Misfolding and aggregation of host proteins are important features of the pathogenesis of neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, frontotemporal dementia and ...prion diseases. In all these diseases, the misfolded protein increases in amount by a mechanism involving seeded polymerization. In prion diseases, host prion protein is misfolded to form a pathogenic protease-resistant form, PrPSc, which accumulates in neurons, astroglia and microglia in the CNS. Here using dual-staining immunohistochemistry, we compared the cell specificity of PrPSc accumulation at early preclinical times post-infection using three mouse scrapie strains that differ in brain regional pathology. PrPSc from each strain had a different pattern of cell specificity. Strain 22L was mainly associated with astroglia, whereas strain ME7 was mainly associated with neurons and neuropil. In thalamus and cortex, strain RML was similar to 22L, but in substantia nigra, RML was similar to ME7. Expression of 90 genes involved in neuroinflammation was studied quantitatively using mRNA from thalamus at preclinical times. Surprisingly, despite the cellular differences in PrPSc accumulation, the pattern of upregulated genes was similar for all three strains, and the small differences observed correlated with variations in the early disease tempo. Gene upregulation correlated with activation of both astroglia and microglia detected in early disease prior to vacuolar pathology or clinical signs. Interestingly, the profile of upregulated genes in scrapie differed markedly from that seen in two acute viral CNS diseases (LaCrosse virus and BE polytropic Friend retrovirus) that had reactive gliosis at levels similar to our prion-infected mice.
Lipid droplet (LD) functions are regulated by a complement of integral and peripheral proteins that associate with the bounding LD phospholipid monolayer. Defining the composition of the LD proteome ...has remained a challenge due to the presence of contaminating proteins in LD-enriched buoyant fractions. To overcome this limitation, we developed a proximity labeling strategy that exploits LD-targeted APEX2 to biotinylate LD proteins in living cells. Application of this approach to two different cell types identified the vast majority of previously validated LD proteins, excluded common contaminating proteins, and revealed new LD proteins. Moreover, quantitative analysis of LD proteome dynamics uncovered a role for endoplasmic reticulum-associated degradation in controlling the composition of the LD proteome. These data provide an important resource for future LD studies and demonstrate the utility of proximity labeling to study the regulation of LD proteomes.
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•Selective enzymatic tagging of lipid droplet proteins using APEX2 fusion proteins•Mapping of high-confidence lipid droplet proteomes in two human cell lines•Inhibition of the AAA ATPase VCP stabilizes c18orf32, an ER-lipid droplet protein•C18orf32 levels on lipid droplets are regulated by a gp78 and derlin-1 ERAD pathway
Lipid droplets (LDs) are dynamic neutral lipid storage organelles. Bersuker et al. employ an APEX2-based proximity labeling strategy to define high-confidence LD proteomes from human cells. They reveal a role for endoplasmic reticulum-associated degradation in controlling the levels of an LD protein identified here that regulates LD lipid composition.
Unravelling the timing of the metazoan radiation is crucial for elucidating the macroevolutionary processes associated with the Cambrian explosion. Because estimates of metazoan divergence times ...derived from molecular clocks range from quite shallow (Ediacaran) to very deep (Mesoproterozoic), it has been difficult to ascertain whether there is concordance or quite dramatic discordance between the genetic and geological fossil records. Here, we show using a range of molecular clock methods that the major pulse of metazoan divergence times was during the Ediacaran, which is consistent with a synoptic reading of the Ediacaran macrobiota. These estimates are robust to changes in priors, and are returned with or without the inclusion of a palaeontologically derived maximal calibration point. Therefore, the two historical records of life both suggest that although the cradle of Metazoa lies in the Cryogenian, and despite the explosion of ecology that occurs in the Cambrian, it is the emergence of bilaterian taxa in the Ediacaran that sets the tempo and mode of macroevolution for the remainder of geological time.
The circumplex model of affect proposes that all affective states arise from cognitive interpretations of core neural sensations that are the product of two independent neurophysiological systems. ...This model stands in contrast to theories of basic emotions, which posit that a discrete and independent neural system subserves every emotion. We propose that basic emotion theories no longer explain adequately the vast number of empirical observations from studies in affective neuroscience, and we suggest that a conceptual shift is needed in the empirical approaches taken to the study of emotion and affective psychopathologies. The circumplex model of affect is more consistent with many recent findings from behavioral, cognitive neuroscience, neuroimaging, and developmental studies of affect. Moreover, the model offers new theoretical and empirical approaches to studying the development of affective disorders as well as the genetic and cognitive underpinnings of affective processing within the central nervous system.
This in-depth review delves into the multifaceted realm of mass shootings and explores their epidemiology from a psychological perspective. The article presents a comprehensive examination of the ...prevalence, perpetrator and victim profiles, motives, and contributing factors associated with mass shootings. By investigating the intricate relationship between masculinity, domestic violence, military service, social media, fame-seeking, suicidal ideation, mental illness, and firearms, this article sheds light on the multifaceted nature of mass shootings. Moreover, it discusses the importance of implementing effective prevention strategies to address this growing public health concern. The findings from this review serve as a valuable resource for researchers, practitioners, policy makers, and the community at large, facilitating a deeper understanding of mass shootings and fostering the development of evidence-based solutions to prevent these tragic incidents. Expected final online publication date for the
, Volume 20 is May 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
ObjectiveThe association with B-type natriuretic peptide (BNP), disease progression and outcomes in patients with atrial fibrillation (AF) has not been thoroughly investigated.MethodsWe evaluated the ...association between BNP levels and outcomes, including AF progression, composite outcome of major adverse cardiovascular or neurological events (MACNE) and major bleeding, via pooled logistic regression and Cox frailty models in Outcomes Registry for Better Informed Treatment of Atrial Fibrillation II registry. AF progression was defined as either paroxysmal becoming persistent or permanent, or persistent becoming permanent at any follow-up.ResultsAmong 13 375 patients with AF, 2797 with BNP values at baseline (median age (IQR), 72.0 (63.0–80.0) years; 43.0% women; median BNP, 238 (102–502) ng/L; 42.3% prior heart failure) were included in the models evaluating the association between BNP levels and MACNE or major bleeding. Of these, 1282 patients with paroxysmal or persistent AF at baseline were analysed in AF progression model. The likelihood of AF progression (adjusted OR, 1.11 for every 100 ng/mL; 95% CI 1.03 to 1.19) and MACNE (adjusted HR, 1.11 for every doubling in BNP values; 95% CI 1.01 to 1.22) increased with BNP concentration, while the elevated BNP values were not associated with increased risks of major bleeding. BNP values improved the risk prediction of AF progression and MACNE when added to conventional risk estimates.ConclusionsBNP levels are associated with increased risk of AF progression and cardiovascular outcomes in patients with AF. Further studies are required to assess whether biomarker-based risk stratification improves patient outcomes.Clinical trial registrationNCT01701817.
BACKGROUND:Studies evaluating the effects of atrial fibrillation (AF) catheter ablation versus antiarrhythmic therapy on outcomes have shown mixed results. In addition, guidelines recommend ...continuing oral anticoagulation (OAC) after ablation for those at risk of stroke, but real-world data are lacking.
METHODS:We evaluated outcomes including death, myocardial infarction, stroke or systemic embolism, intracranial bleeding, major bleeding, and hospitalization in patients undergoing AF ablation compared with a propensity score matched cohort of patients treated with anti-arrhythmic medications only in the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation registries. Cox proportional hazards regression was performed to evaluate the association between AF ablation and outcomes. We then evaluated patterns of treatment with OAC among AF ablation patients.
RESULTS:Among 21 595 patients, 1190 (6%) underwent de novo AF ablation. Our propensity score-matched cohort included 1087 patients who underwent AF ablation matched 1:1 with 1087 patients treated with antiarrhythmic medications only. There were no significant differences in the risk of all-cause and cardiovascular death, and most other major adverse cardiovascular and neurological events. AF catheter ablation was associated with an increased risk of all-cause hospitalization during follow-up (hazard ratio, 1.24 95% CI, 1.05–1.46), particularly in the first 3 months (the standard blanking period) after the procedure. Among those who underwent AF ablation with a CHA2DS2 VASc score ≥2 for men and ≥3 for women, 23% had OAC discontinued after ablation. Among those who discontinued OAC, the median time to discontinuation was 6.2 months.
CONCLUSIONS:In this large US national registry, we found no difference in adjusted rates of cardiovascular or all-cause death between patients treated with AF catheter ablation and antiarrhythmic medications only. Notably, discontinuation of OAC after ablation remains relatively common despite guideline recommendations for continued stroke prevention therapy in patients at risk of stroke.
•Biochar is the solid, carbon-rich residual from the pyrolysis of biomass.•Biochars were produced from wood pellets and pelletized wheat straw.•Both biochars proved acceptable as peat replacements in ...potting substrates at levels up to 15%.
Biochar is the solid, carbon-rich product resulting from the pyrolysis of biomass in the absence of oxygen. We are examining biochars for several horticultural applications, including as a replacement for peat moss in soilless substrates used in the production of containerized greenhouse and nursery crops. Biochars were prepared from hardwood pellets and from pelletized wheat straw. Straw biochar had a higher potassium content and pH than the wood biochar. Fourier transform infrared spectroscopy analyses of the biochars showed much greater volatile content in the straw biochar. Both biochars had significantly higher bulk densities than either peat moss or vermiculite. Substituting biochar pellets (at rates of 5%, 10%, and 15%, v/v) for peat moss increased substrate pHs, bulk densities, and electrical conductivities, while having variable effects on physical properties (air porosities, container capacities, and total porosities). Greenhouse experiments were conducted using tomato (Solanum lycopersicum L.) and marigold (Tagetes erecta L.) plants grown in 3.0-L pots. Addition of either biochar had no effect on dry weights of tomato plants after 4 weeks of growth, but significantly increased plant heights in all treatments. Marigold plant heights were greater than the control in all but the 5% wood biochar, but had only a minor effect on plant dry weights. These results indicate that both pelletized biochars would be suitable as replacements for peat in soilless substrates when used at these replacement rates.
This paper announces a database on the taxonomy and distribution of mites of the family Phytoseiidae Berlese, which is available online at http://www.lea.esalq.usp.br/phytoseiidae/. Synthesis of ...species diversity per genus, subfamily and country are given. Information about use of the database is provided.
Abstract Background Antithrombotic therapy for acute myocardial infarction (MI) with atrial fibrillation (AF) among higher risk older patients treated with percutaneous coronary intervention (PCI) ...remains unclear. Objectives This study sought to determine appropriate antithrombotic therapy for acute MI patients with AF treated with PCI. Methods We examined 4,959 patients ≥65 years of age with acute MI and AF who underwent coronary stenting (Acute Coronary Treatment and Intervention Outcomes Network Registry–Get With the Guidelines). The primary effectiveness outcome was 2-year major adverse cardiac events (MACE) comprising death, readmission for MI, or stroke; the primary safety outcome was bleeding readmission. Outcomes with dual antiplatelet therapy (DAPT) or triple therapy (DAPT plus warfarin) were compared using Cox proportional hazard modeling with inverse probability-weighted propensity adjustment. Results Among 4,959 patients, 27.6% (n = 1,370) were discharged on triple therapy. Relative to DAPT, patients on triple therapy had a similar risk of MACE (adjusted hazard ratio HR: 0.99 95% confidence interval (CI): 0.86 to 1.16) but significantly greater risk of bleeding requiring hospitalization (adjusted HR: 1.61 95% CI: 1.31 to 1.97) and greater risk of intracranial hemorrhage (adjusted HR: 2.04 95% CI: 1.25 to 3.34). Of 1,591 Medicare Part D patients, 90-day post-discharge warfarin persistence among patients discharged on warfarin was 93.2% (n = 412). Results of 90-day landmark analyses comparing triple therapy versus DAPT in patients persistently on warfarin versus those not discharged on warfarin who had not filled a warfarin prescription were similar to our primary findings. Conclusions Approximately 1 in 4 older AF patients undergoing PCI for MI were discharged on triple therapy. Those receiving triple therapy versus DAPT had higher rates of major bleeding without a measurable difference in composite MI, death, or stroke.
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