bluuebunny/crossref_metadata_2025 huggingface dataset:
The motives attributed to trolls in metapragmatic comments on three Hungarian left-wing political blogs
Authors: Petykó Márton
Published: August 2018

This paper investigates the linguistically marked motives that participants attribute to those they call trolls in 178 comment
threads of three Hungarian left-wing political blogs. It is also concerned with how frequently these motives are mentioned and how
they contribute to the discursive construction of trolling and trolls. Another goal of the paper is to examine whether the mainly
emotional motives ascribed to trolls in the academic literature correspond with those that the participants attribute to the
alleged trolls in the threads. The paper identifies five motives for trolling: emotional reasons, financial gain, political
beliefs, being employed by Fidesz or the Hungarian government, and unspecified political affiliation. Depending on these motives,
trolling and trolls are constructed in various ways. Furthermore, by suggesting that Fidesz or the Hungarian government employs
trolls, the posters discursively construct Fidesz as an autocratic and corrupt state party that tries to manipulate the
public.
The multimodal enactment of deontic and epistemic authority in Indian meetings
Authors: Clifton Jonathan , Van De Mieroop Dorien , Sehgal Prachee , Aneet
Published: August 2018

Authority is a much discussed topic in organizational literature, but its in situ enactment is little investigated. Using the
notions of deontic and epistemic authority and using multimodal conversation analysis as a research methodology, the purpose of
this paper is to provide an empirical study of authority-in-action. We particularly focus on both sequences of talk and the
multimodal resources that are mobilised to ‘do’ authority. Furthermore, as research from non-Western contexts remains rare, we
complement insights into authority enactment based on ‘Western’ data by using data that is drawn from a corpus of
naturally-occurring video-recorded faculty meetings at an Indian University. Findings indicate that the doing of authority can be
made visible by explicating participants’ orientation to their respective deontic and epistemic rights and their invocation of
particular identities, which are accomplished by means of a complex intertwining of verbal and non-verbal resources.
Acquisition of sociophonetic variation
Authors: Solon Megan , Linford Bret , Geeslin Kimberly L.
Published: August 2018

This study investigates the acquisition of nativelike variation in the production of Spanish /d/ by English-speaking learners. Specifically, we examine the production of /d/ in word-internal intervocalic position in the speech of 13 highly advanced nonnative speakers (NNSs) and 13 native speakers (NSs) of Spanish in digitally-recorded sociolinguistic interviews. The analysis includes a discrete categorization of /d/ realization based on spectrographic examination (stop vs. spirant vs. deleted) and a continuous intensity difference measure. Tokens were coded for grammatical category, surrounding segments, stress, number of syllables, and lexical frequency. Results indicate that both NNSs and NSs exhibit /d/ spirantization and deletion, but these two processes are affected by different factors both between and across groups: NNS deletion patterns are predicted most significantly by lexical frequency, whereas degree of spirantization is influenced by articulatory/contextual factors of phonetic context and stress. NS patterns for both processes are influenced by most factors in a similar manner.
The acquisition of voicing assimilation by advanced Hungarian learners of Spanish
Authors: Bárkányi Zsuzsanna
Published: August 2018

This study examines the effect of explicit phonological instruction on the acquisition of variable /s/ voicing in Spanish by advanced Hungarian learners. Hungarian and Spanish have very similar, yet not identical, voicing assimilation (VA) systems; the most important difference lies in the pre-sonorant context as sonorant consonants trigger voicing assimilation in Spanish but not in Hungarian. Data were collected in acoustic experiments from 7 native speakers of Northern Peninsular Spanish and 12 Hungarian university students who were advanced learners of Spanish. The latter group was tested twice: before and after a three-monthSpanish phonetics and phonologycourse. Our data reveal that this amount of instruction is not enough for L2 speakers to overcome their first language VA system, which might be attributed, in part, to the variable allophonic nature of the process and the similarity between the two languages’ VA systems.
Modeling World Englishes from a cross-linguistic perspective
Authors: Siemund Peter
Published: August 2018

The increasing diversification of English qua World Englishes contributes to cross-linguistic variation. Still, we tend to consider and model varieties of English from a language-internal perspective. Taking Mair’s (2013) World System of Englishes as a starting point, I here explore how to model World Englishes from a cross-linguistic typological perspective, commenting on the tension between normative pressure and cross-linguistic tendencies and generalizations. Variation studies and language typology investigate micro and macro variation, respectively, though the empirical domains in focus and the methodologies employed show considerable overlap. Moreover, the traditional distinction between language and variety becomes increasingly difficult to draw in today’s multilingual and highly interconnected world. I examine the commonalities and differences of the two approaches to language variation that have largely been working independently of one another focusing on language universals and the ways that grammatical phenomena from World Englishes match up against them. Varieties of English attest a good deal of typological variation, though they also offer curious features rarely found in other languages.
American and/or British influence on L2 Englishes – Does context tip the scale(s)?
Authors: Gilquin Gaëtanelle
Published: August 2018

Taking Mair’s (2013) World System of Englishes as a starting point, this chapter seeks to investigate whether American English is a more important source of influence than British English for the other varieties of English, including English as an institutionalised second language and English as a foreign language. The study is based on twenty pairs of items that are distinctive between American and British English and whose frequency is calculated in data from the Global Web-based English Corpus (GloWbE) and the EF-Cambridge Open Language Database (EFCAMDAT). The results reveal a global influence of American English, as predicted by Mair’s model, but also show that varieties are not necessarily homogeneous in this respect and that more local contextual factors may have an impact on the degree of American and/or British influence.
A corpus-linguistic account of the history of the genitive alternation in Singapore English
Authors: Gries Stefan Th. , Bernaisch Tobias , Heller Benedikt
Published: August 2018

In this paper, we are exploring the history of the genitive alternation (of- vs. s-genitive) in Singapore English based on corpus data covering both British English (as the historical input variety) and Singapore English (as the target variety whose diachronic development we are interested in). Specifically, while earlier research has produced partly diachronic accounts of genitive variability, the diachronic development of the genitive has so far not been studied in ESL contexts, a gap which this study attempts to fill. Nearly 7000 instances of of- and s-genitives were annotated for a large number of predictors including phonetic variables (e.g. final sibilancy of possessor), semantic variables (e.g. animacy of possessor/possessum), syntactic variables (e.g. length of possessor/possessum), and pragmatic variables (e.g. discourse accessibility of possessor/possessum). We then applied the method of Multifactorial Prediction and Deviation Analysis with Regressions/Random Forests to the data to explore (i) how genitive choices in Singapore English differ from those in British English and, after a methodological interlude, (ii) how genitive choices changed over time in Singapore English. We conclude with some important recommendations regarding diachronic studies of structural nativization and their theoretical implications in models such as those of Moag (1982) or Schneider (2003, 2007).
Modeling World Englishes in the 21st century
Authors: Deshors Sandra C. , Gilquin Gaëtanelle
Published: August 2018

This chapter seeks to bring together all the contributions in the volume. We identify converging lines of argumentation and findings across the studies featured in the book and we show how the approaches they adopt and the linguistic patterns they uncover shed new light on globalized Englishes, the diversity of their uses and their emerging functions. Based on these studies, we discuss possible avenues for future research in the modeling process of World Englishes (WEs) and we make suggestions as to what contemporary theoretical models of WEs should look like in order to truly capture the developmental patterns of WEs in the 21st century. Generally, it emerges that theoretical models anchored in the ‘moment of communication’ are likely to reflect most effectively the intricate dynamics that lies behind the development of Englishes worldwide and that is stirred by linguistic, pragmatic, social, ideological and cultural forces, simultaneously.
An analysis of 15 years of trends in children’s connection with nature and its relationship with residential environment
Authors: Imai Haruka , Nakashizuka Tohru , Kohsaka Ryo
Published: August 2018

Intruduction:
We assessed recent trends in children’s connection with nature over the period of 2000–2015, using indices of wildlife awareness that focus on changes in wildlife abundance and the level of apathy among children. We used data from a survey conducted in 63 junior high school districts in the city of Sendai in Japan. In these surveys, children were asked whether they had seen 12 species groups within the past year. To examine changes in children’s connection with nature, we used observed frequencies as an indicator of both the abundance of the species and children’s apathy toward it.

Results and Discussions:
Results indicated an increase in children’s apathy toward species that had low popularity regardless of residential environment. Our results suggest that regular exposure to wildlife would be effective in preventing the loss of children’s connection with nature, particularly by reducing children’s apathy toward less-popular species.
Determining the molecular basis of voltage sensitivity in membrane proteins
Authors: Kasimova Marina A. , Lindahl Erik , Delemotte Lucie
Published: August 2018

Voltage-sensitive membrane proteins are united by their ability to transform changes in membrane potential into mechanical work. They are responsible for a spectrum of physiological processes in living organisms, including electrical signaling and cell-cycle progression. Although the mechanism of voltage-sensing has been well characterized for some membrane proteins, including voltage-gated ion channels, even the location of the voltage-sensing elements remains unknown for others. Moreover, the detection of these elements by using experimental techniques is challenging because of the diversity of membrane proteins. Here, we provide a computational approach to predict voltage-sensing elements in any membrane protein, independent of its structure or function. It relies on an estimation of the propensity of a protein to respond to changes in membrane potential. We first show that this property correlates well with voltage sensitivity by applying our approach to a set of voltage-sensitive and voltage-insensitive membrane proteins. We further show that it correctly identifies authentic voltage-sensitive residues in the voltage-sensor domain of voltage-gated ion channels. Finally, we investigate six membrane proteins for which the voltage-sensing elements have not yet been characterized and identify residues and ions that might be involved in the response to voltage. The suggested approach is fast and simple and enables a characterization of voltage sensitivity that goes beyond mere identification of charges. We anticipate that its application before mutagenesis experiments will significantly reduce the number of potential voltage-sensitive elements to be tested.
Validation of a Claims-Based Frailty Index Against Physical Performance and Adverse Health Outcomes in the Health and Retirement Study
Authors: Kim Dae Hyun , Glynn Robert J , Avorn Jerry , Lipsitz Lewis A , Rockwood Kenneth , Pawar Ajinkya , Schneeweiss Sebastian
Published: August 2018

Background

A claims-based frailty index (CFI) was developed based on a deficit-accumulation approach using self-reported health information. This study aimed to independently validate the CFI against physical performance and adverse health outcomes.

Methods

This retrospective cohort study included 3,642 community-dwelling older adults who had at least 1 health care encounter in the year prior to assessments of physical performance in the 2008 Health and Retirement Study wave. A CFI was estimated from Medicare claims data in the past year. Gait speed, grip strength, and the 2-year risk of death, institutionalization, disability, hospitalization, and prolonged (>30 days) skilled nursing facility (SNF) stay were evaluated for CFI categories (robust: <0.15, prefrail: 0.15–0.24, mildly frail: 0.25–0.34, moderate-to-severely frail: ≥0.35).

Results

The prevalence of robust, prefrail, mildly frail, and moderate-to-severely frail state was 52.7%, 38.0%, 7.1%, and 2.2%, respectively. Individuals with higher CFI had lower mean gait speed (moderate-to-severely frail vs robust: 0.39 vs 0.78 m/s) and weaker grip strength (19.8 vs 28.5 kg). Higher CFI was associated with death (moderate-to-severely frail vs robust: 46% vs 7%), institutionalization (21% vs 5%), activity of daily living disability (33% vs 9%), instrumental activity of daily living disability (100% vs 22%), hospitalization (79% vs 23%), and prolonged SNF stay (17% vs 2%). The odds ratios per 1-SD (=0.07) difference in CFI were 1.46–2.06 for these outcomes, which remained statistically significant after adjustment for age, sex, and a comorbidity index.

Conclusion

The CFI is useful to identify individuals with poor physical function and at greater risks of adverse health outcomes in Medicare data.
Population genomics of wild Chinese rhesus macaques reveals a dynamic demographic history and local adaptation, with implications for biomedical research
Authors: Liu Zhijin , Tan Xinxin , Orozco-terWengel Pablo , Zhou Xuming , Zhang Liye , Tian Shilin , Yan Zhongze , Xu Huailiang , Ren Baoping , Zhang Peng , Xiang Zuofu , Sun Binghua , Roos Christian , Bruford Michael W , Li Ming
Published: August 2018

Background

The rhesus macaque (RM, Macaca mulatta) is the most important nonhuman primate model in biomedical research. We present the first genomic survey of wild RMs, sequencing 81 geo-referenced individuals of five subspecies from 17 locations in China, a large fraction of the species' natural distribution.

Results

Populations were structured into five genetic lineages on the mainland and Hainan Island, recapitulating current subspecies designations. These subspecies are estimated to have diverged 125.8 to 51.3 thousand years ago, but feature recent gene flow. Consistent with the expectation of a larger body size in colder climates and smaller body size in warmer climates (Bergman's rule), the northernmost RM lineage (M. m. tcheliensis), possessing the largest body size of all Chinese RMs, and the southernmost lineage (M. m. brevicaudus), with the smallest body size of all Chinese RMs, feature positively selected genes responsible for skeletal development. Further, two candidate selected genes (Fbp1, Fbp2) found in M. m. tcheliensis are involved in gluconeogenesis, potentially maintaining stable blood glucose levels during starvation when food resources are scarce in winter. The tropical subspecies M. m. brevicaudus showed positively selected genes related to cardiovascular function and response to temperature stimuli, potentially involved in tropical adaptation. We found 118 single-nucleotide polymorphisms matching human disease-causing variants with 82 being subspecies specific.

Conclusions

These data provide a resource for selection of RMs in biomedical experiments. The demographic history of Chinese RMs and their history of local adaption offer new insights into their evolution and provide valuable baseline information for biomedical investigation.
Resisting austerity measures to social policies: multiple explanatory case studies
Authors: O’Campo Patricia , Freiler Alix , Muntaner Carles , Gelormino Elena , Huegaerts Kelly , Puig-Barrachina Vanessa , Mitchell Christiane
Published: August 2018

Since Margaret Thatcher reached power in the United Kingdom, European governments have increasingly turned to neoliberal forms of policy-making, focusing, especially after the 2008 Great Recession on ‘austerity policies’ rather than investing in social protection policies. We applied a multiple explanatory case studies methodology to examine how and why challenges and resistance to these austerity measures are successful or not in four settings for three different social policy issues: using a gender lens in state budgeting in Andalusia (Spain), maintaining unemployment benefits in Italy and cuts to fuel poverty reduction programs in Northern Ireland and England. In particular, we intended to learn about whether resistance strategies are shared across disparate cases or whether there are unique activities that lead to successful resistance to austerity policies. As our approach drew from realist philosophy of science, we started with initial theories concerning collective action, political ideology and political power of affected populations. Our findings suggest that there are similarities between the cases we studied despite differences in political and policy contexts. We found that joint action between advocacy groups was effective in resisting cuts to social spending. Evidence also indicates that the social construction of target populations is important in resisting changes to social programmes. This was observed in both England and Northern Ireland where pensioners held significant political clout.
Characterization of a clinical Clostridioides difficile isolate with markedly reduced fidaxomicin susceptibility and a V1143D mutation in rpoB
Authors: Schwanbeck Julian , Riedel Thomas , Laukien Friederike , Schober Isabel , Oehmig Ines , Zimmermann Ortrud , Overmann Jörg , Groß Uwe , Zautner Andreas E , Bohne Wolfgang
Published: August 2018

Objectives

The identification and characterization of clinical Clostridioides difficile isolates with reduced fidaxomicin susceptibility.

Methods

Agar dilution assays were used to determine fidaxomicin MICs. Genome sequence data were obtained by single-molecule real-time (SMRT) sequencing in addition to amplicon sequencing of rpoB and rpoC alleles. Allelic exchange was used to introduce the identified mutation into C. difficile 630Δerm. Replication rates, toxin A/B production and spore formation were determined from the strain with reduced fidaxomicin susceptibility.

Results

Out of 50 clinical C. difficile isolates, isolate Goe-91 revealed markedly reduced fidaxomicin susceptibility (MIC >64 mg/L). A V1143D mutation was identified in rpoB of Goe-91. When introduced into C. difficile 630Δerm, this mutation decreased fidaxomicin susceptibility (MIC >64 mg/L), but was also associated with a reduced replication rate, low toxin A/B production and markedly reduced spore formation. In contrast, Goe-91, although also reduced in toxin production, showed normal growth rates and only moderately reduced spore formation capacities. This indicates that the rpoBV1143D allele-associated fitness defect is less pronounced in the clinical isolate.

Conclusions

To the best of our knowledge, this is the first description of a pathogenic clinical C. difficile isolate with markedly reduced fidaxomicin susceptibility. The lower-than-expected fitness burden of the resistance-mediating rpoBV1143D allele might be an indication for compensatory mechanisms that take place during in vivo selection of mutants.
RETRACTED: Long noncoding RNA NSCLCAT1 increases non–small cell lung cancer cell invasion and migration through the Hippo signaling pathway by interacting with CDH1
Authors: Zhao Wei , Zhang Le-Ning , Wang Xiao-Long , Zhang Ji , Yu Hai-Xiang
Published: August 2018

Metastatic growth is the leading cause of cancer‐related death in non–small cell lung cancer (NSCLC). Metastasis is believed to be initiated by an increase in cell motility mediated by the loss of cell–cell adhesion because of the suppression of E‐cadherin [encoded by Cadherin 1 (CDH1)]. However, very little is known about the molecular mechanism of CDH1 regulation. Therefore, we hypothesized that non–small cell lung cancer—associated transcript‐1 (NSCLCAT1) suppresses functional CDH1 and mediates the Hippo signaling pathway, resulting in increased cell migration and invasion, and reduced apoptosis. Initially, microarray profiling and target prediction programs were employed to identify whether NSCLCAT1 targets CDH1. Next, quantitative PCR was used to determine the expression pattern of NSCLCAT1 in 114 specimens. The biologic functions of NSCLCAT1 in NSCLC were assessed through the up‐regulation and down‐regulation of the levels of endogenous NSCLCAT1 with the use of NSCLCAT1 vector or small interfering RNA against NSCLCAT1 in NSCLC cells. Furthermore, the Hippo signaling pathway in NSCLC cells was blocked by applying the verteporfin treatment to have a better understanding on the pivotal role of the Hippo signaling pathway in NSCLC. Microarray expression profiles of long noncoding RNAs, GSE19804 and GSE27262), revealed that NSCLCAT1 was up‐regulated in NSCLC. Among patients with NSCLC, we determined that the NSCLCAT1 was robustly induced, whereas CDH1 was suppressed. The luciferase activity determination identified CDH1 as a NSCLCAT1 target. NSCLCAT1 was found to increase cell viability, migration, and invasion and to reduce apoptosis in NSCLC cells. The results from the quantitative PCR and Western blot analysis revealed that NSCLCAT1 modulated the Hippo signaling pathway. Furthermore, the inhibition of the Hippo signaling pathway by verteporfin treatment led to the loss of the effect of NSCLCAT1 on NSCLC cells. In summary, our findings suggested that NSCLCAT1 potentially has a role in NSCLC and NSCLCAT1‐mediated regulation of the Hippo signaling pathway through the transcriptional repression of CDH1; therefore, the functional suppression or inhibition of NSCLCAT1 could be used as a novel therapeutic pathway in the control of aggressive and metastatic NSCLC.—Zhao, W., Zhang, L.‐N., Wang, X.‐L., Zhang, J., Yu, H.‐X.Long noncoding RNA NSCLCAT1 increases non‐small cell lung cancer cell invasion and migration through the Hippo signaling pathway by interacting with CDH1. FASEB J. 33, 1151–1166 (2019). www.fasebj.org
Facilitation of MrgprD by TRP‐A1 promotes neuropathic pain
Authors: Wang Changming , Gu Leying , Ruan Yonglan , Geng Xiao , Xu Miao , Yang Niuniu , Yu Lei , Jiang Yucui , Zhu Chan , Yang Yan , Zhou Yuan , Guan Xiaowei , Luo Wenqin , Liu Qin , Dong Xinzhong , Yu Guang , Lan Lei , Tang Zongxiang
Published: August 2018

Neuropathic pain remains a therapeutic challenge because of its complicated mechanisms. Mas‐related GPCR D (MrgprD) is specifically expressed in small‐diameter, nociceptive neurons of dorsal root ganglia (DRGs) and is implicated in pain modulation. However, the underlying mechanism of MrgprD involved in neuropathic pain remains elusive. In this study, we used behavioral experiments and physiologic examination methods to investigate the role of MrgprD in chronic constriction injury (CCI)–induced neuropathic pain. We found that MrgprD is necessary for the initiation of mechanical hypersensitivity and cold allodynia, but not for heat allodynia. Moreover, we demonstrated that transient receptor potential cation channel (TRP)‐A1 was the ion channel downstream of MrgprD, and the β‐alanine–induced calcium signal was attributed mostly to TRP‐A1 function. We further showed that PKA serves as a downstream mediator of β‐alanine–activated MrgprD signaling to activate TRP‐A1 in DRG neurons and in human embryonic kidney 293 cells, to coexpress MrgprD and TRP‐A1 plasmids. Finally, we found that the β‐alanine–induced pain behavior was increased, whereas the itching behavior was unchanged in CCI models compared with sham‐injured animals. Knockout of TRPA1 also attenuated the β‐alanine–induced pain behavior in CCI models. In conclusion, MrgprD is essential in cold allodynia in CCI‐induced neuropathic pain through the PKA–TRP‐A1 pathway. TRP‐A1 facilitates MrgprD to development of neuropathic pain. Our findings reveal a novel mechanism of neuropathic pain formation and highlight MrgprD as a promising drug target for the treatment of neuropathic pain.—Wang, C., Gu, L., Ruan, Y., Geng, X., Xu, M., Yang, N., Yu, L., Jiang, Y., Zhu, C., Yang, Y., Zhou, Y., Guan, X., Luo, W., Liu, Q., Dong, X., Yu, G., Lan, L., Tang, Z. Facilitation of MrgprD by TRP‐A1 promotes neuropathic pain. FASEB J. 33, 1360–1373 (2019). www.fasebj.org
Generation and analysis of a mouse model of pseudohypoaldosteronism type II caused by KLHL3 mutation in BTB domain
Authors: Lin Chien-Ming , Cheng Chih-Jen , Yang Sung-Sen , Tseng Min-Hua , Yen Ming-Tso , Sung Chih-Chien , Lin Shih-Hua
Published: August 2018

The Kelch‐like 3 (KLHL3) mutations contributed to the most common causative genes in patients with pseudohypoaldosteronism type II (PHAII); however, the molecular mechanisms of PHAII‐causing mutations in BTB domain of KLHL3 in vivo have not been investigated. We generated and analyzed Klhl3 knock‐in (KI) mice carrying a missense M131V mutation in the BTB domain (corresponding to human KLHL3 M78V mutation). Klhl3M131V/+ KI mice exhibited typical PHAII phenotype with an exaggerated diuretic response to hydrochlorothiazide. Their kidney tissues showed an unchanged KLHL3, decreased cullin 3 (Cul3), and increased with‐no‐lysine kinases (WNKs) WNK1 and WNK4 along with an enhanced downstream ste20‐related proline/alanine‐rich kinase/oxidative stress response kinase 1‐N(K)CC phosphorylation. Their Cul3 protein in the cytosol of distal convoluted tubule cells was also significantly attenuated on immunogold‐labeling electron microscopy. In micro‐dissected renal tubules, Klhl3M131V/+ KI mice expressed high levels of Wnk4 mRNA in the distal nephron. In vitro coimmunoprecipitation showed the KLHL3 BTB domain mutation retained intact interaction with WNKs but reduced binding to Cul3, thus leading to the increased abundance of total WNKs. In summary, Klhl3M131V/+ KI mice feature typical PHAII with a simultaneous increase of WNK1 and WNK4 through the impaired KLHL3 BTB domain binding to Cul3.—Lin, C.‐M., Cheng, C.‐J., Yang, S.‐S., Tseng, M.‐H., Yen, M.‐T., Sung, C.‐C., Lin, S.‐H. Generation and analysis of a mouse model of pseudohypoaldosteronism type II caused by KLHL3 mutation in BTB domain. FASEB J. 33, 1051–1061 (2019). www.fasebj.org
Allergen immunotherapy as add-on to biologic agents
Authors: Lombardi Carlo , Canonica Giorgio W. , Passalacqua Giovanni
Published: August 2018

Purpose of review

In this review, we sought to outline many of the recent evidences about the available clinical trials in which biologic agents [i.e. omalizumab (OMA)] were associated as add-on to allergen-specific immunotherapy (AIT).

Recent findings

The available literature shows that OMA may be a valuable option as add-on to AIT for respiratory allergy, or food desensitization, especially in the escalation or build-up phases, in which adverse events are more commonly expected. The encouraging data for hymenoptera venom allergy remain limited to case reports, and no structured clinical trial is available.

Over the past decade, studies of OMA used with AIT have shown promising results. Today, big randomized, double-blind, placebo-controlled trials are needed to better select those patients who would benefit from the addition of OMA (or other biologic agents) to AIT, as well as optimal dosing schedules, optimal duration of treatments and, finally, adequate evaluation about pharmacoeconomic aspects.
Mortality and survival in systemic sclerosis: a review of recent literature
Authors: Poudel Dilli R. , Derk Chris T.
Published: August 2018

Purpose of review

Systemic sclerosis is a debilitating rheumatic disease with high morbidity and mortality. This review attempts to provide the most recent update on mortality and survival and their determinants in systemic sclerosis (SSc).

Recent findings

SSc remains an uncommon rheumatic disease with high mortality. There have been attempts to devise more comprehensive but simpler scoring systems to prognosticate survival in SSc, which will influence triaging of patients and guide the utilization of aggressive treatment strategies.

Updated literature review on mortality and survival in SSc has confirmed its high-case fatality but a slowly improving survival profile over time. It identifies some gaps in knowledge, especially in regards to ethnic differences.
A Prospective Cohort Study of the Association Between Body Mass Index and Incident Bacterial Vaginosis
Authors: Lokken Erica M. , Richardson Barbra A. , Kinuthia John , Mwinyikai Khamis , Abdalla Amina , Jaoko Walter , Mandaliya Kishorchandra , Shafi Juma , Scott McClelland R.
Published: August 2018

Background

Some studies suggest that higher body mass index is associated with increased susceptibility to bacterial vaginosis (BV), but results are conflicting.

Methods

Female sex workers aged 16 to 45 years and participating in an open, prospective cohort study in Mombasa, Kenya between 2000 and 2014 were included in this analysis. Up to 2 years of follow-up were included per woman. Body mass index (BMI) was categorized as underweight (≤18.5), normal (18.5–24.9), overweight (25–29.9), and obese (≥30). Bacterial vaginosis was assessed using Nugent scores. Generalized estimating equations were used to estimate relative risks of the association between BMI and BV.

Results

At baseline, 32.1% (n = 625) of 1946 women had BV. Half of women were overweight (31.1%, n = 606) or obese (20.1%, n = 391). Participants contributed 14,319 follow-up visits. Adjusting for age, compared to women with normal BMI, overweight (adjusted relative risk, 0.91; 95% confidence interval, 0.81–1.02) and obese (adjusted relative risk, 0.82; 95% confidence interval, 0.71–0.94) women were at lower risk for BV (joint P = 0.03).

Conclusions

Obese women had a nearly 20% lower risk of BV compared with women with normal BMI. Potential mechanisms for this effect, including possible effects of diet, obesity-associated changes in the gut microbiome, and systemic estrogen levels, should be explored.
Toll Like Receptor 4 Mediated Lymphocyte Imbalance Induces Nec-Induced Lung Injury
Authors: Jia Hongpeng , Sodhi Chhinder P. , Yamaguchi Yukihiro , Lu Peng , Ladd Mitchell R. , Werts Adam , Fulton William B. , Wang Sanxia , Prindle Thomas , Hackam David J.
Published: August 2018

Necrotizing enterocolitis (NEC) is the leading cause of death from gastrointestinal disease in premature infants, and is associated with the development of severe lung inflammation. The pathogenesis of NEC-induced lung injury remains unknown, yet infiltrating immune cells may play a role. In support of this possibility, we now show that NEC in mice and humans was associated with the development of profound lung injury that was characterized by an influx of Th17 cells and a reduction in T regulatory lymphocytes (Tregs). Importantly, the adoptive transfer of CD4+ T cells isolated from lungs of mice with NEC into the lungs of immune incompetent mice (Rag1−/− mice) induced profound inflammation in the lung, while the depletion of Tregs exacerbated NEC induced lung injury, demonstrating that imbalance of Th17/Treg in the lung is required for the induction of injury. In seeking to define the mechanisms involved, the selective deletion of toll-like receptor 4 (TLR4) from the Sftpc1 pulmonary epithelial cells reversed lung injury, while TLR4 activation induced the Th17 recruiting chemokine (C-C motif) ligand 25 (CCL25) in the lungs of mice with NEC. Strikingly, the aerosolized inhibition of both CCL25 and TLR4 and the administration of all trans retinoic acid restored Tregs attenuated NEC-induced lung injury. In summary, we show that TLR4 activation in Surfactant protein C-1 (Sftpc1) cells disrupts the Treg/Th17 balance in the lung via CCL25 leading to lung injury after NEC and reveal that inhibition of TLR4 and stabilization of Th17/Treg balance in the neonatal lung may prevent this devastating complication of NEC.
Efficacy and Safety of Complete Mesocolic Excision in Patients With Colon Cancer
Authors: Gao Zhidong , Wang Chao , Cui Yancheng , Shen Zhanlong , Jiang Kewei , Shen Danhua , Wang Yi , Zhan Siyan , Guo Peng , Yang Xiaodong , Liu Fangfang , Shen Kai , Liang Bin , Yin Mujun , Xie Qiwei , Wang Youli , Wang Shan , Ye Yingjiang
Published: August 2018

Objective:

The aim of the study was to evaluate the oncological outcomes of complete mesocolic excision (CME) in colon cancer patients.

Summary Background Data:

CME is considered a standard procedure for colon cancer patients. However, previous evidence regarding the effect of CME on prognosis has fundamental limitations that prevent it from being fully accepted.

Methods:

Patients who underwent radical resection for colon cancer were enrolled between November 2012 and March 2016. According to the principles of CME, patients were stratified into 2 groups based on intraoperative surgical fields and specimen photographs. The primary outcome was local recurrence-free survival (LRFS). The clinicopathological data and follow-up information were collected and recorded. The final follow-up date was April 2016. The trial was registered in ClinicalTrials.gov (identifier: NCT01724775).

Results:

There were 220 patients in the CME group and 110 patients in the noncomplete mesocolic excision (NCME) group. Baseline characteristics were well balanced. Compared with NCME, CME was associated with a greater number of total lymph nodes (24 vs 20, P = 0.002). Postoperative complications did not differ between the 2 groups. CME had a positive effect on LRFS compared with NCME (100.0% vs 90.2%, log-rank P < 0.001). Mesocolic dissection (100.0% vs 87.9%, log-rank P < 0.001) and nontumor deposits (97.2% vs 91.6%, log-rank P < 0.022) were also associated with improved LRFS.

Conclusions:

Our findings demonstrate that, compared with NCME, CME improves 3-year LRFS without increasing surgical risks.
Local adaptation and the evolution of inversions on sex chromosomes and autosomes
Authors: Connallon Tim , Olito Colin , Dutoit Ludovic , Papoli Homa , Ruzicka Filip , Yong Lengxob
Published: August 2018

Spatially varying selection with gene flow can favour the evolution of inversions that bind locally adapted alleles together, facilitate local adaptation and ultimately drive genomic divergence between species. Several studies have shown that the rates of spread and establishment of new inversions capturing locally adaptive alleles depend on a suite of evolutionary factors, including the strength of selection for local adaptation, rates of gene flow and recombination, and the deleterious mutation load carried by inversions. Because the balance of these factors is expected to differ between X (or Z) chromosomes and autosomes, opportunities for inversion evolution are likely to systematically differ between these genomic regions, though such scenarios have not been formally modelled. Here, we consider the evolutionary dynamics of X-linked and autosomal inversions in populations evolving at a balance between migration and local selection. We identify three factors that lead to asymmetric rates of X-linked and autosome inversion establishment: (1) sex-biased migration, (2) dominance of locally adapted alleles and (3) chromosome-specific deleterious mutation loads. This theory predicts an elevated rate of fixation, and depressed opportunities for polymorphism, for X-linked inversions. Our survey of data on the genomic distribution of polymorphic and fixed inversions supports both theoretical predictions.

This article is part of the theme issue ‘Linking local adaptation with the evolution of sex differences'.
The interaction between sex-specific selection and local adaptation in species without separate sexes
Authors: Olito Colin , Abbott Jessica K. , Jordan Crispin Y.
Published: August 2018

Local adaptation in hermaphrodite species can be based on a variety of fitness components, including survival, as well as both female and male sex-functions within individuals. When selection via female and male fitness components varies spatially (e.g. due to environmental heterogeneity), local adaptation will depend, in part, on variation in selection through each fitness component, and the extent to which genetic trade-offs between sex-functions maintain genetic variation necessary for adaptation. Local adaptation will also depend on the hermaphrodite mating system because self-fertilization alters several key factors influencing selection and the maintenance of genetic variance underlying trade-offs between the sex-functions (sexually antagonistic polymorphism). As a first step to guide intuition regarding sex-specific adaptation in hermaphrodites, we develop a simple theoretical model incorporating the essential features of hermaphrodite mating and adaptation in a spatially heterogeneous environment, and explore the interaction between sex-specific selection, self-fertilization and local adaptation. Our results suggest that opportunities for sex-specific local adaptation in hermaphrodites depend strongly on the extent of self-fertilization and inbreeding depression. Using our model as a conceptual framework, we provide a broad overview of the literature on sex-specific selection and local adaptation in hermaphroditic plants and animals, emphasizing promising future directions in light of our theoretical predictions.

This article is part of the theme issue ‘Linking local adaptation with the evolution of sex differences'.
Infection dynamics in L.major autophagic machinery is regulated by ATG9-PI3P negative feedback loop
Authors: Kosey Dipali , Soni Bhavnita , Nimsarkar Prajakta , Singh Shailza
Published: August 2018

Autophagy is a self-destructing mechanism of cell via lysosomal degradation, which helps to degrade/ destroy hazardous substances, proteins, degenerating organelles and recycling nutrient. It plays an important role in cellular homeostasis and regulates internal environment of cell, moreover, when needed causes non-apoptotic programmed death of cell. It’s usually detailed with ageing and nutritional stress, but recent researches provide support for its role in innate as well as adaptive immunity. Autophagy has been observed as one of the major factors in parasite clearance in leishmaniasis. Due to intra-cellular pathogen, the cell mediated response is only alternative for adaptive immunity against Leishmania in host. T-cells have been observed as main component of cell mediated immunity in leishmaniasis. The differentiation of T-cells generates either destruction or proliferation of parasite as different kind of cytokine mediate different results. Pro-inflammatory cytokine IL12 and TNFα generate Th2 response which helps in active phagocytosis of parasite whereas an anti-inflammatory cytokine like IL10 mediate parasite promotion by blocking autophagic pathways and inhibiting phagocytic actions. TLR2/6 mediated signaling stimulated by LPG produces many pro-inflammatory cytokines like IL12, TNFα and IL6 etc. In macrophages, it is found that TNFα via autocrine signaling induce autophagy and help in parasite killing of Toxoplasma gondii via JNK phosphorylation in macrophages. The phosphorylated JNK induces Beclin by phosphorylating Bcl2, which inhibits Beclin action, thus releasing Beclin and promoting VpS34 which recruits PI3P for autophagosome formation. Recruitment of PI3P is controlled by ATG9 protein, autophagy related gene protein, which in normal condition is inhibited by mTOR via ULK/ ATG1. IL10 has been observed to inhibit autophagy via starvation induced AKT-PI3K pathway in macrophages and result in inducing mTOR. Thus, we can conclude that IL10 inhibits recruitment of PI3P via mTOR. Through systems aspect, here, we decipher that Atg9-PI3P acts as a negative feedback loop in autophagic machinery of leishmaniasis.
A CATH domain functional family based approach to identify putative cancer driver genes and driver mutations
Authors: Ashford Paul , Pang Camilla S.M. , Moya-García Aurelio A. , Adeyelu Tolulope , Orengo Christine A.
Published: August 2018

Tumour sequencing identifies highly recurrent point mutations in cancer driver genes, but rare functional mutations are hard to distinguish from large numbers of passengers. We developed a novel computational platform applying a multi-modal approach to filter out passengers and more robustly identify putative driver genes. The primary filter identifies enrichment of cancer mutations in CATH functional families (CATH-FunFams) – structurally and functionally coherent sets of evolutionary related domains. Using structural representatives from CATH-FunFams, we subsequently seek enrichment of mutations in 3D and show that these mutation clusters have a very significant tendency to lie close to known functional sites or conserved sites predicted using CATH-FunFams. Our third filter identifies enrichment of putative driver genes in functionally coherent protein network modules confirmed by literature analysis to be cancer associated.

Our approach is complementary to other domain enrichment approaches exploiting Pfam families, but benefits from more functionally coherent groupings of domains. Using a set of mutations from 22 cancers we detect 151 putative cancer drivers, of which 79 are not listed in cancer resources and include recently validated cancer genes EPHA7, DCC netrin-1 receptor and zinc-finger protein ZNF479.
Pharmacovigilance or patient safety: analysis from a patient safety program
Authors: Cortázar C Yira Constanza , Orozco D José Gilberto , López G José Julián
Published: August 2018

Purpose

drugs are the common point of pharmacovigilance and patient safety programs. Despite using a common language, the same epidemiological method and legislation that requires the operation of the two programs, there does not seem to be a clear relationship between them.

Methodology

observational descriptive cross sectional study of the reports database from an institutional patient safety program. Medication errors were classified according to the document The Conceptual Framework for the International Classification for Patient Safety (ICPS) WHO 2009. Adverse Reactions (ADR) were classified according to Uppsala Monitoring Center.

Results

the omission of drugs or doses was the most frequent error with 42.8% followed by ADRs (20.9%). No harm incidents corresponded to 61.2% and the remaining 38.8% was represented in near missincidents and no harm incidents. There were included 41 ADR and 15 therapeutic failures corresponding to a point-prevalence of 57 ADR/10,000 patients-year and 28.6% (56/196) of reports related to drugs. Phlebitis is the most frequently reported with 23, 7% followed by hypersensitivity reactions with 18.4% and excessive neuromuscular blockade with 13.1%.

Conclusions

considering time, level of care and number of bed, ADR prevalence seem low. A very important proportion of reports corresponding to near miss incidents or no harm incidents is not taken into account by the security managers, losing a valuable risk management opportunity in the patient safety programs.
Context dependent roles for RB-E2F transcriptional regulation in tumor suppression
Authors: Thwaites Michael J. , Cecchini Matthew J. , Passos Daniel T. , Dick Frederick A.
Published: August 2018

RB-E2F transcriptional control plays a key role in regulating the timing of cell cycle progression from G1 to S-phase in response to growth factor stimulation. Despite this role, it is genetically dispensable for cell cycle exit in primary fibroblasts in response to growth arrest signals. Mice engineered to be defective for RB-E2F transcriptional control at cell cycle genes were also found to live a full lifespan with no susceptibility to cancer. Based on this background we sought to probe the vulnerabilities of RB-E2F transcriptional control defects found in Rb1R461E,K542E mutant mice (Rb1G) through genetic crosses with other mouse strains. We generated Rb1G/G mice in combination with Trp53 and Cdkn1a deficiencies, as well as in combination with KrasG12D. The Rb1G mutation enhanced Trp53 cancer susceptibility, but had no effect in combination with Cdkn1a deficiency or KrasG12D. Collectively, this study indicates that compromised RB-E2F transcriptional control is not uniformly cancer enabling, but rather has potent oncogenic effects when combined with specific vulnerabilities.
Trans-splicing of theC. elegans let-7primary transcript developmentally regulateslet-7microRNA biogenesis andlet-7family microRNA activity
Authors: Nelson Charles , Ambros Victor
Published: August 2018

let-7is a microRNA whose sequence and roles as a regulator of developmental progression are conserved throughout bilaterians. In most systems, transcription of thelet-7locus occurs relatively early in development, whilst processing oflet-7primary transcript into mature microRNA arises later and is associated with cellular differentiation. InC. elegansand other animals, the RNA binding protein LIN-28 post-transcriptionally inhibitslet-7biogenesis at early developmental stages. The mechanisms by which LIN-28 and other factors developmentally regulatelet-7biogenesis are not fully understood. Nor is it understood how the developmental regulation oflet-7might influence the expression or activities of other microRNAs of the same seed family. Here we show that inC. elegans, the primarylet-7transcript (pri-let-7) is trans-spliced to SL1 splice leader at a position downstream of thelet-7precursor stem-loop, producing a short, polyadenylated downstream mRNA. The trans-splicing event negatively impacts the biogenesis of maturelet-7microRNA incis, likely by destabilizing the upstreampri-let-7fragment. Moreover, the trans-spliced downstream mRNA contains complimentary sequences to multiple members of thelet-7seed family (let-7fam), and thereby serves as a sponge to negatively regulatelet-7famfunction intrans. Thus, this study provides evidence for a mechanism by which splicing of a microRNA primary transcript can negatively regulate said microRNA incisas well as other microRNAs intrans.

HIGHLIGHTS

Thelet-7primary transcript is trans-spliced to produce an RNA that functions as a sponge that negatively regulates thelet-7-familymicroRNAs.

Trans-splicing of this RNA negatively impactslet-7microRNA biogenesis.

LIN-28 regulates this trans-splicing event