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Nashat MA, Arbona RJR, Lepherd ML, Santagostino SF, Livingston RS, Riedel ER, Lipman NS
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Ivermectin-compounded Feed Compared with Topical Moxidectin-Imidacloprid for Eradication of Demodex musculi in Laboratory Mice

JOURNAL OF THE AMERICAN ASSOCIATION FOR LABORATORY ANIMAL SCIENCE 2018 SEP; 57(5):483-497
Demodex musculi is a prostigmatid follicular mite that has rarely been reported in laboratory mice. Although prevalence of this species has not been assessed formally, we have found that many imported mouse strains from noncommercial sources harbor Demodex mites. To assess whether an acaricide can be used to eradicate this mite, infested immunocompromised mice were provided ivermectin-compounded (12 ppm) feed without restriction for 8 wk (n = 10), were treated topically with moxidectin and imidacloprid (MI; 3 and 13 mg/kg, respectively) weekly for 8 wk (n = 10), or remained untreated (n = 10). Mice were confirmed to be mite-infested before treatment and were tested after treatment by using fur plucks (FP), deep skin scrapes (DSS), and PCR analysis of fur swabs. In addition, the presence of mites was confirmed through skin biopsies at 2 study endpoints (1 wk [n = 5] and 12 wk [n = 5] after treatment). Samples collected before treatment and from untreated mice were positive for D. musculi at all time points and by all test modalities. After treatment, all ivermectin-treated animals remained infested, whereas mice treated with MI were repeatedly negative by all test modalities. An additional shortened treatment trial revealed that 4 wk of MI (n = 7) was insufficient to eradicate mites. Neither treatment produced any evidence of adverse effects according to hematology, serum chemistry parameters, behavior, body weight, and histopathology. Of the 70 PCR assays performed in treated mice, 14 were positive when FP+DSS was negative. In 6 cases where PCR results were negative, 5 were positive by FP+DSS and a single sample was positive on skin biopsy. Although PCR analysis has a high detection rate for D. musculi, FP+DSS can further enhance the detection rate. In conclusion, topical MI administered for 8 consecutive weeks can safely eradicate D. musculi from an immunocompromised mouse strain.
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Search for additional neutral MSSM Higgs bosons in the tau tau final state in proton-proton collisions at root s=13 TeV

JOURNAL OF HIGH ENERGY PHYSICS 2018 SEP 3; ?(9):? Article 007
A search is presented for additional neutral Higgs bosons in the tau tau final state in proton-proton collisions at the LHC. The search is performed in the context of the minimal supersymmetric extension of the standard model (MSSM), using the data collected with the CMS detector in 2016 at a center-of-mass energy of 13 TeV, corresponding to an integrated luminosity of 35.9 fb(-1). To enhance the sensitivity to neutral MSSM Higgs bosons, the search includes production of the Higgs boson in association with b quarks. No significant deviation above the expected background is observed. Model-independent limits at 95% confidence level (CL) are set on the product of the branching fraction for the decay into tau leptons and the cross section for the production via gluon fusion or in association with b quarks. These limits range from 18 pb at 90 GeV to 3.5 fb at 3.2 TeV for gluon fusion and from 15 pb (at 90 GeV) to 2.5 fb (at 3.2TeV) for production in association with b quarks, assuming a narrow width resonance. In the m(h)(mod+) scenario these limits translate into a 95% CL exclusion of tan beta > 6 for neutral Higgs boson masses below 250 GeV, where tan beta is the ratio of the vacuum expectation values of the neutral components of the two Higgs doublets. The 95% CL exclusion contour reaches 1.6TeV for tan beta = 60.
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PE, Poudyal N, Sturdy J, Thapa P, Zaleski S, Brodski M, Buchanan J, Caillol C, Carlsmith D, Dasu S, Dodd L, Duric S, Gomber B, Grothe M, Herndon M, Herve A, Hussain U, Klabbers P, Lanaro A, Levine A, Long K, Loveless R, Rekovic V, Ruggles T, Savin A, Smith N, Smith WH, Woods N
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Search for a heavy resonance decaying into a Z boson and a Z or W boson in 2l2q final states at root s=13 TeV

JOURNAL OF HIGH ENERGY PHYSICS 2018 SEP 18; ?(9):? Article 101
A search has been performed for heavy resonances decaying to ZZ or ZW in 2l2q final states, with two charged leptons (l = e, mu) produced by the decay of a Z boson, and two quarks produced by the decay of a W or Z boson. The analysis is sensitive to resonances with masses in the range from 400 to 4500 GeV. Two categories are defined based on the merged or resolved reconstruction of the hadronically decaying vector boson, optimized for high- and low-mass resonances, respectively. The search is based on data collected during 2016 by the CMS experiment at the LHC in proton-proton collisions with a center-of-mass energy of root s = 13 TeV, corresponding to an integrated luminosity of 35.9 fb(-1). No excess is observed in the data above the standard model background expectation. Upper limits on the production cross section of heavy, narrow spin-1 and spin-2 resonances are derived as a function of the resonance mass, and exclusion limits on the production of W' bosons and bulk graviton particles are calculated in the framework of the heavy vector triplet model and warped extra dimensions, respectively.
Zimran E, Tripodi J, Rampal R, Rappoport F, Zirkiev S, Hoffman R, Najfeld V
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Genomic characterization of spleens in patients with myelofibrosis

HAEMATOLOGICA 2018 SEP 30; 103(10):E446-E449
van der Ven AT, Connaughton DM, Ityel H, Mann N, Nakayama M, Chen J, Vivante A, Hwang DY, Schulz J, Braun DA, Schmidt JM, Schapiro D, Schneider R, Warejko JK, Daga A, Majmundar AJ, Tan WZ, Jobst-Schwan T, Hermle T, Widmeier E, Ashraf S, Amar A, Hoogstraaten CA, Hugo H, Kitzler TM, Kause F, Kolvenbach CM, Dai RF, Spaneas L, Amann K, Stein DR, Baum MA, Somers MJG, Rodig NM, Ferguson MA, Traum AZ, Daouk GH, Bogdanovic R, Stajic N, Soliman NA, Kari JA, El Desoky S, Fathy HM, Milosevic D, Al-Saffar M, Awad HS, Eid LA, Selvin A, Senguttuvan P, Sanna-Cherchi S, Rehm HL, MacArthur DG, Lek M, Laricchia KM, Wilson MW, Mane SM, Lifton RP, Lee RS, Bauer SB, Lu WN, Reutter HM, Tasic V, Shril S, Hildebrandt F
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Whole-Exome Sequencing Identifies Causative Mutations in Families with Congenital Anomalies of the Kidney and Urinary Tract

JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY 2018 SEP; 29(9):2348-2361
Background Congenital anomalies of the kidney and urinary tract (CAKUT) are the most prevalent cause of kidney disease in the first three decades of life. Previous gene panel studies showed monogenic causation in up to 12% of patients with CAKUT. Methods We applied whole-exome sequencing to analyze the genotypes of individuals from 232 families with CAKUT, evaluating for mutations in single genes known to cause human CAKUT and genes known to cause CAKUT in mice. In consanguineous or multiplex families, we additionally performed a search for novel monogenic causes of CAKUT. Results In 29 families (13%), we detected a causative mutation in a known gene for isolated or syndromic CAKUT that sufficiently explained the patient's CAKUT phenotype. In three families (1%), we detected a mutation in a gene reported to cause a phenocopy of CAKUT. In 15 of 155 families with isolated CAKUT, we detected deleterious mutations in syndromic CAKUT genes. Our additional search for novel monogenic causes of CAKUT in consanguineous and multiplex families revealed a potential single, novel monogenic CAKUT gene in 19 of 232 families (8%). Conclusions We identified monogenic mutations in a known human CAKUT gene or CAKUT phenocopy gene as the cause of disease in 14% of the CAKUT families in this study. Whole-exome sequencing provides an etiologic diagnosis in a high fraction of patients with CAKUT and will provide a new basis for the mechanistic understanding of CAKUT.
Collins D, Randesi M, da Rosa JC, Zhang Y, Kreek MJ
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Oprm1 A112G, a single nucleotide polymorphism, alters expression of stress-responsive genes in multiple brain regions in male and female mice

PSYCHOPHARMACOLOGY 2018 SEP; 235(9):2703-2711
OPRM1 A118G, a functional human mu-opioid receptor (MOR) polymorphism, is associated with drug dependence and altered stress responsivity in humans as well as altered MOR signaling. MOR signaling can regulate many cellular processes, including gene expression, and many of the long-term, stable effects of drugs and stress may stem from changes in gene expression in diverse brain regions. A mouse model bearing an equivalent polymorphism (Oprm1 A112G) was previously generated and studied. Mice homozygous for the G112 allele show differences in opioid- and stress-related phenotypes. The current study examines the expression of 24 genes related to drug and stress responsivity in the caudoputamen, nucleus accumbens, hypothalamus, hippocampus, and amygdala of drug-na < ve, stress-minimized, male and female mice homozygous for either the G112 variant allele or the wild-type A112 allele. We detected nominal genotype-dependent changes in gene expression of multiple genes. We also detected nominal sex-dependent as well as sex-by-genotype interaction effects on gene expression. Of these, four genotype-dependent differences survived correction for multiple testing: Avp and Gal in the hypothalamus and Oprl1 and Cnr1 in the hippocampus. Changes in the regulation of these genes by mu-opioid receptors encoded by the G112 allele may be involved in some of the behavioral and molecular consequences of this polymorphism observed in mice.
Allen JL, McKenzie SK, Sleith RS, Alter SE
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First genome-wide analysis of the endangered, endemic lichen Cetradonia linearis reveals isolation by distance and strong population structure

AMERICAN JOURNAL OF BOTANY 2018 SEP; 105(9):1556-1567
PREMISE OF THE STUDY: Lichenized fungi are evolutionarily diverse and ecologically important, but little is known about the processes that drive their diversification and genetic differentiation. Distributions are often assumed to be wholly shaped by ecological requirements rather than dispersal limitations. Furthermore, although asexual and sexual reproductive structures are observable, the lack of information about recombination rates makes inferences about reproductive strategies difficult. We investigated the population genomics of Cetradonia linearis, a federally endangered lichen in the southern Appalachians of eastern North America, to test the relative contributions of environmental and geographic distance in shaping genetic structure, and to characterize the mating system and genome-wide recombination. METHODS: Whole-genome shotgun sequencing was conducted to generate data for 32 individuals of C. linearis. A reference genome was assembled, and reads from all samples were aligned to generate a set of single-nucleotide polymorphisms for further analyses. KEY RESULTS: We found evidence for low rates of recombination and for isolation by distance, but not for isolation by environment. The species is putatively unisexual, given that only one mating-type locus was found. Hindcast species distribution models and the distribution of genetic diversity support C. linearis having a larger range during the Last Glacial Maximum in the southern portion of its current extent. CONCLUSIONS: Our findings contribute to the understanding of factors that shape genetic diversity in C. linearis and in fungi more broadly. Because all populations are highly genetically differentiated, the extirpation of any population would mean the loss of unique genetic diversity; therefore, our results support the continued conservation of this species.
Todt D, Moeller N, Praditya D, Kinast V, Friesland M, Engelmann M, Verhoye L, Sayed IM, Behrendt P, Thi VLD, Meuleman P, Steinmann E
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The natural compound silvestrol inhibits hepatitis E virus (HEV) replication in vitro and in vivo

ANTIVIRAL RESEARCH 2018 SEP; 157(?):151-158
Hepatitis E virus (HEV) is the causative agent of hepatitis E in humans and a member of the genus Orthohepevirus in the family Hepeviridae. HEV infections are the common cause of acute hepatitis but can also take chronic courses. Ribavirin is the treatment of choice for most patients and type I interferon (IFN) has been evaluated in a few infected transplantation patients in vivo. However, no effective and specific treatments against HEV infections are currently available. In this study, we evaluated the natural compound silvestrol, isolated from the plant Aglaia foveolata, and known for its specific inhibition of the DEAD-box RNA helicase eIF4A in state-of-the-art HEV experimental model systems. Silvestrol blocked HEV replication of different subgenomic replicons in a dose-dependent manner at low nanomolar concentrations and acted additive to ribavirin (RBV). In addition, HEV p6-based full length replication and production of infectious particles was reduced in the presence of silvestrol. A pangenotypic effect of the compound was further demonstrated with primary isolates from four different human genotypes in HEV infection experiments of hepatocyte-like cells derived from human embryonic and induced pluripotent stem cells. In vivo, HEV RNA levels rapidly declined in the feces of treated mice while no effect was observed in the vehicle treated control animals. In conclusion, silvestrol could be identified as pangenotypic HEV replication inhibitor in vitro with additive effect to RBV and further demonstrated high potency in vivo. The compound therefore may be considered in future treatment strategies of chronic hepatitis E in immunocompromised patients.
Shapiro AJ, Darmon SK, Barad DH, Gleicher N, Kushnir VA
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Vitamin D levels are not associated with ovarian reserve in a group of infertile women with a high prevalance of diminished ovarian reserve

FERTILITY AND STERILITY 2018 SEP; 110(4):761-766.e1
Objective: To determine whether a relationship exists between vitamin D (25OH-D) levels and ovarian reserve parameters (antimullerian hormone [AMH] and FSH levels) in a large cohort of infertile women with a high prevalence of diminished ovarian reserve. Design: Retrospective cohort study. Setting: Academically affiliated private fertility center. Patient(s): A total of 457 infertile women 21-50 years of age who had baseline hormone measurements. Intervention(s): None. Main Outcome Measure(s): Statistical analyses to determine whether a relationship exists between AMH, FSH, and serum 25OH-D levels. Result(s): As defined by 25OH-D <20.0 ng/mL, 74/457 patients (16.2%) had vitamin D deficiency. AMH and FSH levels did not vary between women with vitamin D deficiency and those with normal levels (0.8 +/- 3.0 vs. 0.5 +/- 1.6 ng/mL [P = .18] and 9.4 +/- 7.2 vs. 9.2 +/- 9.5 mIU/mL [P = .54], respectively). Multivariate linear regression analysis of log-transformed AMH and FSH with 25OH-D levels adjusted for age, body mass index, and seasonal variation confirmed lack of association. Receiver operating characteristic (ROC) analysis to determine if 25OH-D levels are predictive of AMH showed areas under the ROC curves (AUCs) for women <38 years of age to be 0.501, 0.554, and 0.511 for AMH threshold values of 0.5 ng/mL, 1.0 ng/mL, and 5.0 ng/mL, respectively. For women >= 38 years respective AUC values were 0.549, 0.545, and 0.557 ng/mL. Conclusion(s): Vitamin D levels were not associated with ovarian reserve in a large group of infertile women with a high prevalence of diminished ovarian reserve. Previously reported vitamin D-associated outcomes in infertility patients may, therefore, be mediated by factors other than ovarian reserve. (C) 2018 by American Society for Reproductive Medicine.
Windisch KA, Reed B, Kreek MJ
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Naltrexone and nalmefene attenuate cocaine place preference in male mice

NEUROPHARMACOLOGY 2018 SEP 15; 140(?):174-183
Cocaine addiction treatment is difficult due to the current lack of approved pharmacotherapuetics. Several preclinical and clinical studies have demonstrated that the mu opioid receptor (MOPr) antagonist/kappa opioid receptor (KOPr) partial agonist naltrexone (NTX) reduces the subjective effects and self-administration of cocaine. However, very limited research has examined the ability of the structurally similar MOPr antagonist/KOPr partial agonist nalmefene (NMF) to reduce cocaine reward. Here we examine the effect of low (1 mg/kg) and high (10 mg/kg) doses of NTX or NMF on cocaine place preference. In vivo characterization of these NTX and NMF doses were performed to examine their effectiveness at MOPr and KOPr. Results: Both NTX doses and high dose NMF significantly reduced cocaine place preference. Conversely, a significant place avoidance was observed for high dose NTX and both NMF doses. Interestingly, neither NTX nor NMF blocked cocaine-induced hyperlocomotion. High dose NTX and both NMF doses fully blocked MOPr agonist morphine-induced thermal analgesia as well as KOPr agonist U50,488H-induced locomotor discoordination. However, low dose NTX fully blocked morphine analgesia but not U50,488H locomotor discoordination suggesting that low dose NIX is effective at MOPr but not KOPr. Conclusion: Both NTX and NMF block the place preference, but not locomotor activating, effects of cocaine. These results suggest that both NTX and NMF may be viable pharmacotheraputics for some aspects of cocaine addiction. This is an important step to understanding the potential mechanism(s) of action of NTX and NMF for the development of more efficacious pharmacological treatments for substance use disorders. (C) 2018 Elsevier Ltd. All rights reserved.