Reports of a recent increase in US outpatient mental health care raise questions about whether it has been driven by rising rates of psychological distress and whether mental health treatment has ...become either more or less focused on people with higher levels of distress.
To characterize national trends in serious psychological distress and trends in outpatient mental health service use by adults with and without serious psychological distress.
The 2004-2005, 2009-2010, and 2014-2015 Medical Expenditure Panel Surveys (MEPS) were nationally representative surveys taken in US households. The analysis was limited to participants 18 years or older. Dates of this analysis were February 2018 to April 2018.
Annual national trends in the percentages of adults with serious psychological distress (Kessler 6 scale score ≥13), outpatient mental health service use (outpatient visit with a mental disorder diagnosis, psychotherapy visit, or psychotropic medication), and type of psychotropic medication use (antidepressants, anxiolytics/sedatives, antipsychotics, mood stabilizers, and stimulants). Age- and sex-adjusted odds ratios of the associations of survey period with the odds of serious psychological distress, outpatient mental health service use, and outpatient mental health service use were stratified by level of psychological distress.
The analysis involved 139 862 adult participants from the 2004-2005, 2009-2010, and 2014-2015 MEPS, including 51.67% women, 48.33% men, 67.11% white adults, and 32.89% nonwhite adults, with an overall mean (SE) age of 46.41 (0.14) years. Serious psychological distress declined overall from 4.82% (2004-2005) to 3.71% (2014-2015), including significant declines among young (3.94% to 3.07%), middle-aged (5.52% to 4.36%), and older adults (5.24% to 3.79%); men (3.94% to 3.09%) and women (5.64% to 4.29%); and major racial/ethnic groups (white, 4.52% to 3.82%; African American, 5.12% to 3.64%; Hispanic, 6.03% to 3.55%; and other, 5.22% to 3.26%). Overall, the percentage of adults receiving any outpatient mental health service increased from 19.08% (2004-2005) to 23.00% (2014-2015) (adjusted odds ratio, 1.25; 95% CI, 1.17-1.34). Although the proportionate increase in outpatient mental health service use for adults with serious psychological distress (54.17% to 68.40%) was larger than that for adults with less serious or no psychological distress (17.26% to 21.08%), the absolute increase in outpatient mental health service use was almost completely the result of growth in outpatient mental health service use by individuals with less serious or no psychological distress.
The recent increase in outpatient mental health service use occurred during a period of decline in serious psychological distress. Adults with less serious psychological distress accounted for most of the absolute increase in outpatient mental health service use, while adults with serious psychological distress experienced a greater relative increase in outpatient mental health service use.
Living cells compartmentalize materials and enzymatic reactions to increase metabolic efficiency. While eukaryotes use membrane‐bound organelles, bacteria and archaea rely primarily on protein‐bound ...nanocompartments. Encapsulins constitute a class of nanocompartments widespread in bacteria and archaea whose functions have hitherto been unclear. Here, we characterize the encapsulin nanocompartment from Myxococcus xanthus, which consists of a shell protein (EncA, 32.5 kDa) and three internal proteins (EncB, 17 kDa; EncC, 13 kDa; EncD, 11 kDa). Using cryo‐electron microscopy, we determined that EncA self‐assembles into an icosahedral shell 32 nm in diameter (26 nm internal diameter), built from 180 subunits with the fold first observed in bacteriophage HK97 capsid. The internal proteins, of which EncB and EncC have ferritin‐like domains, attach to its inner surface. Native nanocompartments have dense iron‐rich cores. Functionally, they resemble ferritins, cage‐like iron storage proteins, but with a massively greater capacity (~30,000 iron atoms versus ~3,000 in ferritin). Physiological data reveal that few nanocompartments are assembled during vegetative growth, but they increase fivefold upon starvation, protecting cells from oxidative stress through iron sequestration.
Synopsis
Bacteria compartmentalize by sequestering components into protein shells. Here, such a nanocompartment is shown to structurally resemble virus capsids and to store large amounts of iron for protection under starvation conditions.
Iron homeostasis in Myxococcus xanthus involves iron sequestration into large protein shells (encapsulin nanocompartments).
The shell is lined with adaptor proteins with ferritin‐like folds that nucleate iron‐rich granules.
The encapsulin system appears to complement a ferritin system.
The encapsulin shell closely resembles capsids of bacteriophages and herpesvirus.
Thus, phages may have arisen from cellular genes, or M. xanthus may have acquired the encapsulin shell gene from a bacteriophage.
Bacteria compartmentalize by sequestering components into protein shells. Here, such a nanocompartment is shown to structurally resemble virus capsids and to store large amounts of iron for protection under starvation conditions.
RNA-based vaccines against SARS-CoV-2 have proven critical to limiting COVID-19 disease severity and spread. Cellular mechanisms driving antigen-specific responses to these vaccines, however, remain ...uncertain. Here we identify and characterize antigen-specific cells and antibody responses to the RNA vaccine BNT162b2 using multiple single-cell technologies for in depth analysis of longitudinal samples from a cohort of healthy participants. Mass cytometry and unbiased machine learning pinpoint an expanding, population of antigen-specific memory CD4
and CD8
T cells with characteristics of follicular or peripheral helper cells. B cell receptor sequencing suggest progression from IgM, with apparent cross-reactivity to endemic coronaviruses, to SARS-CoV-2-specific IgA and IgG memory B cells and plasmablasts. Responding lymphocyte populations correlate with eventual SARS-CoV-2 IgG, and a participant lacking these cell populations failed to sustain SARS-CoV-2-specific antibodies and experienced breakthrough infection. These integrated proteomic and genomic platforms identify an antigen-specific cellular basis of RNA vaccine-based immunity.
Amyloid fibrils are filamentous protein aggregates implicated in several common diseases such as Alzheimer’s disease and type II diabetes. Similar structures are also the molecular principle of the ...infectious spongiform encephalopathies such as Creutzfeldt–Jakob disease in humans, scrapie in sheep, and of the so-called yeast prions, inherited non-chromosomal elements found in yeast and fungi. Scanning transmission electron microscopy (STEM) is often used to delineate the assembly mechanism and structural properties of amyloid aggregates. In this review we consider specifically contributions and limitations of STEM for the investigation of amyloid assembly pathways, fibril polymorphisms and structural models of amyloid fibrils. This type of microscopy provides the only method to directly measure the mass-per-length (MPL) of individual filaments. Made on both
in vitro assembled and
ex vivo samples, STEM mass measurements have illuminated the hierarchical relationships between amyloid fibrils and revealed that polymorphic fibrils and various globular oligomers can assemble simultaneously from a single polypeptide. The MPLs also impose strong constraints on possible packing schemes, assisting in molecular model building when combined with high-resolution methods like solid-state nuclear magnetic resonance (NMR) and electron paramagnetic resonance (EPR).
The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lineages that are more transmissible and resistant to currently approved antibody therapies poses a considerable ...challenge to the clinical treatment of coronavirus disease (COVID-19). Therefore, the need for ongoing discovery efforts to identify broadly reactive monoclonal antibodies to SARS-CoV-2 is of utmost importance. Here, we report a panel of SARS-CoV-2 antibodies isolated using the linking B cell receptor to antigen specificity through sequencing (LIBRA-seq) technology from an individual who recovered from COVID-19. Of these antibodies, 54042-4 shows potent neutralization against authentic SARS-CoV-2 viruses, including variants of concern (VOCs). A cryoelectron microscopy (cryo-EM) structure of 54042-4 in complex with the SARS-CoV-2 spike reveals an epitope composed of residues that are highly conserved in currently circulating SARS-CoV-2 lineages. Further, 54042-4 possesses uncommon genetic and structural characteristics that distinguish it from other potently neutralizing SARS-CoV-2 antibodies. Together, these findings provide motivation for the development of 54042-4 as a lead candidate to counteract current and future SARS-CoV-2 VOCs.
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•LIBRA-seq identifies 54042-4, a potently neutralizing SARS-CoV-2 antibody•54042-4 maintains potent neutralization against Alpha, Beta, Gamma, and Delta VOCs•The epitope of 54042-4 is highly conserved among current SARS-CoV-2 isolates
Kramer et al. demonstrate that antibody 54042-4 recognizes residues highly conserved across global SARS-CoV-2 isolates. Antibody 54042-4 potently neutralizes all known circulating variants of concern (VOCs) and could be developed as a clinical candidate to treat COVID-19 infection.
The immature physiology of cardiomyocytes derived from human induced pluripotent stem cells (hiPSCs) limits their utility for drug screening and disease modelling. Here we show that suitable ...combinations of mechanical stimuli and metabolic cues can enhance the maturation of hiPSC-derived cardiomyocytes, and that the maturation-inducing cues have phenotype-dependent effects on the cells' action-potential morphology and calcium handling. By using microfluidic chips that enhanced the alignment and extracellular-matrix production of cardiac microtissues derived from genetically distinct sources of hiPSC-derived cardiomyocytes, we identified fatty-acid-enriched maturation media that improved the cells' mitochondrial structure and calcium handling, and observed divergent cell-source-dependent effects on action-potential duration (APD). Specifically, in the presence of maturation media, tissues with abnormally prolonged APDs exhibited shorter APDs, and tissues with aberrantly short APDs displayed prolonged APDs. Regardless of cell source, tissue maturation reduced variabilities in spontaneous beat rate and in APD, and led to converging cell phenotypes (with APDs within the 300-450 ms range characteristic of human left ventricular cardiomyocytes) that improved the modelling of the effects of pro-arrhythmic drugs on cardiac tissue.
In yeast cells infected with the PSI+ prion, Sup35p forms aggregates and its activity in translation termination is downregulated. Transfection experiments have shown that Sup35p filaments assembled ...in vitro are infectious, suggesting that they reproduce or closely resemble the prion. We have used several EM techniques to study the molecular architecture of filaments, seeking clues as to the mechanism of downregulation. Sup35p has an N-terminal ‘prion' domain; a highly charged middle (M-)domain; and a C-terminal domain with the translation termination activity. By negative staining, cryo-EM and scanning transmission EM (STEM), filaments of full-length Sup35p show a thin backbone fibril surrounded by a diffuse 65-nm-wide cloud of globular C-domains. In diameter (∼8 nm) and appearance, the backbones resemble amyloid fibrils of N-domains alone. STEM mass-per-unit-length data yield ∼1 subunit per 0.47 nm for N-fibrils, NM-filaments and Sup35p filaments, further supporting the fibril backbone model. The 30 nm radial span of decorating C-domains indicates that the M-domains assume highly extended conformations, offering an explanation for the residual Sup35p activity in infected cells, whereby the C-domains remain free enough to interact with ribosomes.
The efflux transporter P-glycoprotein (P-gp) is an important mediator of various pharmacokinetic parameters, being expressed at numerous physiological barriers and also in multidrug-resistant cancer ...cells. Molecular cloning of homologous cDNAs is an important tool for the characterization of functional differences in P-gp between species. However, plasmids containing mouse mdr1a cDNA display significant genetic instability during cloning in bacteria, indicating that mdr1a cDNA may be somehow toxic to bacteria, allowing only clones containing mutations that abrogate this toxicity to survive transformation. We demonstrate here the presence of a cryptic promoter in mouse mdr1a cDNA that causes mouse P-gp expression in bacteria. This expression may account for the observed toxicity of mdr1a DNA to bacteria. Sigma 70 binding site analysis and GFP reporter plasmids were used to identify sequences in the first 321 bps of mdr1a cDNA capable of initiating bacterial protein expression. An mdr1a M107L cDNA containing a single residue mutation at the proposed translational start site was shown to allow sub-cloning of mdr1a in E. coli while retaining transport properties similar to wild-type P-gp. This mutant mdr1a cDNA may prove useful for efficient cloning of mdr1a in E. coli.
Classical jet noise theory indicates that radiated sound power is proportional to the jet velocity raised to the eighth and third powers for subsonic and supersonic jets, respectively. To connect ...full-scale measurements with classical jet noise theory, this letter presents sound power and acoustic efficiency values for an installed GE-F404 engine. When subsonic, the change in sound power follows the eighth-power law, and the sound power change approximately follows the third-power law at supersonic conditions, with an acoustic efficiency of ∼0.5-0.6%. However, the OAPWL increase from subsonic to supersonic jet velocities is greater than would be predicted.
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