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DNAJB6 isoform specific knockdown: Therapeutic potential for limb girdle muscular dystrophy D1
No full textDominant missense mutations in DNAJB6, a co-chaperone of HSP70, cause limb girdle muscular dystrophy (LGMD) D1. No treatments are currently available. Two isoforms exist, DNAJB6a and DNAJB6b, each with distinct localizations in muscle. Mutations reside in both isoforms, yet evidence suggests that DNAJB6b is primarily responsible for disease pathogenesis. Knockdown treatment strategies involving both isoforms carry risk, as DNAJB6 knockout is embryonic lethal. We therefore developed an isoform-specific knockdown approach using morpholinos. Selective reduction of each isoform was achieved in vitro in primary mouse myotubes and human LGMDD1 myoblasts, as well as in vivo in mouse skeletal muscle. To assess isoform specific knockdown in LGMDD1, we created primary myotube cultures from a knockin LGMDD1 mouse model. Using mass spectrometry, we identified an LGMDD1 protein signature related to protein homeostasis and myofibril structure. Selective reduction of DNAJB6b levels in LGMDD1 myotubes corrected much of the proteomic disease signature toward wild type levels. Additional in vivo functional data is required to determine if selective reduction of DNAJB6b is a viable therapeutic target for LGMDD1
Disks around Young Planetary-mass Objects: Ultradeep Spitzer Imaging of NGC 1333
No full textWe report on a sensitive infrared search for disks around isolated young planetary-mass objects (PMOs) in the NGC 1333 cluster, by stacking 70 Spitzer/IRAC frames at 3.6 and 4.5 μm. Our coadded images go >2.3 mag deeper than single-epoch frames, and cover 50 brown dwarfs, 15 of which have M9 or later spectral types. Spectral types >M9 correspond to masses in the giant-planet domain, i.e., near or below the deuterium-burning limit of 0.015 M_⊙. Five of the 12 PMOs show definitive evidence of excess, implying a disk fraction of 42%, albeit with a large statistical uncertainty given the small sample. Comparing with measurements for higher-mass objects, the disk fraction does not decline substantially with decreasing mass in the substellar domain, consistent with previous findings. Thus, free-floating PMOs have the potential to form their own miniature planetary systems. We note that only one of the six lowest-mass objects in NGC 1333, with spectral type L0 or later, has a confirmed disk. Reviewing the literature, we find that the lowest-mass free-floating objects with firm disk detections have masses ∼0.01 M_⊙ (or ∼10 M_(Jup)). It is not clear yet whether even lower-mass objects harbor disks. If not, it may indicate that ∼10 M_(Jup) is the lower-mass limit for objects that form like stars. Our disk-detection experiment on deep Spitzer images paves the way for studies with JWST at longer wavelengths and higher sensitivity, which will further explore disk prevalence and formation of free-floating PMOs
Two-stream instability with a growth rate insensitive to collisions in a dissipative plasma jet
No full textThe two-stream instability (Buneman instability) is traditionally derived as a collisionless instability with the presumption that collisions inhibit this instability. We show here via a combination of a collisional two-fluid model and associated experimental observations made in the Caltech plasma jet experiment, that in fact, a low frequency mode of the two-stream instability is indifferent to collisions. Despite the collision frequency greatly exceeding the growth rate of the instability, the instability can still cause an exponential growth of electron velocity and a rapid depletion of particle density. High collisionality nevertheless has an important effect as it enables the development of a double layer when the cross-section of the plasma jet is constricted by a kink-instigated Rayleigh-Taylor instability
Fabrication Development for SPT-SLIM, a Superconducting Spectrometer for Line Intensity Mapping
No full textLine Intensity Mapping (LIM) is a new observational technique that uses low-resolution observations of line emission to efficiently trace the large-scale structure of the Universe out to high redshift. Common mm/sub-mm emission lines are accessible from ground-based observatories, and the requirements on the detectors for LIM at mm-wavelengths are well matched to the capabilities of large-format arrays of superconducting sensors. We describe the development of an R = λ/Δλ = 300 on-chip superconducting filter-bank spectrometer covering the 120–180 GHz band for future mm-LIM experiments, focusing on SPT-SLIM, a pathfinder LIM instrument for the South Pole Telescope. Radiation is coupled from the telescope optical system to the spectrometer chip via an array of feedhorn-coupled orthomode transducers. Superconducting microstrip transmission lines then carry the signal to an array of channelizing half-wavelength resonators, and the output of each spectral channel is sensed by a lumped element kinetic inductance detector (leKID). Key areas of development include incorporating new low-loss dielectrics to improve both the achievable spectral resolution and optical efficiency and development of a robust fabrication process to create a galvanic connection between ultra-pure superconducting thin-films to realize multi-material (hybrid) leKIDs. We provide an overview of the spectrometer design, fabrication process, and prototype devices
Dieter Wolf (1941–2023): a life dedicated to understanding protein quality control and the ubiquitin‐proteasome system
No full textProfessor Dieter H. Wolf, a scientist of vision and depth, a role model for his students and colleagues, and a long-standing member of the Editorial Advisory Board of The EMBO Journal, sadly passed away on February 16th, 2023, in Stuttgart-Vaihingen, Germany
Quasiparticle and Optical Properties of Carrier-Doped Monolayer MoTe₂ from First Principles
No full textThe intrinsic weak and highly nonlocal dielectric screening of two-dimensional materials is well-known to lead to high sensitivity of their optoelectronic properties to environment. Less studied theoretically is the role of free carriers in those properties. Here, we use ab initio GW and Bethe-Salpeter equation calculations, with a rigorous treatment of dynamical screening and local-field effects, to study the doping dependence of the quasiparticle and optical properties of a monolayer transition-metal dichalcogenide, 2H MoTe₂. We predict a quasiparticle band gap renormalization of several hundreds of meV for experimentally attainable carrier densities and a similarly sizable decrease in the exciton binding energy. This results in an almost constant excitation energy for the lowest-energy exciton resonance with an increasing doping density. Using a newly developed and generally applicable plasmon-pole model and a self-consistent solution of the Bethe-Salpeter equation, we reveal the importance of accurately capturing both dynamical and local-field effects to understand detailed photoluminescence measurements
Response to comment on “Reexamination of 2.5-Ga ‘whiff’ of oxygen interval points to anoxic ocean before GOE”
No full textSedimentological, textural, and microscale analyses of the Mount McRae Shale revealed a complex postdepositional history, previously unrecognized in bulk geochemical studies. We found that metal enrichments in the shale do not reside with depositional organic carbon, as previously proposed by Anbar
et al
., but with late-stage pyrite, compromising claims for a “whiff” of oxygen ~50 million years before the Great Oxygenation Event
Mechanochemical reactivity of a multimodal 2H-bis-naphthopyran mechanophore
No full textMultimodal mechanophores that react under mechanical force to produce discrete product states with uniquely coupled absorption properties are interesting targets for the design of force-sensing polymers. Herein, we investigate the reactivity of a 2H-bis-naphthopyran mechanophore that generates thermally persistent mono-merocyanine and bis-merocyanine products upon mechanical activation in solution using ultrasonication, distinct from the thermally reversible products generated photochemically. We demonstrate that a force-mediated ester C(O)–O bond scission reaction following ring opening establishes an intramolecular hydrogen bond, locking one merocyanine subunit in the open form. Model compound studies suggest that this locked subunit confers remarkable thermal stability to bis-merocyanine isomers possessing a trans exocyclic alkene on the other subunit, implicating the formation of an unusual trans merocyanine isomer as the product of mechanochemical activation. Density functional theory calculations unexpectedly predict a thermally reversible retro-cyclization reaction of the bis-merocyanine species that could explain the mechanochemical generation of the unusual trans merocyanine isomer
Keck and Gemini spectral characterization of Lucy mission fly-by target (152830) Dinkinesh
No full textRecently, the inner main belt asteroid (152830) Dinkinesh was identified as an additional fly- by target for the Lucy mission. The heliocentric orbit and approximate absolute magnitude of Dinkinesh are known, but little additional information was available prior to its selection as a target. In particular, the lack of color spectrophotometry or spectra made it impossible to assign a spectral type to Dinkinesh from which its albedo could be estimated. We set out to remedy this knowledge gap by obtaining visible wavelength spectra with the Keck telescope on 2022 November 23 and with Gemini-South on 2022 December 27. The spectra measured with the Keck I/Low Resolution Imaging Spectrometer (LRIS) and the Gemini South/Gemini Multi-Object Spectrograph South (GMOS-S) are most similar to the average spectrum of S- and Sq-type asteroids. The most diagnostic feature is the ≈15 ± 1% silicate absorption feature at ≈0.9–1.0 μm. Small S- and Sq-type asteroids have moderately high albedos ranging from 0.17 to 0.35. Using this albedo range for Dinkinesh in combination with measured absolute magnitude, it is possible to derive an effective diameter and surface brightness for this body. The albedo, size and surface brightness are important inputs required for planning a successful encounter by the Lucy spacecraft
IXPE Observations of the Quintessential Wind-accreting X-Ray Pulsar Vela X-1
No full textThe radiation from accreting X-ray pulsars was expected to be highly polarized, with some estimates for the polarization degree of up to 80%. However, phase-resolved and energy-resolved polarimetry of X-ray pulsars is required in order to test different models and to shed light on the emission processes and the geometry of the emission region. Here we present the first results of the observations of the accreting X-ray pulsar Vela X-1 performed with the Imaging X-ray Polarimetry Explorer. Vela X-1 is considered to be the archetypal example of a wind-accreting, high-mass X-ray binary system, consisting of a highly magnetized neutron star accreting matter from its supergiant stellar companion. The spectropolarimetric analysis of the phase-averaged data for Vela X-1 reveals a polarization degree (PD) of 2.3% ± 0.4% at the polarization angle (PA) of −47.°3 ± 5.°4. A low PD is consistent with the results obtained for other X-ray pulsars and is likely related to the inverse temperature structure of the neutron star atmosphere. The energy-resolved analysis shows the PD above 5 keV reaching 6%–10% and a ∼90° difference in the PA compared to the data in the 2–3 keV range. The phase-resolved spectropolarimetric analysis finds a PD in the range 0%–9% with the PA varying between −80° and 40°