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| 2. |
- Alimena, Juliette, et al.
(författare)
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Searching for long-lived particles beyond the Standard Model at the Large Hadron Collider
- 2020
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Ingår i: Journal of Physics G. - : IOP Publishing. - 0954-3899 .- 1361-6471. ; 47:9
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Tidskriftsartikel (refereegranskat)abstract
- Particles beyond the Standard Model (SM) can generically have lifetimes that are long compared to SM particles at the weak scale. When produced at experiments such as the Large Hadron Collider (LHC) at CERN, these long-lived particles (LLPs) can decay far from the interaction vertex of the primary proton-proton collision. Such LLP signatures are distinct from those of promptly decaying particles that are targeted by the majority of searches for new physics at the LHC, often requiring customized techniques to identify, for example, significantly displaced decay vertices, tracks with atypical properties, and short track segments. Given their non-standard nature, a comprehensive overview of LLP signatures at the LHC is beneficial to ensure that possible avenues of the discovery of new physics are not overlooked. Here we report on the joint work of a community of theorists and experimentalists with the ATLAS, CMS, and LHCb experiments-as well as those working on dedicated experiments such as MoEDAL, milliQan, MATHUSLA, CODEX-b, and FASER-to survey the current state of LLP searches at the LHC, and to chart a path for the development of LLP searches into the future, both in the upcoming Run 3 and at the high-luminosity LHC. The work is organized around the current and future potential capabilities of LHC experiments to generally discover new LLPs, and takes a signature-based approach to surveying classes of models that give rise to LLPs rather than emphasizing any particular theory motivation. We develop a set of simplified models; assess the coverage of current searches; document known, often unexpected backgrounds; explore the capabilities of proposed detector upgrades; provide recommendations for the presentation of search results; and look towards the newest frontiers, namely high-multiplicity 'dark showers', highlighting opportunities for expanding the LHC reach for these signals.
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| 3. |
- Klionsky, Daniel J., et al.
(författare)
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Guidelines for the use and interpretation of assays for monitoring autophagy
- 2012
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Ingår i: Autophagy. - : Informa UK Limited. - 1554-8635 .- 1554-8627. ; 8:4, s. 445-544
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Forskningsöversikt (refereegranskat)abstract
- In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
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| 4. |
- Andreou, Charalambos M., et al.
(författare)
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Low-Power, Subthreshold Reference Circuits for the Space Environment : Evaluated with -rays, X-rays, Protons and Heavy Ions
- 2019
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Ingår i: Electronics. - : MDPI. - 2079-9292. ; 8:5
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Tidskriftsartikel (refereegranskat)abstract
- The radiation tolerance of subthreshold reference circuits for space microelectronics is presented. The assessment is supported by measured results of total ionization dose and single event transient radiation-induced effects under -rays, X-rays, protons and heavy ions (silicon, krypton and xenon). A high total irradiation dose with different radiation sources was used to evaluate the proposed topologies for a wide range of applications operating in harsh environments similar to the space environment. The proposed custom designed integrated circuits (IC) circuits utilize only CMOS transistors, operating in the subthreshold regime, and poly-silicon resistors without using any external components such as compensation capacitors. The circuits are radiation hardened by design (RHBD) and they were fabricated using TowerJazz Semiconductor's 0.18 m standard CMOS technology. The proposed voltage references are shown to be suitable for high-precision and low-power space applications. It is demonstrated that radiation hardened microelectronics operating in subthreshold regime are promising candidates for significantly reducing the size and cost of space missions due to reduced energy requirements.
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| 5. |
- Andreou, Charalambos M., et al.
(författare)
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Single Event Transients and Pulse Quenching Effects in Bandgap Reference Topologies for Space Applications
- 2016
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Ingår i: IEEE Transactions on Nuclear Science. - 0018-9499 .- 1558-1578. ; 63:6, s. 2950-2961
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Tidskriftsartikel (refereegranskat)abstract
- An architectural performance comparison of bandgap voltage reference variants, designed in a 0.18 mu m CMOS process, is performed with respect to single event transients. These are commonly induced in microelectronics in the space radiation environment. Heavy ion tests (Silicon, Krypton, Xenon) are used to explore the analog single-event transients and have revealed pulse quenching mechanisms in analogue circuits. The different topologies are compared, in terms of cross-section, pulse duration and pulse amplitude. The measured results, and the explanations behind the findings, reveal important guidelines for designing analog integrated circuits, which are intended for space applications. The paper includes an analysis on how pulse quenching occurs within the indispensable current mirror, which is used in every analog circuit.
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| 7. |
- Dell'Elce, Simone, et al.
(författare)
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3D to 2D reorganization of silver-thiol nanostructures, triggered by solvent vapor annealing
- 2018
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Ingår i: Nanoscale. - : Royal Society of Chemistry (RSC). - 2040-3372 .- 2040-3364. ; 10:48, s. 23018-23026
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Tidskriftsartikel (refereegranskat)abstract
- Metal-organic composites are of great interest for a wide range of applications. The control of their structure remains a challenge, one of the problems being a complex interplay of covalent and supramolecular interactions. This paper describes the self-assembly, thermal stability and phase transitions of ordered structures of silver atoms and thiol molecules spanning from the molecular to the mesoscopic scale. Building blocks of molecularly defined clusters formed from 44 silver atoms, each particle coated by a monolayer of 30 thiol ligands, are used as ideal building blocks. By changing solvent and temperature it is possible to tune the self-assembled 3D crystals of pristine nanoparticles or, conversely, 2D layered structures, with alternated stacks of Ag atoms and thiol monolayers. The study investigates morphological, chemical and structural stability of these materials between 25 and 300 °C in situ and ex situ at the nanoscale by combining optical and electronic spectroscopic and scattering techniques, scanning probe microscopies and density-functional theory (DFT) calculations. The proposed wet-chemistry approach is relatively cheap, easy to implement, and scalable, allowing the fabricated materials with tuned properties using the same building blocks.
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| 8. |
- Klionsky, Daniel J., et al.
(författare)
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Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes
- 2008
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Ingår i: Autophagy. - : Landes Bioscience. - 1554-8627 .- 1554-8635. ; 4:2, s. 151-175
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Forskningsöversikt (refereegranskat)abstract
- Research in autophagy continues to accelerate,1 and as a result many new scientists are entering the field. Accordingly, it is important to establish a standard set of criteria for monitoring macroautophagy in different organisms. Recent reviews have described the range of assays that have been used for this purpose.2,3 There are many useful and convenient methods that can be used to monitor macroautophagy in yeast, but relatively few in other model systems, and there is much confusion regarding acceptable methods to measure macroautophagy in higher eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers of autophagosomes versus those that measure flux through the autophagy pathway; thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from fully functional autophagy that includes delivery to, and degradation within, lysosomes (in most higher eukaryotes) or the vacuole (in plants and fungi). Here, we present a set of guidelines for the selection and interpretation of the methods that can be used by investigators who are attempting to examine macroautophagy and related processes, as well as by reviewers who need to provide realistic and reasonable critiques of papers that investigate these processes. This set of guidelines is not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to verify an autophagic response.
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| 9. |
- Nazerian, Peiman, et al.
(författare)
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Diagnostic Accuracy of Point-of-Care Ultrasound Integrated into Clinical Examination for Acute Diverticulitis: A Prospective Multicenter Study
- 2021
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Ingår i: Ultraschall in der Medizin. - : GEORG THIEME VERLAG KG. - 0172-4614 .- 1438-8782. ; 42:06, s. 614-622
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Tidskriftsartikel (refereegranskat)abstract
- Purpose Diverticulitis is a common cause of abdominal pain and CT scan is commonly used for its diagnosis in the emergency department (ED). The diagnostic performance of point-of-care ultrasound (POCUS) integrated into a clinical exam for diverticulitis is still not established. We evaluate the accuracy of clinical-sonographic assessment for the diagnosis of diverticulitis and whether POCUS could improve the selection of patients needing CT scan for complicated diverticulitis. Materials and Methods This is a multicentric observational study involving adult patients suspected of having diverticulitis presenting at 4 EDs. 21 sonographer physicians were asked to diagnose diverticulitis and complicated diverticulitis based on clinical-sonographic assessment. The final diagnosis was established by two reviewers, blinded to POCUS, based on data collected during the one-month follow-up comprehensive CT scan. Results Among 393 enrolled patients, 218 (55.5 %) were diagnosed with diverticulitis and 33 (8 %) had complicated diverticulitis. The time to diagnosis by the sonographer physicians was shorter compared to standard care (97 +/- 102 vs. 330 +/- 319 minutes, p < 0.001). Clinical-sonographic assessment showed optimal sensitivity (92.7 %) and specificity (90.9 %) for diverticulitis. However, the sensitivity (50 %) for complicated diverticulitis was low. The sonographer physician would have proceeded to CT scan in 194 (49.4 %) patients and the CT scan request compared to the final diagnosis of complicated diverticulitis demonstrated 94 % sensitivity. Conclusion Clinical-sonographic assessment is rapid and accurate for the diagnosis of diverticulitis. Even if POCUS has low sensitivity for complicated diverticulitis, it can be used to safely select patients needing CT.
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| 10. |
- Parenti, Marco Daniele, et al.
(författare)
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Discovery of the 4-aminopiperidine-based compound EM127 for the site-specific covalent inhibition of SMYD3
- 2022
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Ingår i: European Journal of Medicinal Chemistry. - : Elsevier. - 0223-5234 .- 1768-3254. ; 243
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Tidskriftsartikel (refereegranskat)abstract
- Recent findings support the hypothesis that inhibition of SMYD3 methyltransferase may be a therapeutic avenue for some of the deadliest cancer types. Herein, active site-selective covalent SMYD3 inhibitors were designed by introducing an appropriate reactive cysteine trap into reversible first-generation SMYD3 inhibitors. The 4-amino-piperidine derivative EM127 (11C) bearing a 2-chloroethanoyl group as reactive warhead showed selectivity for Cys186, located in the substrate/histone binding pocket. Selectivity towards Cys186 was retained even at high inhibitor/enzyme ratio, as shown by mass spectrometry. The mode of interaction with the SMYD3 substrate/ histone binding pocket was revealed by crystallographic studies. In enzymatic assays, 11C showed a stronger SMYD3 inhibitory effect compared to the reference inhibitor EPZ031686. Remarkably, 11C attenuated the proliferation of MDA-MB-231 breast cancer cell line at the same low micromolar range of concentrations that reduced SMYD3 mediated ERK signaling in HCT116 colorectal cancer and MDA-MB-231 breast cancer cells. Furthermore, 11C (5 mu M) strongly decreased the steady-state mRNA levels of genes important for tumor biology such as cyclin dependent kinase 2, c-MET, N-cadherin and fibronectin 1, all known to be regulated, at least in part, by SMYD3. Thus, 11C is as a first example of second generation SMYD3 inhibitors; this agent represents a covalent and a site specific SMYD3 binder capable of potent and prolonged attenuation of methyltransferase activity.
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| 11. |
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| 12. |
- Talibov, Vladimir O, 1991-, et al.
(författare)
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Discovery of an allosteric ligand binding site in SMYD3 lysine methyltransferase
- 2021
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Ingår i: ChemBioChem. - : Wiley. - 1439-4227 .- 1439-7633. ; 22:9, s. 1597-1608
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Tidskriftsartikel (refereegranskat)abstract
- SMYD3 is a multifunctional epigenetic enzyme with lysine methyl transferase activity and various interaction partners. It is implicated in the pathophysiology of cancers but with an unclear mechanism. To discover tool compounds for clarifying its biochemistry and potential as a therapeutic target, a set of drug-like compounds was screened using a biosensor-based competition assay. Diperodon was identified as an allosteric ligand. The ( R )-and ( S )-enantiomers of the racemic drug were isolated and their affinities determined ( K D > = 42 and 84 ÎŒM). Co-crystallization revealed that both enantiomers bind to a previously unidentified allosteric site in the C-terminal protein binding domain, consistent with its weak inhibitory effect. No competition between diperodon and HSP90 (a known SMYD3 interaction partner) was observed although HSP90-SMYD3 binding was confirmed ( K D = 13 ÎŒM). The allosteric site appears to be druggable and suitable for exploration of non-catalytic SMYD3 functions and therapeutics with new mechanisms of action.
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