Probing Bino-Wino Coannihilation at the LHC

We study bino-wino coannihilation scenario in the so-called spread or mini-split supersymmetry. We show that, in this model, a neutral wino has a macroscopic decay length in a wide range of parameter space. This characteristic feature could be observed as a displaced vertex plus missing transverse energy event at the LHC. In this paper, we study the current constraints and future prospects on the scenario based on the displaced vertex search performed by the ATLAS collaboration. It is found that a sizable parameter region can be probed at the 8 TeV LHC run. This search strategy will considerably extend its reach at the next stage of the LHC running, and thus play a crucial role to examine a possibility of bino dark matter in the mini-split type supersymmetric models.Comment: 21 pages, 7 figures; version accepted for publication in JHE

Higgsino Dark Matter or Not: Role of Disappearing Track Searches at the LHC and Future Colliders

Higgsino in supersymmetric standard models is known to be a promising candidate for dark matter in the Universe. Its phenomenological property is strongly affected by the gaugino fraction in the Higgsino-like state. If this is sizable, in other words, if gaugino masses are less than ${\cal O}(10)$ TeV, we may probe the Higgsino dark matter in future non-accelerator experiments such as dark matter direct searches and measurements of electric dipole moments. On the other hand, if gauginos are much heavier, then it is hard to search for Higgsino in these experiments. In this case, due to a lack of gaugino components, the mass difference between the neutral and charged Higgsinos is uniquely determined by electroweak interactions to be around $350$ MeV, which makes the heavier charged state rather long-lived, with a decay length of about $1$ cm. In this letter, we argue that a charged particle with a flight length of ${\cal O}(1)$ cm can be probed in disappearing-track searches if we require only two hits in the pixel detector. Even in this case, we can reduce background events with the help of the displaced-vertex reconstruction technique. We study the prospects of this search strategy at the LHC and future colliders for the Higgsino dark matter scenario. It is found that an almost pure Higgsino is indeed within the reach of the future $33$ TeV collider experiments. We then discuss that the interplay among collider and non-accelerator experiments plays a crucial role in testing the Higgsino dark matter scenarios. Our strategy for disappearing-track searches can also enlarge the discovery potential of pure wino dark matter as well as other electroweak-charged dark matter candidates.Comment: 7 pages, 3 figure

Extracellular nanovesicles for packaging of CRISPR-Cas9 protein and sgRNA to induce therapeutic exon skipping

Prolonged expression of the CRISPR-Cas9 nuclease and gRNA from viral vectors may cause off-target mutagenesis and immunogenicity. Thus, a transient delivery system is needed for therapeutic genome editing applications. Here, we develop an extracellular nanovesicle-based ribonucleoprotein delivery system named NanoMEDIC by utilizing two distinct homing mechanisms. Chemical induced dimerization recruits Cas9 protein into extracellular nanovesicles, and then a viral RNA packaging signal and two self-cleaving riboswitches tether and release sgRNA into nanovesicles. We demonstrate efficient genome editing in various hard-to-transfect cell types, including human induced pluripotent stem (iPS) cells, neurons, and myoblasts. NanoMEDIC also achieves over 90% exon skipping efficiencies in skeletal muscle cells derived from Duchenne muscular dystrophy (DMD) patient iPS cells. Finally, single intramuscular injection of NanoMEDIC induces permanent genomic exon skipping in a luciferase reporter mouse and in mdx mice, indicating its utility for in vivo genome editing therapy of DMD and beyond

The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force

「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target