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Objective: Obesity is associated with alterations in corticolimbic-striatal brain regions involved in food motivation and reward. Stress and the presence of food cues may each motivate eating and engage corticolimibic-striatal neurocircuitry. It is unknown how these factors interact to influence brain responses and whether these interactions are influenced by obesity, insulin levels, and insulin sensitivity. We hypothesized that obese individuals would show greater responses in corticolimbic-striatal neurocircuitry after exposure to stress and food cues and that brain activations would correlate with subjective food craving, insulin levels, and HOMA-IR.Research Design and Methods: Fasting insulin levels were assessed in obese and lean subjects who were exposed to individualized stress and favorite-food cues during functional MRI.Results: Obese, but not lean, individuals exhibited increased activation in striatal, insular, and hypothalamic regions during exposure to favorite-food and stress cues. In obese but not lean individuals, food craving, insulin, and HOMA-IR levels correlated positively with neural activity in corticolimbic-striatal brain regions during favorite-food and stress cues. The relationship between insulin resistance and food craving in obese individuals was mediated by activity in motivation-reward regions including the striatum, insula, and thalamus.Conclusions: These findings demonstrate that obese, but not lean, individuals exhibit increased corticolimbic-striatal activation in response to favorite-food and stress cues and that these brain responses mediate the relationship between HOMA-IR and food craving. Improving insulin sensitivity and in turn reducing corticolimbic-striatal reactivity to food cues and stress may diminish food craving and affect eating behavior in obesity. [ABSTRACT FROM AUTHOR]

The obesity epidemic has unfolded in a matter of decades, not millennia, and therefore cannot be attributed to a drift in the genome. Rather, the temporal characteristics of the epidemic more closely track environmental and lifestyle changes, such as reduced physical activity, increased availability of palatable and energy-dense foods and drinks, and increased acceptance of eating outside of meal time (among others). One important observation is that not everyone is becoming obese. This suggests that individual factors interact with recent environmental changes to predispose some to overeat. One hypothesis that has been gaining traction in the neuroscience community is that individual differences in the neural encoding of foods may predispose some to overeat in the presence of a surplus of energy-dense, palatable foods and drinks. The aim of this review is to highlight several possible ways by which individual differences in the neurophysiology of food reward may lead to overeating. [ABSTRACT FROM AUTHOR]

Radiotherapy (RT) treatment is an important strategy for the management of non-small cell lung cancer (NSCLC). Local recurrence amongst patients with late-stage NSCLC remains a challenge. The loss of PTEN has been associated with radio-resistance. This study aimed to examine the efficacy of RT combined with ataxia telangiectasia-mutated Rad3-related (ATR) inhibition using Ceralasertib in phosphatase and tensin homolog (PTEN)-depleted NSCLC cells and to assess early inflammatory responses indicative of radiation pneumonitis (RP) after combined-modality treatment. Small hairpin RNA (shRNA) transfections were used to generate H460 and A549 PTEN-depleted models. Ceralasertib was evaluated as a single agent and in combination with RT in vitro and in vivo. Histological staining was used to assess immune cell infiltration in pneumonitis-prone C3H/NeJ mice. Here, we report that the inhibition of ATR in combination with RT caused a significant reduction in PTEN-depleted NSCLC cells, with delayed DNA repair and reduced cell viability, as shown by an increase in cells in Sub G1. Combination treatment in vivo significantly inhibited H460 PTEN-depleted tumour growth in comparison to H460 non-targeting PTEN-expressing (NT) cell-line-derived xenografts (CDXs). Additionally, there was no significant increase in infiltrating macrophages or neutrophils except at 4 weeks, whereby combination treatment significantly increased macrophage levels relative to RT alone. Overall, our study demonstrates that ceralasertib and RT combined preferentially sensitises PTEN-depleted NSCLC models in vitro and in vivo, with no impact on early inflammatory response indicative of RP. These findings provide a rationale for evaluating ATR inhibition in combination with RT in NSCLC patients with PTEN mutations.

LF is a bioactive protein, derived from colostrum and milk that has been found to possess various immunomodulatory, iron chelating, and antimicrobial properties, especially in its apo-form. Recent studies have demonstrated the functionality of LF in attaching to the S proteins of SARS-CoV-2, thereby preventing it from interacting with the ACE-2 receptor. However, the molecular mechanism mediating the process is poorly understood. In this study, molecular docking and MD simulations coupled with free energy calculations were applied to elucidate the key interaction of apo-LF and its N-lobe and C-lobe derivative forms with the RBD of coronavirus S proteins. This has also been extended into evaluating the L452R mutant, which is associated with the delta variant of SARS-CoV-2. The results demonstrate the efficacy of the apo-LF C-lobe in binding to the RBD of both variants, primarily through electrostatic attractions between the acidic residues of the former and the basic residues of each RBD. Furthermore, due to the additional arginine in the L452R variant, the interaction between the C-lobe and the latter is stronger, resulting in a more favourable binding and tightly bound structure. The simulations highlight that the C-lobe, followed by full-length apo-LF can form a multimeric complex with the RBD of SARS-CoV-2, indicating their potential use as novel therapeutics, particularly the cleaved C-lobe of apo-LF to disrupt the S proteins from binding to the host ACE-2 receptor.Communicated by Ramaswamy H. Sarma.

It is well-known that food-cue reactivity (FCR) is positively associated with body mass index (BMI) 1 and weight change 2 , but the mechanisms underlying these relationships are incompletely understood. One prominent theory of craving posits that the elaboration of a desired substance through sensory imagery intensifies cravings, thereby promoting consumption 3 . Olfaction is integral to food perception, yet the ability to imagine odours varies widely 4 . Here we test in a basic observational study whether this large variation in olfactory imagery drives FCR strength to promote adiposity in 45 adults (23 male). We define odour-imagery ability as the extent to which imagining an odour interferes with the detection of a weak incongruent odour (the 'interference effect' 5 ). As predicted in our preregistration, the interference effect correlates with the neural decoding of imagined, but not real, odours. These perceptual and neural measures of odour imagery are in turn associated with FCR, defined by the rated craving intensity of liked foods and cue-potentiated intake. Finally, odour imagery exerts positive indirect effects on changes in BMI and body-fat percentage over one year via its influences on FCR. These findings establish odour imagery as a driver of FCR that in turn confers risk for weight gain., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: A large body of evidence highlights the importance of genetic variants in the development of psychiatric and metabolic conditions. Among these, the TaqIA polymorphism is one of the most commonly studied in psychiatry. TaqIA is located in the gene that codes for the ankyrin repeat and kinase domain containing 1 kinase (Ankk1) near the dopamine D 2 receptor (D2R) gene. Homozygous expression of the A1 allele correlates with a 30% to 40% reduction of striatal D2R, a typical feature of addiction, overeating, and other psychiatric pathologies. The mechanisms by which the variant influences dopamine signaling and behavior are unknown., Methods: Here, we used transgenic and viral-mediated strategies to reveal the role of Ankk1 in the regulation of activity and functions of the striatum., Results: We found that Ankk1 is preferentially enriched in striatal D2R-expressing neurons and that Ankk1 loss of function in the dorsal and ventral striatum leads to alteration in learning, impulsivity, and flexibility resembling endophenotypes described in A1 carriers. We also observed an unsuspected role of Ankk1 in striatal D2R-expressing neurons of the ventral striatum in the regulation of energy homeostasis and documented differential nutrient partitioning in humans with or without the A1 allele., Conclusions: Overall, our data demonstrate that the Ankk1 gene is necessary for the integrity of striatal functions and reveal a new role for Ankk1 in the regulation of body metabolism., (Copyright © 2023 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Western diets rich in fat and sugar promote excess calorie intake and weight gain; however, the underlying mechanisms are unclear. Despite a well-documented association between obesity and altered brain dopamine function, it remains elusive whether these alterations are (1) pre-existing, increasing the individual susceptibility to weight gain, (2) secondary to obesity, or (3) directly attributable to repeated exposure to western diet. To close this gap, we performed a randomized, controlled study (NCT05574660) with normal-weight participants exposed to a high-fat/high-sugar snack or a low-fat/low-sugar snack for 8 weeks in addition to their regular diet. The high-fat/high-sugar intervention decreased the preference for low-fat food while increasing brain response to food and associative learning independent of food cues or reward. These alterations were independent of changes in body weight and metabolic parameters, indicating a direct effect of high-fat, high-sugar foods on neurobehavioral adaptations that may increase the risk for overeating and weight gain., Competing Interests: Declaration of interests O.A.C. reports grants or contracts from Amplyx, Basilea, BMBF, Cidara, DZIF, EU-DG RTD (101037867), F2G, Gilead, Matinas, MedPace, MSD, Mundipharma, Octapharma, Pfizer, and Scynexis; consulting fees from Abbvie, Amplyx, Biocon, Biosys, Cidara, Da Volterra, Gilead, Matinas, MedPace, Menarini, Molecular Partners, MSG-ERC, Noxxon, Octapharma, Pardes, PSI, Scynexis, and Seres; honoraria for lectures from Abbott, Al-Jazeera Pharmaceuticals, Astellas, Grupo Biotoscana/United Medical/Knight, Hikma, MedScape, MedUpdate, Merck/MSD, Mylan, and Pfizer; payment for expert testimony from Cidara; participation on a data safety monitoring board or advisory board for Actelion, Allecra, Cidara, Entasis, IQVIA, Janssen, MedPace, Paratek, PSI, Pulmocide, and Shionogi; a patent at the German Patent and Trade Mark Office (DE 10 2021 113 007.7)., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: Recent work has reported a negative association between BMI and performance on the Penn Line Orientation Task. To determine the reliability of this effect, a comprehensive assessment of visual function in individuals with healthy weight (HW) and those with overweight/obesity (OW/OB) was performed., Methods: Visual acuity/contrast, Penn Line Orientation Task, and higher-order visuospatial function were measured in 80 (40 with HW, 40 with OW/OB) case-control study participants. Adiposity, fasting glucose, hemoglobin A1c, diet, physical activity, and heart rate variability were also assessed. A subgroup of 22 participants plus 5 additional participants (n = 27) underwent functional magnetic resonance imaging scanning., Results: Compared with those with HW, individuals with OW/OB performed worse on tasks requiring judgments of line orientation. This effect was mediated by body fat percentage and was unrelated to other measures. Functional magnetic resonance imaging revealed a negative association between BMI and response in the primary visual cortex (V1) during line orientation judgment. Performance was unrelated to V1 response but positively correlated with response in a network of regions, including the lateral occipital cortex, when BMI was accounted for in the model., Conclusions: These results demonstrate a selective deficit in line orientation perception associated with adiposity and blunted activation in the V1 that cannot be attributed to visual acuity and does not generalize to other visuospatial tasks., (© 2022 The Authors. Obesity published by Wiley Periodicals LLC on behalf of The Obesity Society.)

Lactoferrin is a protein, primarily found in milk that has attracted the interest of the food industries due to its health properties. Nevertheless, the instability of lactoferrin has limited its commercial application. Recent studies have focused on encapsulation to enhance the stability of lactoferrin. However, the molecular insights underlying the changes of structural properties of lactoferrin and the interaction with protectants remain poorly understood. Computational approaches have proven useful in understanding the structural properties of molecules and the key binding with other constituents. In this review, comprehensive information on the structure and function of lactoferrin and the binding with various molecules for food purposes are reviewed, with a special emphasis on the use of molecular dynamics simulations. The results demonstrate the application of modeling and simulations to determine key residues of lactoferrin responsible for its stability and interactions with other biomolecular components under various conditions, which are also associated with its functional benefits. These have also been extended into the potential creation of enhanced lactoferrin for commercial purposes. This review provides valuable strategies in designing novel nutraceuticals for food science practitioners and those who have interests in acquiring familiarity with the application of computational modeling for food and health purposes.

The role of olfaction in eating behavior and body weight regulation is controversial. Here we reanalyzed data from a previous functional magnetic resonance imaging study to test whether central olfactory coding is associated with hunger/satiety state, food intake, and change in body weight over one year in healthy human adults. Since odor quality and category are coded across distributed neural patterns that are not discernible with traditional univariate analyses, we used multi-voxel pattern analyses to decode patterns of brain activation to food versus nonfood odors. We found that decoding accuracies in the piriform cortex and amygdala were greater in the sated compared to hungry state. Sated decoding accuracies in these and other regions were also associated with post-scan ad libitum food intake, but not with weight change. These findings demonstrate that the fidelity of olfactory decoding is influenced by meal consumption and is associated with immediate food intake, but not longer-term body weight regulation., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2022. Published by Elsevier Ltd.)

Objective: Stroma-rich tumours represent a poor prognostic subtype in stage II/III colon cancer (CC), with high relapse rates and limited response to standard adjuvant chemotherapy., Design: To address the lack of efficacious therapeutic options for patients with stroma-rich CC, we stratified our human tumour cohorts according to stromal content, enabling identification of the biology underpinning relapse and potential therapeutic vulnerabilities specifically within stroma-rich tumours that could be exploited clinically. Following human tumour-based discovery and independent clinical validation, we use a series of in vitro and stroma-rich in vivo models to test and validate the therapeutic potential of elevating the biology associated with reduced relapse in human tumours., Results: By performing our analyses specifically within the stroma-rich/high-fibroblast (HiFi) subtype of CC, we identify and validate the clinical value of a HiFi-specific prognostic signature (HPS), which stratifies tumours based on STAT1-related signalling (High-HPS v Low-HPS=HR 0.093, CI 0.019 to 0.466). Using in silico, in vitro and in vivo models, we demonstrate that the HPS is associated with antigen processing and presentation within discrete immune lineages in stroma-rich CC, downstream of double-stranded RNA and viral response signalling. Treatment with the TLR3 agonist poly(I:C) elevated the HPS signalling and antigen processing phenotype across in vitro and in vivo models. In an in vivo model of stroma-rich CC, poly(I:C) treatment significantly increased systemic cytotoxic T cell activity (p<0.05) and reduced liver metastases (p<0.0002)., Conclusion: This study reveals new biological insight that offers a novel therapeutic option to reduce relapse rates in patients with the worst prognosis CC., Competing Interests: Competing interests: ML has received honoraria from Pfizer, EMF Serono and Roche for presentations unrelated to this work; ML has received an unrestricted educational grant from Pfizer for research unrelated to this work. PT has received honoraria and travel expenses from BMS, Merck, Roche, Lilly and Sanofi-Aventis for contributions that are not related to the present work. The authors declare no other potential conflicts of interest., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Secretory leucoprotease inhibitor (SLPI) has multifaceted functions, including inhibition of protease activity, antimicrobial functions, and anti-inflammatory properties. In this study, we show that SLPI plays a role in controlling pulmonary Pseudomonas aeruginosa infection. Mice lacking SLPI were highly susceptible to P. aeruginosa infection, however there was no difference in bacterial burden. Utilising a model of P. aeruginosa LPS-induced lung inflammation, human recombinant SLPI (hrSLPI) administered intraperitoneally suppressed the recruitment of inflammatory cells in the bronchoalveolar lavage fluid (BALF) and resulted in reduced BALF and serum levels of inflammatory cytokines and chemokines. This anti-inflammatory effect of hrSLPI was similarly demonstrated in a systemic inflammation model induced by intraperitoneal injection of LPS from various bacteria or lipoteichoic acid, highlighting the broad anti-inflammatory properties of hrSLPI. Moreover, in bone-marrow-derived macrophages, hrSLPI reduced LPS-induced phosphorylation of p-IkB-α, p-IKK-α/β, p-P38, demonstrating that the anti-inflammatory effect of hrSLPI was due to the inhibition of the NFκB and MAPK pathways. In conclusion, administration of hrSLPI attenuates excessive inflammatory responses and is therefore, a promising strategy to target inflammatory diseases such as acute respiratory distress syndrome or sepsis and could potentially be used to augment antibiotic treatment.

Importance: Major depressive disorder (MDD) is characterized by a substantial burden on health, including changes in appetite and body weight. Heterogeneity of depressive symptoms has hampered the identification of biomarkers that robustly generalize to most patients, thus calling for symptom-based mapping., Objective: To define the functional architecture of the reward circuit subserving increases vs decreases in appetite and body weight in patients with MDD by specifying their contributions and influence on disease biomarkers using resting-state functional connectivity (FC)., Design, Setting, and Participants: In this case-control study, functional magnetic resonance imaging (fMRI) data were taken from the Marburg-Münster FOR 2107 Affective Disorder Cohort Study (MACS), collected between September 2014 and November 2016. Cross-sectional data of patients with MDD (n = 407) and healthy control participants (n = 400) were analyzed from March 2018 to June 2022., Main Outcomes and Measures: Changes in appetite during the depressive episode and their association with FC were examined using fMRI. By taking the nucleus accumbens (NAcc) as seed of the reward circuit, associations with opposing changes in appetite were mapped, and a sparse symptom-specific elastic-net model was built with 10-fold cross-validation., Results: Among 407 patients with MDD, 249 (61.2%) were women, and the mean (SD) age was 36.79 (13.4) years. Reduced NAcc-based FC to the ventromedial prefrontal cortex (vmPFC) and the hippocampus was associated with reduced appetite (vmPFC: bootstrap r = 0.13; 95% CI, 0.02-0.23; hippocampus: bootstrap r = 0.15; 95% CI, 0.05-0.26). In contrast, reduced NAcc-based FC to the insular ingestive cortex was associated with increased appetite (bootstrap r = -0.14; 95% CI, -0.24 to -0.04). Critically, the cross-validated elastic-net model reflected changes in appetite based on NAcc FC and explained variance increased with increasing symptom severity (all patients: bootstrap r = 0.24; 95% CI, 0.16-0.31; patients with Beck Depression Inventory score of 28 or greater: bootstrap r = 0.42; 95% CI, 0.25-0.58). In contrast, NAcc FC did not classify diagnosis (MDD vs healthy control)., Conclusions and Relevance: In this study, NAcc-based FC reflected important individual differences in appetite and body weight in patients with depression that can be leveraged for personalized prediction. However, classification of diagnosis using NAcc-based FC did not exceed chance levels. Such symptom-specific associations emphasize the need to map biomarkers onto more confined facets of psychopathology to improve the classification and treatment of MDD.

Background: Current therapies for obesity treatment are effective at producing short-term weight loss, but weight loss maintenance remains a significant challenge. Here we investigate the impact of pre-intervention dietary fat intake on the efficacy of a dietary supplement to support weight loss maintenance. Preclinical work demonstrates that a vagal afferent pathway critical for sensing dietary lipids is blunted by a high-fat diet (HFD), resulting in a reduced preference for a low-fat emulsion and severe blunting of the dopamine (DA) response to the gastric infusion of lipids. Infusion of the gut lipid messenger oleoylethanolamide (OEA), which is also depleted by HFD, immediately reverses this DA blunting and restores preference for the low-fat emulsion. Studies of OEA supplementation for weight loss in humans have had limited success. Given the strong effect of HFD on this pathway, we designed a study to test whether the efficacy of OEA as a weight loss treatment is related to pre-intervention habitual intake of dietary fat., Methods/design: We employed a randomized, double-blind, placebo-controlled trial in which 100 adults with overweight/obesity (OW/OB) were randomized to receive either OEA or placebo daily for 16 months. Following a baseline evaluation of diet, metabolic health, adiposity, and brain response to a palatable an energy dense food, participants in both groups underwent a 4-month behavioral weight loss intervention (LEARN ® ) followed by a 1-year maintenance period. The study aims are to (1) determine if pre-intervention dietary fat intake moderates the ability of OEA to improve weight loss and weight loss maintenance after a gold standard behavioral weight loss treatment; (2) identify biomarkers that predict outcome and optimize a stratification strategy; and (3) test a model underlying OEA's effectiveness., Discussion: Focusing on interventions that target the gut-brain axis is supported by mounting evidence for the role of gut-brain signaling in food choice and the modulation of this circuit by diet. If successful, this work will provide support for targeting the gut-brain pathway for weight loss maintenance using a precision medicine approach that is easy and inexpensive to implement., Clinical Trial Registration: [www.ClinicalTrials.gov], identifier [NCT04614233]., 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 Fang, Davis, Flack, Duncan, Li, White, Grilo and Small.)

Rationale: Although the cysteine protease cathepsin S has been implicated in the pathogenesis of several inflammatory lung diseases, its role has not been examined in the context of acute respiratory distress syndrome, a condition that still lacks specific and effective pharmacological treatments. Objectives: To characterize the status of cathepsin S in acute lung inflammation and examine the role of cathepsin S in disease pathogenesis. Methods: Human and mouse model BAL fluid samples were analyzed for the presence and activity of cathepsin S and its endogenous inhibitors. Recombinant cathepsin S was instilled directly into the lungs of mice. The effects of cathepsin S knockout and pharmacological inhibition were examined in two models of acute lung injury. Protease-activated receptor-1 antagonism was used to test a possible mechanism for cathepsin S-mediated inflammation. Measurements and Main Results: Pulmonary cathepsin S concentrations and activity were elevated in acute respiratory distress syndrome, a phenotype possibly exacerbated by the loss of the endogenous antiprotease cystatin SN. Direct cathepsin S instillation into the lungs induced key pathologies of acute respiratory distress syndrome, including neutrophilia and alveolar leakage. Conversely, in murine models of acute lung injury, genetic knockdown and prophylactic or therapeutic inhibition of cathepsin S reduced neutrophil recruitment and protein leakage. Cathepsin S may partly mediate its pathogenic effects via protease-activated receptor-1, because antagonism of this receptor abrogated cathepsin S-induced airway inflammation. Conclusions: Cathepsin S contributes to acute lung injury and may represent a novel therapeutic target for acute respiratory distress syndrome.

Optogenetic effectors and sensors provide a novel real-time window into complex physiological processes, enabling determination of molecular signaling processes within functioning cellular networks. However, the combination of these optical tools in mice is made practical by construction of genetic lines that are optically compatible and genetically tractable. We present a new toolbox of 21 mouse lines with lineage-specific expression of optogenetic effectors and sensors for direct biallelic combination, avoiding the multiallelic requirement of Cre recombinase -mediated DNA recombination, focusing on models relevant for cardiovascular biology. Optogenetic effectors (11 lines) or Ca 2+ sensors (10 lines) were selectively expressed in cardiac pacemaker cells, cardiomyocytes, vascular endothelial and smooth muscle cells, alveolar epithelial cells, lymphocytes, glia, and other cell types. Optogenetic effector and sensor function was demonstrated in numerous tissues. Arterial/arteriolar tone was modulated by optical activation of the second messengers InsP 3 (optoα1AR) and cAMP (optoß2AR), or Ca 2+ -permeant membrane channels (CatCh2) in smooth muscle ( Acta2 ) and endothelium ( Cdh5 ). Cardiac activation was separately controlled through activation of nodal/conducting cells or cardiac myocytes. We demonstrate combined effector and sensor function in biallelic mouse crosses: optical cardiac pacing and simultaneous cardiomyocyte Ca 2+ imaging in Hcn4 BAC -CatCh2/ Myh6 -GCaMP8 crosses. These experiments highlight the potential of these mice to explore cellular signaling in vivo, in complex tissue networks., Competing Interests: FL, JL, BS, SR, MJ, DS, JJ, NA, ML, MR, ST, MN, LS, NN, MK No competing interests declared, (© 2021, Lee et al.)

The abundance of energy-dense and palatable diets in the modern food environment tightly contributes to the obesity pandemic. The reward circuit participates to the regulation of body homeostasis by integrating energy-related signals with neural substrates encoding cognitive and motivational components of feeding behaviors. Obesity and lipid-rich diets alter dopamine (DA) transmission leading to reward dysfunctions and food overconsumption. Recent reports indicate that dietary lipids can act, directly and indirectly, as functional modulators of the DA circuit. This raises the possibility that nutritional or genetic conditions affecting 'lipid sensing' mechanisms might lead to maladaptations of the DA system. Here, we discuss the most recent findings connecting dietary lipid sensing with DA signaling and its multimodal influence on circuits regulating food-reward processes., Competing Interests: Declaration of interests The authors declare no conflicts of interest., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Prior work suggests that actual, but not estimated, energy density drives the reinforcing value of food and that energy from fat and carbohydrate can interact to potentiate reward. Here we sought to replicate these findings in an American sample and to determine if the effects are influenced by body mass index (BMI). Thirty participants with healthy weight (HW; BMI 21.92 ± 1.77; M ± SD ) and 30 participants with overweight/obesity (OW/OB; BMI 29.42 ± 4.44) rated pictures of common American snacks in 120-kcal portions for liking, familiarity, frequency of consumption, expected satiety, healthiness, energy content, energy density, and price. Participants then completed an auction task where they bid for the opportunity to consume each food. Snacks contained either primarily carbohydrate, primarily fat, or roughly equal portions of fat and carbohydrate (combo). Replicating prior work, we found that participants with HW bid the most for combo foods in linear mixed model analyses. This effect was not observed among individuals with OW/OB. Additionally, in contrast with previous reports, our linear regression analyses revealed a negative relationship between the actual energy density of the snacks and bid amount that was mediated by food price. Our findings support altered macronutrient reinforcement in obesity and highlight potential influences of the food environment on the regulation of food reward.

Emerging evidence suggests that fat and carbohydrate interact to potentiate the reward value of food (DiFeliceantonio et al., 2018). The primary goal of the current study was to develop a novel picture set to facilitate research into the effects of macronutrient composition on food choice and eating behavior. Toward this aim, we developed "MacroPics." In Experiment 1, we photographed 120-kcal portions of 60 snack foods falling into one of the three macronutrient categories: (1) mostly carbohydrate, (2) mostly fat, or (3) a combination of fat and carbohydrate. Sixty-one participants rated the images for liking, familiarity, frequency of consumption, healthiness, estimated energy content (in kcal), and expected satiation. A subset of these images consisting of 36 items was then selected in an iterative process to minimize differences in ratings between the macronutrient categories while simultaneously ensuring similar within-category variability on a number of food characteristics (e.g., energy density, portion size, retail price) and visual properties (e.g., color, complexity, visual area). In Experiment 2, an independent sample of 67 participants rated the pictures of the final 36-item MacroPics. Both experiments reveal similar participant ratings across categories for item liking, familiarity, frequency, healthiness, and estimated energy content. Protein content was higher in the fat compared to the carbohydrate and combination categories, leading to higher ratings of estimated satiety and energy density for fatty foods. Item and macronutrient category characteristics of the final MacroPics set are reported., (Copyright © 2020. Published by Elsevier Ltd.)

Background: Elevated levels of the cysteine protease cathepsin S (CatS) are associated with chronic mucoobstructive lung diseases such as cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD). We have previously demonstrated that prophylactic treatment with a CatS inhibitor from birth reduces inflammation, mucus plugging, and lung tissue damage in juvenile β -epithelial Na+ channel-overexpressing transgenic ( β ENaC-Tg) mice with chronic inflammatory mucoobstructive lung disease. In this study, we build upon this work to examine the effects of therapeutic intervention with a CatS inhibitor in adult β ENaC-Tg mice with established disease., Methods: β ENaC-Tg mice and wild-type (WT) littermates were treated with a CatS inhibitor from 4 to 6 weeks of age, and CatS -/- β ENaC-Tg mice were analysed at 6 weeks of age. Bronchoalveolar lavage (BAL) fluid inflammatory cell counts were quantified, and lung tissue destruction and mucus obstruction were analysed histologically., Results: At 6 weeks of age, β ENaC-Tg mice developed significant airway inflammation, lung tissue damage, and mucus plugging when compared to WT mice. CatS -/- β ENaC-Tg mice and β ENaC-Tg mice receiving inhibitor had significantly reduced airway mononuclear and polymorphonuclear (PMN) cell counts as well as mucus plugging. However, in contrast to CatS -/- β ENaC-Tg mice, therapeutic inhibition of CatS in β ENaC-Tg mice had no effect on established emphysema-like lung tissue damage., Conclusions: These results suggest that while early CatS targeting may be required to prevent the onset and progression of lung tissue damage, therapeutic CatS targeting effectively inhibited airway inflammation and mucus obstruction. These results indicate the important role CatS may play in the pathogenesis and progression of mucoobstructive lung disease., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2021 Ryan Brown et al.)

Introduction: Healthcare workers (HCW) treating COVID-19 patients are at high risk for infection and may also spread infection through their contact with vulnerable patients. Smell loss has been associated with SARS-CoV-2 infection, but it is unknown whether monitoring for smell loss can be used to identify asymptomatic infection among high risk individuals. In this study we sought to determine if tracking smell sensitivity and loss using an at-home assessment could identify SARS-CoV-2 infection in HCW., Methods and Findings: We performed a prospective cohort study tracking 473 HCW across three months to determine if smell loss could predict SARS-CoV-2 infection in this high-risk group. HCW subjects completed a longitudinal, behavioral at-home assessment of olfaction with household items, as well as detailed symptom surveys that included a parosmia screening questionnaire, and real-time quantitative polymerase chain reaction testing to identify SARS-CoV-2 infection. Our main measures were the prevalence of smell loss in SARS-CoV-2-positive HCW versus SARS-CoV-2-negative HCW, and timing of smell loss relative to SARS-CoV-2 test positivity. SARS-CoV-2 was identified in 17 (3.6%) of 473 HCW. HCW with SARS-CoV-2 infection were more likely to report smell loss than SARS-CoV-2-negative HCW on both the at-home assessment and the screening questionnaire (9/17, 53% vs 105/456, 23%, P < .01). 6/9 (67%) of SARS-CoV-2-positive HCW reporting smell loss reported smell loss prior to having a positive SARS-CoV-2 test, and smell loss was reported a median of two days before testing positive. Neurological symptoms were reported more frequently among SARS-CoV-2-positive HCW who reported smell loss compared to those without smell loss (9/9, 100% vs 3/8, 38%, P < .01)., Conclusions: In this prospective study of HCW, self-reported changes in smell using two different measures were predictive of SARS-CoV-2 infection. Smell loss frequently preceded a positive test and was associated with neurological symptoms., Competing Interests: The authors have declared that no competing interests exist.

Olfactory impairment after a traumatic impact to the head is associated with changes in olfactory cortex, including decreased gray matter density and decreased BOLD response to odors. Much less is known about the role of other cortical areas in olfactory impairment. We used fMRI in a sample of 63 participants, consisting of 25 with post-traumatic functional anosmia, 16 with post-traumatic hyposmia, and 22 healthy controls with normosmia to investigate whole brain response to odors. Similar neural responses were observed across the groups to odor versus odorless stimuli in the primary olfactory areas in piriform cortex, whereas response in the frontal operculum and anterior insula (fO/aI) increased with olfactory function (normosmia > hyposmia > functional anosmia). Unexpectedly, a negative association was observed between response and olfactory perceptual function in the mediodorsal thalamus (mdT), ventromedial prefrontal cortex (vmPFC) and posterior cingulate cortex (pCC). Finally, connectivity within a network consisting of vmPFC, fO, and pCC could be used to successfully classify participants as having functional anosmia or normosmia. We conclude that, at the neural level, olfactory impairment due to head trauma is best characterized by heightened responses and differential connectivity in higher-order areas beyond olfactory cortex.

Experimental evidence suggests a crucial role of the autonomic nervous system in whole body metabolism with major regulatory effects of the parasympathetic branch in postprandial adaptation. However, the relative contribution of this mechanism is still not fully clear in humans. We therefore compared the effects of transcutaneous auricular vagus nerve stimulation (taVNS, Cerbomed Nemos) with sham stimulation during an oral glucose tolerance test in a randomized, single-blind, cross-over design in 15 healthy lean men. Stimulation was performed for 150 min, 30 min before and during the entire oral glucose tolerance test with stimulation cycles of 30 s of on-phase and 30 s of off-phase and a 25 Hz impulse. Heart rate variability and plasma catecholamine levels were assessed as proxies of autonomic tone in the periphery. Neither analyzed heart rate variability parameters nor plasma catecholamine levels were significantly different between the two conditions. Plasma glucose, insulin sensitivity and insulin secretion were also comparable between conditions. Thus, the applied taVNS device or protocol was unable to achieve significant effects on autonomic innervation in peripheral organs. Accordingly, glucose metabolism remained unaltered. Therefore, alternative approaches are necessary to investigate the importance of the autonomic nervous system in postprandial human metabolism.

Reinforcement learning guides food decisions, yet how the brain learns from taste in humans is not fully understood. Existing research examines reinforcement learning from taste using passive condition paradigms, but response-dependent instrumental conditioning better reflects natural eating behavior. Here, we examined brain response during a taste-motivated reinforcement learning task and how measures of task-based network structure were related to behavioral outcomes. During a functional MRI scan, 85 participants completed a probabilistic selection task with feedback via sweet taste or bitter taste. Whole brain response and functional network topology measures, including identification of communities and community segregation, were examined during choice, sweet taste, and bitter taste conditions. Relative to the bitter taste, sweet taste was associated with increased whole brain response in the hippocampus, oral somatosensory cortex, and orbitofrontal cortex. Sweet taste was also related to differential community assignment of the ventromedial prefrontal cortex and ventrolateral prefrontal cortex compared to bitter taste. During choice, increasing segregation of a community containing the amygdala, hippocampus, and right fusiform gyrus was associated with increased sensitivity to punishment on the task's posttest. Further, normal BMI was associated with differential community structure compared to overweight and obese BMI, where high BMI reflected increased connectivity of visual regions. Together, results demonstrate that network topology of learning and memory regions during choice is related to avoiding a bitter taste, and that BMI is associated with increased connectivity of area involved in processing external stimuli. Network organization and topology provide unique insight into individual differences in brain response to instrumental conditioning via taste reinforcers., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: There is increased interest in the food, pharmaceutical and cosmetic industries in using ascorbic acid as an important component in the human diet for health support and disease prevention. However, its use as an ingredient is limited by its high instability and sensitivity to environmental conditions. Microencapsulation technology has been proposed to increase the stability of ascorbic acid. The aim this work was to evaluate the effect of ascorbic acid loading rate on the physicochemical properties of encapsulated ascorbic acid. Loading contents of ascorbic acid of 6%, 9%, 18%, 36%, 54% and 72% were trialled using spray drying in conjunction with starch-based encapsulating agents., Results: The results showed that the loading content has a significant effect on ascorbic acid retention, yield, moisture content, water activity, colour change, particle size and distribution of microcapsules. Morphology of microcapsules also was assessed using environmental scanning electron microscopy, showing that the microcapsules had good structure and integrity for a loading content of 18% and even as high as 54%. At levels beyond this, capsules showed a lack of coherence and integrity of the outer shell., Conclusions: The results indicated that ascorbic acid microparticles at various loading rates have a substantial impact on physical and chemical properties of microcapsules. Loading content can be selected to ensure colour uniformity and minimal effects on colour during food fortification processes. © 2020 Society of Chemical Industry., (© 2020 Society of Chemical Industry.)

The brain plays a central role in the pathophysiology of overweight and obesity. Connectome-based Predictive Modeling (CPM) is a newly developed, data-driven approach that exploits whole-brain functional connectivity to predict a behavior or trait that varies across individuals. We used CPM to determine whether brain "fingerprints" evoked during milkshake consumption could be isolated for common measures of adiposity in 67 adults with overweight and obesity. We found that CPM captures more variance in waist circumference than either percent body fat or BMI, the most frequently used measures to assess brain correlates of obesity. In a post-hoc analysis, we were also able to derive a largely separable functional connectivity network predicting fasting blood insulin. These findings suggest that, in individuals with overweight and obesity, brain network patterns may be more tightly coupled to waist circumference than BMI or percent body fat and that adiposity and glucose tolerance are associated with distinct maps, pointing to dissociable central pathophysiological phenotypes for obesity and diabetes., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Prevailing models of obesity posit that hedonic signals override homeostatic mechanisms to promote overeating in today's food environment. What researchers mean by "hedonic" varies considerably, but most frequently refers to an aggregate of appetitive events including incentive salience, motivation, reinforcement, and perceived pleasantness. Here we define hedonic as orosensory pleasure experienced during eating and set out to test whether there is a relationship between adiposity and the perceived pleasure of a palatable and energy-dense milkshake., Methods: The perceived liking, wanting, and intensity of two palatable and energy-dense milkshakes were assessed using the Labeled Hedonic Scale (1), visual analog scale (VAS), and Generalized Labeled Magnitude Scale (2) in 110 individuals ranging in body mass index (BMI) from 19.3 to 52.1 kg/m 2 . Waist circumference, waist-hip ratio, and percent body fat were also measured. Importantly, unlike the majority of prior studies, we attempted to standardize internal state by instructing participants to arrive to the laboratory neither hungry nor full and at least 1-h fasted. Data were analyzed with general linear and linear mixed effects models (GLMs). Hunger ratings were also examined prior to hedonic measurement and included as covariates in our analyses., Results: We identified a significant association between ratings of hunger and milkshake liking and wanting. By contrast, we found no evidence for a relationship between any measure of adiposity and ratings of milkshake liking, wanting, or intensity., Conclusions: We conclude that adiposity is not associated with the pleasure experienced during consumption of our energy-dense and palatable milkshakes. Our results provide further evidence against the hypothesis that heightened hedonic signals drive weight gain.

Peripheral sources of individual variation in taste intensity perception have been well described. The existence of a central source has been proposed but remains unexplored. Here we used functional magnetic resonance imaging in healthy human participants (20 women, 8 men) to evaluate the hypothesis that the amygdala exerts an inhibitory influence that affects the "gain" of the gustatory system during tasting. Consistent with the existence of a central gain mechanism (CGM), we found that central amygdala response was correlated with mean intensity ratings across multiple tastants. In addition, psychophysiological and dynamic causal modeling analyses revealed that the connection strength between inhibitory outputs from amygdala to medial dorsal and ventral posterior medial thalamus predicted individual differences in responsiveness to taste stimulation. These results imply that inhibitory inputs from the amygdala to the thalamus act as a CGM that influences taste intensity perception. SIGNIFICANCE STATEMENT Whether central circuits contribute to individual variation in taste intensity perception is unknown. Here we used functional magnetic resonance imaging in healthy human participants to identify an amygdala-thalamic circuit where network dynamics and connectivity strengths during tasting predict individual variation in taste intensity ratings. This finding implies that individual differences in taste intensity perception do not arise solely from variation in peripheral gustatory factors., (Copyright © 2020 the authors.)

Insulin acts on the CNS to modulate behaviour and systemic metabolism. Disturbances in brain insulin action represent a possible link between metabolic and cognitive health. Current findings from human research suggest that boosting central insulin action in the brain modulates peripheral metabolism, enhancing whole-body insulin sensitivity and suppressing endogenous glucose production. Moreover, central insulin action curbs food intake by reducing the salience of highly palatable food cues and increasing cognitive control. Animal models show that the mesocorticolimbic circuitry is finely tuned in response to insulin, driven mainly by the dopamine system. These mechanisms are impaired in people with obesity, which might increase their risk of developing type 2 diabetes and associated diseases. Overall, current findings highlight the role of insulin action in the brain and its consequences on peripheral metabolism and cognition. Hence, improving central insulin action could represent a therapeutic option for people at an increased risk of developing metabolic and cognitive diseases., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Chronic pain is a highly prevalent disease with poorly understood pathophysiology. In particular, the brain mechanisms mediating the transition from acute to chronic pain remain largely unknown. Here, we identify a subcortical signature of back pain. Specifically, subacute back pain patients who are at risk for developing chronic pain exhibit a smaller nucleus accumbens volume, which persists in the chronic phase, compared to healthy controls. The smaller accumbens volume was also observed in a separate cohort of chronic low-back pain patients and was associated with dynamic changes in functional connectivity. At baseline, subacute back pain patients showed altered local nucleus accumbens connectivity between putative shell and core, irrespective of the risk of transition to chronic pain. At follow-up, connectivity changes were observed between nucleus accumbens and rostral anterior cingulate cortex in the patients with persistent pain. Analysis of the power spectral density of nucleus accumbens resting-state activity in the subacute and chronic back pain patients revealed loss of power in the slow-5 frequency band (0.01 to 0.027 Hz) which developed only in the chronic phase of pain. This loss of power was reproducible across two cohorts of chronic low-back pain patients obtained from different sites and accurately classified chronic low-back pain patients in two additional independent datasets. Our results provide evidence that lower nucleus accumbens volume confers risk for developing chronic pain and altered nucleus accumbens activity is a signature of the state of chronic pain., Competing Interests: The authors declare no competing interest., (Copyright © 2020 the Author(s). Published by PNAS.)

Energy-dense food alters dopaminergic (DA) transmission in the mesocorticolimbic (MCL) system and can promote reward dysfunctions, compulsive feeding, and weight gain. Yet the mechanisms by which nutrients influence the MCL circuitry remain elusive. Here, we show that nutritional triglycerides (TGs), a conserved post-prandial metabolic signature among mammals, can be metabolized within the MCL system and modulate DA-associated behaviors by gating the activity of dopamine receptor subtype 2 (DRD2)-expressing neurons through a mechanism that involves the action of the lipoprotein lipase (LPL). Further, we show that in humans, post-prandial TG excursions modulate brain responses to food cues in individuals carrying a genetic risk for reduced DRD2 signaling. Collectively, these findings unveil a novel mechanism by which dietary TGs directly alter signaling in the reward circuit to regulate behavior, thereby providing a new mechanistic basis by which energy-rich diets may lead to (mal)adaptations in DA signaling that underlie reward deficit and compulsive behavior., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

There is a general consensus that overconsumption of sugar-sweetened beverages contributes to the prevalence of obesity and related comorbidities such as type 2 diabetes (T2D). Whether a similar relationship exists for no- or low-calorie "diet" drinks is a subject of intensive debate and controversy. Here, we demonstrate that consuming seven sucralose-sweetened beverages with, but not without, a carbohydrate over 10 days decreases insulin sensitivity in healthy human participants, an effect that correlates with reductions in midbrain, insular, and cingulate responses to sweet, but not sour, salty, or savory, taste as assessed with fMRI. Taste perception was unaltered and consuming the carbohydrate alone had no effect. These findings indicate that consumption of sucralose in the presence of a carbohydrate rapidly impairs glucose metabolism and results in longer-term decreases in brain, but not perceptual sensitivity to sweet taste, suggesting dysregulation of gut-brain control of glucose metabolism., Competing Interests: Declaration of Interests Authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Cardiovascular disease is the leading cause of worldwide mortality. Intravital microscopy has provided unprecedented insight into leukocyte biology by enabling the visualization of dynamic responses within living organ systems at the cell-scale. The heart presents a uniquely dynamic microenvironment driven by periodic, synchronous electrical conduction leading to rhythmic contractions of cardiomyocytes, and phasic coronary blood flow. In addition to functions shared throughout the body, immune cells have specific functions in the heart including tissue-resident macrophage-facilitated electrical conduction and rapid monocyte infiltration upon injury. Leukocyte responses to cardiac pathologies, including myocardial infarction and heart failure, have been well-studied using standard techniques, however, certain questions related to spatiotemporal relationships remain unanswered. Intravital imaging techniques could greatly benefit our understanding of the complexities of in vivo leukocyte behavior within cardiac tissue, but these techniques have been challenging to apply. Different approaches have been developed including high frame rate imaging of the beating heart, explantation models, micro-endoscopy, and mechanical stabilization coupled with various acquisition schemes to overcome challenges specific to the heart. The field of cardiac science has only begun to benefit from intravital microscopy techniques. The current focused review presents an overview of leukocyte responses in the heart, recent developments in intravital microscopy for the murine heart, and a discussion of future developments and applications for cardiovascular immunology., (Copyright © 2020 Allan-Rahill, Lamont, Chilian, Nishimura and Small.)

The conscious perception of the hedonic sensory properties of caloric foods is commonly believed to guide our dietary choices. Current and traditional models implicate the consciously perceived hedonic qualities of food as driving overeating, whereas subliminal signals arising from the gut would curb our uncontrolled desire for calories. Here we review recent animal and human studies that support a markedly different model for food reward. These findings reveal in particular the existence of subcortical body-to-brain neural pathways linking gastrointestinal nutrient sensors to the brain's reward regions. Unexpectedly, consciously perceptible hedonic qualities appear to play a less relevant, and mostly transient, role in food reinforcement. In this model, gut-brain reward pathways bypass cranial taste and aroma sensory receptors and the cortical networks that give rise to flavor perception. They instead reinforce behaviors independently of the cognitive processes that support overt insights into the nature of our dietary decisions.

Intravital microscopy is a powerful technique to observe dynamic processes with single-cell resolution in live animals. No intravital window has been developed for imaging the colon due to its anatomic location and motility, although the colon is a key organ where the majority of microbiota reside and common diseases such as inflammatory bowel disease, functional gastrointestinal disorders, and colon cancer occur. Here we describe an intravital murine colonic window with a stabilizing ferromagnetic scaffold for chronic imaging, minimizing motion artifacts while maximizing long-term survival by preventing colonic obstruction. Using this setup, we image fluorescently-labeled stem cells, bacteria, and immune cells in live animal colons. Furthermore, we image nerve activity via calcium imaging in real time to demonstrate that electrical sacral nerve stimulation can activate colonic enteric neurons. The simple implantable apparatus enables visualization of live processes in the colon, which will open the window to a broad range of studies.