Programmable Shape-Shifting Micelles Chien, Miao-Ping; Rush, Anthony M; Thompson, Matthew P ...
Angewandte Chemie (International ed.),
July 12, 2010, Letnik:
49, Številka:
30
Journal Article
Recenzirano
Odprti dostop
Getting in shape: DNA‐brush copolymer amphiphiles assemble into micelles with morphologies determined by selective interactions that allow manipulation of the magnitude of steric and electrostatic ...repulsions in the micelle shells. Cylinder‐to‐sphere phase transitions occur when an input DNA sequence is added to the micelles (see picture).
Managing wildland fire incidents can be fraught with complexity and uncertainty. Myriad human factors can exert significant influence on incident decision making, and can contribute additional ...uncertainty regarding programmatic evaluations of wildfire management and attainment of policy goals. This article develops a framework within which human sources of uncertainty in wildfire management can be classified and managed, specifically identifying social, institutional, and psychological factors that can affect wildland fire incident decision making. These factors are reviewed in the context of wildland fire incident management and the literature regarding fire manager decision making. I then provide specific recommendations for addressing these issues, with a focus on improving incident decision processes. Extending this framework to consider a broader set of human factors and to consider how human factors affect the broader wildfire management spectrum could lead to improved fire management outcomes.
Noise generated by wind turbines has been reported to affect sleep and quality of life (QOL), but the relationship is unclear. Our objective was to explore the association between wind turbine noise, ...sleep disturbance and quality of life, using data from published observational studies. We searched Medline, Embase, Global Health and Google Scholar databases. No language restrictions were imposed. Hand searches of bibliography of retrieved full texts were also conducted. The reporting quality of included studies was assessed using the STROBE guidelines. Two reviewers independently determined the eligibility of studies, assessed the quality of included studies, and extracted the data. We included eight studies with a total of 2433 participants. All studies were cross-sectional, and the overall reporting quality was moderate. Meta-analysis of six studies (n=2364) revealed that the odds of being annoyed is significantly increased by wind turbine noise (OR: 4.08; 95% CI: 2.37 to 7.04; p<0.00001). The odds of sleep disturbance was also significantly increased with greater exposure to wind turbine noise (OR: 2.94; 95% CI: 1.98 to 4.37; p<0.00001). Four studies reported that wind turbine noise significantly interfered with QOL. Further, visual perception of wind turbine generators was associated with greater frequency of reported negative health effects. In conclusion, there is some evidence that exposure to wind turbine noise is associated with increased odds of annoyance and sleep problems. Individual attitudes could influence the type of response to noise from wind turbines. Experimental and observational studies investigating the relationship between wind turbine noise and health are warranted.
•Our results suggest that the odds of being annoyed appear significantly increased by wind turbine noise.•Wind turbine noise significantly increases the odds of experiencing sleep disturbance.•Noise generated by wind turbines appears to correlate with lower quality of life scores.•Community preferences should be a priority during construction of new wind turbines.•Objective outcome measures which separate auditory and visual effects of wind turbines should be developed.
Regeneration of myelin is mediated by oligodendrocyte progenitor cells-an abundant stem cell population in the central nervous system (CNS) and the principal source of new myelinating ...oligodendrocytes. Loss of myelin-producing oligodendrocytes in the CNS underlies a number of neurological diseases, including multiple sclerosis and diverse genetic diseases
. High-throughput chemical screening approaches have been used to identify small molecules that stimulate the formation of oligodendrocytes from oligodendrocyte progenitor cells and functionally enhance remyelination in vivo
. Here we show that a wide range of these pro-myelinating small molecules function not through their canonical targets but by directly inhibiting CYP51, TM7SF2, or EBP, a narrow range of enzymes within the cholesterol biosynthesis pathway. Subsequent accumulation of the 8,9-unsaturated sterol substrates of these enzymes is a key mechanistic node that promotes oligodendrocyte formation, as 8,9-unsaturated sterols are effective when supplied to oligodendrocyte progenitor cells in purified form whereas analogous sterols that lack this structural feature have no effect. Collectively, our results define a unifying sterol-based mechanism of action for most known small-molecule enhancers of oligodendrocyte formation and highlight specific targets to propel the development of optimal remyelinating therapeutics.
Pharmacokinetic (PK) models are increasingly submitted to the FDA to support first-in-human (FIH) dose selection of immune-oncology products. To examine whether a simple PK modeling (SPM) using ...clearance for scaling was acceptable for dose estimation, FIH(SPM) doses were computed and compared to doses that were safely administered to patients. We concluded that the SPM approach is acceptable in FIH dose estimation, but the variables should be carefully selected for CD3 constructs. For CD3 constructs, use of 60 kg BWh, a clearance exponent of 0.75, and a targeted plasma concentration based on relevant and/or sensitive activity assays was an acceptable approach for FIH dose selection; use of 0.85 as the scaling factor is questionable at this time as it resulted in a FIH dose that was too close to the AHD for one product (7%). Immune activating mAbs were not sensitive to changes in the clearance exponent (0.75–0.85) or body weight (60–70 kg). For PD-1/PD-L1 mAbs, using products’ in vitro EC50 in the model resulted in suboptimal FIH doses and clinical data of closely related products informed FIH dose selection. PK models submitted by sponsors were diverse in methods, assumptions, and variables, and the resulting FIH doses were not always optimal.
•A simple PK model may be appropriate for FIH dose estimation of IA products.•CD3 constructs were more sensitive than mAbs to changes in the model's variables.•CL exponent of 0.75 in the model was appropriate for CD3 constructs.•CL exponent of 0.85 was acceptable for mAbs and questionable for CD3 constructs.•Clinical data for closely related mAbs may provide information for dose selection.
The cancer treatment landscape has changed dramatically since the turn of the century, resulting in substantial improvements in outcomes for patients. This Review summarizes trends in the approval of ...oncology therapeutic products by the United States Food and Drug Administration (FDA) from January 2000 to October 2022, based on a categorization of these products by their mechanism of action and primary target. Notably, the rate of oncology indication approvals has increased in this time, driven by approvals for targeted therapies, as has the rate of introduction of new therapeutic approaches. Kinase inhibitors are the dominant product class by number of approved products and indications, yet immune checkpoint inhibitors have the second most approvals despite not entering the market until 2011. Other trends include a slight increase in the share of approvals for biomarker-defined populations and the emergence of tumour-site-agnostic approvals. Finally, we consider the implications of the trends for the future of oncology therapeutic product development, including the impact of novel therapeutic approaches and technologies.
Harnessing metal‐free photoinduced reversible‐deactivation radical polymerization (photo‐RDRP) in organic and aqueous phases, we report a synthetic approach to enzyme‐responsive and pro‐apoptotic ...peptide brush polymers. Thermolysin‐responsive peptide‐based polymeric amphiphiles assembled into spherical micellar nanoparticles that undergo a morphology transition to worm‐like micelles upon enzyme‐triggered cleavage of coronal peptide sidechains. Moreover, pro‐apoptotic polypeptide brushes show enhanced cell uptake over individual peptide chains of the same sequence, resulting in a significant increase in cytotoxicity to cancer cells. Critically, increased grafting density of pro‐apoptotic peptides on brush polymers correlates with increased uptake efficiency and concurrently, cytotoxicity. The mild synthetic conditions afforded by photo‐RDRP, make it possible to access well‐defined peptide‐based polymer bioconjugate structures with tunable bioactivity.
Empowered by light: Photoinduced reversible deactivation radical polymerization (photo‐RDRP) enabled access to a new class of bioactive peptide brush polymers. Those peptide‐based brush polymers exhibited well‐defined structures and tunable bioactivities, highlighting their immense potential in biomedical applications.
Expert decision making often seems impressive, even miraculous. People with genuine expertise in a particular domain can perform quickly and accurately, and with little information. In the series of ...experiments presented here, we manipulate the amount of "information" available to a group of experts whose job it is to identify the source of crime scene fingerprints. In Experiment 1, we reduced the amount of information available to experts by inverting fingerprint pairs and adding visual noise. There was no evidence for an inversion effect-experts were just as accurate for inverted prints as they were for upright prints-but expert performance with artificially noisy prints was impressive. In Experiment 2, we separated matching and nonmatching print pairs in time. Experts were conservative, but they were still able to discriminate pairs of fingerprints that were separated by five-seconds, even though the task was quite different from their everyday experience. In Experiment 3, we separated the print pairs further in time to test the long-term memory of experts compared to novices. Long-term recognition memory for experts and novices was the same, with both performing around chance. In Experiment 4, we presented pairs of fingerprints quickly to experts and novices in a matching task. Experts were more accurate than novices, particularly for similar nonmatching pairs, and experts were generally more accurate when they had more time. It is clear that experts can match prints accurately when there is reduced visual information, reduced opportunity for direct comparison, and reduced time to engage in deliberate reasoning. These findings suggest that non-analytic processing accounts for a substantial portion of the variance in expert fingerprint matching accuracy. Our conclusion is at odds with general wisdom in fingerprint identification practice and formal training, and at odds with the claims and explanations that are offered in court during expert testimony.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Three of the eight RNA segments encoded by the influenza A virus (IAV) undergo alternative splicing to generate distinct proteins. Previously, we found that host proteins hnRNP K and NS1-BP regulate ...IAV M segment splicing, but the mechanistic details were unknown. Here we show NS1-BP and hnRNP K bind M mRNA downstream of the M2 5' splice site (5'ss). NS1-BP binds most proximal to the 5'ss, partially overlapping the U1 snRNP binding site, while hnRNP K binds further downstream and promotes U1 snRNP recruitment. Mutation of either or both the hnRNP K and NS1-BP-binding sites results in M segment mis-splicing and attenuated IAV replication. Additionally, we show that hnRNP K and NS1-BP regulate host splicing events and that viral infection causes mis-splicing of some of these transcripts. Therefore, our proposed mechanism of hnRNP K/NS1-BP mediated IAV M splicing provides potential targets of antiviral intervention and reveals novel host functions for these proteins.
Over the last two decades wildfire activity, damage, and management cost within the US have increased substantially. These increases have been associated with a number of factors including climate ...change and fuel accumulation due to a century of active fire suppression. The increased fire activity has occurred during a time of significant ex-urban development of the Wildland Urban Interface (WUI) along with increased demand on water resources originating on forested landscapes. These increased demands have put substantial pressure on federal agencies charged with wildfire management to continue and expand the century old policy of aggressive wildfire suppression. However, aggressive wildfire suppression is one of the major factors that drive the increased extent, intensity, and damage associated with the small number of large wildfires that are unable to be suppressed. In this paper we discuss the positive feedback loops that lead to demands for increasing suppression response while simultaneously increasing wildfire risk in the future. Despite a wealth of scientific research that demonstrates the limitations of the current management paradigm pressure to maintain the existing system are well entrenched and driven by the existing social systems that have evolved under our current management practice. Interestingly, US federal wildland fire policy provides considerable discretion for managers to pursue a range of management objectives; however, societal expectations and existing management incentive structures result in policy implementation that is straining the resilience of fire adapted ecosystems and the communities that reside in and adjacent to them.
PDF
