Diameter-independent skyrmion Hall angle observed in chiral magnetic multilayers

Magnetic skyrmions are topologically non-trivial nanoscale objects. Their topology, which originates in their chiral domain wall winding, governs their unique response to a motion inducing force. When subjected to an electrical current, the chiral winding of the spin texture leads to a deflection of the skyrmion trajectory, characterised by an angle with respect to the applied force direction. This skyrmion Hall angle is predicted to be skyrmion diameter dependent. In contrast, our experimental study finds that the skyrmion Hall angle is diameter independent for skyrmions with diameters ranging from 35 to 825 nm. At an average velocity of 6 ± 1 ms−1, the average skyrmion Hall angle was measured to be 9° ± 2°. In fact, the skyrmion dynamics is dominated by the local energy landscape such as materials defects and the local magnetic configuration

Discrete Hall resistivity contribution from Néel skyrmions in multilayer nanodiscs

Magnetic skyrmions are knot-like quasiparticles. They are candidates for non-volatile data storage in which information is moved between fixed read and write terminals. The read-out operation of skyrmion-based spintronic devices will rely on the electrical detection of a single magnetic skyrmion within a nanostructure. Here we present Pt/Co/Ir nanodiscs that support skyrmions at room temperature. We measured the Hall resistivity and simultaneously imaged the spin texture using magnetic scanning transmission X-ray microscopy. The Hall resistivity is correlated to both the presence and size of the skyrmion. The size-dependent part matches the expected anomalous Hall signal when averaging the magnetization over the entire disc. We observed a resistivity contribution that only depends on the number and sign of skyrmion-like objects present in the disc. Each skyrmion gives rise to 22 ± 2 nΩ cm irrespective of its size. This contribution needs to be considered in all-electrical detection schemes applied to skyrmion-based devices. Not only the area of Néel skyrmions but also their number and sign contribute to their Hall resistivity

Molecular analysis of pediatric brain tumors identifies microRNAs in pilocytic astrocytomas that target the MAPK and NF-kappa B pathways

RT-qPCR confirms (a) up-regulation of miR-34a, miR-146a, miR-542-3p and miR-503 in pilocytic astrocytomas. (b) low expression of miR-124*, miR-129 and miR-129* in pilocytic astrocytomas. Relative expression shown as Log2 fold change compared to normal adult cerebellum and frontal lobe (normalized to miR-423-3p). Data represent two technical replicates ± SD. (ZIP 516 kb

PI3K/mTOR is a therapeutically targetable genetic dependency in diffuse intrinsic pontine glioma

Diffuse midline glioma (DMG), including tumors diagnosed in the brainstem (diffuse intrinsic pontine glioma; DIPG), are uniformly fatal brain tumors that lack effective treatment. Analysis of CRISPR/Cas9 loss-of-function gene deletion screens identified PIK3CA and MTOR as targetable molecular dependencies across patient derived models of DIPG, highlighting the therapeutic potential of the blood-brain barrier–penetrant PI3K/Akt/mTOR inhibitor, paxalisib. At the human-equivalent maximum tolerated dose, mice treated with paxalisib experienced systemic glucose feedback and increased insulin levels commensurate with patients using PI3K inhibitors. To exploit genetic dependence and overcome resistance while maintaining compliance and therapeutic benefit, we combined paxalisib with the antihyperglycemic drug metformin. Metformin restored glucose homeostasis and decreased phosphorylation of the insulin receptor in vivo, a common mechanism of PI3K-inhibitor resistance, extending survival of orthotopic models. DIPG models treated with paxalisib increased calcium-activated PKC signaling. The brain penetrant PKC inhibitor enzastaurin, in combination with paxalisib, synergistically extended the survival of multiple orthotopic patient-derived and immunocompetent syngeneic allograft models; benefits potentiated in combination with metformin and standard-of-care radiotherapy. Therapeutic adaptation was assessed using spatial transcriptomics and ATAC-Seq, identifying changes in myelination and tumor immune microenvironment crosstalk. Collectively, this study has identified what we believe to be a clinically relevant DIPG therapeutic combinational strategy

MAPK pathway activation in pilocytic astrocytoma

Pilocytic astrocytoma (PA) is the most common tumor of the pediatric central nervous system (CNS). A body of research over recent years has demonstrated a key role for mitogen-activated protein kinase (MAPK) pathway signaling in the development and behavior of PAs. Several mechanisms lead to activation of this pathway in PA, mostly in a mutually exclusive manner, with constitutive BRAF kinase activation subsequent to gene fusion being the most frequent. The high specificity of this fusion to PA when compared with other CNS tumors has diagnostic utility. In addition, the frequency of alteration of this key pathway provides an opportunity for molecularly targeted therapy in this tumor. Here, we review the current knowledge on mechanisms of MAPK activation in PA and some of the downstream consequences of this activation, which are now starting to be elucidated both in vitro and in vivo, as well as clinical considerations and possible future directions

Sir2 deletion prevents lifespan extension in 32 long-lived mutants

Activation of Sir2 orthologs is proposed to increase lifespan downstream of dietary restriction. Here, we describe an examination of the effect of 32 different lifespan-extending mutations and four methods of DR on replicative lifespan (RLS) in the short-lived sir2Δ yeast strain. In every case, deletion of SIR2 prevented RLS extension; however, RLS extension was restored when both SIR2 and FOB1 were deleted in several cases, demonstrating that SIR2 is not directly required for RLS extension. These findings indicate that suppression of the sir2Δ lifespan defect is a rare phenotype among longevity interventions and suggest that sir2Δ cells senesce rapidly by a mechanism distinct from that of wild-type cells. They also demonstrate that failure to observe lifespan extension in a short-lived background, such as cells or animals lacking sirtuins, should be interpreted with caution. © 2011 The Authors. Aging Cell © 2011 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.link_to_subscribed_fulltex