The study of isolated airway myocytes has provided important information relative to specific processes that regulate contraction, proliferation, and synthetic properties of airway smooth muscle ...(ASM). To place this information in physiological context, however, improved methods to examine airway biology
in vivo are needed. Advances in genetic, biochemical, and optical methods provide unprecedented opportunities to improve our understanding of
in vivo physiology and pathophysiology. This article describes 4 important methodologic advances in the study of ASM: (1) the development of transgenic mice that could be used to investigate ASM proliferation and phenotype switching during the development of hypersensitivity, and to investigate excitation-contraction coupling; (2) the use of CD38-deficient mice to confirm the role of CD38-dependent, cyclic adenosine diphosphate-ribose–mediated calcium release in airway responsiveness; (3) investigation of the role of actin filament length and p38 mitogen–activated protein kinase activity in regulating the mechanical plasticity-elasticity balance in contracted ASM; and (d) the use of bronchial biopsies to study ASM structure and phenotype in respiratory science
We perform a comprehensive study of Milky Way (MW) satellite galaxies to constrain the fundamental properties of dark matter (DM). This analysis fully incorporates inhomogeneities in the spatial ...distribution and detectability of MW satellites and marginalizes over uncertainties in the mapping between galaxies and DM halos, the properties of the MW system, and the disruption of subhalos by the MW disk. Our results are consistent with the cold, collisionless DM paradigm and yield the strongest cosmological constraints to date on particle models of warm, interacting, and fuzzy dark matter. At 95% confidence, we report limits on (i) the mass of thermal relic warm DM, m_{WDM}>6.5 keV (free-streaming length, λ_{fs}≲10h^{-1} kpc), (ii) the velocity-independent DM-proton scattering cross section, σ_{0}<8.8×10^{-29} cm^{2} for a 100 MeV DM particle mass DM-proton coupling, c_{p}≲(0.3 GeV)^{-2}, and (iii) the mass of fuzzy DM, m_{ϕ}>2.9×10^{-21} eV (de Broglie wavelength, λ_{dB}≲0.5 kpc). These constraints are complementary to other observational and laboratory constraints on DM properties.
Over the past two decades, the molecular machinery that underlies autophagic responses has been characterized with ever increasing precision in multiple model organisms. Moreover, it has become clear ...that autophagy and autophagy‐related processes have profound implications for human pathophysiology. However, considerable confusion persists about the use of appropriate terms to indicate specific types of autophagy and some components of the autophagy machinery, which may have detrimental effects on the expansion of the field. Driven by the overt recognition of such a potential obstacle, a panel of leading experts in the field attempts here to define several autophagy‐related terms based on specific biochemical features. The ultimate objective of this collaborative exchange is to formulate recommendations that facilitate the dissemination of knowledge within and outside the field of autophagy research.
Autophagy‐related responses are described in an increasing number of distinct biological contexts. This review discusses the use of appropriate terms for autophagic processes with the aim to provide recommendations and avoid confusion in the field of autophagy research.
We present a search for the decays of a neutral scalar boson produced by kaons decaying at rest, in the context of the Higgs portal model, using the MicroBooNE detector. We analyze data triggered in ...time with the Fermilab NuMI neutrino beam spill, with an exposure of 1020 protons on target. We look for monoenergetic scalars that come from the direction of the NuMI hadron absorber, at a distance of 100 m from the detector, and decay to electron-positron pairs. We observe one candidate event, with a standard model background prediction of 1.9±0.8. We set an upper limit on the scalar–Higgs mixing angle of θ<(3.3−4.6)×10−4 at the 95% confidence level for scalar boson masses in the range(100–200) MeV/c2. We exclude, at the 95% confidence level, the remaining model parameters required to explain the central value of a possible excess of KL0→π0νν¯ decays reported by the KOTO collaboration. We also provide a model-independent limit on a new boson X produced in K→πX decays and decaying to e+e−.
Lung squamous cell carcinoma (LSCC) remains a leading cause of cancer death with few therapeutic options. We characterized the proteogenomic landscape of LSCC, providing a deeper exposition of LSCC ...biology with potential therapeutic implications. We identify NSD3 as an alternative driver in FGFR1-amplified tumors and low-p63 tumors overexpressing the therapeutic target survivin. SOX2 is considered undruggable, but our analyses provide rationale for exploring chromatin modifiers such as LSD1 and EZH2 to target SOX2-overexpressing tumors. Our data support complex regulation of metabolic pathways by crosstalk between post-translational modifications including ubiquitylation. Numerous immune-related proteogenomic observations suggest directions for further investigation. Proteogenomic dissection of CDKN2A mutations argue for more nuanced assessment of RB1 protein expression and phosphorylation before declaring CDK4/6 inhibition unsuccessful. Finally, triangulation between LSCC, LUAD, and HNSCC identified both unique and common therapeutic vulnerabilities. These observations and proteogenomics data resources may guide research into the biology and treatment of LSCC.
Autophagy in major human diseases Klionsky, Daniel J; Petroni, Giulia; Amaravadi, Ravi K ...
The EMBO journal,
01 October 2021, Letnik:
40, Številka:
19
Journal Article
Recenzirano
Odprti dostop
Autophagy is a core molecular pathway for the preservation of cellular and organismal homeostasis. Pharmacological and genetic interventions impairing autophagy responses promote or aggravate disease ...in a plethora of experimental models. Consistently, mutations in autophagy‐related processes cause severe human pathologies. Here, we review and discuss preclinical data linking autophagy dysfunction to the pathogenesis of major human disorders including cancer as well as cardiovascular, neurodegenerative, metabolic, pulmonary, renal, infectious, musculoskeletal, and ocular disorders.
This review provides an exhaustive overview of the contribution of autophagy to multiple pathological phenotypes in vivo, and discusses the therapeutic potential of autophagy modulation in disease prevention and treatment.
We report the first electron neutrino cross section measurements on argon, based on data collected by the ArgoNeuT experiment running in the GeV-scale NuMI beamline at Fermilab. A flux-averaged νe + ...νe total and a lepton angle differential cross section are extracted using 13 νe and νe events identified with fully automated selection and reconstruction. We employ electromagnetic-induced shower characterization and analysis tools developed to identify νe / νe-like events among complex interaction topologies present in ArgoNeuT data ( ⟨ E νe ⟩ = 4.3 GeV and ⟨ E νe ⟩ = 10.5 GeV ). The techniques are widely applicable to searches for electron-flavor appearance at short and long baseline using liquid argon time projection chamber technology. Notably, the data-driven studies of GeV-scale νe / νe interactions presented here probe an energy regime relevant for future DUNE oscillation physics.
We describe a method used to calibrate the position- and time-dependent response of the MicroBooNE liquid argon time projection chamber anode wires to ionization particle energy loss. The method ...makes use of crossing cosmic-ray muons to partially correct anode wire signals for multiple effects as a function of time and position, including cross-connected TPC wires, space charge effects, electron attachment to impurities, diffusion, and recombination. The overall energy scale is then determined using fully-contained beam-induced muons originating and stopping in the active region of the detector. Using this method, we obtain an absolute energy scale uncertainty of 2% in data. We use stopping protons to further refine the relation between the measured charge and the energy loss for highly-ionizing particles. This data-driven detector calibration improves both the measurement of total deposited energy and particle identification based on energy loss per unit length as a function of residual range. As an example, the proton selection efficiency is increased by 2% after detector calibration.
Liquid argon time projection chambers (LArTPCs) are now a standard detector technology for making accelerator neutrino measurements, due to their high material density, precise tracking, and ...calorimetric capabilities. An electric field (E-field) is required in such detectors to drift ionization electrons to the anode where they are collected. The E-field of a TPC is often approximated to be uniform between the anode and the cathode planes. However, significant distortions can appear from effects such as mechanical deformations, electrode failures, or the accumulation of space charge generated by cosmic rays. The latter effect is particularly relevant for detectors placed near the Earth's surface and with large drift distances and long drift time. To determine the E-field in situ, an ultraviolet (UV) laser system is installed in the MicroBooNE experiment at Fermi National Accelerator Laboratory. The purpose of this system is to provide precise measurements of the E-field, and to make it possible to correct for 3D spatial distortions due to E-field non-uniformities. Here we describe the methodology developed for deriving spatial distortions, the drift velocity and the E-field from UV-laser measurements.
Autoantibodies against the extracellular domain of the N-methyl-d-aspartate receptor (NMDAR) NR1 subunit cause a severe and common form of encephalitis. To better understand their generation, we ...aimed to characterize and identify human germinal centres actively participating in NMDAR-specific autoimmunization by sampling patient blood, CSF, ovarian teratoma tissue and, directly from the putative site of human CNS lymphatic drainage, cervical lymph nodes. From serum, both NR1-IgA and NR1-IgM were detected more frequently in NMDAR-antibody encephalitis patients versus controls (both P < 0.0001). Within patients, ovarian teratoma status was associated with a higher frequency of NR1-IgA positivity in serum (OR = 3.1; P < 0.0001) and CSF (OR = 3.8, P = 0.047), particularly early in disease and before ovarian teratoma resection. Consistent with this immunoglobulin class bias, ovarian teratoma samples showed intratumoral production of both NR1-IgG and NR1-IgA and, by single cell RNA sequencing, contained expanded highly-mutated IgA clones with an ovarian teratoma-restricted B cell population. Multiplex histology suggested tertiary lymphoid architectures in ovarian teratomas with dense B cell foci expressing the germinal centre marker BCL6, CD21+ follicular dendritic cells, and the NR1 subunit, alongside lymphatic vessels and high endothelial vasculature. Cultured teratoma explants and dissociated intratumoral B cells secreted NR1-IgGs in culture. Hence, ovarian teratomas showed structural and functional evidence of NR1-specific germinal centres. On exploring classical secondary lymphoid organs, B cells cultured from cervical lymph nodes of patients with NMDAR-antibody encephalitis produced NR1-IgG in 3/7 cultures, from patients with the highest serum NR1-IgG levels (P < 0.05). By contrast, NR1-IgG secretion was observed neither from cervical lymph nodes in disease controls nor in patients with adequately resected ovarian teratomas. Our multimodal evaluations provide convergent anatomical and functional evidence of NMDAR-autoantibody production from active germinal centres within both intratumoral tertiary lymphoid structures and traditional secondary lymphoid organs, the cervical lymph nodes. Furthermore, we develop a cervical lymph node sampling protocol that can be used to directly explore immune activity in health and disease at this emerging neuroimmune interface.
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