...we do not recommend that baricitinib or other JAK inhibitors be given to these individuals. In animal models designed to understand the temporal profiles of the SARS and Middle East respiratory ...syndrome diseases, the authors showed that interferon α and interferon β action early in the disease was beneficial, but it was damaging in the later stages.4 This finding suggests that when hospital care is required for patients with a pathogenic SARS-CoV-2 infection, JAK–STAT pathway inhibition might be a potential strategy. Because of the single-arm nature of such studies, data might be difficult to interpret, and we caution against headlines of a so-called cure when most infected individuals will recover.
BenevolentAI's knowledge graph is a large repository of structured medical information, including numerous connections extracted from scientific literature by machine learning.2 Together with ...customisations bespoke to 2019-nCoV, we used BenevolentAI to search for approved drugs that could help, focusing on those that might block the viral infection process. The receptor that 2019-nCoV uses to infect lung cells might be ACE2, a cell-surface protein on cells in the kidney, blood vessels, heart, and, importantly, lung AT2 alveolar epithelial cells (figure). By contrast, one of the six high-affinity AAK1-binding drugs was the janus kinase inhibitor baricitinib, which also binds the cyclin G-associated kinase, another regulator of endocytosis. Because the plasma concentration of baricitinib on therapeutic dosing (either as 2 mg or 4 mg once daily) is sufficient to inhibit AAK1, we suggest it could be trialled, using an appropriate patient population with 2019-nCoV acute respiratory disease, to reduce both the viral entry and the inflammation in patients, using endpoints such as the MuLBSTA score, an early warning model for predicting mortality in viral pneumonia.7 JS is editor-in-chief of Oncogene.
Spin correlations in parton shower simulations Richardson, Peter; Webster, Stephen
The European physical journal. C, Particles and fields,
02/2020, Volume:
80, Issue:
2
Journal Article
Peer reviewed
Open access
Spin correlations are an important, but often neglected, effect in modern Monte Carlo event generators. We show that they can be fully incorporated in
Herwig
7 using the algorithm originally proposed ...by Collins and Knowles in all stages of the event generation process and between the different stages of the event generation. In this paper we present the final missing ingredient, correlations in both the angular-ordered and dipole shower algorithms and between the parton shower and hard production and decay processes.
CXCR4 and Glioblastoma Richardson, Peter J
Anti-cancer agents in medicinal chemistry,
01/2016, Volume:
16, Issue:
1
Journal Article
Peer reviewed
This article focuses on the possible application of antagonists of the G-protein coupled chemokine receptor, CXCR4, for the treatment of glioblastoma and summarises the evidence for CXCR4 antagonism ...being a viable therapeutic approach. Particular attention is paid to the role of this receptor in cancer stem cell biology, and the maintenance of CXCR4 expression by the glioblastoma key driver mutations. The expression of the CXCR4 receptor, and of its ligand stromal derived factor 1 (SDF-1, CXCL12), is maintained by intracellular pathways via positive feedback loops, and is associated with the epithelial mesenchymal transition (EMT) and the generation and self-renewal of cancer stem cells. SDF-1 and CXCR4 also play a role in the generation and maintenance of the perivascular stem cell niche which contains these cancer stem cells. The available data suggest that most, if not all, glioblastoma cancer stem cells rely on CXCR4 mediated signalling to maintain their phenotype. SDF-1 and CXCR4 are alsoinvolved in many other aspects of brain tumour biology including resistance to radio- and chemotherapy, the migration of cancer cells through the brain, the generation of the tumour blood supply and the recruitment of vascular progenitor cells. These properties suggest that a CXCR4 antagonist would help in the control of this disease.
The properties of quark and gluon jets, and the differences between them, are increasingly important at the LHC. However, Monte Carlo event generators are normally tuned to data from
e
+
e
-
...collisions which are primarily sensitive to quark-initiated jets. In order to improve the description of gluon jets we make improvements to the perturbative and the non-perturbative modelling of gluon jets and include data with gluon-initiated jets in the tuning for the first time. The resultant tunes significantly improve the description of gluon jets and are now the default in Herwig 7.1.
There are limited data on the risk of hepatocellular cancer (HCC) in patients with non-alcoholic fatty liver disease (NAFLD). We aimed to estimate the risk of incident HCC among patients with NAFLD.
...We conducted a retrospective cohort study from a total of 130 facilities in the Veterans Health Administration. Patients with NAFLD diagnosed between January 1, 2004 and December 31, 2008 were included and followed until HCC diagnosis, death, or December 31, 2015. We also identified a sex- and age-matched control cohort without NAFLD. We ascertained all new HCC cases from the Central Cancer Registry and manual chart reviews. We calculated incidence rates for HCC by NAFLD status, as well as in subgroups of NAFLD patients. We used competing risk models to compare the risk of HCC in patients with NAFLD vs those without NAFLD. We reviewed electronic medical records of all HCC cases that developed in NAFLD patients without cirrhosis.
We compared 296,707 NAFLD patients with 296,707 matched controls. During 2,382,289 person-years PYs of follow-up, 490 NAFLD patients developed HCC (0.21/1000 PYs). HCC incidence was significantly higher among NAFLD patients vs controls (0.02/1000 PYs; hazard ratio, 7.62; 95% confidence interval, 5.76–10.09). Among patients with NAFLD, those with cirrhosis had the highest annual incidence of HCC (10.6/1000 PYs). Among patients with NAFLD cirrhosis, HCC risk ranged from 1.6 to 23.7 per 1000 PYs based on other demographic characteristics; risk of HCC was the highest in older Hispanics with cirrhosis. In medical record reviews, 20% of NAFLD patients with HCC had no evidence of cirrhosis.
Risk of HCC was higher in NAFLD patients than that observed in general clinical population. Most HCC cases in NAFLD developed in patients with cirrhosis. The absolute risk of HCC was higher than the accepted thresholds for HCC surveillance for most patients with NAFLD cirrhosis.
Baricitinib is an oral Janus kinase (JAK)1/JAK2 inhibitor approved for the treatment of rheumatoid arthritis (RA) that was independently predicted, using artificial intelligence (AI) algorithms, to ...be useful for COVID‐19 infection via proposed anti‐cytokine effects and as an inhibitor of host cell viral propagation. We evaluated the in vitro pharmacology of baricitinib across relevant leukocyte subpopulations coupled to its in vivo pharmacokinetics and showed it inhibited signaling of cytokines implicated in COVID‐19 infection. We validated the AI‐predicted biochemical inhibitory effects of baricitinib on human numb‐associated kinase (hNAK) members measuring nanomolar affinities for AAK1, BIKE, and GAK. Inhibition of NAKs led to reduced viral infectivity with baricitinib using human primary liver spheroids. These effects occurred at exposure levels seen clinically. In a case series of patients with bilateral COVID‐19 pneumonia, baricitinib treatment was associated with clinical and radiologic recovery, a rapid decline in SARS‐CoV‐2 viral load, inflammatory markers, and IL‐6 levels. Collectively, these data support further evaluation of the anti‐cytokine and anti‐viral activity of baricitinib and support its assessment in randomized trials in hospitalized COVID‐19 patients.
Synopsis
This study provides biochemical and cellular evidence confirming artificial intelligence (AI)‐predictions focused on anti‐cytokine signaling and potential anti‐viral effects for baricitinib, along with a case series, supporting its potential utility in hospitalized COVID‐19 patients.
Baricitinib, an oral Janus kinase (JAK)1/JAK2 inhibitor used to treat rheumatoid arthritis, was hypothesised using AI to be useful in COVID‐19.
Baricitinib‐mediated inhibition of numb associated kinases utilized by SARS‐CoV‐2 for its propagation, led to reduced viral infectivity in primary liver spheroids.
Baricitinib reduces levels of cytokines implicated in COVID‐19 and inhibits their signaling.
In patients with bilateral COVID‐19 pneumonia, baricitinib treatment was associated with clinical and radiologic recovery, a rapid decline in SARS‐CoV‐2 viral load, inflammatory markers, and IL‐6 levels.
This study provides biochemical and cellular evidence confirming artificial intelligence (AI)‐predictions focused on anti‐cytokine signaling and potential anti‐viral effects for baricitinib, along with a case series, supporting its potential utility in hospitalized COVID‐19 patients.
Rechargeable solid-state sodium-ion batteries (SSSBs) hold great promise for safer and more energy-dense energy storage. However, the poor electrochemical stability between current sulfide-based ...solid electrolytes and high-voltage oxide cathodes has limited their long-term cycling performance and practicality. Here, we report the discovery of the ion conductor Na
Y
Zr
Cl
(NYZC) that is both electrochemically stable (up to 3.8 V vs. Na/Na
) and chemically compatible with oxide cathodes. Its high ionic conductivity of 6.6 × 10
S cm
at ambient temperature, several orders of magnitude higher than oxide coatings, is attributed to abundant Na vacancies and cooperative MCl
rotation, resulting in an extremely low interfacial impedance. A SSSB comprising a NaCrO
+ NYZC composite cathode, Na
PS
electrolyte, and Na-Sn anode exhibits an exceptional first-cycle Coulombic efficiency of 97.1% at room temperature and can cycle over 1000 cycles with 89.3% capacity retention at 40 °C. These findings highlight the immense potential of halides for SSSB applications.
In the pursuit of urgently needed, energy dense solid-state batteries for electric vehicle and portable electronics applications, halide solid electrolytes offer a promising path forward with ...exceptional compatibility against high-voltage oxide electrodes, tunable ionic conductivities, and facile processing. For this family of compounds, synthesis protocols strongly affect cation site disorder and modulate Li+ mobility. In this work, we reveal the presence of a high concentration of stacking faults in the superionic conductor Li3YCl6 and demonstrate a method of controlling its Li+ conductivity by tuning the defect concentration with synthesis and heat treatments at select temperatures. Leveraging complementary insights from variable temperature synchrotron X-ray diffraction, neutron diffraction, cryogenic transmission electron microscopy, solid-state nuclear magnetic resonance, density functional theory, and electrochemical impedance spectroscopy, we identify the nature of planar defects and the role of nonstoichiometry in lowering Li+ migration barriers and increasing Li site connectivity in mechanochemically synthesized Li3YCl6. We harness paramagnetic relaxation enhancement to enable 89Y solid-state NMR and directly contrast the Y cation site disorder resulting from different preparation methods, demonstrating a potent tool for other researchers studying Y-containing compositions. With heat treatments at temperatures as low as 333 K (60 °C), we decrease the concentration of planar defects, demonstrating a simple method for tuning the Li+ conductivity. Findings from this work are expected to be generalizable to other halide solid electrolyte candidates and provide an improved understanding of defect-enabled Li+ conduction in this class of Li-ion conductors.
First released in 2010, the Rivet library forms an important repository for
analysis code, facilitating comparisons between measurements of the final
state in particle collisions and theoretical ...calculations of those final
states. We give an overview of Rivet's current design and implementation, its
uptake for analysis preservation and physics results, and summarise recent
developments including propagation of MC systematic-uncertainty weights,
heavy-ion and ep physics, and systems for detector emulation. In addition,
we provide a short user guide that supplements and updates the Rivet user
manual.
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