OTULIN protects the intestinal epithelium from apoptosis during inflammation and infection.

The intestinal epithelium is a single cell layer that is constantly renewed and acts as a physical barrier that separates intestinal microbiota from underlying tissues. In inflammatory bowel disease (IBD) in humans, as well as in experimental mouse models of IBD, this barrier is impaired, causing microbial infiltration and inflammation. Deficiency in OTU deubiquitinase with linear linkage specificity (OTULIN) causes OTULIN-related autoinflammatory syndrome (ORAS), a severe inflammatory pathology affecting multiple organs including the intestine. We show that mice with intestinal epithelial cell (IEC)-specific OTULIN deficiency exhibit increased susceptibility to experimental colitis and are highly sensitive to TNF toxicity, due to excessive apoptosis of OTULIN deficient IECs. OTULIN deficiency also increases intestinal pathology in mice genetically engineered to secrete excess TNF, confirming that chronic exposure to TNF promotes epithelial cell death and inflammation in OTULIN deficient mice. Mechanistically we demonstrate that upon TNF stimulation, OTULIN deficiency impairs TNF receptor complex I formation and LUBAC recruitment, and promotes the formation of the cytosolic complex II inducing epithelial cell death. Finally, we show that OTULIN deficiency in IECs increases susceptibility to Salmonella infection, further confirming the importance of OTULIN for intestinal barrier integrity. Together, these results identify OTULIN as a major anti-apoptotic protein in the intestinal epithelium and provide mechanistic insights into how OTULIN deficiency drives gastrointestinal inflammation in ORAS patients.

Characterizing the Heart Rate Effects From Administration of Sugammadex to Reverse Neuromuscular Blockade: An Observational Study in Patients.

BACKGROUND: Reversal of neuromuscular blockade (NMB) with sugammadex can cause marked bradycardia and asystole. Administration of sugammadex typically occurs in a dynamic period when anesthetic adjuvants and gas concentrations are being titrated to achieve emergence. This evaluation examined the heart rate (HR) responses to sugammadex to reverse moderate to deep NMB during a steady-state period and sought mechanisms for HR changes. METHODS: Patients with normal sinus rhythm, who were undergoing elective surgery that included rocuronium for NMB, were evaluated. After surgery, while at steady-state surgical depth anesthesia with sevoflurane and mechanical ventilation, patients received either placebo or 2 or 4 mg/kg of sugammadex to reverse moderate to deep NMB. Study personnel involved in data analysis were blinded to treatment. Continuous electrocardiogram (ECG) was recorded from the 5 minutes before and 5 minutes after sugammadex/placebo administration. R-R intervals were converted to HR and averaged in 1-minute increments. The maximum prolongation of an R-R interval after sugammadex was converted to an instantaneous HR. RESULTS: A total of 63 patients were evaluated: 8 received placebo, and 38 and 17 received 2 and 4 mg/kg sugammadex. Age, body mass index, and patient factors were similar in groups. Placebo did not elicit HR changes, whereas sugammadex caused maximum instantaneous HR slowing (calculated from the longest R-R interval), ranging from 2 to 19 beats/min. There were 7 patients with maximum HR slowing >10 beats/min. The average HR change and 95% confidence interval (CI) during the 5 minutes after 2 mg/kg sugammadex were 3.1 (CI, 2.3-4.1) beats/min, and this was not different from the 4 mg/kg sugammadex group (4.1 beats/min [CI, 2.5-5.6]). HR variability derived from the standard deviation of consecutive R-R intervals increased after sugammadex. CONCLUSIONS: Sugammadex to reverse moderate and deep NMB resulted in a fast onset and variable magnitude of HR slowing in patients. A difference in HR slowing as a function of dose did not achieve statistical significance. The observational nature of the investigation prevented a full understanding of the mechanism(s) of the HR slowing.

Citizens and the state during crisis: Public authority, private behaviour and the Covid-19 pandemic in France.

How do democratic states induce citizens to comply with government directives during times of acute crisis? Focusing on the onset of the Covid-19 pandemic in France, I argue that the tools states use to activate adherence to public health advice have predictable and variable effects on citizens' willingness to change their routine private behaviours, both because of variation in their levels of restrictiveness but also because of differences in people's political motivations to comply with them. Using data collected in March 2020, I show that people's reports of changes in their behavioural routines are affected by the signals governments send, how they send them and the level of enforcement. I find that a nationally televised speech by President Macron calling for cooperative behaviour and announcing new restrictions elevated people's willingness to comply. Moreover, while co-partisanship with the incumbent government increased compliance reports before the President's primetime television address, presidential approval boosted reports of compliance after.

Microbes exploit death-induced nutrient release by gut epithelial cells.

Regulated cell death is an integral part of life, and has broad effects on organism development and homeostasis1. Malfunctions within the regulated cell death process, including the clearance of dying cells, can manifest in diverse pathologies throughout various tissues including the gastrointestinal tract2. A long appreciated, yet elusively defined relationship exists between cell death and gastrointestinal pathologies with an underlying microbial component3-6, but the direct effect of dying mammalian cells on bacterial growth is unclear. Here we advance a concept that several Enterobacteriaceae, including patient-derived clinical isolates, have an efficient growth strategy to exploit soluble factors that are released from dying gut epithelial cells. Mammalian nutrients released after caspase-3/7-dependent apoptosis boosts the growth of multiple Enterobacteriaceae and is observed using primary mouse colonic tissue, mouse and human cell lines, several apoptotic triggers, and in conventional as well as germ-free mice in vivo. The mammalian cell death nutrients induce a core transcriptional response in pathogenic Salmonella, and we identify the pyruvate formate-lyase-encoding pflB gene as a key driver of bacterial colonization in three contexts: a foodborne infection model, a TNF- and A20-dependent cell death model, and a chemotherapy-induced mucositis model. These findings introduce a new layer to the complex host-pathogen interaction, in which death-induced nutrient release acts as a source of fuel for intestinal bacteria, with implications for gut inflammation and cytotoxic chemotherapy treatment.

Humanity's Attitudes about Democracy and Political Leaders: Patterns and Trends.

For decades, researchers have examined people's beliefs across countries and over time using national samples of citizens. Yet, in an era when economies, societies, and policymaking have become increasingly interconnected, nation-states may no longer be the only or most relevant units of analysis for studying public opinion. To examine what people think about politics on a global scale, we develop tools for measuring public opinion that allow us to transcend national and regional boundaries. Starting with the world as the unit of analysis and humans as the relevant population, we measure and then explore patterns and trends in human preferences for democratic government and political leaders with the help of surveys collected around the world since 1994.

RIPK3-Dependent Recruitment of Low-Inflammatory Myeloid Cells Does Not Protect from Systemic Salmonella Infection.

Regulated macrophage death has emerged as an important mechanism to defend against intracellular pathogens. However, the importance and consequences of macrophage death during bacterial infection are poorly resolved. This is especially true for the recently described RIPK3-dependent lytic cell death, termed necroptosis. Salmonella enterica serovar Typhimurium is an intracellular pathogen that precisely regulates virulence expression within macrophages to evade and manipulate immune responses, which is a key factor in its ability to cause severe systemic infections. We combined genetic and pharmacological approaches to examine the importance of RIPK3 for S. Typhimurium-induced macrophage death using conditions that recapitulate bacterial gene expression during systemic infection in vivo Our findings indicate that noninvasive S. Typhimurium does not naturally induce macrophage necroptosis but does so in the presence of pan-caspase inhibition. Moreover, our data suggest that RIPK3 induction (following caspase inhibition) does not impact host survival following S. Typhimurium infection, which differs from previous findings based on inert lipopolysaccharide (LPS) injections. Finally, although necroptosis is typically characterized as highly inflammatory, our data suggest that RIPK3 skews the peritoneal myeloid population away from an inflammatory profile to that of a classically noninflammatory profile. Collectively, these data improve our understanding of S. Typhimurium-macrophage interactions, highlight the possibility that purified bacterial components may not accurately recapitulate the complexity of host-pathogen interactions, and reveal a potential and unexpected role for RIPK3 in resolving inflammation.IMPORTANCE Macrophages employ multiple strategies to limit pathogen infection. For example, macrophages may undergo regulated cell death, including RIPK3-dependent necroptosis, as a means of combatting intracellular bacterial pathogens. However, bacteria have evolved mechanisms to evade or exploit immune responses. Salmonella is an intracellular pathogen that avoids and manipulates immune detection within macrophages. We examined the contribution of RIPK3 to Salmonella-induced macrophage death. Our findings indicate that noninvasive Salmonella does not naturally induce necroptosis, but it does so when caspases are inhibited. Moreover, RIPK3 induction (following caspase inhibition) does not impact host survival following Salmonella systemic infection. Finally, our data show that RIPK3 induction results in recruitment of low-inflammatory myeloid cells, which was unexpected, as necroptosis is typically described as highly inflammatory. Collectively, these data improve our understanding of pathogen-macrophage interactions, including outcomes of regulated cell death during infection in vivo, and reveal a potential new role for RIPK3 in resolving inflammation.

Canceling Out Intensity Mapping Foregrounds.

Intensity mapping of the 21 cm line has arisen as a powerful probe of the high-redshift Universe, but its potential is limited by extremely bright foregrounds and high source confusion. We propose a new analysis which can help solve both problems. From the combination of an intensity map with an overlapping galaxy survey, we construct a new one-point statistic which is unbiased by foregrounds and contains information left out of conventional analyses. We show that our method can measure the HI mass function with unprecedented precision using observations similar to recent 21 cm detections.

Ethanolamine Influences Human Commensal Escherichia coli Growth, Gene Expression, and Competition with Enterohemorrhagic E. coli O157:H7.

A core principle of bacterial pathogenesis is that pathogens preferentially utilize metabolites that commensal bacteria do not in order to sidestep nutritional competition. The metabolite ethanolamine (EA) is well recognized to play a central role in host adaptation for diverse pathogens. EA promotes growth and influences virulence during host infection. Although genes encoding EA utilization have been identified in diverse bacteria (nonpathogenic and pathogenic), a prevailing idea is that commensal bacteria do not utilize EA to enhance growth, and thus, EA is a noncompetitive metabolite for pathogens. Here, we show that EA augments growth of two human commensal strains of Escherichia coli Significantly, these commensal strains grow more rapidly than, and even outcompete, the pathogen enterohemorrhagic E. coli O157:H7 specifically when EA is provided as the sole nitrogen source. Moreover, EA-dependent signaling is similarly conserved in the human commensal E. coli strain HS and influences expression of adhesins. These findings suggest a more extensive role for EA utilization in bacterial physiology and host-microbiota-pathogen interactions than previously appreciated.IMPORTANCE The microbiota protects the host from invading pathogens by limiting access to nutrients. In turn, bacterial pathogens selectively exploit metabolites not readily used by the microbiota to establish infection. Ethanolamine has been linked to pathogenesis of diverse pathogens by serving as a noncompetitive metabolite that enhances pathogen growth as well as a signal that modulates virulence. Although ethanolamine is abundant in the gastrointestinal tract, the prevailing idea is that commensal bacteria do not utilize EA, and thus, EA utilization has been particularly associated with pathogenesis. Here, we provide evidence that two human commensal Escherichia coli isolates readily utilize ethanolamine to enhance growth, modulate gene expression, and outgrow the pathogen enterohemorrhagic E. coli These data indicate a more complex role for ethanolamine in host-microbiota-pathogen interactions.

The Ethanolamine Permease EutH Promotes Vacuole Adaptation of Salmonella enterica and Listeria monocytogenes during Macrophage Infection.

Ethanolamine is a ubiquitous and essential molecule within a host. Significantly, bacterial pathogens exploit ethanolamine during infection to promote growth and regulate virulence. The ethanolamine permease EutH is dispensable for growth in vitro under standard conditions, whereas EutH is required for ethanolamine utilization at low pH. These findings suggested a model in which EutH facilitates diffusion of ethanolamine into the bacterial cell in acidic environments. To date, the ecological significance of this model has not been thoroughly investigated, and the importance of EutH to bacterial growth under physiologically relevant conditions is not known. During infection, immune cells internalize invading bacteria within an acidic, nutrient-depleted vacuole called the phagosome. Here, we investigated the hypothesis that EutH promotes bacterial survival following phagocytosis. Our findings indicate that EutH is important for survival and replication of the facultative intracellular pathogens Salmonella enterica serovar Typhimurium and Listeria monocytogenes during prolonged or transient exposure to the phagosome, respectively. Furthermore, in agreement with EutH being important in the acidic environment, neutralization of the vacuole abolished the requirement for EutH. Significantly, consistent with a role for EutH in promoting intramacrophage survival, EutH was not required during S Typhimurium local intestinal infection but specifically conferred an advantage upon dissemination to peripheral organs. These findings reveal a physiologically relevant and conserved role for EutH in spatiotemporal niche adaptation during infection.

Image-guided biopsy of small (≤4 cm) renal masses: the effect of size and anatomical location on biopsy success rate and complications.

OBJECTIVE: To study the influence of tumour diameter and anatomy on the success and complication rates of small renal mass (SRM, ≤4 cm) core biopsy. METHODS: Retrospective analysis of SRMs that underwent ultrasound or CT-guided biopsy. Diagnostic and complication rates were compared according to tumour size (subcategorised as axial diameter ≤2 cm, >2 to- ≤3 cm, >3-≤4 cm) and anatomical disposition (exophytic/endophytic, centrality, polar location and anterior/posterior). RESULTS: 94 patients (54 male; age range 21.8-84.3 years) with 95 SRMs underwent biopsy. The first biopsy was diagnostic in 81/95 (85.3%). Seven patients underwent repeat biopsy (6/7 diagnostic), to give an overall diagnostic rate of 91.5%. The primary diagnostic rates in the ≤2, >2-≤3 , >3-≤4 cm groups were 21/25 (84%); 38/44 (86.4%) and 22/26 (84.6%) respectively and were similar (p = 1.00). Anterior and upper pole SRMs were more likely to fail initial biopsy (odds ratio 13.8, p < 0.01; and odds ratio 4.35, p = 0.04) respectively, but other anatomical factors were not relevant. Complications occurred in 14% (all conservatively managed perinephric haematomas; Clavien-Dindo Grade 1) and size or location were not relevant. CONCLUSION: Image-guided biopsy of SRMs has a high diagnostic rate irrespective of tumour size. Anterior and upper pole location had lower diagnostic rates. Biopsy should be considered for all patients with SRMs, if the result will impact on management and we list specific scenarios where an SRM biopsy may be helpful. Advances in knowledge: SRM size does not affect the likelihood of a diagnostic biopsy.

Salmonella enterica Serovar Typhimurium Strategies for Host Adaptation.

Bacterial pathogens must sense and respond to newly encountered host environments to regulate the expression of critical virulence factors that allow for niche adaptation and successful colonization. Among bacterial pathogens, non-typhoidal serovars of Salmonella enterica, such as serovar Typhimurium (S. Tm), are a primary cause of foodborne illnesses that lead to hospitalizations and deaths worldwide. S. Tm causes acute inflammatory diarrhea that can progress to invasive systemic disease in susceptible patients. The gastrointestinal tract and intramacrophage environments are two critically important niches during S. Tm infection, and each presents unique challenges to limit S. Tm growth. The intestinal tract is home to billions of commensal microbes, termed the microbiota, which limits the amount of available nutrients for invading pathogens such as S. Tm. Therefore, S. Tm encodes strategies to manipulate the commensal population and side-step this nutritional competition. During subsequent stages of disease, S. Tm resists host immune cell mechanisms of killing. Host cells use antimicrobial peptides, acidification of vacuoles, and nutrient limitation to kill phagocytosed microbes, and yet S. Tm is able to subvert these defense systems. In this review, we discuss recently described molecular mechanisms that S. Tm uses to outcompete the resident microbiota within the gastrointestinal tract. S. Tm directly eliminates close competitors via bacterial cell-to-cell contact as well as by stimulating a host immune response to eliminate specific members of the microbiota. Additionally, S. Tm tightly regulates the expression of key virulence factors that enable S. Tm to withstand host immune defenses within macrophages. Additionally, we highlight the chemical and physical signals that S. Tm senses as cues to adapt to each of these environments. These strategies ultimately allow S. Tm to successfully adapt to these two disparate host environments. It is critical to better understand bacterial adaptation strategies because disruption of these pathways and mechanisms, especially those shared by multiple pathogens, may provide novel therapeutic intervention strategies.

Response to Comment on "Estimating the reproducibility of psychological science".

Gilbert et al. conclude that evidence from the Open Science Collaboration's Reproducibility Project: Psychology indicates high reproducibility, given the study methodology. Their very optimistic assessment is limited by statistical misconceptions and by causal inferences from selectively interpreted, correlational data. Using the Reproducibility Project: Psychology data, both optimistic and pessimistic conclusions about reproducibility are possible, and neither are yet warranted.

Location, location, location. Salmonella senses ethanolamine to gauge distinct host environments and coordinate gene expression.

Chemical and nutrient signaling mediate all cellular processes, ensuring survival in response to changing environmental conditions. Ethanolamine is a component of phosphatidylethanolamine, a major phospholipid of mammalian and bacterial cell membranes. Ethanolamine is abundant in the gastrointestinal (GI) tract from dietary sources as well as from the normal turnover of intestinal epithelial and bacterial cells in the gut. Additionally, mammalian cells maintain intracellular ethanolamine concentrations through low and high-affinity uptake systems and the internal recycling of phosphatidylethanolamine; therefore, ethanolamine is ubiquitous throughout the mammalian host. Although ethanolamine has profound signaling activity within mammalian cells by modulating inflammatory responses and intestinal physiology, ethanolamine is best appreciated as a nutrient for bacteria that supports growth. In our recent work (Anderson, et al. PLoS Pathog (2015), 11: e1005278), we demonstrated that Salmonella enterica serovar Typhimurium (Salmonella) exploits ethanolamine signaling to adapt to distinct host environments to precisely coordinate expression of genes encoding metabolism and virulence, which ultimately enhances disease progression.

Dense magnetized plasma associated with a fast radio burst.

Fast radio bursts are bright, unresolved, non-repeating, broadband, millisecond flashes, found primarily at high Galactic latitudes, with dispersion measures much larger than expected for a Galactic source. The inferred all-sky burst rate is comparable to the core-collapse supernova rate out to redshift 0.5. If the observed dispersion measures are assumed to be dominated by the intergalactic medium, the sources are at cosmological distances with redshifts of 0.2 to 1 (refs 10 and 11). These parameters are consistent with a wide range of source models. One fast burst revealed circular polarization of the radio emission, but no linear polarization was detected, and hence no Faraday rotation measure could be determined. Here we report the examination of archival data revealing Faraday rotation in the fast radio burst FRB 110523. Its radio flux and dispersion measure are consistent with values from previously reported bursts and, accounting for a Galactic contribution to the dispersion and using a model of intergalactic electron density, we place the source at a maximum redshift of 0.5. The burst has a much higher rotation measure than expected for this line of sight through the Milky Way and the intergalactic medium, indicating magnetization in the vicinity of the source itself or within a host galaxy. The pulse was scattered by two distinct plasma screens during propagation, which requires either a dense nebula associated with the source or a location within the central region of its host galaxy. The detection in this instance of magnetization and scattering that are both local to the source favours models involving young stellar populations such as magnetars over models involving the mergers of older neutron stars, which are more likely to be located in low-density regions of the host galaxy.

Current Status of Hemostatic Agents and Sealants in Urologic Surgical Practice.

There has been a recent and near exponential increase in the use of hemostatic agents and sealants to supplement the rapidly evolving methods in the surgical management of urologic patients. This article reviews the use of hemostatic agents and sealants in current urologic practice.

"Men's health--a little in the shadow": a formative evaluation of medical curriculum enhancement with men's health teaching and learning.

BACKGROUND: Enhancing a medical school curriculum with new men's health teaching and learning requires an understanding of the local capacity and the facilitators and barriers to implementing new content, and an approach that accommodates the systemic and cultural differences between medical schools. METHODS: A formative evaluation was undertaken to determine the perspectives of key informants (academics, curriculum developers) from four Australian medical schools about the strategies needed to enhance their curriculum with men's health teaching and learning. Through semi-structured questioning with 17 key informants, interviewees also described the contextual barriers and facilitators to incorporating new topic areas into existing curriculum. Interviews were recorded with consent, transcribed verbatim, and analysed by two researchers to identify key themes. RESULTS: Interviewees were enthusiastic about incorporating men's health content through a men's health curriculum framework but highlighted the need for systems to assist in identifying gaps in their current curriculum where the men's health topics could be integrated. The student experience was identified as a key driver for men's health teaching and learning. Furthermore, core men's health clinical outcomes needed to be defined and topic areas vertically integrated across the curricula. This would ensure that students were appropriately equipped with the skills and knowledge for subsequent clinical practice in a range of geographical settings. Interviewees consistently suggested that the best implementation strategy is to have someone 'on the ground' to work directly with medical school staff and champion the men's health discipline. Providing mechanisms for sharing knowledge and resources across medical schools was highlighted to facilitate implementation, particularly for those medical schools with limited men's health teaching resources. CONCLUSIONS: Despite the unanimous support for men's health teaching and learning, the evaluation highlighted that the student experience must be recognised as paramount when integrating new topic areas into an already packed curriculum. A community of practice, where medical schools share relevant resources and knowledge, could help to ensure a commonality of student experience with respect to men's health learning in medical schools across different geographical settings and with different levels of resourcing. Such an approach could also be adapted to other areas of curriculum enhancement.

Ethanolamine Signaling Promotes Salmonella Niche Recognition and Adaptation during Infection.

Chemical and nutrient signaling are fundamental for all cellular processes, including interactions between the mammalian host and the microbiota, which have a significant impact on health and disease. Ethanolamine is an essential component of cell membranes and has profound signaling activity within mammalian cells by modulating inflammatory responses and intestinal physiology. Here, we describe a virulence-regulating pathway in which the foodborne pathogen Salmonella enterica serovar Typhimurium (S. Typhimurium) exploits ethanolamine signaling to recognize and adapt to distinct niches within the host. The bacterial transcription factor EutR promotes ethanolamine metabolism in the intestine, which enables S. Typhimurium to establish infection. Subsequently, EutR directly activates expression of the Salmonella pathogenicity island 2 in the intramacrophage environment, and thus augments intramacrophage survival. Moreover, EutR is critical for robust dissemination during mammalian infection. Our findings reveal that S. Typhimurium co-opts ethanolamine as a signal to coordinate metabolism and then virulence. Because the ability to sense ethanolamine is a conserved trait among pathogenic and commensal bacteria, our work indicates that ethanolamine signaling may be a key step in the localized adaptation of bacteria within their mammalian hosts.

Streamflow impacts of biofuel policy-driven landscape change.

Likely changes in precipitation (P) and potential evapotranspiration (PET) resulting from policy-driven expansion of bioenergy crops in the United States are shown to create significant changes in streamflow volumes and increase water stress in the High Plains. Regional climate simulations for current and biofuel cropping system scenarios are evaluated using the same atmospheric forcing data over the period 1979-2004 using the Weather Research Forecast (WRF) model coupled to the NOAH land surface model. PET is projected to increase under the biofuel crop production scenario. The magnitude of the mean annual increase in PET is larger than the inter-annual variability of change in PET, indicating that PET increase is a forced response to the biofuel cropping system land use. Across the conterminous U.S., the change in mean streamflow volume under the biofuel scenario is estimated to range from negative 56% to positive 20% relative to a business-as-usual baseline scenario. In Kansas and Oklahoma, annual streamflow volume is reduced by an average of 20%, and this reduction in streamflow volume is due primarily to increased PET. Predicted increase in mean annual P under the biofuel crop production scenario is lower than its inter-annual variability, indicating that additional simulations would be necessary to determine conclusively whether predicted change in P is a response to biofuel crop production. Although estimated changes in streamflow volume include the influence of P change, sensitivity results show that PET change is the significantly dominant factor causing streamflow change. Higher PET and lower streamflow due to biofuel feedstock production are likely to increase water stress in the High Plains. When pursuing sustainable biofuels policy, decision-makers should consider the impacts of feedstock production on water scarcity.

Nasal Carriage of Epidemic Methicillin-Resistant Staphylococcus aureus 15 (EMRSA-15) Clone Observed in Three Chicago-Area Long-Term Care Facilities.

The spread of pandemic methicillin-resistant Staphylococcus aureus (MRSA) clones such as USA300 and EMRSA-15 is a global health concern. As a part of a surveillance study of three long-term care facilities in the Greater Chicago area, phenotypic and molecular characterization of nasal MRSA isolates was performed. We report a cluster of pandemic EMRSA-15, an MRSA clone rarely reported from the United States, detected during this study.