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Dose optimization of sirolimus may further improve outcomes in allogeneic hematopoietic cell transplant (HCT) patients receiving post-transplantation cyclophosphamide (PTCy) to prevent graft-versus-host disease (GVHD). Sirolimus exposure-response association studies in HCT patients (i.e., the association of trough concentration with clinical outcomes) have been conflicting. Sirolimus has important effects on T-cells, including conventional (Tcons) and regulatory T-cells (Tregs), both of which have been implicated in the mechanisms by which PTCy prevents GVHD, but there is an absence of validated biomarkers of sirolimus effects on these cell subsets. Considering the paucity of existing biomarkers and the complexities of the immune system, we conducted a literature review to inform a quantitative systems pharmacology (QSP) model of GVHD. The published literature presented multiple challenges. The sirolimus pharmacokinetic models insufficiently describe sirolimus distribution to relevant physiological compartments. Despite multiple publications describing sirolimus effects on Tcons and Tregs in preclinical and human ex vivo models, consistent parameters relating sirolimus concentrations to circulating Tcons and Tregs could not be found. Each aspect presents a challenge in building a QSP model of sirolimus and its temporal effects on T-cell subsets and GVHD prevention. To optimize GVHD prevention regimens, phase I studies and systematic studies of immunosuppressant concentration-effect association are needed for QSP modeling.

Steroid-associated laminitis remains a major concern with use of corticosteroids in horses. Individual case factors such as joint pathology, pre-existing endocrinopathies, or corticosteroid type, dose, and timing influencing steroid-induced laminitis risk have not been investigated. This study aimed to determine if systemic absorption of triamcinolone acetonide (TA) varies between intrasynovial (antebrachiocarpal) and extrasynovial (sacroiliac) injection sites, and to determine the effects of TA absorption on glucose, insulin, cortisol, and adrenocorticotropic hormone (ACTH). Twenty adult horses were randomized into antebrachiocarpal or sacroiliac joint injection groups, and each horse received bilateral injections with a total dose of 18 mg triamcinolone. Blood was collected prior to injection and at 1, 2, 4, 6, 8, 10, 12, 16, 20, 24, 36, 48, 60, and 72 h post-injection. Peak TA absorption occurred at 8 h in both groups, and was significantly higher in the intrasynovial group compared to the extrasynovial group (1.397 ng/mL, 0.672 ng/mL, p 20 μU/mL) from both groups experienced a more marked hyperinsulinemia, reaching a mean peak insulin of 197.5 μU/mL as compared to 90.06 μU/mL in those with normal baseline insulin. Cortisol and ACTH were significantly decreased from baseline at timepoints from 4-72 h post-injection in both groups. This study is the first to evaluate drug absorption from the sacroiliac site and demonstrates that drug absorption varies between intrasynovial and extrasynovial injection sites. TA absorption causes metabolic derangements, most notably a marked hyperinsulinemia that is more severe in horses with elevated baseline insulin values. The influence of baseline endocrinopathies on response to corticosteroid administration as well as the effect of corticosteroid-induced metabolic derangements warrant further investigation as risk factors for corticosteroid-associated laminitis.

People sometimes explicitly announce that they are being sarcastic. The announcement appears to be particularly common in text-based conversations where prosodic cues are more difficult to identify. In certain cases, the tone of a comment is sufficient to determine non-literal meaning. However, what happens in the absence of these features, or when context forces us to explicitly caveat our sarcasm? In this study, we examined Reddit comments from r/AskReddit for the features that are present in comments tagged with "/s", a convention on the platform for users to denote sarcasm. We found that a host of cues which mimic prosody, and other aspects of figures of speech, were inconsistent predictors of announced sarcasm. In contrast, when talking about sociomoral topics such as politics or race, users were more likely to tag their comments with "/s". This suggests that users are more likely to announce sarcasm in text-based conversations where misinterpretation would be socially detrimental.

Psychologists have noted that analogical reasoning is pervasive in argumentation (Kuhn, 1992; Holyoak, 1997), but the forms these arguments can take varies substantially. Memes are one common format or argument-by-analogy. Memes are widely recognized images or templates that compares two situations to each other for the purpose of making some (often questionable) point. Even though memes-as-arguments are readily visible on social media, the persuasiveness of this category of argument-by-analogy---and specifically the features that predict their persuasiveness---have not been established. This study investigates whether and in what ways arguments by analogy, delivered in the form of a meme, are persuasive. We develop a large set of memes representing common meme structures, political leaning, and familiarity and examined how these factors predict a meme's perceived clarity, persuasiveness, and memorability, along with these memes effects on beliefs about issues such as climate change, immigration, and racism.

Fracture injection/shut-in tests are commonly used to measure the state of stress in the subsurface. Injection creates a hydraulic fracture (or in some cases, opens a preexisting fracture), and then the pressure after shut-in is monitored to identify fracture closure. Different interpretation procedures have been proposed for estimating closure, and the procedures sometimes yield significantly different results. In this study, direct, in-situ strain measurements are used to observe fracture reopening and closure. The tests were performed as part of the EGS Collab project, a mesoscale project performed at 1.25 and 1.5 km depth at the Sanford Underground Research Facility. The tests were instrumented with the SIMFIP tool, a double-packer probe with a high-resolution three-dimensional borehole displacement sensor. The measurements provide a direct observation of the fracture closure signature, enabling a high-fidelity estimate of the fracture closure stress (ie, the normal stress on the fracture). In two of the four tests, injection created an opening mode fracture, and so the closure stress can be interpreted as the minimum principal stress. In the other two tests, injection probably opened preexisting natural fractures, and so the closure stress can be interpreted as the normal stress on the fractures. The strain measurements are compared against different proposed methods for estimating closure stress from pressure transients. The shut-in transients are analyzed with two techniques that are widely used in the field of petroleum engineering – the ‘tangent’ method and the ‘compliance’ method. In three of the four tests, the tangent method significantly underestimates the closure stress. The compliance method is reasonably accurate in all four tests. Closure stress is also interpreted using two other commonly-used methods – ‘first deviation from linearity’ and the method of (Hayashi and Haimson, 1991). In comparison with the SIMFIP data, these methods tend to overestimate the closure stress, evidently because they identify closure from early-time transient effects, such as near-wellbore tortuosity. In two of the tests, microseismic imaging provides an independent estimate of the size of the fracture created by injection. When combined with a simple mass balance calculation, the SIMFIP stress measurements yield predictions of fracture size that are reasonably consistent with the estimates from microseismic. The calculations imply an apparent fracture toughness 2-3x higher than typical laboratory-derived values.

Some sources report increases in alcohol use have been observed since the start of the COVID-19 pandemic, particularly among women. Cross-sectional studies suggest that specific COVID-19-related stressful experiences (e.g., social disconnection) may be driving such increases in the general population. Few studies have explored these topics among individuals with a history of Alcohol Use Disorders (AUD), an especially vulnerable population. Drawing on recent data collected by the Collaborative Study on the Genetics of Alcoholism (COGA; COVID-19 study N = 1651, 62% women, age range: 30-91) in conjunction with AUD history data collected on the sample since 1990, we investigated associations of COVID-19 related stressors and coping activities with changes in drunkenness frequency since the start of the pandemic. Analyses were conducted for those without a history of AUD (N: 645) and three groups of participants with a history of AUD prior to the start of the pandemic: (1) those experiencing AUD symptoms (N: 606), (2) those in remission who were drinking (N: 231), and (3) those in remission who were abstinent (had not consumed alcohol for 5+ years; N: 169). Gender-stratified models were also examined. Exploratory analyses examined the moderating effects of 'problematic alcohol use' polygenic risk scores (PRS) and neural connectivity (i.e., posterior interhemispheric alpha EEG coherence) on associations between COVID-19 stressors and coping activities with changes in the frequency of drunkenness. Increases in drunkenness frequency since the start of the pandemic were higher among those with a lifetime AUD diagnosis experiencing symptoms prior to the start of the pandemic (14% reported increased drunkenness) when compared to those without a history of AUD (5% reported increased drunkenness). Among individuals in remission from AUD prior to the start of the pandemic, rates of increased drunkenness were 10% for those who were drinking pre-pandemic and 4% for those who had previously been abstinent. Across all groups, women reported nominally greater increases in drunkenness frequency when compared with men, although only women experiencing pre-pandemic AUD symptoms reported significantly greater rates of increased drunkenness since the start of the pandemic compared to men in this group (17% of women vs. 5% of men). Among those without a prior history of AUD, associations between COVID-19 risk and protective factors with increases in drunkenness frequency were not observed. Among all groups with a history of AUD (including those with AUD symptoms and those remitted from AUD), perceived stress was associated with increases in drunkenness. Among the remitted-abstinent group, essential worker status was associated with increases in drunkenness. Gender differences in these associations were observed: among women in the remitted-abstinent group, essential worker status, perceived stress, media consumption, and decreased social interactions were associated with increases in drunkenness. Among men in the remitted-drinking group, perceived stress was associated with increases in drunkenness, and increased relationship quality was associated with decreases in drunkenness. Exploratory analyses indicated that associations between family illness or death with increases in drunkenness and increased relationship quality with decreases in drunkenness were more pronounced among the remitted-drinking participants with higher PRS. Associations between family illness or death, media consumption, and economic hardships with increases in drunkenness and healthy coping with decreases in drunkenness were more pronounced among the remitted-abstinent group with lower interhemispheric alpha EEG connectivity. Our results demonstrated that only individuals with pre-pandemic AUD symptoms reported greater increases in drunkenness frequency since the start of the COVID-19 pandemic compared to those without a lifetime history of AUD. This increase was more pronounced among women than men in this group. However, COVID-19-related stressors and coping activities were associated with changes in the frequency of drunkenness among all groups of participants with a prior history of AUD, including those experiencing AUD symptoms, as well as abstinent and non-abstinent participants in remission. Perceived stress, essential worker status, media consumption, social connections (especially for women), and relationship quality (especially for men) are specific areas of focus for designing intervention and prevention strategies aimed at reducing pandemic-related alcohol misuse among this particularly vulnerable group. Interestingly, these associations were not observed for individuals without a prior history of AUD, supporting prior literature that demonstrates that widespread stressors (e.g., pandemics, terrorist attacks) disproportionately impact the mental health and alcohol use of those with a prior history of problems.

PURPOSE OF REVIEW: The volume of public health environmental justice (EJ) research produced by academic institutions increased through 2022. However, the methods used for evaluating EJ in exposure science and epidemiologic studies have not been catalogued. Here, we completed a scoping review of EJ studies published in 19 environmental science and epidemiologic journals from 2018 to 2021 to summarize research types, frameworks, and methods. RECENT FINDINGS: We identified 402 articles that included populations with health disparities as a part of EJ research question and met other inclusion criteria. Most studies (60%) evaluated EJ questions related to socioeconomic status (SES) or race/ethnicity. EJ studies took place in 69 countries, led by the US (n = 246 [61%]). Only 50% of studies explicitly described a theoretical EJ framework in the background, methods, or discussion and just 10% explicitly stated a framework in all three sections. Among exposure studies, the most common area-level exposure was air pollution (40%), whereas chemicals predominated personal exposure studies (35%). Overall, the most common method used for exposure-only EJ analyses was main effect regression modeling (50%); for epidemiologic studies the most common method was effect modification (58%), where an analysis evaluated a health disparity variable as an effect modifier. Based on the results of this scoping review, current methods in public health EJ studies could be bolstered by integrating expertise from other fields (e.g., sociology), conducting community-based participatory research and intervention studies, and using more rigorous, theory-based, and solution-oriented statistical research methods.

BackgroundIncreasingly, marginalized communities are disproportionately facing the worsening effects of environmental hazards, including air pollution, water pollution, and climate change. Language isolation and accessibility has been understudied as a determinant of health. Spanish, despite being the second-most common language in the United States with some 41.8 million speakers, has been neglected among environmental health scientists. Building capacity in high-quality Spanish-language science communication, both for scientific and nonscientific audiences, can yield improvements in health disparities research, public health literacy, international collaborations, and diversity and inclusion efforts.ObjectivesIn this article, we discuss the context of language diversity in environmental health sciences and offer recommendations for improving science communication in Spanish.DiscussionEnglish is currently the predominant language for scientific discourse, but Spanish and other non-English languages are routinely used by many environmental health science students and professionals, as well as much of the public. To more effectively conduct and communicate environmental health work in Spanish, we suggest that researchers and scientific institutions a) foster structural changes, b) train emerging scholars and support established researchers, c) tap into community ways of knowing, and d) leverage emerging technologies. https://doi.org/10.1289/EHP12306.

BackgroundDrugs taken during pregnancy can affect maternal and child health outcomes, but few studies have compared the safety and virological efficacy of different antiretroviral therapy (ART) regimens. We report the primary safety outcomes from enrolment up to 50 weeks post partum and a secondary virological efficacy outcome at 50 weeks post partum of three commonly used ART regimens for HIV-1.MethodsIn this multicentre, open-label, randomised, controlled, phase 3 trial, we enrolled pregnant women aged 18 years or older with confirmed HIV-1 infection at 14-28 weeks of gestation. Women were enrolled at 22 clinical research sites in nine countries (Botswana, Brazil, India, South Africa, Tanzania, Thailand, Uganda, the USA, and Zimbabwe). Participants were randomly assigned (1:1:1) to one of three oral regimens: dolutegravir, emtricitabine, and tenofovir alafenamide; dolutegravir, emtricitabine, and tenofovir disoproxil fumarate; or efavirenz, emtricitabine, and tenofovir disoproxil fumarate. Up to 14 days of antepartum ART before enrolment was permitted. Women with known multiple gestation, fetal anomalies, acute significant illness, transaminases more than 2·5 times the upper limit of normal, or estimated creatinine clearance of less than 60 mL/min were excluded. Primary safety analyses were pairwise comparisons between ART regimens of the proportion of maternal and infant adverse events of grade 3 or higher up to 50 weeks post partum. Secondary efficacy analyses at 50 weeks post partum included a comparison of the proportion of women with plasma HIV-1 RNA of less than 200 copies per mL in the combined dolutegravir-containing groups versus the efavirenz-containing group. Analyses were done in the intention-to-treat population, which included all randomly assigned participants with available data. This trial was registered with ClinicalTrials.gov, NCT03048422.FindingsBetween Jan 19, 2018, and Feb 8, 2019, we randomly assigned 643 pregnant women to the dolutegravir, emtricitabine, and tenofovir alafenamide group (n=217), the dolutegravir, emtricitabine, and tenofovir disoproxil fumarate group (n=215), and the efavirenz, emtricitabine, and tenofovir disoproxil fumarate group (n=211). At enrolment, median gestational age was 21·9 weeks (IQR 18·3-25·3), median CD4 count was 466 cells per μL (308-624), and median HIV-1 RNA was 903 copies per mL (152-5183). 607 (94%) women and 566 (92%) of 617 liveborn infants completed the study. Up to the week 50 post-partum visit, the estimated probability of experiencing an adverse event of grade 3 or higher was 25% in the dolutegravir, emtricitabine, and tenofovir alafenamide group; 31% in the dolutegravir, emtricitabine, and tenofovir disoproxil fumarate group; and 28% in the efavirenz, emtricitabine, and tenofovir disoproxil fumarate group (no significant difference between groups). Among infants, the estimated probability of experiencing at least one adverse event of grade 3 or higher by postnatal week 50 was 28% overall, with small and non-statistically significant differences between groups. By postnatal week 50, 14 infants whose mothers were in the efavirenz-containing group (7%) died, compared with six in the combined dolutegravir groups (1%). 573 (89%) women had HIV-1 RNA data available at 50 weeks post partum: 366 (96%) in the dolutegravir-containing groups and 186 (96%) in the efavirenz-containing group had HIV-1 RNA less than 200 copies per mL, with no significant difference between groups.InterpretationSafety and efficacy data during pregnancy and up to 50 weeks post partum support the current recommendation of dolutegravir-based ART (particularly in combination with emtricitabine and tenofovir alafenamide) rather than efavirenz, emtricitabine, and tenofovir disoproxil fumarate, when started in pregnancy.FundingNational Institute of Allergy and Infectious Diseases, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Institute of Mental Health.

CaV1.2 channels are critical players in cardiac excitation-contraction coupling, yet we do not understand how they are affected by an important therapeutic target of heart failure drugs and regulator of blood pressure, angiotensin II. Signaling through Gq-coupled AT1 receptors, angiotensin II triggers a decrease in PIP2, a phosphoinositide component of the plasma membrane (PM) and known regulator of many ion channels. PIP2 depletion suppresses CaV1.2 currents in heterologous expression systems but the mechanism of this regulation and whether a similar phenomenon occurs in cardiomyocytes is unknown. Previous studies have shown that CaV1.2 currents are also suppressed by angiotensin II. We hypothesized that these two observations are linked and that PIP2 stabilizes CaV1.2 expression at the PM and angiotensin II depresses cardiac excitability by stimulating PIP2 depletion and destabilization of CaV1.2 expression. We tested this hypothesis and report that CaV1.2 channels in tsA201 cells are destabilized after AT1 receptor-triggered PIP2 depletion, leading to their dynamin-dependent endocytosis. Likewise, in cardiomyocytes, angiotensin II decreased t-tubular CaV1.2 expression and cluster size by inducing their dynamic removal from the sarcolemma. These effects were abrogated by PIP2 supplementation. Functional data revealed acute angiotensin II reduced CaV1.2 currents and Ca2+ transient amplitudes thus diminishing excitation-contraction coupling. Finally, mass spectrometry results indicated whole-heart levels of PIP2 are decreased by acute angiotensin II treatment. Based on these observations, we propose a model wherein PIP2 stabilizes CaV1.2 membrane lifetimes, and angiotensin II-induced PIP2 depletion destabilizes sarcolemmal CaV1.2, triggering their removal, and the acute reduction of CaV1.2 currents and contractility.

Ash (Fraxinus spp.) is in rapid decline across the northeastern USA due to the invasive emerald ash borer (Agrilus planipennis Fairmaire). Three recently co-occurring confamilial species may serve as alternative larval host plants for ash-reliant Lepidoptera. These prospective hosts are nonnative shrubs often planted in managed suburban landscapes and are sometimes invasive or naturalized in North America. Given the imminent decline of ash trees, we considered potential downstream effects on insect herbivores historically specialized on ash foliage. We measured the performance of three ash-specialist hawkmoths (Lepidoptera: Sphingidae) on native white ash (Fraxinus americana L.) and alternative host plants: common lilac (Syringa vulgaris L.), weeping forsythia [Forsythia suspensa (Thunb.) Vahl], and European privet (Ligustrum vulgare L.). We found the nonnative host plants provided varied support for larval survival to pupation, with biomass and growth rate affected differently by both plant and insect identity. Nearly all caterpillars reared on one alternative host, European privet, exhibited distinct malformations of the wing buds at pupation. Given caterpillar presence on privet in the field, privet may constitute an ecological trap (i.e., when female moths select a sub-optimal host, offspring survival and fitness are reduced). This work demonstrates how performance testing can reveal species-specific effects of host plant loss on mono- or oligophagous insects. For some ash specialists, alternative nonnative host plants may be suboptimal, but some cultivated host plants may be able to support certain specialist insects during native host decline. We suggest that landscaping decisions can be tailored to support threatened insect species.

Endometriosis is an incurable, under-diagnosed, systemic inflammatory disease affecting millions world-wide. Common symptoms include life-impacting pain, gastrointestinal/urinary symptoms, excessive fatigue, and infertility. Global public health policies are urgently needed to promote awareness, implement multidisciplinary care, and fund research for aetiology, biomarker discovery, and effective therapies for symptoms associated with endometriosis.

BackgroundParents impact their offspring's brain development, neurocognitive function, risk, and resilience for alcohol use disorder (AUD) via both genetic and socio-environmental factors. Individuals with AUD and their unaffected children manifest low parietal P3 amplitude and low frontal theta (FT) power, reflecting heritable neurocognitive deficits associated with AUD. Likewise, children who experience poor parenting tend to have atypical brain development and greater rates of alcohol problems. Conversely, positive parenting can be protective and critical for normative development of self-regulation, neurocognitive functioning and the neurobiological systems subserving them. Yet, the role of positive parenting in resiliency toward AUD is understudied and its association with neurocognitive functioning and behavioral vulnerability to AUD among high-risk offspring is less known. Using data from the Collaborative Study on the Genetics of Alcoholism prospective cohort (N = 1256, mean age [SD] = 19.25 [1.88]), we investigated the associations of closeness with mother and father during adolescence with offspring P3 amplitude, FT power, and binge drinking among high-risk offspring.MethodsSelf-reported closeness with mother and father between ages 12 and 17 and binge drinking were assessed using the Semi-Structured Assessment for the Genetics of Alcoholism. P3 amplitude and FT power were assessed in response to target stimuli using a Visual Oddball Task.ResultsMultivariate multiple regression analyses showed that closeness with father was associated with larger P3 amplitude (p = 0.002) and higher FT power (p = 0.01). Closeness with mother was associated with less binge drinking (p = 0.003). Among male offspring, closeness with father was associated with larger P3 amplitude, but among female offspring, closeness with mother was associated with less binge drinking. These associations remained statistically significant with father's and mothers' AUD symptoms, socioeconomic status, and offspring impulsivity in the model.ConclusionsAmong high-risk offspring, closeness with parents during adolescence may promote resilience for developing AUD and related neurocognitive deficits albeit with important sex differences.

BackgroundParents impact their offspring's brain development, neurocognitive function, risk, and resilience for alcohol use disorder (AUD) via both genetic and socio-environmental factors. Individuals with AUD and their unaffected children manifest low parietal P3 amplitude and low frontal theta (FT) power, reflecting heritable neurocognitive deficits associated with AUD. Likewise, children who experience poor parenting tend to have atypical brain development and greater rates of alcohol problems. Conversely, positive parenting can be protective and critical for normative development of self-regulation, neurocognitive functioning and the neurobiological systems subserving them. Yet, the role of positive parenting in resiliency toward AUD is understudied and its association with neurocognitive functioning and behavioral vulnerability to AUD among high-risk offspring is less known. Using data from the Collaborative Study on the Genetics of Alcoholism prospective cohort (N = 1256, mean age [SD] = 19.25 [1.88]), we investigated the associations of closeness with mother and father during adolescence with offspring P3 amplitude, FT power, and binge drinking among high-risk offspring.MethodsSelf-reported closeness with mother and father between ages 12 and 17 and binge drinking were assessed using the Semi-Structured Assessment for the Genetics of Alcoholism. P3 amplitude and FT power were assessed in response to target stimuli using a Visual Oddball Task.ResultsMultivariate multiple regression analyses showed that closeness with father was associated with larger P3 amplitude (p = 0.002) and higher FT power (p = 0.01). Closeness with mother was associated with less binge drinking (p = 0.003). Among male offspring, closeness with father was associated with larger P3 amplitude, but among female offspring, closeness with mother was associated with less binge drinking. These associations remained statistically significant with father's and mothers' AUD symptoms, socioeconomic status, and offspring impulsivity in the model.ConclusionsAmong high-risk offspring, closeness with parents during adolescence may promote resilience for developing AUD and related neurocognitive deficits albeit with important sex differences.

Endometriosis is a leading cause of pain and infertility affecting millions of women globally. Herein, we characterize variation in DNA methylation (DNAm) and its association with menstrual cycle phase, endometriosis, and genetic variants through analysis of genotype data and methylation in endometrial samples from 984 deeply-phenotyped participants. We estimate that 15.4% of the variation in endometriosis is captured by DNAm and identify significant differences in DNAm profiles associated with stage III/IV endometriosis, endometriosis sub-phenotypes and menstrual cycle phase, including opening of the window for embryo implantation. Menstrual cycle phase was a major source of DNAm variation suggesting cellular and hormonally-driven changes across the cycle can regulate genes and pathways responsible for endometrial physiology and function. DNAm quantitative trait locus (mQTL) analysis identified 118,185 independent cis-mQTLs including 51 associated with risk of endometriosis, highlighting candidate genes contributing to disease risk. Our work provides functional evidence for epigenetic targets contributing to endometriosis risk and pathogenesis. Data generated serve as a valuable resource for understanding tissue-specific effects of methylation on endometrial biology in health and disease.

The cellular mechanisms mediating norepinephrine (NE) functions in brain to result in behaviors are unknown. We identified the L-type Ca2+ channel (LTCC) CaV1.2 as a principal target for Gq-coupled α1-adrenergic receptors (ARs). α1AR signaling increased LTCC activity in hippocampal neurons. This regulation required protein kinase C (PKC)-mediated activation of the tyrosine kinases Pyk2 and, downstream, Src. Pyk2 and Src were associated with CaV1.2. In model neuroendocrine PC12 cells, stimulation of PKC induced tyrosine phosphorylation of CaV1.2, a modification abrogated by inhibition of Pyk2 and Src. Upregulation of LTCC activity by α1AR and formation of a signaling complex with PKC, Pyk2, and Src suggests that CaV1.2 is a central conduit for signaling by NE. Indeed, a form of hippocampal long-term potentiation (LTP) in young mice requires both the LTCC and α1AR stimulation. Inhibition of Pyk2 and Src blocked this LTP, indicating that enhancement of CaV1.2 activity via α1AR-Pyk2-Src signaling regulates synaptic strength.

On the 30th anniversary of the Principles of Environmental Justice established at the First National People of Color Environmental Leadership Summit in 1991 (Principles of Environmental Justice), we continue to call for these principles to be more widely adopted. We propose an environmental justice framework for exposure science to be implemented by all researchers. This framework should be the standard and not an afterthought or trend dismissed by those who believe that science should not be politicized. Most notably, this framework should be centered on the community it seeks to serve. Researchers should meet with community members and stakeholders to learn more about the community, involve them in the research process, collectively determine the environmental exposure issues of highest concern for the community, and develop sustainable interventions and implementation strategies to address them. Incorporating community "funds of knowledge" will also inform the study design by incorporating the knowledge about the issue that community members have based on their lived experiences. Institutional and funding agency funds should also be directed to supporting community needs both during the "active" research phase and at the conclusion of the research, such as mechanisms for dissemination, capacity building, and engagement with policymakers. This multidirectional framework for exposure science will increase the sustainability of the research and its impact for long-term success.

Within internet there exists the 90-9-1 principle (also called the 1% rule), which dictates that a vast majority of user-generated content in any specific community comes from the top 1% active users, with most people only listening in. When combined with other demographic biases among social media users, this casts doubt as to how well these users represent the wider world, which might be problematic considering how user-generated content is used in psychological research and in the wider media. We conduct three computational studies using pre-existing datasets from Reddit and Twitter; we examine the accuracy of the 1% rule and what effect this might have on how user-generated content is perceived by performing and comparing sentiment analyses between user groups. Our findings support the accuracy of the 1% rule, and we report a bias in sentiments between low- and high-frequency users. Limitations of our analyses will be discussed.

Reddit’s subforum ChangeMyView is a subreddit where users post about a specific view they hold and challenge other users to present arguments to change their view. Here, we investigated what distinguishes the most convincing participants on Reddit ChangeMyView, as measured by the all-time deltaboard, from equally active users who are nonetheless less likely to persuade people on the forum. We investigated the most common features of top persuaders and compared them to their similarly active Reddit counterparts. We found that top persuaders were more likely to provide external evidence for their claims and use morality-based reasoning, made longer comments and engaged in more back-and-forth argumentation, were less likely to use informal language in their arguments, and were more likely to show some overlapping semantic content with an original poster’s comment. These findings replicate and expand on previously established effects and may highlight ways to develop more effective educational interventions.

The L-type Ca2+ channel CaV1.2 controls gene expression, cardiac contraction, and neuronal activity. Calmodulin (CaM) governs CaV1.2 open probability (Po) and Ca2+-dependent inactivation (CDI) but the mechanisms remain unclear. Here, we present electrophysiological data that identify a half Ca2+-saturated CaM species (Ca2/CaM) with Ca2+ bound solely at the third and fourth EF-hands (EF3 and EF4) under resting Ca2+ concentrations (50-100 nM) that constitutively preassociates with CaV1.2 to promote Po and CDI. We also present an NMR structure of a complex between the CaV1.2 IQ motif (residues 1644-1665) and Ca2/CaM12', a calmodulin mutant in which Ca2+ binding to EF1 and EF2 is completely disabled. We found that the CaM12' N-lobe does not interact with the IQ motif. The CaM12' C-lobe bound two Ca2+ ions and formed close contacts with IQ residues I1654 and Y1657. I1654A and Y1657D mutations impaired CaM binding, CDI, and Po, as did disabling Ca2+ binding to EF3 and EF4 in the CaM34 mutant when compared to WT CaM. Accordingly, a previously unappreciated Ca2/CaM species promotes CaV1.2 Po and CDI, identifying Ca2/CaM as an important mediator of Ca signaling.

The EGS Collab project, supported by the US Department of Energy, is performing intensively monitored rock stimulation and flow tests at the 10-m scale in an underground research laboratory to address challenges in implementing enhanced geothermal systems (EGS). Data and observations from the field tests are compared to simulations to understand processes and build confidence in numerical modeling of the processes. We have completed Experiment 1 (of 3), which examined hydraulic fracturing in a well-characterized underground fractured phyllite test bed at a depth of approximately 1.5 km at the Sanford Underground Research Facility (SURF) in Lead, South Dakota. Testbed characterization included fracture mapping, borehole acoustic and optical televiewers, full waveform sonic, conductivity, resistivity, temperature, campaign p- and s-wave investigations and electrical resistance tomography. Borehole geophysical techniques including passive seismic, continuous active source seismic monitoring, electrical resistance tomography, fiber-based distributed strain, distributed temperature, and distributed acoustic monitoring, were used to carefully monitor stimulation events and flow tests. More than a dozen stimulations and nearly one year of flow tests were performed. Quality data and detailed observations were collected and analyzed during stimulation and water flow tests using ambient temperature and chilled water. We achieved adaptive control of the tests using real-time monitoring and rapid dissemination of data and near-real-time simulation. More detailed numerical simulation was performed to answer key experimental design questions, forecast fracture propagation trajectories and extents, and analyze and evaluate results. Data are freely available from the Geothermal Data Repository. Experiment 2 examines the potential for hydraulic shearing in amphibolite at a depth of about 1.25 km at SURF. This site has a different set of stress and fracture conditions than Experiment 1. The Experiment 2 testbed consists of nine subhorizontal boreholes configured in two fans of two boreholes which surround the testbed and contain grouted-in electrical resistance tomography, seismic sensors, active seismic sources and distributed fiber sensors. A “five-spot” set of test wells that extends from a custom mined alcove includes an injection well and four production/monitoring wells. The testbed was characterized geophysically and hydrologically, and three stimulations have been performed using the Step-Rate Injection Method for Fracture In-Situ Properties (SIMFIP) tool to measure strains, and a new strain quantifying tool (downhole robotic strain analysis tool -DORSA) was deployed in a monitoring hole during stimulation. Real-time data were broadcast during stimulations to allow real-time response to arising issues.

BackgroundIncreased risk of progression from latent tuberculosis infection (LTBI) to tuberculosis (TB) disease among people living with human immunodeficiency virus (HIV; PLWH) prioritizes them for LTBI testing and treatment. Studies comparing the performance of interferon gamma release assays (IGRAs) and the tuberculin skin test (TST) among PLWH are lacking.MethodsWe used Bayesian latent class analysis to estimate the prevalence of LTBI and diagnostic characteristics of the TST, QuantiFERON Gold In-Tube (QFT), and T.SPOT-TB (TSPOT) among a prospective, multicenter cohort of US-born PLWH ≥5 years old with valid results for all 3 LTBI tests using standard US cutoffs (≥5 mm TST, ≥0.35 IU/mL QFT, ≥8 spots TSPOT). We also explored the performance of varying LTBI test cutoffs.ResultsAmong 1510 PLWH (median CD4+ count 532 cells/mm3), estimated LTBI prevalence was 4.7%. TSPOT was significantly more specific (99.7%) and had a significantly higher positive predictive value (90.0%, PPV) than QFT (96.5% specificity, 50.7% PPV) and TST (96.8% specificity, 45.4% PPV). QFT was significantly more sensitive (72.2%) than TST (54.2%) and TSPOT (51.9%); negative predictive value of all tests was high (TST 97.7%, QFT 98.6%, TSPOT 97.6%). Even at the highest cutoffs evaluated (15 mm TST, ≥1.00 IU/mL QFT, ≥8 spots TSPOT), TST and QFT specificity was significantly lower than TSPOT.ConclusionsLTBI prevalence among this cohort of US-born PLWH was low compared to non-US born persons. TSPOT's higher PPV may make it preferable for testing US-born PLWH at low risk for TB exposure and with high CD4+ counts.

BackgroundThe WHO-recommended tuberculosis screening and diagnostic algorithm in ambulatory people living with HIV is a four-symptom screen (known as the WHO-recommended four symptom screen [W4SS]) followed by a WHO-recommended molecular rapid diagnostic test (eg Xpert MTB/RIF [hereafter referred to as Xpert]) if W4SS is positive. To inform updated WHO guidelines, we aimed to assess the diagnostic accuracy of alternative screening tests and strategies for tuberculosis in this population.MethodsIn this systematic review and individual participant data meta-analysis, we updated a search of PubMed (MEDLINE), Embase, the Cochrane Library, and conference abstracts for publications from Jan 1, 2011, to March 12, 2018, done in a previous systematic review to include the period up to Aug 2, 2019. We screened the reference lists of identified pieces and contacted experts in the field. We included prospective cross-sectional, observational studies and randomised trials among adult and adolescent (age ≥10 years) ambulatory people living with HIV, irrespective of signs and symptoms of tuberculosis. We extracted study-level data using a standardised data extraction form, and we requested individual participant data from study authors. We aimed to compare the W4SS with alternative screening tests and strategies and the WHO-recommended algorithm (ie, W4SS followed by Xpert) with Xpert for all in terms of diagnostic accuracy (sensitivity and specificity), overall and in key subgroups (eg, by antiretroviral therapy [ART] status). The reference standard was culture. This study is registered with PROSPERO, CRD42020155895.FindingsWe identified 25 studies, and obtained data from 22 studies (including 15 666 participants; 4347 [27·7%] of 15 663 participants with data were on ART). W4SS sensitivity was 82% (95% CI 72-89) and specificity was 42% (29-57). C-reactive protein (≥10 mg/L) had similar sensitivity to (77% [61-88]), but higher specificity (74% [61-83]; n=3571) than, W4SS. Cough (lasting ≥2 weeks), haemoglobin (

Plasmaspheric hiss waves at the Earth are well known for causing losses of electrons from the radiation belts through wave particle interactions. At Saturn, however, we show that the different plasma density environment leads to acceleration of the electrons rather than loss. The ratio of plasma frequency to electron gyrofrequency frequently falls below one creating conditions for hiss to accelerate electrons. The location of hiss at high latitudes (>25°) coincides very well with this region of very low density. The interaction between electrons and hiss only occurs at these higher latitudes, therefore the acceleration is limited to mid to low pitch angles leading to butterfly pitch angle distributions. The hiss is typically an order of magnitude stronger than chorus at Saturn and the resulting acceleration is rapid, approaching steady state in one day at 0.4 MeV at L = 7 and the effect is stronger with increasing L-shell.

The EGS Collab project is performing well-monitored rock stimulation and flow tests at the 10-m scale in an underground research laboratory to inform challenges in implementing enhanced geothermal systems (EGS). This project, supported by the US Department of Energy, is gathering data and observations from the field tests and comparing these to simulation results to understand processes and to build confidence in numerical modeling of the processes. Experiment 1 (now complete) examined hydraulic fracturing in an underground test bed at the Sanford Underground Research Facility (SURF) in Lead, South Dakota, at a depth of approximately 1.5 km in a well-characterized phyllite. Geophysical monitoring instrumentation in six of eight sub-horizontal boreholes monitored stimulation events and flow tests. The other two boreholes were used to perform and carefully measure water injection and production. More than a dozen stimulations and nearly one year of flow tests in the testbed were performed. Detailed observations of processes occurring during stimulation and dynamic flow tests were collected and analyzed. Flow tests using ambient-temperature and chilled water were performed with intermittent tracer tests to examine system behavior. We achieved adaptive control of the tests using close monitoring of rapidly disseminated data and near-real-time simulation. Numerical simulation was critical in answering key experimental design questions, forecasting fracture behavior, and analyzing results. We were successful in performing many simulations in near-real-time in conjunction with the field experiments, with more detailed simulations performed later. The primary objective of Experiment 2 is to examine hydraulic shearing of natural fractures at a depth of 1.25 km in amphibolite at SURF. The stresses, rock type, and fracture conditions are different than in Experiment 1. The testbed consists of 9 boreholes, in addition to two earlier-drilled characterization boreholes. One borehole is used for injection, two fans of 2 monitoring wells have several geophysical measurement tools grouted in, and four open boreholes surrounding the injection hole are adaptively used for production and monitoring. We have encountered approximately five fracture set orientations in the testbed, and designed our testbed accordingly to maximize the potential for shear stimulation. Three stimulations have been performed to date from the injection borehole, each intersecting at least one production borehole. Different methods have been used for each stimulation, including a ramped flow, a high flow rate, and oscillating pressure.

Do young children have a teleological conception of the essence of natural kinds? We tested this by examining how the preservation or alteration of an animal’s purpose affected children’s persistence judgments (N = 40, ages 4 - 12, Mean Age = 7.04, 61% female). We found that even when surface-level features of an animal (e.g., a bee) were preserved, if the entity’s purpose changed (e.g., the bee now spins webs), children were more likely to categorize the entity as a member of a different natural kind (e.g., a spider) and these effects were similar in magnitude to altering the surface-features of a natural kind. Our results suggest that we might view teleological properties as partially constitutive of the essence of natural kinds.

Sentence comprehension involves simultaneous processes such as maintaining and integrating different types of verbal representations. As such, it has been argued that sentence comprehension relies on working memory (WM). Some findings suggest that semantic (word meaning) WM rather than phonological (speech sound) WM is critical for comprehension. This study took a case-series multiple regression approach to examine the relationship between sentence comprehension and WM for 56 individuals with aphasia. We examined the independent contribution of phonological and semantic WM in predicting comprehension for higher WM target sentences relative to matched lesser WM sentences, while also controlling for single word processing. We found that only semantic WM had a significant contribution to comprehension for three contrasts. However, for the fourth contrast of trials requiring syntactic processing with those requiring only lexical processing, both WM contributions were significant. The possible backup role of phonological WM for comprehension of role reversals is discussed.

People’s expectations play an important role in their reactions to events. There is often disappointment when events fail to meet expectations and a thrill to having one’s expectations exceeded (e.g. Mellers et al., 1997). Here, we examined how expectations influenced people's reactions to events with serious moral consequences, and their moral decisions concerning such situations. Participants judged pairs of events where a victim experienced a similar harm, but where victims were at different prior risk of being harmed (e.g. someone killed by a drunk driver on a Friday night versus a Saturday morning). People found unexpected harms to be more upsetting and they were more likely to choose to prevent an unexpected harm than an expected one. Further studies explored other factors that might have influenced judgments beyond expectations. This bias may have pernicious moral consequences, potentially leading to reduced concern for victims in most need of help.

The EGS Collab project, supported by the US Department of Energy, is addressing challenges in implementing enhanced geothermal systems (EGS). This includes improving understanding of the stimulation of crystalline rock to create appropriate flow pathways, and the ability to effectively simulate both the stimulation and the flow and transport processes in the resulting fracture network. The project is performing intensively monitored rock stimulation and flow tests at the 10-m scale in an underground research laboratory. Data and observations from the field test are compared to simulations to understand processes and to build confidence in numerical modeling of the processes. In Experiment 1, we examined hydraulic fracturing an underground test bed at the Sanford Underground Research Facility (SURF) in Lead, South Dakota, at a depth of approximately 1.5 km. We drilled eight sub-horizontal boreholes in a well-characterized phyllite. Six of the boreholes were instrumented with many sensor types to allow careful monitoring of stimulation events and flow tests, and the other two boreholes were used for water injection and production. We performed a number of stimulations and flow tests in the testbed. Our monitoring systems allowed detailed observations and collection of numerous data sets of processes occurring during stimulation and during dynamic flow tests. Long-term ambient temperature and chilled water flow tests were performed in addition to many tracer tests to examine system behavior. Data were rapidly analyzed, allowing adaptive control of the tests. Numerical simulation was used to answer key experimental design questions, to forecast fracture propagation trajectories and extents, and to analyze and evaluate results. Many simulations were performed in near-real-time in conjunction with the field experiments, with more detailed process study simulations performed on a longer timeframe. Experiment 2 will examine hydraulic shearing in a test bed being built at the SURF at a depth of about 1.25 km in amphibolite under a different set of stress and fracture conditions than Experiment 1. Five sets of fracture orientations were considered in design, and three orientations seem to be consistently observed.

BackgroundIncreased risk of progression from latent tuberculosis infection (LTBI) to tuberculosis (TB) disease among people living with human immunodeficiency virus (HIV; PLWH) prioritizes them for LTBI testing and treatment. Studies comparing the performance of interferon gamma release assays (IGRAs) and the tuberculin skin test (TST) among PLWH are lacking.MethodsWe used Bayesian latent class analysis to estimate the prevalence of LTBI and diagnostic characteristics of the TST, QuantiFERON Gold In-Tube (QFT), and T.SPOT-TB (TSPOT) among a prospective, multicenter cohort of US-born PLWH ≥5 years old with valid results for all 3 LTBI tests using standard US cutoffs (≥5 mm TST, ≥0.35 IU/mL QFT, ≥8 spots TSPOT). We also explored the performance of varying LTBI test cutoffs.ResultsAmong 1510 PLWH (median CD4+ count 532 cells/mm3), estimated LTBI prevalence was 4.7%. TSPOT was significantly more specific (99.7%) and had a significantly higher positive predictive value (90.0%, PPV) than QFT (96.5% specificity, 50.7% PPV) and TST (96.8% specificity, 45.4% PPV). QFT was significantly more sensitive (72.2%) than TST (54.2%) and TSPOT (51.9%); negative predictive value of all tests was high (TST 97.7%, QFT 98.6%, TSPOT 97.6%). Even at the highest cutoffs evaluated (15 mm TST, ≥1.00 IU/mL QFT, ≥8 spots TSPOT), TST and QFT specificity was significantly lower than TSPOT.ConclusionsLTBI prevalence among this cohort of US-born PLWH was low compared to non-US born persons. TSPOT's higher PPV may make it preferable for testing US-born PLWH at low risk for TB exposure and with high CD4+ counts.

Cutaneous T cell lymphomas (CTCLs) are a heterogeneous group of debilitating, incurable malignancies. Mycosis fungoides (MF) and Sézary syndrome (SS) are the most common subtypes, accounting for ~65% of CTCL cases. Patients with advanced disease have a poor prognosis and low median survival rates of four years. CTCLs develop from malignant skin-homing CD4+ T cells that spread to lymph nodes, blood, bone marrow and viscera in advanced stages. Current treatments options for refractory or advanced CTCL, including chemotherapeutic and biological approaches, rarely lead to durable responses. The exact molecular mechanisms of CTCL pathology remain unclear despite numerous genomic and gene expression profile studies. However, apoptosis resistance is thought to play a major role in the accumulation of malignant T cells. Here we show that NT1721, a synthetic epidithiodiketopiperazine based on a natural product, reduced cell viability at nanomolar concentrations in CTCL cell lines, while largely sparing normal CD4+ cells. Treatment of CTCL cells with NT1721 reduced proliferation and potently induced apoptosis. NT1721 mediated the downregulation of GLI1 transcription factor, which was associated with decreased STAT3 activation and the reduced expression of downstream antiapoptotic proteins (BCL2 and BCL-xL). Importantly, NT1721, which is orally available, reduced tumor growth in two CTCL mouse models significantly better than two clinically used drugs (romidepsin, gemcitabine). Moreover, a combination of NT1721 with gemcitabine reduced the tumor growth significantly better than the single drugs. Taken together, these results suggest that NT1721 may be a promising new agent for the treatment of CTCLs.

The final version of the above article was posted prematurely on 16 July 2021, owing to a technical error. The final, corrected version of record will be made fully available at a later date.

The final version of the above article was posted prematurely on 16 July 2021, owing to a technical error. The final, corrected version of record will be made fully available at a later date.

A liquid scintillator consisting of linear alkylbenzene as the solvent and 2,5-diphenyloxazole as the fluor was developed for the SNO+ experiment. This mixture was chosen as it is compatible with acrylic and has a competitive light yield to pre-existing liquid scintillators while conferring other advantages including longer attenuation lengths, superior safety characteristics, chemical simplicity, ease of handling, and logistical availability. Its properties have been extensively characterized and are presented here. This liquid scintillator is now used in several neutrino physics experiments in addition to SNO+.

A liquid scintillator consisting of linear alkylbenzene as the solvent and 2,5-diphenyloxazole as the fluor was developed for the SNO+ experiment. This mixture was chosen as it is compatible with acrylic and has a competitive light yield to pre-existing liquid scintillators while conferring other advantages including longer attenuation lengths, superior safety characteristics, chemical simplicity, ease of handling, and logistical availability. Its properties have been extensively characterized and are presented here. This liquid scintillator is now used in several neutrino physics experiments in addition to SNO+.

ObjectivesSeptic cardiomyopathy develops frequently in patients with sepsis and likely increases short-term mortality. However, whether septic cardiomyopathy is associated with long-term outcomes after sepsis is unknown. We investigated whether septic patients with septic cardiomyopathy have worse long-term outcomes than septic patients without septic cardiomyopathy.DesignRetrospective cohort study.SettingAdult ICU.PatientsAdult ICU patients with sepsis.InterventionsNone.Measurements and main resultsLeft ventricular global longitudinal systolic strain was our primary measure of septic cardiomyopathy. We employed a suite of multivariable survival analyses to explore linear and nonlinear associations between left ventricular global longitudinal systolic strain and major adverse cardiovascular events, which included death, stroke, and myocardial infarction. Our primary outcome was major adverse cardiovascular event through 24 months after ICU discharge. Among 290 study patients, median left ventricular global longitudinal systolic strain was -16.8% (interquartile range, -20.4% to -12.6%), and 38.3% of patients (n = 111) experienced a major adverse cardiovascular event within 24 months after discharge. On our primary, linear analysis, there was a trend (p = 0.08) toward association between left ventricular global longitudinal systolic strain and major adverse cardiovascular event (odds ratio, 1.03; CI, < 1 to 1.07). On our nonlinear analysis, the association was highly significant (p < 0.001) with both high and low left ventricular global longitudinal systolic strain associated with major adverse cardiovascular event among patients with pre-existing cardiac disease. This association was pronounced among patients who were younger (age < 65 yr) and had Charlson Comorbidity Index greater than 5.ConclusionsAmong patients with sepsis and pre-existing cardiac disease who survived to ICU discharge, left ventricular global longitudinal systolic strain demonstrated a U-shaped association with cardiovascular outcomes through 24 months. The relationship was especially strong among younger patients with more comorbidities. These observations are likely of use to design of future trials.

In this contribution, we achieve the primary goal of the active galactic nucleus (AGN) STORM campaign by recovering velocity-delay maps for the prominent broad emission lines (Lyα, C iv, He ii, and Hβ) in the spectrum of NGC 5548. These are the most detailed velocity-delay maps ever obtained for an AGN, providing unprecedented information on the geometry, ionization structure, and kinematics of the broad-line region. Virial envelopes enclosing the emission-line responses show that the reverberating gas is bound to the black hole. A stratified ionization structure is evident. The He ii response inside 5-10 lt-day has a broad single-peaked velocity profile. The Lyα, C iv, and Hβ responses extend from inside 2 to outside 20 lt-day, with double peaks at ±2500 km s-1 in the 10-20 lt-day delay range. An incomplete ellipse in the velocity-delay plane is evident in Hβ. We interpret the maps in terms of a Keplerian disk with a well-defined outer rim at R = 20 lt-day. The far-side response is weaker than that from the near side. The line-center delay days gives the inclination i ≈ 45°. The inferred black hole mass is M BH ≈ 7 × 107 M o˙. In addition to reverberations, the fit residuals confirm that emission-line fluxes are depressed during the "BLR Holiday"identified in previous work. Moreover, a helical "Barber-Pole"pattern, with stripes moving from red to blue across the C iv and Lyα line profiles, suggests azimuthal structure rotating with a 2 yr period that may represent precession or orbital motion of inner-disk structures casting shadows on the emission-line region farther out.

In this contribution, we achieve the primary goal of the active galactic nucleus (AGN) STORM campaign by recovering velocity-delay maps for the prominent broad emission lines (Lyα, C iv, He ii, and Hβ) in the spectrum of NGC 5548. These are the most detailed velocity-delay maps ever obtained for an AGN, providing unprecedented information on the geometry, ionization structure, and kinematics of the broad-line region. Virial envelopes enclosing the emission-line responses show that the reverberating gas is bound to the black hole. A stratified ionization structure is evident. The He ii response inside 5-10 lt-day has a broad single-peaked velocity profile. The Lyα, C iv, and Hβ responses extend from inside 2 to outside 20 lt-day, with double peaks at ±2500 km s-1 in the 10-20 lt-day delay range. An incomplete ellipse in the velocity-delay plane is evident in Hβ. We interpret the maps in terms of a Keplerian disk with a well-defined outer rim at R = 20 lt-day. The far-side response is weaker than that from the near side. The line-center delay days gives the inclination i ≈ 45°. The inferred black hole mass is M BH ≈ 7 × 107 M o˙. In addition to reverberations, the fit residuals confirm that emission-line fluxes are depressed during the "BLR Holiday"identified in previous work. Moreover, a helical "Barber-Pole"pattern, with stripes moving from red to blue across the C iv and Lyα line profiles, suggests azimuthal structure rotating with a 2 yr period that may represent precession or orbital motion of inner-disk structures casting shadows on the emission-line region farther out.

Endometriosis may exert a profound negative influence on the lives of individuals with the disorder, adversely affecting quality of life, participation in daily and social activities, physical and sexual functioning, relationships, educational and work productivity, mental health, and well-being. Over the course of a lifetime, these daily challenges may translate into limitations in achieving life goals such as pursuing or completing educational opportunities; making career choices or advancing in a chosen career; forming stable, fulfilling relationships; or starting a family, all of which ultimately alter one's life trajectory. The potential for endometriosis to impact the life course is considerable, as symptom onset generally occurs at a time of life (menarche through menopause, adolescence through middle age) when multiple life-changing and trajectory-defining decisions are made. Using a life-course approach, we examine how the known effects of endometriosis on life-domain satisfaction may impact health and well-being across the life course of affected individuals. We provide a quasi-systematic, narrative review of the literature as well as expert opinion on recommendations for clinical management and future research directions.

There is an omission in the Institutional Review Board Statement and Conflict of Interest statements of the paper [...].

Cutaneous T cell lymphomas (CTCLs) are a heterogeneous group of debilitating, incurable malignancies. Mycosis fungoides (MF) and Sézary syndrome (SS) are the most common subtypes, accounting for ~65% of CTCL cases. Patients with advanced disease have a poor prognosis and low median survival rates of four years. CTCLs develop from malignant skin-homing CD4+ T cells that spread to lymph nodes, blood, bone marrow and viscera in advanced stages. Current treatments options for refractory or advanced CTCL, including chemotherapeutic and biological approaches, rarely lead to durable responses. The exact molecular mechanisms of CTCL pathology remain unclear despite numerous genomic and gene expression profile studies. However, apoptosis resistance is thought to play a major role in the accumulation of malignant T cells. Here we show that NT1721, a synthetic epidithiodiketopiperazine based on a natural product, reduced cell viability at nanomolar concentrations in CTCL cell lines, while largely sparing normal CD4+ cells. Treatment of CTCL cells with NT1721 reduced proliferation and potently induced apoptosis. NT1721 mediated the downregulation of GLI1 transcription factor, which was associated with decreased STAT3 activation and the reduced expression of downstream antiapoptotic proteins (BCL2 and BCL-xL). Importantly, NT1721, which is orally available, reduced tumor growth in two CTCL mouse models significantly better than two clinically used drugs (romidepsin, gemcitabine). Moreover, a combination of NT1721 with gemcitabine reduced the tumor growth significantly better than the single drugs. Taken together, these results suggest that NT1721 may be a promising new agent for the treatment of CTCLs.

Ca2+ influx through the L-type Ca2+ channel Cav1.2 triggers each heartbeat. The fight-or-flight response induces the release of the stress response hormone norepinephrine to stimulate β-adrenergic receptors, cAMP production, and protein kinase A activity to augment Ca2+ influx through Cav1.2 and, consequently, cardiomyocyte contractility. Emerging evidence shows that Cav1.2 is regulated by different mechanisms in cardiomyocytes compared to neurons and vascular smooth muscle cells.

Enhanced Geothermal Systems could provide a substantial contribution to the global energy demand if their implementation could overcome inherent challenges. Examples are insufficient created permeability, early thermal breakthrough, and unacceptable induced seismicity. Here we report on the seismic response of a mesoscale hydraulic fracturing experiment performed at 1.5-km depth at the Sanford Underground Research Facility. We have measured the seismic activity by utilizing a 100-kHz, continuous seismic monitoring system deployed in six 60-m length monitoring boreholes surrounding the experimental domain in 3-D. The achieved location uncertainty was on the order of 1 m and limited by the signal-to-noise ratio of detected events. These uncertainties were corroborated by detections of fracture intersections at the monitoring boreholes. Three intervals of the dedicated injection borehole were hydraulically stimulated by water injection at pressures up to 33 MPa and flow rates up to 5 L/min. We located 1,933 seismic events during several injection periods. The recorded seismicity delineates a complex fracture network comprised of multistrand hydraulic fractures and shear-reactivated, preexisting planes of weakness that grew unilaterally from the point of initiation. We find that heterogeneity of stress dictates the seismic outcome of hydraulic stimulations, even when relying on theoretically well-behaved hydraulic fractures. Once hydraulic fractures intersected boreholes, the boreholes acted as a pressure relief and fracture propagation ceased. In order to create an efficient subsurface heat exchanger, production boreholes should not be drilled before the end of hydraulic stimulations.

Acute bacterial endocarditis is a rapid, difficult to manage, and frequently lethal disease. Potent antibiotics often cannot efficiently kill Staphylococcus aureus that colonizes the hearts valves. S. aureus relies on virulence factors to evade therapeutics and the hosts immune response, usurping the hosts clotting system by activating circulating prothrombin with staphylocoagulase and von Willebrand factor-binding protein. An insoluble fibrin barrier then forms around the bacterial colony, shielding the pathogen from immune cell clearance. Targeting virulence factors may provide previously unidentified avenues to better diagnose and treat endocarditis. To tap into this unused therapeutic opportunity, we codeveloped therapeutics and multimodal molecular imaging to probe the host-pathogen interface. We introduced and validated a family of small-molecule optical and positron emission tomography (PET) reporters targeting active thrombin in the fibrin-rich environment of bacterial colonies. The imaging agents, based on the clinical thrombin inhibitor dabigatran, are bound to heart valve vegetations in mice. Using optical imaging, we monitored therapy with antibodies neutralizing staphylocoagulase and von Willebrand factor-binding protein in mice with S. aureus endocarditis. This treatment deactivated bacterial defenses against innate immune cells, decreased in vivo imaging signal, and improved survival. Aortic or tricuspid S. aureus endocarditis in piglets was also successfully imaged with clinical PET/magnetic resonance imaging. Our data map a route toward adjuvant immunotherapy for endocarditis and provide efficient tools to monitor this drug class for infectious diseases.

We investigate the influence of foliation orientation and fine-scale folding on the static and dynamic elastic properties and unconfined strength of the Poorman schist. Measurements from triaxial and uniaxial laboratory experiments reveal a significant amount of variability in the static and dynamic Young’s modulus depending on the sample orientation relative to the foliation plane. Dynamic P-wave modulus and S-wave modulus are stiffer in the direction parallel to the foliation plane as expected for transversely isotropic mediums with average Thomsen parameters values 0.133 and 0.119 for epsilon and gamma, respectively. Static Young’s modulus varies significantly between 21 and 117 GPa, and a peculiar trend is observed where some foliated sample groups show an anomalous decrease in the static Young’s modulus when the symmetry axis (x3-axis) is oriented obliquely to the direction of loading. Utilizing stress and strain relationships for transversely isotropic medium, we derive the analytical expression for Young’s modulus as a function of the elastic moduli E1, E3, ν31, and G13 and sample orientation to fit the static Young’s modulus measurements. Regression of the equation to the Young’s modulus data reveals that the decrease in static Young’s modulus at oblique symmetry axis orientations is directly influenced by a low shear modulus, G13, which we attribute to shear sliding along foliation planes during static deformation that occurs as soon as the foliation is subject to shear stress. We argue that such difference between dynamic and static anisotropy is a characteristic of near-zero porosity anisotropic rocks. The uniaxial compressive strength also shows significant variability ranging from 21.9 to 194.6 MPa across the five sample locations and is the lowest when the symmetry axis is oriented 45° or 60° from the direction of loading, also a result of shear sliding along foliation planes during static deformation.

We present geometric and dynamical modeling of the broad line region (BLR) for the multi-wavelength reverberation mapping campaign focused on NGC 5548 in 2014. The data set includes photometric and spectroscopic monitoring in the optical and ultraviolet, covering the Hβ, C iv, and Ly broad emission lines. We find an extended disk-like Hβ BLR with a mixture of near-circular and outflowing gas trajectories, while the C iv and Ly BLRs are much less extended and resemble shell-like structures. There is clear radial structure in the BLR, with C iv and Ly emission arising at smaller radii than the Hβ emission. Using the three lines, we make three independent black hole mass measurements, all of which are consistent. Combining these results gives a joint inference of . We examine the effect of using the V band instead of the UV continuum light curve on the results and find a size difference that is consistent with the measured UV-optical time lag, but the other structural and kinematic parameters remain unchanged, suggesting that the V band is a suitable proxy for the ionizing continuum when exploring the BLR structure and kinematics. Finally, we compare the Hβ results to similar models of data obtained in 2008 when the active galactic nucleus was at a lower luminosity state. We find that the size of the emitting region increased during this time period, but the geometry and black hole mass remained unchanged, which confirms that the BLR kinematics suitably gauge the gravitational field of the central black hole.

We present geometric and dynamical modeling of the broad line region (BLR) for the multi-wavelength reverberation mapping campaign focused on NGC 5548 in 2014. The data set includes photometric and spectroscopic monitoring in the optical and ultraviolet, covering the Hβ, C iv, and Ly broad emission lines. We find an extended disk-like Hβ BLR with a mixture of near-circular and outflowing gas trajectories, while the C iv and Ly BLRs are much less extended and resemble shell-like structures. There is clear radial structure in the BLR, with C iv and Ly emission arising at smaller radii than the Hβ emission. Using the three lines, we make three independent black hole mass measurements, all of which are consistent. Combining these results gives a joint inference of . We examine the effect of using the V band instead of the UV continuum light curve on the results and find a size difference that is consistent with the measured UV-optical time lag, but the other structural and kinematic parameters remain unchanged, suggesting that the V band is a suitable proxy for the ionizing continuum when exploring the BLR structure and kinematics. Finally, we compare the Hβ results to similar models of data obtained in 2008 when the active galactic nucleus was at a lower luminosity state. We find that the size of the emitting region increased during this time period, but the geometry and black hole mass remained unchanged, which confirms that the BLR kinematics suitably gauge the gravitational field of the central black hole.