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Sensory signals from the body’s visceral organs (e.g. the heart) can robustly influence the perception of exteroceptive sensations. This interoceptive–exteroceptive interaction has been argued to underlie self-awareness by situating one’s perceptual awareness of exteroceptive stimuli in the context of one’s internal state, but studies probing cardiac influences on visual awareness have yielded conflicting findings. In this study, we presented separate grating stimuli to each of subjects’ eyes as in a classic binocular rivalry paradigm – measuring the duration for which each stimulus dominates in perception. However, we caused the gratings to ‘pulse’ at specific times relative to subjects’ real-time electrocardiogram, manipulating whether pulses occurred during cardiac systole, when baroreceptors signal to the brain that the heart has contracted, or in diastole when baroreceptors are silent. The influential ‘Baroreceptor Hypothesis’ predicts the effect of baroreceptive input on visual perception should be uniformly suppressive. In contrast, we observed that dominance durations increased for systole-entrained stimuli, inconsistent with the Baroreceptor Hypothesis. Furthermore, we show that this cardiac-dependent rivalry effect is preserved in subjects who are at-chance discriminating between systole-entrained and diastole-presented stimuli in a separate interoceptive awareness task, suggesting that our results are not dependent on conscious access to heartbeat sensations.

Enterococcus faecium is a microbiota species in humans that can modulate host immunity (Griffin and Hang, 2022), but has also acquired antibiotic resistance and is a major cause of hospital-associated infections (Van Tyne and Gilmore, 2014). Notably, diverse strains of E. faecium produce SagA, a highly conserved peptidoglycan hydrolase that is sufficient to promote intestinal immunity (Rangan et al., 2016; Pedicord et al., 2016; Kim et al., 2019) and immune checkpoint inhibitor antitumor activity (Griffin et al., 2021). However, the functions of SagA in E. faecium were unknown. Here, we report that deletion of sagA impaired E. faecium growth and resulted in bulged and clustered enterococci due to defective peptidoglycan cleavage and cell separation. Moreover, ΔsagA showed increased antibiotic sensitivity, yielded lower levels of active muropeptides, displayed reduced activation of the peptidoglycan pattern-recognition receptor NOD2, and failed to promote cancer immunotherapy. Importantly, the plasmid-based expression of SagA, but not its catalytically inactive mutant, restored ΔsagA growth, production of active muropeptides, and NOD2 activation. SagA is, therefore, essential for E. faecium growth, stress resistance, and activation of host immunity.

Abstract Fin whale (Balaenoptera physalus) song can follow a highly consistent pattern, and regional differences in song patterns can be a valuable indicator of subpopulation identity and distribution. In the Northwest Atlantic, endangered fin whales are currently managed as a single stock despite previous identification of different regional song patterns, which indicates potential subpopulation structuring and vulnerability to anthropogenic disturbance if not managed accordingly. Here we document fin whale song in the New York Bight (NYB) from 2017 to 2020 using passive acoustic data to identify monthly and yearly trends in song patterns and to explore potential subpopulation structuring. The predominant song pattern observed was highly consistent with the pattern documented almost a decade prior in the NYB, with short inter-note intervals (INI) from fall–winter and long-INIs in the spring. However, in one song year the majority of songs were composed of long-INIs. This change in song pattern could be due to a shift in fin whale behavior or possibly multiple fin whale subpopulations using the NYB. Fin whales in the NYB may be particularly vulnerable to disturbance given the increasing anthropogenic pressures in this region, and further research into subpopulation structuring is needed to ensure adequate management of these endangered whales.

Bearing a dismal 5-year survival rate, pancreatic ductal adenocarcinoma (PDAC) is a challenging disease that features a unique fibroinflammatory tumor microenvironment. As major components of the PDAC tumor microenvironment, cancer-associated fibroblasts are still poorly understood and their contribution to the several hallmarks of PDAC, such as resistance to therapies, immunosuppression, and high incidence of metastasis, is likely underestimated. There have been encouraging advances in the understanding of these fascinating cells, but many controversies remain, leaving the field still actively exploring the full scope of their contributions in PDAC progression. Here we pose several important considerations regarding PDAC cancer-associated fibroblast functions. We posit that transcriptomic analyses be interpreted with caution, when aiming to uncover the functional contributions of these cells. Moreover, we propose that normalizing these functions, rather than eliminating them, will provide the opportunity to enhance therapeutic response. Finally, we propose that cancer-associated fibroblasts should not be studied in isolation, but in conjunction with its extracellular matrix, because their respective functions are coordinated and concordant.

Background. Studies have suggested a correlation between periodontitis and reduced male fertility. Inflammation has been described as the link between these ailments. Oral inflammatory load (OIL) can be measured through oral polymorphonuclear neutrophil (oPMN) count, which is associated with periodontal diseases. This cross-sectional study assessed the possible correlation between OIL and the functional parameters of sperm cells. Methods. In 229 volunteers, oral rinse and semen samples were assessed for oPMN, semen polymorphonuclears (sPMNs), sperm concentration, total sperm count, motility, morphology, and sperm DNA fragmentation index (SDFi). A multiple linear regression model was conducted to evaluate the relationships between oPMN and semen parameters. Results. The effect of elevated oPMN counts on total motility rate, progressive rate, and percentage of sperm cells with normal morphology was significant (P

Abstract A central assumption in the behavioral sciences is that choice behavior generalizes enough across individuals that measurements from a sampled group can predict the behavior of the population. Following from this assumption, the unit of behavioral sampling or measurement for most neuroimaging studies is the individual; however, cognitive neuroscience is increasingly acknowledging a dissociation between neural activity that predicts individual behavior and that which predicts the average or aggregate behavior of the population suggesting a greater importance of individual differences than is typically acknowledged. For instance, past work has demonstrated that some, but not all, of the neural activity observed during value-based decision-making is able to predict not just individual subjects’ choices but also the success of products on large, online marketplaces—even when those two behavioral outcomes deviate from one another—suggesting that some neural component processes of decision-making generalize to aggregate market responses more readily across individuals than others do. While the bulk of such research has highlighted affect-related neural responses (i.e. in the nucleus accumbens) as a better predictor of group-level behavior than frontal cortical activity associated with the integration of more idiosyncratic choice components, more recent evidence has implicated responses in visual cortical regions as strong predictors of group preference. Taken together, these findings suggest a role of neural responses during early perception in reinforcing choice consistency across individuals and raise fundamental scientific questions about the role sensory systems in value-based decision-making processes. We use a multivariate pattern analysis approach to show that single-trial visually evoked electroencephalographic (EEG) activity can predict individual choice throughout the post-stimulus epoch; however, a nominally sparser set of activity predicts the aggregate behavior of the population. These findings support an account in which a subset of the neural activity underlying individual choice processes can scale to predict behavioral consistency across people, even when the choice behavior of the sample does not match the aggregate behavior of the population.

BackgroundInfection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can lead to post-acute sequelae of SARS-CoV-2 (PASC) that can persist for weeks to years following initial viral infection. Clinical manifestations of PASC are heterogeneous and often involve multiple organs. While many hypotheses have been made on the mechanisms of PASC and its associated symptoms, the acute biological drivers of PASC are still unknown.MethodsWe enrolled 494 patients with COVID-19 at their initial presentation to a hospital or clinic and followed them longitudinally to determine their development of PASC. From 341 patients, we conducted multi-omic profiling on peripheral blood samples collected shortly after study enrollment to investigate early immune signatures associated with the development of PASC.ResultsDuring the first week of COVID-19, we observed a large number of differences in the immune profile of individuals who were hospitalized for COVID-19 compared to those individuals with COVID-19 who were not hospitalized. Differences between individuals who did or did not later develop PASC were, in comparison, more limited, but included significant differences in autoantibodies and in epigenetic and transcriptional signatures in double-negative 1 B cells, in particular.ConclusionsWe found that early immune indicators of incident PASC were nuanced, with significant molecular signals manifesting predominantly in double-negative B cells, compared with the robust differences associated with hospitalization during acute COVID-19. The emerging acute differences in B cell phenotypes, especially in double-negative 1 B cells, in PASC patients highlight a potentially important role of these cells in the development of PASC.

Purpose: We establish stepwise training program in which laparoscopic suturing is broken down to discrete steps. The purpose is to evaluate the learning outcomes of stepwise training program. Materials and methods: Volunteer participants were enrolled from medical students and surgical trainees. Students took two courses of 2-h stepwise training, and a post-course (1st & 2nd) test was taken after each course; trainees took one course of stepwise training with a pre-course (1st) and a post-course (2nd) test. Attending surgeons took the test as control. Learning outcomes were assessed with laparoscopic suturing competency assessment tool (LS-CAT) and suturing time. Results: There were 10 students, 8 trainees and 6 surgeon controls. Suturing time and LS-CAT scores significantly improved between the 1st and 2nd test (p

BackgroundThe understanding of Post-acute sequelae of SARS-CoV-2 infection (PASC) can be improved by longitudinal assessment of symptoms encompassing the acute illness period. To gain insight into the various disease trajectories of PASC, we assessed symptom evolution and clinical factors associated with the development of PASC over 3 months, starting with the acute illness period.MethodsWe conducted a prospective cohort study to identify parameters associated with PASC. We performed cluster and case control analyses of clinical data, including symptomatology collected over 3 months following infection.ResultsWe identified three phenotypic clusters associated with PASC that could be characterized as remittent, persistent, or incident based on the 3-month change in symptom number compared to study entry: remittent (median; min, max: −4; −17, 3), persistent (−2; −14, 7), or incident (4.5; −5, 17) (p = 0.041 remittent vs. persistent, p < 0.001 remittent vs. incident, p < 0.001 persistent vs. incident). Despite younger age and lower hospitalization rates, the incident phenotype had a greater number of symptoms (15; 8, 24) and a higher proportion of participants with PASC (63.2%) than the persistent (6; 2, 9 and 52.2%) or remittent clusters (1; 0, 6 and 18.7%). Systemic corticosteroid administration during acute infection was also associated with PASC at 3 months [OR (95% CI): 2.23 (1.14, 4.36)].ConclusionAn incident disease phenotype characterized by symptoms that were absent during acute illness and the observed association with high dose steroids during acute illness have potential critical implications for preventing PASC.

Previous research has demonstrated that a night's sleep can consolidate rote and generalized perceptual learning. Over a waking retention period following training, performance gains from learning significantly decline, but sleep can restore performance to levels found immediately after learning. Furthermore, when sleep precedes a waking retention period following training, performance is protected against loss. Other research demonstrating that rote learning can be consolidated by a night's sleep has shown that a relatively brief nap can consolidate rote learning. This suggests that short periods of sleep can produce consolidation, indicating that consolidation may not require successive sleep cycles over an entire night to emerge. However, previous research has demonstrated that there can be differences in sleep-dependent consolidation for rote and generalized learning. In this study, we investigated whether an opportunity for a 90-min midday nap was sufficient to consolidate generalized perceptual learning of synthetic speech. We recruited 75 participants from the University of Chicago community (mean age of 20.83) who completed a pretest, training, and posttest in the morning on perception of synthetic speech. Training and testing in this manner are known to result in substantial generalized learning of synthetic speech. Participants then returned in the afternoon and were either given an opportunity for a 90-min nap or remained awake for 90-min. Participants were then given another posttest later that evening, never hearing the same words twice during the experiment. Results demonstrated that participants who did not nap showed significant loss of learning at the evening posttest. In contrast, individuals who napped retained what they learned, and did not show loss of learning at the evening posttest. These results are consistent with the view that an opportunity for a 90-min midday nap can consolidate generalized learning, as only individuals with consolidated learning should be able to retain what they learned despite an intervening waking retention period. This is the first demonstration that generalized skill learning is subject to sleep-dependent consolidation in short durations of sleep and does not require a full night of sleep. This work has implications for understanding the basic neural mechanisms that operate to stabilize short-term learning experiences.

Abstract Background ReLiAM, Real-Life Assessment of Abilify Maintena, was the first reported long-term prospective non-interventional study for patients with schizophrenia treated with aripiprazole once-monthly injectable formulation (AOM) under real-life conditions. ReLiAM’s primary aim was to evaluate the evolution of global functional status in patients treated with AOM for 12 months in Canada. Methods The objective of this post hoc analysis of the ReLiAM study is to investigate the treatment effects of real-life use of AOM over a 1-year period in the subgroup of patients with reported substance use compared with patients without substance use. Results The results of this post hoc analysis demonstrate that treatment with AOM for 12 months in patients with schizophrenia was comparably effective in improving global functioning in subgroups of patients with and without concomitant substance use. Conclusions These results support the use of AOM for the treatment of schizophrenia in patients with or without concomitant substance use. Trial registration ClinicalTrials.gov NCT02131415, first posted on May 6, 2014. Overall trial status: Terminated.

Abstract Background The antioxidant and anti-inflammatory effects of resveratrol have been reported previously. Particularly, monomeric trans-resveratrol has been demonstrated to produce positive effects in various pathological processes. We reported previously that resveratrol dimer-rich melinjo extract, among others, caused bone healing, decreased local oxidative damage, and activated antioxidants nuclear factor erythroid 2-related factor 2 (Nrf2) pathways in a mouse model of experimentally induced periodontitis (EP). This study aimed to compare the bone-healing effects of the resveratrol monomer to the resveratrol dimer (gnetin C found in melinjo seed extract) in a model of EP and investigate the involvement of Nrf2 for effects of either form of resveratrol. Methods EP was induced experimentally in mice by placement of a 9 − 0 silk ligature around the left second molar. Mice received 10 mg/kg of either resveratrol monomer or dimer intraperitoneally on day 15 after induction of EP. The bone level around the ligated teeth was measured over time, and levels of proinflammatory cytokines and oxidative stress were measured in the periodontal tissues around the ligated teeth. Results Resveratrol dimer induced greater periodontal bone healing as compared to that related to use of the resveratrol monomer. It appears that healing of periodontal bone in either group was likely related to master regulation of antioxidant nuclear factor erythroid 2-related factor 2 (Nrf2) significantly. Downregulation of IL-1β, a proinflammatory cytokine was also demonstrated in the resveratrol dimer group. Conclusion Our results showed that administration of resveratrol in either dimer form or the monomeric form reduced periodontal bone loss with greater inhibition of bone loss being demonstrated in the dimer group as compared to the monomer group and that these effects were related in all likelihood to decreased oxidative stress and hence reduction in local inflammation.

Abstract Pancreatic ductal adenocarcinoma (PDAC) is characterized by an extensive fibroinflammatory stroma and often experiences conditions of insufficient oxygen availability or hypoxia. Cancer-associated fibroblasts (CAF) are a predominant and heterogeneous population of stromal cells within the pancreatic tumor microenvironment. Here, we uncover a previously unrecognized role for hypoxia in driving an inflammatory phenotype in PDAC CAFs. We identify hypoxia as a strong inducer of tumor IL1ɑ expression, which is required for inflammatory CAF (iCAF) formation. Notably, iCAFs preferentially reside in hypoxic regions of PDAC. Our data implicate hypoxia as a critical regulator of CAF heterogeneity in PDAC.

Combining experiments with modeling, Wadhwa et al. propose a model for mechano-adaptation in the bacterial flagellar motor, finding that load-dependent transitions between multiple internal states govern the binding and unbinding of subunits.

Cognitive neuroscientists have been grappling with two related experimental design problems. First, the complexity of neuroimaging data (e.g. often hundreds of thousands of correlated measurements) and analysis pipelines demands bespoke, non-parametric statistical tests for valid inference, and these tests often lack an agreed-upon method for performing a priori power analyses. Thus, sample size determination for neuroimaging studies is often arbitrary or inferred from other putatively but questionably similar studies, which can result in underpowered designs – undermining the efficacy of neuroimaging research. Second, when meta-analyses estimate the sample sizes required to obtain reasonable statistical power, estimated sample sizes can be prohibitively large given the resource constraints of many labs. We propose the use of sequential analyses to partially address both of these problems. Sequential study designs – in which the data is analyzed at interim points during data collection and data collection can be stopped if the planned test statistic satisfies a stopping rule specified a priori – are common in the clinical trial literature, due to the efficiency gains they afford over fixed-sample designs. However, the corrections used to control false positive rates in existing approaches to sequential testing rely on parametric assumptions that are often violated in neuroimaging settings. We introduce a general permutation scheme that allows sequential designs to be used with arbitrary test statistics. By simulation, we show that this scheme controls the false positive rate across multiple interim analyses. Then, performing power analyses for seven evoked response effects seen in the EEG literature, we show that this sequential analysis approach can substantially outperform fixed-sample approaches (i.e. require fewer subjects, on average, to detect a true effect) when study designs are sufficiently well-powered. To facilitate the adoption of this methodology, we provide a Python package “niseq” with sequential implementations of common tests used for neuroimaging: cluster-based permutation tests, threshold-free cluster enhancement, t-max, F-max, and the network-based statistic with tutorial examples using EEG and fMRI data.

Abstract Forage fishes are a critical food web link in marine ecosystems, aggregating in a hierarchical patch structure over multiple spatial and temporal scales. Surface‐level forage fish aggregations (FFAs) represent a concentrated source of prey available to surface‐ and shallow‐foraging marine predators. Existing survey and analysis methods are often imperfect for studying forage fishes at scales appropriate to foraging predators, making it difficult to quantify predator–prey interactions. In many cases, general distributions of forage fish species are known; however, these may not represent surface‐level prey availability to predators. Likewise, we lack an understanding of the oceanographic drivers of spatial patterns of prey aggregation and availability or forage fish community patterns. Specifically, we applied Bayesian joint species distribution models to bottom trawl survey data to assess species‐ and community‐level forage fish distribution patterns across the US Northeast Continental Shelf (NES) ecosystem. Aerial digital surveys gathered data on surface FFAs at two project sites within the NES, which we used in a spatially explicit hierarchical Bayesian model to estimate the abundance and size of surface FFAs. We used these models to examine the oceanographic drivers of forage fish distributions and aggregations. Our results suggest that, in the NES, regions of high community species richness are spatially consistent with regions of high surface FFA abundance. Bathymetric depth drove both patterns, while subsurface features, such as mixed layer depth, primarily influenced aggregation behavior and surface features, such as sea surface temperature, sub‐mesoscale eddies, and fronts influenced forage fish diversity. In combination, these models help quantify the availability of forage fishes to marine predators and represent a novel application of spatial models to aerial digital survey data.

The New York-New Jersey (NY-NJ) Harbour Estuary and surrounding waters support the largest port along the U.S. East Coast, commercial and recreational fishing, and a burgeoning offshore wind energy industry. Despite the high level of anthropogenic use, cetacean sightings have increased in recent years. Here, we investigated the spatiotemporal distribution of harbour porpoise in the NY-NJ Harbour Estuary from 2018–2020 using six archival acoustic recorders. Generalised additive mixed models were used to explore the relationship between weekly harbour porpoise presence and environmental variables. Harbour porpoises were detected at low levels year-round, with seasonal peaks in presence in winter to spring (February to June). Sea surface temperature and chlorophyll-a concentration were significant predictors of harbour porpoise presence, although the relationship warrants further investigation. Our results provide valuable insight into harbour porpoise distribution in the NY-NJ Harbour Estuary, which is likely related to oceanographic processes affecting prey availability. This information is timely for informing mitigation and management actions for forthcoming offshore wind energy development. Harbour porpoises are vulnerable to a range of anthropogenic impacts that have led to population declines in other regions, and therefore further research efforts are recommended for the NY-NJ Harbour Estuary and greater New York Bight.

Introduction: Delandistrogene moxeparvovec (SRP-9001) is an investigational gene transfer therapy designed for targeted expression of SRP-9001 dystrophin protein, a shortened dystrophin retaining key functional domains of the wild-type protein.Methods: This Phase 2, double-blind, two-part (48 weeks per part) crossover study (SRP-9001-102 [Study 102]; NCT03769116) evaluated delandistrogene moxeparvovec in patients, aged ≥4 to

The use of continuous glucose monitors (CGMs) in individuals living without diabetes is increasing. The purpose of this study was to profile various CGM metrics around nutritional intake, sleep and exercise in a large cohort of physically active men and women living without any known metabolic disease diagnosis to better understand the normative glycemic response to these common stimuli. A total of 12,504 physically active adults (age 40 ± 11 years, BMI 23.8 ± 3.6 kg/m2; 23% self-identified as women) wore a real-time CGM (Abbott Libre Sense Sport Glucose Biosensor, Abbott, USA) and used a smartphone application (Supersapiens Inc., Atlanta, GA, USA) to log meals, sleep and exercise activities. A total of >1 M exercise events and 274,344 meal events were analyzed. A majority of participants (85%) presented an overall (24 h) average glucose profile between 90 and 110 mg/dL, with the highest glucose levels associated with meals and exercise and the lowest glucose levels associated with sleep. Men had higher mean 24 h glucose levels than women (24 h—men: 100 ± 11 mg/dL, women: 96 ± 10 mg/dL). During exercise, the % time above >140 mg/dL was 10.3 ± 16.7%, while the % time p < 0.001). Overall, we see small differences in glucose trends during activity and sleep in females as compared to males and higher levels of both TAR and TBR when these active individuals are undertaking or competing in endurance exercise training and/or competitive events.

Treatment options for alcohol use disorders (AUDs) have minimally advanced since 2004, while the annual deaths and economic toll have increased alarmingly. Phosphodiesterase type 4 (PDE4) is associated with alcohol and nicotine dependence. PDE4 inhibitors were identified as a potential AUD treatment using a bioinformatics approach. We prioritized a newer PDE4 inhibitor, apremilast, as ideal for repurposing (i.e., FDA approved for psoriasis, low incidence of adverse events, excellent safety profile) and tested it using multiple animal strains and models, as well as in a human phase IIa study. We found that apremilast reduced binge-like alcohol intake and behavioral measures of alcohol motivation in mouse models of genetic risk for drinking to intoxication. Apremilast also reduced excessive alcohol drinking in models of stress-facilitated drinking and alcohol dependence. Using site-directed drug infusions and electrophysiology, we uncovered that apremilast may act to lessen drinking in mice by increasing neural activity in the nucleus accumbens, a key brain region in the regulation of alcohol intake. Importantly, apremilast (90 mg/d) reduced excessive drinking in non–treatment-seeking individuals with AUD in a double-blind, placebo-controlled study. These results demonstrate that apremilast suppresses excessive alcohol drinking across the spectrum of AUD severity.

Background Inequitable access to high‐technology therapeutics may perpetuate inequities in care. We examined the characteristics of US hospitals that did and did not establish left atrial appendage occlusion (LAAO) programs, the patient populations those hospitals served, and the associations between zip code–level racial, ethnic, and socioeconomic composition and rates of LAAO among Medicare beneficiaries living within large metropolitan areas with LAAO programs. Methods and Results We conducted cross‐sectional analyses of Medicare fee‐for‐service claims for beneficiaries aged 66 years or older between 2016 and 2019. We identified hospitals establishing LAAO programs during the study period. We used generalized linear mixed models to measure the association between zip code–level racial, ethnic, and socioeconomic composition and age‐adjusted rates of LAAO in the most populous 25 metropolitan areas with LAAO sites. During the study period, 507 candidate hospitals started LAAO programs, and 745 candidate hospitals did not. Most new LAAO programs opened in metropolitan areas (97.4%). Compared with non‐LAAO centers, LAAO centers treated patients with higher median household incomes (difference of $913 [95% CI, $197–$1629], P=0.01). Zip code–level rates of LAAO procedures per 100 000 Medicare beneficiaries in large metropolitan areas were 0.34% (95% CI, 0.33%–0.35%) lower for each $1000 zip code–level decrease in median household income. After adjustment for socioeconomic markers, age, and clinical comorbidities, LAAO rates were lower in zip codes with higher proportions of Black or Hispanic patients. Conclusions Growth in LAAO programs in the United States had been concentrated in metropolitan areas. LAAO centers treated wealthier patient populations in hospitals without LAAO programs. Within major metropolitan areas with LAAO programs, zip codes with higher proportions of Black and Hispanic patients and more patients experiencing socioeconomic disadvantage had lower age‐adjusted rates of LAAO. Thus, geographic proximity alone may not ensure equitable access to LAAO. Unequal access to LAAO may reflect disparities in referral patterns, rates of diagnosis, and preferences for using novel therapies experienced by racial and ethnic minority groups and patients experiencing socioeconomic disadvantage.

Interferon-induced transmembrane proteins (IFITM1, 2 and 3) are important host antiviral defense factors. They are active against viruses like the influenza A virus (IAV), dengue virus (DENV), Ebola virus (EBOV), Zika virus (ZIKV) and severe acute respiratory syndrome coronavirus (SARS-CoV). In this review, we focus on IFITM3 S-palmitoylation, a reversible lipid modification, and describe its role in modulating IFITM3 antiviral activity. Our laboratory discovered S-palmitoylation of IFITMs using chemical proteomics and demonstrated the importance of highly conserved fatty acid-modified Cys residues in IFITM3 antiviral activity. Further studies showed that site-specific S-palmitoylation at Cys72 is important for IFITM3 trafficking to restricted viruses (IAV and EBOV) and membrane–sterol interactions. Thus, site-specific lipid modification of IFITM3 directly regulates its antiviral activity, cellular trafficking, and membrane-lipid interactions.

Abstract Background Individuals with mental health problems have many insufficiently met support needs. Across sociocultural contexts, various parties (e.g., governments, families, persons with mental health problems) assume responsibility for meeting these needs. However, key stakeholders' opinions of the relative responsibilities of these parties for meeting support needs remain largely unexplored. This is a critical knowledge gap, as these perceptions may influence policy and caregiving decisions. Methods Patients with first-episode psychosis (n = 250), their family members (n = 228), and clinicians (n = 50) at two early intervention services in Chennai, India and Montreal, Canada were asked how much responsibility they thought the government versus persons with mental health problems; the government versus families; and families versus persons with mental health problems should bear for meeting seven support needs of persons with mental health problems (e.g., housing; help covering costs of substance use treatment; etc.). Two-way analyses of variance were conducted to examine differences in ratings of responsibility between sites (Chennai, Montreal); raters (patients, families, clinicians); and support needs. Results Across sites and raters, governments were held most responsible for meeting each support need and all needs together. Montreal raters assigned more responsibility to the government than did Chennai raters. Compared to those in Montreal, Chennai raters assigned more responsibility to families versus persons with mental health problems, except for the costs of substance use treatment. Family raters across sites assigned more responsibility to governments than did patient raters, and more responsibility to families versus persons with mental health problems than did patient and clinician raters. At both sites, governments were assigned less responsibility for addressing housing- and school/work reintegration-related needs compared to other needs. In Chennai, the government was seen as most responsible for stigma reduction and least for covering substance use services. Conclusions All stakeholders thought that governments should have substantial responsibility for meeting the needs of individuals with mental health problems, reinforcing calls for greater government investment in mental healthcare across contexts. The greater perceived responsibility of the government in Montreal and of families in Chennai may both reflect and influence differences in cultural norms and healthcare systems in India and Canada.

Abstract Background Individuals with mental health problems have multiple, often inadequately met needs. Responsibility for meeting these needs frequently falls to patients, their families/caregivers, and governments. Little is known about stakeholders' views of who should be responsible for these needs and there are no measures to assess this construct. This study’s objectives were to present the newly designed Whose Responsibility Scale (WRS), which assesses how stakeholders apportion responsibility to persons with mental health problems, their families, and the government for addressing various needs of persons with mental health problems, and to report its psychometric properties. Methods The 22-item WRS asks respondents to assign relative responsibility to the government versus persons with mental health problems, government versus families, and families versus persons with mental health problems for seven support needs. The items were modelled on a World Values Survey item comparing the government’s and people’s responsibility for ensuring that everyone is provided for. We administered English, Tamil, and French versions to 57 patients, 60 family members, and 27 clinicians at two early psychosis programs in Chennai, India, and Montreal, Canada, evaluating test–retest reliability, internal consistency, and ease of use. Internal consistency estimates were also calculated for confirmatory purposes with the larger samples from the main comparative study. Results Test–retest reliability (intra-class correlation coefficients) generally ranged from excellent to fair across stakeholders (patients, families, and clinicians), settings (Montreal and Chennai), and languages (English, French, and Tamil). In the standardization and larger confirmatory samples, internal consistency estimates (Cronbach’s alphas) ranged from acceptable to excellent. The WRS scored average on ease of comprehension and completion. Scores were spread across the 1–10 range, suggesting that the scale captured variations in views on how responsibility for meeting needs should be distributed. On select items, scores at one end of the scale were never endorsed, but these reflected expected views about specific needs (e.g., Chennai patients never endorsed patients as being substantially more responsible for housing needs than families). Conclusions The WRS is a promising measure for use across geo-cultural contexts to inform mental health policies, and to foster dialogue and accountability among stakeholders about roles and responsibilities. It can help researchers study stakeholders’ views about responsibilities, and how these shape and are shaped by sociocultural contexts and mental healthcare systems.

Immune responses to pancreatic ductal adenocarcinoma can be inhibited by cancer cells. Here the authors show that high levels of progranulin in PDAC inhibits immune responses by reducing MHC class I antigen presentation through enhanced degradation of MHC class I via autophagy.

Background & Aims: Inactivating mutations of KDM6A, a histone demethylase, were frequently found in pancreatic ductal adenocarcinoma (PDAC). We investigated the role of KDM6A (lysine demethylase 6A) in PDAC development. Methods: We performed a pancreatic tissue microarray analysis of KDM6A protein levels. We used human PDAC cell lines for KDM6A knockout and knockdown experiments. We performed bromouridine sequencing analysis to elucidate the effects of KDM6A loss on global transcription. We performed studies with Ptf1aCre; LSL-KrasG12D; Trp53R172H/+; Kdm6afl/fl or fl/Y, Ptf1aCre; Kdm6afl/fl or fl/Y, and orthotopic xenograft mice to investigate the impacts of Kdm6a deficiency on pancreatic tumorigenesis and pancreatitis. Results: Loss of KDM6A was associated with metastasis in PDAC patients. Bromouridine sequencing analysis showed up-regulation of the epithelial–mesenchymal transition pathway in PDAC cells deficient in KDM6A. Loss of KDM6A promoted mesenchymal morphology, migration, and invasion in PDAC cells in vitro. Mechanistically, activin A and subsequent p38 activation likely mediated the role of KDM6A loss. Inhibiting either activin A or p38 reversed the effect. Pancreas-specific Kdm6a-knockout mice pancreata showed accelerated PDAC progression, developed a more aggressive undifferentiated type of PDAC, and increased metastases in the background of Kras and p53 mutations. Kdm6a-deficient pancreata in a pancreatitis model had a delayed recovery with increased PDAC precursor lesions compared with wild-type pancreata. Conclusions: Loss of KDM6A accelerates PDAC progression and metastasis, most likely by a noncanonical p38-dependent activin A pathway. KDM6A also promotes pancreatic tissue recovery from pancreatitis. Activin A might be used as a therapeutic target for KDM6A-deficient PDACs.

Background & Aims: Oncogenic Kirsten Rat Sarcoma virus (KRAS) is the hallmark mutation of human pancreatic cancer and a driver of tumorigenesis in genetically engineered mouse models of the disease. Although the tumor cell–intrinsic effects of oncogenic Kras expression have been widely studied, its role in regulating the extensive pancreatic tumor microenvironment is less understood. Methods: Using a genetically engineered mouse model of inducible and reversible oncogenic Kras expression and a combination of approaches that include mass cytometry and single-cell RNA sequencing we studied the effect of oncogenic KRAS in the tumor microenvironment. Results: We have discovered that non–cell autonomous (ie, extrinsic) oncogenic KRAS signaling reprograms pancreatic fibroblasts, activating an inflammatory gene expression program. As a result, fibroblasts become a hub of extracellular signaling, and the main source of cytokines mediating the polarization of protumorigenic macrophages while also preventing tissue repair. Conclusions: Our study provides fundamental knowledge on the mechanisms underlying the formation of the fibroinflammatory stroma in pancreatic cancer and highlights stromal pathways with the potential to be exploited therapeutically.

An extensive fibroinflammatory stroma rich in macrophages is a hallmark of pancreatic cancer. In this disease, it is well appreciated that macrophages are immunosuppressive and contribute to the poor response to immunotherapy; however, the mechanisms of immune suppression are complex and not fully understood. Immunosuppressive macrophages are classically defined by the expression of the enzyme Arginase 1 (ARG1), which we demonstrated is potently expressed in pancreatic tumor-associated macrophages from both human patients and mouse models. While routinely used as a polarization marker, ARG1 also catabolizes arginine, an amino acid required for T cell activation and proliferation. To investigate this metabolic function, we used a genetic and a pharmacologic approach to target Arg1 in pancreatic cancer. Genetic inactivation of Arg1 in macrophages, using a dual recombinase genetically engineered mouse model of pancreatic cancer, delayed formation of invasive disease, while increasing CD8+ T cell infiltration. Additionally, Arg1 deletion induced compensatory mechanisms, including Arg1 overexpression in epithelial cells, namely Tuft cells, and Arg2 overexpression in a subset of macrophages. To overcome these compensatory mechanisms, we used a pharmacological approach to inhibit arginase. Treatment of established tumors with the arginase inhibitor CB-1158 exhibited further increased CD8+ T cell infiltration, beyond that seen with the macrophage-specific knockout, and sensitized the tumors to anti-PD1 immune checkpoint blockade. Our data demonstrate that Arg1 drives immune suppression in pancreatic cancer by depleting arginine and inhibiting T cell activation.

Abstract North Atlantic right whale (NARW) distribution shifts have led to increased presence in the US mid‐Atlantic, which includes the New York Bight (NYB), an area with substantial vessel traffic. NARW vessel strikes are mitigated by a seasonal management area (SMA) that is active November–April. Within the SMA, vessels ≥ 19.8 m must travel at ≤10 knots. However, until recently, surveys of the NYB were not conducted after the NARW distribution shifted. Thus, it was unclear whether the SMA captured NARW presence in the NYB. Outside the SMA, voluntary speed restrictions are implemented over a limited area when NARW calls are acoustically detected; therefore, it was important to quantify NARW vocal activity. Acoustic recordings (2016–2020) were analyzed to determine NARW presence, vocal states, and diel pattern of vocal activity. NARWs were detected outside SMA boundaries, and medium/high vocal states (21–69 calls over 3–6 h) occurred while the SMA was inactive. Therefore, the SMA spatiotemporal boundaries should be revised. Vocal activity was highest at night (22:00–1:00), and NARWs were acoustically detected when they were not detected by aerial surveys, illustrating acoustic detections are a viable method for triggering mitigation measures when NARWs are vocalizing but are not visually observed.

The metaverse—a virtual world accessed via virtual reality technology—has been heralded as the next key digital experience. It is meant to provide the next evolution of human interaction after social media and telework. However, in the context of the growing awareness of the risks to mental health posed by current social media technologies, there is a great deal of uncertainty as to the potential effects of this new technology on mental health. This uncertainty is compounded by a lack of clarity regarding what form the metaverse will ultimately take and how widespread its application will be. Despite this, given the nascent state of the metaverse, there is an opportunity to plan the research and regulatory approaches needed to understand it and promote its positive effects while protecting vulnerable groups. In this viewpoint, we examine the following three current technologies whose functions comprise a portion of what the metaverse seeks to accomplish: teleworking, virtual reality, and social media. We attempted to understand in what ways the metaverse may have similar benefits and pitfalls to these technologies but also how it may fundamentally differ from them. These differences suggest potential research questions to be addressed in future work. We found that current technologies have enabled tools such as virtual reality–assisted therapy, avatar therapy, and teletherapy, which have had positive effects on mental health care, and that the metaverse may provide meaningful improvements to these tools. However, given its similarities to social media and its expansion upon the social media experience, the metaverse raises some of the same concerns that we have with social media, such as the possible exacerbation of certain mental health problems. These concerns led us to consider questions such as how the users will be protected and what regulatory mechanisms will be put in place to ensure user safety. Although clear answers to these questions are challenging in this early phase of metaverse research, in this viewpoint, we use the context provided by comparator technologies to provide recommendations to maximize the potential benefits and limit the putative harms of the metaverse. We hope that this paper encourages discussions among researchers and policy makers.

The human microbiota acts as a diverse source of molecular cues that influence the development and homeostasis of the immune system. Beyond endogenous roles in the human holobiont, host-microbial interactions also alter outcomes for immune-related diseases and treatment regimens. Over the past decade, sequencing analyses of cancer patients have revealed correlations between microbiota composition and the efficacy of cancer immunotherapies such as checkpoint inhibitors. However, very little is known about the exact mechanisms that link specific microbiota with patient responses, limiting our ability to exploit these microbial agents for improved oncology care. Here, we summarize current progress towards a molecular understanding of host-microbial interactions in the context of checkpoint inhibitor immunotherapies. By highlighting the successes of a limited number of studies focused on identifying specific, causal molecules, we underscore how the exploration of specific microbial features such as proteins, enzymes, and metabolites may translate into precise and actionable therapies for personalized patient care in the clinic.

The aspartate aminotransaminase GOT1 is important for maintaining redox balance. Here, the authors show that inhibition of GOT1 in pancreatic cancer cells leads to cell death via ferroptosis.

Abstract Primary cilia protrude from the apical surface of many cell types and act as a sensory organelle that regulates diverse biological processes ranging from chemo- and mechanosensation to signaling. Ciliary dysfunction is associated with a wide array of genetic disorders, known as ciliopathies. Polycystic lesions are commonly found in the kidney, liver, and pancreas of ciliopathy patients and mouse models. However, the pathogenesis of the pancreatic phenotype remains poorly understood. Chibby1 (Cby1), a small conserved coiled-coil protein, localizes to the ciliary base and plays a crucial role in ciliogenesis. Here, we report that Cby1-knockout (KO) mice develop severe exocrine pancreatic atrophy with dilated ducts during early postnatal development. A significant reduction in the number and length of cilia was observed in Cby1-KO pancreta. In the adult Cby1-KO pancreas, inflammatory cell infiltration and fibrosis were noticeable. Intriguingly, Cby1-KO acinar cells showed an accumulation of zymogen granules (ZGs) with altered polarity. Moreover, isolated acini from Cby1-KO pancreas exhibited defective ZG secretion in vitro. Collectively, our results suggest that, upon loss of Cby1, concomitant with ciliary defects, acinar cells accumulate ZGs due to defective exocytosis, leading to cell death and progressive exocrine pancreatic degeneration after birth.

Abstract Background and Aim Liver histology changes are the current gold standard for evaluating non‐alcoholic steatohepatitis (NASH), but are limited by their invasiveness and variability for sampling and interpretation. We evaluated noninvasive biomarkers as an indication of histologic changes in NASH. Methods Associations between 12‐month biomarker and NASH Clinical Research Network histologic score changes in 339 patients with NASH in the EMMINENCE trial was examined with multivariable models and partial canonical correlation. A meta‐analysis of 17 NASH trials including 3717 patients examined associations between these same changes and histologic response within treatment groups, and treatment effects on biomarkers and on liver histology. Biopsy measures assessed were changes in ballooning, steatosis, inflammation, and fibrosis, NASH improvement without worsening of fibrosis, and fibrosis improvement without worsening of NASH. All analytic methods suggest that a combination of aspartate aminotransferase (AST), cytokeratin‐18 (CK‐18 [M30 or M65]), and hemoglobin A1C (HbA1c) changes best predicts overall liver biopsy changes in response to interventions. Results The weighted average of standardized mean changes (0.403 × AST, 0.314 × CK‐18, 0.283 × HbA1c) facilitated comparisons of within‐group responses and treatment effects among studies included in the meta‐analysis. This composite in EMMINENCE discriminated between patients with and without NASH resolution without worsening fibrosis with area under the receiver‐operator characteristic curve of 0.7880, and for fibrosis improvement without NASH worsening of 0.7553. Conclusion A composite score based on changes in AST, HbA1c, and CK‐18 could serve as a surrogate for liver histologic improvement and an effective objective, noninvasive tool for comparative assessment of treatment effects of novel interventions.

Abstract The frequency-following response (FFR) provides a measure of phase-locked auditory encoding in humans and has been used to study subcortical processing in the auditory system. While effects of experience on the FFR have been reported, few studies have examined whether individual differences in early sensory encoding have measurable effects on human performance. Absolute pitch (AP), the rare ability to label musical notes without reference notes, provides an excellent model system for testing how early neural encoding supports specialized auditory skills. Results show that the FFR predicts pitch labelling performance better than traditional measures related to AP (age of music onset, tonal language experience, pitch adjustment and just-noticeable-difference scores). Moreover, the stimulus type used to elicit the FFR (tones or speech) impacts predictive performance in a manner that is consistent with prior research. Additionally, the FFR predicts labelling performance for piano tones better than unfamiliar sine tones. Taken together, the FFR reliably distinguishes individuals based on their explicit pitch labeling abilities, which highlights the complex dynamics between sensory processing and cognition.

Marine protected areas (MPAs), particularly large MPAs, are increasing in number and size around the globe in part to facilitate the conservation of marine megafauna under the assumption that large-scale MPAs better align with vagile life histories; however, this alignment is not well established. Using a global tracking dataset from 36 species across five taxa, chosen to reflect the span of home range size in highly mobile marine megafauna, we show most MPAs are too small to encompass complete home ranges of most species. Based on size alone, 40% of existing MPAs could encompass the home ranges of the smallest ranged species, while only < 1% of existing MPAs could encompass those of the largest ranged species. Further, where home ranges and MPAs overlapped in real geographic space, MPAs encompassed < 5% of core areas used by all species. Despite most home ranges of mobile marine megafauna being much larger than existing MPAs, we demonstrate how benefits from MPAs are still likely to accrue by targeting seasonal aggregations and critical life history stages and through other management techniques.

Proper Hedgehog (HH) signaling is essential for embryonic development, while aberrant HH signaling drives pediatric and adult cancers. HH signaling is frequently dysregulated in pancreatic cancer, yet its role remains controversial, with both tumor-promoting and tumor-restraining functions reported. Notably, the GLI family of HH transcription factors (GLI1, GLI2, GLI3), remain largely unexplored in pancreatic cancer. We therefore investigated the individual and combined contributions of GLI1-3 to pancreatic cancer progression. At pre-cancerous stages, fibroblast-specific Gli2/Gli3 deletion decreases immunosuppressive macrophage infiltration and promotes T cell infiltration. Strikingly, combined loss of Gli1/Gli2/Gli3 promotes macrophage infiltration, indicating that subtle changes in Gli expression differentially regulate immune infiltration. In invasive tumors, Gli2/Gli3 KO fibroblasts exclude immunosuppressive myeloid cells and suppress tumor growth by recruiting natural killer cells. Finally, we demonstrate that fibroblasts directly regulate macrophage and T cell migration through the expression of Gli-dependent cytokines. Thus, the coordinated activity of GLI1-3 directs the fibroinflammatory response throughout pancreatic cancer progression.

Mitochondrial glutamate-oxaloacetate transaminase 2 (GOT2) is part of the malate-aspartate shuttle, a mechanism by which cells transfer reducing equivalents from the cytosol to the mitochondria. GOT2 is a key component of mutant KRAS (KRAS*)-mediated rewiring of glutamine metabolism in pancreatic ductal adenocarcinoma (PDA). Here, we demonstrate that the loss of GOT2 disturbs redox homeostasis and halts proliferation of PDA cells in vitro. GOT2 knockdown (KD) in PDA cell lines in vitro induced NADH accumulation, decreased Asp and α-ketoglutarate (αKG) production, stalled glycolysis, disrupted the TCA cycle, and impaired proliferation. Oxidizing NADH through chemical or genetic means resolved the redox imbalance induced by GOT2 KD, permitting sustained proliferation. Despite a strong in vitro inhibitory phenotype, loss of GOT2 had no effect on tumor growth in xenograft PDA or autochthonous mouse models. We show that cancer-associated fibroblasts (CAFs), a major component of the pancreatic tumor microenvironment (TME), release the redox active metabolite pyruvate, and culturing GOT2 KD cells in CAF conditioned media (CM) rescued proliferation in vitro. Furthermore, blocking pyruvate import or pyruvate-to-lactate reduction prevented rescue of GOT2 KD in vitro by exogenous pyruvate or CAF CM. However, these interventions failed to sensitize xenografts to GOT2 KD in vivo, demonstrating the remarkable plasticity and differential metabolism deployed by PDA cells in vitro and in vivo. This emphasizes how the environmental context of distinct pre-clinical models impacts both cell-intrinsic metabolic rewiring and metabolic crosstalk with the TME.

Background The neutrophil‐to‐lymphocyte ratio (NLR) as a marker of systemic inflammation has been associated with worse prognosis in several chronic disease states, including heart failure. However, few data exist on the prognostic impact of elevated baseline NLR or change in NLR levels during follow‐up in patients undergoing transcatheter or surgical aortic valve replacement (TAVR or SAVR) for aortic stenosis. Methods and Results NLR was available in 5881 patients with severe aortic stenosis receiving TAVR or SAVR in PARTNER (Placement of Aortic Transcatheter Valves) I, II, and S3 trials/registries (median [Q1, Q3] NLR, 3.30 [2.40, 4.90]); mean NLR, 4.10; range, 0.5–24.9) and was evaluated as continuous variable and categorical tertiles (low: NLR ≤2.70, n=1963; intermediate: NLR 2.70–4.20, n=1958; high: NLR ≥4.20, n=1960). No patients had known baseline infection. High baseline NLR was associated with increased risk of death or rehospitalization at 3 years (58.4% versus 41.0%; adjusted hazard ratio [aHR], 1.39; 95% CI, 1.18–1.63; P

Data from 318 diverse high school students from three different types of high schools in the United States were collected. School types varied by location (e.g., suburban, urban), size, and student demographics (e.g., race, ethnicity, socioeconomic status). Exploratory Factor Analysis (EFA) was conducted to examine the factor structure of the STRESS-Y. Mean comparisons were performed to assess variations in Racial Stress Appraisal across different school types. The EFA of the STRESS-Y confirmed its factor structure, supporting its validity as a measure of RSA in youth and we were able to extract two robust factors--Racial Threat Appraisal and Racial Support Appraisal. Mean comparisons revealed that Racial Threat Appraisal and Racial Support Appraisal varied across different school types, highlighting the influence of school context on students' experiences of racial stress. This study provides evidence for the validity of the STRESS-Y as a measure of Racial Stress Appraisal in youth. The findings demonstrate the importance of considering school type as a factor influencing students' experiences of racial stress as well as how support, racial coping, and stress management skills may help mitigate ongoing interpersonal harm that youth are experiencing. The validated measure and the understanding of the factors contributing to Racial Stress Appraisal can inform interventions aimed at supporting students in managing and coping with racial stressors in their respective school environments.

We describe 4 cases in which technical challenges were anticipated in delivering a self-expanding TAVR valve due to challenging aortic anatomy or a previous placed surgical aortic valve. An upfront snare strategy is described which facilitates valve centralization and atraumatic valve delivery. (Level of Difficulty: Advanced.)

We describe the case of an 83-year-old man with a history of ischemic cardiomyopathy and severe secondary mitral regurgitation. This case highlights the role of transcatheter edge-to-edge repair with the MitraClip in the management of symptomatic functional mitral regurgitation in a surgically unfavorable patient. (Level of Difficulty: Advanced.)

Cancer-associated fibroblasts (CAFs) execute diverse and complex functions in cancer progression. While reprogramming the crosstalk between CAFs and cancer epithelial cells is a promising avenue to evade the adverse effects of stromal depletion, drugs are limited by their suboptimal pharmacokinetics and off-target effects. Thus, there is a need to elucidate CAF-selective cell surface markers that can improve drug delivery and efficacy. Here, functional proteomic pulldown with mass spectrometry was used to identify taste receptor type 2 member 9 (TAS2R9) as a CAF target. TAS2R9 target characterization included binding assays, immunofluorescence, flow cytometry, and database mining. Liposomes conjugated to a TAS2R9-specific peptide were generated, characterized, and compared to naked liposomes in a murine pancreatic xenograft model. Proof-of-concept drug delivery experiments demonstrate that TAS2R9-targeted liposomes bind with high specificity to TAS2R9 recombinant protein and exhibit stromal colocalization in a pancreatic cancer xenograft model. Furthermore, the delivery of a CXCR2 inhibitor by TAS2R9-targeted liposomes significantly reduced cancer cell proliferation and constrained tumor growth through the inhibition of the CXCL-CXCR2 axis. Taken together, TAS2R9 is a novel cell-surface CAF-selective target that can be leveraged to facilitate small-molecule drug delivery to CAFs, paving the way for new stromal therapies.

Pancreatic ductal adenocarcinoma (PDA), the most common pancreatic cancer, is a nearly universally lethal malignancy. PDA is characterized by extensive infiltration of immunosuppressive myeloid cells, including tumor-associated macrophages and myeloid-derived suppressor cells. Myeloid cells in the tumor microenvironment inhibit cytotoxic T-cell responses promoting carcinogenesis. Immune checkpoint therapy has not been effective in PDA, most likely because of this robust immune suppression, making it critical to elucidate mechanisms behind this phenomenon. Here, we review myeloid cell infiltration and cellular crosstalk in PDA progression and highlight current therapeutic approaches to target myeloid cell-driven immune suppression.

Abstract As part of the Post‐2020 Biodiversity Framework, nations are assessing progress over the past decade in addressing the underlying drivers that influence direct pressures on biodiversity and formulating new policies and strategies for the decade to come. For marine conservation, global marine protected area (MPA) coverage is still falling short of the 10% target set in 2010. Here we show that while this reflects a lack of progress in many low‐ and middle‐income countries, a few of these nations have met or exceeded international commitments. To provide an in‐depth explanation of how this was achieved in Gabon, we summarize the lessons learnt by our consortium of policy makers and practitioners who helped implement a comprehensive and ecologically representative network of 20 MPAs. We show the importance of creating a national framework, building long‐term stakeholder support, and focusing on research that guides implementation and policy; and outline a four‐step approach that countries and donors could use as an example to help meet international commitments. By responding to calls to share lessons learned to inform future Convention on Biological Diversity targets, we show how Gabon's experiences could inform change elsewhere.

Summary: In Caenorhabditis elegans, sensory neurons mediate behavioral response to pathogens. However, how C. elegans intergrades these sensory signals via downstream neuronal and molecular networks remains largely unknown. Here, we report that glutamate transmission mediates behavioral plasticity to Pseudomonas aeruginosa. Deletion in VGLUT/eat-4 renders the mutant animals unable to elicit either an attractive or an aversive preference to a lawn of P. aeruginosa. AMPA-type glutamate receptor GLR-1 promotes the avoidance response to P. aeruginosa. SOD-1 acts downstream of GLR-1 in the cholinergic motor neurons. SOD-1 forms a punctate structure and is localized next to GLR-1 at the ventral nerve cord. Finally, single-copy ALS-causative sod-1 point mutation acts as a loss-of-function allele in both pathogen avoidance and glr-1 dependent phenotypes. Our data showed a link between glutamate signaling and redox homeostasis in C. elegans pathogen response and may provide potential insights into the pathology triggered by oxidative stress in the nervous system.

Abstract Though dentin hypersensitivity (DHS) is one of the most common complaints from patients in dental clinics, there are no universally accepted guidelines for differential diagnosis as well as selection of reliable treatment modalities for this condition. The neurosensory mechanisms underlying DHS remain unclear, but fluid movements within exposed dentinal tubules, i.e., the hydrodynamic theory, has been a widely accepted explanation for DHS pain. As several dental conditions have symptoms that mimic DHS at different stages of their progression, diagnosis and treatment of DHS are often confusing, especially for inexperienced dental practitioners. In this paper we provide an up-to-date review on risk factors that play a role in the development and chronicity of DHS and summarize the current principles and strategies for differential diagnosis and management of DHS in dental practices. We will outline the etiology, predisposing factors and the underlying putative mechanisms of DHS, and provide principles and indications for its diagnosis and management. Though desensitization remains to be the first choice for DHS for many dental practitioners and most of desensitizing agents reduce the symptoms of DHS by occluding patent dentinal tubules, the long-term outcome of such treatment is uncertain. With improved understanding of the underlying nociceptive mechanisms of DHS, it is expected that promising novel therapies will emerge and provide more effective relief for patients with DHS.

Argonaute 2 (AGO2) binds RAS and is required for cellular transformation. Here, the authors establish a KRAS-driven mouse model of pancreatic cancer with conditional loss of AGO2 and show that the early phase of neoplastic lesion initiation is dependent on EGFR/RAS but not AGO2, while AGO2 is required for pancreatic ductal adenocarcinoma progression and metastasis.

Abstract The impact of oral health inequalities on one’s ability to maintain good oral health is cumulative throughout life and accentuated in older age groups. While studies on factors influencing the decisions made by elders to seek dental care have been conducted in Israel and worldwide, the issue of access to and provision of dental care is complex. However, the need to address oral health issues is being voiced in high-level international meetings and there was never a better momentum to rethink the current oral health care delivery model beyond issues related solely to accessibility. Here we outline unique opportunities to ensure sustainable models of preventive services and oral health the effects of which would be amplified in concert with increases in the availability universal dental healthcare.