Hematopoietic stem cell transplantation (HSCT) is a curative therapy for blood and immune diseases with potential for many settings beyond current standard-of-care. Broad HSCT application is ...currently precluded largely due to morbidity and mortality associated with genotoxic irradiation or chemotherapy conditioning. Here we show that a single dose of a CD117-antibody-drug-conjugate (CD117-ADC) to saporin leads to > 99% depletion of host HSCs, enabling rapid and efficient donor hematopoietic cell engraftment. Importantly, CD117-ADC selectively targets hematopoietic stem cells yet does not cause clinically significant side-effects. Blood counts and immune cell function are preserved following CD117-ADC treatment, with effective responses by recipients to both viral and fungal challenges. These results suggest that CD117-ADC-mediated HSCT pre-treatment could serve as a non-myeloablative conditioning strategy for the treatment of a wide range of non-malignant and malignant diseases, and might be especially suited to gene therapy and gene editing settings in which preservation of immunity is desired.
•We investigate how speakers adapt to miscommunication.•We measure speaker hyper-articulation to contextual confusability.•Speakers hyper-articulate in situations of increased contextual ...confusability.•Speakers increase hyper-articulation after miscommunication.•Speaker hyper-articulation was contextually specific.
We ask whether speakers can adapt their productions when feedback from their interlocutors suggests that previous productions were perceptually confusable. To address this question, we use a novel web-based task-oriented paradigm for speech recording, in which participants produce instructions towards a (simulated) partner with naturalistic response times. We manipulate (1) whether a target word with a voiceless plosive (e.g., pill) occurs in the presence of a voiced competitor (bill) or an unrelated word (food) and (2) whether or not the simulated partner occasionally misunderstands the target word. Speakers hyper-articulated the target word when a voiced competitor was present. Moreover, the size of the hyper-articulation effect was nearly doubled when partners occasionally misunderstood the instruction. A novel type of distributional analysis further suggests that hyper-articulation did not change the target of production, but rather reduced the probability of perceptually ambiguous or confusable productions. These results were obtained in the absence of explicit clarification requests, and persisted across words and over trials. Our findings suggest that speakers adapt their pronunciations based on the perceived communicative success of their previous productions in the current environment. We discuss why speakers make adaptive changes to their speech and what mechanisms might underlie speakers’ ability to do so.
Testing for crowd out in social nudges Brandon, Alec; List, John A.; Metcalfe, Robert D. ...
Proceedings of the National Academy of Sciences - PNAS,
03/2019, Letnik:
116, Številka:
12
Journal Article
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This study considers the response of household electricity consumption to social nudges during peak load events. Our investigation considers two social nudges. The first targets conservation during ...peak load events, while the second promotes aggregate conservation. Using data from a natural field experiment with 42,100 households, we find that both social nudges reduce peak load electricity consumption by 2 to 4% when implemented in isolation and by nearly 7% when implemented in combination. These findings suggest an important role for social nudges in the regulation of electricity markets and a limited role for crowd out effects.
SARS-CoV-2 mRNA-based vaccines are about 95% effective in preventing COVID-19
. The dynamics of antibody-secreting plasmablasts and germinal centre B cells induced by these vaccines in humans remain ...unclear. Here we examined antigen-specific B cell responses in peripheral blood (n = 41) and draining lymph nodes in 14 individuals who had received 2 doses of BNT162b2, an mRNA-based vaccine that encodes the full-length SARS-CoV-2 spike (S) gene
. Circulating IgG- and IgA-secreting plasmablasts that target the S protein peaked one week after the second immunization and then declined, becoming undetectable three weeks later. These plasmablast responses preceded maximal levels of serum anti-S binding and neutralizing antibodies to an early circulating SARS-CoV-2 strain as well as emerging variants, especially in individuals who had previously been infected with SARS-CoV-2 (who produced the most robust serological responses). By examining fine needle aspirates of draining axillary lymph nodes, we identified germinal centre B cells that bound S protein in all participants who were sampled after primary immunization. High frequencies of S-binding germinal centre B cells and plasmablasts were sustained in these draining lymph nodes for at least 12 weeks after the booster immunization. S-binding monoclonal antibodies derived from germinal centre B cells predominantly targeted the receptor-binding domain of the S protein, and fewer clones bound to the N-terminal domain or to epitopes shared with the S proteins of the human betacoronaviruses OC43 and HKU1. These latter cross-reactive B cell clones had higher levels of somatic hypermutation as compared to those that recognized only the SARS-CoV-2 S protein, which suggests a memory B cell origin. Our studies demonstrate that SARS-CoV-2 mRNA-based vaccination of humans induces a persistent germinal centre B cell response, which enables the generation of robust humoral immunity.
Dissecting a 30 kpc galactic outflow at z ~ 1.7 Shaban, Ahmed; Bordoloi, Rongmon; Chisholm, John ...
Monthly notices of the Royal Astronomical Society,
10/2023, Letnik:
526, Številka:
4
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ABSTRACT
We present the spatially resolved measurements of a cool galactic outflow in the gravitationally lensed galaxy RCS0327 at z ≈ 1.703 using VLT/MUSE IFU observations. We probe the cool ...outflowing gas, traced by blueshifted Mg ii and Fe ii absorption lines, in 15 distinct regions of the same galaxy in its image-plane. Different physical regions, 5 – 7 kpc apart within the galaxy, drive the outflows at different velocities (Vout ∼ −161 to −240 km s−1), and mass outflow rates ($\dot{M}_{out} \sim 183$ – 527 ${\rm M}_{\odot }\, \mathrm{yr}^{-1}$). The outflow velocities from different regions of the same galaxy vary by 80 km s−1, which is comparable to the variation seen in a large sample of star-burst galaxies in the local universe. Using multiply lensed images of RCS0327, we probe the same star-forming region at different spatial scales (0.5–25 kpc2), we find that outflow velocities vary between ∼ −120 and −242 km s−1, and the mass outflow rates vary between ∼37 and 254 ${\rm M}_{\odot }\, \mathrm{yr}^{-1}$. The outflow momentum flux in this galaxy is ≥ 100% of the momentum flux provided by star formation in individual regions, and outflow energy flux is ≈ 10% of the total energy flux provided by star formation. These estimates suggest that the outflow in RCS0327 is energy driven. This work shows the importance of small scale variations of outflow properties due to the variations of local stellar properties of the host galaxy in the context of galaxy evolution.
Retromer is a protein assembly that plays a central role in orchestrating export of transmembrane-spanning cargo proteins from endosomes into retrieval pathways destined for the Golgi apparatus and ...the plasma membrane 1. Recently, a specific mutation in the retromer component VPS35, VPS35(D620N), has linked retromer dysfunction to familial autosomal dominant and sporadic Parkinson disease 2, 3. However, the effect of this mutation on retromer function remains poorly characterized. Here we established that in cells expressing VPS35(D620N) there is a perturbation in endosome-to-TGN transport but not endosome-to-plasma membrane recycling, which we confirm in patient cells harboring the VPS35(D620N) mutation. Through comparative stable isotope labeling by amino acids in cell culture (SILAC)-based analysis of wild-type VPS35 versus the VPS35(D620N) mutant interactomes, we establish that the major defect of the D620N mutation lies in the association to the actin-nucleating Wiskott-Aldrich syndrome and SCAR homolog (WASH) complex. Moreover, using isothermal calorimetry, we establish that the primary defect of the VPS35(D620N) mutant is a 2.2 ± 0.5-fold decrease in affinity for the WASH complex component FAM21. These data define the primary molecular defect in retromer assembly that arises from the VPS35(D620N) mutation and, by revealing functional effects on retromer-mediated endosome-to-TGN transport, provide new insight into retromer deregulation in Parkinson disease.
•VPS35(D620N) mutation leads to a defect in endosome-to-TGN transport•Mutant has a perturbed association with the actin-polymerizing WASH complex•Primary defect is a reduced affinity for binding WASH component FAM21•Provides new molecular insight into retromer deregulation in Parkinson disease
Using quantitative proteomics and functional analysis in patient-derived fibroblasts, McGough et al. define the primary molecular defect associated with the Parkinson disease-linked retromer VPS35(D620N) mutation and, by revealing effects on retromer-mediated endosome-to-TGN transport, provide new insight into retromer deregulation in this disease.
Abstract Extreme, young stellar populations are considered to be the primary contributor to cosmic reionization. How the Lyman continuum (LyC) escapes these galaxies remains highly elusive, and it is ...challenging to observe this process in actual LyC emitters without resolving the relevant physical scales. We investigate the Sunburst Arc, a strongly lensed LyC emitter at z = 2.37 that reveals an exceptionally small-scale (tens of parsecs) region of high LyC escape. The small (<100 pc) LyC-leaking region has extreme properties: a very blue UV slope ( β = −2.9 ± 0.1), a high ionization state (O iii λ 5007/O ii λ 3727 = 11 ± 3 and O iii λ 5007/H β = 6.8 ± 0.4), strong oxygen emission (EW(O iii ) = 1095 ± 40 Å), and a high Ly α escape fraction (0.3 ± 0.03), none of which are found in nonleaking regions of the galaxy. The leaking region’s UV slope is consistent with approximately “pure” stellar light that is minimally contaminated by the surrounding nebular continuum emission or extinguished by dust. These results suggest a highly anisotropic LyC escape process such that LyC is produced and escapes from a small, extreme starburst region where the stellar feedback from an ionizing star cluster creates one or more “pencil-beam” channels in the surrounding gas through which LyC can directly escape. Such anisotropic escape processes imply that random sight-line effects drive the significant scatters between measurements of galaxy properties and LyC escape fraction, and that strong lensing is a critical tool for resolving the processes that regulate the ionizing budget of galaxies for reionization.
Traumatic brain injury (TBI) causes the release of danger-associated molecular patterns (DAMP) from damaged or dead cells, which contribute to secondary brain damage after TBI. Cell-free DNA (cfDNA) ...is a DAMP known to cause disruption of the blood-brain barrier (BBB), promote procoagulant processes, brain edema, and neuroinflammation. This study tested the hypothesis that administration of deoxyribonuclease-I (DNase-I) has a beneficial effect after TBI. Mice (n = 84) were subjected to controlled cortical impact (CCI) and posttraumatic intraperitoneal injections of low dose (LD) or high dose (HD) of DNase-I or vehicle solution at 30 min and 12 h after CCI. LD was most effective to reduce lesion volume (p = 0.003), brain water content (p < 0.0001) and to stabilize BBB integrity (p = 0.019) 1 day post-injury (dpi). At 6 h post injury LD-treated animals showed less cleavage of fibrin (p = 0.0014), and enhanced perfusion as assessed by micro-computer-tomography (p = 0.027). At 5 dpi the number of Iba1-positive cells (p = 0.037) were reduced, but the number of CD45-positive cells, motoric function and brain lesion volume was not different. Posttraumatic-treatment with DNase-I therefore stabilizes the BBB, reduces the formation of brain edema, immune response, and delays secondary brain damage. DNase-I might be a new approach to extend the treatment window after TBI.
Abstract We present strong gravitational lensing models for 37 galaxy clusters from the Sloan Digital Sky Survey Giant Arcs Survey. We combine data from multi-band Hubble Space Telescope Wide Field ...Camera 3 (WFC3) imaging, with ground-based imaging and spectroscopy from Magellan , Gemini, Apache Point Observatory, and the Multiple Mirror Telescope, in order to detect and spectroscopically confirm new multiply imaged lensed background sources behind the clusters. We report spectroscopic or photometric redshifts of sources in these fields, including cluster galaxies and background sources. Based on all available lensing evidence, we construct and present strong-lensing mass models for these galaxy clusters. The clusters span a redshift range of 0.176 < z < 0.66 with a median redshift of z = 0.45, and sample a wide range of dynamical masses, 1.5 < M 200 < 35 × 10 14 , as estimated from their velocity dispersions. As these clusters were selected as lenses primarily owing to a fortuitous alignment with background galaxies that results in giant arcs, they exhibit a wide range in Einstein radii, 1.″3 < θ E < 23.″1 for a source at z = 2, with a median θ E = 10.″8. The reduced HST images and lens model outputs are made available to the scientific community as high-level data products with this publication.
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