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We present a reduced-order model to calculate response matrices rapidly for filter stack spectrometers (FSSs). The reduced-order model allows response matrices to be built modularly from a set of pre-computed photon and electron transport and scattering calculations through various filter and detector materials. While these modular response matrices are not appropriate for high-fidelity analysis of experimental data, they encode sufficient physics to be used as a forward model in design optimization studies of FSSs, particularly for machine learning approaches that require sampling and testing a large number of FSS designs. [ABSTRACT FROM AUTHOR]

We present an inversion method capable of robustly unfolding MeV x-ray spectra from filter stack spectrometer (FSS) data without requiring an a priori specification of a spectral shape or arbitrary termination of the algorithm. Our inversion method is based upon the perturbative minimization (PM) algorithm, which has previously been shown to be capable of unfolding x-ray transmission data, albeit for a limited regime in which the x-ray mass attenuation coefficient of the filter material increases monotonically with x-ray energy. Our inversion method improves upon the PM algorithm through regular smoothing of the candidate spectrum and by adding stochasticity to the search. With these additions, the inversion method does not require a physics model for an initial guess, fitting, or user-selected termination of the search. Instead, the only assumption made by the inversion method is that the x-ray spectrum should be near a smooth curve. Testing with synthetic data shows that the inversion method can successfully recover the primary large-scale features of MeV x-ray spectra, including the number of x-rays in energy bins of several-MeV widths to within 10%. Fine-scale features, however, are more difficult to recover accurately. Examples of unfolding experimental FSS data obtained at the Texas Petawatt Laser Facility and the OMEGA EP laser facility are also presented. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Fetal hyperinsulinemia and neonatal hyperglycemia are complications of poor maternal glycemic control and may result in increased glucose infusion rate (GIR) requirements in infants of diabetic mothers (IDMs). The objectives of this study were to correlate maternal A1c levels with GIR requirements in IDMs, establish an A1c threshold predictive for GIR requirements, and identify associations between A1c levels and complications in IDMs. STUDY DESIGN: A retrospective review of paired maternal A1c values and GIR requirements of IDMs were compared via logistic regression analysis. A likelihood ratio was calculated to correlate A1c levels with GIR requirements, and identify a maternal A1c threshold. RESULTS: Increasing A1c values were significantly correlated with GIR≥5 mg/kg/min (OR, 1.37; 95% CI 1.04–1.79, p = 0.021). Macrosomia was the most frequent complication (OR, 1.31; 95% CI 1.04–1.67, p = 0.022) and A1c > 6.8% was predictive for increased GIR requirements. CONCLUSION: Increased A1c values were significantly associated with GIR requirements≥5 mg/kg/min. Increased maternal A1c is significantly associated with complications in newborns, specifically macrosomia. A maternal A1c of 6.8% was identified as a threshold predictive of increased GIR requirements. [ABSTRACT FROM AUTHOR]

Culture-based microbial natural product discovery strategies fail to realize the extraordinary biosynthetic potential detected across earth's microbiomes. Here we introduce Small Molecule In situ Resin Capture (SMIRC), a culture-independent method to obtain natural products directly from the environments in which they are produced. We use SMIRC to capture numerous compounds including two new carbon skeletons that were characterized using NMR and contain structural features that are, to the best of our knowledge, unprecedented among natural products. Applications across diverse marine habitats reveal biome-specific metabolomic signatures and levels of chemical diversity in concordance with sequence-based predictions. Expanded deployments, in situ cultivation, and metagenomics facilitate compound discovery, enhance yields, and link compounds to candidate producing organisms, although microbial community complexity creates challenges for the later. This compound-first approach to natural product discovery provides access to poorly explored chemical space and has implications for drug discovery and the detection of chemically mediated biotic interactions., (© 2024. The Author(s).)

Aims: Surgical Antibiotic Prophylaxis (SAP) in Nigeria is often not evidence based. The aim of this study is to test if the GADSA application can change prescription behaviour of surgeons in Nigeria. In addition, the study aims to identify AMS strategies and policies for the future., Methods: The GADSA gamified decision support app uses WHO and Sanford prescribing guidelines to deliver real-time persuasive technology feedback to surgeons through an interactive mentor. The app can advise on whether clinician's decisions align with SAP recommendations and provides the opportunity for clinicians to make adjustments. Twenty surgeons actively participated in a 6-month pilot study in three hospitals in Nigeria. The surgeons determined the risk of infection of a surgical procedure, and the need, type and duration of SAP. The study used a longitudinal approach to test whether the GADSA app significantly changed prescribing behaviour of participating surgeons by analysing the reported prescription decisions within the app., Results: 321 SAP prescriptions were recorded. Concerning the surgical risk decision, 12% of surgeons changed their decision to be in line with guidelines after app feedback (p < 0.001) and 10% of surgeons changed their decision about the need for SAP (p = 0.0035) to align with guidelines. The change in decision making for SAP use in terms of "type" and "duration" to align with guidelines was similar with 6% and 5% respectively (both p-values < 0.001)., Conclusion: This study suggests that the GADSA app, with its game based and feedback feature, could significantly change prescribing behaviour at the point of care in an African setting, which could help tackle the global challenge of antibiotic resistance., (© 2023. The Author(s).)

Aim: Discovery of novel SARS-CoV-2 main protease (M pro ) inhibitors using a structure-based drug discovery strategy. Materials & methods: Virtual screening employing covalent and noncovalent docking was performed to discover M pro inhibitors, which were subsequently evaluated in biochemical and cellular assays. Results: 91 virtual hits were selected for biochemical assays, and four were confirmed as reversible inhibitors of SARS CoV-2 M pro with IC 50 values of 0.4-3 μM. They were also shown to inhibit SARS-CoV-1 M pro and human cathepsin L. Molecular dynamics simulations indicated the stability of the M pro inhibitor complexes and the interaction of ligands at the subsites. Conclusion: This approach led to the discovery of novel thiosemicarbazones as potent SARS-CoV-2 M pro inhibitors.

Vaccine development against COVID-19 has mitigated severe disease. However, reports of rare but serious adverse events following immunization (sAEFI) in the young populations are fuelling parental anxiety and vaccine hesitancy. With a very early season of viral illnesses including COVID-19, respiratory syncytial virus (RSV), influenza, metapneumovirus and several others, children are facing a winter with significant respiratory illness burdens. Yet, COVID-19 vaccine and booster uptake remain sluggish due to the mistaken beliefs that children have low rates of severe COVID-19 illness as well as rare but severe complications from COVID-19 vaccine are common. In this study we examined composite sAEFI reported in association with COVID-19 vaccines in the United States (US) amongst 5-17-year-old children, to ascertain the composite reported risk associated with vaccination. Between December 13, 2020, and April 13, 2022, a total of 467,890,599 COVID-19 vaccine doses were administered to individuals aged 5-65 years in the US, of which 180 million people received at least 2 doses. In association with these, a total of 177,679 AEFI were reported to the Vaccine Adverse Event reporting System (VAERS) of which 31,797 (17.9%) were serious. The rates of ED visits per 100,000 recipients were 2.56 (95% CI: 2.70-3.47) amongst 5-11-year-olds, 18.25 (17.57-18.95) amongst 12-17-year-olds and 33.74 (33.36-34.13) amongst 18-65-year olds; hospitalizations were 1.07 (95% CI 0.87-1.32) per 100,000 in 5-11-year-olds, 6.83 (6.42-7.26) in 12-17-year olds and 8.15 (7.96-8.35) in 18-65 years; life-threatening events were 0.14 (95% CI: 0.08-0.25) per 100,000 in 5-11-year olds, 1.22 (1.05-1.41) in 12-17-year-olds and 2.96 (2.85-3.08) in 18-65 year olds; and death 0.03 (95% CI 0.01-0.10) per 100,000 in 5-11 year olds, 0.08 (0.05-0.14) amongst 12-17-year olds and 0.76 (0.71-0.82) in 18-65 years age group. The results of our study from national population surveillance data demonstrate rates of reported serious AEFIs amongst 5-17-year-olds which appear to be significantly lower than in 18-65-year-olds. These low risks must be taken into account in overall recommendation of COVID-19 vaccination amongst children., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Mangat et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Rationale: There is little information regarding the allergen content of milk feeds in the preterm population. Previous studies have not performed a broad analysis of the allergenic peptide content and protease activity of milk feeds in this population. Methods: To evaluate feasibility, we initially performed mass spectrometry on 4 human milk (HM) samples (2 term and 2 preterm) from the Mommy's Milk Human Milk Biorepository (HMB) and analyzed the results against the University of Nebraska FASTA database and UniProt for a total of 2,211 protein sequences. We then further analyzed five samples from the Microbiome, Atopy, and Prematurity (MAP) study including peptidomic and protease activity analysis. Results: Each HMB sample had between 806 and 1,007 proteins, with 37-44 nonhuman proteins/sample encompassing 26 plant and animal species. In the preterm MAP samples, 784 digested nonhuman proteins were identified, 30 were nonbovine in origin. Proteins from 23 different species including aeroallergens, food, and contact allergens were identified. Protease activity was highest in HM samples without human milk fortifier and lowest in preterm formula. Conclusions: These findings represent the first preterm milk feed mass spectrometry and protease analysis with identification of known allergenic proteins to food, contact, and aeroallergens. These results raise questions of whether the composition of milk feeds in the neonatal intensive care unit impact the development of atopic disease in the preterm population and whether the complex interaction between allergens, proteases, and other HM components can serve to induce sensitization or tolerance to allergens in infants. Clinical Trial Registration Number: NCT04835935.

Objective: To analyze rates of reported severe adverse events after immunization (sAEFI) attributed to SARS-CoV-2 vaccines in the United States (US) using safety surveillance data., Methods: Observational study of sAEFI reported to the vaccine adverse events reporting system (VAERS) between December 13, 2020, to December 13, 2021, and attributed to SARS-CoV-2 vaccination programs across all US states and territories. All sAEFI in conjunction with mRNA (BNT-162b2 or mRNA-1273) or adenovector (Ad26.COV2.S) vaccines were included. The 28-day crude cumulative rates for reported emergency department (ED) visits and sAEFI viz. hospitalizations, life-threatening events and deaths following SARS-CoV-2 vaccination were calculated. Incidence rate ratios (IRRs) of reported sAEFI were compared between mRNA and adenovector vaccines using generalized Poisson regression models., Results: During the study period, 485 million SARS-CoV-2 vaccines doses were administered nationwide, and 88,626 sAEFI reported in VAERS. The 28-day crude cumulative reporting rates per 100,000 doses were 14.97 (95% confidence interval, 14.86-18.38) for ED visits, 5.32 (5.26-5.39) for hospitalizations, 1.72 (1.68-1.76) for life-threatening events, and 1.08 (1.05-1.11) for deaths. Females had two-fold rates for any reported AEFI compared to males, but lower adjusted IRRs for sAEFI. Cumulative rates per dose for reported sAEFI attributed to adenovector vaccine were 2-3-fold higher, and adjusted IRRs 1.5-fold higher than mRNA vaccines., Conclusions: Overall cumulative rates for reported sAEFI following SARS-CoV-2 vaccination in the US over 1 year were very low; single-dose adenovector vaccine had 1.5-fold higher adjusted rates for reported sAEFI, which may however equate with multiple-doses mRNA vaccine regimens. These data indicate absence of high risks of sAEFI following SARS-CoV-2 vaccines and support safety equipoise between mRNA and adenovector vaccines. Public health messaging of these data is critical to overcome heuristic biases. Furthermore, these data may support ongoing adenovector vaccine use, especially in low- and middle-income countries due to affordability, logistical and cold chain challenges., Competing Interests: Author AB was employed by the company Transmissible BV. The remaining 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 Mangat, Musah, Luedtke, Syed, Maramattom, Maruthanal, Bosman and Kostkova.)

The main protease (M pro , 3CL pro ) of SARS-CoV-2 is an attractive target in coronaviruses because of its crucial involvement in viral replication and transcription. Here, we report on the design, synthesis, and structure-activity relationships of novel small-molecule thioesters as SARS-CoV-2 M pro inhibitors. Compounds 3w and 3x exhibited excellent SARS-CoV-2 M pro inhibition with k inac / K s i of 58,700 M -1 s -1 s K i = 0.0141 μM) and 27,200 M -1 s -1 ( K i = 0.0332 μM), respectively. In Calu-3 and Vero76 cells, compounds 3h , 3i, 3l , 3r , 3v , 3w , and 3x displayed antiviral activity in the nanomolar range without host cell toxicity. Co-crystallization of 3w and 3af with SARS-CoV-2 M pro was accomplished, and the X-ray structures showed covalent binding with the catalytic Cys145 residue of the protease. The potent SARS-CoV-2 Mpro inhibitors also inhibited the M pro of other beta-coronaviruses, including SARS-CoV-1 and MERS-CoV, indicating that they might be useful to treat a broader range of coronaviral infections.

Background: In Nigeria, the prescription of surgical antibiotic prophylaxis for prevention of surgical site infection tends to be driven by local policy rather than by published guidelines (e.g. WHO and Sanford)., Objectives: To triangulate three datasets and understand key barriers to implementation using a behavioural science framework., Methods: Surgeons ( N  = 94) from three teaching hospitals in Nigeria participated in an online survey and in focus group discussions about barriers to implementation. The theoretical domains framework (TDF) was used to structure question items and interview schedules. A subgroup ( N  = 20) piloted a gamified decision support app over the course of 6 months and reported barriers at the point of care., Results: Knowledge of guidelines and intention to implement them in practice was high. Key barriers to implementation were related to environmental context and resources and concern over potential consequences of implementing recommendations within the Nigerian context applicable for similar settings in low-to-middle-income countries., Conclusions: The environmental context and limited resource setting of Nigerian hospitals currently presents a significant barrier to implementation of WHO and Sanford guidelines. Research and data collected from the local context must directly inform the writing of future international guidelines to increase rates of implementation., (© The Author(s) 2022. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Antivirals that specifically target SARS-CoV-2 are needed to control the COVID-19 pandemic. The main protease (M pro ) is essential for SARS-CoV-2 replication and is an attractive target for antiviral development. Here we report the use of the Random nonstandard Peptide Integrated Discovery (RaPID) mRNA display on a chemically cross-linked SARS-CoV-2 M pro dimer, which yielded several high-affinity thioether-linked cyclic peptide inhibitors of the protease. Structural analysis of M pro complexed with a selenoether analogue of the highest-affinity peptide revealed key binding interactions, including glutamine and leucine residues in sites S1 and S2, respectively, and a binding epitope straddling both protein chains in the physiological dimer. Several of these M pro peptide inhibitors possessed antiviral activity against SARS-CoV-2 in vitro with EC 50 values in the low micromolar range. These cyclic peptides serve as a foundation for the development of much needed antivirals that specifically target SARS-CoV-2., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

This case report describes an extremely low birth weight infant, born at 26-week gestational age, who developed hypertrophic cardiomyopathy (HCM) and cardiogenic shock a few hours after administration of a small dose of dexamethasone. Although cases of steroid-induced cardiomyopathy in preterm neonates are known in literature, their adverse effects are insidious and are transient in occurrence. This is the first report of HCM and cardiogenic shock occurring acutely after administration of small-dose dexamethasone. This neonate received small-dose dexamethasone initially to prevent reintubation, and again to facilitate successful extubation. Both occurrences were associated with acute cardiac decompensation with reduction in ejection fraction within hours of administration. Cardiac function subsequently improved with discontinuation of drug and use of inotropic pharmacotherapy. Studies outlined in this report show that steroid-induced HCM is known and not isolated to dexamethasone alone; however, little is known on the adverse effect of small-dose steroid in resulting acute cardiac decompensation. This case is of educational value in clinical practice by highlighting the potential adverse effects even at the smaller doses of dexamethasone currently recommended in extremely low birth weight infants., Competing Interests: Disclosures. The authors declare no conflicts or financial interest in any product or service mentioned in the manuscript, including grants, equipment, medications, employment, gifts, and honoraria. The authors had full access to all patient information in this report and take responsibility for the integrity and accuracy of the report., (Copyright. Pediatric Pharmacy Association. All rights reserved. For permissions, email membershipo@pediatricpharmacy.org 2022.)

The COVID-19 pandemic is an unprecedented global crisis in which governments had to act in a situation of rapid change and substantial uncertainty. The governments of Germany, Sweden and the UK have taken different paths allowing learning for future pandemic preparedness. To help inform discussions on preparedness, inspired by resilience frameworks, this paper reviews governance structures, and the role of science and the media in the COVID-19 response of Germany, Sweden and the UK in 2020. We mapped legitimacy, interdependence, knowledge generation and the capacity to deal with uncertainty.Our analysis revealed stark differences which were linked to pre-existing governing structures, the traditional role of academia, experience of crisis management and the communication of uncertainty-all of which impacted on how much people trusted their government. Germany leveraged diversity and inclusiveness, a 'patchwork quilt', for which it was heavily criticised during the second wave. The Swedish approach avoided plurality and largely excluded academia, while in the UK's academia played an important role in knowledge generation and in forcing the government to review its strategies. However, the vivant debate left the public with confusing and rapidly changing public health messages. Uncertainty and the lack of evidence on how best to manage the COVID-19 pandemic-the main feature during the first wave-was only communicated explicitly in Germany. All country governments lost trust of their populations during the epidemic due to a mix of communication and transparency failures, and increased questioning of government legitimacy and technical capacity by the public., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Serotonin discontinuation syndrome (SDS) can result in a constellation of symptoms exhibited by infants exposed to selective serotonin reuptake inhibitors or other psychotropic drugs during pregnancy. Currently, there is no consensus regarding the pharmacologic management of SDS. We report our experience with clonidine for the management of a term infant with poor neonatal adaption. The infant exhibited biphasic symptoms of acute toxicity at birth and a plateauing of symptoms, followed by subsequent withdrawal symptomatology requiring the use of clonidine in doses up to 4 mcg/kg/dose every 3 hours for control of symptoms. The 38-week gestation Caucasian male infant was born to a mother with major depressive disorder, which was managed with sertraline, trazodone, venlafaxine, and buspirone throughout her pregnancy. The infant exhibited severe hypertonia at delivery and continued to have hypertonia, tremors, hypoglycemia, and feeding issues upon admission to the NICU. The initial Modified Finnegan Neonatal Abstinence scores were extremely elevated, and clonidine was started at 1 mcg/kg/dose every 3 hours and then the dose was titrated up to 4 mcg/kg/dose. This is the first report documenting the use of clonidine to manage serotonin toxicity at birth followed by subsequent neonatal withdrawal associated with maternal antidepressant drug use during pregnancy., Competing Interests: Disclosure. The authors declare no conflicts or financial interest in any product or service mentioned in the manuscript, including grants, equipment, medications, employment, gifts, and honoraria. The authors had full access to all patient information in this report and take responsibility for the integrity and accuracy of the report., (Copyright. Pediatric Pharmacy Association. All rights reserved. For permissions, email: mhelms@pediatricpharmacy.org 2021.)

Background: Macrocyclic lactones are arguably the most successful chemical class with efficacy against parasitic nematodes. Here we investigated the effect of the macrocyclic lactone ivermectin on lipid homeostasis in the plant parasitic nematode Globodera pallida and provide new insight into its mode of action., Results: A non-invasive, non-destructive, label-free and chemically selective technique called Coherent anti-Stokes Raman scattering (CARS) spectroscopy was used to study lipid stores in G. pallida. We optimised the protocol using the free-living nematode Caenorhabditis elegans and then used CARS to quantify lipid stores in the pre-parasitic, non-feeding J2 stage of G. pallida. This revealed a concentration of lipid stores in the posterior region of J2 s within 24 h of hatching which decreased to undetectable levels over the course of 28 days. We tested the effect of ivermectin on J2 viability and lipid stores. Within 24 h, ivermectin paralysed J2 s. Counterintuitively, over the same time-course ivermectin increased the rate of depletion of J2 lipid, suggesting that in ivermectin-treated J2 s there is a disconnection between the energy requirements for motility and metabolic rate. This decrease in lipid stores would be predicted to negatively impact on J2 infective potential., Conclusion: These data suggest that the benefit of macrocyclic lactones as seed treatments may be underpinned by a multilevel effect involving both neuromuscular inhibition and acceleration of lipid metabolism. © 2017 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry., (© 2017 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.)

Competing Interests: Conflict of Interest: None.

This review considers the factors involved in the regulation of feeding and metabolism in response to food deprivation using Caenorhabditis elegans as a model organism. Some of the sensory neurons and interneurons involved in food intake are described, together with an overview of pharyngeal pumping. A number of chemical transmitters control feeding in C. elegans including 5-hydroxytryptamine (5-HT, serotonin), acetylcholine, glutamate, dopamine, octopamine, and tyramine. The roles of these transmitters are modified by neuropeptides, including FMRFamide-like peptides (FLPs), neuropeptide-like protein (NLPs), and insulin-like peptides. The precise effects of many of these neuropeptides have yet to be elucidated but increasingly they are being shown to play a role in feeding and metabolism in C. elegans. The regulation of fat stores is complex and appears to involve the expression of a large number of genes, many with mammalian homologues, suggesting that fat regulatory signalling is conserved across phyla. Finally, a brief comparison is made between C. elegans and mammals where for both, despite their evolutionary distance, classical transmitters and neuropeptides have anorectic or orexigenic properties. Thus, there is a rationale to support the argument that an understanding of the molecular and genetic basis of feeding and fat regulation in C. elegans may contribute to efforts aimed at the identification of targets for the treatment of conditions associated with abnormal metabolism and obesity.

Following intensive discussions, review, alignment of procedures and multiple surveys among their member companies, the European Bioanalysis Forum (EBF) is providing a recommendation on how to integrate incurred sample reproducibility (ISR) in the bioanalytical process. The recommendation aims to provide guidance throughout the lifecycle of a validated method, including the application of the method in study support. In its recommendation, the EBF considers both the internal discussions with EBF member companies, as well as the input provided in international meetings where ISR was discussed. The ultimate goal of the EBF recommendation is to ensure that bioanalytical methods can provide accurate and reproducible concentration data for pharmacokinetic and/or toxicokinetic evaluation, without any compromise, while safeguarding the optimal use of laboratory resources.

This report is the first to replicate the earlier findings of Standing et al and validates the inadequacy of reporting of dosage forms used in pediatric drug trials. Journal authors should provide and journal editors should require adequate dosage form information for published reports of pediatric drug trials. We also recommend that compounding pharmacists provide detailed compounding instructions to assure that extemporaneously compounded formulations can be reliably reproduced, and that quality-control data be provided to support formulation stability. Until the problem of insufficient information is addressed, replication of many pediatric drug trials is impossible, calling into question their reliability and validity.

Few data exist in the literature to support the use of high dosages of oral baclofen and clonidine that are frequently required to treat children with spasticity. This study was a retrospective chart review of baclofen and clonidine dosages used in children diagnosed with cerebral palsy or traumatic brain injury. The primary objective was to calculate the mean dosages of baclofen and clonidine based on the duration of spasticity postinjury. Secondary objectives included determining correlations between dosage and age, injury type, location of spasticity, comorbid seizures, or concomitant antispasticity medications. Eighty-seven children receiving baclofen and/or clonidine were included in this study. Mean dosages of 40 mg/day (n = 86) and 0.4 mg/day (n = 31) were required for baclofen and clonidine, respectively. The maximum dosage was 240 mg/day for baclofen and 3.6 mg/day for clonidine. Duration postinjury, age, and concomitant antispasticity medications were the most predictive variables for baclofen dosage as a model (r = .522; P = .000). Duration postinjury and location of spasticity were the most predictive variables for clonidine dosage as a model (r = .523; P = .000). The average dosages of baclofen and clonidine used in this population of children with cerebral palsy or traumatic brain injury were similar to those reported in the literature, with higher maximum dosages found in this investigation.

Invertebrate neuroscience has provided a number of very informative model systems that have been extensively utilized in order to define the neurobiological bases of animal behaviours (Sattelle and Buckingham in Invert Neurosci 6:1-3, 2006). Most eminent among these are a number of molluscs, including Aplysia californica, Lymnaea stagnalis and Helix aspersa, crustacean systems such as the crab stomatogastric ganglion and a wide-range of other arthropods. All of these have been elegantly exploited to shed light on the very important phenomenon of the molecular and cellular basis for synaptic regulation that underpins behavioural plasticity. Key to the successful use of these systems has been the ability to study well-defined, relatively simple neuronal circuits that direct and regulate a quantifiable animal behaviour. Here we describe the pharyngeal system of the nematode C. elegans and its utility as a model for defining the genetic basis of behaviour. The circuitry of the nervous system in this animal is uniquely well-defined. Furthermore, the feeding behaviour of the worm is controlled by the activity of the pharynx and this in turn is regulated in a context-dependent manner by a simple nervous system that integrates external signals, e.g. presence or absence of food, and internal signals, e.g. the nutritional status of the animal to direct an appropriate response. The genetics of C. elegans is being effectively exploited to provide novel insight into genes that function to regulate the neuronal network that controls the pharynx. Here we summarise the progress to date and highlight topics for future research. Two main themes emerge. First, although the anatomy of the pharyngeal system is very well-defined, there is a much poorer understanding of its neurochemistry. Second, it is evident that the neurochemistry is remarkably complex for such a simple circuit/behaviour. This suggests that the pharyngeal activity may be subject to exquisitely precise regulation depending on the animal's environment and status. This therefore provides a very tractable genetic model to investigate neural mechanisms for signal integration and synaptic plasticity in a well-defined neuronal network that directs a quantifiable behaviour, feeding.

At a given degree of adiposity, metabolic and cardiovascular risk varies markedly between individuals. Animal studies suggest that differentially expressed systemic activation of monocytes contributes to the obesity-associated risk variability. We tested the hypothesis that systemic monocyte activation is associated with changes in adipose tissue and skeletal muscle metabolism. In 17 obese hypertensive patients, we assessed CD11b expression on circulating monocytes, gene expression in adipose tissue biopsies, and obtained blood samples and adipose tissue and skeletal muscle microdialysis samples in the fasted state and during a glucose load. Patients were stratified into groups with higher and lower CD11b expression on monocytes. Expression of the macrophage marker CD68 was increased markedly in adipose tissue of subjects with higher CD11b expression. Although no differences in systemic insulin sensitivity were found between both groups, patients with higher peripheral CD11b expression showed a markedly augmented increase in dialysate glucose in adipose tissue during oral glucose tolerance testing and increased adipose tissue lipolysis as well. Our data demonstrate that human monocyte activation is associated with tissue-specific changes in glucose and lipid metabolism. These findings may be explained in part by monocyte/macrophage infiltration of adipose tissue, which appears to interfere with insulin responsiveness.