HILPDA promotes NASH-driven HCC development by restraining intracellular fatty acid flux in hypoxia.

BACKGROUND & AIMS: The prevalence of non-alcoholic steatohepatitis (NASH)-driven hepatocellular carcinoma (HCC) is rising rapidly, yet its underlying mechanisms remain unclear. Herein, we aim to determine the role of hypoxia-inducible lipid droplet associated protein (HILPDA)/hypoxia-inducible gene 2 (HIG2), a selective inhibitor of intracellular lipolysis, in NASH-driven HCC. METHODS: The clinical significance of HILPDA was assessed in human NASH-driven HCC specimens by immunohistochemistry and transcriptomics analyses. The oncogenic effect of HILPDA was assessed in human HCC cells and in 3D epithelial spheroids upon exposure to free fatty acids and either normoxia or hypoxia. Lipidomics profiling of wild-type and HILPDA knockout HCC cells was assessed via shotgun and targeted approaches. Wild-type (Hilpdafl/fl) and hepatocyte-specific Hilpda knockout (HilpdaΔHep) mice were fed a Western diet and high sugar in drinking water while receiving carbon tetrachloride to induce NASH-driven HCC. RESULTS: In patients with NASH-driven HCC, upregulated HILPDA expression is strongly associated with poor survival. In oxygen-deprived and lipid-loaded culture conditions, HILPDA promotes viability of human hepatoma cells and growth of 3D epithelial spheroids. Lack of HILPDA triggered flux of polyunsaturated fatty acids to membrane phospholipids and of saturated fatty acids to ceramide synthesis, exacerbating lipid peroxidation and apoptosis in hypoxia. The apoptosis induced by HILPDA deficiency was reversed by pharmacological inhibition of ceramide synthesis. In our experimental mouse model of NASH-driven HCC, HilpdaΔHep exhibited reduced hepatic steatosis and tumorigenesis but increased oxidative stress in the liver. Single-cell analysis supports a dual role of hepatic HILPDA in protecting HCC cells and facilitating the establishment of a pro-tumorigenic immune microenvironment in NASH. CONCLUSIONS: Hepatic HILPDA is a pivotal oncometabolic factor in the NASH liver microenvironment and represents a potential novel therapeutic target. IMPACT AND IMPLICATIONS: Non-alcoholic steatohepatitis (NASH, chronic metabolic liver disease caused by buildup of fat, inflammation and damage in the liver) is emerging as the leading risk factor and the fastest growing cause of hepatocellular carcinoma (HCC), the most common form of liver cancer. While curative therapeutic options exist for HCC, it frequently presents at a late stage when such options are no longer effective and only systemic therapies are available. However, systemic therapies are still associated with poor efficacy and some side effects. In addition, no approved drugs are available for NASH. Therefore, understanding the underlying metabolic alterations occurring during NASH-driven HCC is key to identifying new cancer treatments that target the unique metabolic needs of cancer cells.

Heart rate variability between hormone phases of the menstrual and oral contraceptive pill cycles of young women.

INTRODUCTION: The interplay between the sympathetic and parasympathetic branches of the autonomic nervous system contribute to adequate hemodynamic responses to stressors, reflected by the variation in intervals between heart beats, known as heart rate variability. The sex hormones estrogen and progesterone have been shown to affect autonomic function. The extent to which autonomic function may vary between different hormone phases of the natural menstrual cycle and how this relationship may differ in women taking oral contraceptives has yet to be fully elucidated. PURPOSE: To investigate differences in heart rate variability between the early follicular and early luteal phases of the menstrual cycle in naturally menstruating women and in oral contraceptive pill users. METHODS: Twenty-two young (22 ± 3 years), healthy women who were naturally menstruating or taking oral contraceptive pills participated in this study. Heart rate variability was measured at rest and during two sympathomimetic stressors: isometric handgrip exercise and cold pressor test. RESULTS: The proportion of successive NN intervals that differ by more than 50 ms was higher in oral contraceptive pill users during the placebo pill phase. Absolute high-frequency power was higher in the naturally menstruating women during the early luteal phase, relative to the early follicular phase. Other indices of vagal modulation were not different at rest or during sympathetic activation between hormone phases or groups. CONCLUSIONS: Vagal modulation may be increased in the early luteal menstrual cycle phase. Further,oral contraceptive use does not appear to adversely affect this modulation in young, healthy women.

The bromodomain protein Brd4 insulates chromatin from DNA damage signalling.

DNA damage activates a signalling network that blocks cell-cycle progression, recruits DNA repair factors and/or triggers senescence or programmed cell death. Alterations in chromatin structure are implicated in the initiation and propagation of the DNA damage response. Here we further investigate the role of chromatin structure in the DNA damage response by monitoring ionizing-radiation-induced signalling and response events with a high-content multiplex RNA-mediated interference screen of chromatin-modifying and -interacting genes. We discover that an isoform of Brd4, a bromodomain and extra-terminal (BET) family member, functions as an endogenous inhibitor of DNA damage response signalling by recruiting the condensin II chromatin remodelling complex to acetylated histones through bromodomain interactions. Loss of this isoform results in relaxed chromatin structure, rapid cell-cycle checkpoint recovery and enhanced survival after irradiation, whereas functional gain of this isoform compacted chromatin, attenuated DNA damage response signalling and enhanced radiation-induced lethality. These data implicate Brd4, previously known for its role in transcriptional control, as an insulator of chromatin that can modulate the signalling response to DNA damage.

The Relationship between Depression Severity and Cognitive Errors.

Cognitive errors (CEs) are evidenced to be related to depressive thinking in major depressive disorder (Beck Et Al., 1979; Dozois & Beck, 2008). Studies using self-report questionnaires demonstrate that CEs are more prevalent in individuals with depression than in non-depressed individuals (Gupta & Kar, 2008) and that CEs are related to depression severity (Miranda & Mennin, 2007). The study discussed in this paper aimed to describe CEs in depressed patients and examined the relationship between CEs and severity of depression. Participants (N = 45) undergoing cognitive therapy were assessed for CEs and for depression at session three using the Cognitive Errors Rating System (CERS; Drapeau et al., 2008) and the Beck Depression Inventory (BDI; Beck et al., 1979). Participants had more negative CEs than positive, and the most prevalent cluster of CEs was selective abstraction. Participants deemed as being "high distorters" on the CERS had significantly more negative CEs, but not positive CEs, than "low distorters" despite not differing on BDI scores. Psychotherapy research and practice implications are discussed.

Glycoengineering of Chinese hamster ovary cells for enhanced erythropoietin N-glycan branching and sialylation.

Sialic acid, a terminal residue on complex N-glycans, and branching or antennarity can play key roles in both the biological activity and circulatory lifetime of recombinant glycoproteins of therapeutic interest. In order to examine the impact of glycosyltransferase expression on the N-glycosylation of recombinant erythropoietin (rEPO), a human α2,6-sialyltransferase (ST6Gal1) was expressed in Chinese hamster ovary (CHO-K1) cells. Sialylation increased on both EPO and CHO cellular proteins as observed by SNA lectin analysis, and HPLC profiling revealed that the sialic acid content of total glycans on EPO increased by 26%. The increase in sialic acid content was further verified by detailed profiling of the N-glycan structures using mass spectra (MS) analysis. In order to enhance antennarity/branching, UDP-N-acetylglucosamine: α-1,3-D-mannoside ß1,4-N-acetylglucosaminyltransferase (GnTIV/Mgat4) and UDP-N-acetylglucosamine:α-1,6-D-mannoside ß1,6-N-acetylglucosaminyltransferase (GnTV/Mgat5), was incorporated into CHO-K1 together with ST6Gal1. Tri- and tetraantennary N-glycans represented approximately 92% of the total N-glycans on the resulting EPO as measured using MS analysis. Furthermore, sialic acid content of rEPO from these engineered cells was increased ∼45% higher with tetra-sialylation accounting for ∼10% of total sugar chains compared to ∼3% for the wild-type parental CHO-K1. In this way, coordinated overexpression of these three glycosyltransferases for the first time in model CHO-K1 cell lines provides a mean for enhancing both N-glycan branching complexity and sialylation with opportunities to generate tailored complex N-glycan structures on therapeutic glycoproteins in the future.

Women who sexually offend display three main offense styles: a reexamination of the descriptive model of female sexual offending.

This study examined a theory constructed to describe the offense process of women who sexually offend-the Descriptive Model of Female Sexual Offending (DMFSO). In particular, this report sets out to establish whether the original three pathways (or offending styles) identified within United Kingdom convicted female sexual offenders and described within the DMFSO (i.e., Explicit-Approach, Directed-Avoidant, Implicit-Disorganized) were applicable to a small sample (N = 36) of North American women convicted of sexual offending. Two independent raters examined the offense narratives of the sample and-using the DMFSO-coded each script according to whether it fitted one of the three original pathways. Results suggested that the three existing pathways of the DMFSO represented a reasonable description of offense pathways for a sample of North American women convicted of sexual offending. No new pathways were identified. A new "Offense Pathway Checklist" devised to aid raters' decision making is described and future research and treatment implications explored.

What did we learn about elite student-athlete mental health systems from the COVID-19 pandemic?

Elite student-athletes (SAs) in higher education (HE) have distinct mental health (MH) risks. The COVID-19 pandemic put pressure on systems and increased elite SA vulnerability to adverse MH outcomes. The aim of this study was to explore the provision and management of MH in elite HE sports settings during the time of COVID-19 pandemic stress. The secondary aim was to identify lessons and opportunities to enhance future mental healthcare systems and services for elite SAs. A qualitative study design was used to investigate the views of three groups (athletic directors, coaches and sport healthcare providers). Ten key leaders were purposively recruited from HE institutions in Canada, the USA and the United Kingdom. They represented various universities from the National College Athletic Association, U SPORTS Canada and British Universities and Colleges Sport. Semistructured interviews were conducted, recorded, transcribed and thematically analysed. Five key themes were identified: (1) The pandemic disruption had salient impacts on motivation and how elite SAs engaged with sport (2) when student sport systems are under pressure, support staff perceive a change in duties and experience their own MH challenges, (3) the pandemic increased awareness about MH care provision and exposed systemic challenges, (4) digital transformation in MH is complex and has additional challenges for SAs and (5) there were some positive outcomes of the pandemic, lessons learnt and a resulting motivation for systems change. Participants highlighted future opportunities for MH provision in elite university sport settings. Four recommendations were generated from the results.

Variant Detection in 3' Exons of PMS2 Using Exome Sequencing Data.

PMS2 is one of the DNA-mismatch repair genes included in routine genetic testing for Lynch syndrome and colorectal, ovarian, and endometrial cancers. PMS2 is also included in the American College of Medical Genetics and Genomics' List of Secondary Findings Genes in the context of clinical exome and genome sequencing. However, sequencing of PMS2 by short-read-based next-generation sequencing technologies is complicated by the presence of the pseudogene PMS2CL, and is often supplemented by long-range-based approaches, such as long-range PCR or long-read-based next-generation sequencing, which increases the complexity and cost. This article describes a bioinformatics homology triage workflow that can eliminate the need for long-read-based testing for PMS2 in the vast majority of patients undergoing exome sequencing, thus simplifying PMS2 testing and reducing the associated cost.

Morphological and transcriptional effects of crude oil and dispersant exposure on the marine sponge Cinachyrella alloclada.

Marine sponges play important roles in benthic ecosystems. More than providing shelter and food to other species, they help maintain water quality by regulating nitrogen and ammonium levels in the water, and bioaccumulate heavy metals. This system, however, is particularly sensitive to sudden environmental changes including catastrophic pollution event such as oil spills. Hundreds of oil platforms are currently actively extracting oil and gas in the Gulf of Mexico. To test the vulnerability of the benthic ecosystems to oil spills, we utilized the Caribbean reef sponge, Cinachyrella alloclada, as a novel experimental indicator. We have exposed organisms to crude oil and oil dispersant for up to 24 h and measured resultant gene expression changes. Our findings indicate that 1-hour exposure to water accommodated fractions (WAF) was enough to elicit massive shifts in gene expression in sponges and host bacterial communities (8052 differentially expressed transcripts) with the up-regulation of stress related pathways, cancer related pathways, and cell integrity pathways. Genes that were upregulated included heat shock proteins, apoptosis, oncogenes (Rab/Ras, Src, CMYC), and several E3 ubiquitin ligases. 24-hour exposure of chemically enhanced WAF (CE-WAF) had the greatest impact to benthic communities, resulting in mostly downregulation of gene expression (4248 differentially expressed transcripts). Gene deregulation from 1-hour treatments follow this decreasing trend of toxicity: WAF > CE-WAF > Dispersant, while the 24-hour treatment showed a shift to CE-WAF > Dispersant > WAF in our experiments. Thus, this study supports the development of Cinachyrella alloclada as a research model organism and bioindicator species for Florida reefs and underscores the importance of developing more efficient and safer ways to remove oil in the event of a spill catastrophe.

Variation in the stringency of COVID-19 public health measures on self-reported health, stress, and overall wellbeing in Canada.

Evidence is building regarding the association between government implemented public health measures aimed at combating COVID-19 and their impacts on health. This study investigated the relationship between the stringency of public health measures implemented in Canada and self-reported mental health, physical health, stress, and wellbeing among a random sample of 6647 Canadians 18 years of age and older. The analysis was based on self-reported health data from the Canadian Perspectives on Environmental Noise Survey. This data was combined with the Oxford COVID-19 Government Response Tracker database, which included overall stringency index (SI), and four of its sub-components, i.e., school and business closures, restrictions on gatherings, and stay at home policies. Adjusted multivariate logistic regression models indicated that the magnitude of the overall SI was associated with higher or lower odds of reporting worse physical health, mental health, stress and/or overall wellbeing, depending on the measure evaluated. Similarly, policy directed at the four sub-components had varying impacts on the odds of reporting worse health, depending on the sub-component, the strength of the policy restriction, and the health outcome evaluated. The association between the strength of the public health measures and self-reported health, and how this may inform future policy, is discussed.

A panel dataset of COVID-19 vaccination policies in 185 countries.

We present a panel dataset of COVID-19 vaccine policies, with data from 01 January 2020 for 185 countries and a number of subnational jurisdictions, reporting on vaccination prioritization plans, eligibility and availability, cost to the individual and mandatory vaccination policies. For each of these indicators, we recorded who is targeted by a policy using 52 standardized categories. These indicators document a detailed picture of the unprecedented scale of international COVID-19 vaccination rollout and strategy, indicating which countries prioritized and vaccinated which groups, when and in what order. We highlight key descriptive findings from these data to demonstrate uses for the data and to encourage researchers and policymakers in future research and vaccination planning. Numerous patterns and trends begin to emerge. For example: 'eliminator' countries (those that aimed to prevent virus entry into the country and community transmission) tended to prioritize border workers and economic sectors, while 'mitigator' countries (those that aimed to reduce the impact of community transmission) tended to prioritize the elderly and healthcare sectors for the first COVID-19 vaccinations; high-income countries published prioritization plans and began vaccinations earlier than low- and middle-income countries. Fifty-five countries were found to have implemented at least one policy of mandatory vaccination. We also demonstrate the value of combining this data with vaccination uptake rates, vaccine supply and demand data, and with further COVID-19 epidemiological data.

Beverage Characteristics Perceived as Healthy among Hispanic and African-American Parents of Young Children.

BACKGROUND: It is recommended that children younger than 6 years of age avoid sugar-sweetened beverages (SSBs); yet, 25% of toddlers and 45% of preschool-aged children consume SSBs on a given day, with the highest intakes reported among Hispanic and African-American children. OBJECTIVE: To investigate characteristics that predominantly low-income Hispanic and African-American parents perceive to reflect a healthy beverage, and to examine the influence of these characteristics on parents' perceptions of the beverages they provide to their young children. DESIGN: This study consisted of two activities: a qualitative activity where parents (n = 102) were asked to report what characteristics they perceive to reflect a healthy beverage and a quantitative activity where parents (n = 96) indicated the extent to which each of the reported characteristics influence parents' perceptions of the beverages they provide to their young children. PARTICIPANTS AND SETTING: Hispanic and African-American parents of young children (younger than 6 years of age) were recruited from the District of Columbia metropolitan area. MAIN OUTCOME MEASURES: Beverage characteristics and influence scores. STATISICAL ANALYSES PERFORMED: Characteristics were categorized by the research team based on their perceived meaning. Perceived influence scores for each characteristic and category were compared across Hispanic and African-American parents using nonparametric, Mann-Whitney U tests, and false discovery rate adjustment was used to correct for multiple testing. RESULTS: The characteristics perceived to be most influential included those pertaining to perceived beverage sugar and sweetener content, being natural, and containing certain nutrients. Characteristics such as being homemade, made with fruit, and containing vitamins were reported to be more influential among Hispanic parents compared with African-American parents. CONCLUSIONS: Findings emphasize the need to address misperceptions about the healthfulness of beverages among Hispanic and African-American parents. Differences in the perceived influence of specific beverage characteristics across Hispanic and African-American parents underscore the importance of developing culturally relevant interventions to improve parents' beverage selection for their children.

Understanding Physical Activity Patterns Across the School Day in Urban Pre-Kindergarten and Elementary Schoolchildren.

PURPOSE: Despite recommendations that children accrue ≥60 min/day of moderate-to-vigorous physical activity (MVPA), numerous barriers may exist. We examined school-day MVPA patterns in lower-income children (pre-K to 5th grade) to determine whether they were meeting the minimum school-day guidelines of at least 30-min/day of MVPA and to identify opportunities for intervention. METHODS: Students (N = 629, pre-K-5th grade) from 4 urban schools wore Actigraph GT3X+ accelerometers over 2 school days. Mixed effects models evaluated sex- and grade-specific differences in MVPA and sedentary time. RESULTS: Only 34.6% of elementary and 25.3% of pre-K students met the school-time MVPA recommendation. Among elementary-aged children, boys accrued more MVPA than girls (30.8 ± 13.3 vs. 23.5 ± 10.7 min/day; p < 0.0001) with similar sex differences observed among pre-K children (51.3 ± 17.1 vs 41.9 ± 17.5 min/day; p < 0.001). Sedentary time also increased significantly with grade among elementary-aged children (207.9 ± 34.7 vs. 252.0 ± 36.1 min/day for those in 1st and 5th grade, respectively; p < 0.001), with girls accruing more sedentary time than boys (242.5 ± 48.2 vs. 233.8 ± 46.8 min/day; p < 0.0001). CONCLUSION: MVPA declines across elementary school years, with sex disparities observed as early as pre-K. Extended sedentary bouts and clustering of activity highlight opportunities for more movement throughout the school day.

Implications of the COVID-19 pandemic on self-reported health status and noise annoyance in rural and non-rural Canada.

The Canadian Perspectives on Environmental Noise Survey (CPENS), conducted between April 12th, 2021 and May 25th, 2021 coincided with the third wave of the COVID-19 pandemic. Canadians 18 years of age and older (n = 6647) reported the degree to which the pandemic affected their physical health, mental health, stress, annoyance toward environmental and indoor noise, and overall well-being. Depending on the outcome evaluated, between 18 and 67% of respondents reported the measure as "somewhat" or "much worse" due to the pandemic. Stress was most affected, followed by mental health, overall well-being, physical health, annoyance toward environmental noise and annoyance toward indoor noise. Logistic regression models indicated that province, geographic region (rural/remote, suburban, urban), age, gender, poor physical/mental health, heart disease, a history of high sleep disturbance (in general) or diagnosed sleep disorders, anxiety/depression, working/schooling from home, and being retired significantly impacted the odds of reporting a worsening by the pandemic to varying degrees and directions, depending on the outcome. Indigenous status was unrelated to any of the modelled outcomes. Future research could address some of the noted study limitations and provide the data to determine if the observations on the reported measures of health are temporary, or long-lasting.

Defensive flexibility and its relation to symptom severity, depression, and anxiety.

Numerous studies have examined which individual defense mechanisms are related with mental health, and which are linked with psychopathology. However, the idea that a flexible use of defensive mechanisms is related to psychological wellbeing remained a clinical assumption, which this study sought to test empirically. A total of 62 (N = 62) outpatients participated in the study and were assessed with the Symptom Checklist-90R and the Social Adjustment Self-rated Scale. A subsample of 40 participants was further assessed using the Hamilton Depression (HAMD-21) and Anxiety scales (HAMA-21). The first therapy session of all participants was transcribed and rated using the Defense Mechanisms Ratings Scales (), and the Overall Defensive Functioning (ODF) score, which indicates the maturity of one's defensive functioning, was computed. An indicator of flexible use of defenses was also calculated based on the Gini Concentration C measure. Results showed that defensive flexibility, but not ODF, could predict anxiety scores. Symptom severity was predicted by both ODF and defensive flexibility, although in directions opposite to our predictions. Results suggest that defensive flexibility captures another aspect of an individual's functioning not assessed by the ODF, and that it is a promising new way of documenting defensive functioning.

Feasibility and acceptability of a randomized controlled trial to investigate withdrawal symptoms in response to caffeinated sugary drink cessation among children.

BACKGROUND: Sugary drinks (SDs) are key contributors to excess added sugar intake and the predominant source of caffeine among children. Chronic caffeine intake causes dependence, and evidence for sugar dependence is emerging. Development of withdrawal symptoms may pose an obstacle to SD cessation among children. We examined the feasibility and acceptability of a three-arm randomized controlled trial (RCT) designed to investigate withdrawal symptoms resulting from replacement of children's usual caffeinated SD intake with either caffeine-free alternatives or caffeine-free and sugar-free alternatives, compared with continued consumption of caffeinated SDs. METHODS: Twenty-nine children 8-12 years old, who consumed ≥12 ounces caffeinated SDs daily, enrolled. The two-week RCT required three in-person meetings and daily completion of electronic questionnaires to assess withdrawal symptoms and intervention adherence. Children were randomized to replace their usual caffeinated SD consumption with 1) caffeine-free alternatives, 2) caffeine-free and sugar-free alternatives, or 3) caffeinated SDs (control), provided by the study team. Feasibility and acceptability were assessed quantitatively and qualitatively. RESULTS: Twenty-eight participants (97%) completed the study. Adherence was high, with 73% reporting compliance with beverage assignments, and 76% completing all questionnaires. In qualitative interviews at follow-up, children described feelings of importance and commitment, and parents did not find the procedures to be overly burdensome. While challenges to adherence were reported (e.g., child wanting other SDs, time commitment), participants described innovative strategies (e.g., designating a place for study drinks in the refrigerator) to maintain adherence. CONCLUSION: Results indicated high levels of RCT feasibility and acceptability. The reported barriers and strategies for adherence will inform modifications required to design a larger and longer-term trial investigating withdrawal symptoms after SD cessation in children.

SODA MAPS: A Framework for Understanding Caffeinated Sugary Drink Consumption Among Children.

Excess sugary drink (SD) consumption is associated with childhood obesity and development of cardiometabolic disease. In addition to having high added sugar content, many SDs also contain caffeine, which may further encourage excess SD consumption among children. The objective of this study was to develop a conceptual framework of children's caffeinated SD consumption using group concept mapping, an applied social research multimethodology that collectively harnesses qualitative and quantitative data from participants to generate a visual representation of their ideas and input. Children, 8-14 years old, who reported consuming ≥12 ounces of caffeinated SDs (e.g., sodas, sweet teas) per day were recruited throughout Washington, D.C. and invited to participate. Concept mapping included three participant-driven activities: (1) brainstorming (n = 51), during which children reported reasons for their SD consumption, from which 58 unique reasons were identified; (2) sorting (n = 70), during which children sorted each of the reported reasons into categories and named each category; and (3) rating (n = 74), during which children rated the influence of each reason on their own caffeinated SD consumption. Similarity matrices, multidimensional scaling, and hierarchical cluster analysis were used to generate concept maps (hereafter "SODA MAPS"), which display the 58 reasons organized within eight overarching clusters. Among these eight clusters, Taste and Feel, Something to Do, and Energy were rated as particularly influential. Children's caffeinated SD consumption is encouraged not only by the palatable taste and reported preferences for these beverages (e.g., Taste and Feel), but also by psychological (e.g., Mood and Focus), biological (e.g., Energy), social (e.g., Something to Do) and environmental reasons (e.g., Nothing Better Available). Thus, the SODA MAPS can inform the development of tailored, multi-level SD reduction interventions that incorporate strategies to address important and currently overlooked reasons for caffeinated SD consumption among children.

A global panel database of pandemic policies (Oxford COVID-19 Government Response Tracker).

COVID-19 has prompted unprecedented government action around the world. We introduce the Oxford COVID-19 Government Response Tracker (OxCGRT), a dataset that addresses the need for continuously updated, readily usable and comparable information on policy measures. From 1 January 2020, the data capture government policies related to closure and containment, health and economic policy for more than 180 countries, plus several countries' subnational jurisdictions. Policy responses are recorded on ordinal or continuous scales for 19 policy areas, capturing variation in degree of response. We present two motivating applications of the data, highlighting patterns in the timing of policy adoption and subsequent policy easing and reimposition, and illustrating how the data can be combined with behavioural and epidemiological indicators. This database enables researchers and policymakers to explore the empirical effects of policy responses on the spread of COVID-19 cases and deaths, as well as on economic and social welfare.

CD73 immune checkpoint defines regulatory NK cells within the tumor microenvironment.

High levels of ecto-5'-nucleotidase (CD73) have been implicated in immune suppression and tumor progression, and have also been observed in cancer patients who progress on anti-PD-1 immunotherapy. Although regulatory T cells can express CD73 and inhibit T cell responses via the production of adenosine, less is known about CD73 expression in other immune cell populations. We found that tumor-infiltrating NK cells upregulate CD73 expression and the frequency of these CD73-positive NK cells correlated with larger tumor size in breast cancer patients. In addition, the expression of multiple alternative immune checkpoint receptors including LAG-3, VISTA, PD-1, and PD-L1 was significantly higher in CD73-positive NK cells than in CD73-negative NK cells. Mechanistically, NK cells transport CD73 in intracellular vesicles to the cell surface and the extracellular space via actin polymerization-dependent exocytosis upon engagement of 4-1BBL on tumor cells. These CD73-positive NK cells undergo transcriptional reprogramming and upregulate IL-10 production via STAT3 transcriptional activity, suppressing CD4-positive T cell proliferation and IFN-γ production. Taken together, our results support the notion that tumors can hijack NK cells as a means to escape immunity and that CD73 expression defines an inducible population of NK cells with immunoregulatory properties within the tumor microenvironment.