Autophagic impairment is implicated in nonalcoholic fatty liver disease (NAFLD), but the molecular mechanism is unclear. We found that autophagic flux was significantly inhibited in 3 murine models ...of NAFLD. Interestingly, the number of acidic organelles and the level of mature cathepsin D were reduced, suggesting defective lysosome acidification. Asparagine synthetase (ASNS) was induced by endoplasmic reticulum stress, leading to the generation of asparagine, which inhibited lysosome acidification. Both steatotic‐ and asparagine‐ treated hepatocytes showed reduced lysosomal acidity and retention of lysosomal calcium. Knockdown of ASNS in steatotic hepatocytes restored autophagic flux. As a potential biomarker, increased serum p62/sequestosome 1 (SQSTM1) level was an independent risk factor for patients with steatosis and lobular inflammation. Impaired autophagy in NAFLD is elicited by defective lysosome acidification, which is caused by ASNS‐induced asparagine synthesis under endoplasmic reticulum stress and subsequent retention of lysosomal calcium. p62/SQSTM1 could be used as a noninvasive biomarker in the diagnosis of NAFLD patients.—Wang, X., Zhang, X., Chu, E. S. H., Chen, X., Kang, W., Wu, F., To, K.‐F., Wong, V. W. S., Chan, H. L. Y., Chan, M. T. V., Sung, J. J. Y., Wu, W. K. K., Yu, J. Defective lysosomal clearance of autophagosomes and its clinical implications in nonalcoholic steatohepatitis. FASEB J. 32, 37‐51 (2018). www.fasebj.org
Galactic cosmic rays consist of protons, electrons and ions, most of which are believed to be accelerated to relativistic speeds in supernova remnants. All components of the cosmic rays show an ...intensity that decreases as a power law with increasing energy (for example as E-2.7). Electrons in particular lose energy rapidly through synchrotron and inverse Compton processes, resulting in a relatively short lifetime (about 105 years) and a rapidly falling intensity, which raises the possibility of seeing the contribution from individual nearby sources (less than one kiloparsec away). Here we report an excess of galactic cosmic-ray electrons at energies of ∼300-800 GeV, which indicates a nearby source of energetic electrons. Such a source could be an unseen astrophysical object (such as a pulsar or micro-quasar) that accelerates electrons to those energies, or the electrons could arise from the annihilation of dark matter particles (such as a Kaluza-Klein particle with a mass of about 620 GeV).
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The mechanical properties of cells influence their cellular and subcellular functions, including cell adhesion, migration, polarization, and differentiation, as well as organelle organization and ...trafficking inside the cytoplasm. Yet reported values of cell stiffness and viscosity vary substantially, which suggests differences in how the results of different methods are obtained or analyzed by different groups. To address this issue and illustrate the complementarity of certain approaches, here we present, analyze, and critically compare measurements obtained by means of some of the most widely used methods for cell mechanics: atomic force microscopy, magnetic twisting cytometry, particle-tracking microrheology, parallel-plate rheometry, cell monolayer rheology, and optical stretching. These measurements highlight how elastic and viscous moduli of MCF-7 breast cancer cells can vary 1,000-fold and 100-fold, respectively. We discuss the sources of these variations, including the level of applied mechanical stress, the rate of deformation, the geometry of the probe, the location probed in the cell, and the extracellular microenvironment.
Artificial intelligence (AI) is a general term that implies the use of a computer to model intelligent behavior with minimal human intervention. AI, particularly deep learning, has recently made ...substantial strides in perception tasks allowing machines to better represent and interpret complex data. Deep learning is a subset of AI represented by the combination of artificial neuron layers. In the last years, deep learning has gained great momentum. In the field of orthopaedics and traumatology, some studies have been done using deep learning to detect fractures in radiographs. Deep learning studies to detect and classify fractures on computed tomography (CT) scans are even more limited. In this narrative review, we provide a brief overview of deep learning technology: we (1) describe the ways in which deep learning until now has been applied to fracture detection on radiographs and CT examinations; (2) discuss what value deep learning offers to this field; and finally (3) comment on future directions of this technology.
Celotno besedilo
Dostopno za:
DOBA, FSPLJ, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Detectors based on liquid argon (LAr) often require surfaces that can shift vacuum ultraviolet (VUV) light and reflect the visible shifted light. For the LAr instrumentation of the LEGEND-200 ...neutrinoless double beta decay experiment, several square meters of wavelength-shifting reflectors (WLSR) were prepared: the reflector Tetratex® (TTX) was in-situ evaporated with the wavelength shifter tetraphenyl butadiene (TPB). For even larger detectors, TPB evaporation will be more challenging and plastic films of polyethylene naphthalate (PEN) are considered as an option to ease scalability. In this work, we first characterized the absorption (and reflectivity) of PEN, TPB (and TTX) films in response to visible light. We then measured TPB and PEN coupled to TTX in a LAr setup equipped with a VUV sensitive photomultiplier tube. The effective VUV photon yield in the setup was first measured using an absorbing reference sample, and the VUV reflectivity of TTX quantified. The characterization and simulation of the setup along with the measurements and modelling of the optical parameters of TPB, PEN and TTX allowed to estimate the absolute quantum efficiency (QE) of TPB and PEN in LAr (at 87K) for the first time: these were found to be above 67 and 49%, respectively (at 90% CL). These results provide relevant input for the optical simulations of experiments that use TPB in LAr, such as LEGEND-200, and for experiments that plan to use TPB or PEN to shift VUV scintillation light.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
EURICA is a project at RIKEN Nishina Center aimed at studying a wide range of exotic nuclei through β-decay measurements and high-resolution γ-ray spectroscopy. The setup is located behind the ...BigRIPS fragment separator and the ZeroDegree spectrometer at the RIBF. EURICA consists of the HPGe cluster detectors from the previous Euroball and RISING projects, together with double-sided silicon-strip detectors for β-decay counting and lifetime measurements. In total, this setup provides us with the possibility to study several aspects of the exotic nuclei produced at the RIBF.
Carbonaceous aerosol is a dominant component of fine particles in Beijing. However, it is challenging to apportion its sources. Here, we applied a
newly developed method which combined radiocarbon ...(14C) with organic tracers to apportion the sources of fine carbonaceous particles at an
urban (IAP) and a rural (PG) site of Beijing. PM2.5 filter samples (24 h) were collected at both sites from 10 November to
11 December 2016 and from 22 May to 24 June 2017. 14C was determined in 25 aerosol samples (13 at IAP and 12 at PG) representing low
pollution to haze conditions. Biomass burning tracers (levoglucosan, mannosan, and galactosan) in the samples were also determined using
gas chromatography–mass spectrometry (GC-MS). Higher contributions of fossil-derived OC (OCf) were found at the urban site. The OCf / OC ratio decreased in the summer
samples (IAP: 67.8 ± 4.0 % in winter and 54.2 ± 11.7 % in summer; PG: 59.3 ± 5.7 % in winter and
50.0 ± 9.0 % in summer) due to less consumption of coal in the warm season. A novel extended Gelencsér (EG) method incorporating the
14C and organic tracer data was developed to estimate the fossil and non-fossil sources of primary and secondary OC (POC and SOC). It
showed that fossil-derived POC was the largest contributor to OC (35.8 ± 10.5 % and 34.1 ± 8.7 % in wintertime for IAP and PG,
28.9 ± 7.4 % and 29.1 ± 9.4 % in summer), regardless of season. SOC contributed 50.0 ± 12.3 % and
47.2 ± 15.5 % at IAP and 42.0 ± 11.7 % and 43.0 ± 13.4 % at PG in the winter and summer sampling periods,
respectively, within which the fossil-derived SOC was predominant and contributed more in winter. The non-fossil fractions of SOC increased in
summer due to a larger biogenic component. Concentrations of biomass burning OC (OCbb) are resolved by the extended Gelencsér method,
with average contributions (to total OC) of 10.6 ± 1.7 % and 10.4 ± 1.5 % in winter at IAP and PG and 6.5 ± 5.2 % and
17.9 ± 3.5 % in summer, respectively. Correlations of water-insoluble OC (WINSOC) and water-soluble OC (WSOC) with POC and SOC showed that
although WINSOC was the major contributor to POC, a non-negligible fraction of WINSOC was found in SOC for both fossil and non-fossil sources,
especially during winter. In summer, a greater proportion of WSOC from non-fossil sources was found in SOC. Comparisons of the source apportionment
results with those obtained from a chemical mass balance model were generally good, except for the cooking aerosol.
Data-centric applications are pushing the limits of energy-efficiency in today's computing systems, including those based on phase-change memory (PCM). This technology must achieve low-power and ...stable operation at nanoscale dimensions to succeed in high-density memory arrays. Here we use a novel combination of phase-change material superlattices and nanocomposites (based on Ge
Sb
Te
), to achieve record-low power density ≈ 5 MW/cm
and ≈ 0.7 V switching voltage (compatible with modern logic processors) in PCM devices with the smallest dimensions to date (≈ 40 nm) for a superlattice technology on a CMOS-compatible substrate. These devices also simultaneously exhibit low resistance drift with 8 resistance states, good endurance (≈ 2 × 10
cycles), and fast switching (≈ 40 ns). The efficient switching is enabled by strong heat confinement within the superlattice materials and the nanoscale device dimensions. The microstructural properties of the Ge
Sb
Te
nanocomposite and its high crystallization temperature ensure the fast-switching speed and stability in our superlattice PCM devices. These results re-establish PCM technology as one of the frontrunners for energy-efficient data storage and computing.
Plasmonic biosensing has emerged as the most sensitive label-free technique to detect various molecular species in solutions and has already proved crucial in drug discovery, food safety and studies ...of bio-reactions. This technique relies on surface plasmon resonances in ~50 nm metallic films and the possibility to functionalize the surface of the metal in order to achieve selectivity. At the same time, most metals corrode in bio-solutions, which reduces the quality factor and darkness of plasmonic resonances and thus the sensitivity. Furthermore, functionalization itself might have a detrimental effect on the quality of the surface, also reducing sensitivity. Here we demonstrate that the use of graphene and other layered materials for passivation and functionalization broadens the range of metals which can be used for plasmonic biosensing and increases the sensitivity by 3-4 orders of magnitude, as it guarantees stability of a metal in liquid and preserves the plasmonic resonances under biofunctionalization. We use this approach to detect low molecular weight HT-2 toxins (crucial for food safety), achieving phase sensitivity~0.5 fg/mL, three orders of magnitude higher than previously reported. This proves that layered materials provide a new platform for surface plasmon resonance biosensing, paving the way for compact biosensors for point of care testing.
KRAS, NRAS and BRAF mutations are among the most important oncogenic drivers in many major cancer types, such as melanoma, lung, colorectal and pancreatic cancer. There is currently no effective ...therapy for the treatment of RAS mutant cancers. LY3009120, a pan-RAF and RAF dimer inhibitor advanced to clinical study has been shown to inhibit both RAS and BRAF mutant cell proliferation in vitro and xenograft tumor growth in vivo. Abemaciclib, a CDK4/6-selective inhibitor, is currently in phase III studies for ER-positive breast cancer and KRAS mutant lung cancer. In this study, we found that combinatory treatment with LY3009120 and abemaciclib synergistically inhibited proliferation of tumor cells in vitro and led to tumor growth regression in xenograft models with a KRAS, NRAS or BRAF mutation at the doses of two drugs that were well tolerated in combination. Further in vitro screen in 328 tumor cell lines revealed that tumor cells with KRAS, NRAS or BRAF mutation, or cyclin D activation are more sensitive, whereas tumor cells with PTEN, PIK3CA, PIK3R1 or retinoblastoma (Rb) mutation are more resistant to this combination treatment. Molecular analysis revealed that abemaciclib alone inhibited Rb phosphorylation partially and caused an increase of cyclin D1. The combinatory treatment cooperatively demonstrated more complete inhibition of Rb phosphorylation, and LY3009120 suppressed the cyclin D1 upregulation mediated by abemaciclib. These results were further verified by CDK4/6 siRNA knockdown. Importantly, the more complete phospho-Rb inhibition and cyclin D1 suppression by LY3009120 and abemaciclib combination led to more significant cell cycle G
/G
arrest of tumor cells. These preclinical findings suggest that combined inhibition of RAF and d-cyclin-dependent kinases might provide an effective approach to treat patients with tumors harboring mutations in RAS or RAF genes.
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