The main neurological manifestation of COVID-19 is loss of smell or taste. The high incidence of smell loss without significant rhinorrhea or nasal congestion suggests that SARS-CoV-2 targets the ...chemical senses through mechanisms distinct from those used by endemic coronaviruses or other common cold-causing agents. Here we review recently developed hypotheses about how SARS-CoV-2 might alter the cells and circuits involved in chemosensory processing and thereby change perception. Given our limited understanding of SARS-CoV-2 pathogenesis, we propose future experiments to elucidate disease mechanisms and highlight the relevance of this ongoing work to understanding how the virus might alter brain function more broadly.
Impairments of smell and taste perception are two of the main symptoms of COVID–19. In this issue of Neuron, Cooper et al. focus on these chemosensory symptoms and review recent hypotheses of the putative mechanisms mediating the loss of taste and smell through COVID–19.
We study dwarf satellite galaxy quenching using observations from the Geha et al. NASA-Sloan Atlas/SDSS catalogue together with Λ cold dark matter cosmological simulations to facilitate selection and ...interpretation. We show that fewer than 30 per cent of dwarfs (M
⋆ ≃ 108.5 − 9.5 M⊙) identified as satellites within massive host haloes (M
host ≃ 1012.5 − 14 M⊙) are quenched, in spite of the expectation from simulations that half of them should have been accreted more than 6 Gyr ago. We conclude that whatever the action triggering environmental quenching of dwarf satellites, the process must be highly inefficient. We investigate a series of simple, one-parameter quenching models in order to understand what is required to explain the low quenched fraction and conclude that either the quenching time-scale is very long ( > 9.5 Gyr, a ‘slow starvation’ scenario) or that the environmental trigger is not well matched to accretion within the virial volume. We discuss these results in light of the fact that most
of the low-mass dwarf satellites in the Local Group are quenched, a seeming contradiction that could point to a characteristic mass scale for satellite quenching.
The increased prescribing of antipsychotics for children and youth has heightened concerns that this practice increases the risk of type 2 diabetes mellitus.
To compare the risk of type 2 diabetes in ...children and youth 6 to 24 years of age for recent initiators of antipsychotic drugs vs propensity score-matched controls who had recently initiated another psychotropic medication.
Retrospective cohort study of the Tennessee Medicaid program with 28 858 recent initiators of antipsychotic drugs and 14 429 matched controls. The cohort excluded patients who previously received a diagnosis of diabetes, schizophrenia, or some other condition for which antipsychotics are the only generally recognized therapy.
Newly diagnosed diabetes during follow-up, as identified from diagnoses and diabetes medication prescriptions.
Users of antipsychotics had a 3-fold increased risk for type 2 diabetes (HR = 3.03 95% CI = 1.73-5.32), which was apparent within the first year of follow-up (HR = 2.49 95% CI = 1.27-4.88). The risk increased with cumulative dose during follow-up, with HRs of 2.13 (95% CI = 1.06-4.27), 3.42 (95% CI = 1.88-6.24), and 5.43 (95% CI = 2.34-12.61) for respective cumulative doses (gram equivalents of chlorpromazine) of more than 5 g, 5 to 99 g, and 100 g or more (P < .04). The risk remained elevated for up to 1 year following discontinuation of antipsychotic use (HR = 2.57 95% CI = 1.34-4.91). When the cohort was restricted to children 6 to 17 years of age, antipsychotic users had more than a 3-fold increased risk of type 2 diabetes (HR = 3.14 95% CI = 1.50-6.56), and the risk increased significantly with increasing cumulative dose (P < .03). The risk was increased for use restricted to atypical antipsychotics (HR = 2.89 95% CI = 1.64-5.10) or to risperidone (HR = 2.20 95% CI = 1.14-4.26).
Children and youth prescribed antipsychotics had an increased risk of type 2 diabetes that increased with cumulative dose.
Sickle cell disease (SCD) is characterized by a single point mutation in the seventh codon of the β-globin gene. Site-specific correction of the sickle mutation in hematopoietic stem cells would ...allow for permanent production of normal red blood cells. Using zinc-finger nucleases (ZFNs) designed to flank the sickle mutation, we demonstrate efficient targeted cleavage at the β-globin locus with minimal off-target modification. By codelivering a homologous donor template (either an integrase-defective lentiviral vector or a DNA oligonucleotide), high levels of gene modification were achieved in CD34+ hematopoietic stem and progenitor cells. Modified cells maintained their ability to engraft NOD/SCID/IL2rγnull mice and to produce cells from multiple lineages, although with a reduction in the modification levels relative to the in vitro samples. Importantly, ZFN-driven gene correction in CD34+ cells from the bone marrow of patients with SCD resulted in the production of wild-type hemoglobin tetramers.
•Delivery of ZFNs and donor templates results in high levels of gene correction in human CD34+ cells from multiple sources, including SCD BM.•Modified CD34+ cells are capable of engrafting immunocompromised NSG mice and produce cells from multiple lineages.
In recent years, inhibition of the interaction between the bromodomain and extra-terminal domain (BET) family of chromatin adaptors and acetyl-lysine residues on chromatin has emerged as a promising ...approach to regulate the expression of important disease-relevant genes, including MYC, BCL-2, and NF-κB. Here we describe the identification and characterization of a potent and selective benzoisoxazoloazepine BET bromodomain inhibitor that attenuates BET-dependent gene expression in vivo, demonstrates antitumor efficacy in an MV-4-11 mouse xenograft model, and is currently undergoing human clinical trials for hematological malignancies (CPI-0610).
The vast majority of dwarf satellites orbiting the Milky Way and M31 are quenched, while comparable galaxies in the field are gas rich and star forming. Assuming that this dichotomy is driven by ...environmental quenching, we use the Exploring the Local Volume in Simulations (ELVIS) suite of N-body simulations to constrain the characteristic time-scale upon which satellites must quench following infall into the virial volumes of their hosts. The high satellite quenched fraction observed in the Local Group demands an extremely short quenching time-scale (∼2 Gyr) for dwarf satellites in the mass range M
⋆ ∼ 106–108 M⊙. This quenching time-scale is significantly shorter than that required to explain the quenched fraction of more massive satellites (∼8 Gyr), both in the Local Group and in more massive host haloes, suggesting a dramatic change in the dominant satellite quenching mechanism at M
⋆ ≲ 108 M⊙. Combining our work with the results of complementary analyses in the literature, we conclude that the suppression of star formation in massive satellites (M
⋆ ∼ 108–1011 M⊙) is broadly consistent with being driven by starvation, such that the satellite quenching time-scale corresponds to the cold gas depletion time. Below a critical stellar mass scale of ∼108 M⊙, however, the required quenching times are much shorter than the expected cold gas depletion times. Instead, quenching must act on a time-scale comparable to the dynamical time of the host halo. We posit that ram-pressure stripping can naturally explain this behaviour, with the critical mass (of M
⋆ ∼ 108 M⊙) corresponding to haloes with gravitational restoring forces that are too weak to overcome the drag force encountered when moving through an extended, hot circumgalactic medium.
Immunotherapy with the adoptive transfer of T cells redirected with CD19-specific chimeric antigen receptors (CARs) for B-lineage acute lymphoblastic leukemia (ALL) can salvage >80% of patients ...having relapsed/refractory disease. The therapeutic index of this emerging modality is attenuated by the occurrence of immunologic toxicity syndromes that occur upon CAR T-cell engraftment. Here, we report on the low incidence of severe cytokine release syndrome (CRS) in a subject treated with a CAR T-cell product composed of a defined ratio CD4:CD8 T-cell composition with a 4-1BB:zeta CAR targeting CD19 who also recieved early intervention treatment. We report that early intervention with tocilizumab and/or corticosteroids may reduce the frequency at which subjects transition from mild CRS to severe CRS. Although early intervention doubled the numbers of subjects dosed with tocilizumab and/or corticosteroids, there was no apparent detrimental effect on minimal residual disease–negative complete remission rates or subsequent persistence of functional CAR T cells compared with subjects who did not receive intervention. Moreover, early intervention therapy did not increase the proportion of subjects who experience neurotoxicity or place subjects at risk for infectious sequelae. These data support the contention that early intervention with tocilizumab and/or corticosteroids in subjects with early signs of CRS is without negative impact on the antitumor potency of CD19 CAR T cells. This intervention serves to enhance the therapeutic index in relapsed/refractory patients and provides the rationale to apply CAR T-cell therapy more broadly in ALL therapy. This trial was registered at www.clinicaltrials.gov as #NCT020284.
•Early intervention with tocilizumab and steroids does not impact the expansion or persistence of SCRI-CAR19v1 CAR T cells in B-ALL.•Administration of tocilizumab and corticosteroids does not negatively impact the efficacy of SCRI-CAR19v1.
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Long-term engraftment of allogeneic cells necessitates eluding immune-mediated rejection, which is currently achieved by matching for human leukocyte antigen (HLA) expression, immunosuppression, ...and/or delivery of donor-derived cells to sanctuary sites. Genetic engineering provides an alternative approach to avoid clearance of cells that are recognized as “non-self” by the recipient. To this end, we developed designer zinc finger nucleases and employed a “hit-and-run” approach to genetic editing for selective elimination of HLA expression. Electro-transfer of mRNA species coding for these engineered nucleases completely disrupted expression of HLA-A on human T cells, including CD19-specific T cells. The HLA-Aneg T-cell pools can be enriched and evade lysis by HLA-restricted cytotoxic T-cell clones. Recognition by natural killer cells of cells that had lost HLA expression was circumvented by enforced expression of nonclassical HLA molecules. Furthermore, we demonstrate that zinc finger nucleases can eliminate HLA-A expression from embryonic stem cells, which broadens the applicability of this strategy beyond infusing HLA-disparate immune cells. These findings establish that clinically appealing cell types derived from donors with disparate HLA expression can be genetically edited to evade an immune response and provide a foundation whereby cells from a single donor can be administered to multiple recipients.
•Allogeneic-donor–derived cells can be genetically modified to eliminate expression of HLA-A.•HLA-A disruption from donor cells is a step toward generating allogeneic cells as an off-the-shelf therapeutic.
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