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In patients with dysphagia that is not explained by upper endoscopy, high-resolution esophageal manometry (HRM) is the next logical step in diagnostic testing. This study investigated predictors of failure to refer for HRM after an upper endoscopy that was performed for but did not explain dysphagia. This was a retrospective cohort study of patients >18 years of age who underwent esophagogastroduodenoscopy (EGD) for dysphagia from 2015 to 2021. Patients with EGD findings that explained dysphagia (e.g. esophageal mass, eosinophilic esophagitis, Schatzki ring, etc.) were excluded from the main analyses. The primary outcome was failure to refer for HRM within 1 year of the index non-diagnostic EGD. We also investigated delayed referral for HRM, defined as HRM performed after the median. Multivariable logistic regression modeling was used to identify risk factors that independently predicted failure to refer for HRM, conditioned on the providing endoscopist. Among 2132 patients who underwent EGD for dysphagia, 1240 (58.2%) did not have findings to explain dysphagia on the index EGD. Of these 1240 patients, 148 (11.9%) underwent HRM within 1 year of index EGD. Endoscopic findings (e.g. hiatal hernia, tortuous esophagus, Barrett's esophagus, surgically altered anatomy not involving the gastroesophageal junction, and esophageal varices) perceived to explain dysphagia were independently associated with failure to refer for HRM (adjusted odds ratio 0.45, 95% confidence interval 0.25-0.80). Of the 148 patients who underwent HRM within 1 year of index EGD, 29.7% were diagnosed with a disorder of esophagogastric junction outflow, 17.6% with a disorder of peristalsis, and 2.0% with both disorders of esophagogastric outflow and peristalsis. The diagnosis made by HRM was similar among those who had incidental EGD findings that were non-diagnostic for dysphagia compared with those who had completely normal EGD findings. Demographic factors including race/ethnicity, insurance type, and income were not associated with failure to refer for HRM or delayed HRM. Patients with dysphagia and endoscopic findings unrelated to dysphagia have a similar prevalence of esophageal motility disorders to those with normal endoscopic examinations, yet these patients are less likely to undergo HRM. Provider education is indicated to increase HRM referral in these patients., (© The Author(s) 2024. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: In patients with inflammatory bowel disease (IBD) for whom medical therapy is unsuccessful or who develop colitis-associated neoplasia, restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) is often indicated. One consideration for surgeons performing this procedure is whether to create this anastomosis using a stapled technique without mucosectomy or using a hand-sewn technique with mucosectomy. This study tested the association between IPAA anastomosis technique and cuffitis and/or pouchitis, assessed endoscopically., Methods: This was a retrospective cohort study. We included consecutive adult patients with IBD who had undergone IPAA and had received index pouchoscopies at Columbia University Irving Medical Center between 2020 and 2022. Patients were then followed up from this index pouchoscopy for ≤12 months to a subsequent pouchoscopy. The primary exposure was mucosectomy vs non-mucosectomy and the primary outcome was cuffitis and/or pouchitis, defined as a Pouch Disease Activity Index endoscopy subscore of ≥1., Results: There were 76 patients who met study criteria including 49 (64%) who had undergone mucosectomy and 27 (36%) who had not. Rates of cuffitis and/or pouchitis were 49% among those with mucosectomy vs 41% among those without mucosectomy ( P  =   0.49). Time-to-event analysis affirmed these findings (log-rank P  =   0.77). Stricture formation was more likely among patients with mucosectomy compared with those without mucosectomy (45% vs 19%, P  =   0.02)., Conclusions: There was no association between anastomosis technique and cuffitis and/or pouchitis among patients with IBD. These results may support the selection of stapled anastomosis over hand-sewn anastomosis with mucosectomy., Competing Interests: B.S. is a consultant for Abbvie, Janssen, and Takeda. D.F. is funded in part by Department of Defense PR181960., (© The Author(s) 2024. Published by Oxford University Press and Sixth Affiliated Hospital of Sun Yat-sen University.)

Direct oral anticoagulants (DOACs) targeting activated factor Xa (FXa) are used to prevent or treat thromboembolic disorders. DOACs reversibly bind to FXa and inhibit its enzymatic activity. However, DOAC treatment carries the risk of anticoagulant-associated bleeding. Currently, only one specific agent, andexanet alfa, is approved to reverse the anticoagulant effects of FXa-targeting DOACs (FXaDOACs) and control life-threatening bleeding. However, because of its mechanism of action, andexanet alfa requires a cumbersome dosing schedule, and its use is associated with the risk of thrombosis. Here, we present the computational design, engineering, and evaluation of FXa-variants that exhibit anticoagulation reversal activity in the presence of FXaDOACs. Our designs demonstrate low DOAC binding affinity, retain FXa-enzymatic activity and reduce the DOAC-associated bleeding by restoring hemostasis in mice treated with apixaban. Importantly, the FXaDOACs reversal agents we designed, unlike andexanet alfa, do not inhibit TFPI, and consequently, may have a safer thrombogenic profile., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

The objective of the current work was to examine the relationships between affective temperaments dimensions, trait anger, and the preference for rap music in a sample of Italian adults. An online survey was administered to 662 subjects. We assessed preference for rap music using a Likert scale. Ina addition, we investigated the sample' affective temperament traits using the Memphis, Pisa, Paris, and San Diego (TEMPS-A) short scale and the trait anger by using the Trait Anger component of the State Trait Anger Expression Inventory 2 (STAXI-2). Multiple linear regression indicated that cyclothymic temperament score, hyperthymic temperament score, and trait anger scores were positive predictors while older age, and depressive temperament and higher education score were negative predictors of preference for rap music. The results expand previous literature on personality and music preference indicating the association of high energy/high activity temperaments and trait anger to preference for rap music.

Background: Neuroimaging studies have shown a complex pattern of brain activation during perception of a pleasant odor and during its olfactory imagery. To date, little is known regarding changes in motor cortex excitability during these tasks. Bergamot essential oil (BEO) is extensively used in perfumes and cosmetics for its pleasantness. Therefore, to further our understanding of the human sense of smell, this study aimed to investigate the effect of perception and imagery of a pleasant odor (BEO) on motor cortex using Transcranial magnetic stimulation (TMS)., Materials and Methods: We examined the primary motor cortex (M1) excitability during perception of a pleasant odor (BEO) or perception of odorless saline (experiment 1). Furthermore, we tested the effect of olfactory imagery (OI) of BEO on corticospinal excitability (experiment 2). The increase in motor evoked potential (MEP) amplitude was correlated with personality dimensions scores, pleasantness, vividness, and general imagery ability., Results: The results indicate that the corticospinal excitability changed after both perception and imagery of a pleasant odor (BEO). The correlation analysis shows an association with neuroticism personality trait (experiment 1) and with general olfactory imagery ability (experiment 2)., Conclusion: Both perception of a pleasant odor and its olfactory imagery modulate motor cortex excitability. The enhanced brain activation is affected by specific individual characteristics. Overall, our findings provide physiological evidence for a complex interaction between the olfactory and motor systems., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Infortuna, Gualano, Freedberg, Patel, Sheikh, Muscatello, Bruno, Mento, Chusid, Han, Thomas and Battaglia.)

Background: Obesity is associated with increased risk for death in most infections but has not been studied as a risk factor for mortality in Clostridioides difficile infection (CDI). This study tested obesity as a risk factor for death in patients hospitalized with CDI. This was a three-center retrospective study that included hospitalized adults with CDI at Columbia University Irving Medical Center, Brigham and Women's Hospital, and NYU Langone from 2010 to 2018. Multivariate logistic regression was used to assess the relationship between obesity, measured by body mass index, and death from any cause within 30 days after the index CDI test., Results: Data for 3851 patients were analyzed, including 373 (9.7%) who died within 30 days following a diagnosis of CDI. After adjusting for other factors, BMI was not associated with increased risk for death in any BMI category [adjusted OR (aOR) 0.96, 95% CI 0.69 to 1.34 for BMI > 30 vs BMI 20-30; aOR 1.02, 95% CI 0.53 to 1.87 for BMI > 40 vs BMI 20-30]. After stratifying into three groups by age, there were trends towards increased mortality with obesity in the middle-aged (56-75 vs ≤ 55 years old) yet decreased mortality with obesity in the old (> 75 vs ≤ 55) (p = NS for all). Advanced age and low albumin were the factors most strongly associated with death., Conclusions: We found no association between obesity and death among patients with CDI, in contrast to most other infections. Obesity is not likely to be useful for risk-stratifying hospitalized patients with CDI., (© 2022. The Author(s).)

Individuals are adept at estimating average properties of group visual stimuli, even following brief presentations. In estimating the directional heading of walking human figures, judgments are biased in a peculiar manner: groups facing intermediate directions are perceived to be more leftward- or rightward-facing than actual averages. This effect was previously explained as a repulsive bias away from a central category boundary; groups along this boundary (directly facing the observer) are estimated with lower variability and with relatively greater accuracy. Here we show that: (i) the original effect replicates and is constant over time in a novel estimation task with persistent directional states; and, (ii) novel patterns of response variability and durations align with the entire range of overestimation. A simple model of additive errors proportional to viewer uncertainty matches the observed bias magnitudes. We furthermore show that the bias generalizes beyond approaching walkers with the use of rearward-facing walkers presented at a nonparallel angle. Overall, the recurring relation between bias and uncertainty is also consistent with top-down and post-perceptual causes of misestimation., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Introduction: The COVID-19 pandemic drastically changed hospital workflows. This study aimed to characterize differences in gastrointestinal endoscopies in the New York metropolitan region before, during, and after the first wave of the pandemic., Methods: Across 3 hospitals, we compared demographics, indications, and yield of endoscopies before and after March 16, 2020, the date on which elective procedures were canceled, as well as a recovery period for 5 months after they were resumed., Results: A total of 9,401 procedures before and 332 procedures during the first wave were performed. Females comprised 57 and 44% of patients (p < 0.01), respectively. There was a decline in the proportion of Black (15 vs. 7%, p < 0.02) and Hispanic patients (29 vs. 16%, p < 0.02) undergoing outpatient procedures. There was a significant rise in urgent indications such as bleeding and jaundice. There was an increase in the diagnostic yield of all esophagogastroduodenoscopies for bleeding (p < 0.01) and of outpatient endoscopic ultrasounds for malignancy (p = 0.01), but no increase in yield of inpatient colonoscopy for bleeding. A review of 7,475 procedures during the recovery period showed a return to many nonurgent indications, but still showed decreased proportions of Hispanic and male patients compared to the prepandemic period., Discussion/conclusion: Lower proportions of Black and Hispanic patients underwent outpatient endoscopies during and after the first wave. The proportion of procedures done for emergent indications and their diagnostic yield increased during the pandemic, suggesting a higher threshold to perform endoscopy. In resource-sparing conditions, clinicians should pay attention to thresholds to perform colonoscopy for bleeding and to racial disparities in outpatient healthcare access., (© 2021 S. Karger AG, Basel.)

Background: Obesity is a risk factor for pneumonia and acute respiratory distress syndrome., Objective: To determine whether obesity is associated with intubation or death, inflammation, cardiac injury, or fibrinolysis in coronavirus disease 2019 (COVID-19)., Design: Retrospective cohort study., Setting: A quaternary academic medical center and community hospital in New York City., Participants: 2466 adults hospitalized with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 infection over a 45-day period with at least 47 days of in-hospital observation., Measurements: Body mass index (BMI), admission biomarkers of inflammation (C-reactive protein [CRP] level and erythrocyte sedimentation rate [ESR]), cardiac injury (troponin level), and fibrinolysis (D-dimer level). The primary end point was a composite of intubation or death in time-to-event analysis., Results: Over a median hospital length of stay of 7 days (interquartile range, 3 to 14 days), 533 patients (22%) were intubated, 627 (25%) died, and 59 (2%) remained hospitalized. Compared with overweight patients, patients with obesity had higher risk for intubation or death, with the highest risk among those with class 3 obesity (hazard ratio, 1.6 [95% CI, 1.1 to 2.1]). This association was primarily observed among patients younger than 65 years and not in older patients ( P for interaction by age = 0.042). Body mass index was not associated with admission levels of biomarkers of inflammation, cardiac injury, or fibrinolysis., Limitations: Body mass index was missing for 28% of patients. The primary analyses were conducted with multiple imputation for missing BMI. Upper bounding factor analysis suggested that the results are robust to possible selection bias., Conclusion: Obesity is associated with increased risk for intubation or death from COVID-19 in adults younger than 65 years, but not in adults aged 65 years or older., Primary Funding Source: National Institutes of Health.

Introduction: In this study, we show new evidence for the role of ventrolateral prefrontal cortex-dorsolateral prefrontal cortex (VLPFC-DLPFC) networks in the cognitive framing of emotional processing., Method: We displayed neutral and aversive images described as having been sourced from artistic material to one cohort of subjects (i.e., the art-frame group; n = 19), while identical images, this time identified as having been sourced from documentary material (i.e., the doc-frame group; n = 20) were shown to a separate cohort., Results: Using functional magnetic resonance imaging (fMRI), we employed a linear parametric model showing that relative to the doc-frame group the art-frame group exhibited a modulation of amygdala activity in response to aversive images. The attenuated amygdala activity in the art-frame group supported our hypothesis that reduced amygdala activity was driven by top-down DLPFC inhibition of limbic responses. A psychophysiological interaction (PPI) analysis demonstrated that VLPFC activity correlated with amygdala activity in the art-frame group, but not in the doc-frame group for the contrast [Aversive > Neutral]., Conclusion: The role of the VLPFC in cognitive control suggests the hypothesis that it alongside DLPFC insulates against embodied emotional responses by inhibiting automatic affective responses., (© 2020 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

The matrix pencil method (MPM) is explored for stable, reproducible data processing in nuclear magnetic resonance (NMR) relaxometry. Data from one-dimensional and two-dimensional relaxometry experiments designed to measure transverse relaxation T 2 , longitudinal relaxation T 1 , diffusion coefficient D values, and their correlations in a standard olive oil/water mixture serve as a platform available to any NMR spectroscopist to compare the performance of the MPM to the benchmark inverse Laplace transform (ILT). The data from two practical examples, including the drying of a solvent polymer system and the enzymatic digestion of polysialic acid, were also explored with the MPM and ILT. In the cases considered here, the MPM appears to outperform the ILT in terms of resolution and stability in the determination of fundamental constants for complex materials and mixtures., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Synonymous codons occur with different frequencies in different organisms, a phenomenon termed codon usage bias. Codon optimization, a common term for a variety of approaches used widely by the biopharmaceutical industry, involves synonymous substitutions to increase protein expression. It had long been presumed that synonymous variants, which, by definition, do not alter the primary amino acid sequence, have no effect on protein structure and function. However, a critical mass of reports suggests that synonymous codon variations may impact protein conformation. To investigate the impact of synonymous codons usage on protein expression and function, we designed an optimized coagulation factor IX (FIX) variant and used multiple methods to compare its properties to the wild-type FIX upon expression in HEK293T cells. We found that the two variants differ in their conformation, even when controlling for the difference in expression levels. Using ribosome profiling, we identified robust changes in the translational kinetics of the two variants and were able to identify a region in the gene that may have a role in altering the conformation of the protein. Our data have direct implications for codon optimization strategies, for production of recombinant proteins and gene therapies.

Objectives: Cholecystectomy (CCY) is associated with increased faecal levels of secondary bile acids. Secondary bile acids confer resistance to Clostridioides difficile infection (CDI, formerly Clostridium difficile infection) in animal studies. This study tested the hypothesis that CCY confers protection against CDI by increasing gut levels of secondary bile acids., Methods: This was a retrospective case-control study. Adults hospitalized between January 2010 and June 2017 at our institution were included. CDI cases were defined as a positive stool PCR followed by anti-CDI treatment and were matched 1:1:1 with two control groups (those who tested negative for CDI and those who were not tested for CDI) by sex, age group, body mass index (BMI), and exposure to antibiotics. CCY was defined as a history of CCY at least 6 months prior to the index C. difficile test or the index admission date in the untested controls. Conditional logistic regression modelling was used to estimate the relationship between remote CCY and risk for CDI., Results: The final study population was 7077 (2359 CDI cases, 2359 matched controls without CDI, and 2359 matched controls not tested for CDI). Rates of remote CCY did not differ among the three groups (14.4% vs. 15.5% vs. 14.2%) and this result was unchanged after adjusting for additional clinical factors (adjusted OR 0.90, 95% CI 0.76-1.06 comparing CDI cases vs. matched controls without CDI; adjusted OR 1.04, 95% CI 0.78-1.39 comparing CDI cases vs. matched controls not tested for CDI)., Conclusions: There was no association between remote CCY and risk for CDI., (Copyright © 2018 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

The optimal duration of contact precautions for vancomycin-resistant enterococcus (VRE)-colonized patients is uncertain and individual patient characteristics alone may not predict risk of prolonged colonization. Using a cohort of adult patients who underwent testing for VRE at intensive care unit (ICU) admission, we tested the association between local (unit-level) vancomycin use and persistent colonization with VRE. Higher unit-level vancomycin use significantly prolonged VRE colonization (P=0.03) independent of patient-level vancomycin use and unit VRE density., (Copyright © 2019 The Healthcare Infection Society. Published by Elsevier Ltd. All rights reserved.)

Recent studies have shed light on how aesthetic judgments are formed following presentations lasting less than a second. Meanwhile, dedicated neural mechanisms are understood to enable the rapid detection of human faces, bodies, and actions. On the basis of cognitive studies of: (i) the speed and acuity of person perception, and (ii) preferential attention given to human imagery (e.g., faces and bodies), we hypothesize that the visual detection of humans in portraits increases the magnitude and stability (i.e., similarity to later responses) of aesthetic ratings. Ease of person perception is also expected to elicit longer durations of preferential viewing time, a surplus measure of viewing behavior that should be positively related to subsequent ratings. To test these ideas, we use a set of cubist portraits previously established to be more or less categorizable in terms of the aggregate time required to perceive the depicted person. Using these images, we track aesthetic judgments made following short and unconstrained presentations; in an intervening task, we measure viewing behavior when subjects are able to selectively reveal regions of these images. We find that highly categorizable artworks (those that require less time to identify the figure as human) elicit higher and more predictive aesthetic ratings following 30 ms presentations while also eliciting longer viewing durations. Changes in ratings throughout the task are positively correlated with cumulative viewing time; critically, an image's categorizability level further moderates the strength of this relationship. These results demonstrate that a particular kind of visual object recognition - the recognition of human forms - modulates aesthetic preferences at a glance, subsequent viewing patterns, as well as rating changes over time., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Vancomycin-resistant enterococcus (VRE) causes 4% of all healthcare-associated infections in the USA. The process by which the local hospital milieu contributes to VRE acquisition is not fully understood., Aim: To determine the importance of specific factors within the local hospital environment for healthcare-associated VRE acquisition., Methods: This retrospective cohort study included patients admitted to six intensive care units at an academic medical centre from January 2012 to December 2016 with negative rectal VRE cultures on admission. VRE acquisition was defined as a positive surveillance swab performed at any time after the initial negative swab during the index hospitalization. The exposures of interest were VRE colonization pressure, VRE importation pressure, and use of vancomycin. Multivariable Cox proportional hazards modelling was performed, with patients followed until VRE acquisition, death, or for up to 30 days., Findings: Of 8485 patients who were initially VRE negative, 161 patients acquired VRE. On univariate analysis, patients with VRE acquisition were more likely to have received vancomycin, to have had a neighbouring patient who received vancomycin, to have high VRE importation pressure, or to have high VRE colonization pressure. On multivariable analysis, only high VRE colonization pressure was an independent predictor of VRE acquisition (adjusted hazard ratio: 1.79; 95% confidence interval: 1.19-2.70)., Conclusion: VRE colonization pressure was the most important risk factor for healthcare-associated VRE acquisition, regardless of VRE importation pressure. Interventions seeking to reduce VRE acquisition should focus on minimizing transmission between patients with known VRE and the local hospital environment., (Published by Elsevier Ltd.)

Perceptual judgments are said to be reference-dependent as they change on the basis of recent experiences. Here we quantify sequence effects within two types of aesthetic judgments: (i) individual ratings of single images (during self-paced trials) and (ii) continuous ratings of image sequences. As in the case of known contrast effects, trial-by-trial aesthetic responses are negatively correlated with judgments made toward the preceding image. During continuous judgment, a different type of bias is observed. The onset of change within a sequence introduces a persistent increase in ratings (relative to when the same images are judged in isolation). Furthermore, subjects indicate adjustment patterns and choices that selectively favor sequences that are rich in change. Sequence effects in aesthetic judgments thus differ greatly depending on the continuity and arrangement of presented stimuli. The effects highlighted here are important in understanding sustained aesthetic responses over time, such as those elicited during choreographic and musical arrangements. In contrast, standard measurements of aesthetic responses (over trials) may represent a series of distinct aesthetic experiences (e.g., viewing artworks in a museum)., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The phenomenon of motor resonance (the increase in motor cortex excitability during observation of actions) has been previously described. Transcranial magnetic stimulation (TMS) studies have demonstrated a similar effect during perception of implied motion (IM). The left dorsolateral prefrontal cortex (DLPFC) seems to be activated during action observation. Furthermore, the role of this brain area in motor resonance to IM is yet to be investigated. Fourteen healthy volunteers were enrolled into the study. We used transcranial direct current stimulation (tDCS) to stimulate DLPFC aiming to investigate whether stimulation with different polarities would affect the amplitude of motor evoked potential collected during observation of images with and without IM. The results of our experiment indicated that Cathodal tDCS over the left DLPFC prevented motor resonance during observation of IM. On the contrary, anodal and sham tDCS did not significantly modulate motor resonance to IM. The current study expands the understanding of the neural circuits engaged during observation of IM. Our results are consistent with the hypothesis that action understanding requires the interaction of large networks and that the left DLPFC plays a crucial role in generating motor resonance to IM., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Following the discovery of mirror neurons, much attention has been de-voted to understanding the neural responses evoked by observation of implied motion in works of art. Neuroimaging studies have demonstrated that dorsal premotor cortex (PMd) is commonly involved during observation of movements but the role of the inhibitory and excitatory connections between PMd and primary motor cortex (M1) during observation of implied motion remains uncertain. In this study, using high and low frequency repetitive transcranial magnetic stimulation (rTMS), we examined PMd-M1 connectivity and plasticity during observation of Michelangelo's frescos with and without implied motion (Sistine Chapel, 1508-1512). We found that observation of implied motion in a painting specifically reduces the activity of inhibitory PMd-M1 connections. On the contrary PMd-M1 facilitatory connections, as examined by means of 5-Hz rTMS, were not modulated during observation of the painting. Our data suggest that observation of implied motion in a painting modulates PMd-M1 connectivity and plasticity. These results are consistent with the hypothesis that art with implied motion might be used as a plasticity-based intervention in rehabilitation.

In the present study we used single and paired-pulse Transcranial Magnetic Stimulation (TMS) to evaluate the effect of implied motion on primary motor cortex microcircuits. We found that observation of the implied motion of a static image increases MEP amplitude and reduces short-interval intracortical inhibition (SICI), without significant modulation of intracortical facilitation and sensory-motor integration. Our results add to the existing literature on the activation of the observation-execution matching system and describe a selective modulation of GABAergic cortical microcircuits during observation of implied motion.

The aim of this study was to test the involvement of sensorimotor cortical circuits during the beholding of the static consequences of hand gestures devoid of any meaning.In order to verify this hypothesis we performed an EEG experiment presenting to participants images of abstract works of art with marked traces of brushstrokes. The EEG data were analyzed by using Event Related Potentials (ERPs). We aimed to demonstrate a direct involvement of sensorimotor cortical circuits during the beholding of these selected works of abstract art. The stimuli consisted of three different abstract black and white paintings by Franz Kline. Results verified our experimental hypothesis showing the activation of premotor and motor cortical areas during stimuli observation. In addition, abstract works of art observation elicited the activation of reward-related orbitofrontal areas, and cognitive categorization-related prefrontal areas. The cortical sensorimotor activation is a fundamental neurophysiological demonstration of the direct involvement of the cortical motor system in perception of static meaningless images belonging to abstract art. These results support the role of embodied simulation of artist's gestures in the perception of works of art.

The role of the motor system in the perception of visual art remains to be better understood. Earlier studies on the visual perception of abstract art (from Gestalt theory, as in Arnheim, 1954 and 1988, to balance preference studies as in Locher and Stappers, 2002, and more recent work by Locher et al., 2007; Redies, 2007, and Taylor et al., 2011), neglected the question, while the field of neuroesthetics (Ramachandran and Hirstein, 1999; Zeki, 1999) mostly concentrated on figurative works. Much recent work has demonstrated the multimodality of vision, encompassing the activation of motor, somatosensory, and viscero-motor brain regions. The present study investigated whether the observation of high-resolution digitized static images of abstract paintings by Lucio Fontana is associated with specific cortical motor activation in the beholder's brain. Mu rhythm suppression was evoked by the observation of original art works but not by control stimuli (as in the case of graphically modified versions of these works). Most interestingly, previous visual exposure to the stimuli did not affect the mu rhythm suppression induced by their observation. The present results clearly show the involvement of the cortical motor system in the viewing of static abstract art works.

The aim of this study was to investigate, using eye-tracking technique, the influence of bottom-up and top-down processes on visual behavior while subjects, naïve to art criticism, were presented with representational paintings. Forty-two subjects viewed color and black and white paintings (Color) categorized as dynamic or static (Dynamism) (bottom-up processes). Half of the images represented natural environments and half human subjects (Content); all stimuli were displayed under aesthetic and movement judgment conditions (Task) (top-down processes). Results on gazing behavior showed that content-related top-down processes prevailed over low-level visually-driven bottom-up processes when a human subject is represented in the painting. On the contrary, bottom-up processes, mediated by low-level visual features, particularly affected gazing behavior when looking at nature-content images. We discuss our results proposing a reconsideration of the definition of content-related top-down processes in accordance with the concept of embodied simulation in art perception.

We examine the effects of the artistic representation - here exemplified by Michelangelo's Expulsion from Paradise - of an action on the motor system. Using single and paired- pulse transcranial magnetic stimulation we analyze corticomotor excitability during observation of an action in the painting, during imagery of the painting, and during observation of a photograph of the same pose. We also analyze the effects of observation of two further paintings, one showing the same muscles at rest, and in the other in a more overtly emotional context. Both observation of the Expulsion and of imagery of the painting increased cortical excitability. Neither the relaxed pose of Michelangelo's Creation nor the flexed posture in the highly emotional context of Bellini's Dead Christ increased cortical excitability. Observation of a photograph of the same extended pose did not increase cortical excitability either. Moreover, intracortical inhibition was reduced during imagery of the painting. Our results offer clear motor correlates of the relationship between the esthetic quality of a work and the perception of implied movement within it.

The implications of the discovery of mirroring mechanisms and embodied simulation for empathetic responses to images in general, and to works of visual art in particular, have not yet been assessed. Here, we address this issue and we challenge the primacy of cognition in responses to art. We propose that a crucial element of esthetic response consists of the activation of embodied mechanisms encompassing the simulation of actions, emotions and corporeal sensation, and that these mechanisms are universal. This basic level of reaction to images is essential to understanding the effectiveness both of everyday images and of works of art. Historical, cultural and other contextual factors do not preclude the importance of considering the neural processes that arise in the empathetic understanding of visual artworks.

The gene celF of the cryptic cel operon of Escherichia coli has been cloned, and the encoded 6-phospho-beta-glucosidase (cellobiose-6-phosphate [6P] hydrolase; CelF [EC 3.2.1.86]) has been expressed and purified in a catalytically active state. Among phospho-beta-glycosidases, CelF exhibits unique requirements for a divalent metal ion and NAD(+) for activity and, by sequence alignment, is assigned to family 4 of the glycosylhydrolase superfamily. CelF hydrolyzed a variety of P-beta-glucosides, including cellobiose-6P, salicin-6P, arbutin-6P, gentiobiose-6P, methyl-beta-glucoside-6P, and the chromogenic analog, p-nitrophenyl-beta-D-glucopyranoside-6P. In the absence of a metal ion and NAD(+), purified CelF was rapidly and irreversibly inactivated. The functional roles of the cofactors have not been established, but NAD(+) appears not to be a reactant and there is no evidence for reduction of the nucleotide during substrate cleavage. In solution, native CelF exists as a homotetramer (M(w), approximately 200,000) composed of noncovalently linked subunits, and this oligomeric structure is maintained independently of the presence or absence of a metal ion. The molecular weight of the CelF monomer (M(r), approximately 50,000), estimated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, is in agreement with that calculated from the amino acid sequence of the polypeptide (450 residues; M(r) = 50,512). Comparative sequence alignments provide tentative identification of the NAD(+)-binding domain (residues 7 to 40) and catalytically important glutamyl residues (Glu(112) and Glu(356)) of CelF.

Background: (1)H and (15)N transverse relaxation measurements on perdeuterated proteins are ideally suited for detecting backbone conformational fluctuations on the millisecond-microsecond timescale. The identification of conformational exchange on this timescale by measuring the relaxation of both (1)H and (15)N holds great promise for the elucidation of functionally relevant conformational changes in proteins., Results: We measured the transverse (1)H and (15)N relaxation rates of backbone amides of HIV-1 protease in its free and inhibitor-bound forms. An analysis of these rates, obtained as a function of the effective rotating frame field, provided information about the timescale of structural fluctuations in several regions of the protein. The flaps that cover the active site of the inhibitor-bound protein undergo significant changes of backbone (&phi;,psi) angles, on the 100 micros timescale, in the free protein. In addition, the intermonomer beta-sheet interface of the bound form, which from protease structure studies appears to be rigid, was found to fluctuate on the millisecond timescale., Conclusions: We present a working model of the flap-opening mechanism in free HIV-1 protease which involves a transition from a semi-open to an open conformation that is facilitated by interaction of the Phe53 ring with the substrate. We also identify a surprising fluctuation of the beta-sheet intermonomer interface that suggests a structural requirement for maturation of the protease. Thus, slow conformational fluctuations identified by (1)H and (15)N transverse relaxation measurements can be related to the biological functions of proteins.

6-Phosphoryl-beta-D-glucopyranosyl:6-phosphoglucohydrolase (P-beta-glucosidase, EC 3.2.1.86) has been purified from Fusobacterium mortiferum. Assays for enzyme activity and results from Western immunoblots showed that P-beta-glucosidase (Mr, 53,000; pI, 4.5) was induced by growth of F. mortiferum on beta-glucosides. The novel chromogenic and fluorogenic substrates, p-nitrophenyl-beta-D-glucopyranoside-6-phosphate (pNPbetaGlc6P) and 4-methylumbelliferyl-beta-D-glucopyranoside-6-phosphate (4MUbetaGlc6P), respectively, were used for the assay of P-beta-glucosidase activity. The enzyme hydrolyzed several P-beta-glucosides, including the isomeric disaccharide phosphates cellobiose-6-phosphate, gentiobiose-6-phosphate, sophorose-6-phosphate, and laminaribiose-6-phosphate, to yield glucose-6-phosphate and appropriate aglycons. The kinetic parameters for each substrate are reported. P-beta-glucosidase from F. mortiferum was inactivated by 6-phosphoglucono-delta-lactone (P-glucono-delta-lactone) derived via oxidation of glucose 6-phosphate. The pbgA gene that encodes P-beta-glucosidase from F. mortiferum has been cloned and sequenced. The first 42 residues deduced from the nucleotide sequence matched those determined for the N terminus by automated Edman degradation of the purified enzyme. From the predicted sequence of 466 amino acids, two catalytically important glutamyl residues have been identified. Comparative alignment of the amino acid sequences of P-beta-glucosidase from Escherichia coli and F. mortiferum indicates potential binding sites for the inhibitory P-glucono-delta-lactone to the enzyme from F. mortiferum.

A tetrahedrally hydrogen-bonded structural water molecule, water 301, is seen in the crystal structure of nearly every HIV-1 protease/inhibitor complex. Although the urea oxygen of the designed inhibitor, DMP323, mimics and replaces water 301, other water molecules are seen in the protease/DMP323 crystal structure. As a first step toward understanding how water molecules may contribute to inhibitor potency and specificity, we have recorded water-NOESY and water-ROESY spectra of the protease/ DMP323 complex. Cross relaxation rates derived from these spectra, together with interproton distances calculated from the crystal structure of the complex, were used to classify the exchange cross peaks as follows: (A) a direct NOE with a water proton, (B) an indirect NOE with water through a labile protein proton, and (C) direct exchange of an amide proton with water. Type A and B cross peaks were analyzed using three models of water dynamics: (1) two-site exchange, with water molecules randomly hopping between bound and free states, (2) bound water with internal motion, and (3) free diffusion. Using the two-site exchange model to analyze the relaxation data of the type A cross peaks, it was found that the water molecules had short residence times, ca. 500 ps. in contrast with the > 9 ns residence time estimated for water 301 in the protease/P9941 complex [Grzesiek et al. (1994) J. Am. Chem. Soc. 116, 1581-1582]. The NMR data are consistent with the X-ray observation that two symmetry-related water molecules, waters 422 and 456, are bound at the DMP323 binding site. Hence, these water molecules may help to stabilize the structure of the complex. Finally, it was found that three buried and hydrogen-bonded Thr hydroxyl protons were in slow exchange with solvent. In contrast, it was found that the DMP323 H4/H5 hydroxyl protons and the Asp25/125 carboxyl protons, which form a buried hydrogen-bonded network at the catalytic site of the protease, are in rapid exchange with solvent, suggesting that solvent can penetrate into the buried protein/inhibitor interface on the millisecond to microsecond time scale.

In order to improve the design of HIV-1 protease inhibitors, it is essential to understand how they interact with active site residues, particularly the catalytic Asp25 and Asp125 residues. KNI-272 is a promising, potent HIV-1 protease inhibitor (K(i) approximately 5 pM), currently undergoing phase 1 clinical trials. Because KNI-272 is asymmetric, the complex it forms with the homodimeric HIV-1 protease also lacks symmetry, and the two protease monomers can have distinct NMR spectra. Monomer specific signal assignments were obtained for amino acid residues in the drug binding site as well as for six of the eight Asp residues in the protease/KNI-272 complex. Using these assignments, the ionization states of the Asp carboxyl groups were determined from measurements of (a) the pD dependence of the chemical shifts of the Asp carboxyl carbons and (b) the H/D isotope effect upon the Asp carboxyl carbon chemical shifts. The results of these measurements indicate that the carboxyl of Asp25 is protonated while that of Asp125 is not protonated. These findings provide not only the first experimental evidence regarding the distinct protonation states of Asp25/125 in HIV-1 protease/drug complexes, but also shed light on interactions responsible for inhibitor binding that should form the basis for improved drug designs.

Early stages of nodulation involve the exchange of signals between the bacterium and the host plant. Bacterial nodulation (nod) genes are required for Rhizobium spp. to synthesize lipooligosaccharide morphogens, termed Nod factors. The common nod genes encode enzymes that synthesize the factor core structure, which is modified by host-specific gene products. Here we show direct in vitro evidence that Rhizobium meliloti NodH, a host-specific nodulation gene, catalyzes the transfer of sulfate from 3'-phosphoadenosine 5'-phosphosulfate to the terminal 6-O position of Nod factors, and we show substrate requirements for the reaction. Our results indicate that polymerization of the chitooligosaccharide backbone likely precedes sulfation and that sulfation is not absolutely dependent on the presence or the particular structure of the N-acyl modification. NodH sulfation provides a tool for the enzymatic in vitro synthesis of novel Nod factors, or putative Nod factors intermediates, with high specific activity.

Four fatty acids (FA, palmitic, myristic, decanoic, hexanoic) were individually conjugated to the N-terminus of the alpha-MSH fragment analog, H-Asp5-His6-D-Phe7-Arg8-Trp9-Lys10-NH2. This resulted in enhanced potency of the conjugates (compared to the unconjugated melanotropin analog) as determined in the lizard skin bioassay and in the mouse melanoma cell tyrosinase bioassay. The shorter conjugates of hexanoic and decanoic acid were at least equipotent to alpha-MSH in the lizard skin bioassay, whereas the longer myristoyl and palmitoyl analogs were 100 times less active. The myristoyl and palmitoyl conjugates exhibited a "creeping" potency in the lizard skin bioassay-that is, potency of the peptides increased with time in contact with the skins. These observations may be related to the more lipid nature of these FA-conjugates. In the tyrosinase assay, the conjugates were 10-100 times more active than alpha-MSH or the unconjugated analog. Each of the FA-melanotropic peptide conjugates exhibited prolonged (residual) melanotropic activity in both the lizard skin and melanoma cell bioassays. In other words, after removal of the melanotropin conjugates from contact with the skins or cells, responses were still manifested for hours or days thereafter. As little as 1 hr of contact with melanoma cells resulted in enhanced enzyme activity as measured 48 hr later. Since the conjugates, but not H-[Asp5, D-Phe7, Lys10]alpha-MSH5-10-NH2, exhibited prolonged activity, the conversion of reversible agonists to irreversible agonists was demonstrated.