Whole apples have not been previously implicated in outbreaks of foodborne bacterial illness. We investigated a nationwide listeriosis outbreak associated with caramel apples. We defined an ...outbreak-associated case as an infection with one or both of two outbreak strains of Listeria monocytogenes highly related by whole-genome multilocus sequence typing (wgMLST) from 1 October 2014 to 1 February 2015. Single-interviewer open-ended interviews identified the source. Outbreak-associated cases were compared with non-outbreak-associated cases and traceback and environmental investigations were performed. We identified 35 outbreak-associated cases in 12 states; 34 (97%) were hospitalized and seven (20%) died. Outbreak-associated ill persons were more likely to have eaten commercially produced, prepackaged caramel apples (odds ratio 326·7, 95% confidence interval 32·2–3314). Environmental samples from the grower's packing facility and distribution-chain whole apples yielded isolates highly related to outbreak isolates by wgMLST. This outbreak highlights the importance of minimizing produce contamination with L. monocytogenes. Investigators should perform single-interviewer open-ended interviews when a food is not readily identified.
•Dysfunction in glutamatergic and cholinergic signaling in schizophrenia is discussed.•The advantages of allosteric modulation are discussed.•Activation of the M1 mAChR targets the cognitive and ...negative symptoms of schizophrenia.•We provide an overview of M1 allosteric agonists and issues hindering development.•M1 positive allosteric modulators (PAMs) represent a productive path forward.
Allosteric modulation of AMPA, NR2B, mGlu2, mGlu5 and M1, targeting glutamatergic dysfunction, represents a significant area of research for the treatment of schizophrenia. Of these targets, clinical promise has been demonstrated using muscarinic activators for the treatment of Alzheimer's disease (AD) and schizophrenia. These diseases have inspired researchers to determine the effects of modulating cholinergic transmission in the forebrain, which is primarily regulated by one of five subtypes of muscarinic acetylcholine receptor (mAChR), a subfamily of G-protein-coupled receptors (GPCRs). Of these five subtypes, M1 is highly expressed in brain regions responsible for learning, cognition and memory. Xanomeline, an orthosteric muscarinic agonist with modest selectivity, was one of the first compounds that displayed improvements in behavioral disturbances in AD patients and efficacy in schizophrenics. Since these initial clinical results, many scientists, including those in our laboratories, have strived to elucidate the role of M1 with compounds that display improved selectivity for this receptor by targeting allosteric modes of receptor activation. A survey of selected compounds in this area will be presented.
Allosteric modulation of a variety of GPCRs, targeting glutamatergic dysfunction, represents a significant area of research for the treatment of schizophrenia. Here, we summarize a group of selective M1 agonists including activity at other muscarinic receptors, ancillary pharmacology and relevant DMPK profiles, results from in vitro assays and native tissue experiments, as well as important in vivo findings.
Accumulating evidence suggests that selective M4 muscarinic acetylcholine receptor (mAChR) activators may offer a novel strategy for the treatment of psychosis. However, previous efforts to develop ...selective M4 activators were unsuccessful because of the lack of M4 mAChR subtype specificity and off-target muscarinic adverse effects. We recently developed VU0152100, a highly selective M4 positive allosteric modulator (PAM) that exerts central effects after systemic administration. We now report that VU0152100 dose-dependently reverses amphetamine-induced hyperlocomotion in rats and wild-type mice, but not in M4 KO mice. VU0152100 also blocks amphetamine-induced disruption of the acquisition of contextual fear conditioning and prepulse inhibition of the acoustic startle reflex. These effects were observed at doses that do not produce catalepsy or peripheral adverse effects associated with non-selective mAChR agonists. To further understand the effects of selective potentiation of M4 on region-specific brain activation, VU0152100 alone and in combination with amphetamine were evaluated using pharmacologic magnetic resonance imaging (phMRI). Key neural substrates of M4-mediated modulation of the amphetamine response included the nucleus accumbens (NAS), caudate-putamen (CP), hippocampus, and medial thalamus. Functional connectivity analysis of phMRI data, specifically assessing correlations in activation between regions, revealed several brain networks involved in the M4 modulation of amphetamine-induced brain activation, including the NAS and retrosplenial cortex with motor cortex, hippocampus, and medial thalamus. Using in vivo microdialysis, we found that VU0152100 reversed amphetamine-induced increases in extracellular dopamine levels in NAS and CP. The present data are consistent with an antipsychotic drug-like profile of activity for VU0152100. Taken together, these data support the development of selective M4 PAMs as a new approach to the treatment of psychosis and cognitive impairments associated with psychiatric disorders such as schizophrenia.
Background and Aims. Dried grapes from Sunmuscat compose more than 50% of Australia’s production. Sunmuscat is late ripening which can lead to suboptimal drying conditions and darkening of the final ...product. The response of Sunmuscat to varying cane number per vine was studied with the aim to promote earlier ripening and optimise berry size and yield, without detrimental effects on dried product quality. Methods and Results. The study was conducted in a trellis dried, commercial vineyard with pruning level treatments of 6, 9, 12, and 15 canes per vine over 3 seasons. It included assessment of budburst and fruitfulness in spring; monitoring of grape ripening; measurement of yield, bunch number, and moisture content at harvest; and post-harvest assessment of dry berry mass and fruit colour. Traits strongly affected by season were fruitfulness, yield, berry development, juice composition (TSS, pH, and TA), and dried grape quality (colour, dry berry mass, and sugar per berry). Retention of high cane numbers produced a slight delay in ripening (i.e., a mean of 1.1°Brix), small berries, and an asymptotic yield response without an effect on dried fruit colour or moisture. A linear response for bunch loss between spring and harvest was found with increasing cane number. Conclusions. Retention of fewer canes increased berry size and promoted earlier ripening, but at the expense of yield. Significance of the Study. Bunch loss between spring and harvest was the major yield determinant being more important than budburst, shoot fruitfulness, or berries per bunch.
Lanthanum tricyanide efficiently catalyzes a benzoin-type coupling between acyl silanes and ketones. Yields range from moderate to excellent over a broad substrate scope encompassing aryl, alkyl, ...electron-rich, and sterically hindered ketones.
This letter describes the chemical optimization of a novel series of M
positive allosteric modulators (PAMs) based on a 5-amino-thieno2,3-cpyridazine core, developed via iterative parallel synthesis, ...and culminating in the highly utilized rodent in vivo tool compound, VU0467154 (5). This is the first report of the optimization campaign (SAR and DMPK profiling) that led to the discovery of VU0467154, and details all of the challenges faced in allosteric modulator programs (steep SAR, species differences in PAM pharmacology and subtle structural changes affecting CNS penetration).
REASONS FOR PERFORMING STUDY: The carrier prevalence of severe combined immunodeficiency (SCID), lavender foal syndrome (LFS) and cerebellar abiotrophy (CA) in Arabian foals in South Africa was ...determined in order to quantify the potential impact of these conditions locally. Furthermore, the carrier prevalence of SCID prior to and following the introduction of a genetic test was compared to evaluate the effect of testing in the population. OBJECTIVES: To estimate the carrier prevalence of SCID, LFS and CA in registered purebred Arabians born in South Africa in the 2004/5 and 2009/10 foaling seasons and compare the changes in prevalence in these disorders between the 2 groups of foals. STUDY DESIGN: Cross‐sectional survey. METHODS: Samples were collected from individuals randomly selected from 2 populations of purebred Arabian foals born during the 2004/5 and 2009/10 foaling seasons. Genetic testing for SCID, LFS and CA was performed on DNA extracts using specific polymerase chain reactions, with the products being analysed using fragment analysis on a genetic analyser. RESULTS: The carrier prevalence of LFS and CA for the 2009/10 season was 11.7% (95% confidence interval CI 7.6–17.0%) and 5.1% (95% CI 2.5–9.1%), respectively, with no statistically significant change in prevalence between the 2004/5 and 2009/10 foaling seasons. However, the carrier prevalence of SCID was found to have decreased significantly from 6.4% (95% CI 4.8–8.3%) in the 2004/5 foals to 3.4% (95% CI 2.2–5.1%) in the 2009/10 foals (P = 0.009). CONCLUSIONS: The results of this study indicate that genetic screening of Arabian horses for SCID may have played a role in significantly reducing the carrier prevalence within the breeding population and thereby reducing the birth of clinically affected individuals. This study provides an indication of the positive effect of genetic screening for specific conditions in horses.
The Hawaiian Islands form as the Pacific Plate moves over a ‘hot spot’ in the earth’s mantle where magma extrudes through the crust to build huge shield volcanos. The islands subside and erode as the ...plate carries them to the north‐west, eventually to become coral atolls and seamounts. Thus islands are ordered linearly by age, with the oldest islands in the north‐west (e.g. Kauai at 5.1 Ma) and the youngest in the south‐east (e.g. Hawaii at 0.43 Ma). K–Ar estimates of the date of an island’s formation provide a maximum age for the taxa inhabiting the island. These ages can be used to calibrate rates of molecular change under the following assumptions: (i) K–Ar dates are accurate; (ii) tree topologies show that derivation of taxa parallels the timing of island formation; (iii) populations do not colonize long after island emergence; (iv) the coalescent point for sister taxa does not greatly predate the formation of the colonized younger island; (v) saturation effects and (vi) among‐lineage rate variation are minimal or correctable; and (vii) unbiased standard errors of distances and regressions can be estimated from multiple pairwise comparisons. We use the approach to obtain overall corrected rate calibrations for: (i) part of the mitochondrial cytochrome b gene in Hawaiian drepanidines (0.016 sequence divergence/Myr); (ii) the Yp1 gene in Hawaiian Drosophila (0.019/Myr Kambysellis et al. 1995); and (iii) parts of the mitochondrial 12S and 16S rRNA and tRNAval in Laupala crickets (0.024–0.102/Myr, Shaw 1996). We discuss the reliability of the estimates given the assumptions (i–vii) above and contrast the results with previous calibrations of Adh in Hawaiian Drosophila and chloroplast DNA in lobeliods.
This letter details the continued chemical optimization of a novel series of M
positive allosteric modulators (PAMs) based on a 5-amino-thieno2,3-cpyridazine core by incorporating a 3-amino azetidine ...amide moiety. The analogs described within this work represent the most potent M
PAMs reported for this series to date. The SAR to address potency, clearance, subtype selectivity, CNS exposure, and P-gp efflux are described. This work culminated in the discovery of VU6000918, which demonstrated robust efficacy in a rat amphetamine-induced hyperlocomotion reversal model at a minimum efficacious dose of 0.3mg/kg.
We report on a case of listeriosis in a patient who probably consumed a prepackaged romaine lettuce-containing product recalled for Listeria monocytogenes contamination. Although definitive ...epidemiological information demonstrating exposure to the specific recalled product was lacking, the patient reported consumption of a prepackaged romaine lettuce-containing product of either the recalled brand or a different brand. A multinational investigation found that patient and food isolates from the recalled product were indistinguishable by pulsed-field gel electrophoresis and were highly related by whole genome sequencing, differing by four alleles by whole genome multilocus sequence typing and by five high-quality single nucleotide polymorphisms, suggesting a common source. To our knowledge, this is the first time prepackaged lettuce has been identified as a likely source for listeriosis. This investigation highlights the power of whole genome sequencing, as well as the continued need for timely and thorough epidemiological exposure data to identify sources of foodborne infections.
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