The persistence of silver nanoparticles in aquatic environments and their subsequent impact on organisms depends on key transformation processes, which include aggregation, dissolution, and surface ...modifications by metal-complexing ligands. Here, we studied how cysteine, an amino acid representative of thiol ligands that bind monovalent silver, can alter the surface chemistry, aggregation, and dissolution of zero-valent silver nanoparticles. We compared nanoparticles synthesized with two coatings, citrate and polyvinylpirrolidone (PVP), and prepared nanoparticle suspensions (approximately 8 μM total Ag) containing an excess of cysteine (400 μM). Within 48 h, up to 47% of the silver had dissolved, as indicated by filtration of the samples with a 0.025-μm filter. Initial dissolution rates were calculated from the increase of dissolved silver concentration when particles were exposed to cysteine and normalized to the available surface area of nanoparticles in solution. In general, the rates of dissolution were almost 3 times faster for citrate-coated nanoparticles relative to PVP-coated nanoparticles. Rates tended to be slower in solutions with higher ionic strength in which the nanoparticles were aggregating. X-ray absorption spectroscopy analysis of the particles suggested that cysteine adsorbed to silver nanoparticles surfaces through the formation of Ag(+I)--sulfhydryl bonds. Overall, the results of this study highlight the importance of modifications by sulfhydryl-containing ligands that can drastically influence the long-term reactivity of silver nanoparticles in the aquatic environment and their bioavailability to exposed organisms. Our findings demonstrate the need to consider multiple interlinked transformation processes when assessing the bioavailability, environmental risks, and safety of nanoparticles, particularly in the presence of metal-binding ligands.
Abstract
When he signed the manifesto published in Tenerife in 1935 to mark the Second International Surrealist Exhibition, Pedro García Cabrera (1905–1981) ratified the fascination exercised on him ...by a movement that, he recalled in 1979, ‘representaba el descubrimiento del mundo interior del hombre’ represented the discovery of man’s inner world. That discovery generated three works: a story he categorized as a ‘narración surrealista,’ Los senos de tinta Breasts of Ink; 1934, and two books of poetry that responded to Surrealism in different ways. By constructing the eight poems of Dársena con despertadores Dock with Alarm Clocks; 1936 out of two lists of words he had assembled, he achieved what he called ‘un cierto automatismo síquico’ a certain psychic automatism and coined images ‘siguiendo los contornos de lo absurdo’ following the contours of the absurd. His experiments with words became a psychic imperative in Entre la guerra y tú Between War and You; 1936–39, whose poems are like the ‘móviles delirios’ mobile ravings he mentioned in one of them, a phrase that evokes the mind that reacts to the disorder of war and imprisonment and the images generated by it.
Shared community scenarios of societal and environmental system changes have underpinned a broad range of research and assessment studies over the past several decades. These scenarios have largely ...aimed to address specific questions within broad issue areas like climate change or biodiversity and generally provided information on the drivers of change. The consequences of those drivers, such as impacts on society and policy responses, have tended to be left to the research community to investigate, using scenarios of drivers as inputs to their studies, producing projections of a disparate set of relevant output metrics. While this approach has had many benefits, it has fallen short of producing a robust, comparable literature describing outcomes across studies in common metrics. We argue that new scenarios are needed that extend current approaches to be organized around common outcome metrics for the well‐being and resilience of society and ecosystems. We propose an approach that would focus on agreed upon outcomes for well‐being and resilience as well as critical drivers of change, cut across issues and scales in multiple sectors, and draw on new systematic methods of scenario generation and discovery to highlight scenarios that are most critical in understanding societal risks and responding to them. Research derived from this outcome‐based scenario development approach would facilitate improved assessment of risks of and responses to a range of stressors and the multi‐sector interactions they generate.
Plain Language Summary
Scenarios are visions of how the world might unfold. They can consist of stories, numerical projections, or both. Typically scenarios describe trends in drivers of change—factors like population and economic growth, how fast technological progress occurs, and changes to the climate system. Historically, small sets of common scenarios have been widely used by the global change research community. Researchers use the scenarios as inputs to project the consequences of the drivers, for example, for agricultural production, water availability, or the costs of decarbonization. We propose that new scenarios are needed that include outcomes (consequences) not just for physical or managed systems, but also for human well‐being and resilience, including health, poverty, and household food, water, and energy security. Further, the scenarios should not only include well‐being outcomes, but be organized around them. That is, scenarios should be designed not necessarily to span a wide range of drivers, but rather to span a wide range of well‐being and resilience outcomes. Designing scenarios around the ultimate outcomes of interest will improve the assessment of risks and responses related to well‐being and resilience. New quantitative methods for generating and identifying scenarios can facilitate this process.
Key Points
Community scenarios facilitate research and assessment but have fallen short of producing a literature with comparable outcomes
New scenarios are needed that are organized around outcomes for human well‐being and resilience
We propose an outcome‐based scenario development approach that would cut across issues, scales, and sectors
Microaspiration is a common phenomenon in healthy subjects, but its frequency is increased in chronic inflammatory airway diseases, and its role in inflammatory and immune phenotypes is unclear. We ...have previously demonstrated that acellular bronchoalveolar lavage samples from half of the healthy people examined are enriched with oral taxa (here called pneumotypeSPT) and this finding is associated with increased numbers of lymphocytes and neutrophils in bronchoalveolar lavage. Here, we have characterized the inflammatory phenotype using a multi-omic approach. By evaluating both upper airway and acellular bronchoalveolar lavage samples from 49 subjects from three cohorts without known pulmonary disease, we observed that pneumotypeSPT was associated with a distinct metabolic profile, enhanced expression of inflammatory cytokines, a pro-inflammatory phenotype characterized by elevated Th-17 lymphocytes and, conversely, a blunted alveolar macrophage TLR4 response. The cellular immune responses observed in the lower airways of humans with pneumotypeSPT indicate a role for the aspiration-derived microbiota in regulating the basal inflammatory status at the pulmonary mucosal surface.
Activation of sonic hedgehog (Shh) signaling occurs in the majority of pancreatic ductal adenocarcinomas. Here we investigate the mechanisms by which Shh contributes to pancreatic tumorigenesis. We ...find that Shh expression enhances proliferation of pancreatic duct epithelial cells, potentially through the transcriptional regulation of the cell cycle regulators cyclin D1 and p21. We further show that Shh protects pancreatic duct epithelial cells from apoptosis through the activation of phosphatidylinositol 3-kinase signaling and the stabilization of Bcl-2 and Bcl-XL. Significantly, Shh also cooperates with activated K-Ras to promote pancreatic tumor development. Finally, Shh signaling enhances K-Ras-induced pancreatic tumorigenesis by reducing the dependence of tumor cells on the sustained activation of the MAPK and phosphatidylinositol 3-kinase/Akt/mTOR signaling pathways. Thus, our data suggest that Shh signaling contributes to tumor initiation in the pancreas through at least two mechanisms and additionally enhances tumor cell resistance to therapeutic intervention. Collectively, our findings demonstrate crucial roles for Shh signaling in multiple stages of pancreatic carcinogenesis.
Bowel movement (BM) frequency is used to titrate lactulose for hepatic encephalopathy (HE). However, stool consistency using the Bristol stool scale (BSS, 0-7) is often ignored.
The study included ...pre-BSS and post-BSS cohorts. BSS was incorporated into decision-making after training in outpatients with cirrhosis. Two to 3 BMs/d and BSS 3-4 were considered normal, whereas the rest were considered high or low; concordance between the metrics was evaluated. Medication changes and 6-month admissions were compared between this group (post-BSS) and a comparable previous group (pre-BSS). Concordance and regression analyses for all-cause admissions and HE-related admissions were performed, and comparisons were made for HE-related medication stability. In the longitudinal analysis, an outpatient group seen twice was analyzed for BSS and BMs.
In the post-BSS cohort, 112 patients were included with only 46% BSS and BMs concordance and modest BSS/BMs correlation (r = 0.27, P = 0.005). Compared with a pre-BSS cohort (N = 114), there was a lower 6-month total (4% vs 0.36%, P < 0.001) or HE-related admission (1% vs 0.12%, P = 0.002). Regression showed model for end-stage liver disease (odds ratio OR: 1.10, P = 0.003) and pre-BSS/post-BSS (OR: 0.04, P < 0.001) for all-cause admissions and HE (OR: 3.59, P = 0.04) and preera/postera (OR: 0.16, P = 0.02) for HE-related admissions as significant. HE medication regimens were more stable post-BSS vs pre-BSS (32% vs 20%, P = 0.04), which was due to patients with BSS > BMs (P = 0.02). In the longitudinal analysis, 33 patients without medication changes or underlying clinical status changes were tested 36 ± 24 days apart. No changes in BSS (P = 0.73) or BMs (P = 0.19) were found.
BSS is complementary and additive to BM frequency, can modulate the risk of readmissions and stabilize HE-related therapy changes in outpatients with cirrhosis, and could help personalize HE management.
Introduction
Understanding synergies between neurodegenerative and cerebrovascular pathologies that modify dementia presentation represents an important knowledge gap.
Methods
This multi‐site, ...longitudinal, observational cohort study recruited participants across prevalent neurodegenerative diseases and cerebrovascular disease and assessed participants comprehensively across modalities. We describe univariate and multivariate baseline features of the cohort and summarize recruitment, data collection, and curation processes.
Results
We enrolled 520 participants across five neurodegenerative and cerebrovascular diseases. Median age was 69 years, median Montreal Cognitive Assessment score was 25, median independence in activities of daily living was 100% for basic and 93% for instrumental activities. Spousal study partners predominated; participants were often male, White, and more educated. Milder disease stages predominated, yet cohorts reflect clinical presentation.
Discussion
Data will be shared with the global scientific community. Within‐disease and disease‐agnostic approaches are expected to identify markers of severity, progression, and therapy targets. Sampling characteristics also provide guidance for future study design.
Multiplex families have higher recurrence risk of schizophrenia compared to the families of sporadic cases, but the source of this increased recurrence risk is unknown. We used schizophrenia ...genome-wide association study data (N = 156,509) to construct polygenic risk scores (PRS) in 1005 individuals from 257 multiplex schizophrenia families, 2114 ancestry-matched sporadic cases, and 2205 population controls, to evaluate whether increased PRS can explain the higher recurrence risk of schizophrenia in multiplex families compared to ancestry-matched sporadic cases. Using mixed-effects logistic regression with family structure modeled as a random effect, we show that SCZ PRS in familial cases does not differ significantly from sporadic cases either with, or without family history (FH) of psychotic disorders (All sporadic cases p = 0.90, FH+ cases p = 0.88, FH- cases p = 0.82). These results indicate that increased burden of common schizophrenia risk variation as indexed by current SCZ PRS, is unlikely to account for the higher recurrence risk of schizophrenia in multiplex families. In the absence of elevated PRS, segregation of rare risk variation or environmental influences unique to the families may explain the increased familial recurrence risk. These findings also further validate a genetically influenced psychosis spectrum, as shown by a continuous increase of common SCZ risk variation burden from unaffected relatives to schizophrenia cases in multiplex families. Finally, these results suggest that common risk variation loading are unlikely to be predictive of schizophrenia recurrence risk in the families of index probands, and additional components of genetic risk must be identified and included in order to improve recurrence risk prediction.
To characterize ocular perfusion pressure (OPP) fluctuations with continuous telemetry over 24-hour periods across multiple days in nonhuman primates (NHPs) to test the hypotheses that OPP differs ...among NHPs and that the diurnal cycle of OPP is characterized by low OPP during sleep.
We have developed and validated two implantable radiotelemetry systems that allow continuous measurement of intraocular pressure (IOP), arterial blood pressure (BP), and OPP up to 500 Hz. OPP was measured unilaterally in 12 male NHPs for periods of 38 to 412 days. IOP transducers were calibrated directly via anterior chamber manometry, and OPP was calculated continuously as central retinal artery BP minus IOP. OPP data were corrected for signal drift between calibrations and averaged hourly.
OPP varied widely among animals, with daily averages ranging from ∼47 to 65 mm Hg. In eight of 12 NHPs, OPP was significantly lower during sleep compared to waking hours. In three animals, the diurnal cycle was reversed and OPP was significantly higher during sleep (P < 0.05), and one NHP showed no diurnal cycle. Day-to-day OPP variability within NHPs was the largest source of overall OPP variability, even larger than the differences between NHPs. Average daily OPP showed an unexplained ∼32-day cyclic pattern in most NHPs.
Average OPP varied widely and exhibited differing diurnal cycles in NHPs, a finding that matches those of prior patient studies and indicates that OPP studies in the NHP model are appropriate. Infrequent snapshot measurements of either IOP or BP are insufficient to capture true IOP, BP, and OPP and their fluctuations.
The optimal approach for continuous measurement of intraocular pressure (IOP), including pressure transducer location and measurement frequency, is currently unknown. This study assessed the ...capability of extraocular (EO) and intraocular (IO) pressure transducers, using different IOP sampling rates and duty cycles, to characterize IOP dynamics. Transient IOP fluctuations were measured and quantified in 7 eyes of 4 male rhesus macaques (NHPs) using the Konigsberg EO system (continuous at 500 Hz), 12 eyes of 8 NHPs with the Stellar EO system and 16 eyes of 12 NHPs with the Stellar IO system (both measure at 200 Hz for 15 s of every 150 s period). IOP transducers were calibrated bi-weekly via anterior chamber manometry. Linear mixed effects models assessed the differences in the hourly transient IOP impulse, and transient IOP fluctuation frequency and magnitude between systems and transducer placements (EO versus IO). All systems measured 8000-12,000 and 5000-6500 transient IOP fluctuations per hour > 0.6 mmHg, representing 8-16% and 4-8% of the total IOP energy the eye must withstand during waking and sleeping hours, respectively. Differences between sampling frequency/duty cycle and transducer placement were statistically significant (p < 0.05) but the effect sizes were small and clinically insignificant. IOP dynamics can be accurately captured by sampling IOP at 200 Hz on a 10% duty cycle using either IO or EO transducers.
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