bluuebunny/crossref_metadata_2025 huggingface dataset:
Genomic perspectives on adaptation and conservation in the endangered long-tailed goral (Naemorhedus caudatus)
Authors: Weber Jessica A. , Chung Oksung , Kim Jungeun , Jun JeHoon , Lee Hyejin , Jho Sungwoong , Cho Yun Sung , Kim Dae-Soo , Paek Woon ki , Kim Soonok , Lee Hanshin , Lee Semin , Edwards Jeremy S. , Cook Joseph A. , An Junghwa , Bhak Jong
Published: December 2018

Native to the mountains of East Asia, the long-tailed goral (Naemorhedus caudatus) is a vulnerable wild ungulate in the tribe Caprini. To understand key conservation issues related to fragmentation and subsequent endangerment of this montane species, we sequenced and analyzed the genome of a long-tailed goral to explore historical demography, contemporary levels of genetic diversity, and potential immune response. When compared to ten additional mammalian reference genomes, we identified 357 positively selected genes (PSGs) in the long-tailed goral and 364 PSGs in the Caprini lineage. Gene Ontology analyses showed statistical enrichment in biological processes related to immune function and in genes and pathways related to blood coagulation. We also identified low levels of heterozygosity (0.00114) in the long-tailed goral along with decreases in population size relative to other species of Caprini. Finally, we provide evidence for positive selection on the muscle development genemyostatin(MSTN) in the Caprini lineage, which may have increased the muscle development and climbing ability in the caprine common ancestor. Low effective population size and decreased heterozygosity of the long-tailed goral raise conservation concern about the effects of habitat fragmentation, over harvest, and inbreeding on this vulnerable species.
Saturation mutagenesis of disease-associated regulatory elements
Authors: Kircher Martin , Xiong Chenling , Martin Beth , Schubach Max , Inoue Fumitaka , Bell Robert J.A. , Costello Joseph F. , Shendure Jay , Ahituv Nadav
Published: December 2018

The majority of common variants associated with common diseases, as well as an unknown proportion of causal mutations for rare diseases, fall in noncoding regions of the genome. Although catalogs of noncoding regulatory elements are steadily improving, we have a limited understanding of the functional effects of mutations within them. Here, we performed saturation mutagenesis in conjunction with massively parallel reporter assays on 20 disease-associated gene promoters and enhancers, generating functional measurements for over 30,000 single nucleotide substitution and deletion mutations. We find that the density of putative transcription factor binding sites varies widely between regulatory elements, as does the extent to which evolutionary conservation or various integrative scores predict functional effects. These data provide a powerful resource for interpreting the pathogenicity of clinically observed mutations in these disease-associated regulatory elements, and also comprise a gold-standard dataset for the further development of algorithms that aim to predict the regulatory effects of noncoding mutations.
High gene dosage changes transcriptional regulation of genetic structures and contributes to diversity and heterogeneity
Authors: Liu Dianbo , Hannam Ryan , Albergante Luca
Published: December 2018

Differences in gene dosages between and within species are widely observed. Nevertheless, our understanding of the impacts of gene dosages on transcriptional regulation is far from complete and it is largely ignored in many genetic studies. In this article, we showed that dynamic properties of three genetic structures became significantly different when gene dosages were high and, for self-inhibiting genes, high gene dosages could facilitate monoallelic expression at single cell level and heterogeneity of cell population. This shed lights on potential links between levels of ploidy and phenotypes. In addition, in the context of modern molecular biology, especially synthetic biology, gene dosage needs to be taken into consideration when designing or modifying genetic circuits.
The genomic landscape of western South America: Andes, Amazonia and Pacific Coast
Authors: Barbieri Chiara , Barquera Rodrigo , Arias Leonardo , Sandoval José R. , Acosta Oscar , Zurita Camilo , Aguilar-Campos Abraham , Tito-Álvarez Ana M. , Serrano-Osuna Ricardo , Gray Russell , Heggarty Paul , Shimizu Kentaro K. , Fujita Ricardo , Stoneking Mark , Pugach Irina , Fehren-Schmitz Lars
Published: December 2018

Studies of Native South American genetic diversity have helped to shed light on the peopling and differentiation of the continent, but available data are sparse for the major ecogeographic domains. These include the Pacific Coast, a potential early migration route; the Andes, home to the most expansive complex societies and to one of the most spoken indigenous language families of the continent (Quechua); and Amazonia, with its understudied population structure and rich cultural diversity. Here we explore the genetic structure of 177 individuals from these three domains, genotyped with the Affymetrix Human Origins array. We infer multiple sources of ancestry within the Native American ancestry component; one with clear predominance on the Coast and in the Andes, and at least two distinct substrates in neighboring Amazonia, with a previously undetected ancestry characteristic of northern Ecuador and Colombia. Amazonian populations are also involved in recent gene-flow with each other and across ecogeographic domains, which does not accord with the traditional view of small, isolated groups. Long distance genetic connections between speakers of the same language family suggest that languages had spread not by cultural contact alone. Finally, Native American populations admixed with post-Columbian European and African sources at different times, with few cases of prolonged isolation. With our results we emphasize the importance of including under-studied regions of the continent in high-resolution genetic studies, and we illustrate the potential of SNP chip arrays for informative regional scale analysis.
Partitioning the genetic architecture of amyotrophic lateral sclerosis
Authors: Broce Iris J. , Fan Chun C. , Olney Nicholas T. , Lomen-Hoerth Catherine , Finkbeiner Steve , Atassi Nazem , Cudkowicz Merit E. , Paganoni Sabrina , Yokoyama Jennifer S. , Kao Aimee , Dillon William P. , Glastonbury Christine M. , Hess Christopher P. , Rheenen Wouter van , Veldink Jan H. , Al-Chalabi Ammar , Andreassen Ole A. , Dale Anders M. , Seeley William W. , Sugrue Leo P. , Ofori-Kuragu Aaron , Karch Celeste M. , Miller Bruce L. , Desikan Rahul S.
Published: December 2018

The genetic basis of sporadic amyotrophic lateral sclerosis (ALS) is not well understood. Using large genome-wide association studies and validated tools to quantify genetic overlap, we systematically identified single nucleotide polymorphisms (SNPs) associated with ALS conditional on genetic data from 65 different traits and diseases from >3 million people. We found strong genetic enrichment between ALS and a number of disparate traits including frontotemporal dementia, coronary artery disease, C-reactive protein, celiac disease and memory function. BeyondC9ORF72, we detected novel genetic signal within numerous loci includingGIPC1, ELMO1andCOL16Aand confirmed previously reported variants, such asATXN2, KIF5A, UNC13AandMOBP.We found that ALS variants form a small-world co-expression network characterized by highly inter-connected ‘hub’ genes. This network clustered into smaller sub-networks, each associated with a unique function. Altered gene expression of several sub-networks and hubs was over-represented in neuropathological samples from ALS patients and SOD1 G93A mice. Our collective findings indicate that the genetic architecture of ALS can be partitioned into distinct components where some genes are highly important for developing disease. These findings have implications for stratification and enrichment strategies for ALS clinical trials.
Human Cytomegalovirus Genomes Sequenced Directly from Clinical Material: Variation, Multiple-Strain Infection, Recombination and Mutation
Authors: Suárez Nicolás M. , Wilkie Gavin S. , Hage Elias , Camiolo Salvatore , Holton Marylouisa , Hughes Joseph , Maabar Maha , Sreenu Vattipally B. , Dhingra Akshay , Gompels Ursula A. , Wilkinson Gavin W. G. , Baldanti Fausto , Furione Milena , Lilleri Daniele , Arossa Alessia , Ganzenmueller Tina , Gerna Giuseppe , Hubáček Petr , Schulz Thomas F. , Wolf Dana , Zavattoni Maurizio , Davison Andrew J.
Published: December 2018

The genomic characteristics of human cytomegalovirus (HCMV) strains sequenced directly from clinical pathology samples were investigated, focusing on variation, multiple-strain infection, recombination and natural mutation. A total of 207 datasets generated in this and previous studies using target enrichment and high-throughput sequencing were analysed, in the process facilitating the determination of genome sequences for 91 strains. Key findings were that (i) it is important to monitor the quality of sequencing libraries in investigating diversity, (ii) many recombinant strains have been transmitted during HCMV evolution, and some have apparently survived for thousands of years without further recombination, (iii) mutants with non-functional genes (pseudogenes) have been circulating and recombining for long periods and can cause congenital infection and resulting clinical sequelae, and (iv) intrahost diversity in single-strain infections is much less than that in multiple-strain infections. Future population-based studies are likely to continue illuminating the evolution, epidemiology and pathogenesis of HCMV.
Fragmentation Through Polymerization (FTP): A New Method to Fragment DNA for Next-Generation Sequencing
Authors: Ignatov Konstantin B. , Blagodatskikh Konstantin A. , Shcherbo Dmitry S. , Kramarova Tatiana , Monakhova Yulia A. , Kramarov Vladimir M.
Published: December 2018

Fragmentation of DNA is the first and very important step in preparing nucleic acids for NGS. Here we report a novel Fragmentation Through Polymerization (FTP) technique, which is simple, robust and low-cost enzymatic method of fragmentation. This method generates double-stranded DNA fragments that are suitable for the direct use in NGS library construction, and allows to eliminate the need of an additional step of reparation of DNA ends.
Symptoms of fatigue and depression is reflected in altered default mode network connectivity in multiple sclerosis
Authors: Høgestøl Einar August , Nygaard Gro Owren , Alnæs Dag , Beyer Mona K. , Westlye Lars T. , Harbo Hanne Flinstad
Published: December 2018

Background: Fatigue and depression are frequent and often co-occurring symptoms in multiple sclerosis (MS). Resting-state functional magnetic resonance imaging (rs-fMRI) represents a promising tool for disentangling differential associations between depression and fatigue and brain network function and connectivity. In this study we tested for associations between symptoms of fatigue and depression and DMN connectivity in patients with MS.
Materials and methods: Seventy-four MS patients were included on average 14 months after diagnosis. They underwent MRI scanning of the brain including rs-fMRI, and symptoms of fatigue and depression were assessed with Fatigue Severity Scale (FSS) and Beck Depression Inventory II (BDI). A principal component analysis (PCA) on FSS and BDI scores was performed, and the component scores were analysed using linear regression models to test for associations with default mode network (DMN) connectivity.
Results: We observed higher DMN connectivity with higher scores on the primary principal component reflecting common symptom burden for fatigue and depression (Cohen's f2=0.075, t=2.17, p=0.03). The secondary principal component reflecting a pattern of low fatigue scores with high scores of depression was associated with lower DMN connectivity (Cohen's f2=0.067, t=-2.1, p=0.04). Using continuous mean scores of FSS we also observed higher DMN connectivity with higher symptom burden (t=3.1, p=0.003), but no significant associations between continuous sum scores of BDI and DMN connectivity (t=0.8, p=0.4).
Conclusion: Multivariate decomposition of FSS and BDI data supported both overlapping and unique manifestation of fatigue and depression in MS patients. Rs-fMRI analyses showed that symptoms of fatigue and depression was reflected in altered DMN connectivity, and that higher DMN activity was seen in MS patients with fatigue even with low depression scores.
Microbiome composition comparison in oral and atherosclerotic plaque from patients with and without periodontitis
Authors: Isoshima Daichi , Yamashiro Keisuke , Matsunaga Kazuyuki , Taniguchi Makoto , Matsubara Takehiro , Tomida Shuta , Omori Kazuhiro , Yamamoto Tadashi , Takashiba Shogo
Published: December 2018

There is no conclusive evidence regarding a causal relationship between periodontitis and atherosclerosis. In this study, we examined the microbiome in the oral cavity and atheromatous plaques from atherosclerosis patients with or without periodontitis to investigate the role of oral bacteria in the formation of atheromatous plaques. We chose four patients with and without periodontitis, who had undergone carotid endarterectomy. Bacterial samples were extracted from saliva on the tongue surface, from periodontal pocket (during the oral examination), and from the atheromatous plaques. We investigated the general and oral conditions from each patient and performed next-generation sequencing analysis for all bacterial samples. There were no significant differences between both groups concerning general conditions. However, the microbiome patterns of the gingival pocket showed differences depending on the absence or presence of periodontitis, while those of the saliva were relatively similar. The microbiome pattern of the atheromatous plaques was entirely different from that in saliva present on the tongue surface and gingival pocket, and oral bacteria were seldom detected. However, the microbiome pattern in atheromatous plaques was different in the presence or absence of periodontitis. These results indicated that oral bacteria did not affect the formation of atheromatous plaques directly. However, the metabolic products of microbiome or the host inflammatory response might indirectly influence the composition of atheromatous plaques.
Actin clearance promotes polarized dynein accumulation at the immunological synapse
Authors: Sanchez Elisa , Liu Xin , Huse Morgan
Published: December 2018

Immunological synapse (IS) formation between a T cell and an antigen-presenting cell is accompanied by the reorientation of the T cell centrosome toward the interface. This polarization response is thought to enhance the specificity of T cell effector function by enabling the directional secretion of cytokines and cytotoxic factors toward the antigen-presenting cell. Centrosome reorientation is controlled by polarized signaling through diacylglycerol (DAG) and protein kinase C (PKC). This drives the recruitment of the motor protein dynein to the IS, where it pulls on microtubules to reorient the centrosome. Here, we used T cell receptor photoactivation and imaging methodology to investigate the mechanisms controlling dynein accumulation at the synapse. Our results revealed a remarkable spatiotemporal correlation between dynein recruitment to the synaptic membrane and the depletion of cortical filamentous actin (F-actin) from the same region, suggesting that the two events were causally related. Consistent with this hypothesis, we found that pharmacological disruption of F-actin dynamics in T cells impaired both dynein accumulation and centrosome reorientation. DAG and PKC signaling were necessary for synaptic F-actin clearance and dynein accumulation, while calcium signaling and microtubules were dispensable for both responses. Taken together, these data provide mechanistic insight into the polarization of cytoskeletal regulators and highlight the close coordination between microtubule and F-actin architecture at the IS.
Community‐level economics spectrum of fine‐roots driven by nutrient limitations in subalpine forests
Authors: Li Fanglan , Hu Hui , McCormlack Michael Luke , Feng De Feng , Liu Xin , Bao Weikai
Published: December 2018

Fine‐root traits show remarkable variation with plant community structure and environmental shifts, but there is limited understanding of how trait covariation that exists among fine‐root traits shifts among different communities, especially in forests. We explored links among the fine‐root traits of forest communities to determine whether community root traits shift predictably according to an economics framework along environmental gradients.

Measurements of root morphology, nitrogen, phosphorus and carbon concentrations, and measures of standing root densities were collected on fine‐roots (diameter ≤ 2 mm) from 129 forest plots in five subalpine forests.

This study demonstrates an existence of a community‐level fine‐root economics spectrum (REScom) in the subalpine forests, in which specific root length was strongly and positively related to root nitrogen and phosphorus contents, but negatively related to root diameter. Soil nutrient limitation was a major driver of the REScom as changes in soil [N], [P] and [C] contents were related to changes in SRL, root [N], root [P]. Variables related to standing fine‐root length and mass were independent of the REScom and were primarily related to forest community structure, particularly in tree closure and herbaceous plant mass.

Synthesis. These results indicate two distinct functional dimensions of community fine‐root trait variation: resource‐use efficiency via changes in root structure and construction, and separately via changes in the standing root system. Identifying shifts in allocation to and investment in fine‐roots enhances our understanding of a root and whole‐plant economics spectrum and community functioning.
‘I didn't want to pass that on to my child, being afraid to go to the dentist': making sense of oral health through narratives of connectedness over the life course
Authors: Emily Kettle Jennifer , Warren Lorna , Glenn Robinson Peter , Walls Angus , Gibson Barry John
Published: December 2018

While previous sociological research on oral health has identified the relevance of personal relationships, there is more scope to analyse the mouth through a lens of connectedness. Recent qualitative interviews with 43 older people (65+) in England and Scotland found that participants constructed relational narratives to make sense of their oral health practices. By drawing on ideas of family practices, family display and personal life, we illustrate how the mouth can be understood relationally. Participants presented their own embodied experiences as connected to the actions of their parents. Narratives also reflected how, as parents and grandparents themselves, participants tried to shape the experiences of others. In this way, oral health practices were conceptualised as being about family. This can be seen in self‐narratives that demonstrated how participants located themselves as embedded in webs of ongoing relationships. We highlight the importance of narrated practices of thinking and feeling, whereby participants imagined doing oral health, and indeed family, in different ways. We thereby demonstrate how oral health practices are constituted through family connectedness and at the same time how these practices contribute to the constitution of family. Policy should therefore pay attention to family relations when promoting improvements in oral health practices.
Do Corporate Governance Analysts Matter? Evidence from the Expansion of Governance Analyst Coverage
Authors: LEHMANN NICO
Published: December 2018

This paper examines the economic consequences of the initiation of governance analyst coverage. Governance analysts process, enhance, and disseminate governance‐related information to capital market participants via, for example, governance reports and ratings. Using an exogenous shock in the United Kingdom, I find that an increase in governance analyst coverage results in increased governance quality, improved liquidity, increased financial analyst following, and improved investor breadth. These findings are consistent with governance analysts creating value for firms via monitoring, information dissemination/production, and investor recognition.
Activity budgets for the sedentary Argentine sea bass Acanthistius patachonicus inferred from accelerometer data loggers
Authors: Beltramino Lucas E. , Venerus Leonardo A. , Trobbiani Gastón A. , Wilson Rory P. , Ciancio Javier E.
Published: December 2018

The amount of energy an animal uses to move may constitute a significant fraction of its energy budget, so detailed descriptions of wild animal activity budgets can help to understand the ecology of a species, both at the individual and at the population levels. The rocky‐reef fishes inhabiting the northern Patagonian gulfs of Argentina are important economic and recreational resources for which no activity or energy budgets are available. This fish assemblage may reach high aggregated biomasses (exceeding several hundreds of kilogrammes of fish distributed along a few hundred metres of linear reef ledges) and is not clear how such biomasses can be supported by the low productivity of the Patagonian coastal waters. We used animal‐attached accelerometers to characterise the behaviours and activity budgets for the most abundant and ubiquitous species of this assemblage, the Argentine sea bass or ‘Mero’ Acanthistius patachonicus (Jenyns, 1840; Osteichthyes: Serranidae). Sixteen individuals were tagged (two in captivity and 14 free‐living) and an ethogram was generated from acceleration recordings in varying environmental conditions. Two algorithms were used to classify the behaviours of wild fish. Both showed generally similar results during the cold‐water season (8–10°C), but differed slightly in the warm‐water season (16–18°C). Overall, sea bass were more active during warm season (mean time spent engaged in active behaviours; 46%, range; 24–60%). In contrast, during cold season fish only spent a mean of 29% of their time in active behaviours (range; 15–49%). No clear response to tidal state or ambient light was found, but some fish were more active during the night in the cold water season. Here, we provide the first activity budgets for the conspicuous Argentine sea bass, which contribute to our understanding of rocky‐reef fish behaviour in Patagonia.
Protein kinase D mediates inflammatory responses of human placental macrophages to Group B Streptococcus
Authors: Sutton Jessica A. , Rogers Lisa M. , Dixon Beverly R.E.A. , Kirk Leslie , Doster Ryan , Algood Holly M. , Gaddy Jennifer A. , Flaherty Rebecca , Manning Shannon D. , Aronoff David M.
Published: December 2018

Problem

During pregnancy, Group B Streptococcus (GBS) can infect fetal membranes to cause chorioamnionitis, resulting in adverse pregnancy outcomes. Macrophages are the primary resident phagocyte in extraplacental membranes. Protein kinase D (PKD) was recently implicated in mediating pro‐inflammatory macrophage responses to GBS outside of the reproductive system. This work aimed to characterize the human placental macrophage inflammatory response to GBS and address the extent to which PKD mediates such effects.

Method

Primary human placental macrophages were infected with GBS in the presence or absence of a specific, small molecule PKD inhibitor, CRT 0066101. Macrophage phenotypes were characterized by evaluating gene expression, cytokine release, assembly of the NLRP3 inflammasome, and NFκB activation.

Results

GBS evoked a strong inflammatory phenotype characterized by the release of inflammatory cytokines (TNFα, IL‐1β, IL‐6 (P ≤ 0.05), NLRP3 inflammasome assembly (P ≤ 0.0005), and NFκB activation (P ≤ 0.05). Pharmacological inhibition of PKD suppressed these responses, newly implicating a role for PKD in mediating immune responses of primary human placental macrophages to GBS.

Conclusion

PKD plays a critical role in mediating placental macrophage inflammatory activation in response to GBS infection.
Does the Helping Babies Breathe Programme impact on neonatal resuscitation care practices? Results from systematic review and meta‐analysis
Authors: Budhathoki Shyam Sundar , Gurung Rejina , Ewald Uwe , Thapa Jeevan , KC Ashish
Published: December 2018

Aim

This paper examines the change in neonatal resuscitation practices after the implementation of the Helping Babies Breathe (HBB) programme.

Methods

A systematic review was carried out on studies reporting the impact of HBB programmes among the literature found in Medline, POPLINE, LILACS, African Index Medicus, Cochrane, Web of Science and Index Medicus for the Eastern Mediterranean Region database. We selected clinical trials with randomised control, quasi‐experimental and cross‐sectional designs. We used a data extraction tool to extract information on intervention and outcome reporting. We carried out a meta‐analysis of the extracted data on the neonatal resuscitation practices following HBB programme using Review Manager.

Results

Four studies that reported on neonatal resuscitation practices before and after the implementation of the HBB programme were identified. The pooled results showed no changes in the use of stimulation (RR‐0.54; 95% CI, 0.21–1.42), suctioning (RR‐0.48; 95% CI, 0.18–1.27) and bag‐and‐mask ventilation (RR‐0.93; 95% CI, 0.47–1.83) after HBB training. The proportion of babies receiving bag‐and‐mask ventilation within the Golden Minute of birth increased by more than 2.5 times (RR‐2.67; 95% CI, 2.17–3.28).

Conclusion

The bag‐and‐mask ventilation within Golden minute has improved following the HBB programme. Implementation of HBB training improves timely initiation of bag‐and‐mask ventilation within one minute of birth.
Regulation of cardiac myocyte cohesion and gap junctions via desmosomal adhesion
Authors: Schinner Camilla , Erber Bernd M. , Yeruva Sunil , Waschke Jens
Published: December 2018

Aims

Mutations in desmosomal proteins can induce arrhythmogenic cardiomyopathy with life‐threatening arrhythmia. Previous data demonstrated adrenergic signalling to be important to regulate desmosomal cohesion in cardiac myocytes. Here, we investigated how signalling pathways including adrenergic signalling, PKC and SERCA regulate desmosomal adhesion and how this controls gap junctions (GJs) in cardiac myocytes.

Methods

Immunostaining, Western blot, dissociation assay and multi‐electrode array were applied in HL‐1 cardiac myocytes to evaluate localization, expression and function of desmosomal and GJ components. cAMP levels were determined by ELISA.

Results

Activation of PKC by PMA or adrenergic signalling increased cell cohesion and desmoglein‐2 and desmoplakin localization at cell‐cell junctions, whereas tryptophan (Trp) treatment to inhibit cadherin binding or inhibition of SERCA by thapsigargin reduced cell cohesion, while cAMP elevation rescued this effect. Despite no changes in protein expression, accumulation of GJ protein connexin‐43 was detectable at cell‐cell contacts in parallel to increased cohesion. Disruption of cell cohesion by Trp, PMA or thapsigargin impaired conduction of excitation comparable to GJ inhibition. cAMP elevation was effective to improve arrhythmia after Trp treatment. Weakened cell cohesion by Trp or depletion of desmoglein‐2 or plakoglobin blocked signalling via the β1‐adrenergic receptor. Moreover, silencing of desmosomal proteins increased arrhythmia and reduced conduction velocity, which were rescued by cAMP elevation.

Conclusion

These data demonstrate the interplay of GJs, desmosomes and the β1‐adrenergic receptor with regulation of their function by cell cohesion, adrenergic and PKC signalling or SERCA inhibition. These results support the identification of new targets to treat arrhythmogenic cardiomyopathy.
Glacial and climate history of the last 24 000 years in the Polar Ural Mountains, Arctic Russia, inferred from partly varved lake sediments
Authors: Regnéll Carl , Haflidason Haflidi , Mangerud Jan , Svendsen John Inge
Published: December 2018

We present a well‐dated, high‐resolution and continuous sediment record spanning the last c. 24 000 years from lake Bolshoye Shchuchye located in the Polar Ural Mountains, Arctic Russia. This is the first continuous sediment succession reaching back into the Last Glacial Maximum (LGM) ever retrieved from this region. We reconstruct the glacial and climate history in the area since the LGM based on sedimentological and geochemical analysis of a 24‐m‐long sediment core. A robust chronology was established using a combination of AMS 14C‐dating, the position of the Vedde Ash and varve counting. The varved part of the sediment core spans across the LGM from 24 to 18.7 cal. ka BP. We conclude that the lake basin remained ice‐free throughout the LGM, but that mountain glaciers were present in the lake catchment. A decrease in both glacial varve preservation and sedimentation rate suggests that these glaciers started to retreat c. 18.7 cal. ka BP and had disappeared from the catchment by 14.35 cal. ka BP. There are no indications of glacier regrowth during the Younger Dryas. We infer a distinct climatic amelioration following the onset of the Holocene and an Early to Middle Holocene thermal optimum between 10–5 cal. ka BP. Our results provide a long‐awaited continuous and high‐resolution record of past climate that supplements the existing, more fragmentary data from moraines and exposed strata along river banks and coastal cliffs around the Russian Arctic.
E2F6 functions as a competing endogenous RNA, and transcriptional repressor, to promote ovarian cancer stemness
Authors: Cheng Frank H. C. , Lin Hon‐Yi , Hwang Tzy‐Wei , Chen Yin‐Chen , Huang Rui‐Lan , Chang Chia‐Bin , Yang Weiqin , Lin Ru‐Inn , Lin Ching‐Wen , Chen Gary C. W. , Mai Shu‐Yuan , Lin Jora M. J. , Chuang Yu‐Ming , Chou Jian‐Liang , Kuo Li‐Wei , Li Chin , Cheng Alfred S. L. , Lai Hung‐Cheng , Wu Shu‐Fen , Tsai Je‐Chiang , Chan Michael W. Y.
Published: December 2018

Ovarian cancer is the most lethal cancer of the female reproductive system. In that regard, several epidemiological studies suggest that long‐term exposure to estrogen could increase ovarian cancer risk, although its precise role remains controversial. To decipher a mechanism for this, we previously generated a mathematical model of how estrogen‐mediated upregulation of the transcription factor, E2F6, upregulates the ovarian cancer stem/initiating cell marker, c‐Kit, by epigenetic silencing the tumor suppressor miR‐193a, and a competing endogenous (ceRNA) mechanism. In this study, we tested that previous mathematical model, showing that estrogen treatment of immortalized ovarian surface epithelial cells upregulated both E2F6 and c‐KIT, but downregulated miR‐193a. Luciferase assays further confirmed that microRNA‐193a targets both E2F6 and c‐Kit. Interestingly, ChIP‐PCR and bisulphite pyrosequencing showed that E2F6 also epigenetically suppresses miR‐193a, through recruitment of EZH2, and by a complex ceRNA mechanism in ovarian cancer cell lines. Importantly, cell line and animal experiments both confirmed that E2F6 promotes ovarian cancer stemness, whereas E2F6 or EZH2 depletion derepressed miR‐193a, which opposes cancer stemness, by alleviating DNA methylation and repressive chromatin. Finally, 118 ovarian cancer patients with miR‐193a promoter hypermethylation had poorer survival than those without hypermethylation. These results suggest that an estrogen‐mediated E2F6 ceRNA network epigenetically and competitively inhibits microRNA‐193a activity, promoting ovarian cancer stemness and tumorigenesis.
DANCR‐mediated microRNA‐665 regulates proliferation and metastasis of cervical cancer through the ERK/SMAD pathway
Authors: Cao Liyan , Jin Haihong , Zheng Yue , Mao Yu , Fu Zhanzhao , Li Xin , Dong Lixin
Published: December 2018

Emerging evidence has indicated that microRNAs (miRNAs) play an important role in cervical cancer (CC). However, the role of miRNA (miR)‐665 in cervical cancer remains unclear. The aim of the present study was to investigate the potential functions of miR‐665 in CC and to identify the underlying mechanisms of action. Herein, we show that miR‐665 was downregulated in CC tissues and cell lines, which is negatively correlated with tumor size, distant metastasis, advanced TNM stage and poor prognosis. Functionally, miR‐665 inhibited cell proliferation, migration and invasion and resistance of cisplatin for CC cells, as well as tumor growth. We validated that transforming growth factor beta receptor 1 (TGFBR1) was a direct target of miR‐665 and mediated the ERK/SMAD pathway. In addition, we identified miR‐665 as the competing endogenous RNA for long noncoding (lnc)‐DANCR. These observations suggested that lnc‐DANCR‐mediated miR‐665 downregulation regulates the malignant phenotype of CC cells by targeting TGFBR1 through the ERK/SMAD pathway, which may present a pathway for novel therapeutic stratagems for CC therapy.
A case of primary cutaneous Ewing sarcoma in a neutropenic patient
Authors: Brown‐Joel Zoe O. , Bellizzi Andrew M. , Darbro Benjamin W. , Snow Anthony N. , Tanas Munir R. , Keeney Matthew E. , Stone Mary S. , Wanat Karolyn A. , Roth Gretchen M.
Published: December 2018

Primary cutaneous Ewing sarcoma is a rare clinical presentation of Ewing sarcoma, usually occurring as a small, localized tumor on the extremities of young adults and associated with favorable prognosis. We report a case of primary cutaneous Ewing sarcoma, which presented on the sole of the foot of a 27‐year‐old patient with relapsed acute myeloid leukemia and neutropenia. Diagnosis was determined through histological features and staining, as well as fluorescence in situ hybridization and molecular testing. The patient underwent wide‐local excision with plan to begin targeted chemotherapy, but unfortunately died from adenovirus pneumonia while neutropenic before targeted chemotherapy was initiated.
Political budget cycles, incumbency advantage, and propaganda
Authors: Bohn Frank
Published: December 2018

This paper combines incumbency advantage and political budget cycle theory. An opportunistic politician is given two instruments: deficit‐financed transfers and propaganda. Unlike earlier analytical models, but in accordance with the empirical literature, government manipulations do actually improve re‐election chances. However, the optimal level of government manipulation depends on country characteristics, in particular the competence dispersion among potential candidates. This may explain why it is easier to detect political budget cycles in, for instance, developing countries or new democracies. Results are robust to alternative competence distribution and propaganda cost assumptions.
Assessing the density of honey bee colonies at ecosystem scales
Authors: Utaipanon Patsavee , Schaerf Timothy M. , Oldroyd Benjamin P.
Published: December 2018

1. Information about the density of wild honey bee (Apisspp.) colonies in an ecosystem is central to understanding the functional role of honey bees in that ecosystem, necessary for effective biosecurity response planning, and useful for determining whether pollination services are adequate. However, direct visual surveys of colony locations are not practical at ecosystem scales. Thus, indirect methods based on population genetic analysis of trapped males have been proposed and implemented.

2. In this review, indirect methods of assessment of honey bee colony densities are described, which can be applied at ecosystem scales. The review also describes how to trap males in the field using the Williams drone trap (or virgin queens) the appropriate genetic markers and statistical analyses, and discusses issues surrounding sample size.

3. The review also discusses some outstanding issues concerning the methods and the conversion of estimated colony number to colony density per km2. The appropriate conversion factor will require further research to determine the area over which a drone trap draws drones.
Empathy among dental students in a Nigerian institution
Authors: Ameh Priscilla O. , Uti Omolara G. , Daramola Opeyemi O.
Published: December 2018

Objectives

To determine the reliability and validity of the Jefferson Scale of Empathy‐Health Profession Students (JSE‐HPS) version as a tool to measure the empathy levels in undergraduate dental students in Nigeria.

Methods

A cross‐sectional study conducted from 15 December 2015 to 12 January 2016 among 234 undergraduate dental students of the University of Lagos, Nigeria. Participants were proportionately selected from the first to sixth year by systematic sampling technique. Data were collected with a self‐administered JSE‐HPS questionnaire with internal consistency determined by Cronbach's α‐coefficient reliability test. Data were analysed with SPSS software. Exploratory factor analysis was used to test for the fundamental construct validity of the scale among the students. P values <0.05 were considered significant.

Results

The response rate of the respondents was 90.60% with 212 completed questionnaires with a mean age (SD) of 21.18 years (2.43) and internal reliability (Cronbach's α‐coefficient) was 0.84. Factor analysis revealed “Compassionate Care,” “Standing in Patients’ Shoes” and “Perspective Taking” as first, second and third factors, respectively. The total mean empathy score (SD) was 104.01 (19.64). The mean empathy for females (SD) of 105.34 (17.31) was not significantly higher than the males (P = 0.08). There was a significant difference in empathy levels between the second‐ and the fourth‐year students (P = 0.01).

Conclusion

The mean JSE‐HPS score was comparable to those reported for dental, medical and other health professions students and physicians. Thus, this study demonstrates the construct validity and reliability of the JSE‐HPS for measuring empathy among Nigerian dental students.
Involvement of non‐melanocytic skin cells in vitiligo
Authors: Bastonini Emanuela , Bellei Barbara , Filoni Angela , Kovacs Daniela , Iacovelli Paolo , Picardo Mauro
Published: December 2018

Despite melanocytes are the key players in vitiligo, a continuous cross‐talk between epidermal and dermal cells may strictly affect their functionality, in both lesional skin and non‐lesional skin. Focusing on this interplay, we have reviewed existing literature supporting evidence on cellular and functional alterations of surrounding epidermal keratinocytes, extracellular matrix (ECM) proteins and fibroblasts in the underlying dermal compartment that may contribute to melanocyte disappearance in vitiligo. We have also examined some clinical and therapeutic aspects of the disease to sustain the non‐exclusive involvement of melanocytes within vitiligo. As a result, a different and more complex scenario has appeared that may enable to provide better understanding about origins and progress of vitiligo and that should be considered in the evaluation of new treatment approaches.
High‐Precision Barium Isotope Measurements of Carbonates by MC‐ICP‐MS
Authors: Zeng Zhen , Li Xiaohua , Liu Yi , Huang Fang , Yu Hui‐Min
Published: December 2018

This study presents a high‐precision method to measure barium (Ba) isotope compositions of international carbonate reference materials and natural carbonates. Barium was purified using chromatographic columns filled with cation exchange resin (AG50W‐X12, 200–400 mesh). Barium isotopes were measured by MC‐ICP‐MS, using a 135Ba–136Ba double‐spike to correct mass‐dependent fractionation during purification and instrumental measurement. The precision and accuracy were monitored by measuring Ba isotope compositions of the reference material JCp‐1 (coral) and a synthetic solution obtained by mixing NIST SRM 3104a with other matrix elements. The mean δ137/134Ba values of JCp‐1 and the synthetic solution relative to NIST SRM 3104a were 0.21 ± 0.03‰ (2s, n = 16) and 0.02 ± 0.03‰ (2s, n = 6), respectively. Replicate measurements of NIST SRM 915b, COQ‐1, natural coral and stalagmite samples gave average δ137/134Ba values of 0.10 ± 0.04‰ (2s, n = 18), 0.08 ± 0.04‰ (2s, n = 20), 0.27 ± 0.04‰ (2s, n = 16) and 0.04 ± 0.03‰ (2s, n = 20), respectively. Barium mass fractions and Ba isotopes of subsamples drilled from one stalagmite profile were also measured. Although Ba mass fractions varied significantly along the profile, Ba isotope signatures were homogeneous, indicating that Ba isotope compositions of stalagmites could be a potential tool (in addition to Ba mass fractions) to constrain the source of Ba in carbonate rocks and minerals.
Voluntary disclosure, mandatory disclosure and the cost of capital
Authors: He Jing , Plumlee Marlene A. , Wen He
Published: December 2018

We examine the association between a firm's cost of capital and its voluntary and mandatory disclosures. We include two types of mandatory disclosure: those that are a function of periodic reports that are realizations of ex‐ante reporting systems and those that arise due to specific corporate events. To capture a firm's voluntary and event‐driven mandatory disclosures, we use information the firm provides via 8K filings. To capture periodic mandatory disclosures, we use earnings quality measures derived from the literature. Consistent with endogenous relations predicted by theory, we find that voluntary disclosure and both types of mandatory disclosure are correlated, although only event‐driven mandatory disclosures are significant in models that explain voluntary disclosure. We also find that the cost of capital is generally influenced by each of these disclosure types. We also find that controlling for periodic mandatory disclosure does not affect the relationship between voluntary disclosure and the cost of capital, while controlling for event‐driven mandatory disclosure sometimes affects the relationship depending on the measures used. Our study suggests that a firm's disclosure environment includes the three types of disclosure examined, although the inclusion of mandatory disclosures does not affect the measured association between voluntary disclosure and the cost of capital.
Perception on family support and predictors’ of satisfaction with the healthcare service among families of children and adolescents with serious mental illnesses who are in active psychiatric treatment
Authors: Svavarsdottir Erla Kolbrun , Gisladottir Margret , Tryggvadottir Gudny Bergthora
Published: December 2018

Problem

Little is known about the factors related to satisfaction with healthcare services among families of children with serious mental illness who were in active psychiatry treatment.

Methods

A cross‐sectional study was conducted to explore perceived family support, illness beliefs, and families’ satisfaction with healthcare services. Sixty‐eight families of children with anxiety, depression, attention‐deficit/hyperactivity disorder, eating disorders, and autism/Asperger's syndrome participated. Data were collected from March 2015 to December 2016.

Findings

Illness beliefs and perceived family support explained 23% of the variance in family satisfaction with the healthcare service.

Conclusion

Family interventions need to specifically focus on the families’ satisfaction with healthcare services and on utilizing the family support network, offering emotional support, and exploring illness beliefs.
Excitation of murine cardiac myocytes by nanosecond pulsed electric field
Authors: Azarov Jan E. , Semenov Iurii , Casciola Maura , Pakhomov Andrei G.
Published: December 2018

Introduction

Opening of voltage‐gated sodium channels takes tens to hundreds of microseconds, and mechanisms of their opening by nanosecond pulsed electric field (nsPEF) stimuli remain elusive. This study was aimed at uncovering the mechanisms of how nsPEF elicits action potentials (APs) in cardiomyocytes.

Methods and Results

Fluorescent imaging of optical APs (FluoVolt) and Ca2+‐transients (Fluo‐4) was performed in enzymatically isolated murine ventricular cardiomyocytes stimulated by 200‐nanosecond trapezoidal pulses. nsPEF stimulation evoked tetrodotoxin‐sensitive APs accompanied or preceded by slow sustained depolarization (SSD) and, in most cells, by transient afterdepolarization waves. SSD threshold was lower than the AP threshold (1.26 ± 0.03 vs 1.34 ± 0.03 kV/cm, respectively,
P < 0.001). Inhibition of
l‐type calcium and sodium‐calcium exchanger currents reduced the SSD amplitude and increased the AP threshold (
P < 0.05). The threshold for Ca
2+‐transients (1.40 ± 0.04 kV/cm) was not significantly affected by a tetrodotoxin‐verapamil cocktail, suggesting the activation of a Ca
2+ entry pathway independent from the opening of Na
+ or Ca
2+ voltage‐gated channels. Removal of external Ca
2+ decreased the SSD amplitude (
P = 0.004) and blocked Ca
2+‐transients but not APs. The incidence of transient afterdepolarization waves was decreased by verapamil and by removal of external Ca
2+ (
P = 0.002).

Conclusions

The study established that nsPEF stimulation caused calcium entry into cardiac myocytes (including routes other than voltage‐gated calcium channels) and SSD. Tetrodotoxin‐sensitive APs were mediated by SSD, whose amplitude depended on the calcium entry. Plasma membrane electroporation was the most likely primary mechanism of SSD with additional contribution from l‐type calcium and sodium‐calcium exchanger currents.
A randomized multicenter study on ambulatory blood pressure and arterial stiffness in patients treated with valsartan/amlodipine or nifedipine GITS
Authors: Xu Shao‐Kun , Huang Qi‐Fang , Zeng Wei‐Fang , Sheng Chang‐Sheng , Li Yan , Wang Ji‐Guang
Published: December 2018

In a pre‐specified subgroup analysis of a 12‐week randomized multicenter study, we investigated effects of valsartan/amlodipine 80/5 mg single‐pill combination (n = 75) and nifedipine GITS 30 mg (n = 75) on ambulatory blood pressure (BP) and arterial stiffness assessed by brachial‐ankle pulse wave velocity (PWV) in patients with uncontrolled hypertension. At week 12, the between‐treatment mean differences in systolic/diastolic BP were smaller for 24‐hour and daytime (–2.1/–1.7 and −2.0/−1.5 mm Hg, respectively, P ≥ 0.22) but greater (P < 0.01) for nighttime (–4.0/‐2.8 mm Hg, P ≤ 0.09), especially in sustained uncontrolled hypertension (−5.0/−4.1 mm Hg, P ≤ 0.04) and non‐dippers (−6.5/−3.7 mm Hg, P ≤ 0.07), in favor of valsartan/amlodipine. At week 12, PWV was significantly reduced from baseline by valsartan/amlodipine (n = 59, P < 0.0001) but not nifedipine (n = 59, P = 0.06). The changes in PWV were significantly associated with that in ambulatory systolic BP and pulse pressure in the nifedipine (P ≤ 0.0008) but not valsartan/amlodipine group (P ≥ 0.57), with a significant interaction (P ≤ 0.045). The valsartan/amlodipine combination was more efficacious than nifedipine GITS in lowering nighttime BP in sustained uncontrolled hypertension and non‐dippers, and in lowering arterial stiffness independent of BP lowering.