LEM All-Sky Survey: Soft X-ray Sky at Microcalorimeter Resolution

The Line Emission Mapper (LEM) is an X-ray Probe with with spectral resolution ~2 eV FWHM from 0.2 to 2.5 keV and effective area >2,500 cm$^2$ at 1 keV, covering a 33 arcmin diameter Field of View with 15 arcsec angular resolution, capable of performing efficient scanning observations of very large sky areas and enabling the first high spectral resolution survey of the full sky. The LEM-All-Sky Survey (LASS) is expected to follow the success of previous all sky surveys such as ROSAT and eROSITA, adding a third dimension provided by the high resolution microcalorimeter spectrometer, with each 15 arcsec pixel of the survey including a full 1-2 eV resolution energy spectrum that can be integrated over any area of the sky to provide statistical accuracy. Like its predecessors, LASS will provide both a long-lasting legacy and open the door to the unknown, enabling new discoveries and delivering the baseline for unique GO studies. No other current or planned mission has the combination of microcalorimeter energy resolution and large grasp to cover the whole sky while maintaining good angular resolution and imaging capabilities. LASS will be able to probe the physical conditions of the hot phases of the Milky Way at multiple scales, from emission in the Solar system due to Solar Wind Charge eXchange, to the interstellar and circumgalactic media, including the North Polar Spur and the Fermi/eROSITA bubbles. It will measure velocities of gas in the inner part of the Galaxy and extract the emissivity of the Local Hot Bubble. By maintaining the original angular resolution, LASS will also be able to study classes of point sources through stacking. For classes with ~$10^4$ objects, it will provide the equivalent of 1 Ms of high spectral resolution data. We describe the technical specifications of LASS and highlight the main scientific objectives that will be addressed. (Abridged)Comment: White Paper in support of a mission concept to be submitted for the 2023 NASA Astrophysics Probes opportunity. This White Paper will be updated when required. 30 pages, 25 figure

Climate Change and Trophic Response of the Antarctic Bottom Fauna

BACKGROUND: As Earth warms, temperate and subpolar marine species will increasingly shift their geographic ranges poleward. The endemic shelf fauna of Antarctica is especially vulnerable to climate-mediated biological invasions because cold temperatures currently exclude the durophagous (shell-breaking) predators that structure shallow-benthic communities elsewhere. METHODOLOGY/PRINCIPAL FINDINGS: We used the Eocene fossil record from Seymour Island, Antarctic Peninsula, to project specifically how global warming will reorganize the nearshore benthos of Antarctica. A long-term cooling trend, which began with a sharp temperature drop approximately 41 Ma (million years ago), eliminated durophagous predators-teleosts (modern bony fish), decapod crustaceans (crabs and lobsters) and almost all neoselachian elasmobranchs (modern sharks and rays)-from Antarctic nearshore waters after the Eocene. Even prior to those extinctions, durophagous predators became less active as coastal sea temperatures declined from 41 Ma to the end of the Eocene, approximately 33.5 Ma. In response, dense populations of suspension-feeding ophiuroids and crinoids abruptly appeared. Dense aggregations of brachiopods transcended the cooling event with no apparent change in predation pressure, nor were there changes in the frequency of shell-drilling predation on venerid bivalves. CONCLUSIONS/SIGNIFICANCE: Rapid warming in the Southern Ocean is now removing the physiological barriers to shell-breaking predators, and crabs are returning to the Antarctic Peninsula. Over the coming decades to centuries, we predict a rapid reversal of the Eocene trends. Increasing predation will reduce or eliminate extant dense populations of suspension-feeding echinoderms from nearshore habitats along the Peninsula while brachiopods will continue to form large populations, and the intensity of shell-drilling predation on infaunal bivalves will not change appreciably. In time the ecological effects of global warming could spread to other portions of the Antarctic coast. The differential responses of faunal components will reduce the endemic character of Antarctic subtidal communities, homogenizing them with nearshore communities at lower latitudes

Distress Associated with Dementia-Related Psychosis and Agitation in Relation to Healthcare Utilization and Costs

ObjectivesExplore the relationship between behavioral and psychological symptoms of dementia (BPSD; specifically, delusions, hallucinations, and agitation/aggression) and associated caregiver distress with emergency department (ED) utilization, inpatient hospitalization, and expenditures for direct medical care.Design/setting/participantsRetrospective cross-sectional cohort of participants with dementia (N = 332) and informants from the Aging, Demographics, and Memory Study, a nationally representative survey of U.S. adults >70 years old.MeasurementsBPSD of interest and associated informant distress (trichotomized as none/low/high) were assessed using the Neuropsychiatric Inventory (NPI). Outcomes were determined from one year of Medicare claims and examined according to presence of BPSD and associated informant distress, adjusting for participant demographics, dementia severity, and comorbidity.ResultsFifty-eight (15%) participants with dementia had clinically significant delusions, hallucinations, or agitation/aggression. ED visits, inpatient admissions, and costs were not significantly higher among the group with significant BPSD. In fully adjusted models, a high level of informant distress was associated with all outcomes: ED visit incident rate ratio (IRR) 3.03 (95% CI: 1.98-4.63; p < 0.001), hospitalization IRR 2.78 (95% CI: 1.73-4.46; p < 0.001), and relative cost ratio 2.00 (95% CI: 1.12-3.59; p = 0.02).ConclusionsA high level of informant distress related to participant BPSD, rather than the symptoms themselves, was associated with increased healthcare utilization and costs. Effectively identifying, educating, and supporting distressed caregivers may help reduce excess healthcare utilization for the growing number of older adults with dementia

Antidepressant Use and Cognitive Decline: The Health and Retirement Study

BACKGROUND: Depression is associated with cognitive impairment and dementia, but whether treatment for depression with antidepressants reduces the risk for cognitive decline is unclear. We assessed the association between antidepressant use and cognitive decline over 6 years. METHODS: Participants were 3,714 adults aged 50 or older enrolled in the nationally-representative Health and Retirement Study (HRS) and with self-reported antidepressant use. Depressive symptoms were assessed using the 8-item Center for Epidemiologic Studies Depression Scale. Cognitive function was assessed at four time-points (2004, 2006, 2008, 2010) through using a validated 27-point scale. Change in cognitive function over the 6-year follow-up period was examined using linear growth models, adjusted for demographics, depressive symptoms, comorbidities, functional limitations and antidepressant anticholinergic activity load. RESULTS: At baseline, cognitive function did not differ significantly between the 445 (12.1%) participants taking antidepressants and those not taking antidepressants (mean 14.9%, 95% CI: 14.3-15.4 vs. mean 15.1%, 95% CI: 14.9-15.3). During the 6-year follow up period, cognition declined in both users and nonusers of antidepressants, ranging from -1.4 change in mean score in those with high depressive symptoms and taking antidepressants to -.5 change in mean score in those with high depressive symptoms and not taking antidepressants. In adjusted models, people taking antidepressants declined at the same rate as those not taking antidepressants. Results remained consistent across different levels of baseline cognitive function, age, and duration of antidepressant use (prolonged versus short-term). CONCLUSIONS: Antidepressant use did not modify the course of 6-year cognitive change in this nationally- representative sample

Discovery of drug-like inhibitors of an essential RNA-editing ligase in Trypanosoma brucei

Trypanosomatid RNA editing is a unique process and essential for these organisms. It therefore represents a drug target for a group of protozoa that includes the causative agents for African sleeping sickness and other devastating tropical and subtropical diseases. Here, we present drug-like inhibitors of a key enzyme in the editing machinery, RNA-editing ligase 1 (REL1). These inhibitors were identified through a strategy employing molecular dynamics to account for protein flexibility. A virtual screen of the REL1 crystal structure against the National Cancer Institute Diversity Set was performed by using AutoDock4. The top 30 compounds, predicted to interact with REL1's ATP-binding pocket, were further refined by using the relaxed complex scheme (RCS), which redocks the compounds to receptor structures extracted from an explicitly solvated molecular dynamics trajectory. The resulting reordering of the ligands and filtering based on drug-like properties resulted in an initial recommended set of 8 ligands, 2 of which exhibited micromolar activity against REL1. A subsequent hierarchical similarity search with the most active compound over the full National Cancer Institute database and RCS rescoring resulted in an additional set of 6 ligands, 2 of which were confirmed as REL1 inhibitors with IC50 values of ≈1 μM. Tests of the 3 most promising compounds against the most closely related bacteriophage T4 RNA ligase 2, as well as against human DNA ligase IIIβ, indicated a considerable degree of selectivity for RNA ligases. These compounds are promising scaffolds for future drug design and discovery efforts against these important pathogens

A glycan gate controls opening of the SARS-CoV-2 spike protein.

SARS-CoV-2 infection is controlled by the opening of the spike protein receptor binding domain (RBD), which transitions from a glycan-shielded 'down' to an exposed 'up' state to bind the human angiotensin-converting enzyme 2 receptor and infect cells. While snapshots of the 'up' and 'down' states have been obtained by cryo-electron microscopy and cryo-electron tomagraphy, details of the RBD-opening transition evade experimental characterization. Here over 130 µs of weighted ensemble simulations of the fully glycosylated spike ectodomain allow us to characterize more than 300 continuous, kinetically unbiased RBD-opening pathways. Together with ManifoldEM analysis of cryo-electron microscopy data and biolayer interferometry experiments, we reveal a gating role for the N-glycan at position N343, which facilitates RBD opening. Residues D405, R408 and D427 also participate. The atomic-level characterization of the glycosylated spike activation mechanism provided herein represents a landmark study for ensemble pathway simulations and offers a foundation for understanding the fundamental mechanisms of SARS-CoV-2 viral entry and infection