Stable perovskites with ionic salts
Ionic liquids have been shown to stabilize organic-inorganic perovskite solar cells with metal oxide carrier-transport layers, but they are incompatible with more ...readily processible organic analogs. Lin
et al.
found that an ionic solid, a piperidinium salt, enhanced the efficiency of positive-intrinsic-negative layered perovskite solar cells with organic electron and hole extraction layers. Aggressive aging testing showed that this additive retarded segregation into impurity phases and pinhole formation in the perovskite layer.
Science
, this issue p.
96
An ionic compound additive improved perovskite solar cell longevity by inhibiting the generation of degradation products.
Longevity has been a long-standing concern for hybrid perovskite photovoltaics. We demonstrate high-resilience positive-intrinsic-negative perovskite solar cells by incorporating a piperidinium-based ionic compound into the formamidinium-cesium lead-trihalide perovskite absorber. With the bandgap tuned to be well suited for perovskite-on-silicon tandem cells, this piperidinium additive enhances the open-circuit voltage and cell efficiency. This additive also retards compositional segregation into impurity phases and pinhole formation in the perovskite absorber layer during aggressive aging. Under full-spectrum simulated sunlight in ambient atmosphere, our unencapsulated and encapsulated cells retain 80 and 95% of their peak and post-burn-in efficiencies for 1010 and 1200 hours at 60° and 85°C, respectively. Our analysis reveals detailed degradation routes that contribute to the failure of aged cells.
LY3009120 is a pan-RAF and RAF dimer inhibitor that inhibits all RAF isoforms and occupies both protomers in RAF dimers. Biochemical and cellular analyses revealed that LY3009120 inhibits ARAF, BRAF, ...and CRAF isoforms with similar affinity, while vemurafenib or dabrafenib have little or modest CRAF activity compared to their BRAF activities. LY3009120 induces BRAF-CRAF dimerization but inhibits the phosphorylation of downstream MEK and ERK, suggesting that it effectively inhibits the kinase activity of BRAF-CRAF heterodimers. Further analyses demonstrated that LY3009120 also inhibits various forms of RAF dimers including BRAF or CRAF homodimers. Due to these unique properties, LY3009120 demonstrates minimal paradoxical activation, inhibits MEK1/2 phosphorylation, and exhibits anti-tumor activities across multiple models carrying KRAS, NRAS, or BRAF mutation.
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•LY3009120 is a pan-RAF inhibitor of three RAF isoforms•LY3009120 occupies both protomers of RAF dimer and is a RAF dimer inhibitor•LY3009120 has minimal paradoxical pathway activation in Ras mutant cells•LY3009120 is active for RAS or BRAF mutant tumor cells in vitro and in vivo
Peng et al. show that LY3009120 inhibits all RAF isoforms and inhibits BRAF and CRAF homodimers and heterodimer. Moreover, LY3009120 induces minimal paradoxical activation in BRAF wild type cells. Importantly, LY3009120 exhibits anti-tumor activities in models carrying oncogenic KRAS, NRAS, or BRAF mutations.
New findings
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What is the central question of this study?
Heart failure is associated with persistent sterile inflammation that worsens disease severity; however, the molecular mechanisms behind ...cytokine recruitment and their relevance in the diseased myocardium remain unknown.
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What is the main finding and its importance?
We show that interleukin‐1β is activated downstream of the Nlrp3 inflammasome in calcineurin‐transgene‐induced structural heart disease. Genetic deletion of Nlrp3 abrogated inflammasome signalling and interleukin‐1β release, improving function. The role of Nlrp3 in non‐ischaemic cardiomyopathy and the utility of inflammasome antagonism have not yet been explored, revealing potential for translational application.
Heart failure is associated with a low‐grade and chronic cardiac inflammation that impairs function; however, the mechanisms by which this sterile inflammation occurs in structural heart disease remain poorly defined. Cardiac‐specific heterozygous overexpression of the calcineurin transgene (CNTg) in mice results in cardiac hypertrophy, inflammation, apoptosis and ventricular dilatation. We hypothesized that activation of the Nlrp3 inflammasome, an intracellular danger‐sensing pathway required for processing the pro‐inflammatory cytokine interleukin‐1β (IL‐1β), may contribute to myocardial dysfunction and disease progression. Here we report that Nlrp3 mRNA was increased in CNTg mice compared with wild‐type. Consistent with inflammasome activation, CNTg animals had increased conversion of pro‐caspase‐1 to cleaved and activated forms, as well as markedly increased serum IL‐1β. Blockade of IL‐1β signalling via chronic IL‐1 receptor antagonist therapy reduced cardiac inflammation and myocyte pathology in CNTg mice, resulting in improved systolic performance. Furthermore, genetic ablation of Nlrp3 in CNTg mice reduced pro‐inflammatory cytokine maturation and cardiac inflammation, as well as improving systolic performance. These findings indicate that activation of the Nlrp3 inflammasome in CNTg mice promotes myocardial inflammation and systolic dysfunction through the production of pro‐inflammatory IL‐1β. Blockade of IL‐1β signalling with the IL‐1 receptor antagonist reverses these phenotypes and offers a possible therapeutic approach in the management of heart failure.
Oncogenic B-RAF V600E mutation is found in 50% of melanomas and drives MEK/ERK pathway and cancer progression. Recently, a selective B-RAF inhibitor, vemurafenib (PLX4032), received clinical approval ...for treatment of melanoma with B-RAF V600E mutation. However, patients on vemurafenib eventually develop resistance to the drug and demonstrate tumor progression within an average of 7 months. Recent reports indicated that multiple complex and context-dependent mechanisms may confer resistance to B-RAF inhibition. In the study described herein, we generated B-RAF V600E melanoma cell lines of acquired-resistance to vemurafenib, and investigated the underlying mechanism(s) of resistance. Biochemical analysis revealed that MEK/ERK reactivation through Ras is the key resistance mechanism in these cells. Further analysis of total gene expression by microarray confirmed a significant increase of Ras and RTK gene signatures in the vemurafenib-resistant cells. Mechanistically, we found that the enhanced activation of fibroblast growth factor receptor 3 (FGFR3) is linked to Ras and MAPK activation, therefore conferring vemurafenib resistance. Pharmacological or genetic inhibition of the FGFR3/Ras axis restored the sensitivity of vemurafenib-resistant cells to vemurafenib. Additionally, activation of FGFR3 sufficiently reactivated Ras/MAPK signaling and conferred resistance to vemurafenib in the parental B-RAF V600E melanoma cells. Finally, we demonstrated that vemurafenib-resistant cells maintain their addiction to the MAPK pathway, and inhibition of MEK or pan-RAF activities is an effective therapeutic strategy to overcome acquired-resistance to vemurafenib. Together, we describe a novel FGFR3/Ras mediated mechanism for acquired-resistance to B-RAF inhibition. Our results have implications for the development of new therapeutic strategies to improve the outcome of patients with B-RAF V600E melanoma.
Background: B-RAF V600E melanomas rapidly develop resistance to B-RAF inhibitors in the clinic.
Results: FGFR3/Ras signaling is elevated and induces resistance to vemurafenib in vemurafenib-resistant cells.
Conclusion: FGFR3/Ras confers resistance to B-RAF inhibition via MAPK pathway reactivation.
Significance: A novel mechanism of resistance to B-RAF inhibitors is described and potential therapeutic strategies are suggested.
Biomedical repositories such as the UK Biobank provide increasing access to prospectively collected cardiac imaging, however these data are unlabeled, which creates barriers to their use in ...supervised machine learning. We develop a weakly supervised deep learning model for classification of aortic valve malformations using up to 4,000 unlabeled cardiac MRI sequences. Instead of requiring highly curated training data, weak supervision relies on noisy heuristics defined by domain experts to programmatically generate large-scale, imperfect training labels. For aortic valve classification, models trained with imperfect labels substantially outperform a supervised model trained on hand-labeled MRIs. In an orthogonal validation experiment using health outcomes data, our model identifies individuals with a 1.8-fold increase in risk of a major adverse cardiac event. This work formalizes a deep learning baseline for aortic valve classification and outlines a general strategy for using weak supervision to train machine learning models using unlabeled medical images at scale.
The persistence of back pain following acute back "sprains" is a serious public health problem with poorly understood pathophysiology. The recent finding that human subjects with chronic low back ...pain (LBP) have increased thickness and decreased mobility of the thoracolumbar fascia measured with ultrasound suggest that the fasciae of the back may be involved in LBP pathophysiology. This study used a porcine model to test the hypothesis that similar ultrasound findings can be produced experimentally in a porcine model by combining a local injury of fascia with movement restriction using a "hobble" device linking one foot to a chest harness for 8 weeks. Ultrasound measurements of thoracolumbar fascia thickness and shear plane mobility (shear strain) during passive hip flexion were made at the 8 week time point on the non-intervention side (injury and/or hobble). Injury alone caused both an increase in fascia thickness (p = .007) and a decrease in fascia shear strain on the non-injured side (p = .027). Movement restriction alone did not change fascia thickness but did decrease shear strain on the non-hobble side (p = .024). The combination of injury plus movement restriction had additive effects on reducing fascia mobility with a 52% reduction in shear strain compared with controls and a 28% reduction compared to movement restriction alone. These results suggest that a back injury involving fascia, even when healed, can affect the relative mobility of fascia layers away from the injured area, especially when movement is also restricted.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Patient reports of unprofessional conduct by surgeons have been linked to postprocedure complications and increased risk for malpractice claims. Coworkers are also positioned to observe and report ...unprofessional behaviors, including concerns related to delivery of competent medical care, clear and respectful communication, integrity, and responsibility. This study compared rates of coworker concerns between plastic surgeons and other physicians (other surgical specialists and nonsurgeons), and characterized whether plastic surgery subspecialties differed in their rates of complaints.
Coworker concern data from January 1, 2014, to December 31, 2019, were retrieved from the Vanderbilt Center for Patient and Professional Advocacy's Coworker Observation Reporting System database. Specialty was classified as plastic surgery, non-plastic surgical, and nonsurgical. The plastic surgery cohort was further characterized by sex, medical school graduation year, predominant practice type (reconstructive only, aesthetic only, or hybrid), and postresidency training (ie, completion of a fellowship).
The study cohort included 34,170 physicians (302 plastic surgeons, 7593 non-plastic surgeons, and 26,275 nonsurgeons). A greater proportion of plastic surgeons (13.6%) had one or more coworker concerns compared with nonsurgeons (10.8%) and non-plastic surgeons (6.1%) ( P < 0.001). The most prevalent concern category reported for plastic surgeons was clear and respectful communication. Among plastic surgeons who had no concerns versus those who had at least one concern, there was no significant difference when comparing sex, medical school graduation year, predominant practice type, or postresidency training.
Plastic surgeons in this cohort study received more coworker reports than other surgeons and nonsurgical physicians. These data may be used by institutions to identify plastic surgeons at risk for preventable postprocedure complications and intervene with peer feedback intended to promote self-regulation.
The role played by the thoracolumbar fascia in chronic low back pain (LBP) is poorly understood. The thoracolumbar fascia is composed of dense connective tissue layers separated by layers of loose ...connective tissue that normally allow the dense layers to glide past one another during trunk motion. The goal of this study was to quantify shear plane motion within the thoracolumbar fascia using ultrasound elasticity imaging in human subjects with and without chronic low back pain (LBP).
We tested 121 human subjects, 50 without LBP and 71 with LBP of greater than 12 months duration. In each subject, an ultrasound cine-recording was acquired on the right and left sides of the back during passive trunk flexion using a motorized articulated table with the hinge point of the table at L4-5 and the ultrasound probe located longitudinally 2 cm lateral to the midline at the level of the L2-3 interspace. Tissue displacement within the thoracolumbar fascia was calculated using cross correlation techniques and shear strain was derived from this displacement data. Additional measures included standard range of motion and physical performance evaluations as well as ultrasound measurement of perimuscular connective tissue thickness and echogenicity.
Thoracolumbar fascia shear strain was reduced in the LBP group compared with the No-LBP group (56.4% ± 3.1% vs. 70.2% ± 3.6% respectively, p < .01). There was no evidence that this difference was sex-specific (group by sex interaction p = .09), although overall, males had significantly lower shear strain than females (p = .02). Significant correlations were found in male subjects between thoracolumbar fascia shear strain and the following variables: perimuscular connective tissue thickness (r = -0.45, p <.001), echogenicity (r = -0.28, p < .05), trunk flexion range of motion (r = 0.36, p < .01), trunk extension range of motion (r = 0.41, p < .01), repeated forward bend task duration (r = -0.54, p < .0001) and repeated sit-to-stand task duration (r = -0.45, p < .001).
Thoracolumbar fascia shear strain was ~20% lower in human subjects with chronic low back pain. This reduction of shear plane motion may be due to abnormal trunk movement patterns and/or intrinsic connective tissue pathology. There appears to be some sex-related differences in thoracolumbar fascia shear strain that may also play a role in altered connective tissue function.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
orbitize! is an open-source, object-oriented software package for fitting the orbits of directly imaged objects. It packages the Orbits for the Impatient (OFTI) algorithm and a parallel-tempered ...Markov Chain Monte Carlo (MCMC) algorithm into a consistent and intuitive Python API. orbitize! makes it easy to run standard astrometric orbit fits; in less than 10 lines of code, users can read in data, perform one fit using OFTI and another using MCMC, and make two publication-ready figures. Extensive pedagogical tutorials, intended to be navigable by both orbit-fitting novices and seasoned experts, are available on our documentation page. We have designed the orbitize! API to be flexible and easy to use/modify for unique cases. orbitize! was designed by members of the exoplanet imaging community to be a central repository for algorithms, techniques, and know-how developed by this community. We intend for it to continue to expand and change as the field progresses and new techniques are developed, and call for community involvement in this process. Complete and up-to-date documentation is available at orbitize.info, and the source code is available at github.com/sblunt/orbitize.
Despite the pervasive use of social media by young adults, there is comparatively little known about whether, and how, engagement in social media influences this group's drinking patterns and risk of ...alcohol‐related problems. We examined the relations between young adults’ alcohol‐related social media engagement (defined as the posting, liking, commenting, and viewing of alcohol‐related social media content) and their drinking behavior and problems. We conducted a systematic review and meta‐analysis of studies evaluating the association of alcohol consumption and alcohol‐related problems with alcohol‐related social media engagement. Summary baseline variables regarding the social media platform used (e.g., Facebook and Twitter), social media measures assessed (e.g., number of alcohol photographs posted), alcohol measures (e.g., Alcohol Use Disorders Identification Test and Timeline Follow back Interview), and the number of time points at which data were collected were extracted from each published study. We used the Q statistic to examine heterogeneity in the correlations between alcohol‐related social media engagement and both drinking behavior and alcohol‐related problems. Because there was significant heterogeneity, we used a random‐effects model to evaluate the difference from zero of the weighted aggregate correlations. We used metaregression with study characteristics as moderators to test for moderators of the observed heterogeneity. Following screening, 19 articles met inclusion criteria for the meta‐analysis. The primary findings indicated a statistically significant relationship and moderate effect sizes between alcohol‐related social media engagement and both alcohol consumption (r = 0.36, 95% CI: 0.29 to 0.44, p < 0.001) and alcohol‐related problems (r = 0.37, 95% CI: 0.21 to 0.51, p < 0.001). There was significant heterogeneity among studies. Two significant predictors of heterogeneity were (i) whether there was joint measurement of alcohol‐related social media engagement and drinking behavior or these were measured on different occasions and (ii) whether measurements were taken by self‐report or observation of social media engagement. We found moderate‐sized effects across the 19 studies: Greater alcohol‐related social media engagement was correlated with both greater self‐reported drinking and alcohol‐related problems. Further research to determine the causal direction of these associations could provide opportunities for social media‐based interventions with young drinkers aimed at reducing alcohol consumption and alcohol‐related adverse consequences.
This systematic review and meta‐analysis of studies evaluating the association of alcohol consumption and related problems with alcohol‐related social‐media engagement found moderate‐sized effects. Engagement was defined as posting, liking, commenting on, and viewing of alcohol‐related content. Greater adolescent and young adult alcohol‐related social‐media engagement was correlated with both greater self‐reported drinking and alcohol‐related problems. The authors called for further research to determine the causal direction of these associations and for interventions to counter alcohol related social media content.
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