bluuebunny/crossref_metadata_2025_split huggingface dataset:
Long-read amplicon denoising
Authors: Kumar Venkatesh , Vollbrecht Thomas , Chernyshev Mark , Mohan Sanjay , Hanst Brian , Bavafa Nicholas , Lorenzo Antonia , Kumar Nikesh , Ketteringham Robert , Eren Kemal , Golden Michael , Oliveira Michelli F , Murrell Ben 
Published: July 2019

AbstractLong-read next-generation amplicon sequencing shows promise for studying complete genes or genomes from complex and diverse populations. Current long-read sequencing technologies have challenging error profiles, hindering data processing and incorporation into downstream analyses. Here we consider the problem of how to reconstruct, free of sequencing error, the true sequence variants and their associated frequencies from PacBio reads. Called ‘amplicon denoising’, this problem has been extensively studied for short-read sequencing technologies, but current solutions do not always successfully generalize to long reads with high indel error rates. We introduce two methods: one that runs nearly instantly and is very accurate for medium length reads and high template coverage, and another, slower method that is more robust when reads are very long or coverage is lower. On two Mock Virus Community datasets with ground truth, each sequenced on a different PacBio instrument, and on a number of simulated datasets, we compare our two approaches to each other and to existing algorithms. We outperform all tested methods in accuracy, with competitive run times even for our slower method, successfully discriminating templates that differ by a just single nucleotide. Julia implementations of Fast Amplicon Denoising (FAD) and Robust Amplicon Denoising (RAD), and a webserver interface, are freely available.
The mRNA degradation factor Xrn1 regulates transcription elongation in parallel to Ccr4
Authors: Begley Victoria , Corzo Daniel , Jordán-Pla Antonio , Cuevas-Bermúdez Abel , Miguel-Jiménez Lola de , Pérez-Aguado David , Machuca-Ostos Mercedes , Navarro Francisco , Chávez María José , Pérez-Ortín José E , Chávez Sebastián 
Published: July 2019

AbstractCo-transcriptional imprinting of mRNA by Rpb4 and Rpb7 subunits of RNA polymerase II (RNAPII) and by the Ccr4–Not complex conditions its post-transcriptional fate. In turn, mRNA degradation factors like Xrn1 are able to influence RNAPII-dependent transcription, making a feedback loop that contributes to mRNA homeostasis. In this work, we have used repressible yeast GAL genes to perform accurate measurements of transcription and mRNA degradation in a set of mutants. This genetic analysis uncovered a link from mRNA decay to transcription elongation. We combined this experimental approach with computational multi-agent modelling and tested different possibilities of Xrn1 and Ccr4 action in gene transcription. This double strategy brought us to conclude that both Xrn1–decaysome and Ccr4–Not regulate RNAPII elongation, and that they do it in parallel. We validated this conclusion measuring TFIIS genome-wide recruitment to elongating RNAPII. We found that xrn1Δ and ccr4Δ exhibited very different patterns of TFIIS versus RNAPII occupancy, which confirmed their distinct role in controlling transcription elongation. We also found that the relative influence of Xrn1 and Ccr4 is different in the genes encoding ribosomal proteins as compared to the rest of the genome.
Prediction of regulatory motifs from human Chip-sequencing data using a deep learning framework
Authors: Yang Jinyu , Ma Anjun , Hoppe Adam D , Wang Cankun , Li Yang , Zhang Chi , Wang Yan , Liu Bingqiang , Ma Qin 
Published: July 2019

Abstract
The identification of transcription factor binding sites and cis-regulatory motifs is a frontier whereupon the rules governing protein–DNA binding are being revealed. Here, we developed a new method (DEep Sequence and Shape mOtif or DESSO) for cis-regulatory motif prediction using deep neural networks and the binomial distribution model. DESSO outperformed existing tools, including DeepBind, in predicting motifs in 690 human ENCODE ChIP-sequencing datasets. Furthermore, the deep-learning framework of DESSO expanded motif discovery beyond the state-of-the-art by allowing the identification of known and new protein–protein–DNA tethering interactions in human transcription factors (TFs). Specifically, 61 putative tethering interactions were identified among the 100 TFs expressed in the K562 cell line. In this work, the power of DESSO was further expanded by integrating the detection of DNA shape features. We found that shape information has strong predictive power for TF–DNA binding and provides new putative shape motif information for human TFs. Thus, DESSO improves in the identification and structural analysis of TF binding sites, by integrating the complexities of DNA binding into a deep-learning framework.
A CRISPR-Cas9 screen identifies essential CTCF anchor sites for estrogen receptor-driven breast cancer cell proliferation
Authors: Korkmaz Gozde , Manber Zohar , Lopes Rui , Prekovic Stefan , Schuurman Karianne , Kim Yongsoo , Teunissen Hans , Flach Koen , Wit Elzo de , Galli Giorgio G , Zwart Wilbert , Elkon Ran , Agami Reuven 
Published: July 2019

AbstractEstrogen receptor α (ERα) is an enhancer activating transcription factor, a key driver of breast cancer and a main target for cancer therapy. ERα-mediated gene regulation requires proper chromatin-conformation to facilitate interactions between ERα-bound enhancers and their target promoters. A major determinant of chromatin structure is the CCCTC-binding factor (CTCF), that dimerizes and together with cohesin stabilizes chromatin loops and forms the boundaries of topologically associated domains. However, whether CTCF-binding elements (CBEs) are essential for ERα-driven cell proliferation is unknown. To address this question in a global manner, we implemented a CRISPR-based functional genetic screen targeting CBEs located in the vicinity of ERα-bound enhancers. We identified four functional CBEs and demonstrated the role of one of them in inducing chromatin conformation changes in favor of activation of PREX1, a key ERα target gene in breast cancer. Indeed, high PREX1 expression is a bona-fide marker of ERα-dependency in cell lines, and is associated with good outcome after anti-hormonal treatment. Altogether, our data show that distinct CTCF-mediated chromatin structures are required for ERα- driven breast cancer cell proliferation.
Cinacalcet use in paediatric dialysis: a position statement from the European Society for Paediatric Nephrology and the Chronic Kidney Disease-Mineral and Bone Disorders Working Group of the ERA-EDTA
Authors: Bacchetta Justine , Schmitt Claus Peter , Ariceta Gema , Bakkaloglu Sevcan A , Groothoff Jaap , Wan Mandy , Vervloet Marc , Shroff Rukshana , Haffner Dieter ,   European Society for Paediatric Nephrology and the Chronic Kidney Disease-Mineral and Bone Disorders and Dialysis Working Group of the ERA-EDTA
Published: July 2019

Abstract
Secondary hyperparathyroidism (SHPT) is an important complication of advanced chronic kidney disease (CKD) in children, which is often difficult to treat with conventional therapy. The calcimimetic cinacalcet is an allosteric modulator of the calcium-sensing receptor. It has proven to be effective and safe in adults to suppress parathyroid hormone (PTH), but data on its use in children are limited. To date, studies in children only consist of two randomized controlled trials, nine uncontrolled interventional or observational studies, and case reports that report the efficacy of cinacalcet as a PTH-lowering compound. In 2017, the European Medical Agency approved the use of cinacalcet for the treatment of SHPT in children on dialysis in whom SHPT is not adequately controlled with standard therapy. Since evidence-based guidelines are so far lacking, we present a position statement on the use of cinacalcet in paediatric dialysis patients based on the available evidence and opinion of experts from the European Society for Paediatric Nephrology, Chronic Kidney Disease-Mineral and Bone Disorder and Dialysis Working Groups, and the ERA-EDTA. Given the limited available evidence the strength of these statements are weak to moderate, and must be carefully considered by the treating physician and adapted to individual patient needs as appropriate. Audit and research recommendations to study key outcome measures in paediatric dialysis patients receiving cinacalcet are suggested.
Relationship between complement deposition and the Oxford classification score and their combined effects on renal outcome in immunoglobulin A nephropathy
Authors: Park Seohyun , Kim Hyung Woo , Park Jung Tak , Chang Tae Ik , Kang Ea Wha , Ryu Dong-Ryeol , Yoo Tae-Hyun , Chin Ho Jun , Jeong Hyeon Joo , Kang Shin-Wook , Lim Beom Jin , Han Seung Hyeok 
Published: July 2019

Abstract

Background
Complement activation has been highlighted in immunoglobulin (Ig) A nephropathy pathogenesis. However, whether the complement system can affect the downstream phenotype of IgA nephropathy remains unknown. Herein, we investigated the association of mesangial C3 deposition with the Oxford classification and their joint effects on worsening kidney function.

Methods
We investigated 453 patients with biopsy-proven IgA nephropathy. C3 deposition was defined as an immunofluorescence intensity of C3 ≥2+ within the mesangium. The subjects were classified according to the combination of C3 deposition and Oxford classification lesions. The primary endpoint was a composite of ≥30% decline in the estimated glomerular filtration rate or an increase in proteinuria ≥3.5 g/g during follow-up.

Results
Among the Oxford classification lesions, mesangial hypercellularity (M1), segmental glomerulosclerosis (S1) and tubulointerstitial fibrosis (T1–2) and crescentic lesion significantly correlated with C3 deposition. During a median follow-up of 33.0 months, the primary endpoint occurred more in patients with M1, S1, T1–2 and mesangial C3 deposition than in those without. In individual multivariable-adjusted Cox analyses, the presence of M1, S1, T1–2 and C3 deposition was significantly associated with higher risk of reaching primary endpoint. In the combined analyses of C3 deposition and the Oxford classification lesions, the hazard ratios for the composite outcome were significantly higher in the presence of C3/M1, C3/S1 and C3/crescent than in the presence of each lesion alone.

Conclusions
Complement deposition can strengthen the significance of the Oxford classification, and the presence of both components portends a poorer prognosis in IgA nephropathy.
Loss of sodium chloride co-transporter impairs the outgrowth of the renal distal convoluted tubule during renal development
Authors: Schnoz Christina , Carrel Monique , Loffing Johannes 
Published: July 2019

Abstract

Background
Loss-of-function mutations in the sodium chloride (NaCl) co-transporter (NCC) of the renal distal convoluted tubule (DCT) cause Gitelman syndrome with hypokalemic alkalosis, hypomagnesemia and hypocalciuria. Since Gitelman patients are usually diagnosed around adolescence, we tested the idea that a progressive regression of the DCT explains the late clinical onset of the syndrome.

Methods
NCC wild-type and knockout (ko) mice were studied at Days 1, 4 and 10 and 6 weeks after birth using blood plasma analysis and morphological and biochemical methods.

Results
Plasma aldosterone levels and renal renin messenger RNA expression were elevated in NCC ko mice during the first days of life. In contrast, plasma ion levels did not differ between genotypes at age 10 days, but a significant hypomagnesemia was observed in NCC ko mice at 6 weeks. Immunofluorescent detection of parvalbumin (an early DCT marker) revealed that the fractional cortical volume of the early DCT is similar for mice of both genotypes at Day 4, but is significantly lower at Day 10 and is almost zero at 6 weeks in NCC ko mice. The DCT atrophy correlates with a marked reduction in the abundance of the DCT-specific Mg2+ channel TRPM6 (transient receptor potential cation channel subfamily M member 6) and an increased proteolytic activation of the epithelial Na+ channel (ENaC).

Conclusion
After an initial outgrowth, DCT development lags behind in NCC ko mice. The impaired DCT development associates at Day 1 and Day 10 with elevated renal renin and plasma aldosterone levels and activation of ENaC, respectively, suggesting that Gitelman syndrome might be present much earlier in life than is usually expected. Despite an early downregulation of TRPM6, hypomagnesemia is a rather late symptom.
Efficacy of EGFR plus TNF inhibition in a preclinical model of temozolomide-resistant glioblastoma
Authors: Guo Gao , Gong Ke , Puliyappadamba Vineshkumar Thidil , Panchani Nishah , Pan Edward , Mukherjee Bipasha , Damanwalla Ziba , Bharia Sabrina , Hatanpaa Kimmo J , Gerber David E , Mickey Bruce E , Patel Toral R , Sarkaria Jann N , Zhao Dawen , Burma Sandeep , Habib Amyn A 
Published: July 2019

Abstract

Background
Glioblastoma (GBM) is the most common primary malignant adult brain tumor. Temozolomide (TMZ) is the standard of care and is most effective in GBMs that lack the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT). Moreover, even initially responsive tumors develop a secondary resistance to TMZ and become untreatable. Since aberrant epidermal growth factor receptor (EGFR) signaling is widespread in GBM, EGFR inhibition has been tried in multiple clinical trials without success. We recently reported that inhibiting EGFR leads to increased secretion of tumor necrosis factor (TNF) and activation of a survival pathway in GBM. Here, we compare the efficacy of TMZ versus EGFR plus TNF inhibition in an orthotopic mouse model of GBM.

Methods
We use an orthotopic model to examine the efficacy of TMZ versus EGFR plus TNF inhibition in multiple subsets of GBMs, including MGMT methylated and unmethylated primary GBMs, recurrent GBMs, and GBMs rendered experimentally resistant to TMZ.

Results
The efficacy of the 2 treatments was similar in MGMT methylated GBMs. However, in MGMT unmethylated GBMs, a combination of EGFR plus TNF inhibition was more effective. We demonstrate that the 2 treatment approaches target distinct and non-overlapping pathways. Thus, importantly, EGFR plus TNF inhibition remains effective in TMZ-resistant recurrent GBMs and in GBMs rendered experimentally resistant to TMZ.

Conclusion
EGFR inhibition combined with a blunting of the accompanying TNF-driven adaptive response could be a viable therapeutic approach in MGMT unmethylated and recurrent EGFR-expressing GBMs.
Molecular profiling of long-term IDH-wildtype glioblastoma survivors
Authors: Burgenske Danielle M , Yang Jie , Decker Paul A , Kollmeyer Thomas M , Kosel Matthew L , Mladek Ann C , Caron Alissa A , Vaubel Rachael A , Gupta Shiv K , Kitange Gaspar J , Sicotte Hugues , Youland Ryan S , Remonde Dioval , Voss Jesse S , Fritcher Emily G Barr , Kolsky Kathryn L , Ida Cristiane M , Meyer Fredric B , Lachance Daniel H , Parney Ian J , Kipp Benjamin R , Giannini Caterina , Sulman Erik P , Jenkins Robert B , Eckel-Passow Jeanette E , Sarkaria Jann N 
Published: July 2019

AbstractBackgroundGlioblastoma (GBM) represents an aggressive cancer type with a median survival of only 14 months. With fewer than 5% of patients surviving 5 years, comprehensive profiling of these rare patients could elucidate prognostic biomarkers that may confer better patient outcomes. We utilized multiple molecular approaches to characterize the largest patient cohort of isocitrate dehydrogenase (IDH)–wildtype GBM long-term survivors (LTS) to date.MethodsRetrospective analysis was performed on 49 archived formalin-fixed paraffin embedded tumor specimens from patients diagnosed with GBM at the Mayo Clinic between December 1995 and September 2013. These patient samples were subdivided into 2 groups based on survival (12 LTS, 37 short-term survivors [STS]) and subsequently examined by mutation sequencing, copy number analysis, methylation profiling, and gene expression.ResultsOf the 49 patients analyzed in this study, LTS were younger at diagnosis (P = 0.016), more likely to be female (P = 0.048), and MGMT promoter methylated (UniD, P = 0.01). IDH-wildtype STS and LTS demonstrated classic GBM mutations and copy number changes. Pathway analysis of differentially expressed genes showed LTS enrichment for sphingomyelin metabolism, which has been linked to decreased GBM growth, invasion, and angiogenesis. STS were enriched for DNA repair and cell cycle control networks.ConclusionsWhile our findings largely report remarkable similarity between these LTS and more typical STS, unique attributes were observed in regard to altered gene expression and pathway enrichment. These attributes may be valuable prognostic markers and are worth further examination. Importantly, this study also underscores the limitations of existing biomarkers and classification methods in predicting patient prognosis.
Cognitive and brain structural changes in long-term oligodendroglial tumor survivors
Authors: Cayuela Nuria , Jaramillo-Jiménez Esteban , Càmara Estela , Majós Carles , Vidal Noemi , Lucas Anna , Gil-Gil Miguel , Graus Francesc , Bruna Jordi , Simó Marta 
Published: July 2019

Abstract

Background
We identify cognitive impairment and MRI structural brain changes in long-term oligodendroglial tumor survivors treated with radiation therapy (RT) alone (21%) or with chemotherapy (CT) (79%).

Methods
Oligodendroglial tumor patients (based on the World Health Organization [WHO] 2007 classification) who completed RT ± CT at least 2 years before the study initiation, were classified into 3 groups according to the time treatment was completed: Group 1 = 2–5 years (n = 22), Group 2 = 6–10 years (n = 13), and Group 3 >10 years (n = 13). All patients had a cross-sectional neuropsychological evaluation (n = 48) and a longitudinal volumetric analysis (gray matter [GM; n = 34]) between postsurgical and last follow-up MRI. White matter (WM) changes on MRI were assessed using a qualitative scale.

Results
There were no differences regarding tumor or treatment-related characteristics between groups. Six of 22 patients (27.3%) in Group 1; 5/13 (38.5%) in Group 2; and 9/13 (69.2%) in Group 3 had cognitive impairment that was considered severe in 3/22 patients (13.6%) in Group 1; 4/13 (30.8%) in Group 2; and 6/13 (46.2%) in Group 3. Patients in Groups 2 and 3 showed significant GM atrophy and more leukoencephalopathy than Group 1. Cognitive deficits were associated with brain atrophy and WM changes.

Conclusions
Long-term oligodendroglial tumor survivors who underwent standard RT ± CT treatment, mainly >5 years of its completion, present cognitive impairment, especially on memory and executive functions, associated with late GM and WM damage, thus highlighting the need of developing future strategies in patients with oligodendroglial tumor and long expected survival.
Temporal muscle thickness is an independent prognostic marker in patients with progressive glioblastoma: translational imaging analysis of the EORTC 26101 trial
Authors: Furtner Julia , Genbrugge Els , Gorlia Thierry , Bendszus Martin , Nowosielski Martha , Golfinopoulos Vassilis , Weller Michael , van den Bent Martin J , Wick Wolfgang , Preusser Matthias 
Published: July 2019

AbstractBackgroundTemporal muscle thickness (TMT) was described as a surrogate marker of skeletal muscle mass. This study aimed to evaluate the prognostic relevance of TMT in patients with progressive glioblastoma.MethodsTMT was analyzed on cranial MR images of 596 patients with progression of glioblastoma after radiochemotherapy enrolled in the European Organisation for Research and Treatment of Cancer 26101 trial. An optimal TMT cutoff for overall survival (OS) and progression-free survival (PFS) was defined in the training cohort (n = 260, phase II). Patients were grouped as “below” or “above” the TMT cutoff and associations with OS and PFS were tested using the Cox model adjusted for important risk factors. Findings were validated in a test cohort (n = 308, phase III).ResultsAn optimal baseline TMT cutoff of 7.2 mm was obtained in the training cohort for both OS and PFS (area under the curve = 0.64). Univariate analyses estimated a hazard ratio (HR) of 0.54 (95% CI: 0.42, 0.70; P &lt; 0.0001) for OS and an HR of 0.49 (95% CI: 0.38, 0.64; P &lt; 0.0001) for PFS for the comparison of training cohort patients above versus below the TMT cutoff. Similar results were obtained in Cox models adjusted for important risk factors with relevance in the trial for OS (HR, 0.54; 95% CI: 0.41, 0.70; P &lt; 0.0001) and PFS (HR, 0.47; 95% CI: 0.36, 0.61; P &lt; 0.0001). Results were confirmed in the validation cohort.ConclusionReduced TMT is an independent negative prognostic parameter in patients with progressive glioblastoma and may help to facilitate patient management by supporting patient stratification for therapeutic interventions or clinical trials.
Gene regulatory network stabilized by pervasive weak repressions: microRNA functions revealed by the May–Wigner theory
Authors: Chen Yuxin , Shen Yang , Lin Pei , Tong Ding , Zhao Yixin , Allesina Stefano , Shen Xu , Wu Chung-I 
Published: July 2019

AbstractFood web and gene regulatory networks (GRNs) are large biological networks, both of which can be analyzed using the May–Wigner theory. According to the theory, networks as large as mammalian GRNs would require dedicated gene products for stabilization. We propose that microRNAs (miRNAs) are those products. More than 30% of genes are repressed by miRNAs, but most repressions are too weak to have a phenotypic consequence. The theory shows that (i) weak repressions cumulatively enhance the stability of GRNs, and (ii) broad and weak repressions confer greater stability than a few strong ones. Hence, the diffuse actions of miRNAs in mammalian cells appear to function mainly in stabilizing GRNs. The postulated link between mRNA repression and GRN stability can be seen in a different light in yeast, which do not have miRNAs. Yeast cells rely on non-specific RNA nucleases to strongly degrade mRNAs for GRN stability. The strategy is suited to GRNs of small and rapidly dividing yeast cells, but not the larger mammalian cells. In conclusion, the May–Wigner theory, supplanting the analysis of small motifs, provides a mathematical solution to GRN stability, thus linking miRNAs explicitly to ‘developmental canalization’.
Topological domain states and magnetoelectric properties in multiferroic nanostructures
Authors: Tian Guo , Yang Wenda , Chen Deyang , Fan Zhen , Hou Zhipeng , Alexe Marin , Gao Xingsen 
Published: July 2019

Abstract
Multiferroic nanostructures have been attracting tremendous attention over the past decade, due to their rich cross-coupling effects and prospective electronic applications. In particular, the emergence of some exotic phenomena in size-confined multiferroic systems, including topological domain states such as vortices, center domains, and skyrmion bubble domains, has opened a new avenue to a number of intriguing physical properties and functionalities, and thus underpins a wide range of applications in future nanoelectronic devices. It is also highly appreciated that nano-domain engineering provides a pathway to control the magnetoelectric properties, which is promising for future energy-efficient spintronic devices. In recent years, this field, still in its infancy, has witnessed a rapid development and a number of challenges too. In this article, we shall review the recent advances in the emergent domain-related exotic phenomena in multiferroic nanostructures. Specific attention is paid to the topological domain structures and related novel physical behaviors as well as the electric-field-driven magnetic switching via domain engineering. This review will end with a discussion of future challenges and potential directions.