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A large body of evidence connects access to greenspace with substantial benefits to physical and mental health. In urban settings where access to greenspace can be limited, park access and use have been associated with higher levels of physical activity, improved physical health, and lower levels of markers of mental distress. Despite the potential health benefits of urban parks, little is known about how park usage varies across locations (between or within cities) or over time.

Stress response pathways detect and alleviate adverse conditions to safeguard cell and tissue homeostasis, yet their prolonged activation induces apoptosis and disrupts organismal health1–3. How stress responses are turned off at the right time and place remains poorly understood. Here we report a ubiquitin-dependent mechanism that silences the cellular response to mitochondrial protein import stress. Crucial to this process is the silencing factor of the integrated stress response (SIFI), a large E3 ligase complex mutated in ataxia and in early-onset dementia that degrades both unimported mitochondrial precursors and stress response components. By recognizing bifunctional substrate motifs that equally encode protein localization and stability, the SIFI complex turns off a general stress response after a specific stress event has been resolved. Pharmacological stress response silencing sustains cell survival even if stress resolution failed, which underscores the importance of signal termination and provides a roadmap for treating neurodegenerative diseases caused by mitochondrial import defects.

Traditionally, critically ill patients requiring prolonged mechanical ventilation benefit from a long-term airway, thus necessitating tracheostomy. The widespread application of extracorporeal membrane oxygenation (ECMO) has exponentially increased in recent years, creating a new subset of patients necessitating tracheostomy with significantly increased bleeding risk. We present a hybrid dilational tracheostomy technique utilizing a Rummel tourniquet developed at our institution to mitigate bleeding risk in patients on ECMO necessitating long-term airway.

Background: Huntingtin (htt) protein is an essential regulator of nervous system function through its various neuroprotective and pro-survival functions, and loss of wild-type htt function is implicated in the etiology of Huntington’s disease. While its pathological role is typically understood as a toxic gain-of-function, some neuronal phenotypes also result from htt loss. Therefore, it is important to understand possible roles for htt in other physiological circumstances.Objective: To elucidate the role of htt in the context of ethanol exposure, we investigated how loss of htt impacts behavioral and physiological responses to ethanol in Drosophila.Methods: We tested flies lacking htt for ethanol sensitivity and tolerance, preference for ethanol using capillary feeder assays, and recovery of mobility after intoxication. Levels of dopamine neurotransmitter and numbers of dopaminergic cells in brains lacking dhttwere also measured.Results: We found that dhtt-null flies are both less sensitive and more tolerant to ethanol exposure in adulthood. Moreover, flies lacking dhttare more averse to alcohol than controls, and they recover mobility faster following acute ethanol intoxication. We showed that dhttmediates these effects at least in part through the dopaminergic system, as dhttis required to maintain normal levels of dopamine in the brain and normal numbers of dopaminergic cells in the adult protocerebrum.Conclusions: Our results demonstrate that htt regulates the physiological response to ethanol and indicate a novel neuroprotective role for htt in the dopaminergic system, raising the possibility that it may be involved more generally in the response to toxic stimuli.

Huntingtin (htt) protein is an essential regulator of nervous system function through its various neuroprotective and pro-survival functions, and loss of wild-type htt function is implicated in the etiology of Huntington’s disease. While its pathological role is typically understood as a toxic gain-of-function, some neuronal phenotypes also result from htt loss. Therefore, it is important to understand possible roles for htt in other physiological circumstances. To elucidate the role of htt in the context of ethanol exposure, we investigated how loss of htt impacts behavioral and physiological responses to ethanol in Drosophila. We tested flies lacking htt for ethanol sensitivity and tolerance, preference for ethanol using capillary feeder assays, and recovery of mobility after intoxication. Levels of dopamine neurotransmitter and numbers of dopaminergic cells in brains lacking dhttwere also measured. We found that dhtt-null flies are both less sensitive and more tolerant to ethanol exposure in adulthood. Moreover, flies lacking dhttare more averse to alcohol than controls, and they recover mobility faster following acute ethanol intoxication. We showed that dhttmediates these effects at least in part through the dopaminergic system, as dhttis required to maintain normal levels of dopamine in the brain and normal numbers of dopaminergic cells in the adult protocerebrum. Our results demonstrate that htt regulates the physiological response to ethanol and indicate a novel neuroprotective role for htt in the dopaminergic system, raising the possibility that it may be involved more generally in the response to toxic stimuli.

Abstract:Scholars from a wide range of disciplines, including communication and rhetoric, have argued that infectious disease has been increasingly securitized in the post-9/11 environment. This essay tracks the rhetoric of seven U.S. pandemic plans from 1978 to 2017 to investigate how the evolving language of these plans supports or undermines the infectious disease securitization thesis. Our analysis reveals stark differences in the arrangement, delivery, and style of U.S. pandemic plans, despite a consistent focus on antigenic shifts of influenza A, vaccines, and medical research and development. Although U.S. pandemic plans reflect connections to security since their earliest inception, they have adopted more explicit linkages to national and global health security since 2005. This move reflects the emergence of the global health security paradigm and raises questions about pandemic planning implementation.

The Republic of South Africa has the highest documented fetal alcohol syndrome prevalence globally. In the Limpopo province, little is known about students’ or community members’ knowledge of fetal alcohol syndrome or fetal alcohol spectrum disorder rates and risk behaviors. The aim of this study was to characterize and compare knowledge about fetal alcohol syndrome and other fetal alcohol spectrum disorders and the related behaviors such as drinking among University of Venda students and local community residents in villages to inform educational efforts to prevent fetal alcohol syndrome. Participants (n=404) were from the University of Venda and two villages, Maungani and Ha-Mangilasi, and completed an epidemiological survey about their characteristics, behaviors, and fetal alcohol spectrum disorder risks. We analyzed differences between the university students and community residents in fetal alcohol syndrome knowledge and the related risk behaviors. University students have heard of fetal alcohol syndrome (Fisher’s exact test p< .001), have seen warning labels about drinking during pregnancy (Fisher’s exact test p= .003), and were aware that a baby is born with birth defects if diagnosed with fetal alcohol syndrome (Fisher’s exact test p= .03) with more knowledge of fetal alcohol syndrome compared to community residents. Most respondents thought it was unacceptable to drink during pregnancy. Despite this, a substantial number of participants thought it was acceptable to have one drink after pregnancy recognition. There was little knowledge of best practices about alcohol consumption to prepare for pregnancy, or once recognized. We recommend an education campaign to raise awareness of fetal alcohol spectrum disorders across Limpopo, especially in smaller villages, and further research to determine demographic and experiential risk factors to aid in prevention efforts.

Cystic fibrosis (CF) airways feature high extracellular levels of the IL‐1 family of proinflammatory mediators. These mediators are cleavage products of caspase‐1, the final protease in the inflammasome cascade. Due to the proven chronic presence of reprogrammed neutrophils in the CF airway lumen, understanding inflammasome signaling in these cells is of great importance to understand how disease is perpetuated in this milieu. Here, we hypothesized that CF airway neutrophils contribute to chronic inflammation, in part, via the packaging of inflammasome‐inducing signals in extracellular vesicles (EVs). We confirmed that CF airway fluid is enriched in IL‐1α, IL‐1β, and IL‐18, and that CF airway neutrophils up‐regulate the activating receptor IL‐1R1. Meanwhile, down‐modulatory signals such as IL‐1R2 and IL‐1RA are unchanged. Active caspase‐1 itself is present in CF airway fluid EVs, with neutrophil‐derived EVs being most enriched. Using a transmigration model of CF airway inflammation, we show that CF airway fluid EVs are necessary and sufficient to induce primary granule exocytosis by naïve neutrophils (hallmark of reprogramming) and concomitantly activate caspase‐1 and IL‐1β production by these cells and that the addition of triple‐combination highly effective CFTR modulator therapy does not abrogate these effects. Finally, EVs from activated neutrophils can deliver active caspase‐1 to primary tracheal epithelial cells and induce their release of IL‐1α. These findings support the existence of a feed‐forward inflammatory process by which reprogrammed CF airway neutrophils bypass 2‐step control of inflammasome activation in neighboring cells (naïve neutrophils and epithelial cells) via the transfer of bioactive EVs. Blood neutrophils are reprogrammed upon entry into cystic fibrosis airways, releasing extracellular vesicles that can readily activate inflammasome signaling in naïve neutrophils and epithelial cells.

Biological sex, being female or male, broadly influences diverse immune phenotypes, including immune responses to diseases at mucosal surfaces. Sex hormones, sex chromosomes, sexual dimorphism, and gender differences all contribute to how an organism will respond to diseases of the urinary tract, such as bladder infection or cancer. Although the incidence of urinary tract infection is strongly sex biased, rates of infection change over a lifetime in women and men, suggesting that accompanying changes in the levels of sex hormones may play a role in the response to infection. Bladder cancer is also sex biased in that 75% of newly diagnosed patients are men. Bladder cancer development is shaped by contributions from both sex hormones and sex chromosomes, demonstrating that the influence of sex on disease can be complex. With a better understanding of how sex influences disease and immunity, we can envision sex-specific therapies to better treat diseases of the urinary tract and potentially diseases of other mucosal tissues.

Biological sex, being female or male, broadly influences diverse immune phenotypes, including immune responses to diseases at mucosal surfaces. Sex hormones, sex chromosomes, sexual dimorphism, and gender differences all contribute to how an organism will respond to diseases of the urinary tract, such as bladder infection or cancer. Although the incidence of urinary tract infection is strongly sex biased, rates of infection change over a lifetime in women and men, suggesting that accompanying changes in the levels of sex hormones may play a role in the response to infection. Bladder cancer is also sex biased in that 75% of newly diagnosed patients are men. Bladder cancer development is shaped by contributions from both sex hormones and sex chromosomes, demonstrating that the influence of sex on disease can be complex. With a better understanding of how sex influences disease and immunity, we can envision sex-specific therapies to better treat diseases of the urinary tract and potentially diseases of other mucosal tissues.

Jupiter’s atmosphere is one of the most turbulent places in the solar system. Whereas observations of lightning and thunderstorms point to moist convection as a small-scale energy source for Jupiter’s large-scale vortices and zonal jets, this has never been demonstrated due to the coarse resolution of pre-Juno measurements. The Juno spacecraft discovered that Jovian high latitudes host a cluster of large cyclones with diameter of around 5,000 km, each associated with intermediate- (roughly between 500 and 1,600 km) and smaller-scale vortices and filaments of around 100 km. Here, we analyse infrared images from Juno with a high resolution of 10 km. We unveil a dynamical regime associated with a significant energy source of convective origin that peaks at 100 km scales and in which energy gets subsequently transferred upscale to the large circumpolar and polar cyclones. Although this energy route has never been observed on another planet, it is surprisingly consistent with idealized studies of rapidly rotating Rayleigh–Bénard convection, lending theoretical support to our analyses. This energy route is expected to enhance the heat transfer from Jupiter’s hot interior to its troposphere and may also be relevant to the Earth’s atmosphere, helping us better understand the dynamics of our own planet.

The increasing rate of resistance of bacterial infection against antibiotics requires next generation approaches to fight potential pandemic spread. The development of vaccines against pathogenic bacteria has been difficult owing, in part, to the genetic diversity of bacteria. Hence, there are many potential target antigens and little a prioriknowledge of which antigen/s will elicit protective immunity. The painstaking process of selecting appropriate antigens could be avoided with whole-cell bacteria; however, whole-cell formulations typically fail to produce long-term and durable immune responses. These complications are one reason why no vaccine against any type of pathogenic E. colihas been successfully clinically translated. As a proof of principle, we demonstrate a method to enhance the immunogenicity of a model pathogenic E. colistrain by forming a slow releasing depot. The E. colistrain CFT073 was biomimetically mineralized within a metal–organic framework (MOF). This process encapsulates the bacteria within 30 min in water and at ambient temperatures. Vaccination with this formulation substantially enhances antibody production and results in significantly enhanced survival in a mouse model of bacteremia compared to standard inactivated formulations.

ABSTRACTObesity is a chronic, relapsing metabolic disease, linked to a number of health risks and serious complications. Although highly prevalent in adults in the United States, it is underdiagnosed and untreated. Primary care providers (PCPs) are uniquely poised to diagnose and treat patients with obesity, using a selection of treatment strategies including lifestyle modifications and pharmacotherapies. As a physiological regulator of appetite and energy intake, the glucagon-like peptide-1 receptor agonist (GLP-1 RA) liraglutide 3.0 mg is approved for chronic weight management in individuals with overweight (pre-obesity) or obesity. In this review, we provide an overview of the clinical data supporting the use of liraglutide 3.0 mg, as well as practical advice for PCPs on the initiation and maintenance of treatment over the long term. This also covers the management of side effects and how to manage patient expectations over time.

PositiveLinks (PL) is a multi-feature smartphone-based platform to improve engagement-in-care and viral suppression (VS) among clinic patients living with HIV. Features include medication reminders, mood/stress check-ins, a community board, and secure provider messaging. Our goal was to examine how PL users interact with the app and determine whether usage patterns correlate with clinical outcomes. Patients (N = 83) at a university-based Ryan White clinic enrolled in PL from June 2016 to March 2017 and were followed for up to 12 months. A subset (N = 49) completed interviews after 3 weeks of enrollment to explore their experiences with and opinions of PL. We differentiated PL members based on 6-month usage of app features using latent class analysis. We explored characteristics associated with class membership, compared reported needs and preferences by class, and examined association between class and VS. The sample of 83 PL members fell into four classes. "Maximizers" used all app features frequently (27%); "Check-in Users" tended to interact only with daily queries (22%); "Moderate All-Feature Users" used all features occasionally (33%); and "As-Needed Communicators" interacted with the app minimally (19%). VS improved or remained high among all classes after 6 months. VS remained high at 12 months among Maximizers (baseline and 12-month VS: 100%, 94%), Check-in Users (82%, 100%), and Moderate All-Feature Users (73%, 94%) but not among As-Needed Communicators (69%, 60%). This mixed-methods study identified four classes based on PL usage patterns that were distinct in characteristics and clinical outcomes. Identifying and characterizing mHealth user classes offers opportunities to tailor interventions appropriately based on patient needs and preferences as well as to provide targeted alternative support to achieve clinical goals.

After one year, the gains will be considered long-term capital gains outside of an IRA and taxed accordingly, whereas the gains inside an IRA will eventually be taxed as regular income. The article seems anchored in the notion that all states do equally well in using the dollars they spend, so a retiree should choose a state based solely on tax amount. Conversely, many people would find a low-tax state an unfriendly place to live, despite the low taxes, if they desire more and better services from government. [Extracted from the article]

Bladder cancer is the fourth most common cancer for men. However, women are often diagnosed with later stage disease and have poorer outcomes. Whether immune-based sex differences contribute to this discrepancy is unclear. In addition, models to investigate tumor-specific immunity in bladder cancer, in the context of tumor development or response to therapy, are lacking. To address this specific unmet need, we incorporated a commonly used model antigen, ovalbumin, into two well-established models of bladder cancer; the orthotopic MB49 cell line model and the carcinogenic BBN bladder cancer model. We tested the utility of these models to investigate tumor-specific immunity in the context of immunotherapy in both sexes. We found that BCG vaccination, prior to weekly BCG instillation does not impart an immune-specific benefit to tumor-bearing mice in the context of multiple BCG instillations. Furthermore, tumors developed in the testes in male mice, precluding the use of the MB49 model to directly investigate sex-based immune differences. In the BBN model, we observed that more tumor antigen-specific CD8+T cells infiltrated male bladders compared to female bladders in the context of BCG immunotherapy whereas regulatory T cells had higher levels of the exhaustion marker PD-1 in female mice. We propose our modified BBN model will contribute to our understanding of how tumor-specific immunity arises in bladder cancer. Additionally, the BBN bladder cancer model may help to uncover sex differences in tumor-specific immunity, which would provide valuable information for the development of new treatments or combination therapies for bladder cancer in women and men.

Urothelial carcinoma of the bladder (UCB) exhibits significant sexual dimorphism in the incidence, etiology, and response to intravesical immunotherapy. Environmental factors such as tobacco use and clinical management issues such as delayed presentation have widely been associated with sex differences in UCB outcomes. Emerging findings from immune checkpoint blockade trials are suggestive of differential outcomes in females compared with males. Sex-specific differences in the way immune system functions and responds to pathogenic insults are well established. As such, an in-depth understanding of the genetic and epigenetic factors contributing to sex-associated differences in response to immunomodulatory therapies is needed urgently for improved management of UCB.

Individuals with recurrent low back pain (LBP) who typically exhibit poor strength and endurance in lumbar paraspinal musculature may experience exercise-related balance deficits. Fifteen participants with a history of recurrent LBP and 15 healthy controls participated (N = 30). Center of pressure (COP) excursions during bilateral and unilateral eyes-closed stance and in response to a perturbation were recorded before and after a standardized treadmill walking exercise protocol. Participants experienced significantly deteriorated postural control after aerobic exercise during single limb and bilateral stances, but there were no differences between groups. During trials with perturbation, individuals with recurrent LBP experienced a significant change in the variability of anteroposterior (AP) COP excursions following aerobic exercise, whereas the control group did not. These changes observed in individuals with recurrent LBP may be indicative of poor trunk control in this population.

Lightning flashes have been observed by a number of missions that visited or flew by Jupiter over the past several decades. Imagery led to a flash rate estimate of about 4 × 10−3flashes per square kilometre per year (refs. 1,2). The spatial extent of Voyager flashes was estimated to be about 30 kilometres (half-width at half-maximum intensity, HWHM), but the camera was unlikely to have detected the dim outer edges of the flashes, given its weak response to the brightest spectral line of Jovian lightning emission, the 656.3-nanometre Hα line of atomic hydrogen1,3–6. The spatial resolution of some cameras allowed investigators to confirm 22 flashes with HWHM greater than 42 kilometres, and to estimate one with an HWHM of 37 to 45 kilometres (refs. 1,7–9). These flashes, with optical energies comparable to terrestrial ‘superbolts’—of (0.02–1.6) × 1010joules—have been interpreted as tracers of moist convection originating near the 5-bar level of Jupiter’s atmosphere (assuming photon scattering from points beneath the clouds)1–3,7,8,10–12. Previous observations of lightning have been limited by camera sensitivity, distance from Jupiter and long exposures (about 680 milliseconds to 85 seconds), meaning that some measurements were probably superimposed flashes reported as one1,2,7,9,10,13. Here we report optical observations of lightning flashes by the Juno spacecraft with energies of approximately 105–108joules, flash durations as short as 5.4 milliseconds and inter-flash separations of tens of milliseconds, with typical terrestrial energies. The flash rate is about 6.1 × 10−2flashes per square kilometre per year, more than an order of magnitude greater than hitherto seen. Several flashes are of such small spatial extent that they must originate above the 2-bar level, where there is no liquid water14,15. This implies that multiple mechanisms for generating lightning on Jupiter need to be considered for a full understanding of the planet’s atmospheric convection and composition.

The bladder is continuously protected by passive defences such as a mucus layer, antimicrobial peptides and secretory immunoglobulins; however, these defences are occasionally overcome by invading bacteria that can induce a strong host inflammatory response in the bladder. The urothelium and resident immune cells produce additional defence molecules, cytokines and chemokines, which recruit inflammatory cells to the infected tissue. Resident and recruited immune cells act together to eradicate bacteria from the bladder and to develop lasting immune memory against infection. However, urinary tract infection (UTI) is commonly recurrent, suggesting that the induction of a memory response in the bladder is inadequate to prevent reinfection. Additionally, infection seems to induce long-lasting changes in the urothelium, which can render the tissue more susceptible to future infection. The innate immune response is well-studied in the field of UTI, but considerably less is known about how adaptive immunity develops and how repair mechanisms restore bladder homeostasis following infection. Furthermore, data demonstrate that sex-based differences in immunity affect resolution and infection can lead to tissue remodelling in the bladder following resolution of UTI. To combat the rise in antimicrobial resistance, innovative therapeutic approaches to bladder infection are currently in development. Improving our understanding of how the bladder responds to infection will support the development of improved treatments for UTI, particularly for those at risk of recurrent infection.

AbstractSome energy consumers require power on an anytime, all-year-round basis with a high level of certainty, including defense installations, isolated communities, and some industrial processes. For these customers, interruptions in electricity or heat can mean substantial financial loss or even loss of life. In the absence of grid-scale energy storage, a high level of power availability can be accomplished only through the robustness and redundancy of power generators. The NuScale small modular reactor design is well suited to provide highly available power because of several features related to both the nuclear steam supply system and the overall plant design. In analogy to Redundant Array of Independent Disks (RAID) systems used to provide highly reliable data storage, a NuScale plant can assure sustained power generation by virtue of its Redundant Array of Integral Reactors (RAIR).This paper describes the NuScale RAIR plant features and summarizes the results of a rigorous analysis of RAIR availability as a function of power or, conversely, the RAIR plant output power as a function of power availability. The analysis utilized the Matrix Laboratory code (MATLAB) and included probability distributions for the frequency and duration of module outages due to planned and unplanned events. The study also evaluated the impact of implementing turbine bypass rather than module shutdown and using one or more modules to supply house loads in the case of loss of off-site power (LOOP). Availability results are presented for a 12-module RAIR plant with and without turbine bypass enabled during a LOOP and for different possible connections to the off-site power distribution grid and dedicated service loads. Results indicate that a very high level of availability can be achieved at relatively high power output levels, regardless of turbine bypass and dedicated load connection, compared to the operating fleet.

Women enter the workforce in roughlythe same numbers as men. though theinequities in advancement start withthe very first promotion. Anne Mulcahy, CEO of Xerox from August2001 until mid-2009, is an example of a glass cliffappointment. Mulcahy was selected by the board of directorsto lead Xerox out of crisis not because of hertechnical skills (she had spent most of her careerin either sales or human resources), but becauseof the qualities she brought. [Extracted from the article]

Following allogeneic hematopoietic cell transplantation (alloHCT) donor T cells infiltrate and damage multiple target organs, resulting in acute GVHD (aGVHD). However, the critical biological mechanisms underpinning the tissue-specificity of aGVHD remains only partially understood. Deciphering the organ-specific alloimmune mechanisms responsible for target organ damage offers new prospects for precisely targeted treatments for acute GVHD, minimizing impact on protective immunity and reducing overall toxicity.

A tribally led Changing High‐Risk Alcohol Use and Increasing Contraception Effectiveness Study (CHOICES) Program has successfully decreased the risk of alcohol‐exposed pregnancies (AEPs) among adult American Indian/Alaska Native (AI/AN) women by either reducing risky drinking or increasing contraception use. However, a community needs assessment revealed a need to implement a similar intervention with AI/AN teens. The goal of the project was to develop and establish the acceptability of CHOICES for AI/AN teens. Key informant interviews were conducted to review the existing OST CHOICES intervention. After modifications to the existing program, focus groups with AI/AN teens were conducted to ensure validity and to finalize the OST CHAT (CHOICES for American Indian Teens) intervention. Key informant (N= 15) participants suggested that a Web‐based intervention may increase teen engagement by making the intervention more interactive and visually stimulating. Based on this formative research, CHAT was developed via Research Electronic Data Capture (REDCap). Feedback on the online CHAT curriculum was given by focus groups comprised of AI/AN adolescents, and participants felt that this type of intervention would be both acceptable and able to implement with a community of reservation‐based teens. This study outlines the development of a Web‐based intervention for an AEP intervention for AI/AN teens and will inform future prevention efforts. Implications include an expansion of the evidence‐based CHOICES intervention for AI/AN teens and also development of a Web‐based intervention for rural, reservation‐based AI/AN communities. Alcohol‐exposed pregnancy (AEP) continues to be a public health issue for a variety of subpopulations of women, including adolescents. The goal of the project was to adapt an existing AEP prevention program – CHOICES – for use with American Indian and Alaska Native teens. Utilizing key informant interviews and focus group, CHOICES for American Indian Teens (CHAT) was developed via REDCap (Research Electronic Data Capture). Feedback on the online CHAT curriculum from focus group participants indicated that this type of intervention would be both acceptable and able to implement with a community of reservation‐based teens.

The paper presents velocity fields with ~3‐km spatial resolution of Saturn's north polar vortex (NPV) retrieved using the optical flow method from a sequence of polar‐projected cloud images captured by the Imaging Science Subsystem camera on board NASA's Cassini spacecraft. The fields of the velocity magnitude, velocity variation, relative vorticity, divergence, and second invariant are determined to characterize the flow structures of the inner core of the NPV. The mean zonal and mean meridional velocity profiles of the NPV are compared with previous measurements. We also describe the relevant details of application of the optical flow method to planetary cloud‐tracking wind measurements. The mean zonal velocity profile is consistent with the previous measurements using correlation image velocimetry methods. The small but significant meridional velocity corresponds to outwardly spiraling streams observed in the region near the north pole (NP). The concentrated vorticity and second invariant within 1° planetographic latitude of the NP indicate strong rotational motion of the fluid. An analysis is presented to explore a possible physical origin of the observed spiraling node at the NP. A swirling flow pattern with wind speeds peaking at about 100 m/s was revealed in Saturn's north polar vortex in high‐resolution images captured by the Imaging Science Subsystem camera on board NASA's Cassini spacecraft in November 2012. Using sequences of images that show clouds in the north polar vortex, the motions of these clouds were analyzed to measure the wind speeds in the north polar region. The high‐precision wind measurements presented in the current report are enabled by the optical flow cloud‐tracking method. The time‐averaged wind field shows a well‐defined counterclockwise (cyclonic) vortex at the pole. In particular, the observed flow structures and wind shear near the pole indicate strong rotational motion of the north polar atmosphere with upwelling at the center. The high‐resolution velocity fields of Saturn's north polar vortex (NPV) are extracted from cloud images by using the optical flow methodThe vorticity, divergence, and second invariant are obtained to characterize the flow structures of the NPVThe strong rotational motion of the fluid with upwelling is found near the pole

The current study builds upon and extends research on the glass cliff by analyzing the antecedents and repercussions of CEO dismissal. Recent research on the relationship between performance, gender, and CEO dismissal has led to contrary conclusions. We build on this nascent work by examining whether negative firm performance places women CEOs of US firms at a greater risk of involuntary dismissal relative to men CEOs. We further explore whether gender moderates market response to the dismissal announcement and replacement. Our analysis relies on data of all CEOs from the United States’ Russell 3000 index, which represents a spectrum of small to large companies, who departed their organizations between 2016 and 2022. We also rely on a novel measure of CEO dismissal, the push-out score, which overcomes previous limitations related to the nature of CEO departures. We find that women are more vulnerable than men to involuntary dismissal during periods of performance decline and that investors reward firms that replace dismissed women CEOs with white men. Our findings have implications for gender equity in the C-Suite.

Smoking remains the leading cause of preventable death, yet physicians inconsistently provide best-practices cessation advice to smokers. Point-of-care digital health tools can prompt and assist physicians to provide improved smoking cessation counseling. QuitAdvisorMD is a comprehensive web-based counseling and management digital health tool designed to guide smoking cessation counseling at the point-of-care. The tool enables clinicians to assess patient readiness to change and then deliver stage-appropriate interventions, while also incorporating Motivational Interviewing techniques. We present the research protocol to assess the efficacy of QuitAdvisorMD to change frequency and quality of smoking cessation counseling and its effect on patient quit rates.

Uropathogenic E. coli(UPEC) is a primary organism responsible for urinary tract infections and a common cause of sepsis. Microbially experienced laboratory mice, generated by cohousing with pet store mice, exhibit increased morbidity and mortality to polymicrobial sepsis or lipopolysaccharide challenge. By contrast, cohoused mice display significant resistance, compared with specific pathogen-free mice, to a monomicrobial sepsis model using UPEC. CD115+monocytes mediate protection in the cohoused mice, as depletion of these cells leads to increased mortality and UPEC pathogen burden. Further study of the cohoused mice reveals increased TNF-α production by monocytes, a skewing toward Ly6ChiCD115+“classical” monocytes, and enhanced egress of Ly6ChiCD115+monocytes from the bone marrow. Analysis of cohoused bone marrow also finds increased frequency and number of myeloid multipotent progenitor cells. These results show that a history of microbial exposure impacts innate immunity in mice, which can have important implications for the preclinical study of sepsis.

Background: Myelodysplastic syndromes (MDS) are a heterogeneous group of hematologic malignancies characterized by ineffective erythropoiesis. Anemia is the most common cytopenia and major clinical problem in MDS. Acquired pyruvate kinase (PK) deficiency has been observed in MDS, and a direct impact on the glycolytic pathway in the pathogenesis of anemia associated with MDS has been demonstrated. AG-946 is an investigational, small-molecule, allosteric activator of PK that has the potential to enhance red blood cell (RBC) functionality and survival by increasing glycolysis and adenosine triphosphate (ATP) production, and improve differentiation of erythroid cells in bone marrow, potentially improving anemia caused by ineffective erythropoiesis in MDS. Previous findings showed that RBCs from patients with MDS treated ex-vivo with AG-946, led to an increase in PK activity. Here, we used two MDS-related mouse models to evaluate the effects of the PK activator AG-946 in this mechanism of anemia.

Multidrug-resistant organism (MDRO) colonization is a fundamental challenge in antimicrobial resistance. Limited studies have shown that fecal microbiota transplantation (FMT) can reduce MDRO colonization, but its mechanisms are poorly understood. We conducted a randomized, controlled trial of FMT for MDRO decolonization in renal transplant recipients called PREMIX (NCT02922816). Eleven participants were enrolled and randomized 1:1 to FMT or an observation period followed by delayed FMT if stool cultures were MDRO positive at day 36. Participants who were MDRO positive after one FMT were treated with a second FMT. At last visit, eight of nine patients who completed all treatments were MDRO culture negative. FMT-treated participants had longer time to recurrent MDRO infection versus PREMIX-eligible controls who were not treated with FMT. Key taxa (Akkermansia muciniphila, Alistipes putredinis, Phocaeicola dorei, Phascolarctobacterium faecium, Alistipesspecies, Mesosutterella massiliensis, Barnesiella intestinihominis, and Faecalibacterium prausnitzii) from the single feces donor used in the study that engrafted in recipients and metabolites such as short-chain fatty acids and bile acids in FMT-responding participants uncovered leads for rational microbiome therapeutic and diagnostic development. Metagenomic analyses revealed a previously unobserved mechanism of MDRO eradication by conspecific strain competition in an FMT-treated subset. Susceptible Enterobacteralesstrains that replaced baseline extended-spectrum β-lactamase–producing strains were not detectable in donor microbiota manufactured as FMT doses but in one case were detectable in the recipient before FMT. These data suggest that FMT may provide a path to exploit strain competition to reduce MDRO colonization.

To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P<5 × 10−8, bringing the number of known independent signals for CRC to ~100. New signals implicate lower-frequency variants, Krüppel-like factors, Hedgehog signaling, Hippo-YAP signaling, long noncoding RNAs and somatic drivers, and support a role for immune function. Heritability analyses suggest that CRC risk is highly polygenic, and larger, more comprehensive studies enabling rare variant analysis will improve understanding of biology underlying this risk and influence personalized screening strategies and drug development.

While brief intervention (BI) for risky alcohol use generally yields positive effects among those identified by screening, effect sizes are small and there is unexplained heterogeneity in outcome. The heterogeneity may be related to differences in intervention style and content, including elements of motivational interviewing (MI). To date, it has been difficult to interpret the role of MI in BI and these gaps in knowledge interfere with efforts to train, disseminate and implement BI that retains and maximizes efficacy. This study sought to develop BI protocols with varying doses of MI and test their differentiability. Differentiable BI protocols could allow for future studies that prospectively evaluate the role MI plays in affecting BI outcome. We developed three intervention protocols: brief advice, standard BI (NIAAA Clinician’s Guide), and MI-enhanced BI and administered them to 45 primary care patients who reported exceeding recommended drinking limits. We then rated the BI sessions for fidelity to the assigned protocol as well as MI consistency based on Motivational Interviewing Treatment Integrity (MITI) scale scores. The differentiability of BI protocols was determined by calculating fidelity to assigned protocols and comparing MITI scores using pairwise, Tukey-adjusted comparisons of least squares mean scores. High rates of fidelity to each protocol were achieved. The three BI protocols were also highly differentiable based on MITI scores. The three interventions can be used in future trials to prospectively examine the role MI has in determining BI outcome. Trial registrationclinicaltrials.gov NCT02978027, retrospectively registered 11/28/16

Recruitment of neutrophils to the airways, and their pathological conditioning therein, drive tissue damage and coincide with the loss of lung function in patients with cystic fibrosis (CF). So far, these key processes have not been adequately recapitulated in models, hampering drug development. Here, we hypothesized that the migration of naïve blood neutrophils into CF airway fluid in vitro would induce similar functional adaptation to that observed in vivo, and provide a model to identify new therapies. We used multiple platforms (flow cytometry, bacteria‐killing, and metabolic assays) to characterize functional properties of blood neutrophils recruited in a transepithelial migration model using airway milieu from CF subjects as an apical chemoattractant. Similarly to neutrophils recruited to CF airways in vivo, neutrophils migrated into CF airway milieu in vitro display depressed phagocytic receptor expression and bacterial killing, but enhanced granule release, immunoregulatory function (arginase‐1 activation), and metabolic activities, including high Glut1 expression, glycolysis, and oxidant production. We also identify enhanced pinocytic activity as a novel feature of these cells. In vitro treatment with the leukotriene pathway inhibitor acebilustat reduces the number of transmigrating neutrophils, while the metabolic modulator metformin decreases metabolism and oxidant production, but fails to restore bacterial killing. Interestingly, we describe similar pathological conditioning of neutrophils in other inflammatory airway diseases. We successfully tested the hypothesis that recruitment of neutrophils into airway milieu from patients with CF in vitro induces similar pathological conditioning to that observed in vivo, opening new avenues for targeted therapeutic intervention. Active degranulation and metabolic licensing of neutrophils recruited to cystic fibrosis airways can be recapitulated and modulated by drugs in vitro.