bluuebunny/crossref_metadata_2025 huggingface dataset:
Increased CXCR3+ T Cells Impairs Recruitment of T-Helper Type 17 Cells via Interferon γ and Interleukin 18 in the Small Intestine Mucosa During Treated HIV-1 Infection
Authors: Loiseau C , Requena M , Nayrac M , Mavigner M , Cazabat M , Iscache A L , Carrere N , Suc B , Alric L , Izopet J , Delobel P
Published: March 2019

The restoration of CD4+ T cells, especially T-helper type 17 (Th17) cells, remains incomplete in the gut mucosa of most human immunodeficiency virus type 1 (HIV-1)–infected individuals despite sustained antiretroviral therapy (ART). Herein, we report an increase in the absolute number of CXCR3+ T cells in the duodenal mucosa during ART. The frequencies of Th1 and CXCR3+ CD8+ T cells were increased and negatively correlated with CCL20 and CCL25 expression in the mucosa. In ex vivo analyses, we showed that interferon γ, the main cytokine produced by Th1 and effector CD8+ T cells, downregulates the expression of CCL20 and CCL25 by small intestine enterocytes, while it increases the expression of CXCL9/10/11, the ligands of CXCR3. Interleukin 18, a pro-Th1 cytokine produced by enterocytes, also contributes to the downregulation of CCL20 expression and increases interferon γ production by Th1 cells. This could perpetuate an amplification loop for CXCR3-driven Th1 and effector CD8+ T cells recruitment to the gut, while impairing Th17 cells homing through the CCR6-CCL20 axis in treated HIV-1–infected individuals.
Public Health Surveillance: Ethical Considerations
Authors: Lee Lisa M.
Published: March 2019

Public health surveillance is one approach used by public health professionals to gather evidence to inform public health policies and actions. Related ethical considerations have evolved over time, from those common to infectious disease surveillance, such as privacy and confidentiality, consent, discrimination, and stigma, to additional considerations related to the surveillance of noncommunicable conditions, such as self-determination justice, and provision of benefit. Recent advances in technology, data science, data collection, and expectations of how public health surveillance can serve the public good have substantial implications for how public health professionals should design and conduct ethical surveillance systems. Public health professionals can anticipate, address, and potentially avoid ethical conflicts by integrating ethical considerations throughout the development and implementation of a public health surveillance system.
Mobile Space and Agility as the Subversive Partner
Authors: Marvin Carolyn
Published: March 2019

This chapter discusses how digital technologiesrevisit the role that space and mobility play in communication processes. Digital research tools make it possible to develop innovative research approaches and a richer empirical and theoretical understanding of how space shapes social dynamics. The argument centers on the tensions between the unimpeded sweep of mobile communication across space and time and the sticky local embeddedness that characterizes on-the-ground bodies, political cultures, and social networks. The discussion sketches out exciting new research frontiers while paying attention to cautions that must be observed going forward.
Educational Justice for Students with Intellectual Disabilities
Authors: Terzi Lorella
Published: March 2019

This chapter argues that a capability perspective on justice in education provides a normative framework that is sensitive to the educational interests of students with intellectual disabilities. It argues that a “threshold” approach, specified in terms of a threshold of capabilities for equal participation in society, is an appropriate principle for educational justice, when equal participation is a condition for the well-being of the child, both as a child and future adult. It also offers a rich and pluralistic account of citizenship, which, linked to a capability notion of well-being and flourishing, includes children with intellectual disabilities.
Epistemic Exclusion, Injustice, and Disability
Authors: Scully Jackie Leach
Published: March 2019

This chapter examines the ways in which disabled people are subject to epistemic injustice. It starts by introducing how social epistemology models the creation of shared knowledge and then uses feminist epistemology to highlight the role of social and political power in producing epistemic privilege, exclusion, and oppression. The well-known concepts of testimonial and hermeneutic epistemic injustice are discussed in relation to disability, showing how these forms of injustice are frequently experienced within the lives of disabled people. In particular, disabled experience has features that distinguish it from the experiences of sexism and racism most commonly used as illustrations of epistemic injustice. The chapter ends by arguing that the potential for epistemic injustice poses unprecedented risks for disabled people in the current context, which could be minimized by recognizing that ignorance about disabled lives is not inevitable, but something that can and should be challenged.
Managing Macrofinancial Crises
Authors: Honohan Patrick , Lombardi Domenico , St. Amand Samantha
Published: March 2019

Central banks have a mandate—either explicit or implicit—to guard against systemic financial crises and manage them if and when they occur. Given the need to make urgent decisions in the face of rapidly evolving circumstances, the central bank in a crisis faces challenges of economic analysis, market judgment, and political legitimacy. Lacking a simple criterion such as the rate of inflation, crisis-management decisions are inevitably contested in terms of both technical success and democratic legitimacy. Focusing on the mandates and the toolkit of central banks, this chapter illustrates how shortcomings can arise in responding to macrofinancial crises and then highlights directions for improvement. A selection of case studies identifies how political economy dynamics had an impact on historic episodes, for better or worse.
Can the Central Bank Alleviate Fiscal Burdens?
Authors: Reis Ricardo
Published: March 2019

Central banks affect the resources available to fiscal authorities through the impact of their policies on the public debt, as well as through their income, their mix of assets, their liabilities, and their own solvency. This chapter inspects the ability of the central bank to alleviate the fiscal burden by influencing different terms in the government resource constraint. It discusses five channels: (i) how inflation can (and cannot) lower the real burden of the public debt, (ii) how seigniorage is generated and subject to what constraints, (iii) whether central bank liabilities should count as public debt, (iv) how central bank assets create income risk and whether or not this threatens its solvency, and (v) how the central bank balance sheet can be used for fiscal redistributions. Overall, it concludes that the scope for the central bank to lower the fiscal burden is limited.
“Each in Our Own Village”
Authors: Ingram Catherine
Published: March 2019

This article explains the importance of creating sustainable interactions between custodian communities and archives, arguing that an archive is truly sustainable if it promotes and supports forms of sustainable and unmediated interactions and dialogue between its own organization and custodian communities. It first provides an overview of some of the contemporary concerns of cultural custodians as well as the contemporary concerns of archives before discussing interactions related to stakeholder communities and archived collections of musical recordings. It then describes the author’s experiences from her own research within Kam minority communities in southwestern China over the past thirteen years, and more specifically her involvement in archiving recordings of Kam music, to demonstrate how insights from the perspective of the fieldworker/archivist might be used in the process of developing new initiatives that assist in establishing sustainable custodian-archive dialogue and thus archival sustainability. The author’s work involved collaboration with Kam custodians to create and establish a sustainably archived digital collection of recorded materials with the Pacific and Regional Archive of Digital Sources in Endangered Cultures (PARADISEC). Drawing on this experience, she proposes several new initiatives aimed at enhancing custodian–archive communication founded on two features integral to sustainable digital archives: using the very audiovisual means that form the basis of the archive, and using the archive’s online streaming capabilities (or digital recordable media such as VCDs and DVDs as substitutes where online streaming is not available).
Language and Aging
Authors: Peelle Jonathan E.
Published: March 2019

Language processing in older adulthood is a model of balance between preservation and decline. Despite widespread changes to physiological mechanisms supporting perception and cognition, older adults’ language abilities are frequently well preserved. At the same time, the neural systems engaged to achieve this high level of success change, and individual differences in neural organization appear to differentiate between more and less successful performers. This chapter reviews anatomical and cognitive changes that occur in aging and popular frameworks for age-related changes in brain function, followed by an examination of how these principles play out in the context of language comprehension and production.
Language Development in Deaf Children
Authors: Newman Aaron J.
Published: March 2019

Hearing loss affects over 1 billion people around the world and is the fifth leading cause of disability. In the United States, approximately 10,000 babies are born each year with significant hearing loss. Although assistive technologies such as cochlear implants (CIs) are available to restore hearing, deaf children who receive CIs on average show significantly poorer language skills and academic outcomes than their normally hearing peers. At the same time, a relatively small percentage of deaf children are born to deaf parents and learn sign language as their first language, and grow up to be excellent, fluent communicators who are bilingual in signed and spoken language. Historically, there has been significant tension between advocates of sign language and “oralists” who discouraged sign language use. This chapter provides a critical review of language development in deaf children, including those with CIs and those exposed to different kinds, and amounts, of signed language. The linguistic and educational outcomes of deaf children are considered in light of current understanding of neurodevelopment, sensitive periods, and neuroplasticity, while highlighting areas of controversy and important directions for future research. The chapter concludes with evidence-based recommendations in favor of sign language exposure for all deaf children.
Hedged Assertion
Authors: Benton Matthew A. , van Elswyk Peter
Published: March 2019

Surprisingly little has been written about hedged assertion. Linguists often focus on semantic or syntactic theorizing about, for example, grammatical evidentials or epistemic modals, but they pay far less attention to what hedging does at the level of action. By contrast, philosophers have focused extensively on normative issues regarding what epistemic position is required for proper assertion, yet they have almost exclusively considered unqualified declaratives. This article considers the linguistic and normative issues side by side. It aims to bring some order and clarity to thinking about hedging, so as to illuminate aspects of interest to both linguists and philosophers. In particular, it considers three broad questions. (1) The structural question: when one hedges, what is the speaker’s commitment weakened from? (2) The functional question: what is the best way to understand how a hedge weakens? And (3) the taxonomic question: are hedged assertions genuine assertions, another speech act, or what?
Causation, Value Judgments, Verstehen
Authors: Turner Stephen
Published: March 2019

Weber’s “methodological writings” are some of the most influential parts of his work; they are his philosophical and technical explication of the basic problems of social science and history and their relation to other forms of knowledge, as well as the relation of knowledge to action and values. They explain his basic concepts, such as ideal type, values and value-free science, Verstehen, and the notion of causality that is appropriate to social and historical concepts. These ideas have often been misrepresented in the subsequent literature but remain a powerful source of insight and provide valuable critical tools for assessing social science claims.
Chloride Channels in Nociceptors
Authors: Oh Uhtaek , Jung Jooyoung
Published: March 2019

Pain may be induced by activation of various ion channels expressed in primary afferent neurons. These channels function as molecular sensors that detect noxious chemical, temperature, or tactile stimuli and transduce them into nociceptor electrical signals. Transient receptor potential channels are good examples because they are activated by chemicals, heat, cold, and acid in nociceptors. Anion channels were little studied in nociception because of the notion that anion channels might induce hyperpolarization of nociceptors on opening. In contrast, opening of Cl- channels in dorsal root ganglion (DRG) neurons depolarizes sensory neurons, resulting in excitation of nociceptors, thereby inducing pain. Anoctamin 1(ANO1)/TMEM16A is a Ca2+-activated Cl- channel expressed mainly in small DRG neurons, suggesting a nociception role. ANO1 is a heat sensor that detects heat over 44°C. Ano1-deficient mice elicit less nocifensive behaviors to hot temperatures. In addition, mechanical allodynia and hyperalgesia induced by inflammation or nerve injury are alleviated in Ano1-/- mice. More important, Ano1 transcripts are increased in chronic pain models. Bestrophin 1 (Best1) is another Ca2+-activated Cl- channel expressed in nociceptors. Best1 is increased in axotomized DRG neurons. The role of Best1 in nociception is not clear. GABAA receptors are in the central process of DRG neurons; GABA depolarizes the primary afferents. This depolarization consists of primary afferent depolarization essential for inhibiting nociceptive input to second-order neurons in the spinal cord, regulating pain signals to the brain. Thus, although Cl- channels in nociceptors are not as numerous as TRP channels, their role in nociception is distinct and significant.
Efficacy of Social Commentary through Cartooning
Authors: Shwed Ally
Published: March 2019

In an attempt to better understand the efficacy of editorial cartooning, one must explore the medium’s functionality, intent, adaptability, and impact on the societies in which it exists. One must comprehend the medium’s use of image-text interdependence, consider the history of the medium as a template, and incorporate literary, psychological, aesthetics, and media studies approaches into one’s understanding. By doing so, one can further a discussion of what the medium should and can be doing in terms of social commentary, thus constructing a spectrum of efficacy on which cartooning functions. Although a cartoon need not effect drastic change in order to be considered successful, its role is as a conduit for readers to gain the knowledge with which they can choose to be empowered to act.
Why There Is No “Language of Comics”
Authors: Bramlett Frank
Published: March 2019

This chapter aims to account for gaps between language as a linguistic system and comics as a visual semiotic system. It is not uncommon in comics studies to encounter the claim that comics are a language. While this metaphor is an attractive way of explaining the nature of comics, it ultimately does a disservice to comics studies because it unnecessarily limits the theoretical and analytical frameworks available to us. This chapter explores what language is from a linguistic perspective, including sociolinguistic and discourse perspectives, dialect, language acquisition, and translation studies. It concludes by calling for scholars to turn away from “the language of comics” as a theoretical framework.
Urban Marvell
Authors: McDowell Sean H.
Published: March 2019

After his return to London from his Continental travels in the 1640s, Andrew Marvell comported himself as an avowed Londoner, deeply focused on politics, diplomacy, and the hurly-burly of everyday life in the capital. Indeed, life in the capital powerfully shaped his literary expression. The booming coffee-house culture informed his approach to raillery and animadversion. Popular Restoration plays inspired his controversialist prose. And specific sensational events, news items, or public works occasioned much of his satirical verse. Through layers of allusion and resonance arising from these various contexts, Marvell’s later writings provide an impressionistic portrayal of urban London, the vibrancy of which animated Marvell’s imagination during the last eighteen years of his life.
‘A Greater Errour in Chronology’
Authors: Dzelzainis Martin
Published: March 2019

While few of Marvell’s lyrics can be dated with any precision, critics no longer find it ‘comforting to reflect’, as Frank Kermode did in 1952, ‘that the date of “The Garden” is quite unknown, so that it cannot be positively stated to be the direct record of some personal experience at Nun Appleton’. Recent attempts to reassign some of the poems traditionally associated with the time Marvell spent with the Fairfax family (principally ‘The Garden’ and ‘The Mower against Gardens’) to the Restoration phase of his career have met with mixed success. This chapter accordingly asks what kinds of evidence we can or should bring to bear in addressing the closely related issues of the dating and circulation of Marvell’s writings. The three test cases considered are ‘An Horatian Ode upon Cromwell’s Return from Ireland’, ‘The Garden’, and the anonymous prose piece, ‘An Epitaph upon—’.
Marvell’s Latin Poetry and the Art of Punning
Authors: Haan Estelle
Published: March 2019

This chapter analyses the linguistic ingenuity of Marvell’s Latin poetry, in which, it is argued, a pseudo-Lucretian sensitivity to the parallelism between the structure of Latin words and the structure of the world coexists with a linguistic methodology that approximates the Marinesque. Etymological play and bilingual punning enables the neo-Latin poetic text to serve both as a microcosm of the literary contexts in which these devices are employed, and as a reinvention of the artifice, extravagant conceits, and baroque wit of Marinism. The result is a neo-Latin ‘echoing song’ that is both intra- and intertextual. Through bilingual punning and phonological wit Marvell plays with a classical language only to demonstrate its transformative potential. The chapter concludes by discussing the labyrinthine punning and sense of displacement in Hortus in relation to the garden sections of Marino’s L’Adone, in which an extravagantly luscious setting ultimately confounds the senses.
‘Mr. Bayes in Mr. Bayes’
Authors: Silver Victoria
Published: March 2019

Hobbes and Marvell have more affinities than one, not least in their turn for ecclesiastical satire. Both fashion to their own ends even as they excel at the art the seventeenth century termed ‘personation’—the satirical portrait of a subject that ridicules to the point of caricaturing its target. But until The Rehearsal Transpros’d undertook to personate the Anglican polemicist Samuel Parker, Hobbes’ words had yet to appear on the same page with Marvell’s. It is Parker who plays midwife to this unheralded event, which he does by his attacks on Hobbes and Hobbism, hoping to deflect attention from his own plagiarism of Leviathan’s model of absolute sovereignty. For Marvell’s personation of Parker as ‘Mr. Bayes the Second’—Buckingham’s figure of authorial absurdity in his popular play The Rehearsal—wickedly likens him to the Hobbes of Parker’s personation, making that caricature of Hobbes ‘Mr. Bayes the Third’.
Marvell and Nineteenth-Century Poetry
Authors: O'Neill Michael
Published: March 2019

Influence always leaves a wraith-like path, invisible to one person, transparent to another. The danger of reading-in is evident. This chapter proposes that Marvell’s influence on nineteenth-century poetry is manifold but frequently fugitive, now like centrifugal ripples in a still pond, now a sudden shower of meteors across the night sky. Nigel Smith reminds us that ‘The important point to remember is that Marvell was not unrecognized as a poet until the later nineteenth century, as has often been claimed’. Poets from Wordsworth to Tennyson are studied in relation to the nuanced ambivalence of Marvellian poetry; so too are critics and anthologists; so too is the range of poetic genres affected by Marvell’s influence.
Marvell and Diplomacy
Authors: Holberton Edward
Published: March 2019

This chapter examines Marvell’s diplomatic career, with a particular focus on his role as secretary to the Earl of Carlisle’s 1663 embassy to Muscovy, Sweden, and Denmark. Modern accounts of the embassy have tended to represent it as a failure, which can be blamed partly on the haughtiness of speeches and letters written by Marvell and presented by Carlisle. The chapter discusses what constituted success and failure in the wider context of European diplomacy at this time, and asks whether Marvell might not have been judged too harshly. It explores the importance of contests over ceremony in early modern diplomacy, and argues that Marvell and Carlisle put together rhetorical performances of considerable skill and resourcefulness in the context of these contests. The speeches and papers written by Marvell in Muscovy throw into relief affinities between poetic and diplomatic forms of representation, particularly around the figure of prosopopoeia. The chapter ends by looking at Marvell’s continued interest in this figure following the end of his diplomatic career, and his ongoing aptitude for ventriloquizing royalty.
Challenging and Adverse Meditation Experiences
Authors: Lindahl Jared R. , Britton Willoughby B. , Cooper David J. , Kirmayer Laurence J.
Published: March 2019

Challenging meditation experiences have been documented in Buddhist literature, in psychological research, and in a recent qualitative study by the authors. Some of the central questions in the investigation of this topic are: How are meditation-related challenges to be interpreted or appraised? Through which processes are experiences determined to be expected or “normative” aspects of contemplative development versus undesirable “adverse effects” or psychopathology? And is it possible to differentiate or disambiguate the two? A review of available research suggests that distinguishing between experiences that are religious or mystical and those that indicate psychopathology depends on detailed knowledge of the specific contexts in which these experiences occur. Furthermore, research that specifically examines meditation-related challenges shows that interpretations, causal explanations, and recommended responses are often negotiated between practitioners and other people in their practice settings and larger social communities. This chapter considers some of the social dynamics of these appraisal processes and explores some of the consequences of adopting different appraisals. However, because there can be a lack of consensus around how experiences should be interpreted or appraised, a more useful question may be: What type of support does this particular experience require? Systematic attention to social context can both inform research on meditation-related challenges and provide guidance on the issues surrounding their appraisal and management in both clinical and non-clinical contexts.
Patient-centered Outcomes in Participants of a Buprenorphine Monthly Depot (BUP-XR) Double-blind, Placebo-controlled, Multicenter, Phase 3 Study
Authors: Ling Walter , Nadipelli Vijay R. , Solem Caitlyn T. , Ronquest Naoko A. , Yeh Yu-Chen , Learned Susan M. , Mehra Vishaal , Heidbreder Christian
Published: March 2019

Objective:

Opioid use disorder (OUD) is associated with physical, social, psychological, and economic burden. This analysis assessed the effects of RBP-6000, referred to as BUP-XR (extended-release buprenorphine), a subcutaneously injected, monthly buprenorphine treatment for OUD compared with placebo on patient-centered outcomes measuring meaningful life changes.

Methods:

Patient-centered outcomes were collected in a 24-week, phase 3, placebo-controlled study assessing the efficacy, safety, and tolerability of BUP-XR 300/300 mg (6 × 300 mg) and 300/100 mg (2 × 300 mg followed by 4 × 100 mg) injections in treatment-seeking participants with moderate-to-severe OUD. Measures included the EQ-5D-5L, SF-36v2, Medication Satisfaction Questionnaire, employment/insurance status, and healthcare resource utilization (HCRU). Changes from baseline to end of study were compared across treatment arms, using mixed models for repeated measures.

Results:

Participants receiving BUP-XR (n = 389) versus placebo (n = 98) had significantly greater changes from baseline on the EQ-5D-5L index (300/300 mg: difference = 0.0636, P 
= 0.003), EQ-5D-5L visual analog scale (300/300 mg: difference = 5.9, P 
= 0.017; 300/100 mg: difference = 7.7, P 
= 0.002), and SF-36v2 physical component summary score (300/300 mg: difference = 3.8, P 
< 0.001; 300/100 mg: difference = 3.2, P 
= 0.002). Satisfaction was significantly higher for participants receiving BUP-XR 300/300 mg (88%, P < 0.001) and 300/100 mg (88%, P < 0.001) than placebo (46%). Employment and percentage of insured participants increased by 10.8% and 4.1% with BUP-XR 300/300 mg and 10.0% and 4.7% with 300/100 mg but decreased by 12.6% and 8.4% with placebo. Participants receiving BUP-XR compared with placebo had significantly fewer hospital days per person-year observed.

Conclusions:

These results show the feasibility of measuring patient-centered life changes in substance use disorder clinical studies. Participants receiving up to 6 monthly injections of BUP-XR, compared with placebo, reported better health, increased medication satisfaction, increased employment, and decreased healthcare utilization.
Factors Associated With Accuracy of Self-Assessment Compared With Tested Non–English Language Proficiency Among Primary Care Providers
Authors: Diamond Lisa , Toro Bejarano Marcela , Chung Sukyung , Ferguson Warren , Gonzalez Javier , Genoff Garzon Margaux , Mujawar Imran , Gany Francesca
Published: March 2019

Background:

There are no accepted best practices for clinicians to report their non–English language (NEL) fluencies. Language discordance between patients with limited English proficiency and their clinicians may contribute to suboptimal quality of care.

Objectives:

To compare self-assessed clinician NEL proficiency with a validated oral language proficiency test. To identify clinician characteristics associated with self-assessment accuracy.

Subjects:

Primary care providers from California and Massachusetts.

Research Design:

We surveyed 98 clinicians about demographics and their NEL self-assessment using an adapted version of the Interagency Language Roundtable (ILR) scale followed by an oral proficiency interview: The Clinician Cultural and Linguistic Assessment (CCLA). We compared the ILR to the CCLA and analyzed factors associated with the accuracy of self-assessment.

Results:

Ninety-eight primary care providers participated: 75.5% were women, 62.2% were white, and Spanish was the most common NEL reported (81.6%). The average CCLA score was 78/100 with a 70% passing-rate. There was a moderate correlation between the ILR and CCLA (0.512; P<0.0001). Participants whose self-reported levels were “fair” and “poor” had a 0% pass-rate and 100% who self-reported “excellent” passed the CCLA. Middle ILR levels showed a wider variance. Clinicians who reported a NEL other than Spanish and whose first language was not English were more likely to accurately self-assess their abilities.

Conclusions:

Self-assessment showed a moderate correlation with the validated CCLA test. Additional testing may be required for clinicians at the middle levels. Clinicians whose native languages were not English and those using languages other than Spanish with patients may be more accurate in their self-assessment.
Hospital Volume and Operative Mortality for General Surgery Operations Performed Emergently in Adults
Authors: Becher Robert D. , DeWane Michael P. , Sukumar Nitin , Stolar Marilyn J. , Gill Thomas M. , Maung Adrian A. , Schuster Kevin M. , Davis Kimberly A.
Published: March 2019

Objective:

This study aimed to answer 2 questions: first, to what degree does hospital operative volume affect mortality for adult patients undergoing 1 of 10 common emergency general surgery (EGS) operations? Second, at what hospital operative volume threshold will nearly all patients undergoing an emergency operation realize the average mortality risk?

Background:

Nontrauma surgical emergencies are an underappreciated public health crisis in the United States; redefining where such emergencies are managed may improve outcomes. The field of trauma surgery established regionalized systems of care in part because studies demonstrated a clear relationship between hospital volume and survival for traumatic emergencies. Such a relationship has not been well-studied for nontrauma surgical emergencies.

Methods:

Retrospective cohort study of all acute care hospitals in California performing nontrauma surgical emergencies. We employed a novel use of an ecological analysis with beta regression to investigate the relationship between hospital operative volume and mortality.

Results:

A total of 425 acute care hospitals in California performed 165,123 EGS operations. Risk-adjusted mortality significantly decreased as volume increased for all 10 EGS operations (P < 0.001 for each); the relative magnitude of this inverse relationship differed substantially by procedure. Hospital operative volume thresholds were defined and varied by operation: from 75 cases over 2 years for cholecystectomy to 7 cases for umbilical hernia repair.

Conclusions:

Survival rates for nontrauma surgical emergencies were improved when operations were performed at higher-volume hospitals. The use of ecological analysis is widely applicable to the field of surgical outcomes research.
Stratification of Postsurgical Computed Tomography Surveillance Based on the Extragastric Recurrence of Early Gastric Cancer
Authors: Seo Nieun , Han Kyunghwa , Hyung Woo Jin , Chung Yong Eun , Park Chan Hyuk , Kim Jie-Hyun , Lee Sang Kil , Kim Myeong-Jin , Noh Sung Hoon , Lim Joon Seok
Published: March 2019

Objective:

To stratify the postsurgical computed tomography (CT) surveillance based on a risk-scoring system for predicting extragastric recurrence after surgical resection of early gastric cancer (EGC).

Summary of Background Data:

Postsurgical CT surveillance should not be routinely performed in all patients because of the low incidence of extragastric recurrence and potential risk of radiation exposure.

Methods:

Data from 3162 patients who underwent surgical resection for EGC were reviewed to develop a risk-scoring system to predict extragastric recurrence. Risk scores were based on the predictive factors for extragastric recurrence, which were determined using Cox proportional hazard regression model. The risk-scoring system was validated by Uno censoring adjusted C-index. External validation was performed using an independent dataset (n = 430).

Results:

The overall incidence of extragastric recurrence was 1.4% (44/3162). Five risk factors (lymph node metastasis, indications for endoscopic resection, male sex, positive lymphovascular invasion, and elevated macroscopic type), which were significantly associated with extragastric recurrence, were incorporated into the risk-scoring system, and the patients were categorized into 2 risk groups. The 10-year extragastric recurrence-free survival differed significantly between low- and high-risk groups (99.7% vs 96.5%; P < 0.001). The predictive accuracy of the risk-scoring system in the development cohort was 0.870 [Uno C-index; 95% confidence interval (95% CI), 0.800–0.939]. Discrimination was good after internal (0.859) and external validation (0.782, 0.549–1.000).

Conclusion:

This risk-scoring system might be useful to predict extragastric recurrence of EGC after curative surgical resection. We suggest that postsurgical CT surveillance to detect extragastric recurrence should be avoided in the low-risk group.
A widespread toxin-antitoxin system exploiting growth control via alarmone signalling
Authors: Jimmy Steffi , Saha Chayan Kumar , Stavropoulos Constantine , Oliveira Sofia Raquel Alves , Kurata Tatsuaki , Koh Alan , Cepauskas Albinas , Takada Hiraku , Tenson Tanel , Strahl Henrik , Garcia-Pino Abel , Hauryliuk Vasili , Atkinson Gemma C.
Published: March 2019

Under stressful conditions, bacterial RelA-SpoT Homologue (RSH) enzymes synthesise the alarmone (p)ppGpp, a nucleotide messenger. (p)ppGpp rewires bacterial transcription and metabolism to cope with stress, and at high concentrations inhibits the process of protein synthesis and bacterial growth to save and redirect resources until conditions improve. Single domain Small Alarmone Synthetases (SASs) are RSH family members that contain the (p)ppGpp synthesis (SYNTH) domain, but lack the hydrolysis (HD) domain and regulatory C-terminal domains of the long RSHs such as Rel, RelA and SpoT. We have discovered that multiple SAS subfamilies can be encoded in broadly distributed conserved bicistronic operon architectures in bacteria and bacteriophages that are reminiscent of those typically seen in toxin-antitoxin (TA) operons. We have validated five of these SASs as being toxic (toxSASs), with neutralisation by the protein products of six neighbouring antitoxin genes. The toxicity ofCellulomonas marinaToxSAS FaRel is mediated by alarmone accumulation combined with depletion of cellular ATP and GTP pools, and this is counteracted by its HD domain-containing antitoxin. Thus, the ToxSAS-antiToxSAS system is a novel TA paradigm comprising multiple different antitoxins that exemplifies how ancient nucleotide-based signalling mechanisms can be repurposed as TA modules during evolution, potentially multiple times independently.
Multi-task learning predicts drug combination synergy in cells and in the clinic
Authors: Gilvary Coryandar , Dry Jonathan R , Elemento Olivier
Published: March 2019

Combination therapies for various cancers have been shown to increase efficacy, lower toxicity, and circumvent resistance. However, despite the promise of combinatorial therapies, the biological mechanisms behind drug synergy have not been fully characterized, and the systematic testing of all possible synergistic therapies is experimentally infeasible due to the sheer volume of potential combinations. Here we apply a novel big data approach in the evaluation and prediction of drug synergy by using the recently released NCI-ALMANAC. We found that each traditional drug synergy metric (Bliss, Loewe, ZIP, HSA, ALMANAC Score) identified unique synergistic drug pairs with distinct underlying joint mechanisms of action. Leveraging these findings, we developed a suite of context specific drug synergy predictive models for each distinct synergy type and achieved significant predictive performance (AUC = 0.89-0.953). Furthermore, our models accurately identified clinically tested drug pairs and characterized the clinical relevance of each drug synergy metric, with Bliss Independence capturing clinically tested combinations best. Our findings demonstrate that drug synergy can be obtained from numerous unique joint mechanisms of action, captured by different synergy metrics. Additionally, we show that drug synergy, of all kinds, can be predicted with high degrees of accuracy with significant clinical potential. This breakthrough understanding of joint mechanisms of action will allow for the design of rational combinatorial therapeutics on a large scale, across various cancer types.
Publicly available transcriptomes provide the opportunity for dual RNA-Seq meta-analysis inPlasmodiuminfection
Authors: Mukherjee Parnika , Burgio Gaétan , Heitlinger Emanuel
Published: March 2019

Dual RNA-Seq is the simultaneous transcriptomic analysis of interacting symbionts, for example, in malaria. Potential cross-species interactions identified by correlated gene expression might highlight interlinked signaling, metabolic or gene regulatory pathways in addition to physically interacting proteins. Often, malaria studies address one of the interacting organisms – host or parasite – rendering the other “contamination”. Here we perform a meta-analysis using such studies for cross-species expression analysis.

We screened experiments for gene expression from host andPlasmodium. Out of 171 studies inHomo sapiens, Macaca mulattaandMus musculus, we identified 63 potential studies containing host and parasite data. While 16 studies (1950 samples) explicitly performed dual RNA-Seq, 47 (1398 samples) originally focused on one organism. We found 915 experimental replicates from 20 blood studies to be suitable for co-expression analysis and used orthologs for meta-analysis across different host-parasite systems. Centrality metrics from the derived gene expression networks correlated with gene essentiality in the parasites. We found indications of host immune response to elements of thePlasmodiumprotein degradation system, an antimalarial drug target. We identified well-studied immune responses in the host with our co-expression networks as our approach recovers known broad processes interlinked between hosts and parasites in addition to individual host and parasite protein associations.

The set of core interactions represents commonalities between human malaria and its model systems for prioritization in laboratory experiments. Our approach might also allow insights into the transferability of model systems for different pathways in malaria studies.

Importance

Malaria still causes about 400,000 deaths a year and is one the most studied infectious diseases. The disease is studied in mice and monkeys as lab models to derive potential therapeutic intervention in human malaria. Interactions betweenPlasmodiumspp. and its hosts are either conserved across different host-parasite systems or idiosyncratic to those systems. Here we use correlation of gene expression from different RNA-Seq studies to infer common host-parasite interactions across human, mouse and monkey studies. We, firstly, find a set of very conserved interactors, worth further scrutiny in focussed laboratory experiments. Secondly, this work might help assess to which extent experiments and knowledge on different pathways can be transferred from models to humans for potential therapy.
The Antagonism of Folate Receptor by the Integrase Inhibitor Dolutegravir: Developmental Toxicity Reduction by Supplemental Folic Acid
Authors: Cabrera Robert M. , Souder Jaclyn P. , Steele John W. , Yeo Lythou , Tukeman Gabriel , Gorelick Daniel A. , Finnell Richard H.
Published: March 2019

Human immunodeficiency virus (HIV) integrase inhibitors are increasingly being used for antiretroviral therapy (ART), and dolutegravir (DTG/Tivicay) has emerged as a leading core agent. In 2018, the Tsepamo study reported a 6- to 9-fold increase for neural tube defect (NTD) risk among the offspring of mothers receiving DTG during early gestation. Maternal folate (vitamin B9) status is the largest known modifier of NTD risk, so we evaluated folate-related mechanisms of action and the critical period for DTG developmental toxicity. Folate receptor (FOLR1) binding studies indicate DTG is a non-competitive FOLR1 antagonist at therapeutic concentrations.In vitrotesting indicates calcium (2mM) increases FOLR1-folate interactions and alters DTG-FOLR1-folate interactions and cytotoxicity. DTG does not inhibit downstream folate metabolism by dihydrofolate reductase (DHFR). Early embryonic exposure to DTG is developmentally toxic in zebrafish, and supplemental folic acid can mitigate DTG developmental toxicity. The results from these studies are expected to inform and guide future animal models and clinical studies of DTG-based ART in women of childbearing age.
Brain meta-state transitions demarcate thoughts across task contexts, exposing the mental noise of trait neuroticism
Authors: Tseng Julie , Poppenk Jordan
Published: March 2019

Using new methods to capture streams of neural meta-state transitions in single participants, we characterize the psychological meaning of these regular neural events. Similar to past group-average-based analyses, participants’ individual transition streams aligned to meaningful events during movie-viewing. However, our individual-based approach also afforded observation of participants’ idiosyncratic transition timing at rest. Across these two dramatically different task contexts, transitions featured similar trait-like frequency, concurrence with activation of regions associated with spontaneous thought, and suppression by attention regions. Based on this generalization, as well as the centrality of semantics to thought, we argue transitions serve as a general, implicit neurobiological marker of new thoughts, and that their frequency therefore approximates participants’ mentation rate. Finally, to contribute convergent validity and illustrate the utility of our approach for thought dynamics, we regressed resting transition rate and movie-viewing group temporal conformity against trait neuroticism, yielding a first neural confirmation of the “mental noise” theory.
Regulation of antimycin biosynthesis is controlled by the ClpXP protease
Authors: Bilyk Bohdan , Kim Sora , Fazal Asif , Baker Tania A. , Seipke Ryan F.
Published: March 2019

The survival of any microbe relies upon its ability to respond to environmental change. Use of Extra Cytoplasmic Function (ECF) RNA polymerase sigma (σ) factors is a major strategy enabling dynamic responses to extracellular signals. Streptomyces species harbor a large number of ECF σ factors; nearly all of which regulate genes required for morphological differentiation and/or response to environmental stress, except for σAntA, which regulates starter-unit biosynthesis in the production of antimycin, an anticancer compound. Unlike a canonical ECF σ factor, whose activity is regulated by a cognate anti-σ factor, σAntA is an orphan, raising intriguing questions about how its activity may be controlled. Here, we reconstitute in vitro ClpXP proteolysis of σAntA, but not a variant lacking a C-terminal di-alanine motif. Furthermore, we show that the abundance of σAntAin vivo is enhanced by removal of the ClpXP recognition sequence, and that levels of the protein rise when cellular ClpXP protease activity is abolished. These data establish direct proteolysis as an alternative and thus far unique control strategy for an ECF RNA polymerase σ factor and expands the paradigmatic understanding of microbial signal transduction regulation.

Importance

Natural products produced by Streptomyces species underpin many industrially- and medically-important compounds. However, the majority of the ~30 biosynthetic pathways harboured by an average species are not expressed in the laboratory. This undiscovered biochemical diversity is believed to comprise an untapped resource for natural products drug discovery. A major roadblock preventing the exploitation of unexpressed biosynthetic pathways is a lack of insight into their regulation and limited technology for activating their expression. Our findings reveal that the abundance of σAntA, which is the cluster-situated regulator of antimycin biosynthesis, is controlled by the ClpXP protease. These data link proteolysis to the regulation of natural product biosynthesis for the first time and we anticipate that this will emerge as a major strategy by which actinobacteria regulate production of their natural products. Further study of this process will advance understanding of how expression of secondary metabolism is controlled and will aid pursuit of activating unexpressed biosynthetic pathways.
The sequence of the extruded non-template strand determines the architecture of R-loops
Authors: Carrasco-Salas Yeraldinne , Malapert Amélie , Sulthana Shaheen , Molcrette Bastien , Chazot-Franguiadakis Léa , Bernard Pascal , Chédin Frédéric , Faivre-Moskalenko Cendrine , Vanoosthuyse Vincent
Published: March 2019

Three-stranded R-loop structures have been associated with genomic instability phenotypes. What underlies their wide-ranging effects on genome stability remains poorly understood. Here we combined biochemical and atomic force microscopy approaches with single molecule R-loop footprinting to demonstrate that R-loops formed at the model Airn locus in vitro adopt a defined set of three-dimensional conformations characterized by distinct shapes and volumes, which we call R-loop objects. Interestingly, we show that these R-loop objects impose specific physical constraints on the DNA, as revealed by the presence of stereotypical angles in the surrounding DNA. Biochemical probing and mutagenesis experiments revealed that the formation of R-loop objects at Airn is dictated by the sequence of the extruded non-template strand, suggesting that R-loops possess intrinsic sequence-driven properties. Consistent with this, we show that R-loops formed at the fission yeast gene sum3 do not form detectable R-loop objects. Our results reveal that R-loops differ by their architectures and that the organization of the non-template strand is a fundamental characteristic of R-loops, which could explain that only a subset of R-loops is associated with replication-dependent DNA breaks.
Plasma Circular RNA Panel to Diagnose Hepatitis B Virus-Related Hepatocellular Carcinoma
Authors: Yu Jian , Wang Meng-chao , Ding Wen-bing , Guo Xing-gang , Xu Jian , Xu Qing-guo , Yang Yuan , Sun Shu-han , Liu Jing-feng , Qin Lun-xiu , Liu Hui , Yang Fu , Zhou Wei-ping
Published: March 2019

To explore whether plasma circular RNAs (circRNAs) can diagnose hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), microarray and qPCR were used to identify plasma circRNAs that were increased in HCC patients compared with controls (including healthy controls, chronic hepatitis B, HBV-related liver cirrhosis and HCC patients). A logistic regression model was constructed using a training set (n=313) and then validated using another two independent sets (n=306 and 526, respectively). Area under the receiver operating characteristic curve (AUC) was used to evaluate diagnostic accuracy. We identified a plasma circRNA panel (CircPanel) containing three circRNAs (hsa_circ_0000976, hsa_circ_0007750 and hsa_circ_0139897) that could detect HCC. CircPanel showed a higher accuracy than AFP (alpha-fetoprotein) to distinguish individuals with HCC from controls in all three sets (AUC 0.863 [95% CI 0.819–0.907] vs 0.790 [0.738–0.842], P=0.036 in training set; 0.843 [0.796–0.890] vs 0.747 [0.691–0.804], P=0.011 in validation set 1 and 0.864 [0.830–0.898] vs 0.769 [0.728–0.810], P<0.001 in validation set 2). CircPanel also performed well in detecting Small-HCC (solitary, ≤3cm), AFP-negative HCC and AFP-negative Small-HCC.

Significance of this study

What is already known about this subject?

The diagnostic accuracy of alpha-fetoprotein (AFP) in detecting hepatocellular carcinoma (HCC) is unsatisfactory.

Circular RNA (circRNA) expression profiles in HCC and adjacent nontumor liver tissues are significantly different.

Plasma circRNAs are enriched, stable and can be biomarkers for various diseases.

What are the new findings?

The expression of circRNAs in the plasma from HCC patients and chronic hepatitis B is significantly different.

Plasma circRNA panel (CircPanel, including hsa_circ_0000976, hsa_circ_0007750 and hsa_circ_0139897) has a higher accuracy than AFP to distinguish individuals with HCC or Small-HCC (solitary, ≤3cm) from controls (healthy controls, chronic hepatitis B and HBV-related liver cirrhosis).

CircPanel also performs well in diagnosing AFP-negative HCC and AFP-negative Small-HCC.

How might it impact on clinical practice in the foreseeable future?

Plasma CircPanel can be a diagnostic biomarker in detecting HCC and improves the diagnostic accuracy.