Vaccination induces maturation in a mouse model of diverse unmutated VRC01-class precursors to HIV-neutralizing antibodies with >50% breadth.

Vaccine elicitation of broadly neutralizing antibodies (bnAbs) is a key HIV-research goal. The VRC01 class of bnAbs targets the CD4-binding site on the HIV-envelope trimer and requires extensive somatic hypermutation (SHM) to neutralize effectively. Despite substantial progress, vaccine-induced VRC01-class antibodies starting from unmutated precursors have exhibited limited neutralization breadth, particularly against viruses bearing glycan on loop D residue N276 (glycan276), present on most circulating strains. Here, using sequential immunization of immunoglobulin (Ig)-humanized mice expressing diverse unmutated VRC01-class antibody precursors, we elicited serum responses capable of neutralizing viruses bearing glycan276 and isolated multiple lineages of VRC01-class bnAbs, including two with >50% breadth on a 208-strain panel. Crystal structures of representative bnAbs revealed the same mode of recognition as known VRC01-class bnAbs. Structure-function studies further pinpointed key mutations and correlated their induction with specific immunizations. VRC01-class bnAbs can thus be matured by sequential immunization from unmutated ancestors to >50% breadth, and we delineate immunogens and regimens inducing key SHM.

The phenotype of recovery XI: associations of sleep quality and perceived stress with discounting and quality of life in substance use recovery.

PURPOSE: Sleep and stress show an interdependent relationship in physiology, and both are known risk factors for relapse in substance use disorder (SUD) recovery. However, sleep and stress are often investigated independently in addiction research. In this exploratory study, the associations of sleep quality and perceived stress with delay discounting (DD), effort discounting (ED), and quality of life (QOL) were examined concomitantly to determine their role in addiction recovery. DD has been proposed as a prognostic indicator of SUD treatment response, ED is hypothesized to be relevant to the effort to overcome addiction, and QOL is an important component in addiction recovery. METHOD: An online sample of 118 individuals recovering from SUDs was collected through the International Quit and Recovery Registry. Exhaustive model selection, using the Bayesian Information Criterion to determine the optimal multiple linear model, was conducted to identify variables (i.e., sleep quality, perceived stress, and demographics) contributing to the total variance in DD, ED, and QOL. RESULTS: After model selection, sleep was found to be significantly associated with DD. Stress was found to be significantly associated with psychological health, social relationships, and environment QOL. Both sleep and stress were found to be significantly associated with physical health QOL. Neither sleep nor stress was supported as an explanatory variable of ED. CONCLUSION: Together, these findings suggest sleep and stress contribute uniquely to the process of addiction recovery. Considering both factors when designing interventions and planning for future research is recommended.

Magnetic-Field-Induced Dielectric Anomalies in Cobalt-Containing Garnets.

Here we present a comparative study of the magnetic and crystal chemical properties of two Co2+ containing garnets. CaY2Co2Ge3O12 (which has been reported previously) and NaCa2Co2V3O12 both exhibit the onset of antiferromagnetic order around 6 K as well as field-induced transitions around 7 and 10 T, respectively, that manifest as anomalies in the dielectric properties of the material. We perform detailed crystal-chemistry analyses and complementary density functional theory calculations to show that very minor changes in the local environment of the Co ions explain the differences in the two magnetic structures and their respective properties.

Canting of the Magnetic Moments on the Octahedral Site of an Iron Oxide Garnet in Response to Diamagnetic Cation Substitution.

Using neutron powder diffraction and magnetic susceptibility measurements, we report on the preparation and characterization of the temperature- and field-dependent properties of CaY2ZrFe4O12, a composition closely related to the high-temperature ferrimagnet Y3Fe5O12. By diluting the concentration of paramagnetic ions on the octahedral sublattice of the garnet structure, we find temperature-dependent canting of the magnetic moments. This reflects the importance of the octahedral sublattice in mediating the magnetic interactions between the tetrahedral sites and offers insight into a large number of competing magnetic interactions in the garnet structure.

Influence of the Cubic Sublattice on Magnetic Coupling between the Tetrahedral Sites of Garnet.

We present a study on the nuclear and magnetic structures of two iron-based garnets with magnetic cations isolated on tetrahedral sites. Ca2YZr2Fe3O12 and Ca2LaZr2Fe3O12 offer an interesting comparison for examining the effect of increasing cation size within the diamagnetic backbone of the garnet crystal structure, and how such changes affect the magnetic order. Despite both systems exhibiting well-pronounced magnetic transitions at low temperatures, we also find evidence for diffuse magnetic scattering due to a competition between the nearest-neighbor, next nearest-neighbor, and so on, within the tetrahedral sites. This competition results in a complex noncollinear magnetic structure on the tetrahedral sublattice creating a mixture of ferro- and antiferromagnetic interactions above the long-range ordering temperature near 20 K and suggests that the cubic site of the garnet plays a significant role in mediating the superexchange interactions between tetrahedral cations.

Natural killer cell regulation of breast cancer stem cells mediates metastatic dormancy.

Breast cancer patients with estrogen receptor positive tumors face a constant risk of disease recurrence for the remainder of their lives. Dormant tumor cells residing in tissues such as the bone marrow may generate clinically significant metastases many years after initial diagnosis. Previous studies suggest that dormant cells display "stem like" properties (CSCs), which may be regulated by the immune system. Although many studies have examined tumor cell intrinsic characteristics of dormancy, the role of the immune system in controlling dormancy and its escape is not well understood. This scientific gap is due, in part, to a lack of immunocompetent mouse models of breast cancer dormancy with many studies involving human xenografts in immunodeficient mice. To overcome this limitation, we studied dormancy in immunocompetent, syngeneic mouse breast cancer models. We find that PyMT, Met-1 and D2.0R cell lines contain CSCs that display both short- and long-term metastatic dormancy in vivo, which is dependent on the host immune system. Natural killer cells were key for the metastatic dormancy phenotype observed for D2.0R and the role of NK cells in regulating CSCs was further investigated.Quiescent D2.0R CSC are resistant to NK cytotoxicity, while proliferative D2.0R CSC were sensitive to NK cytotoxicity both in vitro and in vivo. This resistance was mediated, in part, by the expression of Bach1 and Sox2 transcription factors. NK killing was enhanced by the STING agonist MSA-2. Collectively, our findings demonstrate the important role of immune regulation of breast tumor dormancy and highlight the importance of utilizing immunocompetent models to study this phenomenon.

Economic burden of lives lost due to COVID-19 in California State.

Aim: To examine the economic impact of lives lost due to the coronavirus pandemic across California and Los Angeles (LA) County. Patients & methods: Years of potential life lost (YPLL) and the value of statistical life (VSL) were calculated using mortality data from the California Department of Public Health, the LA County Department of Public Health and the Social Security Administration websites. Results: In California and LA County, the average YPLL per person were 14.3 and 14.7 and the VSLs were approximately US$219.9 billion and $82.7 billion, respectively. YPLL and VSL were greatest for Latinos aged 50-64. Conclusion: The economic burden of lives lost due to the coronavirus across California and LA County is substantial. Latinos aged 50-64 were most affected.

Economic burden of lives lost due to COVID-19 in New York State.

Aim: To examine the economic impact of lives lost due to the COVID-19 pandemic across New York State. Materials & methods: Death counts by age range and period life expectancy were extracted from the NYS Department of Health, NYC Department of Health and Mental Hygiene, and Social Security Administration website. Years of potential life lost and value of statistical life (VSL) were calculated. Results: The average years of potential life lost per person was 12.72 and 15.13, and the VSL was US$119.62 and 90.45 billion, in NYS and NYC, respectively. VSL was greatest in Queens and Brooklyn, followed by the Bronx, Manhattan and Staten Island. Conclusion: New York City, specifically Queens and Brooklyn, bore the greatest economic burden of lives lost across the state.

Development of a Robust Manufacturing Route for Molnupiravir, an Antiviral for the Treatment of COVID-19.

Herein is described the development of a large-scale manufacturing process for molnupiravir, an orally dosed antiviral that was recently demonstrated to be efficacious for the treatment of patients with COVID-19. The yield, robustness, and efficiency of each of the five steps were improved, ultimately culminating in a 1.6-fold improvement in overall yield and a dramatic increase in the overall throughput compared to the baseline process.

Stay Mindful and Carry on: Mindfulness Neutralizes COVID-19 Stressors on Work Engagement via Sleep Duration.

We examine whether mindfulness can neutralize the negative impact of COVID-19 stressors on employees' sleep duration and work engagement. In Study 1, we conducted a field experiment in Wuhan, China during the lockdown between February 20, 2020, and March 2, 2020, in which we induced state mindfulness by randomly assigning participants to either a daily mindfulness practice or a daily mind-wandering practice. Results showed that the sleep duration of participants in the mindfulness condition, compared with the control condition, was less impacted by COVID-19 stressors (i.e., the increase of infections in the community). In Study 2, in a 10-day daily diary study in the United Kingdom between June 8, 2020, and June 19, 2020, we replicate our results from Study 1 using a subjective measure of COVID-19 stressors and a daily measure of state mindfulness. In addition, we find that mindfulness buffers the negative effect of COVID-19 stressors on work engagement mediated by sleep duration. As the COVID-19 pandemic is ongoing and the number of reported cases continues to rise globally, our findings suggest that mindfulness is an evidence-based practice that can effectively neutralize the negative effect of COVID-19 stressors on sleep and work outcomes. The findings of the present study contribute to the employee stress and well-being literature as well as the emerging organizational research on mindfulness.