Essential guidelines for computational method benchmarking

In computational biology and other sciences, researchers are frequently faced with a choice between several computational methods for performing data analyses. Benchmarking studies aim to rigorously compare the performance of different methods using well-characterized benchmark datasets, to determine the strengths of each method or to provide recommendations regarding suitable choices of methods for an analysis. However, benchmarking studies must be carefully designed and implemented to provide accurate, unbiased, and informative results. Here, we summarize key practical guidelines and recommendations for performing high-quality benchmarking analyses, based on our experiences in computational biology.Comment: Minor update

Essential guidelines for computational method benchmarking

In computational biology and other sciences, researchers are frequently faced with a choice between several computational methods for performing data analyses. Benchmarking studies aim to rigorously compare the performance of different methods using well-characterized benchmark datasets, to determine the strengths of each method or to provide recommendations regarding suitable choices of methods for an analysis. However, benchmarking studies must be carefully designed and implemented to provide accurate, unbiased, and informative results. Here, we summarize key practical guidelines and recommendations for performing high-quality benchmarking analyses, based on our experiences in computational biology

Nlz1/Znf703 acts as a repressor of transcription

<p>Abstract</p> <p>Background</p> <p>Members of the NET subfamily of zinc-finger proteins are related to the Sp-family of transcription factors and are required during embryogenesis. In particular, Nlz1/Znf703 and Nlz2/Znf503 are required for formation of rhombomere 4 of the vertebrate hindbrain. While NET family proteins have been hypothesized to regulate transcription, it remains unclear if they function as activators or repressors of transcription.</p> <p>Results</p> <p>Here we demonstrate that Nlz proteins repress transcription both in cell lines and in developing zebrafish embryos. We first use standard cell culture-based reporter assays to demonstrate that Nlz1/Znf703 represses transcription of a luciferase reporter in four different cell lines. Structure-function analyses and pharmacological inhibition further reveal that Nlz1-mediated repression requires histone deacetylase activity. We next generate a stable transgenic zebrafish reporter line to demonstrate that Nlz1 promotes histone deacetylation at the transgenic promoter and repression of transgene expression during embryogenesis. Lastly, taking a genetic approach we find that endogenous Nlz proteins are required for formation of hindbrain rhombomere 4 during zebrafish embryogenesis by repressing expression of non-rhombomere 4 genes.</p> <p>Conclusion</p> <p>We conclude that Nlz1/Znf703 acts as a repressor of transcription and hypothesize that other NET family members function in a similar manner.</p

Activation of alpha4* nAChRs is necessary and sufficient for varenicline-induced reduction of alcohol consumption

Recently, the smoking cessation therapeutic varenicline, a nicotinic acetylcholine receptor (nAChR) partial agonist, has been shown to reduce alcohol consumption. However, the mechanism and nAChR subtype(s) involved are unknown. Here we demonstrate that varenicline and alcohol exposure, either alone or in combination, selectively activates dopaminergic (DAergic) neurons within the posterior, but not the anterior, ventral tegmental area (VTA). To gain insight into which nAChR subtypes may be involved in the response to alcohol, we analyzed nAChR subunit gene expression in posterior VTA DAergic neurons. Ethanol-activated DAergic neurons expressed higher levels of alpha4, alpha6, and beta3 subunit genes compared with nonactivated neurons. To examine the role of nicotinic receptors containing the alpha4 subunit (alpha4* nAChRs) in varenicline-induced reduction of alcohol consumption, we examined the effect of the drug in two complementary mouse models, a knock-out line that does not express the alpha4 subunit (alpha4 KO) and another line that expresses alpha4* nAChRs hypersensitive to agonist (Leu9\u27Ala). While varenicline (0.1-0.3 mg/kg, i.p.) reduced 2% and 20% alcohol consumption in wild-type (WT) mice, the drug did not significantly reduce consumption in alpha4 KO animals. Conversely, low doses of varenicline (0.0125-0.05 mg/kg, i.p.) that had little effect in WT mice dramatically reduced ethanol intake in Leu9\u27Ala mice. Infusion of varenicline into the posterior, but not the anterior VTA was sufficient to reduce alcohol consumption. Together, our data indicate that activation of alpha4* nAChRs is necessary and sufficient for varenicline reduction of alcohol consumption

Dopamine D_2-receptor activation elicits akinesia, rigidity, catalepsy, and tremor in mice expressing hypersensitive 4 nicotinic receptors via a cholinergic-dependent mechanism

Recent studies suggest that high-affinity neuronal nicotinic acetylcholine receptors (nAChRs) containing α4 and β2 subunits (α4β2*) functionally interact with G-protein-coupled dopamine (DA) D_2 receptors in basal ganglia. We hypothesized that if a functional interaction between these receptors exists, then mice expressing an M2 point mutation (Leu9'Ala) rendering 4 nAChRs hypersensitive to ACh may exhibit altered sensitivity to a D_2-receptor agonist. When challenged with the D_(2)R agonist, quinpirole (0.5–10 mg/kg), Leu9'Ala mice, but not wild-type (WT) littermates, developed severe, reversible motor impairment characterized by rigidity, catalepsy, akinesia, and tremor. While striatal DA tissue content, baseline release, and quinpirole-induced DA depletion did not differ between Leu9'Ala and WT mice, quinpirole dramatically increased activity of cholinergic striatal interneurons only in mutant animals, as measured by increased c-Fos expression in choline acetyltransferase (ChAT)-positive interneurons. Highlighting the importance of the cholinergic system in this mouse model, inhibiting the effects of ACh by blocking muscarinic receptors, or by selectively activating hypersensitive nAChRs with nicotine, rescued motor symptoms. This novel mouse model mimics the imbalance between striatal DA/ACh function associated with severe motor impairment in disorders such as Parkinson’s disease, and the data suggest that a D_(2)R–α4*-nAChR functional interaction regulates cholinergic interneuron activity.—Zhao-Shea, R., Cohen, B. N., Just, H., McClure-Begley, T., Whiteaker, P., Grady, S. R., Salminen, O., Gardner, P. D., Lester, H. A., Tapper, A. R. Dopamine D2-receptor activation elicits akinesia, rigidity, catalepsy, and tremor in mice expressing hypersensitive α4 nicotinic receptors via a cholinergic-dependent mechanism

Novel Barriers to Prevent Dogwood Borer (Lepidoptera: Sesiidae) and Rodent Damage in Apple Plantings

We evaluated a combination of noninsecticidal alternatives to control trunk-damaging dogwood borer, Synanthedon scitula (Harris), consisting of novel barrier technologies, used alone or in combination with mating disruption. Barrier formulations evaluated included fibrous barriers of nonwoven ethylene vinyl acetate (EVA) and nonfibrous barriers of rubberized paint (elastomer) used in building coatings. To examine efficacy of dogwood borer control in orchards, all barrier trials were replicated in field tests, both in combination with mating disruption and without it. Trunk inspections to determine whether mating disruption and barriers effectively reduced actual tree infestation showed pheromone disruption significantly reduced infestation compared with the untreated check, but was not as effective as trunk handgun sprays of chlorpyrifos. EVA trunk barriers were effective in preventing borer infestation compared with untreated trees. The elastomer did not differ from the check or the EVA treatment. There was no interaction between disruption and barrier treatments. Barrier field life and durability was assessed over 2 yr by comparing degradation over time due to weathering and other environmental effects including animal damage. The EVA persisted and remained more intact than the elastomer, but was in need of reapplication after 2 yr. Barriers were also screened for efficacy against voles in small-plot trials in nonorchard locations with known high vole pressure; they were tested either alone, combined with a repellent (thiram), or, in the case of the elastomer only, combined with an abrasive (sand). Only the EVA significantly lowered vole chewing damage relative to the untreated check

The Wow Factor? A Comparative Study of the Development of Student Music Teachers' Talents in Scotland and Australia

For some time there has been debate about differing perspectives on musical gift and musical intelligence. One view is that musical gift is innate: that it is present in certain individuals from birth and that the task of the teacher is to develop the potential which is there. A second view is that musical gift is a complex concept which includes responses from individuals to different environments and communities (Howe and Sloboda, 1997). This then raises the possibility that musical excellence can be taught. We have already explored this idea with practising musicians (Stollery and McPhee, 2002). Our research has now expanded to include music teachers in formation, and, in this paper, we look at the influences in their musical development which have either 'crystallised' or 'paralysed' the musical talent which they possess. Our research has a comparative dimension, being carried out in Scotland and in Australia. We conclude that there are several key influences in the musical development of the individual, including home and community support, school opportunities and teaching styles and that there may be education and culture-specific elements to these influences

Multi-messenger astronomy with a Southern-Hemisphere gravitational-wave observatory

Joint observations of gravitational waves and electromagnetic counterparts will answer questions about cosmology, gamma-ray bursts, and the behaviour of matter at supranuclear densities. The addition of a Southern-Hemisphere gravitational-wave observatory to proposed global networks creates a longer baseline, which is beneficial for sky localisation. We analyse how an observatory in Australia can enhance the multi-messenger astronomy capabilities of future networks. We estimate the number of binary neutron star mergers with joint observations of gravitational waves and kilonova counterparts detectable by the Vera C. Rubin Observatory. First, we consider a network of upgrades to current observatories. Adding an Australian observatory to a three-observatory network (comprising two observatories in the USA and one in Europe) boosts the rate of joint observations from $2.5^{+4.5}_{-2.0}$ per year to $5.6^{+10}_{-4.5}$ per year (a factor of two improvement). Then, we consider a network of next-generation observatories. Adding a $20$ km Australian observatory to a global network of a Cosmic Explorer $40$ km in the USA and an Einstein Telescope in Europe only marginally increases the rate from $40^{+71}_{-32}$ per year to $44^{+79}_{-35}$ per year (a factor of 1.1 improvement). The addition of an Australian observatory, however, ensures that at least two observatories are online far more often. When the Cosmic Explorer $40$ km is offline for a major upgrade, the Australian observatory increases the joint observation rate from $0.5^{+0.8}_{-0.4}$ per year to $38^{+68}_{-30}$ per year (a factor of 82 improvement). When the Einstein Telescope is offline, the joint observation rate increases from $0.2^{+0.3}_{-0.1}$ per year to $19^{+34}_{-15}$ per year (a factor of 113 improvement). We sketch out the broader science case for a Southern-Hemisphere gravitational-wave observatory.Comment: v1, 13 pages, 7 figures. Submitted to PRD on August 24 202

miRNAome analysis of the mammalian neuronal nicotinic acetylcholine receptor gene family

Nicotine binds to and activates a family of ligand-gated ion channels, neuronal nicotinic acetylcholine receptors (nAChRs). Chronic nicotine exposure alters the expression of various nAChR subtypes, which likely contributes to nicotine dependence; however, the underlying mechanisms regulating these changes remain unclear. A growing body of evidence indicates that microRNAs (miRNAs) may be involved in nAChR regulation. Using bioinformatics, miRNA library screening, site-directed mutagenesis, and gene expression analysis, we have identified a limited number of miRNAs that functionally interact with the 3\u27-untranslated regions (3\u27 UTRs) of mammalian neuronal nAChR subunit genes. In silico analyses revealed specific, evolutionarily conserved sites within the 3\u27 UTRs through which the miRNAs regulate gene expression. Mutating these sites disrupted miRNA regulation confirming the in silico predictions. In addition, the miRNAs that target nAChR 3\u27 UTRs are expressed in mouse brain and are regulated by chronic nicotine exposure. Furthermore, we show that expression of one of these miRNAs, miR-542-3p, is modulated by nicotine within the mesocorticolimbic reward pathway. Importantly, overexpression of miR-542-3p led to a decrease in the protein levels of its target, the nAChR beta2 subunit. Bioinformatic analysis suggests that a number of the miRNAs play a general role in regulating cholinergic signaling. Our results provide evidence for a novel mode of nicotine-mediated regulation of the mammalian nAChR gene family