Mouse tissue harvest-induced hypoxia rapidly alters the in vivo metabolome, between-genotype metabolite level differences, and 13C-tracing enrichments

OBJECTIVE: Metabolomics as an approach to solve biological problems is exponentially increasing in use. Thus, this a pivotal time for the adoption of best practices. It is well known that disrupted tissue oxygen supply rapidly alters cellular energy charge. However, the speed and extent to which delayed mouse tissue freezing after dissection alters the broad metabolome is not well described. Furthermore, how tissue genotype may modulate such metabolomic drift and the degree to which traced METHODS: By combined liquid chromatography (LC)- and gas chromatography (GC)-mass spectrometry (MS), we measured how levels of 255 mouse liver metabolites changed following 30-second, 1-minute, 3-minute, and 10-minute freezing delays. We then performed test-of-concept delay-to-freeze experiments evaluating broad metabolomic drift in mouse heart and skeletal muscle, differential metabolomic change between wildtype (WT) and mitochondrial pyruvate carrier (MPC) knockout mouse livers, and shifts in RESULTS: Our data demonstrate that delayed mouse tissue freezing after dissection leads to rapid hypoxia-driven remodeling of the broad metabolome, induction of both false-negative and false-positive between-genotype differences, and restructuring of CONCLUSIONS: Our findings provide a previously absent, systematic illustration of the extensive, multi-domain metabolomic changes occurring within the early minutes of delayed tissue freezing. They also provide a novel, detailed resource of mouse liver ex vivo, hypoxic metabolomic remodeling

Summary of the Very Large Hadron Collider Physics and Detector Workshop

One of the options for an accelerator beyond the LHC is a hadron collider with higher energy. Work is going on to explore accelerator technologies that would make such a machine feasible. This workshop concentrated on the physics and detector issues associated with a hadron collider with an energy in the center of mass of the order of 100 to 200 TeV

Government Spending Cycles: Ideological or Opportunistic?

ands. The time series analysis, covering the period 1953–1993, allows for different types of government spending. In general, spending is inspired by ideological and opportunistic motives: all government expenditure categories show an upward drift during election times and the partisan motives behind government spending are clearly revealed: left-wing cabinets attach greater importance to social security and health care than right-wing cabinets and right-wing cabinets value expenditure on infrastructure and defense more than left-wing parties. Constructive comments by Frans van Winden, Wilko Letterie, Peter Cornelisse, Arie Ros, André de Moor, Harry ter Rele and an anonymous referee are gratefully acknowledged

All eyes on the signal? - Mapping cohesive discourse structures with eye-tracking data of explanation videos

In this paper, we consider the issue of how the fine-grained multimodal design of educational explanation videos, such as those widely available on YouTube and other platforms, may be made accessible to empirical studies of reception and effectiveness. This is necessary because previous research has often led to conflicting conclusions concerning the roles of particular design elements. We argue that this may largely be due to insufficient characterizations of multimodal design itself. To achieve tighter control of this potential source of variation, we present a multimodal descriptive annotation framework drawing on multimodal (cohesive) film discourse analysis. This framework is seen as a critical first step toward being able to highlight just those differences in design that have functional consequences. For such consequences to accrue, however, viewers need to attend differently to corresponding design differences. The goal of the current paper, therefore, is to use eye-tracking techniques to explore the extent to which discourse structures revealed by our analytic framework relate to recipients' attention allocation. We hypothesize that any potentially emerging anomalies in regards to discourse organization, such as instances of unsuccessful cohesion signaling, may have correlations in the behavioral data. We report our current state of development for performing this kind of multimodal cohesion analysis and some of the unresolved challenges raised when considering how such analyses may be related to performance data

Treatment of Travel Expenses by Golf Course Patrons: Sunk or Bundled Costs and the First and Third Laws of Demand

To attract golf patrons, sport managers must understand consumption patterns of the golfer. Importantly, the treatment of travel costs must be understood. According to the Alchian-Allen (1964) theorem, golfers treat travel costs as bundled costs (third law of economic demand) whereas classical consumer theory indicates that golfers treat travel costs as sunk costs (first law of economic demand). The purpose of this study was to determine if golf patrons treated travel costs as sunk costs or if they treated travel costs as a bundled cost. Data from a survey of course patrons in Ohio support the treatment of travel costs as bundled costs by golf course patrons, especially those classified as tourists. The strong, positive correlation found between distance traveled and the cost of greens fees enables managers to utilize geographic segmentation in choosing to whom to market their course based upon their product’s price compared to area competitors

A Precise Measurement of the Weak Mixing Angle in Neutrino-Nucleon Scattering

We report a precise measurement of the weak mixing angle from the ratio of neutral current to charged current inclusive cross-sections in deep-inelastic neutrino-nucleon scattering. The data were gathered at the CCFR neutrino detector in the Fermilab quadrupole-triplet neutrino beam, with neutrino energies up to 600 GeV. Using the on-shell definition, ${\rm sin ^2\theta_W} \equiv 1 - \frac{{\rm M_W} ^2}{{\rm M_Z} ^2}$, we obtain ${\rm sin ^2\theta_W} = 0.2218 \pm 0.0025 ({\rm stat.}) \pm 0.0036 ({\rm exp.\: syst.}) \pm 0.0040 ({\rm model})$.Comment: 10 pages, Nevis Preprint #1498 (Submitted to Phys. Rev. Lett.

Calpain-5 Expression in the Retina Localizes to Photoreceptor Synapses

Purpose: We characterize calpain-5 (CAPN5) expression in retinal and neuronal subcellular compartments. Methods: CAPN5 gene variants were classified using the exome variant server, and RNA-sequencing was used to compare expression of CAPN5 mRNA in the mouse and human retina and in retinoblastoma cells. Expression of CAPN5 protein was ascertained in humans and mice in silico, in mouse retina by immunohistochemistry, and in neuronal cancer cell lines and fractionated central nervous system tissue extracts by Western analysis with eight antibodies targeting different CAPN5 regions. Results: Most CAPN5 genetic variation occurs outside its protease core; and searches of cancer and epilepsy/autism genetic databases found no variants similar to hyperactivating retinal disease alleles. The mouse retina expressed one transcript for CAPN5 plus those of nine other calpains, similar to the human retina. In Y79 retinoblastoma cells, the level of CAPN5 transcript was very low. Immunohistochemistry detected CAPN5 expression in the inner and outer nuclear layers and at synapses in the outer plexiform layer. Western analysis of fractionated retinal extracts confirmed CAPN5 synapse localization. Western blots of fractionated brain neuronal extracts revealed distinct subcellular patterns and the potential presence of autoproteolytic CAPN5 domains. Conclusions: CAPN5 is moderately expressed in the retina and, despite higher expression in other tissues, hyperactive disease mutants of CAPN5 only manifest as eye disease. At the cellular level, CAPN5 is expressed in several different functional compartments. CAPN5 localization at the photoreceptor synapse and with mitochondria explains the neural circuitry phenotype in human CAPN5 disease alleles

Determination of the Strange Quark Content of the Nucleon from a Next-to-Leading-Order QCD Analysis of Neutrino Charm Production

We present the first next-to-leading-order QCD analysis of neutrino charm production, using a sample of 6090 $\nu_\mu$- and $\bar\nu_\mu$-induced opposite-sign dimuon events observed in the CCFR detector at the Fermilab Tevatron. We find that the nucleon strange quark content is suppressed with respect to the non-strange sea quarks by a factor \kappa = 0.477 \: ^{+\:0.063}_{-\:0.053}, where the error includes statistical, systematic and QCD scale uncertainties. In contrast to previous leading order analyses, we find that the strange sea $x$-dependence is similar to that of the non-strange sea, and that the measured charm quark mass, $m_c = 1.70 \pm 0.19 \:{\rm GeV/c}^2$, is larger and consistent with that determined in other processes. Further analysis finds that the difference in $x$-distributions between $xs(x)$ and $x\bar s(x)$ is small. A measurement of the Cabibbo-Kobayashi-Maskawa matrix element $|V_{cd}|=0.232 ^{+\:0.018}_{-\:0.020}$ is also presented. uufile containing compressed postscript files of five Figures is appended at the end of the LaTeX source.Comment: Nevis R#150

Study of Zγ events and limits on anomalous ZZγ and Zγγ couplings in pp̄ collisions at s=1.96TeV

We present a measurement of the Zγ production cross section and limits on anomalous ZZγ and Zγγ couplings for form-factor scales of Λ=750 and 1000 GeV. The measurement is based on 138 (152) candidates in the eeγ (μμγ) final state using 320(290)pb-1 of pp̄ collisions at s=1.96TeV. The 95% C.L. limits on real and imaginary parts of individual anomalous couplings are |h10,30Z|<0.23, |h20,40Z|<0.020, |h10,30γ|<0.23, and |h20,40γ|<0.019 for Λ=1000GeV. © 2005 The American Physical Society

MEK inhibition synergizes with TYK2 inhibitors in NF1-associated malignant peripheral nerve sheath tumors

PURPOSE: Malignant peripheral nerve sheath tumors (MPNST) are aggressive sarcomas with limited treatment options and poor survival rates. About half of MPNST cases are associated with the neurofibromatosis type 1 (NF1) cancer predisposition syndrome. Overexpression of TYK2 occurs in the majority of MPNST, implicating TYK2 as a therapeutic target. EXPERIMENTAL DESIGN: The effects of pharmacologic TYK2 inhibition on MPNST cell proliferation and survival were examined using IncuCyte live cell assays in vitro, and downstream actions were analyzed using RNA-sequencing (RNA-seq), qPCR arrays, and validation of protein changes with the WES automated Western system. Inhibition of TYK2 alone and in combination with MEK inhibition was evaluated in vivo using both murine and human MPNST cell lines, as well as MPNST PDX. RESULTS: Pharmacologic inhibition of TYK2 dose-dependently decreased proliferation and induced apoptosis over time. RNA-seq pathway analysis on TYK2 inhibitor-treated MPNST demonstrated decreased expression of cell cycle, mitotic, and glycolysis pathways. TYK2 inhibition resulted in upregulation of the MEK/ERK pathway gene expression, by both RNA-seq and qPCR array, as well as increased pERK1/2 levels by the WES Western system. The compensatory response was tested with dual treatment with TYK2 and MEK inhibitors, which synergistically decreased proliferation and increased apoptosis in vitro. Finally, combination therapy was shown to inhibit growth of MPNST in multiple in vivo models. CONCLUSIONS: These data provide the preclinical rationale for the development of a phase I clinical trial of deucravacitinib and mirdametinib in NF1-assosciated MPNST