Genetic Disruption of System xc-Mediated Glutamate Release from Astrocytes Increases Negative-Outcome Behaviors While Preserving Basic Brain Function in Rat.

The importance of neuronal glutamate to synaptic transmission throughout the brain illustrates the immense therapeutic potential and safety risks of targeting this system. Astrocytes also release glutamate, the clinical relevance of which is unknown as the range of brain functions reliant on signaling from these cells hasn't been fully established. Here, we investigated system xc- (Sxc), which is a glutamate release mechanism with an in vivo rodent expression pattern that is restricted to astrocytes. As most animals do not express Sxc, we first compared the expression and sequence of the obligatory Sxc subunit xCT among major classes of vertebrate species. We found xCT to be ubiquitously expressed and under significant negative selective pressure. Hence, Sxc likely confers important advantages to vertebrate brain function that may promote biological fitness. Next, we assessed brain function in male genetically modified rats (MSxc) created to eliminate Sxc activity. Unlike other glutamatergic mechanisms, eliminating Sxc activity was not lethal and didn't alter growth patterns, telemetry measures of basic health, locomotor activity, or behaviors reliant on simple learning. However, MSxc rats exhibited deficits in tasks used to assess cognitive behavioral control. In a pavlovian conditioned approach, MSxc rats approached a food-predicted cue more frequently than WT rats, even when this response was punished. In attentional set shifting, MSxc rats displayed cognitive inflexibility because of an increased frequency of perseverative errors. MSxc rats also displayed heightened cocaine-primed drug seeking. Hence, a loss of Sxc-activity appears to weaken control over nonreinforced or negative-outcome behaviors without altering basic brain function.SIGNIFICANCE STATEMENT Glutamate is essential to synaptic activity throughout the brain, which illustrates immense therapeutic potential and risk. Notably, glutamatergic mechanisms are expressed by most types of brain cells. Hence, glutamate likely encodes multiple forms of intercellular signaling. Here, we hypothesized that the selective manipulation of astrocyte to neuron signaling would alter cognition without producing widespread brain impairments. First, we eliminated activity of the astrocytic glutamate release mechanism, Sxc, in rat. This impaired cognitive flexibility and increased expression of perseverative, maladaptive behaviors. Notably, eliminating Sxc activity did not alter metrics of health or noncognitive brain function. These data add to recent evidence that the brain expresses cognition-specific molecular mechanisms that could lead to highly precise, safe medications for impaired cognition.

Ultrafast X-Ray Scattering Reveals Composite Amplitude Collective Mode in the Weyl Charge Density Wave Material (TaSe_{4})_{2}I.

We report ultrafast x-ray scattering experiments of the quasi-1D charge density wave (CDW) material (TaSe_{4})_{2}I following ultrafast infrared photoexcitation. From the time-dependent diffraction signal at the CDW sidebands we identify a 0.11 THz amplitude mode derived primarily from a transverse acoustic mode of the high-symmetry structure. From our measurements we determine that this mode interacts with the valence charge indirectly through another collective mode, and that the CDW system in (TaSe_{4})_{2}I has a composite nature supporting multiple dynamically active structural degrees of freedom.

Evaluating methods to create protein functionalized catanionic vesicles.

Catanionic surfactant vesicles (SVs) composed of sodium dodecylbenzenesulfonate (SDBS) and cetyltrimethylammonium tosylate (CTAT) have potential applications as targeted drug delivery systems, vaccine platforms, and diagnostic tools. To facilitate these applications, we evaluated various methods to attach proteins to the surface of SDBS/CTAT vesicles. Acid phosphatase from wheat germ was used as a model protein. Acid phosphatase was successfully conjugated to vesicles enriched with a Triton-X 100 derivative containing an unsaturated ester. Enzymatic activity of acid phosphatase attached to vesicles was assessed using an acid phosphatase assay. Results from the acid phosphatase assay indicated that 15 ± 3% of the attached protein remained functional but the presence of vesicles interferes with the assay. DLS and zeta potential results correlated with the protein functionalization studies. Acid phosphatase functionalized vesicles had an average diameter of 175 ± 85 nm and an average zeta potential of -61 ± 5 mV in PBS. As a control, vesicles enriched with Triton-X 100 were prepared and analyzed by DLS and zeta potential measurements. Triton X-100 enriched vesicles had an average diameter of 140 ± 67 nm and an average zeta potential of -49 ± 2 mV in PBS. Functionalizing the surface of SVs with proteins may be a key step in developing vesicle-based technologies. For drug delivery, antibodies could be used as targeting molecules; for vaccine formulation, functionalizing the surface with spike proteins may produce novel vaccine platforms.

Expanded ensemble predictions of absolute binding free energies in the SAMPL9 host-guest challenge.

As part of the SAMPL9 community-wide blind host-guest challenge, we implemented an expanded ensemble workflow to predict absolute binding free energies for 13 small molecules against pillar[6]arene. Notable features of our protocol include consideration of a variety of protonation and enantiomeric states for both host and guests, optimization of alchemical intermediates, and analysis of free energy estimates and their uncertainty using large numbers of simulation replicates performed using distributed computing. Our predictions of absolute binding free energies resulted in a mean absolute error of 2.29 kcal mol-1 and an R2 of 0.54. Overall, results show that expanded ensemble calculations using all-atom molecular dynamics simulations are a valuable and efficient computational tool in predicting absolute binding free energies.

Antibiotics for chronic pulmonary infection in children with a neurodisability (neurodevelopmental disorder).

BACKGROUND: 'Neurodisability' refers to a group of conditions that result primarily from a neurological problem (e.g. cerebral palsy), neuromuscular problem (e.g. a muscular dystrophy) or developmental problems (e.g. developmental impairment, Down syndrome). Children and young people with these conditions may have similar problems with mobility, feeding and airway clearance. Chest and breathing problems (including pulmonary infections) are commonly experienced by children and young people with neurodisabilities and are often a cause for them requiring hospital care. For those who are unable to completely clear their airway of secretions, or have frequent infections, pulmonary infections may not be able to be completely eradicated and therefore become chronic. It is unclear what treatment is best for children and young people in this position. OBJECTIVES: To assess the effectiveness and adverse effects of antibiotic treatment for chronic pulmonary infection in children and young people living with a neurodisability, including quality-of-life measures, effects on hospitalisation and healthcare contacts. SEARCH METHODS: We searched the Cochrane Airways Trials Register, Cochrane Acute Respiratory Infections Group Register of Trials (CARIGRT), Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (Ovid), Embase (Ovid), Cumulative Index to Nursing and Allied Health Literature (CINAHL), OpenGrey (www.opengrey.eu) and three trials registries up to 8 February 2022. Additionally, we identified related systematic reviews through Epistemonikos.org (8 February 2022) and searched reference lists of these. SELECTION CRITERIA: All randomised controlled trials of antibiotic therapy for chronic pulmonary infection in children and young people up to the age of 18 living with a neurodisability were eligible. DATA COLLECTION AND ANALYSIS: Two independent review authors screened results of the searches against predetermined inclusion criteria, resolving any discrepancies by discussion. MAIN RESULTS: We identified a total of 1968 independent records through our searches, of which we assessed six full-text articles for eligibility. We identified one ongoing study as well as one related substudy but did not identify any completed studies eligible for inclusion in this systematic review. AUTHORS' CONCLUSIONS: The findings of this systematic review highlight a lack of evidence in the antibiotic treatment of chronic pulmonary infection in children and young people up to the age of 18 living with a neurodisability. Further research examining this topic is therefore required.

Investigating relationships between post-prandial gut hormone responses and taste liking ratings prior to and following bariatric surgery: a pilot study.

BACKGROUND: Alterations in gut hormone secretion and reported changes in taste preferences have been suggested to contribute to the weight-reducing effects of bariatric surgery. However, a link between changes in gut hormone secretion and taste preferences following bariatric surgery has yet to be elucidated. METHODS: Here we examined the potential relationships between gut hormone responses (GLP-1 and PYY3-36 peak, ghrelin trough) to a test meal of Ensure and liking ratings for taste mixtures varying in sugar and fat content before and following bariatric surgery (vertical sleeve gastrectomy (VSG): N = 4; Roux-en Y gastric bypass (RYGB): N = 8). RESULTS: Significant increases in GLP-1 and PYY3-36 peak and a significant drop in ghrelin trough were observed following surgery. Pre- and postoperation, patients with higher postprandial GLP-1 or PYY3-36 peaks gave lower liking ratings for mixtures containing a combination of fat and sugar (half and half + 20% added sugar) whereas, for the combined surgery analyses, no relationships were found with solutions comprised of high fat (half and half + 0% sugar), predominantly high sugar (skim milk + 20% added sugar), or low fat and low sugar (skim milk + 0% added sugar). Within the RYGB patients, patients with the greatest increase in postprandial GLP-1 peak from preoperation to postoperation also demonstrated the greatest decrease in liking for half & half + 20% added sugar and skim milk + 20% added sugar, but not the unsweetened version of each solution. No pre- or postoperative relationship between ghrelin and liking ratings were observed. CONCLUSION: Gut hormone responses following bariatric surgery may contribute to taste processing of sugar+fat mixtures and together influence weight loss.

Adolescent female rats recovered from the activity-based anorexia display blunted hedonic responding.

OBJECTIVE: As patients with anorexia nervosa tend to "like" palatable tastants less than controls, we set out to model this preclinically by using the taste reactivity test (TRT) to assess hedonic state in rats following weight restoration from a bout of activity-based anorexia (ABA). METHOD: Female rats (n = 31) were surgically implanted with an intraoral catheter, which allowed experimenters to assess baseline TRT to six tastants. Following baseline TRT, animals were either exposed to the activity-based anorexia condition (ABA; 1.5HR chow/ad lib wheel until 25% weight loss), kept sedentary (SED; ad lib chow/locked wheel), given access to running wheels with ad lib chow access (RW; ad lib chow/wheel), or were body weight matched to the ABA group (BWM; restricted chow/locked wheel). Following 25% weight loss, wheels were locked and food returned to ABA rats. Paired RW groups had their wheels locked and paired BWM rats were given ad lib access to food. Animals were given 10 days to recover prior to a second TRT. Videos were analyzed for liking (tongue protrusions) and disliking (gape) behaviors. RESULTS: The ABA group displayed a significant within-subject reduction in cumulative lick responses to water and 1 M sucrose. Additionally, we found the SED and ABA group displayed a significant within-subject reduction in cumulative lick responses to .1 M sucrose. Positive hedonic responses did not decline in either the BWM or the RW groups. DISCUSSION: The data show a novel phenomenon that a history of ABA results in an anhedonia phenotype that mirrors aspects of AN. SIGNIFICANCE STATEMENT: Patients recovered from anorexia nervosa report anhedonia, or the lack of pleasure in consuming palatable foods. Unfortunately, the biological mechanism underpinning anhedonia in anorexia nervosa is not well understood. The current study assessed hedonic state in adolescent female rats prior to and 10 days recovered following the activity-based anorexia paradigm. Age-matched, running wheel-matched and body weight-matched control groups were also tested at the same time points.

Adolescent female rats prone to the activity based anorexia (ABA) paradigm have altered hedonic responses and cortical astrocyte density compared to resistant animals.

OBJECTIVE: Anhedonia, which in part involves the lack of pleasure in consuming palatable food, is a long-lasting symptom observed in patients both when acutely ill and when long term recovered from Anorexia Nervosa. The neurocircuitry underlying this phenomenon is not well understood. Here we use the preclinical activity-based anorexia (ABA) model in adolescent female rats to assess the impact of excessive exercise, limited food intake and acute weight loss, on adolescent female rat orofacial responding to intraoral sucrose, as measured by the taste reactivity test (TRT). Animals were identified as either prone or resistant to this paradigm based on a weight loss criterion. Measures of food intake, running wheel activity, taste reactivity and medial prefrontal cortex astrocyte expression were compared across groups. METHODS: Adolescent female rats implanted with an intraoral catheter were given a TRT using 1 M (M) sucrose at baseline, max weight loss (25% weight loss from start of ABA or 7 full days on the paradigm) or 10 days recovered from the ABA paradigm. Animals were sacrificed after the final TRT and astrocyte density was measured via immunohistochemistry. RESULTS: Animals resistant to the ABA paradigm ran less than prone animals during the ABA period. Additionally, we found that resistant animals displayed more cumulative 'liking' responses to sucrose compared to prone animals at maximum weight loss. Finally, we found prone animals 10-days recovered from ABA had reduced medial prefrontal cortex astrocyte density compared to levels in resistant animals. DISCUSSION: Rats presented with the physiological challenge of the ABA paradigm either adapt their behavior to stabilize their body weight (i.e. resistant), or rapidly lose weight (i.e. prone). Furthermore, we found that prone animals have reduced orofacial responding to 1 M sucrose at maximum weight loss compared to responses in resistant animals, and this anhedonia-like behavior may be a result of reduced astrocyte density that affects cortical function.

An ex vivo cystic fibrosis model recapitulates key clinical aspects of chronic Staphylococcus aureus infection.

Staphylococcus aureus is the most prevalent organism isolated from the airways of people with cystic fibrosis (CF), predominantly early in life. Yet its role in the pathology of lung disease is poorly understood. In mice, and many experiments using cell lines, the bacterium invades cells or interstitium, and forms abscesses. This is at odds with the limited available clinical data: interstitial bacteria are rare in CF biopsies and abscesses are highly unusual. Bacteria instead appear to localize in mucus plugs in the lumens of bronchioles. We show that, in an established ex vivo model of CF infection comprising porcine bronchiolar tissue and synthetic mucus, S. aureus demonstrates clinically significant characteristics including colonization of the airway lumen, with preferential localization as multicellular aggregates in mucus, initiation of a small colony variant phenotype and increased antibiotic tolerance of tissue-associated aggregates. Tissue invasion and abscesses were not observed. Our results may inform ongoing debates relating to clinical responses to S. aureus in people with CF.

Metal-Binding Q-Proline Macrocycles.

We introduce the efficient Fmoc-SPPS and peptoid synthesis of Q-proline-based, metal-binding macrocycles (QPMs), which bind metal cations and display nine functional groups. Metal-free QPMs are disordered, evidenced by NMR and a crystal structure of QPM-3 obtained through racemic crystallization. Upon addition of metal cations, QPMs adopt ordered structures. Notably, the addition of a second functional group at the hydantoin amide position (R2) converts the proline ring from Cγ-endo to Cγ-exo, due to steric interactions.

Metal Cation-Binding Mechanisms of Q-Proline Peptoid Macrocycles in Solution.

The rational design of foldable and functionalizable peptidomimetic scaffolds requires the concerted application of both computational and experimental methods. Recently, a new class of designed peptoid macrocycle incorporating spiroligomer proline mimics (Q-prolines) has been found to preorganize when bound by monovalent metal cations. To determine the solution-state structure of these cation-bound macrocycles, we employ a Bayesian inference method (BICePs) to reconcile enhanced-sampling molecular simulations with sparse ROESY correlations from experimental NMR studies to predict and design conformational and binding properties of macrocycles as functional scaffolds for peptidomimetics. Conformations predicted to be most populated in solution were then simulated in the presence of explicit cations to yield trajectories with observed binding events, revealing a highly preorganized all-trans amide conformation, whose formation is likely limited by the slow rate of cis/trans isomerization. Interestingly, this conformation differs from a racemic crystal structure solved in the absence of cation. Free energies of cation binding computed from distance-dependent potentials of mean force suggest Na+ has a higher affinity to the macrocycle than K+, with both cations binding much more strongly in acetonitrile than water. The simulated affinities are able to correctly rank the extent to which different macrocycle sequences exhibit preorganization in the presence of different metal cations and solvents, suggesting our approach is suitable for solution-state computational design.

Activity-based anorexia disrupts systemic oxidative state and induces cortical mitochondrial fission in adolescent female rats.

OBJECTIVE: Patients with Anorexia Nervosa (AN) display increased levels of oxidative stress that correlates with disease severity. Unfortunately, the biological ramifications of AN-induced oxidative stress on the brain are largely unknown. Our lab uses the preclinical activity-based anorexia (ABA) paradigm to model symptoms of AN. The goal of the present study was to determine how ABA experience affects oxidative state and its consequences in adolescent female rats. METHOD: We compared systemic glutathione and cysteine plasma concentrations and medial prefrontal cortex (mPFC) mitochondrial fission in ABA animals at maximum weight loss or following 10-days of weight recovery to levels in age-matched sedentary (SED) control rats. RESULTS: ABA animals at maximum weight loss had significantly lower plasma levels of cysteine and glutathione compared to SED controls. Additionally, ABA animals at max weight loss have significantly more mPFC mitochondrial fission. There were no significant differences in plasma analyte levels or mitochondrial fission between weight recovered ABA animals and SED controls. DISCUSSION: These data suggest that ABA experience results in oxidative stress that is remedied after weight restoration. The long-lasting ramifications of transient periods of increased oxidative stress are unknown and can lead to significant consequences on brain function and behavior.

A regional evaluation of the health care utilization and outcomes of children and young people with long-term ventilation needs.

BACKGROUND: Globally, the number of children and young people (CYP) with long-term ventilation (LTV) needs is increasing, with high associated health care costs, due to frequent hospital admissions and contact with community health care services. However, demographic, health care utilization and outcome details of the CYP cared for locally is unknown. This study aimed to examine health care utilization and outcomes for this patient population. METHODS: Routinely collected data from 2014 to 2018 were extracted from local LTV team records and from hospital electronic patient records. Descriptive and inferential statistical analysis was performed using SPSS 17. RESULTS: A total of 112 CYP aged 0-17 years old were included in the evaluation. Sixty per cent (n = 67) commenced ventilation in hospital, and 62% (n = 69) had at-least one hospitalization event whilst they were on LTV, with a median length of stay of 3 days. Most hospitalizations were unplanned and respiratory in nature. Ninety-five per cent (n = 106) of CYP accessed at least one clinic appointment whilst on LTV, with a median of 20 outpatient clinic appointments during the study period. The majority of CYP received time-intensive support from LTV nurses and physiotherapists during the period that they received LTV. Minimal seasonal variation existed in relation to hospital admissions. Year on year increasing trend of hospital admissions was noted. The observed mortality rate was 3.6% (n = 4), 72.3% (n = 81) remained active on LTV, 14% (n = 16) were liberated from their ventilation and 9% (n = 10) transitioned to adult care by the end of the study. CONCLUSION: The study highlights the most common modes of health care utilization for CYP with LTV needs. To enable formalization of future resource planning and accurate assessment of health care utilization in evaluations, there is an urgent need to create a systematic approach for relevant LTV data collection.

Acute Blockade of PACAP-Dependent Activity in the Ventromedial Nucleus of the Hypothalamus Disrupts Leptin-Induced Behavioral and Molecular Changes in Rats.

Leptin signaling pathways, stemming primarily from the hypothalamus, are necessary for maintaining normal energy homeostasis and body weight. In both rodents and humans, dysregulation of leptin signaling leads to morbid obesity and diabetes. Since leptin resistance is considered a primary factor underlying obesity, understanding the regulation of leptin signaling could lead to therapeutic tools and provide insights into the causality of obesity. While leptin actions in some hypothalamic regions such as the arcuate nuclei have been characterized, less is known about leptin activity in the hypothalamic ventromedial nuclei (VMN). Recently, pituitary adenylate cyclase-activating polypeptide (PACAP) has been shown to reduce feeding behavior and alter metabolism when administered into the VMN in a pattern similar to that of leptin. In the current study, we examined whether leptin and PACAP actions in the VMN share overlapping pathways in the regulation of energy balance. Interestingly, PACAP administration into the VMN increased STAT3 phosphorylation and SOCS3 mRNA expression, both of which are hallmarks of leptin receptor activation. In addition, BDNF mRNA expression in the VMN was increased by both leptin and PACAP administration. Moreover, antagonizing PACAP receptors fully reversed the behavioral and cellular effects of leptin injections into the VMN. Electrophysiological studies further illustrated that leptin-induced effects on VMN neurons were blocked by antagonizing PACAP receptors. We conclude that leptin dependency on PACAP signaling in the VMN suggests a potential common signaling cascade, allowing a tonically and systemically secreted neuropeptide to be more precisely regulated by central neuropeptides.

Antibiotic adjuvant therapy for pulmonary infection in cystic fibrosis.

BACKGROUND: Cystic fibrosis is a multi-system disease characterised by the production of thick secretions causing recurrent pulmonary infection, often with unusual bacteria. This leads to lung destruction and eventually death through respiratory failure. There are no antibiotics in development that exert a new mode of action and many of the current antibiotics are ineffective in eradicating the bacteria once chronic infection is established. Antibiotic adjuvants - therapies that act by rendering the organism more susceptible to attack by antibiotics or the host immune system, by rendering it less virulent or killing it by other means, would be a significant therapeutic advance. This is an update of a previously published review. OBJECTIVES: To determine if antibiotic adjuvants improve clinical and microbiological outcome of pulmonary infection in people with cystic fibrosis. SEARCH METHODS: We searched the Cystic Fibrosis Trials Register which is compiled from database searches, hand searches of appropriate journals and conference proceedings. Date of most recent search: 16 January 2020. We also searched MEDLINE (all years) on 14 February 2019 and ongoing trials registers on 06 April 2020. SELECTION CRITERIA: Randomised controlled trials and quasi-randomised controlled trials of a therapy exerting an antibiotic adjuvant mechanism of action compared to placebo or no therapy for people with cystic fibrosis. DATA COLLECTION AND ANALYSIS: Two of the authors independently assessed and extracted data from identified trials. MAIN RESULTS: We identified 42 trials of which eight (350 participants) that examined antibiotic adjuvant therapies are included. Two further trials are ongoing and five are awaiting classification. The included trials assessed ß-carotene (one trial, 24 participants), garlic (one trial, 34 participants), KB001-A (a monoclonal antibody) (two trials, 196 participants), nitric oxide (two trials, 30 participants) and zinc supplementation (two trials, 66 participants). The zinc trials recruited children only, whereas the remaining trials recruited both adults and children. Three trials were located in Europe, one in Asia and four in the USA. Three of the interventions measured our primary outcome of pulmonary exacerbations (ß-carotene, mean difference (MD) -8.00 (95% confidence interval (CI) -18.78 to 2.78); KB001-A, risk ratio (RR) 0.25 (95% CI 0.03 to 2.40); zinc supplementation, RR 1.85 (95% CI 0.65 to 5.26). ß-carotene and KB001-A may make little or no difference to the number of exacerbations experienced (low-quality evidence); whereas, given the moderate-quality evidence we found that zinc probably makes no difference to this outcome. Respiratory function was measured in all of the included trials. ß-carotene and nitric oxide may make little or no difference to forced expiratory volume in one second (FEV1) (low-quality evidence), whilst garlic probably makes little or no difference to FEV1 (moderate-quality evidence). It is uncertain whether zinc or KB001-A improve FEV1 as the certainty of this evidence is very low. Few adverse events were seen across all of the different interventions and the adverse events that were reported were mild or not treatment-related (quality of the evidence ranged from very low to moderate). One of the trials (169 participants) comparing KB001-A and placebo, reported on the time to the next course of antibiotics; results showed there is probably no difference between groups, HR 1.00 (95% CI 0.69 to 1.45) (moderate-quality evidence). Quality of life was only reported in the two KB001-A trials, which demonstrated that there may be little or no difference between KB001-A and placebo (low-quality evidence). Sputum microbiology was measured and reported for the trials of KB001-A and nitric oxide (four trials). There was very low-quality evidence of a numerical reduction in Pseudomonas aeruginosa density with KB001-A, but it was not significant. The two trials looking at the effects of nitric oxide reported significant reductions in Staphylococcus aureus and near-significant reductions in Pseudomonas aeruginosa, but the quality of this evidence is again very low. AUTHORS' CONCLUSIONS: We could not identify an antibiotic adjuvant therapy that we could recommend for treating of lung infection in people with cystic fibrosis. The emergence of increasingly resistant bacteria makes the reliance on antibiotics alone challenging for cystic fibrosis teams. There is a need to explore alternative strategies, such as the use of adjuvant therapies. Further research is required to provide future therapeutic options.

Fluorinated Aromatic Monomers as Building Blocks To Control α-Peptoid Conformation and Structure.

Peptoids are peptidomimetics of interest in the fields of drug development and biomaterials. However, obtaining stable secondary structures is challenging, and designing these requires effective control of the peptoid tertiary amide cis/trans equilibrium. Herein, we report new fluorine-containing aromatic monomers that can control peptoid conformation. Specifically, we demonstrate that a fluoro-pyridine group can be used to circumvent the need for monomer chirality to control the cis/trans equilibrium. We also show that incorporation of a trifluoro-methyl group ( NCF3Rpe) rather than a methyl group ( NRpe) at the α-carbon of a monomer gives rise to a 5-fold increase in cis-isomer preference.

Pituitary adenylate cyclase-activating polypeptide (PACAP) acts in the nucleus accumbens to reduce hedonic drive.

Obesity develops, in part, due to frequent overconsumption. Therefore, it is important to identify the regulatory mechanisms that promote eating beyond satiety. Previously, we have demonstrated that an acute microinjection of the neuropeptide PACAP into the nucleus accumbens (NAcc) attenuates palatable food consumption in satiated rats. To better understand the mechanism by which intra-NAcc PACAP selectively blocks palatable food intake, the current work employed a rodent taste reactivity paradigm to assess the impact of PACAP on the hedonic processing of a 1% sucrose solution. Our results revealed that bilateral intra-NAcc PACAP infusions significantly reduced appetitive orofacial responses to sucrose. Interestingly, the effect of PACAP on the expression of aversive responses to sucrose was dependent on the rostral-caudal placement of the microinjection. In a separate group of rats, PACAP was microinjected into the hypothalamus (a region of the brain in which PACAP does not attenuate palatable feeding). Here we found that PACAP had no effect on the hedonic perception of the sucrose solution. Taken together, this dataset indicates that PACAP acts in specific subregions of the NAcc to attenuate palatability-induced feeding by reducing the perceived hedonic value of palatable food.

The top 10 research priorities in cystic fibrosis developed by a partnership between people with CF and healthcare providers.

There remain many treatment uncertainties in cystic fibrosis (CF). With limited resources, research should focus on questions which are most important to the CF community. We conducted a James Lind Alliance Priority Setting Partnership in CF. Research questions were elicited and then prioritised in successive surveys. A workshop agreed the final top 10. Online methods avoided cross infection and widened participation. The elicitation survey had 482 respondents (1080 questions) and prioritisation survey 677 respondents. Participants were drawn equally from the patient and clinical communities globally. We have achieved a consensus on 10 research priorities which will be attractive to funders.

Efficacy of a Sonicating Swab for Removal and Capture of Microorganisms from Experimental and Natural Contaminated Surfaces.

Enhancements in swabbing technology to increase sample collection efficacy would benefit the food industry. Specifically, these enhancements would assist the food industry in implementing the FDA Food Safety Modernization Act (FSMA) requirements by improving environmental monitoring effectiveness. A sonicating swab device, an example of an enhanced swabbing technology, was demonstrated previously to remove biofilm from stainless steel more efficiently than a standard cotton swab. Within this study, the performance of the sonicating swab was compared to that of the standard cotton swab for the recovery of Listeria monocytogenes from inoculated surfaces (plastic cutting board, wood cutting board, vinyl floor tile, and quarry clay floor tile). Additionally, we demonstrate the sonicating swab performance for collection of a microbiological sample from used commercial plastic cutting boards (noninoculated) in comparison to cotton swabs, foam swabs, and sponges. The sonicating swab captured significantly (P ≤ 0.05) more L. monocytogenes than the cotton swab for both the quarry tile and wood cutting board, while no significant differences were observed for the plastic cutting board or the vinyl floor tile. The sonicating swab consistently recovered significantly (P ≤ 0.05) more bacteria from the used cutting boards than did the standard cotton swab or the 3M Enviro swab, and it recovered significantly (P ≤ 0.05) more bacteria than the sponge swab for a majority of the time (4 of 6 trials). The results of this study indicate that swab technology can still be improved and that the sonicating swab is a viable technological enhancement which aids microbiological sample collection.IMPORTANCE Swabbing of surface areas for microbial contamination has been the standard for the detection and enumeration of microorganisms for many years. Inadequate surface sampling can result in foodborne illness outbreaks due to biotransfer of harmful microorganisms from food contact surfaces to foods. Swab material type, surface characteristics, and swabbing method used are a few of the factors associated with swabbing that can result in the variability of bacterial cell recovery for detection and enumeration. A previous study highlighted a sonicating swab prototype and its ability to recover cells from a stainless steel surface more efficiently and reliably than a standard swab method (T. A. Branck, M. J. Hurley, G. N. Prata, C. A. Crivello, and P. J. Marek, Appl Environ Microbiol 83:e00109-17, 2017, https://doi.org/10.1128/AEM.00109-17). This study expands upon the capabilities of the sonicating swab technology to recover cells from multiple surface types with increased performance over traditional swabbing methods as a tool to further assist in the prevention of foodborne illness outbreaks.

Staphylococcus aureus in cystic fibrosis: pivotal role or bit part actor?

PURPOSE OF REVIEW: The cystic fibrosis (CF) lung has long been appreciated as a competitive niche for complex interactions between bacterial species. The individual relationships between effects on the host, and thereafter clinical outcomes, has been poorly understood. We aim to describe the role of Staphyloccus aureus, one of the most commonly encountered bacteria cultured from the respiratory tracts of people with CF, and it's complex interplay with other organisms, with particular attention to Pseudomonas aeruginosa. RECENT FINDINGS: We describe the challenges posed in understanding the role that S. aureus plays in the CF lung, including the difficulties in interpreting culture results depending upon sampling technique, relationships with P. aeruginosa and the rest of the microbiome, as well as discussing the relative merits and potential harms of antibiotic prophylaxis. Finally, we describe the particular challenge of methicillin-resistant S. aureus. SUMMARY: We describe research underway that will address the long-held contentious issues of antibiotic prophylaxis. We also describe the emerging research interest in determining whether, at differences phases in the evolution of CF airways infection, S. aureus infection can have both harmful and protective effects for the host.