bluuebunny/crossref_metadata_2025 huggingface dataset:
Disclosure of Sexual Orientation Among Women Who Have Sex With Women During Gynecological Care: A Qualitative Study In Brazil
Authors: Rufino Andréa Cronemberger , Madeiro Alberto , Trinidad Adriana Silva , Rodrigues dos Santos Raiza , Freitas Isadora
Published: June 2018

Background

Evidence shows that women who have sex with women (WSW) face disparities in access to health care when compared to heterosexual women in several countries.

Aim

To investigate the experiences WSW have after disclosure of sexual orientation during gynecological care in Brazil.

Methods

We performed a qualitative study using content analysis. We recorded and transcribed interviews with 34 WSW from the 5 regions in Brazil. Data were analyzed using descriptive content analysis.

Outcomes

The main categories of analysis were decision-making process to disclose and attitude of gynecologists after disclosure.

Results

WSW disclosed their sexual orientation in an un-favorable environment. Gynecologists rarely asked about patients’ sexual orientation and used a script for hetero-normative anamnesis. The reactions of gynecologists were discriminatory, resulting in abbreviated consultations and un-comfortable gynecological exams. They missed a window of opportunity for prevention, diagnosis, and treatment of various diseases. The experiences Brazilian WSW had during gynecological care demonstrated the dominant hetero-normativity in the health care scenario. The attitudes of the gynecologists precarized the existence of WSW in health service.

Clinical Implications

This study suggests that gynecologists missed an opportunity to use WSW's sexual orientation disclosure to offer specific care to them.

Strengths & Limitations

This is the first qualitative study about WSW’s experiences during gynecological care in Brazil. Future studies should be developed from a wider sampling, especially among lower-class WSW.

Conclusion

The results point out the need for a change in medical training and guidelines to assist WSW in the country.
Sexual Health Care Practitioners' Evaluation of Men Who Have Sex With Men
Authors: Saheb Kashaf Michael , Butler Peter R. , Cordon-Galiano Billy H. , Herati Amin S.
Published: June 2018

Background

The Institute of Medicine Report and Department of Health and Human Services Healthy People 2020 Initiative have called for steps to address health disparities facing sexual minorities.

Aim

We sought to characterize the practice patterns of sexual health specialists as they relate to men who have sex with men (MSM).

Methods

Surveys were electronically mailed to 696 members of the Sexual Medicine Society of North America (SMSNA). Responses were compared using descriptive statistics and χ2 analysis with Yates correction where appropriate.

Outcomes

Outcomes were SMSNA members' demographics, their assessment of their patients' sexual orientation, and adaptation of care to address the specific needs of their MSM patients.

Results

92 (13.2%) Members responded. While 93.3% of respondents reported treating MSM patients, only 51.7% routinely asked about sexual orientation. Of those that do not ask, 41.9% responded that sexual orientation is irrelevant to their patients' care and 25.6% responded that patients will disclose this information if the patient thinks it is important. Practitioners inquiring about sexual orientation were more likely to practice in urban settings; more likely to inquire about a greater number of sexual behaviors; more likely to tailor their care to lesbian, gay, bisexual, and transgender needs; and more likely to endorse the notion that homosexual/bisexual patients have unique sexual dysfunction concerns.

Clinical Translation

Limited and uneven inquiry about sexual orientation necessitates efforts aimed at tailoring care to the needs of sexual minority patients.

Strengths & Limitations

This survey addresses a gap in the literature by investigating predictors and practical consequences of practitioner inquiry about sexual orientation.

Limitations include a low response rate, disparate study population, the potential influence of respondent social desirability biases, and spurious associations due to a multiplicity of statistical tests.

Conclusion

Only about half of surveyed SMSNA members ask their patients' sexual orientation; inquiry about sexual orientation was associated with practice setting and with provider practice patterns and attitudes.
Role of PERK‐eIF2α signaling pathway in fetal male rats with hypospadias induced by di‐n‐butyl phthalate
Authors: Zhao Zhang , Liu Guo‐Chang , Fu Wen
Published: June 2018

This study aims to explore the role of PERK‐eIF2α signaling pathway in fetal male rats with hypospadias induced by maternal exposure to di‐n‐butyl phthalate (DBP). DBP was used to treat pregnant SD rats by gastric intubation from gestation day (GD) 14–18 to construct a hypospadias rat model. The amount, weight, anogenital distance (AGD), and hypospadias incidence of rats were recorded and the genital tubercle (GT) of fetal male rats was collected on GD 19. Western blotting was performed to detect the expressions of PERK‐eIF2α pathway‐ and autophagy‐related proteins, and cell apoptosis was detected using TUNEL method. Then, GT fibroblasts of fetal rats were obtained and transfected with PERK‐siRNA to detect cell apoptosis and autophagy in each transfected group. The incidence of hypospadias was 43.49% in fetal male rats induced by DBP. The fetal rats in DBP group presented the decreased birth weight and anogenital distance (AGD)/body weight ratio than the Control group (all P < 0.05). Further, p‐PERK, p‐eIF2α and ATF4 protein expressions and the ratio of LC3‐II/LC3‐I were greatly increased in the GTs of fetal rats, while apoptosis index (AI) and P62 protein expression were evidently decreased (all P < 0.05). In addition, the apoptosis rate was increased in GT fibroblasts after transfection of PERK‐siRNA with the increased P62 and reduced LC3‐II/LC3‐I ratio (all P < 0.05). Activation of PERK‐eIF2α signaling pathway can influence the GT development of fetal male rats with hypospadias induced by DBP through activation of autophagy and inhibition of apoptosis.
Impact of antibiotics on smell dysfunction
Authors: Wang Jing‐Jie , Chen Jonathan , Doty Richard L.
Published: June 2018

Objective

Viral or bacterial respiratory infections can cause long‐lasting olfactory dysfunction. Antibiotic therapy is indicated in severe cases; however, it is unclear whether antibiotic use produces a positive, negative, or null effect on olfactory function. This retrospective study sought to determine whether antibiotic use has an influence on odor identification and detection threshold test scores of patients with smell dysfunction secondary to upper respiratory infections (URIs), lower respiratory infections (LRIs), or rhinosinusitis.

Methods

Data from a total of 288 patients presenting to the University of Pennsylvania Smell and Taste Center were evaluated.

Results

Patients with a URI etiology who had taken bactericidal antibiotics had lower detection thresholds than did patients who had not taken antibiotics (P < 0.023; analysis of covariance with age and time since infection onset as covariates). Moreover, thresholds were lower for bactericidal antibiotic users than for bacteriostatic antibiotic users with either URI (P = 0.023) or rhinosinusitis (P = 0.028) etiologies. No meaningful influences of antibiotics on the odor identification test scores were evident.

Conclusions

These findings, which need to be confirmed in prospective double‐blind studies, suggest that bactericidal antibiotic therapy may be beneficial in mitigating, at least to some degree, chronic decrements in smell sensitivity due to URIs and rhinosinusitis.
Editorial
Authors: Barrett Steve
Published: June 2018

Toyota is grabbing the headlines again this month, with its announcement of a major ramping-up of new production facilities for its fuel cell stacks and hydrogen storage tanks [see page 1 ].
The Sociology of Law and the Global Transformation of Democracy
Authors: Thornhill Chris
Published: June 2018

This book provides a new legal-sociological account of contemporary democracy. It is based on a revision of standard positions in democratic theory, reflecting the impact of global legal norms on the institutions of national states. Chris Thornhill argues that the establishment of fully democratic, fully inclusive governance systems in national societies was generally impeded by inner-societal structural factors, and that inclusive patterns of democratic citizenship only evolved on the foundation of global legal norms that were consolidated after 1945. He claims that this process can be best understood through a transposition of key insights of classical legal sociology onto the form of global society. Extensive analysis of select case studies in different regions illustrate these claims. Thornhill offers a sociological theory of global law to explain contemporary processes of democratic integration and institutional formation, and contemporary constructions of citizenship and political rights. This title is also available as Open Access.
Association between multimorbidity and undiagnosed obstructive sleep apnea severity and their impact on quality of life in men over 40 years old
Authors: Ruel G. , Martin S. A. , Lévesque J.-F. , Wittert G. A. , Adams R. J. , Appleton S. L. , Shi Z. , Taylor A. W.
Published: June 2018

Background.

Multimorbidity is common but little is known about its relationship with obstructive sleep apnea (OSA).

Methods.

Men Androgen Inflammation Lifestyle Environment and Stress Study participants underwent polysomnography. Chronic diseases (CDs) were determined by biomedical measurement (diabetes, dyslipidaemia, hypertension, obesity), or self-report (depression, asthma, cardiovascular disease, arthritis). Associations between CD count, multimorbidity, apnea-hyponea index (AHI) and OSA severity and quality-of-life (QoL; mental & physical component scores), were determined using multinomial regression analyses, after adjustment for age.

Results.

Of the 743 men participating in the study, overall 58% had multimorbidity (2+ CDs), and 52% had OSA (11% severe). About 70% of those with multimorbidity had undiagnosed OSA. Multimorbidity was associated with AHI and undiagnosed OSA. Elevated CD count was associated with higher AHI value and increased OSA severity.

Conclusion.

We demonstrate an independent association between the presence of OSA and multimorbidity in this representative sample of community-based men. This effect was strongest in men with moderate to severe OSA and three or more CDs, and appeared to produce a greater reduction in QoL when both conditions were present together.
From Speech Acts to Literary Genres: Toward a Factual and Fictional Discourses Typology
Authors: FOURNIER SIMON
Published: June 2018

In recent decades, speech act theorists began analyzing discourses in order to describe the logic that governs the use and understanding of language in the context of interlocutions. This paper is in the wake of those studies. It questions the fruitfulness of the notion of speech acts in literary pragmatics, analyzes some literary genres and proposes a discourse typology containing eight generic categories that reflect the possible links between factual and fictional discourses. In doing so, it offers a response to a question raised many years ago by a literary theorist that is directed to speech act theorists.
Conceivability, Minimalism and the Generalization Problem
Authors: OMS SERGI
Published: June 2018

One of the main problems that Paul Horwich’s Minimalist theory of truth must face is the generalization problem, which shows that Minimalism is too weak to have the fundamental explanatory role Horwich claims it has. In this paper, I defend Horwich’s response to the generalization problem from an objection raised by Bradley Armour-Garb. I also argue that, given my response to Armour-Garb, Horwich’s proposal to cope with the generalization problem can be simplified.
SHORT MATURITY ASIAN OPTIONS FOR THE CEV MODEL
Authors: Pirjol Dan , Zhu Lingjiong
Published: June 2018

We present a rigorous study of the short maturity asymptotics for Asian options with continuous-time averaging, under the assumption that the underlying asset follows the constant elasticity of variance (CEV) model. The leading order short maturity limit of the Asian option prices under the CEV model is obtained in closed form. We propose an analytical approximation for the Asian options prices which reproduces the exact short maturity asymptotics, and demonstrate good numerical agreement of the asymptotic results with Monte Carlo simulations and benchmark test cases for option parameters relevant for practical applications.
Navigation Information Fusion in a Redundant Marine Rotational Inertial Navigation System Configuration
Authors: Wang Lin , Wu Wenqi , Wei Guo , Pan Xianfei , Lian Junxiang
Published: June 2018

A Rotational Inertial Navigation System (RINS) redundant configuration is commonly adopted in high-accuracy marine navigation. Single-axis RINS and dual-axis RINS redundant configurations are good choices with single-axis RINS being a hot backup system, and are trade-offs between position accuracy, reliability as well as cost. However, lack of information fusion between systems is common. Therefore, a novel navigation information fusion method based on an augmented error state Kalman filter is proposed for a RINS redundant configuration. The azimuth gyro drift of a single-axis RINS whose influence cannot be averaged out by single-axis rotation can be estimated, whereby the deterministic position error can be predicted and compensated. Hence, the position accuracy in the event of dual-axis RINS failure can be guaranteed by improving the performance of a single-axis RINS. In addition, an online performance evaluation method is proposed to select the better performance dual-axis RINS as master RINS in a triple RINS configuration, including two sets of dual-axis RINS and a single-axis RINS, which is used in some particularly high reliability applications. Semi-physical simulations and experiments show the proposed method works well.
Pharmacotherapy of schizophrenia: toward a metabolomic-based approach
Authors: Tayeb Haythum O. , Murad Hussam A. , Rafeeq Misbahuddin M. , Tarazi Frank I.
Published: June 2018

Approximately 20%–30% of schizophrenia patients are resistant to current standard pharmacotherapies. Recent schizophrenia research aims to identify specific pathophysiological abnormalities and novel targets in the disease, with the goals of identifying at-risk individuals, facilitating diagnosis, prompting early and personalized interventions, and helping predict response to treatment. Metabolomics involves the systematic study of the profile of biochemical alterations early in the course of a given disorder. Major aspects of the schizophrenia metabolome have been characterized, uncovering potential selective biomarkers for the disease that may change how the disorder is diagnosed, and how patients are stratified and treated. This review focuses on the most common metabolomic fingerprints of the different pathways involved in the pathophysiology of schizophrenia, and the potential development of novel metabolomic-related pharmacotherapies for improved treatment of schizophrenia and other related idiopathic psychotic disorders.
No sense of ownership in weak participation: a forest conservation experiment in Tanzania
Authors: Handberg Øyvind Nystad
Published: June 2018

Sense of ownership is often advocated as an argument for local participation within the epistemic development and nature conservation communities. Stakeholder participation in initiating, designing or implementing institutions is claimed to establish a sense of ownership among the stakeholders and subsequently improve the intended outcomes of the given institution. Theoretical and empirical justifications of the hypothesis remain scarce. A better understanding of the effects of local participation can motivate more extensive and stronger participation of local stakeholders and improve institutional performance. This paper applies theories from psychology and behavioral economics to sense of ownership. The empirical investigation is a framed field experiment in the context of tropical forest conservation and payments for environmental services in Tanzania. The results lend little support to the hypothesis in this context. The participation treatment in the experiment is weak, and a possible explanation is that sense of ownership is sensitive to the participation form.
SYLLOGISTIC LOGIC WITH CARDINALITY COMPARISONS, ON INFINITE SETS
Authors: MOSS LAWRENCE S. , TOPAL SELÇUK
Published: June 2018

This article enlarges classical syllogistic logic with assertions having to do with comparisons between the sizes of sets. So it concerns a logical system whose sentences are of the following forms: Allxareyand Somexarey, There are at least as manyxasy, and There are morexthany. Herexandyrange over subsets (not elements) of a giveninfiniteset. Moreover,xandymay appear complemented (i.e., as$\bar{x}$and$\bar{y}$), with the natural meaning. We formulate a logic for our language that is based on the classical syllogistic. The main result is a soundness/completeness theorem. There are efficient algorithms for proof search and model construction.
Seismic Anisotropy of the Upper Mantle Below the Western Rift, East Africa
Authors: Tepp G. , Ebinger C. J. , Zal H. , Gallacher R. , Accardo N. , Shillington D. J. , Gaherty J. , Keir D. , Nyblade A. A. , Mbogoni G. J. , Chindandali P. R. N. , Ferdinand‐Wambura R. , Mulibo G. D. , Kamihanda G.
Published: June 2018

Although the East African rift system formed in cratonic lithosphere above a large‐scale mantle upwelling, some sectors have voluminous magmatism, while others have isolated, small‐volume eruptive centers. We conduct teleseismic shear wave splitting analyses on data from 5 lake‐bottom seismometers and 67 land stations in the Tanganyika‐Rukwa‐Malawi rift zone, including the Rungwe Volcanic Province (RVP), and from 5 seismometers in the Kivu rift and Virunga Volcanic Province, to evaluate rift‐perpendicular strain, rift‐parallel melt intrusion, and regional flow models for seismic anisotropy patterns beneath the largely amagmatic Western rift. Observations from 684 SKS and 305 SKKS phases reveal consistent patterns. Within the Malawi rift south of the RVP, fast splitting directions are oriented northeast with average delays of ~1 s. Directions rotate to N‐S and NNW north of the volcanic province within the reactivated Mesozoic Rukwa and southern Tanganyika rifts. Delay times are largest (~1.25 s) within the Virunga Volcanic Province. Our work combined with earlier studies shows that SKS‐splitting is rift parallel within Western rift magmatic provinces, with a larger percentage of null measurements than in amagmatic areas. The spatial variations in direction and amount of splitting from our results and those of earlier Western rift studies suggest that mantle flow is deflected by the deeply rooted cratons. The resulting flow complexity, and likely stagnation beneath the Rungwe province, may explain the ca. 17 Myr of localized magmatism in the weakly stretched RVP, and it argues against interpretations of a uniform anisotropic layer caused by large‐scale asthenospheric flow or passive rifting.
Effective Radiative Forcing and Climate Response to Short‐Lived Climate Pollutants Under Different Scenarios
Authors: Zhang H. , Xie B. , Wang Z.
Published: June 2018

We used an online aerosol‐climate model (BCC_AGCM2.0_CUACE/Aero) to simulate effective radiative forcing and climate response to changes in the concentrations of short‐lived climatic pollutants (SLCPs), including methane, tropospheric ozone, and black carbon, for the period 2010–2050 under Representative Concentration Pathway scenarios (RCPs) 8.5, 4.5, and 2.6. Under these three scenarios, the global annual mean effective radiative forcing were 0.1, −0.3, and −0.5 W m−2, respectively. Under RCP 8.5, the change in SLCPs caused significant increases in surface air temperature (SAT) in middle and high latitudes of the Northern Hemisphere and significant decreases in precipitation in the Indian Peninsula and equatorial Pacific. Global mean SAT and precipitation increased by 0.13 K and 0.02 mm d−1, respectively. The reduction in SLCPs from 2010 to 2050 under RCPs 4.5 and 2.6 led to significant decreases in SAT at high latitudes in the Northern Hemisphere. Precipitation increased slightly in most continental regions, and the Intertropical Convergence Zone moved southward under both of these mitigation scenarios. Global mean SAT decreased by 0.20 and 0.44 K, and global averaged precipitation decreased by 0.02 and 0.03 mm d−1 under RCPs 4.5 and 2.6, respectively.
In Appreciation of AGU’s Outstanding Reviewers of 2017
Authors: Hanson Brooks , Tauxe Lisa
Published: June 2018

As AGU editors recognize the contributions of reviewers, our journals are providing new online tools, such as a short questionnaire for reviewer feedback, to improve the peer review process itself.
Solar Flare Caused Increased Oxygen Loss from Mars’s Atmosphere
Authors: Cartier Kimberly
Published: June 2018

Measurements by a Mars-orbiting spacecraft indicated heating and chemistry changes in the planet’s atmosphere following an extreme solar eruption last year.
Dune Casts Preserved by Partial Burial: The First Identification of Ghost Dune Pits on Mars
Authors: Day Mackenzie D. , Catling David C.
Published: June 2018

Eolian sediment transport is active on modern Mars and has been for billions of years. Dune fields dot the surface of the planet, and examples of preserved eolian strata confirm that dunes were active on ancient Mars. As is also true on Earth, most Martian eolian sandstones preserve only a small fraction of the strata that constituted ancient dunes, and whole dunes fields are rarely preserved. In this study, we focus on two fields of >300 pits each and compare the pit morphologies, scales, and orientations to modern Martian dunes. It is hypothesized that the pit fields studied in Noctis Labyrinthus and Hellas basin represent casts of dunes from two ancient dune fields that were partially buried in the Hesperian. The flood material concentrated in the interdune area then became indurated, while the loose eolian dune sands eroded away, leaving behind the ~102‐m‐scale dune‐shaped pits or ghost dune pits. Modern barchan dunes in Oyama and Herschel craters are used for comparison to the pit fields, and the topography of these modern dunes is used to model pit morphologies after partial burial. Basalt flows and low‐energy fluviolacustrine deposition are possible mechanisms for partial burial. The potential for eolian strata to be preserved within the pits at a once warm or water‐rich interface makes the pits of interest for astrobiology. The inferred ancient dune fields record in their morphology a wind regime that differs from the modern and provide rare evidence of whole dune field preservation.
Dual-color deep-tissue three-photon microscopy with a multiband infrared laser
Authors: Guesmi Khmaies , Abdeladim Lamiae , Tozer Samuel , Mahou Pierre , Kumamoto Takuma , Jurkus Karolis , Rigaud Philippe , Loulier Karine , Dray Nicolas , Georges Patrick , Hanna Marc , Livet Jean , Supatto Willy , Beaurepaire Emmanuel , Druon Frédéric
Published: June 2018

Multiphoton microscopy combined with genetically encoded fluorescent indicators is a central tool in biology. Three-photon (3P) microscopy with excitation in the short-wavelength infrared (SWIR) water transparency bands at 1.3 and 1.7 µm opens up new opportunities for deep-tissue imaging. However, novel strategies are needed to enable in-depth multicolor fluorescence imaging and fully develop such an imaging approach. Here, we report on a novel multiband SWIR source that simultaneously emits ultrashort pulses at 1.3 and 1.7 µm that has characteristics optimized for 3P microscopy: sub-70 fs duration, 1.25 MHz repetition rate, and µJ-range pulse energy. In turn, we achieve simultaneous 3P excitation of green fluorescent protein (GFP) and red fluorescent proteins (mRFP, mCherry, tdTomato) along with third-harmonic generation. We demonstrate in-depth dual-color 3P imaging in a fixed mouse brain, chick embryo spinal cord, and live adult zebrafish brain, with an improved signal-to-background ratio compared to multicolor two-photon imaging. This development opens the way towards multiparametric imaging deep within scattering tissues.
Low activity of lytic pelagiphages in coastal marine waters
Authors: Alonso-Sáez Laura , Morán Xosé Anxelu G , Clokie Martha R J
Published: June 2018

Phages infect marine bacteria impacting their dynamics, diversity and physiology, but little is known about specific phage–host interactions in situ. We analyzed the joint dynamics in the abundance of phage-related transcripts, as an indicator of viral lytic activity, and their potential hosts using a metatranscriptomic dataset obtained over 2 years in coastal temperate waters of the NE Atlantic. Substantial temporal variability was identified in the expression levels of different phages, likely in response to host availability. Indeed, a significant positive relationship between the abundance of transcripts from some of the most abundant phage types (infecting SAR11, SAR116 and cyanobacteria) and their putative hosts was found. Yet, the ratio of increase in phage transcripts per host cell was significantly lower for pelagiphages than for the HMO-2011 phage, which infects SAR116. Despite the high abundance of pelagiphages in the ocean, they may be less active than other phage types in coastal waters.
A multiethnic genome-wide association study of primary open-angle glaucoma identifies novel risk loci
Authors: Choquet Hélène , Paylakhi Seyyedhassan , Kneeland Stephen C. , Thai Khanh K. , Hoffmann Thomas J. , Yin Jie , Kvale Mark N. , Banda Yambazi , Tolman Nicholas G. , Williams Pete A. , Schaefer Catherine , Melles Ronald B. , Risch Neil , John Simon W. M. , Nair K. Saidas , Jorgenson Eric
Published: June 2018

Primary open-angle glaucoma (POAG) is a leading cause of irreversible vision loss, yet much of the genetic risk remains unaccounted for, especially in African-Americans who have a higher risk for developing POAG. We conduct a multiethnic genome-wide association study (GWAS) of POAG in the GERA cohort, with replication in the UK Biobank (UKB), and vice versa, GWAS in UKB with replication in GERA. We identify 24 loci (P < 5.0 × 10−8), including 14 novel, of which 9 replicate (near FMNL2, PDE7B, TMTC2, IKZF2, CADM2, DGKG, ANKH, EXOC2, and LMX1B). Functional studies support intraocular pressure-related influences of FMNL2 and LMX1B, with certain Lmx1b mutations causing high IOP and glaucoma resembling POAG in mice. The newly identified loci increase the proportion of variance explained in each GERA race/ethnicity group, with the largest gain in African-Americans (0.5–3.1%). A meta-analysis combining GERA and UKB identifies 24 additional loci. Our study provides important insights into glaucoma pathogenesis.
Identifying gene targets for brain-related traits using transcriptomic and methylomic data from blood
Authors: Qi Ting , Wu Yang , Zeng Jian , Zhang Futao , Xue Angli , Jiang Longda , Zhu Zhihong , Kemper Kathryn , Yengo Loic , Zheng Zhili ,   eQTLGen Consortium, Agbessi Mawussé , Ahsan Habibul , Alves Isabel , Andiappan Anand , Awadalla Philip , Battle Alexis , Beutner Frank , Jan Bonder Marc , Boomsma Dorret , Christiansen Mark , Claringbould Annique , Deelen Patrick , Esko Tõnu , Favé Marie-Julie , Franke Lude , Frayling Timothy , Gharib Sina , Gibson Gregory , Hemani Gibran , Jansen Rick , Kähönen Mika , Kalnapenkis Anette , Kasela Silva , Kettunen Johannes , Kim Yungil , Kirsten Holger , Kovacs Peter , Krohn Knut , Kronberg-Guzman Jaanika , Kukushkina Viktorija , Kutalik Zoltan , Lee Bernett , Lehtimäki Terho , Loeffler Markus , Marigorta Urko M. , Metspalu Andres , Milani Lili , Müller-Nurasyid Martina , Nauck Matthias , Nivard Michel , Penninx Brenda , Perola Markus , Pervjakova Natalia , Pierce Brandon , Powell Joseph , Prokisch Holger , Psaty Bruce , Raitakari Olli , Ring Susan , Ripatti Samuli , Rotzschke Olaf , Ruëger Sina , Saha Ashis , Scholz Markus , Schramm Katharina , Seppälä Ilkka , Stumvoll Michael , Sullivan Patrick , Teumer Alexander , Thiery Joachim , Tong Lin , Tönjes Anke , van Dongen Jenny , van Meurs Joyce , Verlouw Joost , Völker Uwe , Võsa Urmo , Yaghootkar Hanieh , Zeng Biao , Marioni Riccardo E. , Montgomery Grant W. , Deary Ian J. , Wray Naomi R. , Visscher Peter M. , McRae Allan F. , Yang Jian
Published: June 2018

Understanding the difference in genetic regulation of gene expression between brain and blood is important for discovering genes for brain-related traits and disorders. Here, we estimate the correlation of genetic effects at the top-associated cis-expression or -DNA methylation (DNAm) quantitative trait loci (cis-eQTLs or cis-mQTLs) between brain and blood (r
b
). Using publicly available data, we find that genetic effects at the top cis-eQTLs or mQTLs are highly correlated between independent brain and blood samples ($$\hat r_b = 0.70$$

r

^

b

=
0.70
for cis-eQTLs and $$\hat r_ b = 0.78$$

r

^

b

=
0.78
for cis-mQTLs). Using meta-analyzed brain cis-eQTL/mQTL data (n = 526 to 1194), we identify 61 genes and 167 DNAm sites associated with four brain-related phenotypes, most of which are a subset of the discoveries (97 genes and 295 DNAm sites) using data from blood with larger sample sizes (n = 1980 to 14,115). Our results demonstrate the gain of power in gene discovery for brain-related phenotypes using blood cis-eQTL/mQTL data with large sample sizes.
Modular cell-internalizing aptamer nanostructure enables targeted delivery of large functional RNAs in cancer cell lines
Authors: Porciani David , Cardwell Leah N. , Tawiah Kwaku D. , Alam Khalid K. , Lange Margaret J. , Daniels Mark A. , Burke Donald H.
Published: June 2018

Large RNAs and ribonucleoprotein complexes have powerful therapeutic potential, but effective cell-targeted delivery tools are limited. Aptamers that internalize into target cells can deliver siRNAs (<15 kDa, 19–21 nt/strand). We demonstrate a modular nanostructure for cellular delivery of large, functional RNA payloads (50–80 kDa, 175–250 nt) by aptamers that recognize multiple human B cell cancer lines and transferrin receptor-expressing cells. Fluorogenic RNA reporter payloads enable accelerated testing of platform designs and rapid evaluation of assembly and internalization. Modularity is demonstrated by swapping in different targeting and payload aptamers. Both modules internalize into leukemic B cell lines and remained colocalized within endosomes. Fluorescence from internalized RNA persists for ≥2 h, suggesting a sizable window for aptamer payloads to exert influence upon targeted cells. This demonstration of aptamer-mediated, cell-internalizing delivery of large RNAs with retention of functional structure raises the possibility of manipulating endosomes and cells by delivering large aptamers and regulatory RNAs.
Structural basis for the regulation of human 5,10-methylenetetrahydrofolate reductase by phosphorylation and S-adenosylmethionine inhibition
Authors: Froese D. Sean , Kopec Jolanta , Rembeza Elzbieta , Bezerra Gustavo Arruda , Oberholzer Anselm Erich , Suormala Terttu , Lutz Seraina , Chalk Rod , Borkowska Oktawia , Baumgartner Matthias R. , Yue Wyatt W.
Published: June 2018

The folate and methionine cycles are crucial for biosynthesis of lipids, nucleotides and proteins, and production of the methyl donor S-adenosylmethionine (SAM). 5,10-methylenetetrahydrofolate reductase (MTHFR) represents a key regulatory connection between these cycles, generating 5-methyltetrahydrofolate for initiation of the methionine cycle, and undergoing allosteric inhibition by its end product SAM. Our 2.5 Å resolution crystal structure of human MTHFR reveals a unique architecture, appending the well-conserved catalytic TIM-barrel to a eukaryote-only SAM-binding domain. The latter domain of novel fold provides the predominant interface for MTHFR homo-dimerization, positioning the N-terminal serine-rich phosphorylation region near the C-terminal SAM-binding domain. This explains how MTHFR phosphorylation, identified on 11 N-terminal residues (16 in total), increases sensitivity to SAM binding and inhibition. Finally, we demonstrate that the 25-amino-acid inter-domain linker enables conformational plasticity and propose it to be a key mediator of SAM regulation. Together, these results provide insight into the molecular regulation of MTHFR.
Current status of Zika vaccine development: Zika vaccines advance into clinical evaluation
Authors: Barrett Alan D. T.
Published: June 2018

Zika virus (ZIKV), a mosquito-borne flavivirus, was first identified in the 1940s in Uganda in Africa and emerged in the Americas in Brazil in May 2015. In the 30 months since ZIKV emerged as a major public health problem, spectacular progress has been made with vaccine development cumulating with the publication of three reports of phase 1 clinical trials in the 4th quarter of 2017. Clinical trials involving candidate DNA and purified inactivated virus vaccines showed all were safe and well-tolerated in the small number of volunteers and all induced neutralizing antibodies, although these varied by vaccine candidate and dosing regimen. These results suggest that a Zika vaccine can be developed and that phase 2 clinical trials are warranted. However, it is difficult to compare the results from the different phase 1 studies or with neutralizing antibodies induced by licensed flavivirus vaccines (Japanese encephalitis, tick-borne encephalitis, and yellow fever) as neutralizing antibody assays vary and, unfortunately, there are no standards for Zika virus neutralizing antibodies. In addition to clinical studies, substantial progress continues to be made in nonclinical development, particularly in terms of the ability of candidate vaccines to protect reproductive tissues, and the potential use of monoclonal antibodies for passive prophylaxis.
The Translational and Rotational Dynamics of a Colloid Moving Along the Air-Liquid Interface of a Thin Film
Authors: Das Subhabrata , Koplik Joel , Farinato Raymond , Nagaraj D. R. , Maldarelli Charles , Somasundaran Ponisseril
Published: June 2018

This study examines the translation and rotation of a spherical colloid straddling the (upper) air/liquid interface of a thin, planar, liquid film bounded from below by either a solid or a gas/liquid interface. The goal is to obtain numerical solutions for the hydrodynamic flow in order to understand the influence of the film thickness and the lower interface boundary condition. When the colloid translates on a film above a solid, the viscous resistance increases significantly as the film thickness decreases due to the fluid-solid interaction, while on a free lamella, the drag decreases due to the proximity to the free (gas/liquid) surface. When the colloid rotates, the contact line of the interface moves relative to the colloid surface. If no-slip is assumed, the stress becomes infinite and prevents the rotation. Here finite slip is used to resolve the singularity, and for small values of the slip coefficient, the rotational viscous resistance is dominated by the contact line stress and is surprisingly less dependent on the film thickness and the lower interface boundary condition. For a colloid rotating on a semi-infinite liquid layer, the rotational resistance is largest when the colloid just breaches the interface from the liquid side.
Author Correction: India Is Overtaking China as the World’s Largest Emitter of Anthropogenic Sulfur Dioxide
Authors: Li Can , McLinden Chris , Fioletov Vitali , Krotkov Nickolay , Carn Simon , Joiner Joanna , Streets David , He Hao , Ren Xinrong , Li Zhanqing , Dickerson Russell R.
Published: June 2018

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.
Association between oral health and general health indicators in older adults
Authors: Tran Trung Dung , Krausch-Hofmann Stefanie , Duyck Joke , de Almeida Mello Johanna , De Lepeleire Jan , Declerck Dominique , Declercq Anja , Lesaffre Emmanuel
Published: June 2018

Oral health (OH) and general health (GH) indicators are representations of the health status of the body. The OH indicators provide information about the oral health status while the GH indicators are used to assess the functional, cognitive, and mental conditions. OH is reported to be associated with GH. However, some specific associations, especially longitudinal relationships between OH and GH indicators, have not been fully explored. We examined the prediction ability from OH to GH and vice versa using a Belgian registry. We collected information from 8359 elderly participants, who were older than 65, lived at home, and received home care. The demographic and clinical information including three binary OH indicators and four ordinal GH indicators were collected. The participants were recorded at baseline and every six months afterwards. We opted for a generalization of a vector autoregressive model to ordinal responses. This model allows to estimate autocorrelations and cross-lagged correlations, addressing the prediction of GH from OH in a cross-sectional and longitudinal manner. We showed that individuals who had poorer OH had a higher risk of suffering from poor GH status. The percentages of correct or close prediction for GH indicators from OH indicators are high, being around 80% for all GH indicators. Additionally, having a poor OH (resp. GH) status was additionally predictive of a poor GH (resp. OH) status at following assessments. Our finding suggests using historical records of OH as well as GH indicators to draw better health care plan for geriatrics population.
Real-life speech production and perception have a shared premotor-cortical substrate
Authors: Glanz Olga , Derix Johanna , Kaur Rajbir , Schulze-Bonhage Andreas , Auer Peter , Aertsen Ad , Ball Tonio
Published: June 2018

Motor-cognitive accounts assume that the articulatory cortex is involved in language comprehension, but previous studies may have observed such an involvement as an artefact of experimental procedures. Here, we employed electrocorticography (ECoG) during natural, non-experimental behavior combined with electrocortical stimulation mapping to study the neural basis of real-life human verbal communication. We took advantage of ECoG’s ability to capture high-gamma activity (70–350 Hz) as a spatially and temporally precise index of cortical activation during unconstrained, naturalistic speech production and perception conditions. Our findings show that an electrostimulation-defined mouth motor region located in the superior ventral premotor cortex is consistently activated during both conditions. This region became active early relative to the onset of speech production and was recruited during speech perception regardless of acoustic background noise. Our study thus pinpoints a shared ventral premotor substrate for real-life speech production and perception with its basic properties.
Airway brushing as a new experimental methodology to detect airway gene expression signatures in mouse lung squamous cell carcinoma
Authors: Pan Jing , Xiong Donghai , Zhang Qi , Szabo Eva , Miller Mark Steven , Lubet Ronald A. , Wang Yian , You Ming
Published: June 2018

As a consequence of exposure to environmental toxicants, a “field cancerization” effect occurs in the lung, resulting in the development of a field of initiated, but morphologically normal appearing cells within a damaged epithelium containing mutations in oncogene or tumor suppressor genes. Unlike humans, whose airway field of injury associated with lung cancer has long been investigated with airway brushings obtained via bronchoscopy, no methods are available for similar studies in the mouse due to the small size of the murine airways. In this protocol, we describe a detailed method for performing airway brushing from a live mouse, which enables repeated sampling from the same mouse and thus, mimicking the bronchoscopy protocol used in humans. Using this approach in the N-nitroso-tris-chloroethylurea (NTCU)-induced mouse lung squamous cell carcinoma (SCC) model, we isolated airway epithelial cells with intact cell membrane structure and then performed transcriptome sequencing (RNA-Seq). We found activation of the PI3K signaling network to be the most significant in cytologically normal bronchial airway epithelial cells of mice with preneoplastic lung SCC lesions. Prolonged exposure to NTCU also induced activation of NF-kappaB (NFƙB), the downstream pathway of PI3K; this NTCU-induced lung SCC progression can be reversed by blocking the NFƙB pathway.
PQQ ameliorates D-galactose induced cognitive impairments by reducing glutamate neurotoxicity via the GSK-3β/Akt signaling pathway in mouse
Authors: Zhou Xing-qin , Yao Zhi-wen , Peng Ying , Mao Shi-shi , Xu Dong , Qin Xiao-feng , Zhang Rong-jun
Published: June 2018

Oxidative stress is known to be associated with various age-related diseases. D-galactose (D-gal) has been considered a senescent model which induces oxidative stress response resulting in memory dysfunction. Pyrroloquinoline quinone (PQQ) is a redox cofactor which is found in various foods. In our previous study, we found that PQQ may be converted into a derivative by binding with amino acid, which is beneficial to several pathological processes. In this study, we found a beneficial glutamate mixture which may diminish neurotoxicity by oxidative stress in D-gal induced mouse. Our results showed that PQQ may influence the generation of proinflammatory mediators, including cytokines and prostaglandins during aging process. D-gal-induced mouse showed increased MDA and ROS levels, and decreased T-AOC activities in the hippocampus, these changes were reversed by PQQ supplementation. Furthermore, PQQ statistically enhanced Superoxide Dismutase SOD2 mRNA expression. PQQ could ameliorate the memory deficits and neurotoxicity induced by D-gal via binding with excess glutamate, which provide a link between glutamate-mediated neurotoxicity, inflammation and oxidative stress. In addition, PQQ reduced the up-regulated expression of p-Akt by D-gal and maintained the activity of GSK-3β, resulting in a down-regulation of p-Tau level in hippocampus. PQQ modulated memory ability partly via Akt/GSK-3β pathway.
Impact of nicotine replacement therapy as an adjunct to anti-tuberculosis treatment and behaviour change counselling in newly diagnosed pulmonary tuberculosis patients: an open-label, randomised controlled trial
Authors: Sharma Surendra Kumar , Mohan Alladi , Singh Achintya Dinesh , Mishra Hridesh , Jhanjee Sonali , Pandey Ravindra Mohan , Singh Binit Kumar , Sharma Rohini , Pallipamu Prakash Babu , Pai Madhukar , Dheda Keertan
Published: June 2018

We evaluated the impact of intensive smoking cessation activities as an adjunct to anti-tuberculosis treatment on patient-related treatment outcomes. In this open-label, randomised controlled trial, self-reporting smokers with pulmonary tuberculosis who initiated standard anti-tuberculosis treatment were randomised to either nicotine replacement therapy and behaviour change counselling (n = 400) or counselling alone (n = 400) provided at baseline and two follow-up visits. The primary outcomes were change in TBscore at 24-weeks and culture conversion at 8-weeks. Biochemical smoking quit rates defined as serum cotinine levels <10 ng/mL and/or exhaled carbon monoxide levels <6 ppm (47·8% vs 32·4%, p-value =< 0·001) and self-reported quit rates (69.3% vs 38·7%, p-value =< 0·001) were significantly higher in the intervention arm at 24-weeks. Though the TBscores at 24 weeks (95% CI) were lower in the intervention arm [2·07 (1·98, 2·17) versus 2.12 (2·02, 2·21)], the difference was not clinically meaningful. Patients in the control arm required treatment extension more often than intervention arm (6·4% vs 2·6%, p-value = 0·02). Combining nicotine replacement therapy with behaviour change counselling resulted in significantly higher quit rates and lower cotinine levels, however, impact on patient-related (TBscore) or microbiological outcomes (culture conversion) were not seen.
Water Vapor Transfer and Near-Surface Salinity Contrasts in the North Atlantic Ocean
Authors: Reagan James , Seidov Dan , Boyer Tim
Published: June 2018

Maintaining North Atlantic (NA) intra-basin near-surface salinity (NSS) contrast between the high NSS (>37.0) in the subtropical NA (STNA) and low NSS (<35.0) in the subpolar NA (SPNA) has been shown to be important in sustaining the strength of the Atlantic Meridional Overturning Circulation. Evaporation (E) exceeding precipitation (P) in the STNA is primarily responsible for the high NSS there, whereas P dominating E in the SPNA contributes to its low NSS. With a basic understanding of NA intra-basin moisture transport, a correlation analysis was conducted between E-P/NSS over the NA subpolar gyre (SPG) and E-P across the rest of the NA over the 1985–2012 time period. Significant anti-correlations exist between E-P/NSS over the NA SPG and E-P over the central/northern STNA. This suggests that during times of high E over the central/northern STNA there is high (low) precipitation (NSS) over the SPG demonstrating a relationship likely exists between E over the STNA and NSS over the SPG. The maximum anti-correlated area is poleward of the maximum E-P location in the STNA, which is examined. These results provide a first step to ultimately utilizing NSS in the NA as a proxy for estimating changes in the hydrological cycle.
Confirmation of high-throughput screening data and novel mechanistic insights into VDR-xenobiotic interactions by orthogonal assays
Authors: Mahapatra Debabrata , Franzosa Jill A. , Roell Kyle , Kuenemann Melaine Agnes , Houck Keith A. , Reif David M. , Fourches Denis , Kullman Seth W.
Published: June 2018

High throughput screening (HTS) programs have demonstrated that the Vitamin D receptor (VDR) is activated and/or antagonized by a wide range of structurally diverse chemicals. In this study, we examined the Tox21 qHTS data set generated against VDR for reproducibility and concordance and elucidated functional insights into VDR-xenobiotic interactions. Twenty-one potential VDR agonists and 19 VDR antagonists were identified from a subset of >400 compounds with putative VDR activity and examined for VDR functionality utilizing select orthogonal assays. Transient transactivation assay (TT) using a human VDR plasmid and Cyp24 luciferase reporter construct revealed 20/21 active VDR agonists and 18/19 active VDR antagonists. Mammalian-2-hybrid assay (M2H) was then used to evaluate VDR interactions with co-activators and co-regulators. With the exception of a select few compounds, VDR agonists exhibited significant recruitment of co-regulators and co-activators whereas antagonists exhibited considerable attenuation of recruitment by VDR. A unique set of compounds exhibiting synergistic activity in antagonist mode and no activity in agonist mode was identified. Cheminformatics modeling of VDR-ligand interactions were conducted and revealed selective ligand VDR interaction. Overall, data emphasizes the molecular complexity of ligand-mediated interactions with VDR and suggest that VDR transactivation may be a target site of action for diverse xenobiotics.