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Patients undergoing methadone maintenance treatment self-report enhanced preferences for, and excessive consumption of, foods rich in sugar. However, it is unclear whether these are direct pharmacological effects of methadone or the consequences of metabolic dysfunctions induced by addiction to illicit opiates. Hence, the current study in drug-naive male Sprague-Dawley rats explored the effects of steady-state methadone delivered by osmotic mini-pumps (13 days; 0, 10, 30 mg/kg/day) on consumption of rat chow and a palatable, sweet, liquid high fructose corn syrup solution. Six days after the removal of the pumps, mRNA expression of genes involved in responses to stress and rewards were quantified: pro-opiomelanocortin in the hypothalamus, mu-opioid receptor in the nucleus accumbens, and dopamine D2 receptor in the dorsal striatum. Taste reactivity and locomotion tests were also performed throughout the study. It was found that methadone increased caloric intake from high fructose corn syrup and reduced caloric intake from chow, effects that could not be directly ascribed to changes in high fructose corn syrup taste reactivity or motor functions. However, the changes in caloric intake displayed significant tolerance, and mRNA expression analysis suggested that methadone attenuated the effect of high fructose corn syrup on pro-opiomelanocortin mRNA, and possibly on dopamine D2 receptor mRNA. These findings in rats suggest that the pharmacological effect of methadone, administered to achieve steady-state maintenance, may not be the primary cause of dietary alterations reported by patients maintained on methadone.

In social insects, natural selection operates at the level of the colony, rather than the individual, but our understanding of how colony-level phenotypes arise and vary between species is lacking. Here, we test how colony-level phenotypes vary within the fire ants by measuring the composition of colonies of the tropical fire ant, Solenopsis geminata, over a wide range of sizes at multiple times throughout the year. Similar to the well-studied fire ant species S. invicta, we find that S. geminata colony composition varies strongly with colony size, such that as colonies grow they produce increasingly large workers as well as queens and males. However, major production increases more rapidly with colony size in S. geminata than in S. invicta, which may explain our observation that S. geminata also possesses a smaller maximum colony size. Unlike S. geminata or S. invicta in the USA, we find no evidence for seasonal variation in colony composition in S. geminata in Costa Rica. Solenopsis geminata colonies from Costa Rica also exhibit continuous variation in queen number, from one to two to hundreds. Overall, this research describes how colony-level features vary within the fire ants, providing basic data that can be used to study the mechanisms underlying the development and evolution of colony-level phenotypes in social insects.

A search is presented for narrow heavy resonances decaying to a top quark and a bottom quark using data collected by the CMS experiment at root s= 13 TeV in 2016. The data set analyzed corresponds to an integrated luminosity of 35.9fb(-1). Final states that include a single lepton (e, mu), multiple jets, and missing transverse momentum are analyzed. No evidence is found for the production of a W' boson, and the production of right-handed W' bosons is excluded at 95% confidence level for masses up to 3.6 TeV depending on the scenario considered. Exclusion limits for W' bosons are also presented as a function of their coupling strength to left- and right-handed fermions. These limits on a W' boson decaying via a top and a bottom quark are the most stringent published to date. (c) 2017 The Author. Published by Elsevier B.V.

Patients with psoriasis have an increased risk of myocardial infarction, and psoriasis is now recognized as an independent risk factor for coronary heart disease and cardiovascular mortality. To understand the effects of psoriasis medications on systemic inflammation associated with cardiovascular risks, we studied blood proteins related to inflammation and cardiovascular disease archived from a phase 3 clinical trial of tofacitinib and etanercept in adults with moderate-to-severe psoriasis. A total of 157 blood proteins were quantified by a proximity extension assay from 266 patients at baseline and week 4. Protein changes in the blood after 1 month of treatment were compared between tofacitinib (10 mg two times a day) and etanercept (50 mg biweekly), and by response status at week 12. Tofacitinib and etanercept commonly reduced IL-6, CCL20, and CXCL10, but IL-17A was significantly reduced only in responders of either treatment. Compared with etanercept, tofacitinib showed a wider spectrum of cardiovascular blood protein reduction, but the protein reduction effects of tofacitinib were strictly confined to treatment responders. Tumor necrosis factor receptor 1, E-selectin, hK11, tumor necrosis factorerelated activation-induced cytokine, CHI3L1, IL-16, and matrix metalloproteinase-12 were cardiovascular proteins significantly reduced only in tofacitinib responders. Our data suggest that a short-term systemic psoriasis treatment can cause reductions in circulating inflammatory and other proteins associated with cardiovascular risks.

Fanconi anemia (FA) is a rare recessive DNA repair deficiency resulting from mutations in one of at least 22 genes. Two-thirds of FA families harbor mutations in FANCA. To genotype patients in the International Fanconi Anemia Registry (IFAR) we employed multiple methodologies, screening 216 families for FANCA mutations. We describe identification of 57 large deletions and 261 sequence variants, in 159 families. All but seven families harbored distinct combinations of two mutations demonstrating high heterogeneity. Pathogenicity of the 18 novel missense variants was analyzed functionally by determining the ability of the mutant cDNA to improve the survival of a FANCA-null cell line when treated with MMC. Overexpressed pathogenic missense variants were found to reside in the cytoplasm, and nonpathogenic in the nucleus. RNA analysis demonstrated that two variants (c.522G>C and c.1565A>G), predicted to encode missense variants, which were determined to be nonpathogenic by a functional assay, caused skipping of exons 5 and 16, respectively, and are most likely pathogenic. We report 48 novel FANCA sequence variants. Defining both variants in a large patient cohort is a major step toward cataloging all FANCA variants, and permitting studies of genotype-phenotype correlations.

Equine serum hepatitis (i.e., Theiler's disease) is a serious and often life-threatening disease of unknown etiology that affects horses. A horse in Nebraska, USA, with serum hepatitis died 65 days after treatment with equine-origin tetanus antitoxin. We identified an unknown parvovirus in serum and liver of the dead horse and in the administered antitoxin. The equine parvovirus-hepatitis (EqPV-H) shares <50% protein identity with its phylogenetic relatives of the genus Copiparvovirus. Next, we experimentally infected 2 horses using a tetanus antitoxin contaminated with EqPV-H. Viremia developed, the horses seroconverted, and acute hepatitis developed that was confirmed by clinical, biochemical, and histopathologic testing. We also determined that EqPV-H is an endemic infection because, in a cohort of 100 clinically normal adult horses, 13 were viremic and 15 were seropositive. We identified a new virus associated with equine serum hepatitis and confirmed its pathogenicity and transmissibility through contaminated biological products.

Viruses that are typically benign sometimes invade the brainstem in otherwise healthy children. We report bi-allelic DBR1 mutations in unrelated patients from different ethnicities, each of whom had brainstem infection due to herpes simplex virus 1 (HSV1), influenza virus, or norovirus. DBR1 encodes the only known RNA lariat debranching enzyme. We show that DBR1 expression is ubiquitous, but strongest in the spinal cord and brainstem. We also show that all DBR1 mutant alleles are severely hypomorphic, in terms of expression and function. The fibroblasts of DBR1-mutated patients contain higher RNA lariat levels than control cells, this difference becoming even more marked during HSV1 infection. Finally, we show that the patients' fibroblasts are highly susceptible to HSV1. RNA lariat accumulation and viral susceptibility are rescued by wild-type DBR1. Autosomal recessive, partial DBR1 deficiency underlies viral infection of the brainstem in humans through the disruption of tissue-specific and cell-intrinsic immunity to viruses.

8% of the US population has asthma. Air pollution is linked to exacerbation in susceptible individuals. The objective was to identify air pollutants that increased the risk of asthma emergency department visits during a time wherein a polluting factory was criminally convicted, changing local air pollutant levels. An ecological time-series design used a daily count of asthma emergency visits from 2007 to 2012 as the dependent variable. Independent variables air pollutants (NO2, PM2.5 CO, and O-3), controlling for meteorological conditions, were analyzed using time-series and Poisson GLM models. 76,651 emergency asthma visits were included with an average of 35 visits per day (SD = 9.2, range 11-80) in a stationary time series. Increased visit volume in fall and spring had no associations to the air pollutants. Associations between individual air pollutants occurred in otherwise low-volume months for asthma emergency visits. The strongest relationship was an 11.6% increase in the asthma emergency visit rate during the month of June. In monthly groupings that removed most of the autumn and spring months, O-3, PM2.5, CO, and NO2 were associated with 5, 4, 2, and 2% increases in asthma emergency visits, respectively. CO was the only pollutant with a negative association with asthma emergency visits, occurring in the month of April. Pollutants NO2, PM2.5 CO, and O-3 were associated with increased emergency asthma visits in some, but not all months of the year. Air pollution's impact on asthma emergencies may be masked by other, more influential seasonal triggers, such as infections or allergies.

Nearly all eukaryotic messenger RNA precursors must undergo cleavage and polyadenylation at their 3'-end for maturation. A crucial step in this process is the recognition of the AAUAAA polyadenylation signal (PAS), and the molecular mechanism of this recognition has been a long-standing problem. Here, we report the cryo-electron microscopy structure of a quaternary complex of human CPSF-160, WDR33, CPSF-30, and an AAUAAA RNA at 3.4-angstrom resolution. Strikingly, the AAUAAA PAS assumes an unusual conformation that allows this short motif to be bound directly by both CPSF-30 and WDR33. The A1 and A2 bases are recognized specifically by zinc finger 2 (ZF2) of CPSF-30 and the A4 and A5 bases by ZF3. Interestingly, the U3 and A6 bases form an intramolecular Hoogsteen base pair and directly contact WDR33. CPSF-160 functions as an essential scaffold and preorganizes CPSF-30 and WDR33 for high-affinity binding to AAUAAA. Our findings provide an elegant molecular explanation for how PAS sequences are recognized for mRNA 3'-end formation.

Neuronal Elav-like (nElavl or neuronal Hu) proteins are RNA-binding proteins that regulate RNA stability and alternative splicing, which are associated with axonal and synaptic structures. nElavl proteins promote the differentiation and maturation of neurons via their regulation of RNA. The functions of nElavl in mature neurons are not fully understood, although Elavl3 is highly expressed in the adult brain. Furthermore, possible associations between nElavl genes and several neurodegenerative diseases have been reported. We investigated the relationship between nElavl functions and neuronal degeneration using Elavl3(-/-) mice. Elavl3(-/-) mice exhibited slowly progressive motor deficits leading to severe cerebellar ataxia, and axons of Elavl3(-/-) Purkinje cells were swollen (spheroid formation), followed by the disruption of synaptic formation of axonal terminals. Deficit in axonal transport and abnormalities in neuronal polarity was observed in Elavl3(-/-) Purkinje cells. These results suggest that nElavl proteins are crucial for the maintenance of axonal homeostasis in mature neurons. Moreover, Elavl3(-/-) mice are unique animal models that constantly develop slowly progressive axonal degeneration. Therefore, studies of Elavl3(-/-) mice will provide new insight regarding axonal degenerative processes.