bluuebunny/crossref_metadata_2025 huggingface dataset:
Psoroma nivale (Pannariaceae, lichenized Ascomycota) a new species with dark, elongate squamules and bacilliform ascospores from arctic Québec, Canada
Authors: FRYDAY Alan M. , ELVEBAKK Arve , ANDERSON Frances L. , GAGNON Jean Y.
Published: November 2019

The new species Psoroma nivale is described from an area of late snow-lie in the Keglo Bay area on the eastern side of Ungava Bay, northern Québec, Canada. It is superficially similar to P. hypnorum but has a dark, brownish black thallus colour without reddish hues, much-branched, proliferating squamules, thick paraphyses, distinct but inconspicuous IKI+ ascus tube structures, and characteristic elongate, bacilliform, often asymmetrical ascospores. The new species is compared with possible related taxa and its systematic position discussed. A key to the species of pannarioid lichens reported from arctic areas of North America is also provided.
Beyond conflict: exploring the spectrum of human–wildlife interactions and their underlying mechanisms
Authors: Bhatia Saloni , Redpath Stephen Mark , Suryawanshi Kulbhushansingh , Mishra Charudutt
Published: November 2019

Humans have lived alongside and interacted with wild animals throughout evolutionary history. Even though wild animals can damage property, or injure humans and domesticated animals, not all interactions between humans and wildlife are negative. Yet, research has tended to focus disproportionately on negative interactions leading to negative outcomes, labelling this human–wildlife conflict. Studies have identified several factors, ranging from gender, religion, socio-economics and literacy, which influence people's responses to wildlife. We used the ISI Web of Knowledge database to assess quantitatively how human–wildlife interactions are framed in the scientific literature and to understand the hypotheses that have been invoked to explain these. We found that the predominant focus of research was on human–wildlife conflict (71%), with little coverage of coexistence (2%) or neutral interactions (8%). We suggest that such a framing is problematic as it can lead to biases in conservation planning by failing to consider the nuances of people's relationships with wildlife and the opportunities that exist for conservation. We propose a typology of human responses to wildlife impacts, ranging from negative to positive, to help moderate the disproportionate focus on conflict. We suggest that standardizing terminology and considering interactions beyond those that are negative can lead to a more nuanced understanding of human–wildlife relations and help promote greater coexistence between people and wildlife. We also list the various influential factors that are reported to shape human–wildlife interactions and, to generate further hypotheses and research, classify them into 55 proximate (correlates) and five ultimate (mechanisms) factors.
Evidence for the taxonic latent structure for DSM-5 intermittent explosive disorder in adults
Authors: Fanning Jennifer R. , Marcus David K. , Preszler Jonathan R. , Coccaro Emil F.
Published: November 2019

Background

Identification of individuals with clinically significant aggressive behavior is critical for the prevention and management of human aggressive behavior. A previous population-based taxometric study reported that the Diagnostic and Statistical Manual of Mental Disorders-4th Edition (DSM-IV) intermittent explosive disorder (IED) belongs to its own discrete class (taxon) rather than existing along a continuum.

Methods

This study sought to extend previous population-based findings in a clinical research sample of adults with DSM-5 IED (n = 346), adults with non-aggressive DSM-5 disorders (n = 293), and adults without any DSM-5 disorder (n = 174), using standardized assessments of DSM-5 diagnoses, aggression, and other related measures not available in past studies.

Results

Analyses revealed a taxonic latent structure that overlapped with the DSM-5 diagnosis of IED. Within the sample, taxon group members had higher scores on a variety of measures of psychopathology than did the complement members of the sample. Comorbidity of other diagnoses with IED did not affect these results.

Conclusion

These findings support the proposition that DSM-5 IED represents a distinct behavioral disorder rather than the severe end of an aggressive behavior continuum.
Autobiographical memory and default mode network function in schizophrenia: an fMRI study
Authors: Martin-Subero Marta , Fuentes-Claramonte Paola , Salgado-Pineda Pilar , Salavert Josep , Arevalo Antoni , Bosque Clara , Sarri Carmen , Guerrero-Pedraza Amalia , Santo-Angles Aniol , Capdevila Antoni , Sarró Salvador , Salvador Raymond , McKenna Peter J. , Pomarol-Clotet Edith
Published: November 2019

Background

The brain functional correlates of autobiographical recall are well established, but have been little studied in schizophrenia. Additionally, autobiographical memory is one of a small number of cognitive tasks that activates rather than de-activates the default mode network, which has been found to be dysfunctional in this disorder.

Methods

Twenty-seven schizophrenic patients and 30 healthy controls underwent functional magnetic resonance imaging while viewing cue words that evoked autobiographical memories. Control conditions included both non-memory-evoking cues and a low level baseline (cross fixation).

Results

Compared to both non-memory evoking cues and low level baseline, autobiographical recall was associated with activation in default mode network regions in the controls including the medial frontal cortex, the posterior cingulate cortex and the hippocampus, as well as other areas. Clusters of de-activation were seen outside the default mode network. There were no activation differences between the schizophrenic patients and the controls, but the patients showed clusters of failure of de-activation in non-default mode network regions.

Conclusions

According to this study, patients with schizophrenia show intact activation of the default mode network and other regions associated with recall of autobiographical memories. The finding of failure of de-activation outside the network suggests that schizophrenia may be associated with a general difficulty in de-activation rather than dysfunction of the default mode networkper se.
Severe fetal cardiomegaly caused by multiple non-giant placental chorioangiomas
Authors: Yamamoto Hidenori , Fukasawa Yoshie , Kato Taichi
Published: November 2019

A pregnant woman was referred to our hospital due to fetal cardiomegaly. We recognised a dilated umbilical vein, which raised a suspicion of placental chorioangioma. A male neonate was delivered at 37 weeks of gestation. The cardiomegaly was gradually improved. Pathological examination identified five non-giant placental chorioangiomas. Multiple non-giant chorioangiomas may cause fetal complications despite the difficulty of prenatal diagnosis.
Transcatheter closure of right pulmonary artery to left atrium fistula in an infant: technical consideration and possible closure techniques
Authors: Arya Vikas , Azad Sushil , Radhakrishnan Sitaraman
Published: November 2019

Congenital right pulmonary artery to left atrium fistula is rare cause of cyanosis. It is an abnormal fistulous connection between right pulmonary artery and left atrium representing a direct communication between a pulmonary artery and vein with absence of capillary network connecting between these two. Cardiovascular examination usually remains normal. High index of suspicion on clinical examination and subsequent transthoracic echocardiography is needed to suspect this entity. Bubble contrast echocardiography usually confirms the diagnosis. Cardiac catheterization is used as diagnostic as well as therapeutic modality. Cardiac catheterization is useful in classifying the fistula and helps in transcatheter closure by embolization devices. Choice of devices depends on type of fistula, vascular access, and presence of atrial communication. Here, we are reporting 8-month-old girl presenting with type 2 right pulmonary artery to left atrium fistula, which underwent successful transcatheter closure by 6 mm/4 mm duct occluder (Heart R, Lifetech Scientific, Shenzhen, China). Early closure in this young age will prevent complications of cyanosis. The technical consideration, possible access, and closure techniques are discussed in this young infant.
Individual Sanctions of Competition Law: A Comparison between the UK and Turkey
Authors: Caliskan Samet , Oner Saliha
Published: November 2019

It is a highly advocated view that a competition law with sanctions targeting individuals would achieve a greater deterrent impact than one that does not. Having introduced individual sanctions does not, however, guarantee that a market would have less anticompetitive conduct, because these sanctions are effective only insofar as they are severely implemented on wrongdoing individuals. UK competition law is one example of this issue because cases where individuals have been targeted and punished are significantly fewer than the authorities expected, in spite of it being more than 15 years since individual sanctions were introduced amidst high expectations. This article examines the individual sanctions of competition law in the UK and Turkey. It argues that Turkey is on the right path by departing from the way in which EU law enforces the rules of competition law, and is moving closer to UK law. However, it is argued that further steps should be cautiously considered to avoid the same issues which UK competition law is currently experiencing, as there are serious doubts that the latter has achieved the desired deterrent effect.
Model Dependency in the Analysis of Women's Electoral Success
Authors: Jankowski Michael , Marcinkiewicz Kamil
Published: November 2019

Maciej Górecki provides a detailed and interesting discussion of our analysis regarding women's electoral success in the Polish open-list proportional representation (PR) system and the impact of a gender quota implemented in 2011. In essence, he claims that it remains an open question whether the gender quota had a ‘paradoxical’ effect (i.e., whether the introduction of the gender quota had a negative impact on female candidates) due to ‘debatable’ methodological choices in our analysis. In this article, we respond to Górecki's critique. First, we demonstrate that we do not necessarily disagree on the paradoxical impact of the gender quota but rather on the strength of the paradoxical effect. Second, we discuss some drawbacks of using the raw number of votes cast for a candidate as the dependent variable. Finally, we respond to the critique of including the ballot position in the regression model. We emphasize that even if one agrees with Górecki's critique that the ballot position is endogenous, excluding this variable leads to a severely misspecified model that does not allow one to reliably identify the effect of gender.
A new genus and species of Micromalthidae from Burmese amber (Coleoptera: Archostemata)
Authors: TIHELKA Erik , HUANG Diying , CAI Chenyang
Published: November 2019

Micromalthidae is a small relictual family of archostematan beetles that is well known for its unusual asexual reproductive system characterised by parthenogenetic, viviparous, larviform females and sterile adults. Here we describe the first micromalthid beetle from mid-Cretaceous Burmese amber (ca.100Ma). Protomalthus burmaticus gen. et sp. nov. differs from all presently known micromalthid beetles by the presence of distinct frontoclypeal, labroclypeal, and medicranial sutures. The finding represents the first Mesozoic record of an adult micromalthid beetle and confirms a Gondwanan distribution of the family during the Cretaceous. A list of micromalthid beetles is provided, together with a key to extant and fossil species.
Predicting strength distributions of MEMS structures using flaw size and spatial density
Authors: Cook Robert F. , DelRio Frank W. , Boyce Brad L.
Published: November 2019

The populations of flaws in individual layers of microelectromechanical systems (MEMS) structures are determined and verified using a combination of specialized specimen geometry, recent probabilistic analysis, and topographic mapping. Strength distributions of notched and tensile bar specimens are analyzed assuming a single flaw population set by fabrication and common to both specimen geometries. Both the average spatial density of flaws and the flaw size distribution are determined and used to generate quantitative visualizations of specimens. Scanning probe-based topographic measurements are used to verify the flaw spacings determined from strength tests and support the idea that grain boundary grooves on sidewalls control MEMS failure. The findings here suggest that strength controlling features in MEMS devices increase in separation, i.e., become less spatially dense, and decrease in size, i.e., become less potent flaws, as processing proceeds up through the layer stack. The method demonstrated for flaw population determination is directly applicable to strength prediction for MEMS reliability and design.
Effect of dapagliflozin on obstructive sleep apnea in patients with type 2 diabetes: a preliminary study
Authors: Tang Yi , Sun Qin , Bai Xiao-Yan , Zhou Yun-Fan , Zhou Qiong-Lan , Zhang Min
Published: November 2019

Objective

The aim of this case-control study was to assess the efficacy of dapagliflozin combined with metformin for type-2 diabetes mellitus (T2DM) with obstructive sleep apnea hypopnea syndrome (OSAHS).

Methods

A total of 36 patients with newly-diagnosed T2DM and OSAHS were randomized divided into two groups. Eighteen OSAHS patients with T2DM, who were treated with dapagliflozin and metformin, were assigned as the dapagliflozin group. These patients were given dapagliflozin and metformin for 24 weeks between February 2017 and February 2018. Another 18 OSAHS patients with T2DM, who were treated with glimepiride and metformin for 24 weeks, were assigned as the control group. Fasting plasma glucose (FPG) level, postprandial blood glucose (PPG), hemoglobin A1C (HbA1c), fasting insulin, homeostasis model assessment of insulin resistance (HOMA-IR), blood lipids, body mass index (BMI), blood pressure, apnea-hypopnea index (AHI), minimum oxygen saturation (LSpO2), and Epworth Somnolence Scale (ESS) score were measured before and at 24 weeks after the initiation of treatment.

Results

In the dapagliflozin group, triglyceride (TG), systolic pressure (SBP) and diastolic pressure (DBP) significantly decreased following treatment, while high-density lipoprotein cholesterol (HDL-C) significantly increased (P < 0.05). Furthermore, a reduction in AHI, an increase in LSpO2 and a decrease in ESS score were observed in the dapagliflozin group (P < 0.05), but not in the control group. Moreover, blood glucose, HbA1c, HOMA-IR, and BMI significantly decreased in these two groups, and the decrease was more significant in the dapagliflozin group.

Conclusion

These present results indicate that dapagliflozin can significantly reduce glucose, BMI, blood pressure and AHI, and improve hypoxemia during sleep and excessive daytime sleepiness, which thereby has potential as an effective treatment approach for OSAHS.
Hyperpolarized 13C-pyruvate MRI detects real-time metabolic flux in prostate cancer metastases to bone and liver: a clinical feasibility study
Authors: Chen Hsin-Yu , Aggarwal Rahul , Bok Robert A. , Ohliger Michael A. , Zhu Zi , Lee Philip , Gordon Jeremy W. , van Criekinge Mark , Carvajal Lucas , Slater James B. , Larson Peder E. Z. , Small Eric J. , Kurhanewicz John , Vigneron Daniel B.
Published: November 2019

Background

Hyperpolarized (HP) 13C-pyruvate MRI is a stable-isotope molecular imaging modality that provides real-time assessment of the rate of metabolism through glycolytic pathways in human prostate cancer. Heretofore this imaging modality has been successfully utilized in prostate cancer only in localized disease. This pilot clinical study investigated the feasibility and imaging performance of HP 13C-pyruvate MR metabolic imaging in prostate cancer patients with metastases to the bone and/or viscera.

Methods

Six patients who had metastatic castration-resistant prostate cancer were recruited. Carbon-13 MR examination were conducted on a clinical 3T MRI following injection of 250 mM hyperpolarized 13C-pyruvate, where pyruvate-to-lactate conversion rate (kPL) was calculated. Paired metastatic tumor biopsy was performed with histopathological and RNA-seq analyses.

Results

We observed a high rate of glycolytic metabolism in prostate cancer metastases, with a mean kPL value of 0.020 ± 0.006 (s−1) and 0.026 ± 0.000 (s−1) in bone (N = 4) and liver (N = 2) metastases, respectively. Overall, high kPL showed concordance with biopsy-confirmed high-grade prostate cancer including neuroendocrine differentiation in one case. Interval decrease of kPL from 0.026 at baseline to 0.015 (s−1) was observed in a liver metastasis 2 months after the initiation of taxane plus platinum chemotherapy. RNA-seq found higher levels of the lactate dehydrogenase isoform A (Ldha,15.7 ± 0.7) expression relative to the dominant isoform of pyruvate dehydrogenase (Pdha1, 12.8 ± 0.9).

Conclusions

HP 13C-pyruvate MRI can detect real-time glycolytic metabolism within prostate cancer metastases, and can measure changes in quantitative kPL values following treatment response at early time points. This first feasibility study supports future clinical studies of HP 13C-pyruvate MRI in the setting of advanced prostate cancer.
Quantitative proteomic analyses reveal that GPX4 downregulation during myocardial infarction contributes to ferroptosis in cardiomyocytes
Authors: Park Tae-Jun , Park Jei Hyoung , Lee Ga Seul , Lee Ji-Yoon , Shin Ji Hye , Kim Min Wook , Kim Yong Sook , Kim Jeong-Yoon , Oh Kyoung-Jin , Han Baek-Soo , Kim Won-Kon , Ahn Youngkeun , Moon Jeong Hee , Song Jaewhan , Bae Kwang-Hee , Kim Do Han , Lee Eun-Woo , Lee Sang Chul
Published: November 2019

Ischaemic heart disease (IHD) is the leading cause of death worldwide. Although myocardial cell death plays a significant role in myocardial infarction (MI), its underlying mechanism remains to be elucidated. To understand the progression of MI and identify potential therapeutic targets, we performed tandem mass tag (TMT)-based quantitative proteomic analysis using an MI mouse model. Gene ontology (GO) analysis and gene set enrichment analysis (GSEA) revealed that the glutathione metabolic pathway and reactive oxygen species (ROS) pathway were significantly downregulated during MI. In particular, glutathione peroxidase 4 (GPX4), which protects cells from ferroptosis (an iron-dependent programme of regulated necrosis), was downregulated in the early and middle stages of MI. RNA-seq and qRT-PCR analyses suggested that GPX4 downregulation occurred at the transcriptional level. Depletion or inhibition of GPX4 using specific siRNA or the chemical inhibitor RSL3, respectively, resulted in the accumulation of lipid peroxide, leading to cell death by ferroptosis in H9c2 cardiomyoblasts. Although neonatal rat ventricular myocytes (NRVMs) were less sensitive to GPX4 inhibition than H9c2 cells, NRVMs rapidly underwent ferroptosis in response to GPX4 inhibition under cysteine deprivation. Our study suggests that downregulation of GPX4 during MI contributes to ferroptotic cell death in cardiomyocytes upon metabolic stress such as cysteine deprivation.
GATA3 recruits UTX for gene transcriptional activation to suppress metastasis of breast cancer
Authors: Yu Wenqian , Huang Wei , Yang Yang , Qiu Rongfang , Zeng Yi , Hou Yongqiang , Sun Gancheng , Shi Hang , Leng Shuai , Feng Dandan , Chen Yang , Wang Shuang , Teng Xu , Yu Hefen , Wang Yan
Published: November 2019

GATA3 has emerged as a prominent transcription factor required for maintaining mammary-gland homeostasis. GATA3 loss is associated with aggressive breast cancer development, but the mechanism by which breast cancer is affected by the loss of GATA3 function remains unclear. Here, we report that GATA3 expression is positively correlated with the expression of UTX, a histone H3K27 demethylase contained in the MLL4 methyltransferase complex, and that GATA3 recruits the chromatin-remodeling MLL4 complex and interacts directly with UTX, ASH2L, and RBBP5. Using RNA sequencing and chromatin immunoprecipitation and sequencing, we demonstrate that the GATA3/UTX complex synergistically regulates a cohort of genes including Dicer and UTX, which are critically involved in the epithelial-to-mesenchymal transition (EMT). Our results further show that the GATA3-UTX-Dicer axis inhibits EMT, invasion, and metastasis of breast cancer cells in vitro and the dissemination of breast cancer in vivo. Our study implicates the GATA3-UTX-Dicer axis in breast cancer metastasis and provides new mechanistic insights into the pathophysiological function of GATA3.
Pancreatic cancer-educated macrophages protect cancer cells from complement-dependent cytotoxicity by up-regulation of CD59
Authors: Zhang Ronghua , Liu Qiaofei , Peng Junya , Wang Mengyi , Gao Xiang , Liao Quan , Zhao Yupei
Published: November 2019

Tumor-associated macrophages (TAMs) are versatile immune cells that promote a variety of malignant behaviors of pancreatic cancer. CD59 is a GPI-anchored membrane protein that prevents complement activation by inhibiting the formation of the membrane attack complex, which may protect cancer cells from complement-dependent cytotoxicity (CDC). The interactions between CD59, TAMs and pancreatic cancer remain largely unknown. A tissue microarray of pancreatic cancer patients was used to evaluate the interrelationship of CD59 and TAMs and their survival impacts were analyzed. In a coculture system, THP-1 cells were used as a model to study the function of TAMs and the roles of pancreatic cancer-educated macrophages in regulating the expression of CD59 in pancreatic cancer cells were demonstrated by real-time PCR, western blot and immunofluorescence staining. The effects of macrophages on regulating CDC in pancreatic cancer cells were demonstrated by an in vitro study. To explore the potential mechanisms, RNA sequencing of pancreatic cancer cells with or without co-culture of THP-1 macrophages was performed, and the results showed that the IL-6R/STAT3 signaling pathway might participate in the regulation, which was further demonstrated by target-siRNA transfection, antibody neutralization and STAT3 inhibitors. Our data revealed that the infiltration of TAMs and the expression of CD59 of pancreatic cancer were paralleled, and higher infiltration of TAMs and higher expression of CD59 predicted worse survival of pancreatic cancer patients. Pancreatic cancer-educated macrophages could protect cancer cells from CDC by up-regulating CD59 via the IL-6R/STAT3 signaling pathway. These findings uncovered the novel mechanisms between TAMs and CD59, and contribute to providing a new promising target for the immunotherapy of pancreatic cancer.
The paracrine induction of prostate cancer progression by caveolin-1
Authors: Lin Chun-Jung , Yun Eun-Jin , Lo U-Ging , Tai Yu-Ling , Deng Su , Hernandez Elizabeth , Dang Andrew , Chen Yu-An , Saha Debabrata , Mu Ping , Lin Ho , Li Tsai-Kun , Shen Tang-Long , Lai Chih-Ho , Hsieh Jer-Tsong
Published: November 2019

A subpopulation of cancer stem cells (CSCs) plays a critical role of cancer progression, recurrence, and therapeutic resistance. Many studies have indicated that castration-resistant prostate cancer (CRPC) is associated with stem cell phenotypes, which could further promote neuroendocrine transdifferentiation. Although only a small subset of genetically pre-programmed cells in each organ has stem cell capability, CSCs appear to be inducible among a heterogeneous cancer cell population. However, the inductive mechanism(s) leading to the emergence of these CSCs are not fully understood in CRPC. Tumor cells actively produce, release, and utilize exosomes to promote cancer development and metastasis, cancer immune evasion as well as chemotherapeutic resistance; the impact of tumor-derived exosomes (TDE) and its cargo on prostate cancer (PCa) development is still unclear. In this study, we demonstrate that the presence of Cav-1 in TDE acts as a potent driver to induce CSC phenotypes and epithelial–mesenchymal transition in PCa undergoing neuroendocrine differentiation through NFκB signaling pathway. Furthermore, Cav-1 in mCRPC-derived exosomes is capable of inducing radio- and chemo-resistance in recipient cells. Collectively, these data support Cav-1 as a critical driver for mCRPC progression.
RBBP6, a RING finger-domain E3 ubiquitin ligase, induces epithelial–mesenchymal transition and promotes metastasis of colorectal cancer
Authors: Xiao Chao , Wu Gang , Zhou Zhijie , Zhang Xin , Wang YuPeng , Song Guohe , Ding Erxun , Sun Xing , Zhong Lin , Li Shanbao , Weng Junyong , Zhu Zhonglin , Chen Jian , Wang Xiaoliang
Published: November 2019

RBBP6 has been implicated in tumorigenesis but its role in tumor metastasis and progression has not been evaluated. Interestingly, here we show that RBBP6 is upregulated in colorectal cancer (CRC) where its expression level is positively correlated with distant metastasis. In this study, we identified RBBP6, a RING Finger-domain E3 ubiquitin ligase, served as an independent prognostic factor and predicted poor outcome for CRC patients. RBBP6 promoted cell proliferation, migration, and invasion in CRC cells and promoted tumor growth, lung metastasis, and liver metastasis in mouse models. Mechanistically, we revealed that RBBP6 bound and ubiquitylated IκBα, an inhibitor of the NF-κB-signaling pathway. RBBP6-mediated ubiquitination and degradation of IκBα significantly enhanced p65 nuclear translocation, which triggered the activation of NF-κB pathway and then induced the epithelial–mesenchymal transition (EMT) process and cell metastasis. Furthermore, by DNA methylation results and ChIP analysis, we demonstrated that the promoter of RBBP6 was hypomethylated, and was activated by multi-oncogenic transcription factors. In conclusion, our findings suggest that RBBP6 may be a potential prognostic biomarker and therapeutic target for CRC invasion and metastasis.
A novel mouse model demonstrates that oncogenic melanocyte stem cells engender melanoma resembling human disease
Authors: Sun Qi , Lee Wendy , Mohri Yasuaki , Takeo Makoto , Lim Chae Ho , Xu Xiaowei , Myung Peggy , Atit Radhika P. , Taketo M. Mark , Moubarak Rana S. , Schober Markus , Osman Iman , Gay Denise L. , Saur Dieter , Nishimura Emi K. , Ito Mayumi
Published: November 2019

Melanoma, the deadliest skin cancer, remains largely incurable at advanced stages. Currently, there is a lack of animal models that resemble human melanoma initiation and progression. Recent studies using a Tyr-CreER driven mouse model have drawn contradictory conclusions about the potential of melanocyte stem cells (McSCs) to form melanoma. Here, we employ a c-Kit-CreER-driven model that specifically targets McSCs to show that oncogenic McSCs are a bona fide source of melanoma that expand in the niche, and then establish epidermal melanomas that invade into the underlying dermis. Further, normal Wnt and Endothelin niche signals during hair anagen onset are hijacked to promote McSC malignant transformation during melanoma induction. Finally, molecular profiling reveals strong resemblance of murine McSC-derived melanoma to human melanoma in heterogeneity and gene signatures. These findings provide experimental validation of the human melanoma progression model and key insights into the transformation and heterogeneity of McSC-derived melanoma.
Author Correction: Layer 4 of mouse neocortex differs in cell types and circuit organization between sensory areas
Authors: Scala Federico , Kobak Dmitry , Shan Shen , Bernaerts Yves , Laturnus Sophie , Cadwell Cathryn Rene , Hartmanis Leonard , Froudarakis Emmanouil , Castro Jesus Ramon , Tan Zheng Huan , Papadopoulos Stelios , Patel Saumil Surendra , Sandberg Rickard , Berens Philipp , Jiang Xiaolong , Tolias Andreas Savas
Published: November 2019

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Author Correction: KDM3 epigenetically controls tumorigenic potentials of human colorectal cancer stem cells through Wnt/β-catenin signalling
Authors: Li Jiong , Yu Bo , Deng Peng , Cheng Yingduan , Yu Yongxin , Kevork Kareena , Ramadoss Sivakumar , Ding Xiangming , Li Xinmin , Wang Cun-Yu
Published: November 2019

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Microdroplet-guided intercalation and deterministic delamination towards intelligent rolling origami
Authors: Xu Borui , Zhang Xinyuan , Tian Ziao , Han Di , Fan Xingce , Chen Yimeng , Di Zengfeng , Qiu Teng , Mei Yongfeng
Published: November 2019

Three-dimensional microstructures fabricated by origami, including folding, rolling and buckling, gain great interests in mechanics, optics and electronics. We propose a general strategy on on-demand and spontaneous rolling origami for artificial microstructures aiming at massive and intelligent production. Deposited nanomembranes are rolled-up in great amount triggered by the intercalation of tiny droplet, taking advantage of a creative design of van der Waals interaction with substrate. The rolling of nanomembranes delaminated by liquid permits a wide choice in materials as well as precise manipulation in rolling direction by controlling the motion of microdroplet, resulting in intelligent construction of rolling microstructures with designable geometries. Moreover, this liquid-triggered delamination phenomenon and constructed microstructures are demonstrated in the applications among vapor sensing, microresonators, micromotors, and microactuators. This investigation offers a simple, massive, low-cost, versatile and designable construction of rolling microstructures for fundamental research and practical applications.
Targeted resequencing identifies genes with recurrent variation in cerebral palsy
Authors: van Eyk C. L. , Corbett M. A. , Frank M. S. B. , Webber D. L. , Newman M. , Berry J. G. , Harper K. , Haines B. P. , McMichael G. , Woenig J. A. , MacLennan A. H. , Gecz J.
Published: November 2019

A growing body of evidence points to a considerable and heterogeneous genetic aetiology of cerebral palsy (CP). To identify recurrently variant CP genes, we designed a custom gene panel of 112 candidate genes. We tested 366 clinically unselected singleton cases with CP, including 271 cases not previously examined using next-generation sequencing technologies. Overall, 5.2% of the naïve cases (14/271) harboured a genetic variant of clinical significance in a known disease gene, with a further 4.8% of individuals (13/271) having a variant in a candidate gene classified as intolerant to variation. In the aggregate cohort of individuals from this study and our previous genomic investigations, six recurrently hit genes contributed at least 4% of disease burden to CP:COL4A1,TUBA1A, AGAP1,L1CAM,MAOBandKIF1A. Significance of Rare VAriants (SORVA) burden analysis identified four genes with a genome-wide significant burden of variants,AGAP1,ERLIN1,ZDHHC9andPROC, of which we functionally assessedAGAP1using a zebrafish model. Our investigations reinforce that CP is a heterogeneous neurodevelopmental disorder with known as well as novel genetic determinants.
The Empusa code generator and its application to GBOL, an extendable ontology for genome annotation
Authors: van Dam Jesse C. J. , Koehorst Jasper J. , Vik Jon Olav , Martins dos Santos Vitor A. P. , Schaap Peter J. , Suarez-Diez Maria
Published: November 2019

The RDF data model facilitates integration of diverse data available in structured and semi-structured formats. To obtain a coherent RDF graph the chosen ontology must be consistently applied. However, addition of new diverse data causes the ontology to evolve, which could lead to accumulation of unintended erroneous composites. Thus, there is a need for a gate keeping system that compares the intended content described in the ontology with the actual content of the resource. The Empusa code generator facilitates creation of composite RDF resources from disparate sources. Empusa can convert a schema into an associated application programming interface (API), that can be used to perform data consistency checks and generates Markdown documentation to make persistent URLs resolvable. Using Empusa consistency is ensured within and between the ontology and the content of the resource. As an illustration of the potential of Empusa, we present the Genome Biology Ontology Language (GBOL). GBOL uses and extends current ontologies to provide a formal representation of genomic entities, along with their properties, relations and provenance.
Localized delivery of compounds into articular cartilage by using high-intensity focused ultrasound
Authors: Nieminen Heikki J. , Lampsijärvi Eetu , Barreto Gonçalo , Finnilä Mikko A. J. , Salmi Ari , Airaksinen Anu J. , Eklund Kari K. , Saarakkala Simo , Pritzker Kenneth P. H. , Hæggström Edward
Published: November 2019

Localized delivery of drugs into an osteoarthritic cartilaginous lesion does not yet exist, which limits pharmaceutical management of osteoarthritis (OA). High-intensity focused ultrasound (HIFU) provides a means to actuate matter from a distance in a non-destructive way. In this study, we aimed to deliver methylene blue locally into bovine articular cartilage in vitro. HIFU-treated samples (n = 10) were immersed in a methylene blue (MB) solution during sonication (f = 2.16 MHz, peak-positive-pressure = 3.5 MPa, mechanical index = 1.8, pulse repetition frequency = 3.0 kHz, cycles per burst: 50, duty cycle: 7%). Adjacent control 1 tissue (n = 10) was first pre-treated with HIFU followed by immersion into MB; adjacent control 2 tissue (n = 10) was immersed in MB without ultrasound exposure. The MB content was higher (p < 0.05) in HIFU-treated samples all the way to a depth of 600 µm from AC surface when compared to controls. Chondrocyte viability and RNA expression levels associated with cartilage degeneration were not different in HIFU-treated samples when compared to controls (p > 0.05). To conclude, HIFU delivers molecules into articular cartilage without major short-term concerns about safety. The method is a candidate for a future approach for managing OA.
Novel sustainable biobased flame retardant from functionalized vegetable oil for enhanced flame retardancy of engineering plastic
Authors: Chang Boon Peng , Thakur Suman , Mohanty Amar K. , Misra Manjusri
Published: November 2019

The flame retardancy of an engineering plastic, poly(butylene terephthalate) (PBT), with a biobased flame retardant (FR) made from phosphorylated linseed oil (PLO) and phosphorylated downstream corn oil (PCO) was studied. Different phosphorus moieties were incorporated into the vegetable oil backbone through a ring-opening reaction. The chemical structure of the phosphorylated oil was confirmed by Fourier-transform infrared (FTIR) and nuclear resonance magnetic (NMR) spectroscopy. It was found that the incorporation of only 7.5 wt% of PLO was sufficient to change the UL-94 fire class of PBT from non-rating to V-0. The flame-retardancy mechanism of the PBT/PLO blends was evaluated from TGA-FTIR analysis. The combined effects of the gas phase mechanism and the dripping tendency of the blends aided to retard the flame propagation effectively. As the synthesized PLO and PCO contained high free fatty acids, the acid-ester exchange reaction occurred in the blends to form oligomers during the ignition. As a result, the blend dripped immediately and the drips carried all the heat to prevent fire. This work suggests that this sustainable biobased FR could be a desirable alternative to halogen-based FRs for PBT and other engineering polymers to develop more environmentally friendly FR products for various future applications.
An Exploratory Study of Predictors of Response to Vagus Nerve Stimulation Paired with Upper-Limb Rehabilitation After Ischemic Stroke
Authors: Dickie David Alexander , Kimberley Teresa Jacobson , Pierce David , Engineer Navzer , Tarver W. Brent , Dawson Jesse
Published: November 2019

We have previously shown the safety and feasibility of vagus nerve stimulation (VNS) paired with upper-limb rehabilitation after ischemic stroke. In this exploratory study, we assessed whether clinical and brain MRI variables predict response to treatment. We used data from two completed randomised and blinded clinical trials (N = 35). All participants had moderate to severe upper-limb weakness and were randomised to 6-weeks intensive physiotherapy with or without VNS. Participants had 3 T brain MRI at baseline. The primary outcome was change in Fugl-Meyer Assessment, upper-extremity score (FMA-UE) from baseline to the first day after therapy completion. We used general linear regression to identify clinical and brain MRI predictors of change in FMA-UE. VNS-treated participants had greater improvement in FMA-UE at day-1 post therapy than controls (8.63 ± 5.02 versus 3.79 ± 5.04 points, t = 2.83, Cohen’s d = 0.96, P = 0.008). Higher cerebrospinal fluid volume was associated with less improvement in FMA-UE in the control but not VNS group. This was also true for white matter hyperintensity volume but not after removal of an outlying participant from the control group. Responders in the VNS group had more severe arm impairment at baseline than responders to control. A phase III trial is now underway to formally determine whether VNS improves outcomes and will explore whether these differ in people with more severe baseline upper-limb disability and cerebrovascular disease.
Network-based Biased Tree Ensembles (NetBiTE) for Drug Sensitivity Prediction and Drug Sensitivity Biomarker Identification in Cancer
Authors: Oskooei Ali , Manica Matteo , Mathis Roland , Martínez María Rodríguez
Published: November 2019

We present the Network-based Biased Tree Ensembles (NetBiTE) method for drug sensitivity prediction and drug sensitivity biomarker identification in cancer using a combination of prior knowledge and gene expression data. Our devised method consists of a biased tree ensemble that is built according to a probabilistic bias weight distribution. The bias weight distribution is obtained from the assignment of high weights to the drug targets and propagating the assigned weights over a protein-protein interaction network such as STRING. The propagation of weights, defines neighborhoods of influence around the drug targets and as such simulates the spread of perturbations within the cell, following drug administration. Using a synthetic dataset, we showcase how application of biased tree ensembles (BiTE) results in significant accuracy gains at a much lower computational cost compared to the unbiased random forests (RF) algorithm. We then apply NetBiTE to the Genomics of Drug Sensitivity in Cancer (GDSC) dataset and demonstrate that NetBiTE outperforms RF in predicting IC50 drug sensitivity, only for drugs that target membrane receptor pathways (MRPs): RTK, EGFR and IGFR signaling pathways. We propose based on the NetBiTE results, that for drugs that inhibit MRPs, the expression of target genes prior to drug administration is a biomarker for IC50 drug sensitivity following drug administration. We further verify and reinforce this proposition through control studies on, PI3K/MTOR signaling pathway inhibitors, a drug category that does not target MRPs, and through assignment of dummy targets to MRP inhibiting drugs and investigating the variation in NetBiTE accuracy.
Correlated impurity complex in the asymmetric tunneling contact: an ideal system to observe negative tunneling conductivity
Authors: Maslova N. S. , Arseyev P. I. , Mantsevich V. N.
Published: November 2019

We studied theoretically electron transport through the impurity complex localized between the tunneling contact leads by means of the generalized Keldysh diagram technique. The formation of multiple well pronounced regions with negative tunneling conductivity in the I-V characteristics was revealed. The appearance of negative tunneling conductivity is caused by the presence of both strong Coulomb correlations and the asymmetry of tunneling rates, which lead to the blockade of the electron transport through the system for a certain values of applied bias. The developed theory and obtained results may be useful for the application of impurity (dopant) atoms as a basic elements in modern nanoelectronic circuits.
A sensitive fluorescence-based assay to monitor enzymatic activity of the essential integral membrane protein Apolipoprotein N-acyltransferase (Lnt)
Authors: Nozeret Karine , Boucharlat Alix , Agou Fabrice , Buddelmeijer Nienke
Published: November 2019

Lipoprotein modification is an essential process in Gram-negative bacteria. The action of three integral membrane proteins that catalyze the transfer of fatty acids derived from membrane phospholipids or cleave the signal peptide of the lipoprotein substrate result in the formation of mature triacylated proteins. Inactivation of the enzymes leads to mis-localization of immature lipoproteins and consequently cell death. Biochemical studies and the development of in vitro assays are challenging due to the fact that the enzymes and substrates are all membrane-embedded proteins difficult to overproduce and purify. Here we describe a sensitive fluorescence-based assay to monitor bacterial apolipoprotein N-acyltransferase activity.
α-Synuclein oligomers mediate the aberrant form of spike-induced calcium release from IP3 receptor
Authors: Yamamoto Kenji , Izumi Yasuhiko , Arifuku Monami , Kume Toshiaki , Sawada Hideyuki
Published: November 2019

Emerging evidence implicates α-synuclein oligomers as potential culprits in the pathogenesis of Lewy body disease (LBD). Soluble oligomeric α-synuclein accumulation in cytoplasm is believed to modify neuronal activities and intraneural Ca2+dynamics, which augment the metabolic burden in central neurons vulnerable to LBD, although this hypothesis remains to be fully tested. We evaluated how intracellular α-synuclein oligomers affect the neuronal excitabilities and Ca2+dynamics of pyramidal neurons in neocortical slices from mice. Intracellular application of α-synuclein containing stable higher-order oligomers (αSNo) significantly reduced spike frequency during current injection, elongated the duration of spike afterhyperpolarization (AHP), and enlarged AHP current charge in comparison with that of α-synuclein without higher-order oligomers. This αSNo-mediated alteration was triggered by spike-induced Ca2+release from inositol trisphosphate receptors (IP3R) functionally coupled with L-type Ca2+channels and SK-type K+channels. Further electrophysiological and immunochemical observations revealed that α-synuclein oligomers greater than 100 kDa were directly associated with calcium-binding protein 1, which is responsible for regulating IP3R gating. They also block Ca2+-dependent inactivation of IP3R, and trigger Ca2+-induced Ca2+release from IP3R during multiple spikes. This aberrant machinery may result in intraneural Ca2+dyshomeostasis and may be the molecular basis for the vulnerability of neurons in LBD brains.
Satellite Laser-Ranging as a Probe of Fundamental Physics
Authors: Ciufolini Ignazio , Matzner Richard , Paolozzi Antonio , Pavlis Erricos C. , Sindoni Giampiero , Ries John , Gurzadyan Vahe , Koenig Rolf
Published: November 2019

Satellite laser-ranging is successfully used in space geodesy, geodynamics and Earth sciences; and to test fundamental physics and specific features of General Relativity. We present a confirmation to approximately one part in a billion of the fundamental weak equivalence principle (“uniqueness of free fall”) in the Earth’s gravitational field, obtained with three laser-ranged satellites, at previously untested range and with previously untested materials. The weak equivalence principle is at the foundation of General Relativity and of most gravitational theories.
Human papillomavirus and human telomerase RNA component gene in cervical cancer progression
Authors: Liu Yang , Fan Pianping , Yang Yingying , Xu Changjun , Huang Yajuan , Li Daizhu , Qing Qing , Sun Chunyi , Zhou Honglin
Published: November 2019

This study aimed to examine hTERC gene in different grades of cervical intraepithelial neoplasia (CIN) and cervical cancer, and the association between hTERC and high risk-human papillomavirus (HR-HPV) infection. Patients who underwent cervical cancer screening at the Second Affiliated Hospital of Kunming Medical University between October 2010 and December 2011 were enrolled. All patients underwent liquid-based cytology test and hybrid capture 2 (HC2) for HPV detection. hTERC was examined using fluorescence in situ hybridization (FISH). Cervical colposcopy biopsy was performed if any of the three results was positive. HC2, FISH, and pathology were compared. A total of 1200 women underwent screening, 150 patients underwent cervical biopsy: 32 in the normal group, 38 in the CIN1 group, 66 in the CIN2/3 group, and 14 in the invasive cervical cancer group. More patients had HR-HPV infection in the CIN2/3 group and ICC group compared with the CIN1 group. hTERC increased with increasing histological dysplasia. There was significant difference in hTERC positive rate between each of the three groups. More patients with hTERC gene amplification were observed in the positive HR-HPV group than in the HR-HPV negative group. In conclusion, hTERC is a potential marker for precancerous cervical cancer lesions. hTERC might be correlated with HR-HPV infection in cervical diseases.
Examining environmental contaminant mixtures among adults with type 2 diabetes in the Cree First Nation communities of Eeyou Istchee, Canada
Authors: Zuk Aleksandra M. , Tsuji Leonard J. S. , Nieboer Evert , Martin Ian D. , Liberda Eric N.
Published: November 2019

Type 2 diabetes mellitus (T2DM) disproportionately affects Indigenous populations. It is possible that exposure to complex mixtures of environmental contaminants contribute to T2DM development. This study examined the association between complex environmental contaminant mixtures and T2DM among Canadian Indigenous communities from the Eeyou Istchee territory, Quebec, Canada. Using data from the cross-sectional Multi-Community Environment-and-Health Study (2005–2009) Principal Component Analysis (PCA) was used to reduce the dimensionality of the following contaminants: 9-polychlorinated biphenyl congeners; 7-organic pesticides; and 4-metal/metalloids. Following this data reduction technique, we estimated T2DM prevalence ratios (PR) and 95% confidence intervals using modified Poisson regression with robust error variance across derived principal components, adjusting for a priori covariates. For both First Nation adult males (n = 303) and females (n = 419), factor loadings showed dichlorodiphenyltrichloroethane (DDT) and lead (Pb) highly loaded on the second principal component (PC) axis: DDT negatively loaded, and Pb positively loaded. T2DM was significantly associated with PC-2 across all adjusted models. Because PCA produces orthogonal axes, increasing PC-2 scores in the fully adjusted model for females and males showed (PR = 0.84; 95% CI 0.72, 0.98) and (PR = 0.78; 95% CI 0.62, 0.98), respectively. This cross-sectional study suggests that our observed association with T2DM is the result of DDT, and less likely the result of Pb exposure. Further, detectable levels of DDT among individuals may possibly contribute to disease etiology.