Effects of genetic deficiency of cyclooxygenase-1 or cyclooxygenase-2 on functional and histological outcomes following traumatic brain injury in mice

<p>Abstract</p> <p>Background</p> <p>Neuroinflammation contributes to the pathophysiology of acute CNS injury, including traumatic brain injury (TBI). Although prostaglandin lipid mediators of inflammation contribute to a variety of inflammatory responses, their importance in neuroinflammation is not clear. There are conflicting reports as to the efficacy of inhibiting the enzymes required for prostaglandin formation, cyclooxygenase (COX) -1 and COX-2, for improving outcomes following TBI. The purpose of the current study was to determine the role of the COX isoforms in contributing to pathological processes resulting from TBI by utilizing mice deficient in COX-1 or COX-2.</p> <p>Results</p> <p>Following a mild controlled cortical impact injury, the amount of cortical tissue loss, the level of microglial activation, and the capacity for functional recovery was compared between COX-1-deficient mice or COX-2-deficient mice, and their matching wild-type controls. The deficiency of COX-2 resulted in a minor (6%), although statistically significant, increase in the sparing of cortical tissue following TBI. The deficiency of COX-1 resulted in no detectable effect on cortical tissue loss following TBI. As determined by ³[H]-PK11195 autoradiography, TBI produced a similar increase in microglial activation in multiple brain regions of both COX-1 wild-type and COX-1-deficient mice. In COX-2 wild-type and COX-2-deficient mice, TBI increased ³[H]-PK11195 binding in all brain regions that were analyzed. Following injury, ³[H]-PK11195 binding in the dentate gyrus and CA1 region of the hippocampus was greater in COX-2-deficient mice, as compared to COX-2 wild-type mice. Cognitive assessment was performed in the wild-type, COX-1-deficient and COX-2-deficient mice following 4 days of recovery from TBI. There was no significant cognitive effect that resulted from the deficiency of either COX-1 or COX-2, as determined by acquisition and spatial memory retention testing in a Morris water maze.</p> <p>Conclusion</p> <p>These findings suggest that the deficiency of neither COX-1 nor COX-2 is sufficient to alter cognitive outcomes following TBI in mice.</p

Exact synthesis of multiqubit Clifford-cyclotomic circuits

Let $n\geq 8$ be an integer divisible by 4. The Clifford-cyclotomic gate set $\mathcal{G}_n$ is the universal gate set obtained by extending the Clifford gates with the $z$-rotation $T_n = \mathrm{diag}(1,\zeta_n)$, where $\zeta_n$ is a primitive $n$-th root of unity. In this note, we show that, when $n$ is a power of 2, a multiqubit unitary matrix $U$ can be exactly represented by a circuit over $\mathcal{G}_n$ if and only if the entries of $U$ belong to the ring $\mathbb{Z}[1/2,\zeta_n]$. We moreover show that $\log(n)-2$ ancillas are always sufficient to construct a circuit for $U$. Our results generalize prior work to an infinite family of gate sets and show that the limitations that apply to single-qubit unitaries, for which the correspondence between Clifford-cyclotomic operators and matrices over $\mathbb{Z}[1/2,\zeta_n]$ fails for all but finitely many values of $n$, can be overcome through the use of ancillas

The Politics of Parliamentary Restoration and Renewal: Decisions, Discretion, Democracy

An extensive literature on aversive constitutionalism and elite blockages outlines the manner in which embedded political elites will generally reject or dilute reform agendas that threaten their privileged position within a constitutional configuration. It is for exactly this reason that the same seam of scholarship frequently highlights the role of crises in terms of providing a ‘window of opportunity’ through which a significant or fundamental recalibration of a political system may be achieved. ‘The Palace of Westminster’ the Joint Committee on Restoration and Renewal (R&R) concluded in September 2016 ‘faces an impending crisis which we cannot possibly ignore’. Their recommendation was that the Palace be completely vacated for five to eight years so that a multibillion-pound programme of rebuilding work can be undertaken. This article offers the first research-based analysis of the ‘Scoping & Planning’ stage (2012–2016) and reveals the ‘hidden politics’ of R&R in the sense of how it threatens both the British Political Tradition and the position of the two main parties. This explains the nature of the very closed and secretive decision-making processes that have characterised this stage and why a number of formative decision-making points that have been deployed to frame and restrict the reform parameters

Induction of miR-155 after Brain Injury Promotes Type 1 Interferon and has a Neuroprotective Effect.

Traumatic brain injury (TBI) produces profound and lasting neuroinflammation that has both beneficial and detrimental effects. Recent evidence has implicated microRNAs (miRNAs) in the regulation of inflammation both in the periphery and the CNS. We examined the expression of inflammation associated miRNAs in the context of TBI using a mouse controlled cortical impact (CCI) model and found increased levels of miR-21, miR-223 and miR-155 in the hippocampus after CCI. The expression of miR-155 was elevated 9-fold after CCI, an increase confirmed by in situ hybridization (ISH). Interestingly, expression of miR-155 was largely found in neuronal nuclei as evidenced by co-localization with DAPI in MAP2 positive neurons. In miR-155 knock out (KO) mice expression of type I interferons IFNα and IFNβ, as well as IFN regulatory factor 1 and IFN-induced chemokine CXCL10 was decreased after TBI relative to wild type (WT) mice. Unexpectedly, miR-155 KO mice had increased levels of microglial marker Iba1 and increased neuronal degeneration as measured by fluoro-jade C (FJC) staining, suggesting a neuroprotective role for miR-155 in the context of TBI. This work demonstrates a role for miR-155 in regulation of the IFN response and neurodegeneration in the aftermath of TBI. While the presence of neuronal nuclear miRNAs has been described previously, their importance in disease states is relatively unknown. Here, we show evidence of dynamic regulation and pathological function of a nuclear miRNA in TBI

Traumatic brain injury increases levels of miR-21 in extracellular vesicles: implications for neuroinflammation

Traumatic brain injury (TBI) is an important health concern and effective treatment strategies remain elusive. Understanding the complex multicellular response to TBI may provide new avenues for intervention. In the context of TBI, cell–cell communication is critical. One relatively unexplored form of cell–cell communication in TBI is extracellular vesicles (EVs). These membrane‐bound vesicles can carry many different types of cargo between cells. Recently, miRNA in EVs have been shown to mediate neuroinflammation and neuronal injury. To explore the role of EV‐associated miRNA in TBI, we isolated EVs from the brain of injured mice and controls, purified RNA from brain EVs, and performed miRNA sequencing. We found that the expression of miR‐212 decreased, while miR‐21, miR‐146, miR‐7a, and miR‐7b were significantly increased with injury, with miR‐21 showing the largest change between conditions. The expression of miR‐21 in the brain was primarily localized to neurons near the lesion site. Interestingly, adjacent to these miR‐21‐expressing neurons were activated microglia. The concurrent increase in miR‐21 in EVs with the elevation of miR‐21 in neurons, suggests that miR‐21 is secreted from neurons as potential EV cargo. Thus, this study reveals a new potential mechanism of cell–cell communication not previously described in TBI

Author Correction: Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Correction to this paper has been published: https://doi.org/10.1038/s41467-020-20128-w

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Author Correction:Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples (Nature Communications, (2020), 11, 1, (4748), 10.1038/s41467-020-18151-y)

The original version of this Article omitted from the author list the 9th author Yize Li, who is from the ‘The McDonnell Genome Institute at Washington University, St. Louis, MO 63108, USA and Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, MO 63108, USA’. This has been corrected in both the PDF and HTML versions of the Article

A Leptophobic Z' And Dark Matter From Grand Unification

We explore the phenomenology of Grand Unified Models based on the E_6 group, focusing on the Z' with suppressed couplings to leptons that can appear in such models. We find that this Z' can accommodate the W+dijets anomaly reported by the CDF collaboration. Furthermore, a viable dark matter candidate in the form of a right-handed sneutrino is also present within the fundamental 27-dimensional representation of E_6. Through its sizable couplings to the Z', the dark matter is predicted to possess an elastic scattering cross section with neutrons which can generate the signals reported by the CoGeNT and DAMA/LIBRA collaborations. To avoid being overproduced in the early universe, the dark matter must annihilate to leptons through the exchange of charged or neutral fermions which appear in the 27 of E_6, providing an excellent fit to the gamma ray spectrum observed from the Galactic Center by the Fermi Gamma Ray Space Telescope.Comment: 6 pages, 2 figur

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts.publishedVersio