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The study implements and investigates an innovative learning approach that incorporates Flipped Classroom (FC) methodologies and electronic assessment (e-assessment) in Context-Based Learning (CBL) in chemistry among middle school students. The study incorporated mixed methods strategies and (a) examined learners' attitudes toward and perceptions of CBL in a hybrid environment in learning chemistry by using a structured, open-ended questionnaire; (b) examined learners' awareness of the relevance of chemistry concepts and content to real-life and real-world situations by using a learning diary to examine activities initiated by the learners themselves; and (c) examined the correlation between learners' achievements on online tasks and their achievements on a final written test. The findings revealed the students' positive attitudes toward CBL in a hybrid environment using FC strategy. In addition, learning chemistry in a context-based approach helped learners see that the curriculum is relevant to phenomena that they encounter in real life and the real world. Furthermore, a strong correlation emerged between the learners' achievements on the online assignments and their achievements on a conventional written test. This study adds knowledge about attitudes toward a context-based FC approach with e-assessments among middle school students, a population that has been the topic of very little exploration.

Machine learning, a subdomain of artificial intelligence, is a widespread technology that is molding how chemists interact with data. Therefore, it is a relevant skill to incorporate into the toolbox of any chemistry student. This work presents a workshop that introduces machine learning for chemistry students based on a set of Python notebooks and assignments. Python, one of the most popular programming languages, is open source, free to use, and has plenty of learning resources. The workshop is designed for students without previous experience in programming, and it aims for a deeper understanding of the complexity of concepts in programming and machine learning. The examples used correspond to real data from physicochemical characterizations of wine, a content that is of interest for students. The contents of the workshop are introduction to Python, basic statistics, data visualization, and dimension reduction, classification, and regression.

This quantitative exploratory study investigated factors related to the fail rate of first-year students in Introduction to General Chemistry courses (CHEM 1xx) at a mid-sized public research university. This course represents a gateway course for many scientific, medical, and healthcare majors. The sample consisted of 595 undergraduate students and used binary logistic regression to analyze the data. We found individual instructors were a significant predictor of students' grade in the Introduction to General Chemistry course. The students' American College Testing (ACT) math scores, SAT, or originally the Scholastic Aptitude Test, math scores, and high school grade point average (GPA) were also significant predictors. Interestingly, receipt of a Pell Grant was not a significant predictor of academic performance. Implications include course design, academic advising, tutoring and peer support, institutional research office reporting, as well as considerations for faculty course loads and emphasizing student success in the tenure and promotion process.

Community colleges educate nearly half of all students who complete postsecondary degrees in science, technology, engineering, and mathematics (STEM) disciplines. For many matriculated students, chemistry is a required gatekeeping course for postsecondary retention and advancement in STEM majors. This research explored community college student enrollment and performance in introductory chemistry courses for STEM majors, and how chemistry achievement related to student background characteristics and degree persistence. Data included grades, demographics, enrollment patterns, and degree status for 1,690 chemistry students who matriculated at a diverse, suburban community college from 2011 to 2014. Descriptive statistics indicated 32% of students received grades of D, F, or W in introductory chemistry; 49% of these students changed their majors after taking the course, with four-fifths of those degree changers switching to non-STEM fields. Binary logistic regression models revealed that chemistry enrollment was a significant predictor of degree change to non-STEM disciplines, with biology and anatomy/physiology coursetaking predicting STEM persistence. Degree change to non-STEM was predicted by chemistry performance but not by student characteristics including gender, ethnicity, and socioeconomic status. The results indicate that chemistry coursetaking and performance are notable factors affecting student persistence in STEM disciplines, and achievement is largely independent of student background variables. Implications for community college chemistry teaching and STEM academic advisement are discussed.

By taking into account our previously described series of 1,3,5-tris[(4-(substituted-aminomethyl)phenyl)methyl]benzene compounds, we have now designed, prepared, and evaluated in vitro against Plasmodium falciparum a novel series of structural analogues of these molecules, i.e., the 1,3,5-tris[(4-(substituted-aminomethyl)phenoxy)methyl]benzene derivatives. The pharmacological data showed antimalarial activity with IC50 values in the sub and μM range. The in vitro cytotoxicity of these new nitrogen polyphenoxymethylbenzene compounds was also evaluated on human HepG2 cells. The 1,3,5-tris[(4-(substituted-aminomethyl)phenoxy)methyl]benzene derivative 1m was found as one of the most potent and promising antimalarial candidates with favorable cytotoxic to antiprotozoal properties in the P. falciparum strains W2 and 3D7. In conclusion, this 1,3,5-tris[(4-(pyridin-3-ylmethylaminomethyl)phenoxyl)methyl]benzene 1m (IC50 = 0.07 μM on W2, 0.06 μM on 3D7, and 62.11 μM on HepG2) was identified as the most promising antimalarial derivative with selectivity indexes (SI) of 887.29 on the W2 P. falciparum chloroquine-resistant strain, and of 1035.17 on the chloroquine-sensitive and mefloquine decreased sensitivity strain 3D7. It has been previously described that the telomeres of P. falciparum could represent potential targets for these types of polyaromatic compounds; therefore, the capacity of our novel derivatives to stabilize the parasitic telomeric G-quadruplexes was assessed using a FRET melting assay. However, with regard to the stabilization of the protozoal G-quadruplex, we observed that the best substituted derivatives 1, which exhibited some interesting stabilization profiles, were not the most active antimalarial compounds against the two Plasmodium strains. Thus, there were no correlations between their antimalarial activities and selectivities of their respective binding to G-quadruplexes.

Research projects conducted by faculty in STEM departments served as the inspiration for a new curriculum of inquiry-based, multiweek laboratory modules in the general chemistry 1 course. The purpose of this curriculum redesign was to improve students' attitudes about chemistry as well as their self-efficacy and skills in performing inquiry activities. Students' ability to plan experiments and interpret data improved throughout the semester, as did their confidence in conducting research-like lab activities. Improved confidence was observed among men and women, science and engineering students, and Caucasian and international students. These outcomes are similar to those found with authentic research-based experiments. The curriculum had less of an impact on students' attitudes about chemistry. A research-inspired curriculum offers many benefits to students without the difficulties of designing actual research-based projects for general chemistry classes.

The fraction of urban volatile organic compound (VOC) emissions attributable to fossil fuel combustion has been declining in many parts of the world, resulting in a need to better constrain other anthropogenic sources of these emissions. During the National Institute of Environmental Research (NIER) and National Aeronautics and Space Administration (NASA) Korea-United States Air Quality (KORUS-AQ) field study in Seoul, South Korea, during May–June 2016, air quality models underestimated ozone, formaldehyde, and peroxyacetyl nitrate (PAN), indicating an underestimate of VOCs in the emissions inventory. Here, we use aircraft observations interpreted with the GEOS-Chem chemical transport model (version 13.4.0) to assess the need for increases in VOC emissions and for a revised chemical mechanism to improve treatment of VOC speciation and chemistry. We find that the largest needed VOC emissions increases are attributable to compounds associated with volatile chemical products, liquefied petroleum gas (LPG) and natural gas emissions, and long-range transport. Revising model chemistry to better match observed VOC speciation together with increasing model emissions of underestimated VOC species increased calculated OH reactivity by +2 s−1 and ozone production by +2 ppb h−1. Ozone increased by +6 ppb below 2 km and +9 ppb at the surface, and formaldehyde and acetaldehyde increased by +30 % and +120 % aloft, respectively, all in better agreement with observations. The larger increase in acetaldehyde was attributed to ethanol emissions, which we found to be as important for ozone production as isoprene or alkenes. The increased acetaldehyde significantly reduced the model PAN bias. The need for additional unmeasured VOCs, however, was indicated by a remaining model bias of −0.8 ppb in formaldehyde and a −57 % and −52 % underestimate in higher peroxynitrates (PNs) and alkyl nitrates (ANs), respectively. We added additional chemistry to the model to represent an additional six PNs from observed VOCs but were unable to account for the majority of missing PNs. However, four of these PNs were modeled at concentrations similar to other commonly measured PNs (> 2 % of PAN) indicating that these should be measured in future campaigns and considered from other VOC emission sources (e.g., fires). We hypothesize that emissions of oxygenated VOCs (OVOCs) such as ≥ C5 aldehydes from cooking and/or alkenes associated with volatile chemical products could produce both PNs and ANs and improve remaining model biases. Emerging research on the emissions and chemistry of these species will soon allow for modeling of their impact on local and regional photochemistry.

Ozone (O3) is an important secondary pollutant that impacts air quality and human health. Eastern Asia has high regional O3 background due to the numerous sources and increasing and rapid industrial growth, which also impacts the Seoul Metropolitan Area (SMA). However, the SMA has also been experiencing increasing O3 driven by decreasing NOx emissions, highlighting the role of the local in situ O3 production on the SMA. Here, comprehensive gas-phase measurements collected on the NASA DC-8 during the National Institute of Environmental Research (NIER)/NASA Korea–United States Air Quality (KORUS-AQ) study are used to constrain the instantaneous O3 production rate over the SMA. The observed NOx oxidized products support the importance of non-measured peroxy nitrates (PNs) in the O3 chemistry in the SMA, as they accounted for ∼49 % of the total PNs. Using the total measured PNs (ΣPNs) and alkyl and multifunctional nitrates (ΣANs), unmeasured volatile organic compound (VOC) reactivity (R(VOC)) is constrained and found to range from 1.4–2.1 s−1. Combining the observationally constrained R(VOC) with the other measurements on the DC-8, the instantaneous net O3 production rate, which is as high as ∼10 ppbv h−1, along with the important sinks of O3 and radical chemistry, is constrained. This analysis shows that ΣPNs play an important role in both the sinks of O3 and radical chemistry. Since ΣPNs are assumed to be in a steady state, the results here highlight the role that ΣPNs play in urban environments in altering the net O3 production, but ΣPNs can potentially lead to increased net O3 production downwind due to their short lifetime (∼1 h). The results provide guidance for future measurements to identify the missing R(VOCs) and ΣPN production.

Israel suffers from a growing problem of socio-economic gaps between those who live in the center of the country and residents of outlying areas. As a result, there is a low level of accessibility to higher education among the peripheral population. The goal of the Sidney Warren Science Education Center for Youth at Tel-Hai College is to strengthen the potential of middle and high school students and encourage them to pursue higher education, with an emphasis on majoring in science and technology. This study investigated the implementation and evaluation of the enrichment science academic program, as an example of informal learning environment, with an emphasis on physics studies. About 500 students conducted feedback survey after participating in science activities in four domains: biology, chemistry, physics, and computer science. Results indicated high level of satisfaction among the students. No differences were found with respect to gender excluding in physics with a positive attitudes advantage among boys. In order to get a deeper understanding of this finding, about 70 additional students conducted special questionnaires, both 1 week before the physics enrichment day and at the end of that day. Questionnaires were intended to assess both their attitudes toward physics and their knowledge and conceptions of the physical concept "pressure." We found that the activity moderately improved boys' attitudes toward physics, but that girls displayed decreased interest in and lower self-efficacy toward physics. Research results were used to the improvement of the instructional design of the physics activity demonstrating internal evaluation process for effective intervention.

We describe accommodations that we have made to our applied computational-theoretical chemistry laboratory to provide access for blind and visually impaired students interested in independent investigation of structure-function relationships. Our approach utilizes tactile drawings, molecular model kits, existing software, Bash and Perl scripts written in-house, and three-dimensional printing in a process that allows a blind or visually impaired student to satisfy her or his curiosity about structure-function relationships with minimal assistance from sighted co-workers. (Contains 1 table and 1 figure.)

A simple in class laboratory illustrating the principles of ion exchange chromatography as a bioseparation technique is described. A protein's isoelectric point as a driving force for ion exchange chromatography is easily demonstrated by using combinations of proteins with natural color or fluorescence, such as DsRed2, enhanced green fluorescent protein (EGFP), and flavodoxin. Simple equipment is required for this separation which can be performed on a desk top. The experiment can stimulate a range of discussion about process parameters that would create a more efficient separation of the proteins, other types of chromatography, and bioseparations in general. (Contains 4 tables and 4 figures.)

The declining trend in vehicle emissions has underscored the growing significance of volatile organic compound (VOC) emissions from volatile chemical products (VCPs). However, accurately representing VOC chemistry in simplified chemical mechanisms remains challenging due to its chemical complexity including speciation and reactivity. Previous studies have predominantly focused on VOCs from fossil fuel sources, leading to an underrepresentation of VOC chemistry from VCP sources. We developed an integrated chemical mechanism, RACM2B-VCP, that is compatible with WRF-Chem and is aimed at enhancing the representation of VOC chemistry, particularly from VCP sources, within the present urban environment. Evaluation against the Air Quality System (AQS) network data demonstrates that our model configured with RACM2B-VCP reproduces both the magnitude and spatial variability of O3 and PM2.5 in Los Angeles. Furthermore, evaluation against comprehensive measurements of O3 and PM2.5 precursors from the Reevaluating the Chemistry of Air Pollutants in California (RECAP-CA) airborne campaign and the Southwest Urban NOx and VOC Experiment (SUNVEx) ground site and mobile laboratory campaign confirm the model's accuracy in representing NOx and many VOCs and highlight remaining biases. Although there exists an underprediction in the total VOC reactivity of observed VOC species, our model with RACM2B-VCP exhibits good agreement for VOC markers emitted from different sectors, including biogenic, fossil fuel, and VCP sources. Through sensitivity analyses, we probe the contributions of VCP and fossil fuel emissions to total VOC reactivity and O3. Our results reveal that 52 % of the VOC reactivity and 35 % of the local enhancement of MDA8 O3 arise from anthropogenic VOC emissions in Los Angeles. Significantly, over 50 % of this anthropogenic fraction of either VOC reactivity or O3 is attributed to VCP emissions. The RACM2B-VCP mechanism created, described, and evaluated in this work is ideally suited for accurately representing ozone for the right reasons in the present urban environment where mobile, biogenic, and VCP VOCs are all important contributors to ozone formation.

China stands out as a major contributor to anthropogenic methane (CH4) emissions, with coal mine methane (CMM) playing a crucial role. To control and reduce CH4 emissions, China has made a dedicated commitment and formulated an ambitious mitigation plan. To verify the progress made, the consistent acquisition of independent CH4 emission data is required. This paper aims to implement a wind-assigned anomaly method for the precise determination of regional-scale CMM emissions within the coal-rich Shanxi province. We use the TROPOspheric Monitoring Instrument (TROPOMI) CH4 observations from May 2018 to May 2023, coupled with ERA5 wind and a bottom-up inventory dataset based on the IPCC (Intergovernmental Panel on Climate Change) Tier 2 approach covering the Changzhi, Jincheng, and Yangquan regions of the Shanxi province. The derived emission strengths are 8.4 × 1026 molec. s−1 (0.706 Tg yr−1, ±25 %), 1.4 × 1027 molec. s−1 (1.176 Tg yr−1, ±20 %), and 4.9 × 1026 molec. s−1 (0.412 Tg yr−1, ±21 %), respectively. Our results exhibit biases of −18 %, 8 %, and 14 %, respectively, when compared to the IPCC Tier 2 bottom-up inventory. Larger discrepancies are found when comparing the estimates to the Copernicus Atmosphere Monitoring Service global anthropogenic emissions (CAMS-GLOB-ANT) and Emissions Database for Global Atmospheric Research (EDGARv7.0) inventories (64 %–176 %), suggesting that the two inventories may be overestimating CH4 emissions from the studied coal mining regions. Our estimates provide a comprehensive characterization of the regions within the Shanxi province, contribute to the validation of emission inventories, and provide additional insights into CMM emission mitigation.

China's Shanxi Province accounts for 12 % of global coal output and therefore is responsible for a very large fraction of the total global methane (CH4) emissions, as well as being a large source of uncertainty due to the lack of in situ and field measurements. This work introduces the first comprehensive attempt to compute the coal mine methane (CMM) emissions throughout Shanxi, using a mixture of bottom-up and top-down approaches. First, public and private data from 636 individual coal mines in Shanxi Province were analyzed following the IPCC Tier 2 approach, using three to five sets of observed emission factors and rank information based on methods issued by the National Coal Mine Safety Administration and the National Energy Administration, to compile a range of bottom-up CMM on a mine-by-mine basis. An eddy covariance tower is set up near the output flue of a well-characterized high-rank coal mine in Changzhi and used to produce an average observed CH4 flux over two 2-month-long periods (Winter 2021 and Autumn 2022). The observed half-hourly CH4 flux variability is found to be roughly stable over the entire observed time and is subsequently used to produce a set of scaling factors (ratio correction) to update the preliminary bottom-up coal mine methane emissions to account for both bias and high-frequency temporal variability. The resulting emissions dataset has been compared against commonly used global CMM datasets including EDGAR and GFEI v2, and there are three unique scientific conclusions. First, their total CH4 emissions over Shanxi lie between this work's 50th percentile and 70th percentile range, meaning they are slightly high. Second, both datasets have a very large amount of emissions which occur where there are no coal mines and no CH4-emitting industry, indicating that there are significant spatial disparities, with the overlapped portion of CMM emissions where mines exist consistently close to the 30th percentile of this work's emissions, meaning they underestimate CMM in general on a mine-by-mine basis. Third, some of the mines have average emissions values which are more than the 90th percentile of the computed mine-by-mine emissions, while many are far below the 10th percentile, showing that there is a significant issue with the sampling not capturing the observed temporal variability. It is hoped that this mine-by-mine and high-frequency approximation of CMM emissions can both improve top-down observation campaigns and provide quantitative support and identification of mitigation opportunities.

A partnership is formed between the University of Pennsylvania and local elementary, middle and high schools in West Philadelphia, with the general goal of creating mutually beneficial science partnership between K-12 schools and colleges and universities. Access to expertise and resources not ordinarily available are given to West Philadelphia high school by this partnership.

Spleen tyrosine kinase (SYK) is a non-receptor tyrosine kinase that is activated by phosphorylation events downstream of FcR, B-cell and T-cell receptors, integrins, and C-type lectin receptors. When the tandem Src homology 2 (SH2) domains of SYK bind to phosphorylated immunoreceptor tyrosine-based activation motifs (pITAMs) contained within these immunoreceptors, or when SYK is phosphorylated in interdomain regions A and B, SYK is activated. SYK gain-of-function (GoF) variants were previously identified in six patients that had higher levels of phosphorylated SYK and phosphorylated downstream proteins JNK and ERK. Furthermore, the increased SYK activation resulted in the clinical manifestation of immune dysregulation, organ inflammation, and a predisposition for lymphoma. The knowledge that the SYK GoF variants have enhanced activity was leveraged to develop a SYK NanoBRET cellular target engagement assay in intact live cells with constructs for the SYK GoF variants. Herein, we developed a potent SYK-targeted NanoBRET tracer using a SYK donated chemical probe, MRL-SYKi, that enabled a NanoBRET cellular target engagement assay for SYK GoF variants, SYK(S550Y), SYK(S550F), and SYK(P342T). We determined that ATP-competitive SYK inhibitors bind potently to these SYK variants in intact live cells. Additionally, we demonstrated that MRL-SYKi can effectively reduce the catalytic activity of SYK variants, and the phosphorylation levels of SYK(S550Y) in an epithelial cell line (SW480) stably expressing SYK(S550Y).

Evaluating global chemistry models in the upper troposphere–lower stratosphere (UTLS) is an important step toward an improved understanding of the chemical composition in this region. This composition is regularly sampled through in situ measurements based on passenger aircraft, in the framework of the In-service Aircraft for a Global Observing System (IAGOS) research infrastructure. This study focuses on the comparison of the IAGOS measurements in ozone, carbon monoxide (CO), nitrogen reactive species (NOy) and water vapour, with a 25-year simulation output from the LMDZ-OR-INCA chemistry–climate model. For this purpose, we present and apply an extension of the Interpol-IAGOS software that projects the IAGOS data onto any model grid, in order to derive a gridded IAGOS product and a masked (sub-sampled) model product that are directly comparable to one another. Climatologies are calculated in the upper troposphere (UT) and in the lower stratosphere (LS) separately but also in the UTLS as a whole, as a demonstration for the models that do not sort out the physical variables necessary to distinguish between the UT and the LS. In the northern extratropics, the comparison in the UTLS layer suggests that the geographical distribution in the tropopause height is well reproduced by the model. In the separated layers, the model simulates well the water vapour climatologies in the UT and the ozone climatologies in the LS. There are opposite biases in CO in both UT and LS, which suggests that the cross-tropopause transport is overestimated. The NOy observations highlight the difficulty of the model in parameterizing the lightning emissions. In the tropics, the upper-tropospheric climatologies are remarkably well simulated for water vapour. They also show realistic CO peaks due to biomass burning in the most convective systems, and the ozone latitudinal variations are well correlated between the observations and the model. Ozone is more sensitive to lightning emissions than to biomass burning emissions, whereas the CO sensitivity to biomass burning emissions strongly depends on location and season. The present study demonstrates that the Interpol-IAGOS software is a tool facilitating the assessment of global model simulations in the UTLS, which is potentially useful for any modelling experiment involving chemistry climate or chemistry transport models.

This paper presents a novel three-dimensional (3D) minimally actuated serial robot (MASR) and its unique kinematic analysis. Unlike traditional robots, the 3D MASR features a passive arm devoid of wires or motors, comprising passive rotational and prismatic joints. A single mobile actuator (MA) traverses the arm, engages designated joints for operation, and locks them in place with a worm gear setup. A gripper is attached to the MA, enabling object transportation along the arm, reducing joint actuation, and optimizing task completion time. Our key contributions include the mechanical design, and in particular the robot’s passive joints with their automated actuation mechanism, and a novel optimization algorithm leveraging neural networks (NNs) to minimize task completion time through advanced kinematic analysis. Experiments with a physical prototype of the 3D MASR demonstrate its major advantages: it is remarkably lightweight (2.3 kg for a 1 m long arm and a 1 kg payload) compared to similar robots; it is highly modular (five joints R and P actuated by a single MA); and part replacement is effortless due to the absence of wiring along the arm. These features are visually depicted in the accompanying video.

Included are the general guidelines, outline, a summary of major intermedia transport processes, model features, a discussion of multimedia exposure and health risk, and a list of 50 suggested references for this course. (CW)

Progress in laser-driven proton acceleration requires increasing the proton maximum energy and laser-to-proton conversion efficiency while reducing the divergence of the proton beam. However, achieving all these qualities simultaneously has proven challenging experimentally, with the increase in beam energy often coming at the cost of beam quality. Numerical simulations suggest that coupling multi-PW laser pulses with ultrathin foils could offer a route for such simultaneous improvement. Yet, experimental investigations have been limited by the scarcity of such lasers and the need for very stringent temporal contrast conditions to prevent premature target expansion before the pulse maximum. Here, combining the newly commissioned Apollon laser facility that delivers high-power ultrashort (∼24fs) pulses with a double plasma mirror scheme to enhance its temporal contrast, we demonstrate the generation of up to 35 MeV protons with only 5 J of laser energy. This approach also achieves improved laser-to-proton energy conversion efficiency, reduced beam divergence, and optimized spatial beam profile. Therefore, despite the laser energy losses induced by the plasma mirror, the proton beams produced by this method are enhanced on all accounts compared to those obtained under standard conditions. Particle-in-cell simulations reveal that this improvement mainly results from a better space–time synchronization of the maximum of the accelerating charge-separation field with the proton bunch.

GBA1-associated Parkinson’s disease (GBA1-PD) is increasingly recognized as a distinct entity within the spectrum of parkinsonian disorders. This review explores the unique pathophysiological features, clinical progression, and genetic underpinnings that differentiate GBA1-PD from idiopathic Parkinson’s disease (iPD). GBA1-PD typically presents with earlier onset and more rapid progression, with a poor response to standard PD medications. It is marked by pronounced cognitive impairment and a higher burden of non-motor symptoms compared to iPD. Additionally, patients with GBA1-PD often exhibit a broader distribution of Lewy bodies within the brain, accentuating neurodegenerative processes. The pathogenesis of GBA1-PD is closely associated with mutations in the GBA1 gene, which encodes the lysosomal enzyme beta-glucocerebrosidase (GCase). In this review, we discuss two mechanisms by which GBA1 mutations contribute to disease development: ‘haploinsufficiency,’ where a single functional gene copy fails to produce a sufficient amount of GCase, and ‘gain of function,’ where the mutated GCase acquires harmful properties that directly impact cellular mechanisms for alpha-synuclein degradation, leading to alpha-synuclein aggregation and neuronal cell damage. Continued research is advancing our understanding of how these mechanisms contribute to the development and progression of GBA1-PD, with the ‘gain of function’ mechanism appearing to be the most plausible. This review also explores the implications of GBA1 mutations for therapeutic strategies, highlighting the need for early diagnosis and targeted interventions. Currently, small molecular chaperones have shown the most promising clinical results compared to other agents. This synthesis of clinical, pathological, and molecular aspects underscores the assertion that GBA1-PD is a distinct clinical and pathobiological PD phenotype, necessitating specific management and research approaches to better understand and treat this debilitating condition.

Surprisingly, spectator ions are responsible for unexpected kinetics in the biphasic copper(II)-aluminum displacement reaction, with the rate of reaction dependent on the identity of the otherwise ignored spectator ions. Application of a published kinetic analysis developed for a reaction between a rotating Al disk and a Cu(II) ion solution to the simple reaction using aluminum foil and a copper solution is demonstrated. The chloride-acceleration effect is found to be true for both chloride and bromide and should be more generally termed a halide-acceleration effect. This interesting and simple reaction can be used to deepen students' understanding of biphasic processes that are important industrially, that is, aluminum corrosion, and to "burst the bubble" of rigid thinking that spectator ions always can be ignored. (Contains 1 table and 2 figures.)

Antisense oligonucleotide (ASO) analogs have been used to counteract the effects of mutated genes and have been developed as therapeutic agents. Several such formulations have been subjected to clinical trials against cancer and have been passed by the FDA for clinical use. However, cancer is a complex genetic disease in which multiple mutations are known to occur for tumors to develop. Three basic stages have been delineated: 1. Loss of cell growth control by both oncogenes and tumor suppressor genes; 2. Angiogenesis, the production of capillary growth factors to allow blood supply; 3. Metastasis allows cancer cells to invade normal tissue. In principle, using three ASOs to down-regulate the products of the mutated genes controlling these specific processes should be possible and this could be an effective preventive method against cancer. In an alternative approach, genetic analysis of cancer cells using microarrays have shown that cassettes of genes are up- and down-regulated compared to normal tissue. Using this information ASOs could be used to down-regulate mutated genes that are up-regulated. In general ASO analog sequences could be used to target the unique pre-mRNA splice sites of selected genes in order to suppress carcinogenesis in vitro in selected cancer cell lines and subsequently in vivo in chosen mouse models. Computer programs will be used to calculate doses of a cocktail of ASOs to be administered to individual mice and ultimately patients as their tumor genetic profile changes over time.

Nitrogen oxides (NOx≡NO+NO2) are involved in most atmospheric photochemistry, including the formation of tropospheric ozone (O3). While various methods exist to accurately measure NOx concentrations, it is still a challenge to quantify the source and flux of NOx emissions. We present airborne measurements of NOx and winds used to infer the emission of NOx across Los Angeles. The measurements were obtained during the research aircraft campaign RECAP-CA (Re-Evaluating the Chemistry of Air Pollutants in CAlifornia) in June 2021. Geographic allocations of the fluxes are compared to the NOx emission inventory from the California Air Resources Board (CARB). We find that the NOx fluxes have a pronounced weekend effect and are highest in the eastern part of the San Bernardino Valley. The comparison of the RECAP-CA and the modeled CARB NOx fluxes suggests that the modeled emissions are higher than expected near the coast and in Downtown Los Angeles and lower than expected further inland in the eastern part of the San Bernardino Valley.

The SO2 emission rates from three power plants in North Carolina are estimated using the HYSPLIT Lagrangian dispersion model and aircraft measurements made on 26 March 2019. To quantify the underlying modeling uncertainties in the plume rise calculation, dispersion simulations are carried out in an ensemble using a total of 15 heat release parameters. For each heat release, the SO2 emission rates are estimated using a transfer coefficient matrix (TCM) approach and compared with the Continuous Emissions Monitoring Systems (CEMS) data. An “optimal” member is first selected based on the correlation coefficient calculated for each of the six segments that delineate the plumes from the three power plants during the morning and afternoon flights. The segment influenced by the afternoon operations of Belews Creek power plant has negative correlation coefficients for all the plume rise options and is first excluded from the emission estimate here. Overestimations are found for all the segments before considering the background SO2 mixing ratios. Both constant background mixing ratios and several segment-specific background values are tested in the HYSPLIT inverse modeling. The estimation results by assuming the 25th percentile observed SO2 mixing ratios inside each of the five segments agree well with the CEMS data, with relative errors of 18 %, −12 %, 3 %, 93.5 %, and −4 %. After emission estimations are performed for all the plume rise runs, the lowest root mean square errors (RMSEs) between the predicted and observed mixing ratios are calculated to select a different set of optimal plume rise runs which have the lowest RMSEs. Identical plume rise runs are chosen as the optimal members for Roxboro and Belews Creek morning segments, but different members for the other segments yield smaller RMSEs than the previous correlation-based optimal members. It is also no longer necessary to exclude the Belews Creek afternoon segment that has a negative correlation between predictions and observations. The RMSE-based optimal runs result in much better agreement with the CEMS data for the previously severely overestimated segment and do not deteriorate much for the other segments, with relative errors of 18 %, −18 %, 3 %, −9 %, and 27 % for the five segments and 2 % for the Belews Creek afternoon segment. In addition, the RMSE-based optimal heat emissions appear to be more reasonable than the correlation-based values when they are significantly different for CPI Roxboro power plant.

The San Joaquin Valley is an agricultural region in California that suffers from poor air quality. Since traffic emissions are decreasing, other sources of volatile organic compounds (VOCs) are gaining importance in the formation of secondary air pollutants. Using airborne eddy covariance, we conducted direct, spatially resolved flux observations of a wide range of VOCs in the San Joaquin Valley during June 2021 at 23–36 ∘C. Through land-cover-informed footprint disaggregation, we were able to attribute emissions to sources and identify tracers for distinct source types. VOC mass fluxes were dominated by alcohols, mainly from dairy farms, while oak isoprene and citrus monoterpenes were important sources of reactivity. Comparisons with two commonly used inventories showed that isoprene emissions in the croplands were overestimated, while dairy and highway VOC emissions were generally underestimated in the inventories, and important citrus and biofuel VOC point sources were missing from the inventories. This study thus presents unprecedented insights into the VOC sources in an intensive agricultural region and provides much needed information for the improvement of inventories, air quality predictions, and regulations.

Abstract Combined molecular, physicochemical and chemical properties of electrophilic warheads can be applied to create covalent drugs with diverse facets. Here we study these properties in fluorinated diketones (FDKs) and their multicomponent equilibrium systems in the presence of protic nucleophiles, revealing the potential of the CF2(CO)2 group to act as a multifaceted warhead for reversible covalent drugs. The equilibria compositions of various FDKs in water/octanol contain up to nine species. A simultaneous direct species-specific 19F-NMR-based log P determination of these complex equilibria systems was achieved and revealed in some cases lipophilic to hydrophilic shifts, indicating possible adaptation to different environments. This was also demonstrated in 19F-MAS-NMR-based water-membrane partitioning measurements. An interpretation of the results is suggested by the aid of a DFT study and 19F-DOSY-NMR spectroscopy. In dilute solutions, a model FDK reacted with protected cysteine to form two hemi-thioketal regioisomers, indicating possible flexible regio-reactivity of CF2(CO)2 warheads toward cysteine residues.

In this paper, we examine the use of the Single-Sideband Transform (SSBT) for convolutive beamformers. We explore its unique properties and implications for beamformer design. Our study sheds light on the tradeoffs involved in using the SSBT in beamforming applications, offering insights into both its strengths and limitations. Despite the advantage of having real-valued coefficients, we show that the convolution handling of the transform presents challenges that impact fundamental beamforming principles. When compared to the Short-Time Fourier Transform (STFT), the SSBT displays lower robustness, especially in scenarios involving mismatch and modeling noise. Notably, we establish a direct equivalence between the SSBT and STFT when using identical transform parameters, enabling their seamless interchangeability and joint use in time–frequency signal enhancements. We validate our theoretical findings through realistic simulations using the Minimum-Power Distortionless Response beamformer. These simulations illustrate that although the STFT performs marginally better than the SSBT under optimal conditions, it outperforms significantly in non-ideal scenarios.

This study examines the adoption and implementation of an information system in a mandatory context focusing on an Israeli governmental organization. The system referred to as “Slot” is an online platform for managing educational activities within this organization. The research investigates the impact of the system on its functionality users and the results of its usage. Additionally, the study explores factors that influence the acceptance and utilization of information systems, including whether the willingness to use the system under instruction depends on other variables. The key findings of this study are: perceived ease of use significantly and positively influences perceived usefulness; perceived usefulness significantly and positively affects symbolic adoption; and supervisor influence significantly and positively impacts perceived usefulness. Moreover, the relationship between perceived ease of use and symbolic adoption is entirely mediated by perceived usefulness as is the relationship between supervisor influence and symbolic adoption. The study’s limitations include the relatively small sample size and the specific context of the research, which may limit the generalizability of the findings. Future research could explore similar models in different organizational settings to validate and extend the applicability of the results. The findings suggest that enhancing the perceived ease of use and usefulness of mandatory systems can significantly impact their symbolic adoption, with supervisory influence playing a crucial role in shaping user perceptions. These insights can inform strategies for more effective implementation and management of information systems in mandatory settings.

Smith–Magenis Syndrome (SMS) is a rare genetic disorder, characterized by intellectual disability (ID), behavioral impairments, and sleep disturbances, as well as multiple organ anomalies in some affected individuals. The syndrome is caused by a deletion in the chromosome band around 17p11.2, including the Retinoic Acid Induced 1 (RAI1) gene, a multifaceted transcriptional regulator that modulates the expression of genes involved in cellular proliferation and neurodevelopment. This gene has a positive role in regulating BDNF and, importantly, affects several cell mechanisms and pathways such as the nigro-striatal pathway, which is crucial for motor function. Parkinson’s disease (PD) is one of the most common neurodegenerative diseases in older populations. It is characterized by various physical symptoms including tremors, loss of balance, bradykinesia, and a stooping posture. We present a case study of a patient diagnosed with both SMS and early-onset PD (at the age of 49). The association between both conditions is as yet ambiguous. Genome-wide association studies (GWAS) implicate an association between the RAI1 gene and PD. Similarly, the co-existence of both SMS and PD in the patient suggests a possible association between RAI1 copy number variations (CNVs) and PD, further indicating that RAI1 has strong implications for PD pathogenesis. Our results suggest that RAI1 CNVs and the pathophysiology of PD may be related, underscoring the need for further research in this field. Therefore, caregivers of SMS patients should pay careful attention to the possibility of their patients developing EOPD and should consider starting treatment for PD as soon as the first symptoms appear.

The synthesis, biochemical evaluation and radiosynthesis of a cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor and radioligand was performed. NT431, a newly synthesized 4-fluorobenzyl-abemaciclib, exhibited high potency to CDK4/6 and against four cancer cell lines with IC50 similar to that of the parent abemaciclib. We performed a two-step one-pot radiosynthesis to produce [18F]NT431 with good radiochemical yield (9.6 ± 3%, n = 3, decay uncorrected), high radiochemical purity (>95%), and high molar activity (>370 GBq/µmol (>10.0 Ci/µmol). In vitro autoradiography confirmed the specific binding of [18F]NT431 to CDK4/6 in brain tissues. Dynamic PET imaging supports that both [18F]NT431 and the parent abemaciclib crossed the BBB albeit with modest brain uptake. Therefore, we conclude that it is unlikely that NT431 or abemaciclib (FDA approved drug) can accumulate in the brain in sufficient concentrations to be potentially effective against breast cancer brain metastases or brain cancers. However, despite the modest BBB penetration, [18F]NT431 represents an important step towards the development and evaluation of a new generation of CDK4/6 inhibitors with superior BBB penetration for the treatment and visualization of CDK4/6 positive tumors in the CNS. Also, [18F]NT431 may have potential application in peripheral tumors such as breast cancer and other CDK4/6 positive tumors.

A series of new 1,3,5-tris[(4-(substituted-aminomethyl)phenyl)methyl]benzene compounds were designed, synthesized, and evaluated in vitro against two parasites (Plasmodium falciparum and Leishmania donovani). The biological results showed antimalarial activity with IC50 values in the sub and μM range. The in vitro cytotoxicity of these new aza polyaromatic derivatives was also evaluated on human HepG2 cells. The 1,3,5-tris[(4-(substituted-aminomethyl)phenyl)methyl]benzene 1m was found as one of the most potent and promising antimalarial candidates with a ratio of cytotoxic to antiprotozoal activities of 83.67 against the P. falciparum CQ-sensitive strain 3D7. In addition, derivative 1r was also identified as the most interesting antimalarial compound with a selectivity index (SI) of 17.28 on the W2 P. falciparum CQ-resistant strain. It was previously described that the telomeres of P. falciparum could be considered as potential targets of these kinds of aza heterocycles; thus, the ability of these new derivatives to stabilize the parasitic telomeric G-quadruplexes was measured through a FRET melting assay.

Nitrogen oxides (NOx) are principle components of air pollution and serve as important ozone precursors. As the San Joaquin Valley (SJV) experiences some of the worst air quality in the United States, reducing NOx emissions is a pressing need, yet quantifying current emissions is complicated due to a mixture of mobile and agriculture sources. We performed airborne eddy covariance flux measurements during the Re-Evaluating the Chemistry of Air Pollutants in California (RECAP-CA) field campaign in June 2021. Combining footprint calculations and land cover statistics, we disaggregate the observed fluxes into component fluxes characterized by three different land cover types. On average, we find emissions of 0.95 mg N m−2 h−1 over highways, 0.43 mg N m−2 h−1 over urban areas, and 0.30 mg N m−2 h−1 over croplands. The calculated NOx emissions using flux observations are utilized to evaluate anthropogenic emissions inventories and soil NOx emissions schemes. We show that two anthropogenic inventories for mobile sources, EMFAC (EMission FACtors) and FIVE (Fuel-based Inventory for Vehicle Emissions), yield strong agreement with emissions derived from measured fluxes over urban regions. Three soil NOx schemes, including the MEGAN v3 (Model of Emissions of Gases and Aerosols from Nature), BEIS v3.14 (Biogenic Emission Inventory System), and BDISNP (Berkeley–Dalhousie–Iowa Soil NO Parameterization), show substantial underestimates over the study domain. Compared to the cultivated soil NOx emissions derived from measured fluxes, MEGAN and BEIS are lower by more than 1 order of magnitude, and BDISNP is lower by a factor of 2.2. Despite the low bias, observed soil NOx emissions and BDISNP present a similar spatial pattern and temperature dependence. We conclude that soil NOx is a key feature of the NOx emissions in the SJV and that a biogeochemical-process-based model of these emissions is needed to simulate emissions for modeling air quality in the region.

Abstract Recent research on two-dimensional (2D) transition metal dichalcogenides (TMDCs) has led to remarkable discoveries of fundamental phenomena and to device applications with technological potential. Large-scale TMDCs grown by chemical vapor deposition (CVD) are now available at continuously improving quality, but native defects and natural degradation in these materials still present significant challenges. Spectral hysteresis in gate-biased photoluminescence (PL) measurements of WSe2 further revealed long-term trapping issues of charge carriers in intrinsic defect states. To address these issues, we apply here a two-step treatment with organic molecules, demonstrating the “healing” of native defects in CVD-grown WSe2 and WS2 by substituting atomic sulfur into chalcogen vacancies. We uncover that the adsorption of thiols provides only partial defect passivation, even for high adsorption quality, and that thiol adsorption is fundamentally limited in eliminating charge traps. However, as soon as the molecular backbone is trimmed and atomic sulfur is released to the crystal, both bonds of the sulfur are recruited to passivate the divalent defect and the semiconductor quality improves drastically. Time-dependent X-ray photoelectron spectroscopy (XPS) is applied here together with other methods for the characterization of defects, their healing, leading energies and occupation. First-principles calculations support a unified picture of the electronic passivation of sulfur-healed WSe2 and WS2. This work provides a simple and efficient method for improving the quality of 2D semiconductors and has the potential to impact device performance even after natural degradation.

This work presents a new model-free inversion estimation framework (MFIEF) using daily TROPOspheric Monitoring Instrument (TROPOMI) NO2 columns and observed fluxes from the continuous emission monitoring system (CEMS) to quantify 3 years of daily scale emissions of NOx at 0.05∘×0.05∘ over Shanxi Province, a major world-wide energy-producing and energy-consuming region. The NOx emissions, day-to-day variability, and uncertainty on a climatological basis are computed to be 1.86, 1.03, and 1.05 Tg yr−1 respectively. The highest emissions are concentrated in the lower Fen River valley, which accounts for 25 % of the area, 53 % of the NOx emissions, and 72 % of CEMS sources. Two major forcing factors (10th to 90th percentile) are horizontal transport distance per day (63–508 km) and lifetime of NOx (7.1–18.1 h). Both of these values are consistent with NOx emissions to both the surface layer and the free troposphere. The third forcing factor, the ratio of NOx/NO2, on a pixel-to-pixel basis, is demonstrated to correlate with the combustion temperature and energy efficiency of large energy consuming sources. Specifically, thermal power plants, cement, and iron and steel companies have a relatively high NOx/NO2 ratio, while coking, industrial boilers, and aluminum oxide factories show a relatively lower ratio. Variance maximization is applied to daily TROPOMI NO2 columns, which facilitates identification of three orthogonal and statistically significant modes of variability, and successfully attributes them both spatially and temporally to (a) this work's computed emissions, (b) remotely sensed TROPOMI ultraviolet aerosol index (UVAI), and (c) computed transport based on TROPOMI NO2.

Abstract Single spin-defects in 2D transition-metal dichalcogenides are natural spin-photon interfaces for quantum applications. Here we report high-field magneto-photoluminescence spectroscopy from three emission lines (Q1, Q2, and Q*) of He-ion induced sulfur vacancies in monolayer MoS2. Analysis of the asymmetric PL lineshapes in combination with the diamagnetic shift of Q1 and Q2 yields a consistent picture of localized emitters with a wave function extent of ~3.5 nm. The distinct valley-Zeeman splitting in out-of-plane B-fields and the brightening of dark states through in-plane B-fields necessitates spin-valley selectivity of the defect states and lifted spin-degeneracy at zero field. Comparing our results to ab initio calculations identifies the nature of Q1 and Q2 and suggests that Q* is the emission from a chemically functionalized defect. Analysis of the optical degree of circular polarization reveals that the Fermi level is a parameter that enables the tunability of the emitter. These results show that defects in 2D semiconductors may be utilized for quantum technologies.

The lifetime and concentration of nitrogen oxides (NOx) are susceptible to nonlinear production and loss and to the resolution of a chemical transport model (CTM). This is due to the strong spatial gradients of NOx and the dependence of its own chemical loss on such gradients. In this study, we use the GEOS-Chem CTM in its high-performance implementation (GCHP) to investigate NOx simulations over the eastern United States across a wide range of spatial model resolutions (six different horizontal grids from 13 to 181 km). Following increasing grid size, afternoon surface NOx mixing ratios over July 2015 generally decrease over the Great Lakes region (GL) and increase over the southern states of the US region (SS), yielding regional differences (181 km vs. 13 km) of −16 % (in the GL) to 7 % (in the SS); meanwhile, hydrogen oxide radicals (HOx) increase over both regions, consistent with their different chemical regimes (i.e., NOx-saturated in the GL and NOx-limited in the SS). Nighttime titration of ozone by surface nitric oxide (NO) was found to be more efficient at coarser resolutions, leading to longer NOx lifetimes and higher surface mixing ratios of nitrogen dioxide (NO2) over the GL in January 2015. The tropospheric NO2 column density at typical afternoon satellite overpass time has spatially more coherent negative biases (e.g., −8 % over the GL) at coarser resolutions in July, which reversed the positive biases of surface NOx over the SS. The reduced NOx aloft (>1 km altitude) at coarser resolutions was attributable to the enhanced HOx that intrudes into the upper troposphere. Application of coarse-resolution simulations for interpreting satellite NO2 columns will generally underestimate surface NO2 over the GL and overestimate surface NO2 over the SS in summer, but it will uniformly overestimate NOx emissions over both regions. This study significantly broadens understanding of factors contributing to NOx resolution effects and the role of fine-resolution data in accurately simulating and interpreting NOx and its relevance to air quality.

Tissue engineering is considered a promising approach to treating advanced degenerative maculopathies such as nonexudative age-related macular degeneration (AMD), the leading cause of blindness worldwide. The retina consists of several hierarchical tissue layers, each of which is supported by a layer underneath. Each of these layers has a different morphology and requires distinct conditions for proper assembly. In fact, a prerequisite step for the assembly of each of these layers is the organization of the layer underneath. Advanced retinal degeneration includes degeneration of the other retina layers, including the choroid, the retinal pigmented epithelium (RPE), and the photoreceptors. Here, we report a step-by-step fabrication process of a three-layer retina-like structure. The process included the 3D printing of a choroid-like structure in an extracellular matrix (ECM) hydrogel, followed by deposition of the RPE monolayer. After the formation of the blood vessel–RPE interface, the photoreceptor cells were deposited to interact with the RPE layer. At the end of the fabrication process, each layer was characterized for its morphology and expression of specific markers, and the integration of the three-layer retina was evaluated. We envision that such a retina-like structure may be able to attenuate the deterioration of a degenerated retina and improve engraftment and regeneration. This retinal implant may potentially be suitable for a spectrum of macular degenerative diseases for which there are currently no cures and may save millions from complete blindness.

Heart failure with preserved ejection fraction (HFpEF) is more prevalent in post- compared to pre-menopausal women. The underlying mechanisms are not fully understood. Data in humans is confounded by age and co-morbidities. We investigated the effects of ovariectomy and estrogen replacement on the left ventricular (LV) gene expression of pro-inflammatory and pro-fibrotic factors involved in HFpEF and putative regulating miRNAs. Nine-week-old C57BL/6 female mice were subjected to ovariectomy (OVX) or SHAM operation. OVX and SHAM groups were sacrificed 1-, 6-, and 12-weeks post-surgery (T1/SHAM; T1/OVX; T6/SHAM; T6/OVX, T12/SHAM). 17β-estradiol (E2) or vehicle (VEH) was then administered to the OVX groups for 6 weeks (T12/OVX/E2; T12/OVX/VEH). Another SHAM group was sacrificed 12-weeks post-surgery. RNA and miRNAs were extracted from the LV apex. An early 3-fold increase in the gene expression of IL-1α, IL-6, Mmp9, Mmp12, Col1α1, and Col3α1 was observed one-week post-surgery in T1/OVX vs. T1/SHAM, but not at later time points. miRNA-26a was lower in T1/OVX vs. T1/SHAM and was inversely correlated with Col1α1 and Col3α1 expression 1-week post-surgery (r = −0.79 p < 0.001; r = −0.6 p = 0.007). miRNAs-26a, 29b, and 133a were significantly higher, while Col1α1, Col3α1, IL-1α, IL-6, Tnfα, Mmp12, and FasL gene expression was significantly lower in E2- compared to vehicle-treated OVX mice. miRNA-26a was inversely correlated with Col3α1 in T12/OVX/ E2 (r = −0.56 p = 0.02). OVX triggered an early increase in the gene expression of pro-inflammatory and pro-fibrotic factors, highlighting the importance of the early phase post-cessation of ovarian function. E2 replacement therapy, even if it was not immediately initiated after OVX, reversed these unfavorable changes and upregulated cardiac miRNA-26a, previously unknown to be affected by menopausal status.

Myocardial necrosis following the successful reperfusion of a coronary artery occluded by thrombus in a patient presenting with ST-elevation myocardial infarction (STEMI) continues to be a serious problem, despite the multiple attempts to attenuate the necrosis with agents that have shown promise in pre-clinical investigations. Possible reasons include confounding clinical risk factors, the delayed application of protective agents, poorly designed pre-clinical investigations, the possible effects of routinely administered agents that might unknowingly already have protected the myocardium or that might have blocked protection, and the biological differences of the myocardium in humans and experimental animals. A better understanding of the pathobiology of myocardial infarction is needed to stem this reperfusion injury. P2Y12 receptor antagonists minimize platelet aggregation and are currently part of the standard treatment to prevent thrombus formation and propagation in STEMI protocols. Serendipitously, these P2Y12 antagonists also dramatically attenuate reperfusion injury in experimental animals and are presumed to provide a similar protection in STEMI patients. However, additional protective agents are needed to further diminish reperfusion injury. It is possible to achieve additive protection if the added intervention protects by a mechanism different from that of P2Y12 antagonists. Inflammation is now recognized to be a critical factor in the complex intracellular response to ischemia and reperfusion that leads to tissue necrosis. Interference with cardiomyocyte inflammasome assembly and activation has shown great promise in attenuating reperfusion injury in pre-clinical animal models. And the blockade of the executioner protease caspase-1, indeed, supplements the protection already seen after the administration of P2Y12 antagonists. Importantly, protective interventions must be applied in the first minutes of reperfusion, if protection is to be achieved. The promise of such a combination of protective strategies provides hope that the successful attenuation of reperfusion injury is attainable.

The ubiquitin–proteasome system (UPS) is an essential mechanism responsible for the selective degradation of substrate proteins via their conjugation with ubiquitin. Since cardiomyocytes have very limited self-renewal capacity, as they are prone to protein damage due to constant mechanical and metabolic stress, the UPS has a key role in cardiac physiology and pathophysiology. While altered proteasomal activity contributes to a variety of cardiac pathologies, such as heart failure and ischemia/reperfusion injury (IRI), the environmental cues affecting its activity are still unknown, and they are the focus of this work. Following a recent study by Ciechanover’s group showing that amino acid (AA) starvation in cultured cancer cell lines modulates proteasome intracellular localization and activity, we tested two hypotheses in human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs, CMs): (i) AA starvation causes proteasome translocation in CMs, similarly to the observation in cultured cancer cell lines; (ii) manipulation of subcellular proteasomal compartmentalization is associated with electrophysiological abnormalities in the form of arrhythmias, mediated via altered intracellular Ca2+ handling. The major findings are: (i) starving CMs to AAs results in proteasome translocation from the nucleus to the cytoplasm, while supplementation with the aromatic amino acids tyrosine (Y), tryptophan (W) and phenylalanine (F) (YWF) inhibits the proteasome recruitment; (ii) AA-deficient treatments cause arrhythmias; (iii) the arrhythmias observed upon nuclear proteasome sequestration(-AA+YWF) are blocked by KB-R7943, an inhibitor of the reverse mode of the sodium–calcium exchanger NCX; (iv) the retrograde perfusion of isolated rat hearts with AA starvation media is associated with arrhythmias. Collectively, our novel findings describe a newly identified mechanism linking the UPS to arrhythmia generation in CMs and whole hearts.

IL-1α is a dual function cytokine that affects inflammatory and immune responses and plays a pivotal role in cancer. The effects of intracellular IL-1α on the development of triple negative breast cancer (TNBC) in mice were assessed using the CRISPR/Cas9 system to suppress IL-1α expression in 4T1 breast cancer cells. Knockout of IL-1α in 4T1 cells modified expression of multiple genes, including downregulation of cytokines and chemokines involved in the recruitment of tumor-associated pro-inflammatory cells. Orthotopical injection of IL-1α knockout (KO) 4T1 cells into BALB/c mice led to a significant decrease in local tumor growth and lung metastases, compared to injection of wild-type 4T1 (4T1/WT) cells. Neutrophils and myeloid-derived suppressor cells were abundant in tumors developing after injection of 4T1/WT cells, whereas more antigen-presenting cells were observed in the tumor microenvironment after injection of IL-1α KO 4T1 cells. This switch correlated with increased infiltration of CD3+CD8+ and NKp46+cells. Engraftment of IL-1α knockout 4T1 cells into immunodeficient NOD.SCID mice resulted in more rapid tumor growth, with increased lung metastasis in comparison to engraftment of 4T1/WT cells. Our results suggest that tumor-associated IL-1α is involved in TNBC progression in mice by modulating the interplay between immunosuppressive pro-inflammatory cells vs. antigen-presenting and cytotoxic cells.

Skin microbiota, and its diversity and balance, play a key role in skin health and beauty, influencing skin moisture, barrier function, and radiance. A healthy skin microbiota limits the growth of detrimental species, protecting the skin from pathologies. Prebiotics can support beneficial populations in outcompeting detrimental ones. Dragon fruit (Hylocereus undatus) contains prebiotic polysaccharides effective on gut bacteria. Its extract was tested in vitro, in a coculture model including representative beneficial and detrimental species, and in double-blind, placebo-controlled clinical trials. Effects on the skin microbiota were measured via 16S rDNA sequencing, and skin health and beauty benefits were evaluated through image analysis, TEWL measurement, and chromametry. Doppler flowmetry measured skin resilience. The extract supported S. epidermidis and S. hominis (beneficial species), while limiting S. aureus and C. acnes (representing pathogens) in vitro. Clinical results demonstrated its beneficial effects on skin microbiota diversity, especially in older volunteers (Faith’s index up to +20% vs. placebo). Improvements were shown in skin sensitivity and resilience (by ca. 30% vs. placebo), skin redness (reflecting inflammation status), pigmentation and radiance (+11% ITA), barrier function (−13% TEWL), and wrinkling. This demonstrates this extract’s positive effects on the beauty, health, and microbiota balance of the skin.

Thin-film composite (TFC) polyamide (PA) RO membrane modified with a layer of tethered poly(acrylic acid) (PAA) chains displayed intrinsic rejections of nitrate, boron, As(III), and As(V) of 98.0%, 90.7%, 96%, and 99.6%, respectively. The solute permeability coefficients for nitrate, boron, As(III), and As(V) by the SNS-PAA-PA membrane were lower by 31–38%, 49–63%, 57–72% and 87–93% relative to tested commercial membranes. The above results indicate that the SNS-PAA-PA membrane should be suitable for purification of brackish source water contaminated with nitrate, boron, As(III), and As(V) to levels 1219 ppm, 2 ppm, 95 ppb, and 948 ppb, respectively. The study results suggest that there is merit in further exploration of the potential of the present approach for enhancing RO membranes performance for targeted solute removal.

The availability of formaldehyde (HCHO) (a proxy for volatile organic compound reactivity) and nitrogen dioxide (NO2) (a proxy for nitrogen oxides) tropospheric columns from ultraviolet–visible (UV–Vis) satellites has motivated many to use their ratios to gain some insights into the near-surface ozone sensitivity. Strong emphasis has been placed on the challenges that come with transforming what is being observed in the tropospheric column to what is actually in the planetary boundary layer (PBL) and near the surface; however, little attention has been paid to other sources of error such as chemistry, spatial representation, and retrieval uncertainties. Here we leverage a wide spectrum of tools and data to quantify those errors carefully. Concerning the chemistry error, a well-characterized box model constrained by more than 500 h of aircraft data from NASA's air quality campaigns is used to simulate the ratio of the chemical loss of HO2 + RO2 (LROx) to the chemical loss of NOx (LNOx). Subsequently, we challenge the predictive power of HCHO/NO2 ratios (FNRs), which are commonly applied in current research, in detecting the underlying ozone regimes by comparing them to LROx/LNOx. FNRs show a strongly linear (R2=0.94) relationship with LROx/LNOx, but only on the logarithmic scale. Following the baseline (i.e., ln(LROx/LNOx) = −1.0 ± 0.2) with the model and mechanism (CB06, r2) used for segregating NOx-sensitive from VOC-sensitive regimes, we observe a broad range of FNR thresholds ranging from 1 to 4. The transitioning ratios strictly follow a Gaussian distribution with a mean and standard deviation of 1.8 and 0.4, respectively. This implies that the FNR has an inherent 20 % standard error (1σ) resulting from not accurately describing the ROx–HOx cycle. We calculate high ozone production rates (PO3) dominated by large HCHO × NO2 concentration levels, a new proxy for the abundance of ozone precursors. The relationship between PO3 and HCHO × NO2 becomes more pronounced when moving towards NOx-sensitive regions due to nonlinear chemistry; our results indicate that there is fruitful information in the HCHO × NO2 metric that has not been utilized in ozone studies. The vast amount of vertical information on HCHO and NO2 concentrations from the air quality campaigns enables us to parameterize the vertical shapes of FNRs using a second-order rational function permitting an analytical solution for an altitude adjustment factor to partition the tropospheric columns into the PBL region. We propose a mathematical solution to the spatial representation error based on modeling isotropic semivariograms. Based on summertime-averaged data, the Ozone Monitoring Instrument (OMI) loses 12 % of its spatial information at its native resolution with respect to a high-resolution sensor like the TROPOspheric Monitoring Instrument (TROPOMI) (> 5.5 × 3.5 km2). A pixel with a grid size of 216 km2 fails at capturing ∼ 65 % of the spatial information in FNRs at a 50 km length scale comparable to the size of a large urban center (e.g., Los Angeles). We ultimately leverage a large suite of in situ and ground-based remote sensing measurements to draw the error distributions of daily TROPOMI and OMI tropospheric NO2 and HCHO columns. At a 68 % confidence interval (1σ), errors pertaining to daily TROPOMI observations, either HCHO or tropospheric NO2 columns, should be above 1.2–1.5 × 1016 molec. cm−2 to attain a 20 %–30 % standard error in the ratio. This level of error is almost non-achievable with the OMI given its large error in HCHO. The satellite column retrieval error is the largest contributor to the total error (40 %–90 %) in the FNRs. Due to a stronger signal in cities, the total relative error (< 50 %) tends to be mild, whereas areas with low vegetation and anthropogenic sources (e.g., the Rocky Mountains) are markedly uncertain (> 100 %). Our study suggests that continuing development in the retrieval algorithm and sensor design and calibration is essential to be able to advance the application of FNRs beyond a qualitative metric.