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Optical illumination of quantum dot qubit devices at cryogenic temperatures, while not well studied, is often used to recover operating conditions after undesired shocking events or charge injection. Here, we demonstrate systematic threshold-voltage shifts in a dopant-free Si/Si0.7Ge0.3 field-effect transistor using a near-infrared (780-nm) laser diode. We find that illumination under an applied gate voltage can be used to set a specific, stable, and reproducible threshold voltage that, over a wide range in gate bias, is equal to that gate bias. Outside this range, the threshold voltage can still be tuned, although the resulting threshold voltage is no longer equal to the applied gate bias during illumination. We present a simple and intuitive model that provides a mechanism for the tunability in the gate bias. The model presented also explains why cryogenic illumination is successful at resetting quantum dot qubit devices after undesired charging events.

Environmentally persistent free radicals (EPFRs) play an important role in aerosol effects on air quality and public health, but their atmospheric abundance and sources are poorly understood. We measured EPFRs contained in PM2.5 collected in Fairbanks, Alaska, in winter 2022. We find that EPFR concentrations were enhanced during surface-based inversion and correlate strongly with incomplete combustion markers, including carbon monoxide and elemental carbon (R2 > 0.75). EPFRs exhibit moderately good correlations with PAHs, biomass burning organic aerosols, and potassium (R2 > 0.4). We also observe strong correlations of EPFRs with hydrocarbon-like organic aerosols, Fe and Ti (R2 > 0.6), and single-particle mass spectrometry measurements reveal internal mixing of PAHs, with potassium and iron. These results suggest that residential wood burning and vehicle tailpipes are major sources of EPFRs and nontailpipe emissions, such as brake wear and road dust, may contribute to the stabilization of EPFRs. Exposure to the observed EPFR concentrations (18 ± 12 pmol m-3) would be equivalent to smoking ∼0.4-1 cigarette daily. Very strong correlations (R2 > 0.8) of EPFR with hydroxyl radical formation in surrogate lung fluid indicate that exposure to EPFRs may induce oxidative stress in the human respiratory tract.

Dispersal of reproductive propagules determines recruitment patterns and connectivity among populations and can influence how populations respond to major disturbance events. Dispersal distributions can depend on propagule release strategies. For instance, the bull kelp, Nereocystis luetkeana, can release propagules (spores) from two heights in the water column ("bimodal release"): at the water surface, directly from the reproductive tissues (sori) on the kelp's blades, and near the seafloor after the sori abscise and sink through the water column. N. luetkeana is a foundation species that occurs from central California to Alaska and is experiencing unprecedented levels of population declines near its southern range limit. We know little of the kelp's dispersal distributions, which could influence population recovery and restoration. Here, we quantify how bimodal spore release heights affect dispersal outcomes based on a numerical model specifically designed for N. luetkeana. The model incorporates oceanographic conditions typical of the species' coastal range and kelp biological traits. With bimodal release heights, 34% of spores are predicted to settle within 10 m of the parental alga and 60% are predicted to disperse beyond 100 m. As an annual species, bimodal release heights can facilitate the local regeneration of adults within a source kelp forest while also supporting connectivity among multiple forests within broader bull kelp metapopulations. To leverage this pattern of bimodal spore dispersal in bull kelp restoration management, directing resources toward strategically located focal populations that can seed other ones could amplify the scale of recovery.

Ninu (greater bilby, Macrotis lagotis) are desert-dwelling, culturally and ecologically important marsupials. In collaboration with Indigenous rangers and conservation managers, we generated the Ninu chromosome-level genome assembly (3.66 Gbp) and genome sequences for the extinct Yallara (lesser bilby, Macrotis leucura). We developed and tested a scat single-nucleotide polymorphism panel to inform current and future conservation actions, undertake ecological assessments and improve our understanding of Ninu genetic diversity in managed and wild populations. We also assessed the beneficial impact of translocations in the metapopulation (N = 363 Ninu). Resequenced genomes (temperate Ninu, 6; semi-arid Ninu, 6; and Yallara, 4) revealed two major population crashes during global cooling events for both species and differences in Ninu genes involved in anatomical and metabolic pathways. Despite their 45-year captive history, Ninu have fewer long runs of homozygosity than other larger mammals, which may be attributable to their boom-bust life history. Here we investigated the unique Ninu biology using 12 tissue transcriptomes revealing expression of all 115 conserved eutherian chorioallantoic placentation genes in the uterus, an XY1Y2 sex chromosome system and olfactory receptor gene expansions. Together, we demonstrate the holistic value of genomics in improving key conservation actions, understanding unique biological traits and developing tools for Indigenous rangers to monitor remote wild populations.

This White Paper presents an overview of the current status and future perspective of QCD research, based on the community inputs and scientific conclusions from the 2022 Hot and Cold QCD Town Meeting. We present the progress made in the last decade toward a deep understanding of both the fundamental structure of the sub-atomic matter of nucleon and nucleus in cold QCD, and the hot QCD matter in heavy ion collisions. We identify key questions of QCD research and plausible paths to obtaining answers to those questions in the near future, hence defining priorities of our research over the coming decades.

Heparan sulfate (HS) is degraded in lysosome by a series of glycosidases. Before the glycosidases can act, the terminal glucosamine of HS must be acetylated by the integral lysosomal membrane enzyme heparan-α-glucosaminide N-acetyltransferase (HGSNAT). Mutations of HGSNAT cause HS accumulation and consequently mucopolysaccharidosis IIIC, a devastating lysosomal storage disease characterized by progressive neurological deterioration and early death where no treatment is available. HGSNAT catalyzes a unique transmembrane acetylation reaction where the acetyl group of cytosolic acetyl-CoA is transported across the lysosomal membrane and attached to HS in one reaction. However, the reaction mechanism remains elusive. Here we report six cryo-EM structures of HGSNAT along the reaction pathway. These structures reveal a dimer arrangement and a unique structural fold, which enables the elucidation of the reaction mechanism. We find that a central pore within each monomer traverses the membrane and controls access of cytosolic acetyl-CoA to the active site at its luminal mouth where glucosamine binds. A histidine-aspartic acid catalytic dyad catalyzes the transfer reaction via a ternary complex mechanism. Furthermore, the structures allow the mapping of disease-causing variants and reveal their potential impact on the function, thus creating a framework to guide structure-based drug discovery efforts.

Electronic cigarette smoking (or vaping) is on the rise, presenting questions about the effects of secondhand exposure. The chemical composition of vape emissions was examined in the exhaled breath of eight human volunteers with the high chemical specificity of complementary online and offline techniques. Our study is the first to take multiple exhaled puff measurements from human participants and compare volatile organic compound (VOC) concentrations between two commonly used methods, proton-transfer-reaction time-of-flight mass spectrometry (PTR-ToF-MS) and gas chromatography (GC). Five flavor profile groups were selected for this study, but flavor compounds were not observed as the main contributors to the PTR-ToF-MS signal. Instead, the PTR-ToF-MS mass spectra were overwhelmed by e-liquid thermal decomposition and fragmentation products, which masked other observations regarding flavorings and other potentially toxic species associated with secondhand vape exposure. Compared to the PTR-ToF-MS, GC measurements reported significantly different VOC concentrations, usually below those from PTR-ToF-MS. Consequently, PTR-ToF-MS mass spectra should be interpreted with caution when reporting quantitative results in vaping studies, such as doses of inhaled VOCs. Nevertheless, the online PTR-ToF-MS analysis can provide valuable qualitative information by comparing relative VOCs in back-to-back trials. For example, by comparing the mass spectra of exhaled air with those of direct puffs, we can conclude that harmful VOCs present in the vape emissions are largely absorbed by the participants, including large fractions of nicotine.

Transmembrane (TM) domains as simple as a single span can perform complex biological functions using entirely lipid-embedded chemical features. Computational design has the potential to generate custom tool molecules directly targeting membrane proteins at their functional TM regions. Thus far, designed TM domain-targeting agents have been limited to mimicking the binding modes and motifs of natural TM interaction partners. Here, we demonstrate the design of de novo TM proteins targeting the erythropoietin receptor (EpoR) TM domain in a custom binding topology competitive with receptor homodimerization. The TM proteins expressed in mammalian cells complex with EpoR and inhibit erythropoietin-induced cell proliferation. In vitro, the synthetic TM domain complex outcompetes EpoR homodimerization. Structural characterization reveals that the complex involves the intended amino acids and agrees with our designed molecular model of antiparallel TM helices at 1:1 stoichiometry. Thus, membrane protein TM regions can now be targeted in custom-designed topologies.

This paper explores obstacles to recruiting and retaining teachers of color and Indigenous teachers (TOCIT) in California’s schools. The researchers used a mix of qualitative and quantitative data collected over the course of one year from system leaders in teacher preparation, pre-service teachers, in-service teachers, and former teachers to better understand current policies and practices that may be contributing to teacher burnout, turnover and early retirement.

Approximately 5% of Alzheimer's disease patients develop symptoms before age 65 (early-onset Alzheimer's disease), with either sporadic (sporadic early-onset Alzheimer's disease) or dominantly inherited (dominantly inherited Alzheimer's disease) presentations. Both sporadic early-onset Alzheimer's disease and dominantly inherited Alzheimer's disease are characterized by brain amyloid-β accumulation, tau tangles, hypometabolism and neurodegeneration, but differences in topography and magnitude of these pathological changes are not fully elucidated. In this study, we directly compared patterns of amyloid-β plaque deposition and glucose hypometabolism in sporadic early-onset Alzheimer's disease and dominantly inherited Alzheimer's disease individuals. Our analysis included 134 symptomatic sporadic early-onset Alzheimer's disease amyloid-Positron Emission Tomography (PET)-positive cases from the University of California, San Francisco, Alzheimer's Disease Research Center (mean ± SD age 59.7 ± 5.6 years), 89 symptomatic dominantly inherited Alzheimer's disease cases (age 45.8 ± 9.3 years) and 102 cognitively unimpaired non-mutation carriers from the Dominantly Inherited Alzheimer Network study (age 44.9 ± 9.2). Each group underwent clinical and cognitive examinations, 11C-labelled Pittsburgh Compound B-PET and structural MRI. 18F-Fluorodeoxyglucose-PET was also available for most participants. Positron Emission Tomography scans from both studies were uniformly processed to obtain a standardized uptake value ratio (PIB50-70 cerebellar grey reference and FDG30-60 pons reference) images. Statistical analyses included pairwise global and voxelwise group comparisons and group-independent component analyses. Analyses were performed also adjusting for covariates including age, sex, Mini-Mental State Examination, apolipoprotein ε4 status and average composite cortical of standardized uptake value ratio. Compared with dominantly inherited Alzheimer's disease, sporadic early-onset Alzheimer's disease participants were older at age of onset (mean ± SD, 54.8 ± 8.2 versus 41.9 ± 8.2, Cohen's d = 1.91), with more years of education (16.4 ± 2.8 versus 13.5 ± 3.2, d = 1) and more likely to be apolipoprotein ε4 carriers (54.6% ε4 versus 28.1%, Cramer's V = 0.26), but similar Mini-Mental State Examination (20.6 ± 6.1 versus 21.2 ± 7.4, d = 0.08). Sporadic early-onset Alzheimer's disease had higher global cortical Pittsburgh Compound B-PET binding (mean ± SD standardized uptake value ratio, 1.92 ± 0.29 versus 1.58 ± 0.44, d = 0.96) and greater global cortical 18F-fluorodeoxyglucose-PET hypometabolism (mean ± SD standardized uptake value ratio, 1.32 ± 0.1 versus 1.39 ± 0.19, d = 0.48) compared with dominantly inherited Alzheimer's disease. Fully adjusted comparisons demonstrated relatively higher Pittsburgh Compound B-PET standardized uptake value ratio in the medial occipital, thalami, basal ganglia and medial/dorsal frontal regions in dominantly inherited Alzheimer's disease versus sporadic early-onset Alzheimer's disease. Sporadic early-onset Alzheimer's disease showed relatively greater 18F-fluorodeoxyglucose-PET hypometabolism in Alzheimer's disease signature temporoparietal regions and caudate nuclei, whereas dominantly inherited Alzheimer's disease showed relatively greater hypometabolism in frontal white matter and pericentral regions. Independent component analyses largely replicated these findings by highlighting common and unique Pittsburgh Compound B-PET and 18F-fluorodeoxyglucose-PET binding patterns. In summary, our findings suggest both common and distinct patterns of amyloid and glucose hypometabolism in sporadic and dominantly inherited early-onset Alzheimer's disease.

PURPOSE: To describe the clinical, electrophysiological and genetic spectrum of inherited retinal diseases associated with variants in the PRPH2 gene. METHODS: A total of 241 patients from 168 families across 15 sites in 9 countries with pathogenic or likely pathogenic variants in PRPH2 were included. Records were reviewed for age at symptom onset, visual acuity, full-field ERG, fundus colour photography, fundus autofluorescence (FAF), and SD-OCT. Images were graded into six phenotypes. Statistical analyses were performed to determine genotype-phenotype correlations. RESULTS: The median age at symptom onset was 40 years (range, 4-78 years). FAF phenotypes included normal (5%), butterfly pattern dystrophy, or vitelliform macular dystrophy (11%), central areolar choroidal dystrophy (28%), pseudo-Stargardt pattern dystrophy (41%), and retinitis pigmentosa (25%). Symptom onset was earlier in retinitis pigmentosa as compared with pseudo-Stargardt pattern dystrophy (34 vs 44 years; P = 0.004). The median visual acuity was 0.18 logMAR (interquartile range, 0-0.54 logMAR) and 0.18 logMAR (interquartile range 0-0.42 logMAR) in the right and left eyes, respectively. ERG showed a significantly reduced amplitude across all components (P < 0.001) and a peak time delay in the light-adapted 30-Hz flicker and single-flash b-wave (P < 0.001). Twenty-two variants were novel. The central areolar choroidal dystrophy phenotype was associated with 13 missense variants. The remaining variants showed marked phenotypic variability. CONCLUSIONS: We described six distinct FAF phenotypes associated with variants in the PRPH2 gene. One FAF phenotype may have multiple ERG phenotypes, demonstrating a discordance between structure and function. Given the vast spectrum of PRPH2 disease our findings are useful for future clinical trials.

How human genetic variation contributes to vaccine effectiveness in infants is unclear, and data are limited on these relationships in populations with African ancestries. We undertook genetic analyses of vaccine antibody responses in infants from Uganda (n = 1391), Burkina Faso (n = 353) and South Africa (n = 755), identifying associations between human leukocyte antigen (HLA) and antibody response for five of eight tested antigens spanning pertussis, diphtheria and hepatitis B vaccines. In addition, through HLA typing 1,702 individuals from 11 populations of African ancestry derived predominantly from the 1000 Genomes Project, we constructed an imputation resource, fine-mapping class II HLA-DR and DQ associations explaining up to 10% of antibody response variance in our infant cohorts. We observed differences in the genetic architecture of pertussis antibody response between the cohorts with African ancestries and an independent cohort with European ancestry, but found no in silico evidence of differences in HLA peptide binding affinity or breadth. Using immune cell expression quantitative trait loci datasets derived from African-ancestry samples from the 1000 Genomes Project, we found evidence of differential HLA-DRB1 expression correlating with inferred protection from pertussis following vaccination. This work suggests that HLA-DRB1 expression may play a role in vaccine response and should be considered alongside peptide selection to improve vaccine design.

We assembled the first gridded burned area (BA) database of national wildfire data (ONFIRE), a comprehensive and integrated resource for researchers, non-government organisations, and government agencies analysing wildfires in various regions of the Earth. We extracted and harmonised records from different regions and sources using open and reproducible methods, providing data in a common framework for the whole period available (starting from 1950 in Australia, 1959 in Canada, 1985 in Chile, 1980 in Europe, and 1984 in the United States) up to 2021 on a common 1° × 1° grid. The data originate from national agencies (often, ground mapping), thus representing the best local expert knowledge. Key opportunities and limits in using this dataset are discussed as well as possible future expansions of this open-source approach that should be explored. This dataset complements existing gridded BA data based on remote sensing and offers a valuable opportunity to better understand and assess fire regime changes, and their drivers, in these regions. The ONFIRE database can be freely accessed at https://zenodo.org/record/8289245 .

Indirect Drive Inertial Confinement Fusion Experiments on the National Ignition Facility (NIF) have achieved a burning plasma state with neutron yields exceeding 170 kJ, roughly 3 times the prior record and a necessary stage for igniting plasmas. The results are achieved despite multiple sources of degradations that lead to high variability in performance. Results shown here, for the first time, include an empirical correction factor for mode-2 asymmetry in the burning plasma regime in addition to previously determined corrections for radiative mix and mode-1. Analysis shows that including these three corrections alone accounts for the measured fusion performance variability in the two highest performing experimental campaigns on the NIF to within error. Here we quantify the performance sensitivity to mode-2 symmetry in the burning plasma regime and apply the results, in the form of an empirical correction to a 1D performance model. Furthermore, we find the sensitivity to mode-2 determined through a series of integrated 2D radiation hydrodynamic simulations to be consistent with the experimentally determined sensitivity only when including alpha-heating.

The indoor air quality of a residential home during winter in Fairbanks, Alaska, was investigated and contrasted with outdoor levels. Twenty-four-hour average indoor and outdoor filter samples were collected from January 17 to February 25, 2022, in a residential area with high outdoor PM2.5 concentrations. The oxidative potential of PM2.5 was determined using the dithiothreitol-depletion assay (OPDTT). For the unoccupied house, the background indoor-to-outdoor (I/O) ratio of mass-normalized OP (OPmDTT), a measure of the intrinsic health-relevant properties of the aerosol, was less than 1 (0.53 ± 0.37), implying a loss of aerosol toxicity as air was transported indoors. This may result from transport and volatility losses driven by the large gradients in temperature (average outdoor temperature of -19°C/average indoor temperature of 21 °C) or relative humidity (average outdoor RH of 78%/average indoor RH of 11%), or both. Various indoor activities, including pellet stove use, simple cooking experiments, incense burning, and mixtures of these activities, were conducted. The experiments produced PM2.5 with a highly variable OPmDTT. PM2.5 from cooking emissions had the lowest OP values, while pellet stove PM2.5 had the highest. Correlations between volume-normalized OPDTT (OPvDTT), relevant to exposure, and indoor PM2.5 mass concentration during experiments were much lower compared to those in outdoor environments. This suggests that mass concentration alone can be a poor indicator of possible adverse effects of various indoor emissions. These findings highlight the importance of considering both the quantity of particles and sources (chemical composition), as health metrics for indoor air quality.

The oxidative potential (OP) of outdoor PM2.5 in wintertime Fairbanks, Alaska, is investigated and compared to those in wintertime Atlanta and Los Angeles. Approximately 40 filter samples collected in January-February 2022 at a Fairbanks residential site were analyzed for OP utilizing dithiothreitol-depletion (OPDTT) and hydroxyl-generation (OPOH) assays. The study-average PM2.5 mass concentration was 12.8 μg/m3, with a 1 h average maximum of 89.0 μg/m3. Regression analysis, correlations with source tracers, and contrast between cold and warmer events indicated that OPDTT was mainly sensitive to copper, elemental carbon, and organic aerosol from residential wood burning, and OPOH to iron and organic aerosol from vehicles. Despite low photochemically-driven oxidation rates, the water-soluble fraction of OPDTT was unusually high at 77%, mainly from wood burning emissions. In contrast to other locations, the Fairbanks average PM2.5 mass concentration was higher than Atlanta and Los Angeles, whereas OPDTT in Fairbanks and Atlanta were similar, and Los Angeles had the highest OPDTT and OPOH. Site differences were observed in OP when normalized by both the volume of air sampled and the particle mass concentration, corresponding to exposure and the intrinsic health-related properties of PM2.5, respectively. The sensitivity of OP assays to specific aerosol components and sources can provide insights beyond the PM2.5 mass concentration when assessing air quality.

The Alaskan Layered Pollution And Chemical Analysis (ALPACA) field experiment was a collaborative study designed to improve understanding of pollution sources and chemical processes during winter (cold climate and low-photochemical activity), to investigate indoor pollution, and to study dispersion of pollution as affected by frequent temperature inversions. A number of the research goals were motivated by questions raised by residents of Fairbanks, Alaska, where the study was held. This paper describes the measurement strategies and the conditions encountered during the January and February 2022 field experiment, and reports early examples of how the measurements addressed research goals, particularly those of interest to the residents. Outdoor air measurements showed high concentrations of particulate matter and pollutant gases including volatile organic carbon species. During pollution events, low winds and extremely stable atmospheric conditions trapped pollution below 73 m, an extremely shallow vertical scale. Tethered-balloon-based measurements intercepted plumes aloft, which were associated with power plant point sources through transport modeling. Because cold climate residents spend much of their time indoors, the study included an indoor air quality component, where measurements were made inside and outside a house to study infiltration and indoor sources. In the absence of indoor activities such as cooking and/or heating with a pellet stove, indoor particulate matter concentrations were lower than outdoors; however, cooking and pellet stove burns often caused higher indoor particulate matter concentrations than outdoors. The mass-normalized particulate matter oxidative potential, a health-relevant property measured here by the reactivity with dithiothreiol, of indoor particles varied by source, with cooking particles having less oxidative potential per mass than pellet stove particles.

Children who receive cochlear implants develop spoken language on a protracted timescale. The home environment facilitates speech-language development, yet it is relatively unknown how the environment differs between children with cochlear implants and typical hearing. We matched eighteen preschoolers with implants (31-65 months) to two groups of children with typical hearing: by chronological age and hearing age. Each child completed a long-form, naturalistic audio recording of their home environment (appx. 16 hours/child; >730 hours of observation) to measure adult speech input, child vocal productivity, and caregiver-child interaction. Results showed that children with cochlear implants and typical hearing were exposed to and engaged in similar amounts of spoken language with caregivers. However, the home environment did not reflect developmental stages as closely for children with implants, or predict their speech outcomes as strongly. Home-based speech-language interventions should focus on the unique input-outcome relationships for this group of children with hearing loss.

X-chromosomal genetic variants are understudied but can yield valuable insights into sexually dimorphic human traits and diseases. We performed a sex-stratified cross-ancestry X-chromosome-wide association meta-analysis of seven kidney-related traits (n = 908,697), identifying 23 loci genome-wide significantly associated with two of the traits: 7 for uric acid and 16 for estimated glomerular filtration rate (eGFR), including four novel eGFR loci containing the functionally plausible prioritized genes ACSL4, CLDN2, TSPAN6 and the female-specific DRP2. Further, we identified five novel sex-interactions, comprising male-specific effects at FAM9B and AR/EDA2R, and three sex-differential findings with larger genetic effect sizes in males at DCAF12L1 and MST4 and larger effect sizes in females at HPRT1. All prioritized genes in loci showing significant sex-interactions were located next to androgen response elements (ARE). Five ARE genes showed sex-differential expressions. This study contributes new insights into sex-dimorphisms of kidney traits along with new prioritized gene targets for further molecular research.

Judgments about the harmfulness of trial errors have profound consequences for defendants, the criminal justice system, and the public. Judges are expected to assess harm accurately, but they cannot hear directly from jurors and may only speculate about the difference a trial error made. Even experienced judges have a hard time predicting what jurors think and what juries will do. Fortunately, scientific principles and research can assist judges in conducting harmless error analysis. This Article offers a framework for testing claims about the harmfulness oftrial errors. It specifies the prosecution’s burden to prove a trial error was harmless on direct appeal as well as the defendant’s burden to prove a trial error was harmful in post-conviction proceedings. Hypotheses about the harmfulness of errors can be visualized and tested rigorously. Scientific analysis of trial errors can help courts assess the harmfulness of trial errors more accurately, efficiently, and confidently.

Previous studies indicate that CNS administration of oxytocin (OT) reduces body weight in high fat diet-induced obese (DIO) rodents by reducing food intake and increasing energy expenditure (EE). We recently demonstrated that hindbrain (fourth ventricular [4V]) administration of OT elicits weight loss and elevates interscapular brown adipose tissue temperature (TIBAT, a surrogate measure of increased EE) in DIO mice. What remains unclear is whether OT-elicited weight loss requires increased sympathetic nervous system (SNS) outflow to IBAT. We hypothesized that OT-induced stimulation of SNS outflow to IBAT contributes to its ability to activate BAT and elicit weight loss in DIO mice. To test this hypothesis, we determined the effect of disrupting SNS activation of IBAT on the ability of 4V OT administration to increase TIBAT and elicit weight loss in DIO mice. We first determined whether bilateral surgical SNS denervation to IBAT was successful as noted by ≥ 60% reduction in IBAT norepinephrine (NE) content in DIO mice. NE content was selectively reduced in IBAT at 1-, 6- and 7-weeks post-denervation by 95.9 ± 2.0, 77.4 ± 12.7 and 93.6 ± 4.6% (P

PurposePersistent gastrointestinal (GI) symptoms are frequently experienced by colon cancer survivors and may help identify patients with higher utilization of healthcare services. To assess the relationship between GI symptoms and specialty care utilization among colon cancer survivors.MethodsA prospective longitudinal cohort study at an academic medical center of 126 adults surgically treated for stage I-IV colon cancer between February 2017 and June 2022. Participants reported GI symptoms through the EORTC QLQ-C30 and QLQ-CR29 at enrollment and as frequently as every 6 months for 5 years. Main outcome measures were visits, telephone encounters, and secure messages with a medical provider within specialty oncology clinics within 6 months after each survey completion. Generalized linear mixed regression model for repeated measurements with random trajectory for each participant was performed to estimate the associations between symptoms and healthcare use. Models were adjusted for demographics, clinical and surgical factors, and timing in relation to onset of the COVID-19 pandemic.ResultsIn the 6 months after each survey time point, patients averaged 1.2 visits, 0.5 telephone encounters, and 3.2 patient-initiated messages. In adjusted models, those with any abdominal pain (RR 1.45; p = 0.002), buttock pain (RR 1.30; p = 0.050), or increased stool frequency (RR 1.26; p = 0.046) had more clinic visits in the following 6 months than those without these symptoms. Including these three symptoms in one model revealed that only abdominal pain was statistically significantly associated with increased clinic visits (RR 1.36; p = 0.016). Patients with any blood or mucus in stool (RR 2.46; p = 0.009) had significantly more telephone encounters, and those with any abdominal pain (RR 1.65; p = 0.002) had significantly more patient-initiated messages than those without these symptoms.ConclusionsOur findings identify GI symptoms associated with increased use of oncologic specialty care among colon cancer survivors, with abdominal pain as an important predictor of utilization.Implications for cancer survivorsEarly identification and anticipatory management of colon cancer survivors experiencing abdominal pain may decrease healthcare utilization.

INTRODUCTION: Laparoscopic surgery requires significant training, and prior studies have shown that surgical residents lack key laparoscopic skills. Many educators have implemented simulation curricula to improve laparoscopic training. Given limited time for dedicated, in-person simulation center practice, at-home training has emerged as a possible mechanism by which to expand training and promote practice. There remains a gap in published at-home laparoscopic curricula employing embedded feedback mechanisms. METHODS: We developed a nine-task at-home laparoscopic curriculum and an end-of-curriculum assessment following Kerns six-step approach. We implemented the curriculum over 4 months with first- to third-year residents. RESULTS: Of 47 invited residents from general surgery, obstetrics/gynecology, and urology, 37 (79%) participated in the at-home curriculum, and 25 (53%) participated in the end-of-curriculum assessment. Residents who participated in the at-home curriculum completed a median of six of nine tasks (interquartile range: 3-8). Twenty-two residents (47%) responded to a postcurriculum survey. Of these, 19 (86%) reported that their laparoscopic skills improved through completion of the curriculum, and the same 19 (86%) felt that the curriculum should be continued for future residents. Residents who completed more at-home curriculum tasks scored higher on the end-of-curriculum assessment (p = .009 with adjusted R 2 of .28) and performed assessment tasks in less time (p = .004 with adjusted R 2 of .28). DISCUSSION: This learner-centered laparoscopic curriculum provides guiding examples, spaced practice, feedback, and graduated skill development to enable junior residents to improve their laparoscopic skills in a low-stakes, at-home environment.

Abstract: Water diversions for agriculture reduce ecosystem services provided by saline lakes around the world. Exposed lakebed surfaces are major sources of dust emissions that may exacerbate existing environmental inequities. This paper studies the effects of water diversions and their impacts on particulate pollution arising from reduced inflows to the Salton Sea in California via a spatially explicit particle transport model and changing lakebed exposure. We demonstrate that lakebed dust emissions increased ambient and concentrations and worsened environmental inequalities, with historically disadvantaged communities receiving a disproportionate increase in pollution. Water diversion decisions are often determined by political processes; our findings demonstrate the need for distributional analysis of such decisions to ensure equitable compensation.

We present the genome assembly of the pennate diatom Epithemia pelagica strain UHM3201 (Ochrophyta; Bacillariophyceae; Rhopalodiales; Rhopalodiaceae) and that of its cyanobacterial endosymbiont (Chroococcales: Aphanothecaceae). The genome sequence of the diatom is 60.3 megabases in span, and the cyanobacterial genome has a length of 2.48 megabases. Most of the diatom nuclear genome assembly is scaffolded into 15 chromosomal pseudomolecules. The organelle genomes have also been assembled, with the mitochondrial genome 40.08 kilobases and the plastid genome 130.75 kilobases in length. A number of other prokaryote MAGs were also assembled.

Adults with Down syndrome have a genetic form of Alzheimer's disease (AD) and evidence of cerebrovascular disease across the AD continuum, despite few systemic vascular risk factors. The onset and progression of AD in Down syndrome is highly age-dependent, but it is unknown at what age cerebrovascular disease emerges and what factors influence its severity. In the Alzheimer's Biomarker Consortium-Down Syndrome study (ABC-DS; n = 242; age = 25-72), we estimated the age inflection point at which MRI-based white matter hyperintensities (WMH), enlarged perivascular spaces (PVS), microbleeds, and infarcts emerge in relation to demographic data, risk factors, amyloid and tau, and AD diagnosis. Enlarged PVS and infarcts appear to develop in the early 30s, while microbleeds, WMH, amyloid, and tau emerge in the mid to late 30s. Age-residualized WMH were higher in women, in individuals with dementia, and with lower body mass index. Participants with hypertension and APOE-ε4 had higher age-residualized PVS and microbleeds, respectively. Lifespan trajectories demonstrate a dramatic cerebrovascular profile in adults with Down syndrome that appears to evolve developmentally in parallel with AD pathophysiology approximately two decades prior to dementia symptoms.

Adults often learn new semantic information in face-to-face communication with other adults (e.g., teachers, colleagues). More knowledgeable individuals provide an ensemble of multimodal behaviours that can shape the information that their interlocutors learn. Using the naturalistic ECOLANG corpus of dyadic conversations, we ask whether multimodal behaviours (pitch, speaking rate, representational gestures, points, object manipulations, and gaze) support adults' semantic learning of unknown objects above and beyond verbal properties of utterances (number of utterances, lexical diversity, mean length of utterances, concreteness) and learners' individual differences (vocabulary, working memory). We found that individual differences, pointing and object manipulations affected learning, with verbal and multimodal factors also interacting to predict adult semantic learning. Our results highlight the relevance of accounts of multimodal learning in adulthood and the importance of considering naturalistic interaction in its complexity to understand the factors that influence adult learning.

Alongside the linguistic input, young children leverage multimodal cues (e.g., prosody, gestures) to learn novel words in face-to-face interactions. It is unclear whether multimodal cues play a similar role in adults. Here, we used ECOLANG, a corpus of semi-naturalistic dyadic conversations where English-speaking adults incidentally learned about unknown objects and their names by interacting with a partner who knew those objects. We examined whether multimodal cues (prosodic, indexical, and iconic) predicted learners' ability to learn the objects' names, above and beyond individual differences and linguistic predictors. We found that the number of repetitions of the label predicted word learning. Additionally, learners with lower working memory abilities benefited from speakers producing representational gestures while labelling the unknown objects. We discuss implications for theories of word learning and approaches of situated cognition.

In this paper I analyze the work on exchange rates and external imbalances by University of Chicago faculty members during the university’s first 100 years, 1892 to 1992. Many people associate Chicago’s views with Milton Friedman’s advocacy for flexible exchange rates. But, of course, there was much more than that, including the work of J. Laurence Laughlin on bimetallism, Jacob Viner on the balance of payments, Lloyd Metzler on transfers, Harry Johnson on trade and currencies, Lloyd Mints on exchange rate regimes, Robert Mundell on optimal currency areas, and Arnold Harberger on shadow exchange rates, among others. The analysis shows that, although different scholars emphasized different issues, there was a common thread in this research, anchored on the role of relative prices’ changes during the adjustment process.

Adults with Down syndrome are less likely to have hypertension than neurotypical adults. However, whether blood pressure measures are associated with brain health and clinical outcomes in this population has not been studied in detail. Here, we assessed whether pulse pressure is associated with markers of cerebrovascular disease and is linked to a diagnosis of dementia in adults with Down syndrome via structural imaging markers of cerebrovascular disease and atrophy. The study included participants with Down syndrome from the Alzheimers Disease - Down Syndrome study (n = 195, age = 50.6 ± 7.2 years, 44% women, 18% diagnosed with dementia). Higher pulse pressure was associated with greater global, parietal and occipital white matter hyperintensity volume but not with enlarged perivascular spaces, microbleeds or infarcts. Using a structural equation model, we found that pulse pressure was associated with greater white matter hyperintensity volume, which in turn was related to increased neurodegeneration, and subsequent dementia diagnosis. Pulse pressure is an important determinant of brain health and clinical outcomes in individuals with Down syndrome despite the low likelihood of frank hypertension.

BACKGROUND: Cross-reactive SARS-CoV-2-specific memory CD4+ and CD8+ T cells are present in up to 50% of unexposed, pre-pandemic, healthy individuals (UPPHIs). However, the characteristics of cross-reactive memory CD4+ and CD8+ T cells associated with subsequent protection of asymptomatic coronavirus disease 2019 (COVID-19) patients (i.e., unvaccinated individuals who never develop any COVID-19 symptoms despite being infected with SARS-CoV-2) remains to be fully elucidated. METHODS: This study compares the antigen specificity, frequency, phenotype, and function of cross-reactive memory CD4+ and CD8+ T cells between common cold coronaviruses (CCCs) and SARS-CoV-2. T-cell responses against genome-wide conserved epitopes were studied early in the disease course in a cohort of 147 unvaccinated COVID-19 patients who were divided into six groups based on the severity of their symptoms. RESULTS: Compared to severely ill COVID-19 patients and patients with fatal COVID-19 outcomes, the asymptomatic COVID-19 patients displayed significantly: (i) higher rates of co-infection with the 229E alpha species of CCCs (α-CCC-229E); (ii) higher frequencies of cross-reactive functional CD134+CD137+CD4+ and CD134+CD137+CD8+ T cells that cross-recognized conserved epitopes from α-CCCs and SARS-CoV-2 structural, non-structural, and accessory proteins; and (iii) lower frequencies of CCCs/SARS-CoV-2 cross-reactive exhausted PD-1+TIM3+TIGIT+CTLA4+CD4+ and PD-1+TIM3+TIGIT+CTLA4+CD8+ T cells, detected both ex vivo and in vitro. CONCLUSIONS: These findings (i) support a crucial role of functional, poly-antigenic α-CCCs/SARS-CoV-2 cross-reactive memory CD4+ and CD8+ T cells, induced following previous CCCs seasonal exposures, in protection against subsequent severe COVID-19 disease and (ii) provide critical insights into developing broadly protective, multi-antigen, CD4+, and CD8+ T-cell-based, universal pan-Coronavirus vaccines capable of conferring cross-species protection.

Text-to-image artificial intelligence (AI) programs are popular public-facing tools that generate novel images based on user prompts. Given that they are trained from Internet data, they may reflect societal biases, as has been shown for text-to-text large language model programs. We sought to investigate whether 3 common text-to-image AI systems recapitulated stereotypes held about surgeons and other health care professionals. All platforms queried were able to reproduce common aspects of the profession including attire, equipment, and background settings, but there were differences between programs most notably regarding visible race and gender diversity. Thus, historical stereotypes of surgeons may be reinforced by the publics use of text-to-image AI systems, particularly those without procedures to regulate generated output. As AI systems become more ubiquitous, understanding the implications of their use in health care and for health care-adjacent purposes is critical to advocate for and preserve the core values and goals of our profession.

BackgroundThe Critical Assessment of Genome Interpretation (CAGI) aims to advance the state-of-the-art for computational prediction of genetic variant impact, particularly where relevant to disease. The five complete editions of the CAGI community experiment comprised 50 challenges, in which participants made blind predictions of phenotypes from genetic data, and these were evaluated by independent assessors.ResultsPerformance was particularly strong for clinical pathogenic variants, including some difficult-to-diagnose cases, and extends to interpretation of cancer-related variants. Missense variant interpretation methods were able to estimate biochemical effects with increasing accuracy. Assessment of methods for regulatory variants and complex trait disease risk was less definitive and indicates performance potentially suitable for auxiliary use in the clinic.ConclusionsResults show that while current methods are imperfect, they have major utility for research and clinical applications. Emerging methods and increasingly large, robust datasets for training and assessment promise further progress ahead.

IntroductionSome caregivers are hesitant about topical fluoride for their children despite evidence that fluoride prevents caries and is safe. Recent work described a five domain model of caregivers' topical fluoride hesitancy. We developed the Fluoride Hesitancy Identification Tool (FHIT) item pool based on the model. This study sought to evaluate the FHIT's psychometric properties in an effort to generate a short, simple to score, reliable, and valid tool that measures caregivers' topical fluoride hesitancy.MethodsIn 2021 and 2022, we conducted an observational, cross-sectional study of caregivers, collecting data from two independent caregiver samples (n1 = 523; n2 = 612). The FHIT item pool included 33 items. We used confirmatory factor analyses (CFA) to examine whether the FHIT items measured five separate domains as hypothesized and to reduce the number of items. We then fit item response theory (IRT) models and computed Cronbach's alpha for each domain. Last, we examined the construct validity of the FHIT and evaluated scoring approaches.ResultsAfter dropping 8 items, CFA supported a five factor model of topical fluoride hesitancy, with no cross-loadings (RMSEA = 0.079; SRMR = 0.057; CFI = 0.98; TLI = 0.98). We further reduced the items to four per domain (20 items total). Marginal alphas showed that the item sets provided reliability of ≥0.90 at hesitancy levels at and above average. The domains correlated more strongly with each other and topical fluoride refusal than with other questions on the survey.DiscussionOur results support the FHIT's ability to reliably and validly measure five domains of topical fluoride hesitancy using the average score of the four items in each domain.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has created one of the largest global health crises in almost a century. Although the current rate of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections has decreased significantly, the long-term outlook of COVID-19 remains a serious cause of morbidity and mortality worldwide, with the mortality rate still substantially surpassing even that recorded for influenza viruses. The continued emergence of SARS-CoV-2 variants of concern (VOCs), including multiple heavily mutated Omicron sub-variants, has prolonged the COVID-19 pandemic and underscores the urgent need for a next-generation vaccine that will protect from multiple SARS-CoV-2 VOCs. METHODS: We designed a multi-epitope-based coronavirus vaccine that incorporated B, CD4+, and CD8+ T- cell epitopes conserved among all known SARS-CoV-2 VOCs and selectively recognized by CD8+ and CD4+ T-cells from asymptomatic COVID-19 patients irrespective of VOC infection. The safety, immunogenicity, and cross-protective immunity of this pan-variant SARS-CoV-2 vaccine were studied against six VOCs using an innovative triple transgenic h-ACE-2-HLA-A2/DR mouse model. RESULTS: The pan-variant SARS-CoV-2 vaccine (i) is safe , (ii) induces high frequencies of lung-resident functional CD8+ and CD4+ TEM and TRM cells , and (iii) provides robust protection against morbidity and virus replication. COVID-19-related lung pathology and death were caused by six SARS-CoV-2 VOCs: Alpha (B.1.1.7), Beta (B.1.351), Gamma or P1 (B.1.1.28.1), Delta (lineage B.1.617.2), and Omicron (B.1.1.529). CONCLUSION: A multi-epitope pan-variant SARS-CoV-2 vaccine bearing conserved human B- and T- cell epitopes from structural and non-structural SARS-CoV-2 antigens induced cross-protective immunity that facilitated virus clearance, and reduced morbidity, COVID-19-related lung pathology, and death caused by multiple SARS-CoV-2 VOCs.

This study assessed whether the effect of vascular risk on cerebral blood flow (CBF) varies by gene dose of apolipoprotein (APOE) ε4 alleles. 144 older adults without dementia from the Alzheimers Disease Neuroimaging Initiative underwent arterial spin labeling and T1-weighted MRI, APOE genotyping, fluorodeoxyglucose positron emission tomography (FDG-PET), lumbar puncture, and blood pressure (BP) assessment. Vascular risk was assessed using pulse pressure (systolic BP - diastolic BP). CBF was examined in six AD-vulnerable regions: entorhinal cortex, hippocampus, inferior temporal cortex, inferior parietal cortex, rostral middle frontal gyrus, and medial orbitofrontal cortex. Linear regressions tested the interaction between APOE ε4 dose and pulse pressure on CBF in each region, adjusting for age, sex, cognitive classification, antihypertensive medication use, FDG-PET, reference CBF region, and AD biomarker positivity. There was a significant interaction between pulse pressure and APOE ɛ4 dose on CBF in the entorhinal cortex, hippocampus, and inferior parietal cortex, such that higher pulse pressure was associated with lower CBF only among ε4 homozygous participants. These findings demonstrate that the association between pulse pressure and regional CBF differs by APOE ε4 dose, suggesting that targeting modifiable vascular risk factors may be particularly important for those genetically at risk for AD.

Disclosure of HIV status to potential and current sex partners by HIV-positive people (HIVPP) is a complex issue that has received a significant amount of attention. Research has found that disclosure depends upon the evaluation by HIVPP of potential benefits and risks, especially of the risks stemming from the profound social stigma of HIV and AIDS. Drawing on concepts from Goffman's classic stigma theory and Anderson's more recently developed cultural-identity theory of drug abuse, we analyzed data from in-depth, post-intervention qualitative interviews with 116 heterosexually active, HIV-positive injection drug users enrolled in a randomized trial of a behavioral intervention to prevent HIV transmission. We explored how disclosure experiences lead to “identity impacts” defined as: (1) identity challenges (i.e. interactions that challenge an individual's self-concept as a “normal” or non-deviant individual); and (2) identity transformations (i.e. processes whereby an individual comes to embrace a new identity and reject behaviors and values of an old one, resulting in the conscious adoption of a social and/or public identity as an HIV-positive individual). Participants engaged in several strategies to manage the identity impacts associated with disclosure. Implications of these findings for research and prevention programming are discussed.

INTRODUCTION: Activating RAS gene mutations occur in approximately 55% of patients with metastatic colorectal cancer (mCRC) and are associated with poorer clinical outcomes due to epidermal growth factor receptor (EGFR) blockade resistance. Combined EGFR and mitogen-activated protein kinase (MEK) inhibition may extend response to EGFR inhibition and overcome acquired resistance. This phase Ib/II dose escalation trial evaluated the safety and activity of dual inhibition with binimetinib (MEK1/2 inhibitor) and panitumumab (EGFR inhibitor [EGFRi]) in patients with RAS mutant or BRAF wild type (WT)/RAS WT mCRC. METHODS: Phase Ib dose escalation started with binimetinib 45 mg twice daily plus panitumumab 6 mg/kg administered every 2 weeks. In the phase II study, patients with measurable mCRC were enrolled into 4 groups based on previous anti-EGFR monoclonal antibody therapy and RAS mutational status. RESULTS: No patients in the phase Ib portion (n = 10) had a response; 70% of patients had stable disease. In the phase II portion (n = 43), overall response rate (ORR, confirmed) was 2.3% with one partial response in the RAS WT group, DCR was 30.2%, and median progression-free survival was 1.8 months (95%CI, 1.6-3.3). All patients experienced ≥1 adverse event, with the most common being diarrhea (71.7%), vomiting (52.8%), nausea (50.9%), fatigue (49.1%), dermatitis acneiform (43.4%), and rash (41.5%). Most patients required treatment interruption or dose reduction due to difficulties tolerating treatment. CONCLUSIONS: The combination of binimetinib and panitumumab had substantial toxicity and limited clinical activity for patients with mutant or WT RAS mCRC, independent of EGFRi treatment history (Trial registration: NCT01927341).

Breast cancer brain metastasis (BCBM) is a lethal disease with no effective treatments. Prior work has shown that brain cancers and metastases are densely infiltrated with anti-inflammatory, protumourigenic tumour-associated macrophages, but the role of brain-resident microglia remains controversial because they are challenging to discriminate from other tumour-associated macrophages. Using single-cell RNA sequencing, genetic and humanized mouse models, we specifically identify microglia and find that they play a distinct pro-inflammatory and tumour-suppressive role in BCBM. Animals lacking microglia show increased metastasis, decreased survival and reduced natural killer and T cell responses, showing that microglia are critical to promote anti-tumour immunity to suppress BCBM. We find that the pro-inflammatory response is conserved in human microglia, and markers of their response are associated with better prognosis in patients with BCBM. These findings establish an important role for microglia in anti-tumour immunity and highlight them as a potential immunotherapy target for brain metastasis.

IntroductionOxidative stress mediated by reactive oxygen species (ROS) is a key process for adverse aerosol health effects. Secondary organic aerosols (SOA) account for a major fraction of particulate matter with aerodynamic diameter ≤2.5 µm (PM2.5). PM2.5 inhalation and deposition into the respiratory tract causes the formation of ROS by chemical reactions and phagocytosis of macrophages in the epithelial lining fluid (ELF), but their relative contributions are not well quantified and their link to oxidative stress remains uncertain. The specific aims of this project were (1) elucidating the chemical mechanism and quantifying the formation kinetics of ROS in the ELF by SOA; (2) quantifying the relative importance of ROS formation by chemical reactions and macrophages in the ELF.MethodsSOA particles were generated using reaction chambers from oxidation of various precursors including isoprene, terpenes, and aromatic compounds with or without nitrogen oxides (NOx). We collected size-segregated PM at two highway sites in Anaheim, CA, and Long Beach, CA, and at an urban site in Irvine, CA, during two wildfire events. The collected particles were extracted into water or surrogate ELF that contained lung antioxidants. ROS generation was quantified using electron paramagnetic resonance (EPR) spectroscopy with a spin-trapping technique. PM oxidative potential (OP) was also quantified using the dithiothreitol assay. In addition, kinetic modeling was applied for analysis and interpretation of experimental data. Finally, we quantified cellular superoxide release by RAW264.7 macrophage cells upon exposure to quinones and isoprene SOA using a chemiluminescence assay as calibrated with an EPR spin-probing technique. We also applied cellular imaging techniques to study the cellular mechanism of superoxide release and oxidative damage on cell membranes.ResultsSuperoxide radicals (·O2-) were formed from aqueous reactions of biogenic SOA generated by hydroxy radical (·OH) photooxidation of isoprene, β-pinene, α-terpineol, and d-limonene. The temporal evolution of ·OH and ·O2- formation was elucidated by kinetic modeling with a cascade of aqueous reactions, including the decomposition of organic hydroperoxides (ROOH), ·OH oxidation of primary or secondary alcohols, and unimolecular decomposition of α-hydroxyperoxyl radicals. Relative yields of various types of ROS reflected the relative abundance of ROOH and alcohols contained in SOA, which generated under high NOx conditions, exhibited lower ROS yields. ROS formation by SOA was also affected by pH. Isoprene SOA had higher ·OH and organic radical yields at neutral than at acidic pH. At low pH ·O2- was the dominant species generated by all types of SOA. At neutral pH, α-terpineol SOA exhibited a substantial yield of carbon-centered organic radicals (R·), while no radical formation was observed by aromatic SOA.Organic radicals in the ELF were formed by mixtures of Fe2+ and SOA generated from photooxidation of isoprene, α-terpineol, and toluene. The molar yields of organic radicals by SOA were 5-10 times higher in ELF than in water. Fe2+ enhanced organic radical yields by a factor of 20-80. Ascorbate mediated redox cycling of iron ions and sustained organic peroxide decomposition, as supported by kinetic modeling reproducing time- and concentration-dependence of organic radical formation, as well as by additional experiments observing the formation of Fe2+ and ascorbate radicals in mixtures of ascorbate and Fe3+. ·OH and superoxide were found to be efficiently scavenged by antioxidants.Wildfire PM mainly generated ·OH and R· with minor contributions from superoxide and oxygen-centered organic radicals (RO·). PM OP was high in wildfire PM, exhibiting very weak correlation with radical forms of ROS. These results were in stark contrast with PM collected at highway and urban sites, which generated much higher amounts of radicals dominated by ·OH radicals that correlated well with OP. By combining field measurements of size-segregated chemical composition, a human respiratory tract model, and kinetic modeling, we quantified production rates and concentrations of different types of ROS in different regions of the ELF by considering particle-size-dependent respiratory deposition. While hydrogen peroxide (H2O2) and ·O2- production were governed by Fe and Cu ions, ·OH radicals were mainly generated by organic compounds and Fenton-like reactions of metal ions. We obtained mixed results for correlations between PM OP and ROS formation, providing rationale and limitations of the use of oxidative potential as an indicator for PM toxicity in epidemiological and toxicological studies.Quinones and isoprene SOA activated nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in macrophages, releasing massive amounts of superoxide via respiratory burst and overwhelming the superoxide formation by aqueous chemical reactions in the ELF. The threshold dose for macrophage activation was much smaller for quinones compared with isoprene SOA. The released ROS caused lipid peroxidation to increase cell membrane fluidity, inducing oxidative damage and stress. Further increases of doses led to the activation of antioxidant response elements, reducing the net cellular superoxide production. At very high doses and long exposure times, chemical production became comparably important or dominant if the escalation of oxidative stress led to cell death.ConclusionsThe mechanistic understandings and quantitative information on ROS generation by SOA particles provided a basis for further elucidation of adverse aerosol health effects and oxidative stress by PM2.5. For a comprehensive assessment of PM toxicity and health effects via oxidative stress, it is important to consider both chemical reactions and cellular processes for the formation of ROS in the ELF. Chemical composition of PM strongly influences ROS formation; further investigations are required to study ROS formation from various PM sources. Such research will provide critical information to environmental agencies and policymakers for the development of air quality policy and regulation.

The disproportionate use of chemical straighteners and skin lighteners by women of color is a growing public health concern given the link between product use and adverse health effects. Prior studies examined product use as an individual choice but neglected social-structural factors, which influence beauty perceptions and personal decisions around product use. We used a community-based participatory research approach to characterize product use by demographics and investigated how racialized beauty norms impact use among 297 women and femme-identifying individuals in Northern Manhattan and the South Bronx. Product use varied by race/ethnicity, nativity, and messaging from family and peers. Black respondents were more likely to ever use chemical straighteners than non-Black respondents (OR = 2.0; 95% CI = 1.2-3.2), as were respondents who heard that family members express a preference for straight hair compared with respondents whose family members expressed mixed preferences about hairstyles (OR = 2.0; 95% CI = 1.1-3.7). Compared with non-Asian respondents and respondents born in the United States, Asian respondents and respondents born in other countries, respectively, had threefold higher odds of ever using skin lighteners (Asian: OR = 3.2; 95% CI = 1.4-7.0; born in other countries: OR = 3.4; 95% CI = 1.9-6.1). Respondents' perceptions that others believe straight hair or lighter skin confer benefits such as beauty, professionalism, or youth were associated with greater use of chemical straighteners and skin lighteners. These findings highlight the pervasiveness of racialized beauty norms and point to the need to reduce the demand for and sale of these products through community education, market-based strategies, and public policy.

Regions of hypoxia occur in most tumors and are a predictor of poor patient prognosis. Hypoxia-activated prodrugs (HAPs) provide an ideal strategy to target the aggressive, hypoxic, fraction of a tumor, while protecting the normal tissue from toxicity. A key challenge associated with the development of novel HAPs, however, is the ability to visualize the delivery of the prodrug to hypoxic regions and determine where it has been activated. Here, we report a modified version of the commonly used nitroimidazole bioreductive group that incorporates the fluoroethyl epitope of the antibody-based hypoxia imaging agent, EF5. Attachment of this group to the red fluorescent dye, dicyanomethylene (DCM), enabled us to correlate the release of the DCM dye with imaging of the reduced bioreductive group using the EF5 antibody. This study confirmed that the antibody was imaging reduction and fragmentation of the pro-fluorophore. We next employed the modified bioreductive group to synthesize a new prodrug of the KDAC inhibitor Panobinostat, EF5-Pano. Release of EF5-Pano in hypoxic multiple myeloma cells was imaged using the EF5 antibody, and the presence of an imaging signal correlated with apoptosis and a reduction in cell viability. Therefore, EF5-Pano is an imageable HAP with a proven cytotoxic effect in multiple myeloma, which could be utilized in future in vivo experiments.

Background and aimsCAM photosynthesis is hypothesized to have evolved in atmospheres of low CO2 concentration in recent geological time because of its ability to concentrate CO2 around Rubisco and boost water use efficiency relative to C3 photosynthesis. We assess this hypothesis by compiling estimates of when CAM clades arose using phylogenetic chronograms for 73 CAM clades. We further consider evidence of how atmospheric CO2 affects CAM relative to C3 photosynthesis.ResultsWhere CAM origins can be inferred, strong CAM is estimated to have appeared in the past 30 million years in 46 of 48 examined clades, after atmospheric CO2 had declined from high (near 800 ppm) to lower (

Background and scopeThe growth of experimental studies of crassulacean acid metabolism (CAM) in diverse plant clades, coupled with recent advances in molecular systematics, presents an opportunity to re-assess the phylogenetic distribution and diversity of species capable of CAM. It has been more than two decades since the last comprehensive lists of CAM taxa were published, and an updated survey of the occurrence and distribution of CAM taxa is needed to facilitate and guide future CAM research. We aimed to survey the phylogenetic distribution of these taxa, their diverse morphology, physiology and ecology, and the likely number of evolutionary origins of CAM based on currently known lineages.Results and conclusionsWe found direct evidence (in the form of experimental or field observations of gas exchange, day-night fluctuations in organic acids, carbon isotope ratios and enzymatic activity) for CAM in 370 genera of vascular plants, representing 38 families. Further assumptions about the frequency of CAM species in CAM clades and the distribution of CAM in the Cactaceae and Crassulaceae bring the currently estimated number of CAM-capable species to nearly 7 % of all vascular plants. The phylogenetic distribution of these taxa suggests a minimum of 66 independent origins of CAM in vascular plants, possibly with dozens more. To achieve further insight into CAM origins, there is a need for more extensive and systematic surveys of previously unstudied lineages, particularly in living material to identify low-level CAM activity, and for denser sampling to increase phylogenetic resolution in CAM-evolving clades. This should allow further progress in understanding the functional significance of this pathway by integration with studies on the evolution and genomics of CAM in its many forms.

BACKGROUND: Quantifying the dose and distribution of tobacco smoke in the respiratory system is critical for understanding its toxicity, addiction potential, and health impacts. Epidemiologic studies indicate that the incidence of lung tumors varies across different lung regions, suggesting there may be a heterogeneous deposition of smoke particles leading to greater health risks in specific regions. Despite this, few studies have examined the lobar spatial distribution of inhaled particles from tobacco smoke. This gap in knowledge, coupled with the growing popularity of little cigars among youth, underscores the need for additional research with little cigars. RESULTS: In our study, we analyzed the lobar deposition in rat lungs of smoke particles from combusted regular and mentholated Swisher Sweets little cigars. Twelve-week-old male and female Sprague-Dawley rats were exposed to smoke particles at a concentration of 84 ± 5 mg/m3 for 2 h, after which individual lung lobes were examined. We utilized Inductively Coupled Plasma Mass Spectrometry to quantify lobar chromium concentrations, serving as a smoke particle tracer. Our findings demonstrated an overall higher particle deposition from regular little cigars than from the mentholated ones. Higher particle deposition fraction was observed in the left and caudal lobes than other lobes. We also observed sex-based differences in the normalized deposition fractions among lobes. Animal study results were compared with the multi-path particle dosimetry (MPPD) model predictions, which showed that the model overestimated particle deposition in certain lung regions. CONCLUSIONS: Our findings revealed that the particle deposition varied between different little cigar products. The results demonstrated a heterogenous deposition pattern, with higher particle deposition observed in the left and caudal lobes, especially with the mentholated little cigars. Additionally, we identified disparities between our measurements and the MPPD model. This discrepancy highlights the need to enhance the accuracy of models before extrapolating animal study results to human lung deposition. Overall, our study provides valuable insights for estimating the dose of little cigars during smoking for toxicity research.

Mexican, Puerto Rican, and Central American Ancestry (MPRCA) individuals represent 82% of US Latinos. An intergenerational group of MPRCA women and allies met to discuss persistent underrepresentation of MPRCA women in STEM, identifying multi-level challenges and solutions. Implementation of these solutions is important and will benefit MPRCA women and the entire academic community.