bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of Naturally Processed Mumps Virus Epitopes by Mass Spectrometry: Confirmation of Multiple CD8+ T-Cell Responses in Mumps Patients
Authors: de Wit Jelle , Emmelot Maarten E , Meiring Hugo , van Gaans-van den Brink Jacqueline A M , van Els Cécile A C M , Kaaijk Patricia
Published: September 2019

Background

The re-emergence of mumps among vaccinated young adults has become a global issue. Besides waning of antibody responses, suboptimal induction of T-cell responses may reduce protection. In a recent study, we observed a dominant polyfunctional CD8+ T-cell response after natural mumps virus (MuV) infection that was not present after vaccination. Unraveling the MuV epitope repertoire can provide insight in the specificity, functionality, and breadth of the T-cell response against MuV.

Methods

Peptides were eluted from human leukocyte antigen (HLA) class I molecules of MuV-infected cells and characterized by advanced mass spectrometry. Selected identified MuV peptides were tested for in vitro and ex vivo immunogenicity.

Results

In this study, we identified a broad landscape of 83 CD8+ T-cell epitopes of MuV, 41 of which were confirmed based on synthetic peptide standards. For 6 epitopes, we showed induction of an HLA-A*02-restriced CD8+ T-cell response. Moreover, robust T-cell responses against 5 selected MuV epitopes could be detected in all tested mumps patients using peptide/HLA-A*02:01 dextramers.

Conclusions

The identified CD8+ T-cell epitopes will help to further characterize MuV-specific T-cell immunity after natural MuV infection or vaccination. These MuV epitopes may provide clues for a better understanding of, and possibly for preventing, mumps vaccine failure.

We identified for the first time 41 mumps virus (MuV)-specific HLA-A*02 epitopes. For 6 epitopes, CD8+ T-cell responses were confirmed in T cells derived from several mumps cases, and MuV-specific CD8+ T cells could be identified by peptide/dextramer staining.
“Essential Things Such as Typewriters”: Development Discourse, Trade Union Expertise, and the Dialogues of Decolonization between the Caribbean and West Africa
Authors: James Leslie
Published: September 2019

This article examines how the liberatory ideals of transnational projects could become codified in particular processes of thought, deed, and expression. During his term of service in Nigeria between 1960 and 1962 the Trinidadian union leader McDonald Moses mobilized a number of phenomena central to the transformative projects of the mid-twentieth century: the paramountcy of psychology to “true” transformation and change; the embrace of programmatic action; and the belief that both psychological transformation and programmatic action could be articulated through new and enlightened forms of expression. While histories that embrace a “cultural turn” tend to look for this expression in creative forms and artistic production, this article looks to daily administrivia as part of an explicitly political project that aimed to improve the lives of workers by changing their modes of organizing and, consequently, the culture of politics and labor.
Decommissioning in Brazil: legal aspects of a technical analysis
Authors: Kowarski Clarissa Brandão , de Souza Marcelo Igor Lourenço , de Souza Renato Barcellos
Published: September 2019

This paper presents legal contributions to the technical analysis of the decommissioning stages of the oil industry. We seek to contribute to decision making based on multicriteria analysis about the options for uninstalling specific equipment in the production chain: subsea equipment. The objective is to demonstrate that there is legal predictability supported by the technical aspect for the options that are possible in each case. The methodology used was the literary revision combined with a national and international legislative analysis that allowed the presentation of the final conclusion. The comparison between the international norms, as well as the Brazilian legislation, in particular, the national solid waste policy demonstrated the legality of the application of a multicriteria analysis to base the decisions by the companies, as well as the inspection agencies.
The hidden satellites of massive galaxies and quasars at high redshift
Authors: Costa Tiago , Rosdahl Joakim , Kimm Taysun
Published: September 2019

Using cosmological, radiation-hydrodynamic simulations targeting a rare ${\approx}2 \times 10^{12} \, \rm {\rm M}_{\odot }$ halo at $z = 6$, we show that the number counts and internal properties of satellite galaxies within the massive halo are sensitively regulated by a combination of local stellar radiative feedback and strong tidal forces. Radiative feedback operates before the first supernova explosions erupt and results in less tightly bound galaxies. Satellites are therefore more vulnerable to tidal stripping when they accrete on to the main progenitor and are tidally disrupted on a significantly shorter time-scale. Consequently, the number of satellites with $M_{\rm \star } \gt 10^{7} \, \rm {\rm M}_{\odot }$ within the parent system’s virial radius drops by up to $60 \, {\rm per\, cent}$ with respect to an identical simulation performed without stellar radiative feedback. Radiative feedback also impacts the central galaxy, whose effective radius increases by a factor ≲3 due to the presence of a more extended and diffuse stellar component. We suggest that the number of satellites in the vicinity of massive high-redshift galaxies is an indication of the strength of stellar radiative feedback and can be anomalously low in the extreme cosmic environments of high-redshift quasars.
AGN jet feedback on a moving mesh: lobe energetics and X-ray properties in a realistic cluster environment
Authors: Bourne Martin A , Sijacki Debora , Puchwein Ewald
Published: September 2019

Jet feedback from active galactic nuclei (AGN) harboured by brightest cluster galaxies is expected to play a fundamental role in regulating cooling in the intracluster medium (ICM). While observations and theory suggest energy within jet lobes balances ICM radiative losses, the modus operandi of energy communication with the ICM remains unclear. We present simulations of very high resolution AGN-driven jets launching in a live, cosmological galaxy cluster, within the moving mesh code arepo. As the jet propagates through the ICM the majority of its energy, which is initially in the kinetic form, thermalizes quickly through internal shocks and inflates lobes of very hot gas. The jets effectively heat the cluster core, with PdV work and weather-aided mixing being the main channels of energy transfer from the lobes to the ICM, while strong shocks and turbulence are subdominant. We additionally present detailed mock X-ray maps at different stages of evolution, revealing clear cavities surrounded by X-ray bright rims, with lobes being detectable for up to ∼108 yr even when magnetic draping is ineffective. We find bulk motions in the cluster can significantly affect lobe propagation, offsetting them from the jet direction and imparting bulk velocities that can dominate over the buoyantly rising motion.
Advances in Intraoperative Optics: A Brief Review of Current Exoscope Platforms
Authors: Langer David J , White Timothy G , Schulder Michael , Boockvar John A , Labib Mohamed , Lawton Michael T
Published: September 2019

BACKGROUND

The advent of the operating microscope (OM) revolutionized the field of neurosurgery. It allowed surgeons to operate on and effectively treat diseases previously inaccessible with conventional eyesight because of magnification and illumination. Improvements in the essential methods of visualization and the quality of the optics have plateaued. Another main limitation of the OM remains its ergonomics because of the need of the surgeon and assistant to directly interface with the OM objective. Recently, exoscopes have been introduced to overcome some shortcomings of the conventional OM.

OBJECTIVE

To subjectively review the individual authors experience with the current exoscope platforms in an attempt to provide a resource to the neurosurgeon when considering imaging options.

METHODS

Experts with previous use of each individual platform were contacted and asked to contribute their experiences.

RESULTS

In total, 4 systems are discussed. They include the VITOM (Karl Storz, Tuttlingen, Germany), the Olympus ORBEYE (Olympus, Tokyo, Japan), the Synaptive Modus V (Synaptive Medical, Toronto, Canada), and the Zeiss KINEVO (Carl Zeiss AG, Oberkochen, Germany).

CONCLUSION

The advent of exoscopes has the potential to begin to allow surgeons to move beyond solely the microscope for intraoperative visualization while improving upon its ergonomic disadvantages.
An Apple B-Box Protein MdBBX37 Modulates Anthocyanin Biosynthesis and Hypocotyl Elongation Synergistically with MdMYBs and MdHY5
Authors: An Jian-Ping , Wang Xiao-Fei , Espley Richard V , Lin-Wang Kui , Bi Si-Qi , You Chun-Xiang , Hao Yu-Jin
Published: September 2019

As an important environment factor, light affects plant growth and development throughout life. B-BOX (BBX) proteins play key roles in the regulation of light signaling. Although the multiple roles of BBX proteins have been extensively studied in Arabidopsis, the research in apple is much less extensive. In this study, we systematically characterized the negative role of an apple BBX protein MdBBX37 in light signaling, including inhibiting anthocyanin biosynthesis and promoting hypocotyl elongation. We found that MdBBX37 interacted with MdMYB1 and MdMYB9, two key positive regulators of anthocyanin biosynthesis, and inhibited the binding of those two proteins to their target genes and, therefore, negatively regulated anthocyanin biosynthesis. In addition, MdBBX37 directly bound to the promoter of MdHY5, a positive regulator of light signaling, and suppressed its expression, and thus relieved MdHY5-mediated hypocotyl inhibition. Taken together, our investigations suggest that MdBBX37 is a negative regulator of light signaling in apple. Our study will provide reference for further study on the functions of BBX proteins in apple.
Interrogating Genomic-Scale Data for Squamata (Lizards, Snakes, and Amphisbaenians) Shows no Support for Key Traditional Morphological Relationships
Authors: Burbrink Frank T , Grazziotin Felipe G , Pyron R Alexander , Cundall David , Donnellan Steve , Irish Frances , Keogh J Scott , Kraus Fred , Murphy Robert W , Noonan Brice , Raxworthy Christopher J , Ruane Sara , Lemmon Alan R , Lemmon Emily Moriarty , Zaher Hussam
Published: September 2019

Genomics is narrowing uncertainty in the phylogenetic structure for many amniote groups. For one of the most diverse and species-rich groups, the squamate reptiles (lizards, snakes, and amphisbaenians), an inverse correlation between the number of taxa and loci sampled still persists across all publications using DNA sequence data and reaching a consensus on the relationships among them has been highly problematic. In this study, we use high-throughput sequence data from 289 samples covering 75 families of squamates to address phylogenetic affinities, estimate divergence times, and characterize residual topological uncertainty in the presence of genome-scale data. Importantly, we address genomic support for the traditional taxonomic groupings Scleroglossa and Macrostomata using novel machine-learning techniques. We interrogate genes using various metrics inherent to these loci, including parsimony-informative sites (PIS), phylogenetic informativeness, length, gaps, number of substitutions, and site concordance to understand why certain loci fail to find previously well-supported molecular clades and how they fail to support species-tree estimates. We show that both incomplete lineage sorting and poor gene-tree estimation (due to a few undesirable gene properties, such as an insufficient number of PIS), may account for most gene and species-tree discordance. We find overwhelming signal for Toxicofera, and also show that none of the loci included in this study supports Scleroglossa or Macrostomata. We comment on the origins and diversification of Squamata throughout the Mesozoic and underscore remaining uncertainties that persist in both deeper parts of the tree (e.g., relationships between Dibamia, Gekkota, and remaining squamates; among the three toxicoferan clades Iguania, Serpentes, and Anguiformes) and within specific clades (e.g., affinities among gekkotan, pleurodont iguanians, and colubroid families).
Consequences of dietary sugar consumption
Authors: Cole Shannon , Hopkins Leslie
Published: September 2019

The US industrial revolution led to a significant increase in the amount of dietary sugar consumed annually. The impact has become a public health crisis over the past several decades. The consequences are seen in the dramatic rise in rates of obesity, type 2 diabetes mellitus, and cardiovascular disease.
How Left Ventricular Size Affects Severity of Disease and Long-term Prognosis in Patients with Severe Systolic Dysfunction?
Authors: Amin Ahmad , Chitsazan Mitra , Ofoghi Mahdis , Taghavi Sepideh , Naderi Nasim , Chitsazan Mandana
Published: September 2019

Background:

We compared the severity of disease, heart failure (HF) rehospitalization and trend of changes over a 12-month follow-up in clinical and biochemical measurements between dilated cardiomyopathy (DCM) patients and those with left ventricular systolic dysfunction with normal LV size (NLVS). The existing definition of DCM failed to justify our observations in some clinical circumstances resulting in diagnostic and prognostic challenges.

Methods:

A total of 77 patients [52 (67.5%) male] including 40 patients in the NLVS group and 37 patients in the DCM group were enrolled and followed up for a median of 12 months [interquartile range, 11–14 months].

Results:

Mean left ventricular ejection fraction was statistically comparable between NLVS and DCM patients (22 ± 8% vs. 19 ± 6%, P = 0.08]. The New York Heart Association class was statistically comparable in both groups (P = 0.23). Laboratory measurements including hemoglobin, sodium, creatinine, uric acid, and NT-proBNP level were also statistically similar in both groups (all P > 0.05). During follow-up, HF rehospitalization occurred in 16 (76%) patients in NLVS and 5 (24%) patients in DCM groups (P = 0.009). Except for left ventricular ejection fraction which improved in both NLVS and DCM groups, no significant changes were observed in clinical (New York Heart Association class) and laboratory measurements during follow-up in both NLVS and DCM groups.

Conclusions:

Our study showed that NLVS defines a group of systolic HF patients which not only did not have less severe disease than those with enlarged left ventricules (i.e., DCM), also had more HF rehospitalization. These NLVS patients also had steady clinical, laboratory, and echocardiographic profile during follow-up.
Improving Shared Decision Making For Asian American Pacific Islander Sexual and Gender Minorities
Authors: Bi Stephanie , Gunter Kathryn E. , López Fanny Y. , Anam Seeba , Tan Judy Y. , Polin Danielle J. , Jia Justin L. , Xu Lucy J. , Laiteerapong Neda , Pho Mai T. , Kim Karen E. , Chin Marshall H.
Published: September 2019

Background:

Asian American Pacific Islander (AAPI) sexual and gender minorities (SGM) face unique challenges in mental health and accessing high-quality health care.

Objective:

The objective of this study was to identify barriers and facilitators for shared decision making (SDM) between AAPI SGM and providers, especially surrounding mental health.

Research Design:

Interviews, focus groups, and surveys.

Subjects:

AAPI SGM interviewees in Chicago (n=20) and San Francisco (n=20). Two focus groups (n=10) in San Francisco.

Measures:

Participants were asked open-ended questions about their health care experiences and how their identities impacted these encounters. Follow-up probes explored SDM and mental health. Participants were also surveyed about attitudes towards SGM disclosure and preferences about providers. Transcripts were analyzed for themes and a conceptual model was developed.

Results:

Our conceptual model elucidates the patient, provider, and encounter-centered factors that feed into SDM for AAPI SGM. Some participants shared the stigma of SGM identities and mental health in their AAPI families. Their AAPI and SGM identities were intertwined in affecting mental health. Some providers inappropriately controlled the visibility of the patient’s identities, ignoring or overemphasizing them. Participants varied on whether they preferred a provider of the same race, and how prominently their AAPI and/or SGM identities affected SDM.

Conclusions:

Providers should understand identity-specific challenges for AAPI SGM to engage in SDM. Providers should self-educate about AAPI and SGM history and intracommunity heterogeneity before the encounter, create a safe environment conducive to patient disclosure of SGM identity, and ask questions about patient priorities for the visit, pronouns, and mental health.
Modeling the Health and Budgetary Impacts of a Team-based Hypertension Care Intervention That Includes Pharmacists
Authors: Overwyk Katherine J. , Dehmer Steven P. , Roy Kakoli , Maciosek Michael V. , Hong Yuling , Baker-Goering Madeleine M. , Loustalot Fleetwood , Singleton Christa-Marie , Ritchey Matthew D.
Published: September 2019

Objective:

The objective of this study was to assess the potential health and budgetary impacts of implementing a pharmacist-involved team-based hypertension management model in the United States.

Research Design:

In 2017, we evaluated a pharmacist-involved team-based care intervention among 3 targeted groups using a microsimulation model designed to estimate cardiovascular event incidence and associated health care spending in a cross-section of individuals representative of the US population: implementing it among patients with: (1) newly diagnosed hypertension; (2) persistently (≥1 year) uncontrolled blood pressure (BP); or (3) treated, yet persistently uncontrolled BP—and report outcomes over 5 and 20 years. We describe the spending thresholds for each intervention strategy to achieve budget neutrality in 5 years from a payer’s perspective.

Results:

Offering this intervention could prevent 22.9–36.8 million person-years of uncontrolled BP and 77,200–230,900 heart attacks and strokes in 5 years (83.8–174.8 million and 393,200–922,900 in 20 years, respectively). Health and economic benefits strongly favored groups 2 and 3. Assuming an intervention cost of $525 per enrollee, the intervention generates 5-year budgetary cost-savings only for Medicare among groups 2 and 3. To achieve budget neutrality in 5 years across all groups, intervention costs per person need to be around $35 for Medicaid, $180 for private insurance, and $335 for Medicare enrollees.

Conclusions:

Adopting a pharmacist-involved team-based hypertension model could substantially improve BP control and cardiovascular outcomes in the United States. Net cost-savings among groups 2 and 3 make a compelling case for Medicare, but favorable economics may also be possible for private insurers, particularly if innovations could moderately lower the cost of delivering an effective intervention.
Symbolic transfer entropy reveals the age structure of pandemic influenza transmission from high-volume influenza-like illness data
Authors: Kissler Stephen M , Viboud Cécile , Grenfell Bryan T , Gog Julia R
Published: September 2019

Abstract

Existing methods to infer the relative roles of age groups in epidemic transmission can normally only accommodate a few age classes, and/or require data that are highly specific for the disease being studied. Here, symbolic transfer entropy (STE), a measure developed to identify asymmetric transfer of information between stochastic processes, is presented as a way to determine which age groups drive an epidemic. STE provides a ranking of which age groups dominate transmission, rather than a reconstruction of the explicit between-age-group transmission matrix. Using simulations, we establish that STE can identify which age groups dominate transmission, even when there are differences in reporting rates between age groups and even if the data is noisy. Then, the pairwise STE is calculated between time series of influenza-like illness for 12 age groups in 884 US cities during the autumn of 2009. Elevated STE from 5-19 year-olds indicates that school-aged children were the most important transmitters of infection during the autumn wave of the 2009 pandemic in the US. The results may be partially confounded by higher rates of physician-seeking behaviour in children compared to adults, but it is unlikely that differences in reporting rates can explain the observed differences in STE.
Improving personalized prediction of cancer prognoses with clonal evolution models
Authors: Tao Yifeng , Rajaraman Ashok , Cui Xiaoyue , Cui Ziyi , Eaton Jesse , Kim Hannah , Ma Jian , Schwartz Russell
Published: September 2019

Cancer occurs via an accumulation of somatic genomic alterations in a process of clonal evolution. There has been intensive study of potential causal mutations driving cancer development and progression. However, much recent evidence suggests that tumor evolution is normally driven by a variety of mechanisms of somatic hypermutability, known as mutator phenotypes, which act in different combinations or degrees in different cancers. Here we explore the question of how and to which degree different mutator phenotypes act in a cancer predict its future progression. We develop a computational paradigm using evolutionary tree inference (tumor phylogeny) algorithms to derive features quantifying single-tumor mutational preferences, followed by a machine learning frame-work to identify key features predictive of progression. We build phylogenies tracing the evolution of subclones of cells in tumor tissues using a variety of somatic genomic alterations, including single nucleotide variations, copy number alterations, and structural variations. We demonstrate that mutation preference features derived from the phylogenies are predictive of clinical outcomes of cancer progression – overall survival and disease-free survival – based on the analyses on breast invasive carcinoma, lung adenocarcinoma, and lung squamous cell carcinoma. We further show that mutational phenotypes have predictive power even after accounting for traditional clinical and driver-centric predictors of progression. These results confirm the power of mutational phenotypes as an independent class of predictive biomarkers and suggest a strategy for enhancing the predictive power of conventional clinical or driver-centric genomic features.
Mesoamerica is a cradle and the Atlantic Forest is a museum of Neotropical butterfly diversity: Insights from the evolution and biogeography of Brassolini (Lepidoptera: Nymphalidae)
Authors: Matos-Maraví Pável , Wahlberg Niklas , Freitas André V. L. , DeVries Phil , Antonelli Alexandre , Penz Carla M.
Published: September 2019

Regional species diversity is ultimately explained by speciation, extinction, and dispersal. Here we estimate dispersal and speciation rates of Neotropical butterflies to propose an explanation for their distribution and diversity of extant species. We focus on the tribe Brassolini (owl butterflies and allies): a Neotropical group that comprises 17 genera and 108 species, most of them endemic to rainforest biomes. We infer a robust species tree using the multispecies coalescent framework and a dataset including molecular and morphological characters. This formed the basis for three changes in Brassolini classification: 1) Naropina, SYN. NOV. is subsumed within Brassolina; 2)Aponarope, SYN. NOV. is subsumed withinNarope; 3)Selenophanes orgetorix, COMB. NOV. is reassigned fromCatoblepiatoSelenophanes. By applying biogeographical stochastic mapping, we found contrasting species diversification and dispersal dynamics across rainforest biomes, which might be partly explained by the geological and environmental history of each bioregion. Our results reveal a mosaic of biome-specific evolutionary histories within the Neotropics, where butterfly species have diversified rapidly (cradles: Mesoamerica), have accumulated gradually (museums: Atlantic Forest), or have alternately diversified and accumulated (Amazonia). Our study contributes evidence from a major butterfly lineage that the Neotropics are a museum and cradle of species diversity.
Broadening the ecology of fear: non-lethal effects arise from diverse responses to predation and parasitism
Authors: Daversa D.R. , Hechinger R.F. , Madin E. , Fenton A. , Dell A.I. , Ritchie E. , Rohr J. , Rudolf V.H.W.
Published: September 2019

The ecology of fear demonstrates how prey responses to avoid predation cause non-lethal effects at all ecological scales. Parasites also elicit defensive responses in hosts with associated non-lethal effects, which raises the longstanding, yet unresolved question of how non-lethal effects of parasites compare with those of predators. We developed a framework for systematically answering this question for all types of predator and parasite systems. Our framework predicts that trait responses and their non-lethal effects should be strongest from predators and parasites that do not kill individuals to feed on them, but which nevertheless damage fitness. Analysing trait response data on amphibians, which have been well-studied for this area of research, showed that individuals generally responded more directly to short-term predation risks than to parasitism. Apart from studies using amphibians, there have been few direct comparisons of responses to predation and parasitism, and none have incorporated responses to micropredators, parasitoids, or parasitic castrators, or examined their long-term consequences. Addressing these and other data gaps highlighted by our general framework can advance the field toward understanding how non-lethal effects shape real food webs, which contain multiple predator and parasite species.
Gain modulation and odor concentration invariance in early olfactory networks
Authors: Marachlian Emiliano , Huerta Ramon , Locatelli Fernando F.
Published: September 2019

A conserved principle of the olfactory system, in most, if not all animals, is that each olfactory receptor interacts with different odorant molecules and each odorant molecule interacts with different olfactory receptors. This broad receptive field of the receptors constitutes the basis of a combinatorial code that allows animals to discriminate many more odorants than the actual number of receptor types that they express. A drawback is that high odorant concentrations recruit lower affinity receptors, which can give rise to the perception of qualitatively different odors. Here we addressed the contribution that early signal-processing in the honey bee antennal lobe does to keep odor representation stable across concentrations. We describe the contribution that GABA-A and GABA-B receptors-dependent-inhibition plays in terms of the amplitude and temporal profiles of the signals that convey odor information from the antennal lobes to the mushroom bodies. GABA reduces the amplitude of odor elicited signals and the number of glomeruli that are recruited in a concentration-dependent way. Blocking GABA-A and GABA-B receptors decreases the correlation among glomerular activity patterns elicited by different concentrations of the same odor. Based on the results we built a realistic computational model of the antennal lobe that could be further used to evaluate the signal processing properties of the AL network under conditions that cannot be achieved in physiology experiments. Interestingly, even though based on rather simplistic topology and interactions among cells solely mediated by GABA-A and GABA-B interactions, the AL model reproduced the key features of the AL stable response in relation to different concentrations.
DMSO potentiates the suppressive effect of dronabinol, a cannabinoid, on sleep apnea and REM sleep
Authors: Calik Michael W. , Carley David W.
Published: September 2019

Purpose

Dimethyl sulfoxide (DMSO) is an amphipathic molecule with innate biological activity that also is used to dissolve both polar and nonpolar compounds in preclinical and clinical studies. Recent investigations of dronabinol, a cannabinoid, dissolved in DMSO demonstrated decreased sleep apnea frequency and time spent in REM sleep in rats. Here, we tested the effects of dronabinol dissolved in 25% DMSO (diluted in phosphate-buffered saline) to rule out potentiating effects of DMSO.

Methods

Sprague-Dawley rats were anesthetized and implanted with bilateral stainless steel screws into the skull for electroencephalogram recording and bilateral wire electrodes into the nuchal muscles for electromyogram recording. Each animal was recorded by polysomnography. The study was a fully nested, repeated measures crossover design, such that each rat was recorded following each of 8 intraperitoneal injections separated by three days: vehicle (25% DMSO/PBS); vehicle and CB1 antagonist (AM 251); vehicle and CB2 antagonist (AM 630); vehicle and CB1/CB2 antagonist; dronabinol (CB1/CB2 agonist); dronabinol and CB1 antagonist; dronabinol and CB2 antagonist; and dronabinol and CB1/CB2 antagonist. Sleep was manually scored into NREM and REM stages, and apneas were quantified.

Results

Dronabinol dissolved in 25% DMSO did not suppress apnea or modify sleep efficiency compared to vehicle controls, in contrast to previously published results. However, dronabinol did suppress REM sleep, which is in line with previously published results.

Conclusions

Dronabinol in 25% DMSO partially potentiated dronabinol’s effects, suggesting a concomitant biological effect of DMSO on breathing during sleep.
Pupil diameter tracks statistical structure in the environment
Authors: Schwiedrzik Caspar M. , Sudmann Sandrin S.
Published: September 2019

Pupil diameter determines how much light hits the retina, and thus, how much information is available for visual processing. This is regulated by a brainstem reflex pathway. Here, we investigate whether this pathway is under the control of internal models about the environment. If so, this would allow adjusting pupil dynamics to environmental statistics, and hence optimize information transmission. We manipulate environmental temporal statistics by presenting sequences of images that contain internal temporal structure to humans and macaque monkeys. We then measure whether the pupil tracks this structure not only at the rate that immediately arises from variations in luminance, but also at the rate of higher order statistics that are not available from luminance information alone. We find entrainment to environmental statistics in both species during the image sequences. Furthermore, pupil entrainment predicts later performance in an offline task that taps into the same internal models. Thus, the dynamics of the pupil are under control of internal models which adaptively match pupil diameter to the temporal structure of the environment, in line with an active sensing account.
Rheumatoid arthritis patients express a skewed repertoire of polyclonal, hypomutated B-cell receptors
Authors: Cowan Graeme J.M. , Miles Katherine , Capitani Lorenzo , Giguere Sophie S.B. , Johnsson Hanna , Goodyear Carl , McInnes Iain B. ,   Scottish Early Rheumatoid Arthritis Inception cohort Investigators, Breusch Steffen , Gray David , Gray Mohini
Published: September 2019

Objectives

The success of B cell depletion therapy in rheumatoid arthritis (RA) therapy testifies to their importance in disease pathogenesis, but the precise B cells mediating this are unclear. For example, it is unknown if RA patients predominantly express a limited number of circulating clonally expanded populations of B cells with highly mutated B cell antigen receptors (BCRs) that would constitute a shared antigen driven response.

Methods

To address this, we have undertaken the largest study to date utilising next generation sequencing (NGS), to identify the full length of the peripheral blood BCR sequences from the antigen-binding heavy chain. Between 25,000 to 200,000 BCR sequences per patient were analysed from 127 newly diagnosed RA patients, 16 heathy controls, 16 RA patients with established disease and 8 paired blood and synovial samples. This was complemented with B cell subset analysis from an additional 64 RA patients and 22 healthy controls.

Results

RA patients expressed a significantly higher percentage of circulating poorly mutated polyclonal IgG+vevariable heavy (IgG-Vh) BCR sequences, both at the time of diagnosis and following treatment. These sequences resided predominantly within TNF-alpha secreting IgG+veCD27−veB cells, that were expanded in RA peripheral blood and enriched in the rheumatoid synovium. Surprisingly, peripheral and synovial B cell repertoires of RA patients are quite distinct, sharing very few IgG sequences.

Conclusions

This is the first report to conclusively establish that a substantial component of the peripheral B cell repertoire in RA consists of polyclonal hypomutated IgG+veBCRs that may play a critical role in driving an autoimmune mediated inflammation.
Structural changes in the gut microbiome of short-term and long-term medical workers compared to normal controls
Authors: Zheng Ning , Li Shenghui , Dong Bo , Sun Wen , Li Huairui , Zhang Yongli , Li Peng , Fang Zhiwei , Chen Changming , Han Xiuyan , Li Bo , Zhang Siyi , Xu Miao , Zhang Guixin , Xin Yi , Ma Yufang , Wan Xianyao , Yan Qiulong
Published: September 2019

Objective

Hospital environment has been implicated in enrichment and exchange of pathogens and antibiotic resistances, but its potential in shaping the symbiotic microbial community of the hospital staff is unclear. This study was designed to evaluate the alteration of gut microbiome in medical workers compared to non-medical controls.

Design

Prospective cross-sectional cohort study.

Setting

Intensive care unit (ICU) and other departments from a center in northeast China.

Subjects

175 healthy medical workers (1-3 months short-term workers, n = 80; >1 year long-term workers, n = 95) and 80 healthy normal controls.

Interventions

None.

Measurements and Main Results

Fecal samples of all subjects were analyzed using the 16S rRNA gene sequencing. Medical workers exhibited remarkable deviation in gut microbial within-sample diversity and enterotypes stratification, and shift in overall microbial structure. Short-term workers were significantly more abundant in taxa including Lactobacillus, Butyrivibrio, Clostridiaceae_Clostridium, Ruminococcus, Dialister, Bifidobacterium, Odoribacter and Desulfovibrio, and with lower abundances of Bacteroides and Blautia compared with the controls. While long-term workers were enriched in taxa including Dialister, Veillonella, Clostridiaceae_Clostridium, Bilophila, Desulfovibrio, Pseudomonas and Akkermansia, with lower abundances of Bacteroides and Coprococcus compared with the controls. In addition, medical worker’s working years (short-term vs. long-term), hospital department (resident doctor vs. nursing staff) and work position (ICU vs. not-ICU) revealed considerable effects on their gut microbiome. Moreover, by analyzing the environmental samples (n = 9) around the inpatient wards and the hospital, we showed that the gut microbiota of medical workers was closer to environmental microbiota than that of the normal controls, probably in correlation to lasting exposure to the pathogenic taxa (e.g. Pseudomonas) in health workers.

Conclusions

Our findings demonstrated structural changes in the gut microbial community of the medical workers. Further studies are proposed for investigating the potentially physiological influence of the altered gut microbiome in medical participants.

IMPORTANCE

In this study, we for the first time focused on the influence of hospital environmental factors on gut microbiota of medical workers. The significance of our study is not limited to revealing the remodeling effect of the hospital environment on the gut microbiota of medical workers. Based on these, we also propose targeted and operational recommendations that can promote the health of hospital staff.
Microstructure Diffusion Scalar Measures from Reduced MRI Acquisitions
Authors: Aja-Fernández Santiago , de Luis-García Rodrigo , Afzali Maryam , Molendowska Malwina , Pieciak Tomasz , Tristán-Vega Antonio
Published: September 2019

In diffusion MRI, the Ensemble Average diffusion Propagator (EAP) provides relevant microstructural information and meaningful descriptive maps of the white matter previously obscured by traditional techniques like the Diffusion Tensor. The direct estimation of the EAP, however, requires a dense sampling of the Cartesian q-space. Due to the huge amount of samples needed for an accurate reconstruction, more efficient alternative techniques have been proposed in the last decade. Even so, all of them imply acquiring a large number of diffusion gradients with different b-values. In order to use the EAP in practical studies, scalar measures must be directly derived, being the most common the return-to-origin probability (RTOP) and the return-to-plane and return-to-axis probabilities (RTPP, RTAP).

In this work, we propose the so-called “Apparent Measures Using Reduced Acquisitions” (AMURA) to drastically reduce the number of samples needed for the estimation of diffusion properties. AMURA avoids the calculation of the whole EAP by assuming the diffusion anisotropy is roughly independent from the radial direction. With such an assumption, and as opposed to common multi-shell procedures based on iterative optimization, we achieve closed-form expressions for the measures using information from one single shell. This way, the new methodology remains compatible with standard acquisition protocols commonly used for HARDI (based on just one b-value). We report extensive results showing the potential of AMURA to reveal microstructural properties of the tissues compared to state of the art EAP estimators, and is well above that of Diffusion Tensor techniques. At the same time, the closed forms provided for RTOP, RTPP, and RTAP-like magnitudes make AMURA both computationally efficient and robust.
Not so dry after all – DRY mutants of the AT1A receptor and H1 receptor can induce G protein-dependent signaling
Authors: Pietraszewska-Bogiel A , Joosen L , Goedhart J
Published: September 2019

GPCRs are seven transmembrane spanning receptors that regulate a wide array of intracellular signaling cascades in response to various stimuli. To do so, they couple to different heterotrimeric G proteins and adaptor proteins, including arrestins. Importantly, arrestins were shown to regulate GPCR signaling through G proteins, as well as promote G protein-independent signaling events. Several research groups have reported successful isolation of exclusively G protein-dependent and arrestin-dependent signaling downstream of GPCR activation using biased agonists or receptor mutants incapable of coupling to either arrestins or G proteins. In the latter category, the DRY mutant of the angiotensin II type 1 receptor was extensively used to characterize functional selectivity downstream of AT1AR. In an attempt to understand histamine 1 receptor signaling, we characterized the signaling capacity of the H1R DRY mutant in a panel of dynamic, live cell biosensor assays, including arrestin recruitment, heterotrimeric G-protein activation, Ca2+ signaling, protein kinase C activity, GTP binding of RhoA, and activation of ERK1/2. Here we show that both H1R DRY mutant and the AT1AR DRY mutant (used as a reference) are capable of efficient activation of G protein-mediated signaling. Therefore, contrary to common belief, they do not constitute suitable tools for dissection of arrestin-mediated, G protein-independent signaling downstream of these receptors.
Y-RNAs Lead an Endogenous Program of RIG-I Agonism Mobilized upon RNA Virus Infection and Targeted by HIV
Authors: Vabret Nicolas , Najburg Valérie , Solovyov Alexander , Šulc Petr , Balan Sreekumar , Beauclair Guillaume , Chazal Maxime , Varet Hugo , Legendre Rachel , Sismeiro Odile , David Raul Y. Sanchez , McClain Christopher , Gopal Ramya , Chauveau Lise , Schwartz Olivier , Jouvenet Nolwenn , Markowitz Martin , Tangy Frédéric , Bhardwaj Nina , Greenbaum Benjamin D. , Komarova Anastasia V.
Published: September 2019

Pattern recognition receptors (PRRs) protect against host invasion by detecting specific molecular patterns found in pathogens and initiating an immune response. While microbial-derived PRR ligands have been extensively characterized, the contribution and relevance of endogenous ligands to PRR activation during viral infection remain overlooked. In this work, we characterize the landscape of endogenous ligands that engage RIG-I-like receptors (RLRs) upon infection by a positive-sense RNA virus, a negative-sense RNA virus or a retrovirus. We found that several endogenous RNAs transcribed by RNA polymerase 3 (Pol3) specifically engage RLRs, and in particular the family of small non-coding repeats Y-RNAs, which presents the highest affinity as RIG-I ligands. We show that this recognition is dependent on Y-RNA mimicking viral secondary structure and its 5’-triphosphate extremity. Further, we found that HIV-1 infection triggers a VPR-dependent downregulation of RNA triphosphatase DUSP11in vitroandin vivo, leading to an increase of Y-RNA 5’-triphosphorylation that enables their immunogenicity. Importantly, we show that altering DUSP11 expression is sufficient to induce a type-I interferon and T cell activation transcriptional program associated with HIV-1 infection. Overall, our work uncovers the critical contribution of endogenous repeat RNAs ligands to antiviral immunity and demonstrates the role of this pathway in HIV-1 infection.
Environmental decomposition of cuticular hydrocarbons generates a volatile pheromone that guides insect social behavior
Authors: Hatano Eduardo , Wada-Katsumata Ayako , Schal Coby
Published: September 2019

Once emitted, semiochemicals are exposed to reactive environmental factors that may alter them, thus disrupting chemical communication. Some species, however, might have adapted to detect environmentally mediated breakdown products of their natural chemicals as semiochemicals. We demonstrate that air, water vapor, and ultraviolet (UV) radiation break down unsaturated cuticular hydrocarbons (CHCs) of Periplaneta americana (American cockroach), resulting in the emission of volatile organic compounds (VOCs). In behavioral assays, nymphs strongly avoided aggregating in shelters exposed to the breakdown VOCs from cuticular alkenes. The three treatments (air, water vapor, UV) produced the same VOCs, but at different time-courses and ratios. Fourteen VOCs from UV-exposed CHCs elicited electrophysiological responses in nymph antennae; 10 were identified as 1-pentanol, 1-octanol, 1-nonanol, tetradecanal, acetic acid, propanoic acid, butanoic acid, pentanoic acid and hexanoic acid. When short-chain fatty acids were tested as a mix and a blend of the alcohols and aldehyde was tested as a second mix, nymphs exhibited no preference for control or treated shelters. However, nymphs avoided shelters that were exposed to VOCs from the complete 10-compound mix. Conditioned shelters (occupied by cockroaches with feces and CHCs deposited on the shelters), which are normally highly attractive to nymphs, were also avoided after UV-exposure, confirming that breakdown products from deposited metabolites, including CHCs, mediate this behavior. Our results demonstrate that common environmental and anthropogenic agents degrade CHCs into volatile semiochemicals that may serve as necromones or epideictic pheromones, mediating group formation and dissolution.

Significance Statement

Cuticular hydrocarbons (CHCs) cover the outer surface of insects, where they prevent water loss and serve as sex pheromones and in nest-mate recognition in social insects. Although CHCs are not volatile, they can be broken into volatile fragments by reacting with environmental agents. We demonstrate that volatile breakdown products of CHCs affect the social behavior of the American cockroach. A synthetic mix of volatiles dispersed cockroaches away from shelters, signaling an unsuitable shelter. These results highlight that some insect species have evolved communication strategies that exploit environmental and anthropogenic agents to produce bioactive compounds that mediate ecological interactions.
A tale of winglets: evolution of flight morphology in stick insects
Authors: Zeng Yu , O’Malley Conner , Singhal Sonal , Rahim Faszly , Park Sehoon , Chen Xin , Dudley Robert
Published: September 2019

The evolutionary transition between winglessness and a full-winged morphology requires selective advantage for intermediate forms. Conversely, repeated secondary wing reductions among the pterygotes indicates relaxation of such selection. However, evolutionary trajectories of such transitions are not well characterized. The stick insects (Phasmatodea) exhibit diverse wing sizes at both interspecific and intersexual levels, and thus provide a system for examining how selection on flight capability, along with other selective forces, drives the evolution of flight-related morphology. Here, we examine variation in relevant morphology for stick insects using data from 1100+ individuals representing 765 species. Although wing size varies along a continuous spectrum, taxa with either long or miniaturized wings are the most common, whereas those with intermediate-sized wings are relatively rare. In a morphological space defined by wing and body size, the aerodynamically relevant parameter termed wing loading (the average pressure exerted on the air by the wings) varies according to sex-specific scaling laws; volant but also flightless forms are the most common outcomes in both sexes. Using phylogenetically-informed analyses, we show that relative wing size and body size are inversely correlated in long-winged insects regardless of sexual differences in morphology and ecology. These results demonstrate the diversity of flight-related morphology in stick insects, and also provide a general framework for addressing evolutionary coupling between wing and body dimensions. We also find indirect evidence for a ‘fitness valley’ associated with intermediate-sized wings, suggesting relatively rapid evolutionary transitions between wingless and volant forms.
Estimation of Mediation Effect for High-dimensional Omics Mediators with Application to the Framingham Heart Study
Authors: Yang Tianzhong , Niu Jingbo , Chen Han , Wei Peng
Published: September 2019

Environmental exposures can regulate intermediate molecular phenotypes, such as gene expression, by different mechanisms and thereby lead to various health outcomes. It is of significant scientific interest to unravel the role of potentially high-dimensional intermediate phenotypes in the relationship between environmental exposure and traits. Mediation analysis is an important tool for investigating such relationships. However, it has mainly focused on low-dimensional settings, and there is a lack of a good measure of the total mediation effect. Here, we extend an R-squared (Rsq) effect size measure, originally proposed in the single-mediator setting, to the moderate- and high-dimensional mediator settings in the mixed model framework. Based on extensive simulations, we compare our measure and estimation procedure with several frequently used mediation measures, including product, proportion, and ratio measures. Our Rsq measure has small bias and variance under the correctly specified model. To mitigate potential bias induced by non-mediators, we examine two variable selection procedures, i.e., iterative sure independence screening and false discovery rate control, to exclude the non-mediators. We evaluate the consistency of the proposed estimation procedures and introduce a resampling-based confidence interval. By applying the proposed estimation procedure, we find that more than half of the aging-related variations in systolic blood pressure can be explained by gene expression profiles in the Framingham Heart Study.