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Vascular disease remains the leading cause of death and disability, the etiology of which often involves atherosclerosis. The current treatment of atherosclerosis by pharmacotherapy has limited therapeutic efficacy. Here we report a biomimetic drug delivery system derived from macrophage membrane coated ROS-responsive nanoparticles (NPs). The macrophage membrane not only avoids the clearance of NPs from the reticuloendothelial system, but also leads NPs to the inflammatory tissues, where the ROS-responsiveness of NPs enables specific payload release. Moreover, the macrophage membrane sequesters proinflammatory cytokines to suppress local inflammation. The synergistic effects of pharmacotherapy and inflammatory cytokines sequestration from such a biomimetic drug delivery system lead to improved therapeutic efficacy in atherosclerosis. Comparison to macrophage internalized with ROS-responsive NPs, as a live-cell based drug delivery system for treatment of atherosclerosis, suggests that cell membrane coated drug delivery approach is likely more suitable for dealing with an inflammatory disease than the live-cell approach. Due to poor specificity, the current pharmacotherapy of atherosclerosis has limited therapeutic efficacy. Here, the authors show that a macrophage-biomimetic nanomedicine effectively alleviates atherosclerosis via targeted pharmacotherapy and sequestration of proinflammatory cytokines and chemokines.

Paraquat, as one of the most widely used herbicides globally, is highly toxic to humans, and chronic exposure and acute ingestion leads to high morbidity and mortality rates. Here, we report user-friendly, photo-responsive paraquat-loaded supramolecular vesicles, prepared via one-pot self-assembly of amphiphilic, ternary host-guest complexes between cucurbit[8]uril, paraquat, and an azobenzene derivative. In this vesicle formulation, paraquat is only released upon UV or sunlight irradiation that converts the azobenzene derivative from its trans - to its  cis - form, which in turn dissociates the ternary host-guest complexations and the vesicles. The cytotoxicity evaluation of this vesicle formulation of paraquat on in vitro cell models, in vivo zebrafish models, and mouse models demonstrates an enhanced safety profile. Additionally, the PQ-loaded vesicles’ herbicidal activity against a model of invasive weed is nearly identical to that of free paraquat under natural sunlight. This study provides a safe yet effective herbicide formulation. Paraquat is a widely used herbicide that is highly toxic to humans upon acute ingestion or chronic exposure. Here, the authors generate a photosensitive formulation that releases paraquat upon exposure to UV light or sunlight, which shows an improved safety profile in zebrafish and mouse models, while maintaining substantial herbicidal activity.

Weather regimes have been defined over multiple regions and used in a range of practical applications, including subseasonal‐to‐seasonal forecasting and climate model evaluation. Despite their widespread use, the extent to which regimes reflect physical modes of the atmosphere is seldom investigated. Here, we adopt a year‐round classification of four North American weather regimes, with a fifth “no regime” class, and leverage dynamical systems theory to investigate their dynamical properties. We find that when the atmospheric flow is assigned to a regime, it displays persistent characteristics and a lifecycle‐like temporal evolution. We further find that, regardless of season, these characteristics are enhanced when the atmospheric flow displays a comparatively strong projection onto the cluster‐mean of the regime to which it is assigned (while the reverse is true for a weaker projection). We interpret these results as evidence that the four North American weather regimes are physically‐meaningful, with a clear dynamical footprint. Plain Language Summary Surface weather and extremes in North America can be related to a small number of atmospheric patterns stretching over scales of thousands of kilometers. These patterns, known as weather regimes, vary over timescales of several days to weeks and occur repeatedly: depending on the exact definition, between a third and a fifth of all days typically fall within a given regime. Weather regimes have a number of practical applications, hinging around making statistical predictions of the weather over a large region several weeks in advance. Even though they have proven useful in practice, there is no simple way of determining to what extent weather regimes are actually linked to the dynamics and physics of the atmosphere. While different definitions of weather regimes exist for different seasons, there have been recent efforts to identify weather regimes that may be applicable year‐round. In this study, we adopt a four‐regime, year‐round classification for the North American continent, and investigate whether the regimes have a clear physical footprint. We find that when the atmosphere falls within a given regime, it displays persistent flow characteristics with a systematic evolution in time. These results support interpreting the regimes as physically‐meaningful, rather than simply a statistical characterization of atmospheric patterns. Key Points Four year‐round North American regimes exhibit a clear dynamical footprint, supporting their interpretation as physically‐meaningful The regimes are persistent atmospheric states with a coherent lifecycle‐like temporal evolution The stronger the atmospheric flow projects onto the assigned regime, the more evident the above properties become

Membrane-camouflaged nanomedicines often suffer from reduced efficacy caused by membrane protein disintegration and spatial disorder caused by separation and reassembly of membrane fragments during the coating process. Here we show that intracellularly gelated macrophages (GMs) preserve cell membrane structures, including protein content, integration and fluidity, as well as the membrane lipid order. Consequently, in our testing GMs act as cellular sponges to efficiently neutralize various inflammatory cytokines via receptor-ligand interactions, and serve as immune cell-like carriers to selectively bind inflammatory cells in culture medium, even under a flow condition. In a rat model of collagen-induced arthritis, GMs alleviate the joint injury, and suppress the overall arthritis severity. Upon intravenous injection, GMs efficiently accumulate in the inflammatory lungs of acute pneumonia mice for anti-inflammatory therapy. Conveniently, GMs are amenable to lyophilization and can be stored at ambient temperatures for at least 1 month without loss of integrity and bio-activity. This intracellular gelation technology provides a universal platform for targeted inflammation neutralization treatment. Membrane-decorated nanomedicines often suffer from reduced efficacy caused by membrane artefacts during the coating process. Here the authors show that intracellularly gelated macrophages preserve membrane properties, stay stable under ambient temperature, and show therapeutic effects in murine models of joint and lung inflammation.

A machine learning approach to zero-inflated Poisson (ZIP) regression is introduced to address common difficulty arising from imbalanced financial data. The suggested ZIP can be interpreted as an adaptive weight adjustment procedure that removes the need for post-modeling re-calibration and results in a substantial enhancement of predictive accuracy. Notwithstanding the increased complexity due to the expanded parameter set, we utilize a cyclic coordinate descent optimization to implement the ZIP regression, with adjustments made to address saddle points. We also study how various approaches alleviate the potential drawbacks of incomplete exposures in insurance applications. The procedure is tested on real-life data. We demonstrate a significant improvement in performance relative to other popular alternatives, which justifies our modeling techniques.

Background Muscle atrophy and weakness are adverse effects of high dose or the sustained usage of glucocorticoids. Loss of mitochondria and degradation of protein are highly correlated with muscle dysfunction. The deacetylase sirtuin 1 (SIRT1) plays a vital role in muscle remodelling. The current study was designed to identify myricanol as a SIRT1 activator, which could protect skeletal muscle against dexamethasone‐induced wasting. Methods The dexamethasone‐induced atrophy in C2C12 myotubes was evaluated by expression of myosin heavy chain, muscle atrophy F‐box (atrogin‐1), and muscle ring finger 1 (MuRF1), using western blots. The mitochondrial content and oxygen consumption were assessed by MitoTracker staining and extracellular flux analysis, respectively. Muscle dysfunction was established in male C57BL/6 mice (8–10 weeks old, n = 6) treated with a relatively high dose of dexamethasone (25 mg/kg body weight, i.p., 10 days). Body weight, grip strength, forced swimming capacity, muscle weight, and muscle histology were assessed. The expression of proteolysis‐related, autophagy‐related, apoptosis‐related, and mitochondria‐related proteins was analysed by western blots or immunoprecipitation. Results Myricanol (10 μM) was found to rescue dexamethasone‐induced muscle atrophy and dysfunction in C2C12 myotubes, indicated by increased expression of myosin heavy chain (0.33 ± 0.14 vs. 0.89 ± 0.21, *P < 0.05), decreased expression of atrogin‐1 (2.31 ± 0.67 vs. 1.53 ± 0.25, *P < 0.05) and MuRF1 (1.55 ± 0.08 vs. 0.99 ± 0.12, **P < 0.01), and elevated ATP production (3.83 ± 0.46 vs. 5.84 ± 0.79 nM/mg protein, **P < 0.01), mitochondrial content (68.12 ± 10.07% vs. 116.38 ± 5.12%, *P < 0.05), and mitochondrial oxygen consumption (166.59 ± 22.89 vs. 223.77 ± 22.59 pmol/min, **P < 0.01). Myricanol directly binds and activates SIRT1, with binding energy of −5.87 kcal/mol. Through activating SIRT1 deacetylation, myricanol inhibits forkhead box O 3a transcriptional activity to reduce protein degradation, induces autophagy to enhance degraded protein clearance, and increases peroxisome proliferator‐activated receptor γ coactivator‐1α activity to promote mitochondrial biogenesis. In dexamethasone‐induced muscle wasting C57BL/6 mice, 5 mg/kg myricanol treatment reduces the loss of muscle mass; the percentages of quadriceps and gastrocnemius muscle in myricanol‐treated mice are 1.36 ± 0.02% and 0.87 ± 0.08%, respectively (cf. 1.18 ± 0.06% and 0.78 ± 0.05% in dexamethasone‐treated mice, respectively). Myricanol also rescues dexamethasone‐induced muscle weakness, indicated by improved grip strength (70.90 ± 4.59 vs. 120.58 ± 7.93 g, **P < 0.01) and prolonged swimming exhaustive time (48.80 ± 11.43 vs. 83.75 ± 15.19 s, **P < 0.01). Myricanol prevents dexamethasone‐induced muscle atrophy and weakness by activating SIRT1, to reduce muscle protein degradation, enhance autophagy, and promote mitochondrial biogenesis and function in mice. Conclusions Myricanol ameliorates dexamethasone‐induced skeletal muscle wasting by activating SIRT1, which might be developed as a therapeutic agent for treatment of muscle atrophy and weakness.

Objectives The objective of this systematic review was to assess the effects of interleukin-1β (IL-1β) inhibitors on gout flares. Methods Studies published between 2011 and 2022 that evaluated the effects of IL-1β inhibitors in adult patients experiencing gout flares were eligible for inclusion. Outcomes including pain, frequency and intensity of gout flares, inflammation, and safety were assessed. Five electronic databases (Pubmed/Medline, Embase, Biosis/Ovid, Web of Science and Cochrane Library) were searched. Two independent reviewers performed study screening, data extraction and risk of bias assessments (Cochrane Risk of Bias Tool 2 for randomised controlled trials [RCTs] and Downs and Black for non-RCTs). Data are reported as a narrative synthesis. Results Fourteen studies (10 RCTs) met the inclusion criteria, with canakinumab, anakinra, and rilonacept being the three included IL-1β inhibitors. A total of 4367 patients with a history of gout were included from the 14 studies ( N  = 3446, RCTs; N  = 159, retrospective studies [with a history of gout]; N  = 762, post hoc analysis [with a history of gout]). In the RCTs, canakinumab and rilonacept were reported to have a better response compared to an active comparator for resolving pain, while anakinra appeared to be not inferior to an active comparator for resolving pain. Furthermore, canakinumab and rilonacept reduced the frequency of gout flares compared to the comparators. All three medications were mostly well-tolerated compared to their comparators. Conclusion IL-1β inhibitors may be a beneficial and safe medication for patients experiencing gout flares for whom current standard therapies are unsuitable. Review protocol registration PROSPERO ID: CRD42021267670.

Weather regimes defined through cluster analysis concisely categorize the anomalous regional circulation pattern on any given day. Owing to their persistence and low dimensionality, regimes are increasingly used in subseasonal-to-seasonal prediction and in analysis of climate variability and change. However, a limitation of existing regime classifications for North America is their seasonal dependence, with most existing studies defining regimes for winter only. Here, we normalize the seasonal cycle in daily geopotential height variance and use empirical orthogonal function analysis combined with k -means clustering to define a new set of year-round North American weather regimes: the Pacific Trough, Pacific Ridge, Alaskan Ridge, and Greenland High regimes. We additionally define a “No Regime” state to represent conditions close to climatology. To demonstrate the robustness of the classification, a thorough assessment of the sensitivity of the clustering solution to various methodological choices is provided. The median persistence of all four regimes, obtained without imposing a persistence criterion, is found to be one week, approximately 3 times longer than the median persistence of the No Regime state. Regime-associated temperature and precipitation anomalies are reported, together with the relationship between the regimes and modes of climate variability. We also quantify historical trends in the frequency of the regimes since 1979, finding a decrease in the annual frequency of the Pacific Trough regime and an increase in the summertime frequency of the Greenland High regime. This study serves as a foundation for the future use of these regimes in a variety of weather and climate applications.

Major disruptions of the stratospheric polar vortex can improve subseasonal forecast skill for surface climate, as negative North Atlantic Oscillation‐like (NAO−) states can follow sudden stratospheric warmings (SSWs). Yet most insights come from observational studies or large operational forecast archives. Here we use Stratospheric Nudging And Predictable Surface Impacts (SNAPSI) project experiments, which applies stratospheric nudging to forecasts of two SSWs (2018 and 2019) followed by differing tropospheric evolutions. We show that SSWs systematically shift the atmosphere toward negative NAO‐like regimes (stronger Greenland anticyclone) in both the North Atlantic‐European and North American regions. Comparisons among nudged, free, and control runs quantify the benefits of improving and removing SSW representation in diagnosing tropospheric regime shifts. In 2018, accurate stratospheric representation improved weather regime forecasts. However, in 2019, despite persistent observed ridged regimes, nudged SSWs still induced negative NAO‐like patterns, implying that subseasonal models sometimes underrepresent other teleconnections and overrepresent stratosphere‐troposphere coupling.

Lack of standardization of outcome measures limits the usefulness of clinical trial evidence to inform health care decisions. This can be addressed by agreeing on a minimum core set of outcome measures per health condition, containing measures relevant to patients and decision makers. Since 1992, the Outcome Measures in Rheumatology (OMERACT) consensus initiative has successfully developed core sets for many rheumatologic conditions, actively involving patients since 2002. Its expanding scope required an explicit formulation of its underlying conceptual framework and process. Literature searches and iterative consensus process (surveys and group meetings) of stakeholders including patients, health professionals, and methodologists within and outside rheumatology. To comprehensively sample patient-centered and intervention-specific outcomes, a framework emerged that comprises three core “Areas,” namely Death, Life Impact, and Pathophysiological Manifestations; and one strongly recommended Resource Use. Through literature review and consensus process, core set development for any specific health condition starts by identifying at least one core “Domain” within each of the Areas to formulate the “Core Domain Set.” Next, at least one applicable measurement instrument for each core Domain is identified to formulate a “Core Outcome Measurement Set.” Each instrument must prove to be truthful (valid), discriminative, and feasible. In 2012, 96% of the voting participants (n=125) at the OMERACT 11 consensus conference endorsed this model and process. The OMERACT Filter 2.0 explicitly describes a comprehensive conceptual framework and a recommended process to develop core outcome measurement sets for rheumatology likely to be useful as a template in other areas of health care.