Machine learning-based automated phenotyping of inflammatory nocifensive behavior in mice.

The discovery and development of new and potentially nonaddictive pain therapeutics requires rapid, yet clinically relevant assays of nociception in preclinical models. A reliable and scalable automated scoring system for nocifensive behavior of mice in the formalin assay would dramatically lower the time and labor costs associated with experiments and reduce experimental variability. Here, we present a method that exploits machine learning techniques for video recordings that consists of three components: key point detection, per frame feature extraction using these key points, and classification of behavior using the GentleBoost algorithm. This approach to automation is flexible as different model classifiers or key points can be used with only small losses in accuracy. The adopted system identified the behavior of licking/biting of the hind paw with an accuracy that was comparable to a human observer (98% agreement) over 111 different short videos (total 284 min) at a resolution of 1 s. To test the system over longer experimental conditions, the responses of two inbred strains, C57BL/6NJ and C57BL/6J, were recorded over 90 min post formalin challenge. The automated system easily scored over 80 h of video and revealed strain differences in both response timing and amplitude. This machine learning scoring system provides the required accuracy, consistency, and ease of use that could make the formalin assay a feasible choice for large-scale genetic studies

Effects of Engineered Nanoparticles on the Assembly of Exopolymeric Substances from Phytoplankton

The unique properties of engineered nanoparticles (ENs) that make their industrial applications so attractive simultaneously raise questions regarding their environmental safety. ENs exhibit behaviors different from bulk materials with identical chemical compositions. Though the nanotoxicity of ENs has been studied intensively, their unintended environmental impacts remain largely unknown. Herein we report experimental results of EN interactions with exopolymeric substances (EPS) from three marine phytoplankton species: Amphora sp., Ankistrodesmus angustus and Phaeodactylum tricornutum. EPS are polysaccharide-rich anionic colloid polymers released by various microorganisms that can assemble into microgels, possibly by means of hydrophobic and ionic mechanisms. Polystyrene nanoparticles (23 nm) were used in our study as model ENs. The effects of ENs on EPS assembly were monitored with dynamic laser scattering (DLS). We found that ENs can induce significant acceleration in Amphora sp. EPS assembly; after 72 hours EN-EPS aggregation reached equilibrium, forming microscopic gels of ∼4–6 µm in size. In contrast, ENs only cause moderate assembly kinetic acceleration for A. angustus and P. tricornutum EPS samples. Our results indicate that the effects of ENs on EPS assembly kinetics mainly depend on the hydrophobic interactions of ENs with EPS polymers. The cycling mechanism of EPS is complex. Nonetheless, the change of EPS assembly kinetics induced by ENs can be considered as one potential disturbance to the marine carbon cycle

Comprehensive ECG reference intervals in C57BL/6N substrains provide a generalizable guide for cardiac electrophysiology studies in mice.

Reference ranges provide a powerful tool for diagnostic decision-making in clinical medicine and are enormously valuable for understanding normality in pre-clinical scientific research that uses in vivo models. As yet, there are no published reference ranges for electrocardiography (ECG) in the laboratory mouse. The first mouse-specific reference ranges for the assessment of electrical conduction are reported herein generated from an ECG dataset of unprecedented scale. International Mouse Phenotyping Consortium data from over 26,000 conscious or anesthetized C57BL/6N wildtype control mice were stratified by sex and age to develop robust ECG reference ranges. Interesting findings include that heart rate and key elements from the ECG waveform (RR-, PR-, ST-, QT-interval, QT corrected, and QRS complex) demonstrate minimal sexual dimorphism. As expected, anesthesia induces a decrease in heart rate and was shown for both inhalation (isoflurane) and injectable (tribromoethanol) anesthesia. In the absence of pharmacological, environmental, or genetic challenges, we did not observe major age-related ECG changes in C57BL/6N-inbred mice as the differences in the reference ranges of 12-week-old compared to 62-week-old mice were negligible. The generalizability of the C57BL/6N substrain reference ranges was demonstrated by comparison with ECG data from a wide range of non-IMPC studies. The close overlap in data from a wide range of mouse strains suggests that the C57BL/6N-based reference ranges can be used as a robust and comprehensive indicator of normality. We report a unique ECG reference resource of fundamental importance for any experimental study of cardiac function in mice

Epilepsy and Psychiatric Comorbidities: Drug Selection.

Purpose of review The pharmacological treatment of patients with epilepsy and psychiatric comorbidities may sometimes represent a therapeutic challenge. This review is focused on the pharmacological management of patients with epilepsy and psychiatric problems in terms of rationalization of the antiepileptic drug (AED) treatment and the pharmacological management of the most clinically relevant psychiatric comorbidities, namely mood and anxiety disorders, psychoses, and attention deficit hyperactivity disorder (ADHD). Recent findings Up to 8% of patients with drug-resistant epilepsy develop treatment-emergent psychiatric adverse events of AED regardless of the mechanism of action of the drug and this is usually related to an underlying predisposition given by the previous psychiatric history and the involvement of mesolimbic structures. Careful history taking, periodic screening for mood and anxiety disorders, low starting doses, and slow titration schedules can reduce the possibility of AED-related problems. A pragmatic checklist for the pharmacological management of patients with epilepsy and psychiatric disorders is presented. Summary patients should be informed of potential behavioral effects of AEDs but no drugs should be excluded a priori. Any psychiatric comorbidity should be addressed in the appropriate setting and full remission and recovery should always represent the first goal of any therapeutic intervention. Neurologists should be aware of the side effects of major psychotropic drug classes in order to fully counsel their patients and other health professionals involved

Measurement of the B0s→μ+μ− Branching Fraction and Effective Lifetime and Search for B0→μ+μ− Decays

See paper for full list of authors - All figures and tables, along with any supplementary material and additional information, are available at https://lhcbproject.web.cern.ch/lhcbproject/Publications/LHCbProjectPublic/LHCb-PAPER-2017-001.html - Submitted to Phys. Rev. Lett.International audienceA search for the rare decays B0s→μ+μ− and B0→μ+μ− is performed at the LHCb experiment using data collected in pp collisions corresponding to a total integrated luminosity of 4.4 fb−1. An excess of B0s→μ+μ− decays is observed with a significance of 7.8 standard deviations, representing the first observation of this decay in a single experiment. The branching fraction is measured to be B(B0s→μ+μ−)=(3.0±0.6+0.3−0.2)×10−9, where the first uncertainty is statistical and the second systematic. The first measurement of the B0s→μ+μ− effective lifetime, τ(B0s→μ+μ−)=2.04±0.44±0.05 ps, is reported. No significant excess of B0→μ+μ− decays is found and a 95 % confidence level upper limit, B(B0→μ+μ−)<3.4×10−10, is determined. All results are in agreement with the Standard Model expectations

Searches for rare B-s(0) and B-0 decays into four muons

Searches for rare $B_s^0$ and $B^0$ decays into four muons are performed using proton-proton collision data recorded by the LHCb experiment, corresponding to an integrated luminosity of 9 $\text{fb}^{-1}$. Direct decays and decays via light scalar and $J/\psi$ resonances are considered. No evidence for the six decays searched for is found and upper limits at the 95% confidence level on their branching fractions ranging between $1.8\times10^{-10}$ and $2.6\times10^{-9}$ are set

TGFβ signaling limits lineage plasticity in prostate cancer

<div><p>Although treatment options for localized prostate cancer (CaP) are initially effective, the five-year survival for metastatic CaP is below 30%. Mutation or deletion of the <i>PTEN</i> tumor suppressor is a frequent event in metastatic CaP, and inactivation of the transforming growth factor (TGF) ß signaling pathway is associated with more advanced disease. We previously demonstrated that mouse models of CaP based on inactivation of Pten and the TGFß type II receptor (Tgfbr2) rapidly become invasive and metastatic. Here we show that mouse prostate tumors lacking Pten and Tgfbr2 have higher expression of stem cell markers and genes indicative of basal epithelial cells, and that basal cell proliferation is increased compared to Pten mutants. To better model the primarily luminal phenotype of human CaP we mutated Pten and Tgfbr2 specifically in luminal cells, and found that these tumors also progress to invasive and metastatic cancer. Accompanying the transition to invasive cancer we observed de-differentiation of luminal tumor cells to an intermediate cell type with both basal and luminal markers, as well as differentiation to basal cells. Proliferation rates in these de-differentiated cells were lower than in either basal or luminal cells. However, de-differentiated cells account for the majority of cells in micro-metastases consistent with a preferential contribution to metastasis. We suggest that active TGFß signaling limits lineage plasticity in prostate luminal cells, and that de-differentiation of luminal tumor cells can drive progression to metastatic disease.</p></div

Expression of genes associated with proliferation and stem like function.

<p>A) Overlap between genes with increased expression (log2 fold change > +1.0, p adjusted < 0.0001) in tumors compared to wild type for each of the four tumor groups shown. B) Enrichment analysis for putative transcription factor binding and GO biological process terms in genes with increased expression in double mutant tumors or in all four groups. C) Overlap between genes with lower expression (log2 fold change < -1.0, p adjusted < 0.0001) in tumors compared to wild type for each of the four tumor groups shown. D) Heat-map showing relative changes in expression for a selection of genes with links to stem cell-like function in cancer. E) A selection of the gene expression changes from D were validated by qRT-PCR in Pten and Pten;Tgfbr2 tumors (N = 4 each) shown as mean + sd. F) GSEA analysis of the CIN70 dataset that is associated with more aggressive tumors. G) qRT-PCR validation in Pten and Pten;Tgfbr2 tumors of a selection of genes from the CIN70 set and from the other GSEA shown in <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1007409#pgen.1007409.s001" target="_blank">S1 Fig</a>. * p < 0.05 by student’s T test.</p