In-vitro and in-vivo evidence for uncoupling of BCR internalization and signaling in chronic lymphocytic leukemia

B-cell receptor activation, occurring within lymph nodes, plays a key role in the pathogenesis of chronic lymphocytic leukemia and is linked to prognosis. As well as activation of downstream signaling, receptor ligation triggers internalization, transit to acidified endosomes and degradation of ligand-receptor complexes. In the present study we investigated the relationship between these two processes in normal and leukemic B-cells. We found that leukemic B-cells, particularly anergic cases lacking the capacity to initiate downstream signaling, internalize and accumulate ligand in acidified endosomes more efficiently than normal B-cells. Furthermore, ligation of either surface CD79B, a Bcell receptor component required for downstream signaling, or surface IgM by cognate agonistic antibody, showed that the two molecules internalize independently of each other in leukemic but not normal B-cells. Since association with surface CD79B is required for surface retention of IgM, this suggests that uncoupling of B-cell receptor internalization from signaling may be due to dissociation of these two molecules in leukemic cells. Comparison of lymph node with peripheral blood cells from chronic lymphocytic leukemia patients showed that, despite recent B-cell receptor activation, lymph node B-cells expressed higher levels of surface IgM. This surprising finding suggests that the B-cell receptors of lymph node and peripheral blood derived leukemic cells might be functionally distinct. Finally, long-term therapy with the Bruton’s tyrosine kinase inhibitors ibrutinib or acalabrutinib resulted in a switch to an anergic pattern of B-cell receptor function with reduced signaling capacity, surface IgM expression and more efficient internalization

SN 2021hpr and its two siblings in the Cepheid calibrator galaxy NGC 3147: A hierarchical BayeSN analysis of a Type Ia supernova trio, and a Hubble constant constraint

To improve Type Ia supernova (SN Ia) standardisability, the consistency of distance estimates to siblings -- SNe in the same host galaxy -- should be investigated. We present Young Supernova Experiment Pan-STARRS-1 $grizy$ photometry of SN 2021hpr, the third spectroscopically confirmed SN Ia in the high-stellar-mass Cepheid-calibrator galaxy NGC 3147. We analyse NGC 3147's trio of SN Ia siblings: SNe 1997bq, 2008fv and 2021hpr, using a new version of the BayeSN model of SN Ia spectral-energy distributions, retrained simultaneously using optical-NIR $BgVrizYJH$ (0.35--1.8 $\mu$m) data. The distance estimates to each sibling are consistent, with a sample standard deviation $\lesssim$0.01 mag, much smaller than the total intrinsic scatter in the training sample: $\sigma_0\approx0.09$ mag. Fitting normal SN Ia siblings in three additional galaxies, we estimate a $\approx$90% probability that the siblings' intrinsic scatter is smaller than $\sigma_0$. We build a new hierarchical model that fits light curves of siblings in a single galaxy simultaneously; this yields more precise estimates of the common distance and the dust parameters. Fitting the trio for a common dust law shape yields $R_V=2.69\pm0.52$. Our work motivates future hierarchical modelling of more siblings, to tightly constrain their intrinsic scatter, and better understand SN-host correlations. Finally, we estimate the Hubble constant, using a Cepheid distance to NGC 3147, the siblings trio, and 109 Hubble flow ($0.01 < z_{\rm{CMB}} < 0.08$) SNe Ia; marginalising over the siblings' and population's intrinsic scatters, and the peculiar velocity dispersion, yields $H_0=77.9\pm6.5 \text{ km s}^{-1}\text{Mpc}^{-1}$.Comment: Submitted to MNRAS; 30 pages, 22 figure

Phenotype and immune function of lymph node and peripheral blood CLL cells are linked to transendothelial migration

everal lines of evidence suggest that homing of tumor cells to lymphoid tissue contributes to disease progression in chronic lymphocytic leukemia (CLL). Here, we demonstrate that lymph node (LN)-derived CLL cells possess a distinct phenotype, and exhibit enhanced capacity for T-cell activation and superior immune synapse formation when compared with paired peripheral blood (PB) samples. LN-derived CLL cells manifest a proliferative, CXCR4(dim)CD5(bright) phenotype compared with those in the PB and higher expression of T-cell activation molecules including CD80, CD86, and HLA-D-related (DR). In addition, LN-CLL cells have higher expression of α4β1 (CD49d) which, as well as being a co-stimulatory molecule, is required for CLL cells to undergo transendothelial migration (TEM) and enter the proliferation centers of the LNs. Using an in vitro system that models circulation and TEM, we showed that the small population of CLL cells that migrate are CXCR4(dim)CD5(bright) with higher CD49d, CD80, CD86, and HLA-DR compared with those that remain circulating; a phenotype strikingly similar to LN-derived CLL cells. Furthermore, sorted CD49d(hi) CLL cells showed an enhanced capacity to activate T cells compared with CD49d(lo) subpopulations from the same patient. Thus, although PB-CLL cells have a reduced capacity to form immune synapses and activate CD4(+) T cells, this was not the case for LN-CLL cells or those with the propensity to undergo TEM. Taken together, our study suggests that CLL cell immunologic function is not only modulated by microenvironmental interactions but is also a feature of a subpopulation of PB-CLL cells that are primed for lymphoid tissue homing and interaction with T cells

Flight of the Bumblebee: the Early Excess Flux of Type Ia Supernova 2023bee revealed by TESSTESS, SwiftSwift and Young Supernova Experiment Observations

We present high-cadence ultraviolet through near-infrared observations of the Type Ia supernova (SN Ia) 2023bee in NGC~2708 ($D = 32 \pm 3$ Mpc), finding excess flux in the first days after explosion relative to the expected power-law rise from an expanding fireball. This deviation from typical behavior for SNe Ia is particularly obvious in our 10-minute cadence $TESS$ light curve and $Swift$ UV data. Compared to a few other normal SNe Ia with detected early excess flux, the excess flux in SN 2023bee is redder in the UV and less luminous. We present optical spectra of SN 2023bee, including two spectra during the period where the flux excess is dominant. At this time, the spectra are similar to those of other SNe Ia but with weaker Si II, C II and Ca II absorption lines, perhaps because the excess flux creates a stronger continuum. We compare the data to several theoretical models that have been proposed to explain the early flux excess in SNe Ia. Interaction with either a nearby companion star or close-in circumstellar material is expected to produce a faster evolution than seen in the data. Radioactive material in the outer layers of the ejecta, either from a double detonation explosion or simply an explosion with a $^{56}$Ni clump near the surface, can not fully reproduce the evolution either, likely due to the sensitivity of early UV observable to the treatment of the outer part of ejecta in simulation. We conclude that no current model can adequately explain the full set of observations. We find that a relatively large fraction of nearby, bright SNe Ia with high-cadence observations have some amount of excess flux within a few days of explosion. Considering potential asymmetric emission, the physical cause of this excess flux may be ubiquitous in normal SNe Ia.Comment: 21 pages, 12 figures. Accepted by the astrophysical journa

SN 2022oqm: A Multi-peaked Calcium-rich Transient from a White Dwarf Binary Progenitor System

We present the photometric and spectroscopic evolution of SN 2022oqm, a nearby multi-peaked hydrogen- and helium-weak calcium-rich transient (CaRT). SN 2022oqm was detected 19.9 kpc from its host galaxy, the face-on spiral galaxy NGC 5875. Extensive spectroscopic coverage reveals a hot (T >= 40,000 K) continuum and carbon features observed ~1 day after discovery, SN Ic-like photospheric-phase spectra, and strong forbidden calcium emission starting 38 days after discovery. SN 2022oqm has a relatively high peak luminosity (MB = -17 mag) for CaRTs, making it an outlier in the population. We determine that three power sources are necessary to explain SN 2022oqm's light curve, with each power source corresponding to a distinct peak in its light curve. The first peak of the light curve is powered by an expanding blackbody with a power law luminosity, consistent with shock cooling by circumstellar material. Subsequent peaks are powered by a double radioactive decay model, consistent with two separate sources of photons diffusing through an optically thick ejecta. From the optical light curve, we derive an ejecta mass and 56Ni mass of ~0.89 solar masses and ~0.09 solar masses, respectively. Detailed spectroscopic modeling reveals ejecta that is dominated by intermediate-mass elements, with signs that Fe-peak elements have been well-mixed. We discuss several physical origins for SN 2022oqm and favor a white dwarf progenitor model. The inferred ejecta mass points to a surprisingly massive white dwarf, challenging models of CaRT progenitors.Comment: 33 pages, 17 figures, 5 tables, Submitted to Ap

Strong Carbon Features and a Red Early Color in the Underluminous Type Ia SN 2022xkq

We present optical, infrared, ultraviolet, and radio observations of SN 2022xkq, an underluminous fast-declining type Ia supernova (SN Ia) in NGC 1784 ($\mathrm{D}\approx31$ Mpc), from $<1$ to 180 days after explosion. The high-cadence observations of SN 2022xkq, a photometrically transitional and spectroscopically 91bg-like SN Ia, cover the first days and weeks following explosion which are critical to distinguishing between explosion scenarios. The early light curve of SN 2022xkq has a red early color and exhibits a flux excess which is more prominent in redder bands; this is the first time such a feature has been seen in a transitional/91bg-like SN Ia. We also present 92 optical and 19 near-infrared (NIR) spectra, beginning 0.4 days after explosion in the optical and 2.6 days after explosion in the NIR. SN 2022xkq exhibits a long-lived C I 1.0693 $\mu$m feature which persists until 5 days post-maximum. We also detect C II $\lambda$6580 in the pre-maximum optical spectra. These lines are evidence for unburnt carbon that is difficult to reconcile with the double detonation of a sub-Chandrasekhar mass white dwarf. No existing explosion model can fully explain the photometric and spectroscopic dataset of SN 2022xkq, but the considerable breadth of the observations is ideal for furthering our understanding of the processes which produce faint SNe Ia.Comment: 38 pages, 16 figures, accepted for publication in ApJ, the figure 15 input models and synthetic spectra are now available at https://zenodo.org/record/837925

Flight of the bumblebee : the early excess flux of Type Ia supernova 2023bee revealed by TESS, Swift, and Young Supernova Experiment observations

We present high-cadence ultraviolet through near-infrared observations of the Type Ia supernova (SN Ia) 2023bee at D = 32 ± 3 Mpc, finding excess flux in the first days after explosion, particularly in our 10 minutes cadence TESS light curve and Swift UV data. Compared to a few other normal SNe Ia with early excess flux, the excess flux in SN 2023bee is redder in the UV and less luminous. We present optical spectra of SN 2023bee, including two spectra during the period where the flux excess is dominant. At this time, the spectra are similar to those of other SNe Ia but with weaker Si ii, C ii, and Ca ii absorption lines, perhaps because the excess flux creates a stronger continuum. We compare the data to several theoretical models on the origin of early excess flux in SNe Ia. Interaction with either the companion star or close-in circumstellar material is expected to produce a faster evolution than observed. Radioactive material in the outer layers of the ejecta, either from double detonation explosion or from a 56Ni clump near the surface, cannot fully reproduce the evolution either, likely due to the sensitivity of early UV observable to the treatment of the outer part of ejecta in simulation. We conclude that no current model can adequately explain the full set of observations. We find that a relatively large fraction of nearby, bright SNe Ia with high-cadence observations have some amount of excess flux within a few days of explosion. Considering potential asymmetric emission, the physical cause of this excess flux may be ubiquitous in normal SNe Ia

The Toddler Autism Symptom Inventory (TASI): Use in Diagnostic Evaluations of Toddlers

Although symptoms of autism are present early in life and early diagnosis can lead to better outcomes, there is a lack of validated parent interviews for children under the age of three. We developed the Toddler Autism Symptom Inventory (TASI), an interview form designed to assess the presence and absence of skills and symptoms in children aged 12-36 months. Reliability of symptoms and diagnosis, and validity of algorithms designed in accordance with Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) and International Classification of Diseases, Tenth Revision (ICD-10) diagnostic criteria were established. Reliability and validity of four algorithms were found to be good (n = 204). A validation sample (n = 91) confirmed these findings, and algorithms showed no reduction in validity in two subsamples of children: those under age 24 months and those with a developmental age below 18 months

The Toddler Autism Symptom Inventory (TASI): Use in Diagnostic Evaluations of Toddlers

Although symptoms of autism are present early in life and early diagnosis can lead to better outcomes, there is a lack of validated parent interviews for children under the age of three. We developed the Toddler Autism Symptom Inventory (TASI), an interview form designed to assess the presence and absence of skills and symptoms in children aged 12-36 months. Reliability of symptoms and diagnosis, and validity of algorithms designed in accordance with Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) and International Classification of Diseases, Tenth Revision (ICD-10) diagnostic criteria were established. Reliability and validity of four algorithms were found to be good (n = 204). A validation sample (n = 91) confirmed these findings, and algorithms showed no reduction in validity in two subsamples of children: those under age 24 months and those with a developmental age below 18 months

Does Treatment Fidelity of the Early Start Denver Model Impact Skill Acquisition in Young Children with Autism?

There is increasing evidence supporting the effectiveness of the Early Start Denver Model (ESDM) for children on the autism spectrum. However, substantial variability in response to the ESDM has been reported across participants. We examined the plausible yet untested hypothesis that variations in the fidelity level of therapists delivering the intervention contribute to variability in childrens response to the ESDM. Videotaped sessions (n = 40) of toddlers on the autism spectrum who received the ESDM from trained therapists were coded to obtain measures of therapist fidelity and childrens learning in response to the therapists instruction. Variations in overall fidelity, along with variations in most items included in the ESDM fidelity checklist, contributed to the childrens learning response during the sessions