the high silver loading mixed metal Eu(III) complexes. The results from a crystal structure determination and Raman experiments are also presented in this paper and provide information about metallophilic interactions in the closed-shell d(10) metal-metal [Ag(x)Au(1-x)(CN(2)](-) dicyanide clusters.

A novel series of 2-amino-4-(3-bromo-4,5-dimethoxy-phenyl)-3-cyano-4H-chromenes was identified as potent apoptosis inducers through a cell-based high throughput screening assay. Six compounds from this series, MX-58151, MX-58276, MX-76747, MX-116214, MX-116407, and MX-126303, were further profiled and shown to have potent in vitro cytotoxic activity toward proliferating cells only and to interact with tubulin at the colchicine-binding site, thereby inhibiting tubulin polymerization and leading to cell cycle arrest and apoptosis. Furthermore, these compounds were shown to disrupt newly formed capillary tubes in vitro at low nanomolar concentrations. These data suggested that the compounds might have vascular targeting activity. In this study, we have evaluated the ability of these compounds to disrupt tumor vasculature and to induce tumor necrosis. We investigated the pharmacokinetic and toxicity profiles of all six compounds and examined their ability to induce tumor necrosis. We next examined the antitumor efficacy of a subset of compounds in three different human solid tumor xenografts. In the human lung tumor xenograft (Calu-6), MX-116407 was highly active, producing tumor regressions in all 10 animals. Moreover, MX-116407 significantly enhanced the antitumor activity of cisplatin, resulting in 40% tumor-free animals at time of sacrifice. Our results identify MX-116407 as the lead candidate and strongly support its continued development as a novel anticancer agent for human use.

The discovery of a novel class of HCV NS5B polymerase inhibitors, 3-arylsulfonylamino-5-phenyl-thiophene-2-carboxylic acids is described. SAR studies have yielded several potent inhibitors of HCV polymerase as well as of HCV subgenomic RNA replication in Huh-7 cells.

Background/aims: An adequate model to study liver regeneration in humans is presently unavailable. We explored the feasibility of studying liver regeneration in a genetically similar species to man, the non-human primate Rhesus macaque., Methods: Five animals were studied; two underwent 60% hepatectomy, one underwent 30% hepatectomy, and cholecystectomy alone was performed on two animals. Laparoscopic-guided or open liver biopsies were performed on days 1, 2, 7, 14, 21, 30 and 60 following all surgeries. Liver regeneration was evaluated by measuring Ki-67, proliferating cell nuclear antigen expression and mitotic index, calculating changes in the surface area of the liver remnant and assessing intrahepatic production of cytokines., Results: Significant liver regeneration was induced in the animals that underwent 60% hepatectomy, peaking between days 21-30 postoperatively. Regeneration was minimal in all other animals studied. Cytokine production followed a similar pattern. Maximal liver regeneration correlated with restoration of surface area in the liver remnant., Conclusions: Sixty percent hepatectomy in a non-human primate model induced significant liver regeneration, maximizing 21-30 days following partial hepatectomy, suggesting a significant interspecies difference when compared to a rodent hepatectomy model. A partial hepatectomy model in Rhesus macaques may allow further characterization of liver regeneration in a species closer to humans., (Copyright 2002 European Association for the Study of the Liver)

Background: We first introduced the orthotopic liver transplantation utilizing cavaplasty technique in 1994. This paper describes the surgical technique and assesses the outcome of the cavaplasty OLT., Methods: The cavaplasty procedure was used in 115 consecutive orthotopic liver transplantations, including six left lateral and two right lobe transplantations, between November 1994 and September 2000. Fifty-three (66.3%) transplantations required femoro-axillary veno-venous bypass in the initial 4 years, whereas only eight (22.9%) needed VB in the subsequent 2 years. Conversion to piggyback or standard technique was not necessary in any patient., Results: Median results are as follows: operative time 4.5 hr, warm ischemia time 25 min, and blood transfused (packed red blood cells) 6 units. These findings did not differ between first transplantation and retransplantation. There were no perioperative deaths related to the cavaplasty technique. No hepatic venous outflow obstruction was observed, including living-related OLTs. No patient required postoperative hemodialysis for acute renal failure. The median intensive care and hospital stays were 2 days and 10 days, respectively., Conclusions: The cavaplasty technique requires no retrocaval, hepatic vein, or short hepatic vein dissection, and the inferior vena cava can be preserved, which provides advantages for hepatectomy and easy hemostasis, especially during retransplantation. The wide-open triangular caval anastomosis is easy to perform, allowing short implantation time and size matching and avoiding outflow obstruction. The short implantation time reduces the need for veno-venous bypass. Our experience indicates that the cavaplasty technique can be applied to all patients and is justified by minimal technical complications.

Six months of abstinence from alcohol is a commonly used criterion for liver transplantation eligibility for patients with alcoholic cirrhosis. There is limited evidence to document the validity of this criterion with regard to risk of alcoholism relapse. Ninety-one patients with alcoholic cirrhosis were interviewed for relapse risk using the High Risk Alcoholism Relapse (HRAR) Scale. The HRAR model can be used to predict relapse risk independent of duration of sobriety and therefore can be used to examine the validity of the 6 months of abstinence criteria in this clinical population. The two methods demonstrated poor to fair agreement. Agreement was highest with a cutoff allowing a 5% 6-month relapse risk when 79% agreement (c = 0.56) was demonstrated between the two methods. Using the 6-month abstinence criterion alone disallows a significant number of candidates who have a low relapse risk based on their HRAR score. The validity of the 6-month abstinence criterion is supported somewhat by comparison with the HRAR model. However, use of the 6-month abstinence criterion alone forces a significant number of patients with a low relapse risk by HRAR to wait for transplant listing. A relapse risk model based on an estimate of alcoholism severity in addition to duration of sobriety may more accurately select patients who are most likely to benefit from liver transplantation.