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During the 2019 coronavirus pandemic, stay-at-home policies such as New York's (NY) NY on Pause dramatically reduced traffic congestion. Despite high traffic burden in NY's environmental justice communities, this reduction has not been evaluated through an environmental justice lens-our objective in this analysis. We obtained census tract-level traffic congestion data from Google traffic maps hourly for 2018-2020. We defined congestion as the percent of streets in a census tract with heavy traffic (red- or maroon-color). We used the Index of Concentration at the Extremes (ICE) to measure racialized economic segregation and the CDC's Environmental Justice Index (EJI) as a measure of combined environmental, social, and chronic disease burden. We divided census tracts into quintiles of ICE and EJI and used linear mixed models stratified by ICE and EJI quintile in an interrupted time series design. Prior to NY on Pause, less marginalized and burdened census tracts (Q5) tended to have higher levels of traffic congestion; during NY on Pause, this trend reversed. For both ICE and EJI, more marginalized and burdened (Q1-Q2 vs. Q4-Q5) tracts had smaller absolute decreases in percent traffic congestion. For example, percent traffic congestion in ICE Q5 decreased by 7.8% (% change: -36.6%), but in Q1, it decreased by 4.2% (% change: -51.7%). NY on Pause, while protecting residents during COVID-19, may have resulted in inequitable reductions in traffic congestion. It is critical that such inequities are measured and acknowledged so that future policies to reduce traffic congestion and respond to pandemics can enhance equity., Competing Interests: The authors declare no conflicts of interest relevant to this study., (© 2024 The Author(s). GeoHealth published by Wiley Periodicals LLC on behalf of American Geophysical Union.)

Janus kinase 2 (JAK2) plays a critical role in orchestrating hematopoiesis, and its deregulation leads to various blood disorders, most importantly myeloproliferative neoplasms (MPNs). Ruxolitinib, fedratinib, momelotinib, and pacritinib are FDA-/EMA-approved JAK inhibitors effective in relieving symptoms in MPN patients but show variable clinical profiles due to poor JAK selectivity. The development of next-generation JAK2 inhibitors is hampered by the lack of comparative functional analysis and knowledge of the molecular basis of their selectivity. Here, we provide mechanistic profiling of the four approved and six clinical-stage JAK2 inhibitors and connect selectivity data with high-resolution structural and thermodynamic analyses. All of the JAK inhibitors potently inhibited JAK2 activity. Inhibitors differed in their JAK isoform selectivity and potency for erythropoietin signaling, but their general cytokine inhibition signatures in blood cells were comparable. Structural data indicate that high potency and moderate JAK2 selectivity can be obtained by targeting the front pocket of the adenosine 5'-triphosphate-binding site.

This paper aims to give an overview of corpus-based research that investigates processes of language change from the theoretical perspective of Construction Grammar. Starting in the early 2000s, a dynamic community of researchers has come together in order to contribute to this effort. Among the different lines of work that have characterized this enterprise, this paper discusses the respective roles of qualitative approaches, diachronic collostructional analysis, multivariate techniques, distributional semantic models, and analyses of network structure. The paper tries to contextualize these approaches and to offer pointers for future research., (© 2024 Walter de Gruyter GmbH, Berlin/Boston.)

High-intensity femtosecond pulses from an X-ray free-electron laser enable pump-probe experiments for the investigation of electronic and nuclear changes during light-induced reactions. On timescales ranging from femtoseconds to milliseconds and for a variety of biological systems, time-resolved serial femtosecond crystallography (TR-SFX) has provided detailed structural data for light-induced isomerization, breakage or formation of chemical bonds and electron transfer 1,2 . However, all ultrafast TR-SFX studies to date have employed such high pump laser energies that nominally several photons were absorbed per chromophore 3-17 . As multiphoton absorption may force the protein response into non-physiological pathways, it is of great concern 18,19 whether this experimental approach 20 allows valid conclusions to be drawn vis-à-vis biologically relevant single-photon-induced reactions 18,19 . Here we describe ultrafast pump-probe SFX experiments on the photodissociation of carboxymyoglobin, showing that different pump laser fluences yield markedly different results. In particular, the dynamics of structural changes and observed indicators of the mechanistically important coherent oscillations of the Fe-CO bond distance (predicted by recent quantum wavepacket dynamics 21 ) are seen to depend strongly on pump laser energy, in line with quantum chemical analysis. Our results confirm both the feasibility and necessity of performing ultrafast TR-SFX pump-probe experiments in the linear photoexcitation regime. We consider this to be a starting point for reassessing both the design and the interpretation of ultrafast TR-SFX pump-probe experiments 20 such that mechanistically relevant insight emerges., (© 2024. The Author(s).)

Background: Fine particulate matter (PM 2.5 ) exposure is a known risk factor for numerous adverse health outcomes, with varying estimates of component-specific effects. Populations with compromised health conditions such as diabetes can be more sensitive to the health impacts of air pollution exposure. Recent trends in PM 2.5 in primarily American Indian- (AI-) populated areas examined in previous work declined more gradually compared to the declines observed in the rest of the US. To further investigate components contributing to these findings, we compared trends in concentrations of six PM 2.5 components in AI- vs. non-AI-populated counties over time (2000-2017) in the contiguous US., Methods: We implemented component-specific linear mixed models to estimate differences in annual county-level concentrations of sulfate, nitrate, ammonium, organic matter, black carbon, and mineral dust from well-validated surface PM 2.5 models in AI- vs. non-AI-populated counties, using a multi-criteria approach to classify counties as AI- or non-AI-populated. Models adjusted for population density and median household income. We included interaction terms with calendar year to estimate whether concentration differences in AI- vs. non-AI-populated counties varied over time., Results: Our final analysis included 3108 counties, with 199 (6.4%) classified as AI-populated. On average across the study period, adjusted concentrations of all six PM 2.5 components in AI-populated counties were significantly lower than in non-AI-populated counties. However, component-specific levels in AI- vs. non-AI-populated counties varied over time: sulfate and ammonium levels were significantly lower in AI- vs. non-AI-populated counties before 2011 but higher after 2011 and nitrate levels were consistently lower in AI-populated counties., Conclusions: This study indicates time trend differences of specific components by AI-populated county type. Notably, decreases in sulfate and ammonium may contribute to steeper declines in total PM 2.5 in non-AI vs. AI-populated counties. These findings provide potential directives for additional monitoring and regulations of key emissions sources impacting tribal lands., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Few studies have evaluated Electronic Nicotine Delivery Systems (ENDS) in longitudinal studies, as a potential source of metals which may have carcinogenic, neurotoxic, and cardiotoxic effects. We evaluated metal body burden by ENDS use status in a longitudinal population-based national survey., Methods: We used the Population Assessment of Tobacco and Health (PATH) Study wave 1 (2013-2014), wave 2 (2014-2015), and wave 3 (2015-2016) adult data to assess urinary concentrations of seven metals among (1) ENDS only users who never used any nonelectronic tobacco products (n = 50), (2) ENDS only users who were former users of any nonelectronic tobacco products (n = 123) and (3) Never users (n = 1501) of any tobacco product., Results: Among ENDS only users who never used any nonelectronic tobacco products (n = 50), the geometric mean ratios (GMRs) of Cd and Pb were 1.25 (95%CI: 1.09-1.42) and 1.19 (95%CI: 1.05-1.34), respectively, compared to never users after adjustment for PATH Study wave, age, sex, race/ethnicity, education, region, secondhand smoke at home and work, and cannabis and other substance use. After the same adjustment, the corresponding GMRs were 1.48 (95%CI: 1.32-1.67) and 1.43 (95%CI: 1.28-1.60) for ENDS only users who were former users of any nonelectronic tobacco products (n = 123). No difference was observed in urinary concentrations of other metals comparing ENDS users to never users of any tobacco product., Discussion: ENDS users show higher urinary levels of Cd and Pb, including lifetime exclusive ENDS users compared to never users of any tobacco product. These findings are limited by the small sample size and could be related to underreporting of past combustible tobacco use or other factors. Metals typical of ENDS such as nickel and chromium unfortunately are not available in PATH. Studies assessing metal exposure associated with long term lifetime exclusive ENDS use (≥5 years) with larger sample size are needed., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: Traffic-related air pollution can trigger myocardial infarction (MI). However, the hourly hazard period of exposure to nitrogen dioxide (NO 2 ), a common traffic tracer, for incident MI has not been fully evaluated. Thus, the current hourly US national air quality standard (100 ppb) is based on limited hourly-level effect estimates, which may not adequately protect cardiovascular health., Objectives: We characterized the hourly hazard period of NO 2 exposure for MI in New York state (NYS), USA, from 2000 to 2015., Methods: For nine cities in NYS, we obtained data on MI hospitalizations from the NYS Department of Health Statewide Planning and Research Cooperative System and hourly NO 2 concentrations from the US Environmental Protection Agency's Air Quality System database. We used city-wide exposures and a case-crossover study design with distributed lag non-linear terms to assess the relationship between hourly NO 2 concentrations over 24 h and MI, adjusting for hourly temperature and relative humidity., Results: The mean NO 2 concentration was 23.2 ppb (standard deviation: 12.6 ppb). In the six hours preceding MI, we found linearly increased risk with increasing NO 2 concentrations. At lag hour 0, a 10 ppb increase in NO 2 was associated with 0.2 % increased risk of MI (Rate Ratio [RR]: 1.002; 95 % Confidence Interval [CI]: 1.000, 1.004). We estimated a cumulative RR of 1.015 (95 % CI: 1.008, 1.021) for all 24 lag hours per 10 ppb increase in NO 2 . Lag hours 2-3 had consistently elevated risk ratios in sensitivity analyses., Conclusions: We found robust associations between hourly NO 2 exposure and MI risk at concentrations far lower than current hourly NO 2 national standards. Risk of MI was most elevated in the six hours after exposure, consistent with prior studies and experimental work evaluating physiologic responses after acute traffic exposure. Our findings suggest that current hourly standards may be insufficient to protect cardiovascular health., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Knee osteoarthritis (OA) is a degenerative joint disease of the knee that results from the progressive loss of articular cartilage. It is most common in the elderly and affects millions of people worldwide, leading to a continuous increase in the number of total knee replacement surgeries. These surgeries improve the patient's physical mobility, but can lead to late infection, loosening of the prosthesis, and persistent pain. We would like to investigate if cell-based therapies can avoid or delay such surgeries in patients with moderate OA by injecting expanded autologous peripheral blood derived CD34+ cells (ProtheraCytes ® ) into the articular joint. In this study we evaluated the survival of ProtheraCytes ® when exposed to synovial fluid and their performance in vitro with a model consisting of their co-culture with human OA chondrocytes in separate layers of Transwells and in vivo with a murine model of OA. Here we show that ProtheraCytes ® maintain high viability (>95%) when exposed for up to 96 hours to synovial fluid from OA patients. Additionally, when co-cultured with OA chondrocytes, ProtheraCytes ® can modulate the expression of some chondrogenic (collagen II and Sox9) and inflammatory/degrading (IL1β, TNF, and MMP-13) markers at gene or protein levels. Finally, ProtheraCytes ® survive after injection into the knee of a collagenase-induced osteoarthritis mouse model, engrafting mainly in the synovial membrane, probably due to the fact that ProtheraCytes ® express CD44, a receptor of hyaluronic acid, which is abundantly present in the synovial membrane. This report provides preliminary evidence of the therapeutic potential of CD34+ cells on OA chondrocytes in vitro and their survival after in vivo implantation in the knee of mice and merits further investigation in future preclinical studies in OA models., Competing Interests: CV, AG, MK, PH, and IG were employees and stockholders of CellProthera. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Vignon, Hilpert, Toupet, Goubaud, Noël, de Kalbermatten, Hénon, Jorgensen, Barbero and Garitaonandia.)

Introduction: An in vitro model that appropriately recapitulates the degenerative disc disease (DDD) microenvironment is needed to explore clinically relevant cell-based therapeutic strategies for early-stage degenerative disc disease. We developed an advanced 3D nucleus pulposus (NP) microtissues (µT) model generated with cells isolated from human degenerating NP tissue (Pfirrmann grade: 2-3), which were exposed to hypoxia, low glucose, acidity and low-grade inflammation. This model was then used to test the performance of nasal chondrocytes (NC) suspension or spheroids (NCS) after pre-conditioning with drugs known to exert anti-inflammatory or anabolic activities. Methods: NPµTs were formed by i) spheroids generated with NP cells (NPS) alone or in combination with ii) NCS or iii) NC suspension and cultured in healthy or degenerative disc disease condition. Anti-inflammatory and anabolic drugs (amiloride, celecoxib, metformin, IL-1Ra, GDF-5) were used for pre-conditioning of NC/NCS. The effects of pre-conditioning were tested in 2D, 3D, and degenerative NPµT model. Histological, biochemical, and gene expression analysis were performed to assess matrix content (glycosaminoglycans, type I and II collagen), production and release of inflammatory/catabolic factors (IL-6, IL-8, MMP-3, MMP-13) and cell viability (cleaved caspase 3). Results: The degenerative NPµT contained less glycosaminoglycans, collagens, and released higher levels of IL-8 compared to the healthy NPµT. In the degenerative NPµT, NCS performed superior compared to NC cell suspension but still showed lower viability. Among the different compounds tested, only IL-1Ra pre-conditioning inhibited the expression of inflammatory/catabolic mediators and promoted glycosaminoglycan accumulation in NC/NCS in DDD microenvironment. In degenerative NPµT model, preconditioning of NCS with IL-1Ra also provided superior anti-inflammatory/catabolic activity compared to non-preconditioned NCS. Conclusion: The degenerative NPµT model is suitable to study the responses of therapeutic cells to microenvironment mimicking early-stage degenerative disc disease. In particular, we showed that NC in spheroidal organization as compared to NC cell suspension exhibited superior regenerative performance and that IL-1Ra pre-conditioning of NCS could further improve their ability to counteract inflammation/catabolism and support new matrix production within harsh degenerative disc disease microenvironment. Studies in an orthotopic in vivo model are necessary to assess the clinical relevance of our findings in the context of IVD repair., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Kasamkattil, Gryadunova, Schmid, Gay-Dujak, Dasen, Hilpert, Pelttari, Martin, Schären, Barbero, Krupkova and Mehrkens.)

Introduction: Policy responses to the COVID-19 pandemic, such as the NY on Pause stay-at-home order (March 22 - June 8, 2020), substantially reduced traffic and traffic-related air pollution (TRAP) in New York City (NYC). We evaluated the magnitude of TRAP decreases and examined the role of modifying factors such as weekend/weekday, road proximity, location, and time-of-day., Methods: Hourly nitrogen dioxide (NO 2 ) concentrations from January 1, 2018 through June 8, 2020 were obtained from the Environmental Protection Agency's Air Quality System for all six hourly monitors in the NYC area. We used an interrupted time series design to determine the impact of NY on Pause on NO 2 concentrations, using a mixed effects model with random intercepts for monitor location, adjusted for meteorology and long-term trends. We evaluated effect modification through stratification., Results: NO 2 concentrations decreased during NY on Pause by 19% (-3.2 ppb, 95% confidence interval [CI]: -3.5, -3.0), on average, compared to pre-Pause time trends. We found no evidence for modification by weekend/weekday, but greater decreases in NO 2 at non-roadside monitors and weak evidence for modification by location. For time-of-day, we found the largest decreases for 5 am (27%, -4.5 ppb, 95% CI: -5.7, -3.3) through 7 am (24%, -4.0 ppb, 95% CI: -5.2, -2.8), followed by 6 pm and 7 pm (22%, -3.7 ppb, 95% CI: -4.8, -2.6 and 22%, -4.8, -2.5, respectively), while the smallest decreases occurred at 11 pm and 1 am (both: 11%, -1.9 ppb, 95% CI: -3.1, -0.7)., Conclusion: NY on Pause's impact on TRAP varied greatly diurnally. Decreases during early morning and evening time periods are likely due to decreases in traffic. Our results may be useful for planning traffic policies that vary by time of day, such as congestion tolling policies., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)