bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of Surgical Treatment for Recurrence After 2-Stage Hepatectomy for Colorectal Liver Metastases, on Patient Outcome
Authors: Imai Katsunori , Benitez Carlos Castro , Allard Marc-Antoine , Vibert Eric , Cunha Antonio Sa , Cherqui Daniel , Castaing Denis , Bismuth Henri , Baba Hideo , Adam René 
Published: August 2017

Objective:
To evaluate the impact of repeat surgery for recurrence on the long-term survival after 2-stage hepatectomy (TSH) for extensive colorectal liver metastases (CRLM).

Background:
Although TSH is now deemed effective for selected patients with extensive bilobar CRLM, disease recurrence after TSH is very frequent because of the extensive tumor load.

Methods:
Among a total cohort of 1235 patients who underwent hepatectomy for CRLM between 1992 and 2012, 139 with extensive bilobar CRLM were scheduled for TSH. Of these, 93 patients had completion of TSH and were enrolled in this study.

Results:
The 5-year overall survival (OS) rate after TSH was 41.3%. Twenty-two patients (23.7%) had a concomitant extrahepatic disease (EHD), and curative resection of concomitant EHD was achieved in 13 patients. Among the 81 patients who achieved complete tumor removal for primary, CRLM, and concomitant EHD, 62 (76.5%) had recurrence. Repeat surgery was performed in 38 patients; 35 for recurrence after curative surgery and 3 for liver recurrence with unresected concomitant EHD or primary tumor. Of these 38 patients, 31 were salvaged. The patients who underwent repeat surgery had a significantly longer OS than those who did not (45.8% vs 26.3%; P = 0.0041). A multivariate analysis revealed that repeat surgery was an independent prognostic factor of the OS after TSH (hazard ratio 0.31, P = 0.0012).

Conclusions:
Repeat surgery for recurrence after TSH may be crucial for the long-term survival in patients with extensive bilobar CRLM. Intensive oncosurgical surveillance is essential to avoid missing the chance for repeat surgery after TSH.
A Comparative Study of the Predictive Values of Urinary Acute Kidney Injury Markers Angiogenin and Kidney Injury Molecule 1 for the Outcomes of Kidney Allografts
Authors: Tavernier Quentin , Tinel Claire , Rabant Marion , Morin Lise , Anglicheau Dany , Pallet Nicolas 
Published: August 2017

Background
Whether injury-related molecules in urines of individuals with ischemia-reperfusion injury (IRI) are independent predictors of graft outcomes and provide additional information compared with usual risk factors remains to be established.

Methods
We explored a cohort of 244 kidney transplant recipients who systematically had a urine collection 10 days after transplantation. The injury-related markers kidney injury molecule-1 (KIM-1) and angiogenin (ANG) levels in urines were measured. We determined the prognostic values of these markers on graft outcomes.

Results
Urinary KIM-1 and ANG concentrations were strongly correlated to each other and were significantly and independently associated with cold ischemia time, delayed graft function, and plasma creatinine 10 days after transplantation, indicating that these markers reflect the severity of IRI. However, urinary ANG and KIM-1 were not predictive of histological changes on protocol biopsies performed 3 and 12 months after transplantation. Finally, urinary ANG and urinary KIM-1 were not associated with graft survival.

Conclusions
Together, our results indicate that, in a cohort of 244 kidney transplant recipients, urinary ANG and KIM-1 levels in a single measurement 10 days after transplantation reflect the severity of IRI after kidney transplantation, but are neither independent predictors of renal function, histological changes and graft survival.
Frequent lack of repressive capacity of promoter DNA methylation identified through genome-wide epigenomic manipulation
Authors: Ford Ethan , Grimmer Matthew R. , Stolzenburg Sabine , Bogdanovic Ozren , Mendoza Alex de , Farnham Peggy J. , Blancafort Pilar , Lister Ryan 
Published: August 2017

AbstractIt is widely assumed that the addition of DNA methylation at CpG rich gene promoters silences gene transcription. However, this conclusion is largely drawn from the observation that promoter DNA methylation inversely correlates with gene expression in natural conditions. The effect of induced DNA methylation on endogenous promoters has yet to be comprehensively assessed. Here, we induced the simultaneous methylation of thousands of promoters in the genome of human cells using an engineered zinc finger-DNMT3A fusion protein, enabling assessment of the effect of forced DNA methylation upon transcription, histone modifications, and DNA methylation persistence after the removal of the fusion protein. We find that DNA methylation is frequently insufficient to transcriptionally repress promoters. Furthermore, DNA methylation deposited at promoter regions associated with H3K4me3 is rapidly erased after removal of the zinc finger-DNMT3A fusion protein. Finally, we demonstrate that induced DNA methylation can exist simultaneously on promoter nucleosomes that possess the active histone modification H3K4me3, or DNA bound by the initiated form of RNA polymerase II. These findings suggest that promoter DNA methylation is not generally sufficient for transcriptional inactivation, with implications for the emerging field of epigenome engineering.One Sentence SummaryGenome-wide epigenomic manipulation of thousands of human promoters reveals that induced promoter DNA methylation is unstable and frequently does not function as a primary instructive biochemical signal for gene silencing and chromatin reconfiguration.
Conformational states during vinculin unlocking differentially regulate focal adhesion properties
Authors: Chorev Dror S. , Volberg Tova , Livne Ariel , Eisenstein Miriam , Martins Bruno , Kam Zvi , Jockusch Brigitte M. , Medalia Ohad , Sharon Michal , Geiger Benny 
Published: August 2017

AbstractFocal adhesions (FAs) are multi-protein complexes that connect the actin cytoskeleton to the extracellular matrix, via integrin receptors. The growth, stability and adhesive functionality of these structures are tightly regulated by mechanical stress, yet, despite the extensive characterization of the integrin adhesome, the mechanisms underlying FA mechanosensitivity are still poorly understood. One of the key candidates for regulating FA-associated mechanosensing is vinculin, a prominent FA component, which was proposed to possess either closed (“auto-inhibited”) or open (active) conformations. However, a direct demonstration of the nature of conformational transition between the two states is still absent. In this study we combined multiple structural and biological approaches to probe the transition from auto-inhibited to active conformation, and determine its effects on FA structure and dynamics. We further show here that the closed to open transition requires two sequential steps that can differentially regulate FA growth and stability.
A shift in aggregation avoidance strategy marks a long-term direction to protein evolution
Authors: Foy S.G. , Wilson B.A. , Bertram J. , Cordes M.H.J. , Masel J. 
Published: August 2017

AbstractTo detect a direction to evolution, without the pitfalls of reconstructing ancestral states, we need to compare “more evolved” to “less evolved” entities. But because all extant species have the same common ancestor, none are chronologically more evolved than any other. However, different gene families were born at different times, allowing us to compare young protein-coding genes to those that are older and hence have been evolving for longer. To be retained during evolution, a protein must not only have a function, but must also avoid toxic dysfunction such as protein aggregation. There is conflict between the two requirements; hydrophobic amino acids form the cores of protein folds, but also promote aggregation. Young genes avoid strongly hydrophobic amino acids, which is presumably the simplest solution to the aggregation problem. Here we show that young genes’ few hydrophobic residues are clustered near one another along the primary sequence, presumably to assist folding. The higher aggregation risk created by the higher hydrophobicity of older genes is counteracted by more subtle effects in the ordering of the amino acids, including a reduction in the clustering of hydrophobic residues until they eventually become more interspersed than if distributed randomly. This interspersion has previously been reported to be a general property of proteins, but here we find that it is restricted to old genes. Quantitatively, the index of dispersion delineates a gradual trend, i.e. a decrease in the clustering of hydrophobic amino acids over billions of years.
N6-Methyladenine DNA Modification in Human Genome
Authors: Xiao Chuan-Le , Zhu Song , He Minghui , Chen De , Zhang Qian , Chen Ying , Yu Guoliang , Liu Jinbao , Xie Shang-Qian , Luo Feng , Liang Zhe , Wang De-Peng , Bo Xiao-Chen , Gu Xiao-Feng , Wang Kai , Yan Guang-Rong 
Published: August 2017

SummaryDNA N6-methyladenine (6mA) modification is the most prevalent DNA modification in prokaryotes, but whether it exists in human cells and whether it plays a role in human diseases remain enigmatic. Here, we showed that 6mA is extensively present in human genome, and we cataloged 881,240 6mA sites accounting for ∼0.051% of the total adenines. [G/C]AGG[C/T] was the most significantly associated motif with 6mA modification. 6mA sites were enriched in the coding regions and mark actively transcribed genes in human cells. We further found that DNA N6-methyladenine and N6-demethyladenine modification in human genome were mediated by methyltransferase N6AMT1 and demethylase ALKBH1, respectively. The abundance of 6mA was significantly lower in cancers, accompaning with decreased N6AMT1 and increased ALKBH1 levels, and down-regulation of 6mA modification levels promoted tumorigenesis. Collectively, our results demonstrate that DNA 6mA modification is extensively present in human cells and the decrease of genomic DNA 6mA promotes human tumorigenesis.
Variable dose analysis: A novel RNAi-based method for detection of synthetic lethal interactions
Authors: Housden Benjamin E. , Li Zhongchi , Kelley Colleen , Wang Yuanli , Hu Yanhui , Valvezan Alexander J. , Manning Brendan D. , Perrimon Norbert 
Published: August 2017

AbstractSynthetic sick or synthetic lethal (SS/L) screens are a powerful way to identify candidate drug targets to specifically kill tumor cells but such screens generally suffer from low reproducibility. We found that many SS/L interactions involve essential genes and are therefore detectable within a limited range of knockdown efficiency. Such interactions are often missed by overly efficient RNAi reagents. We therefore developed an assay that measures viability over a range of knockdown efficiency within a cell population. This method, called variable dose analysis (VDA), is highly sensitive to viability phenotypes and reproducibly detects SS/L interactions. We applied the VDA method to search for SS/L interactions withTSC1andTSC2, the two tumor suppressors underlying tuberous sclerosis complex (TSC) and generated a SS/L network for TSC. Using this network, we identified four FDA-approved drugs that selectively affect viability of TSC deficient cells, representing promising candidates for repurposing to treat TSC-related tumors.
Sex-Biased Gene Expression Resolves Sexual Conflict through the Evolution of Sex-Specific Genetic Architecture
Authors: Wright Alison E. , Fumagalli Matteo , Cooney Christopher R. , Bloch Natasha I. , Vieira Filipe G. , Buechel Severine D. , Kolm Niclas , Mank Judith E. 
Published: August 2017

ABSTRACTMany genes are subject to contradictory selection pressures in males and females, and balancing selection resulting from sexual conflict has the potential to substantially increase standing genetic diversity in populations and thereby act as an important force in adaptation. However, the underlying causes of sexual conflict, and the potential for resolution, remains hotly debated. Using transcriptome resequencing data from male and female guppies, we use a novel approach, combining patterns of genetic diversity and inter-sexual divergence in allele frequency, to distinguish the different scenarios that give rise to sexual conflict, and how this conflict may be resolved through regulatory evolution. We show that reproductive fitness is the main source of sexual conflict, and this is resolved via the evolution of male-biased expression. Furthermore, resolution of sexual conflict produces significant differences in genetic architecture between males and females, which in turn leads to specific alleles influencing sex-specific viability. Together, our findings suggest an important role for sexual conflict in shaping broad patterns of genome diversity, and show that regulatory evolution is a rapid and efficient route to the resolution of conflict.
Small Molecules Attenuate the Interplay between Conformational Fluctuations, Early Oligomerization and Amyloidosis of Alpha Synuclein
Authors: Kundu Amrita , Ghosh Sumanta , Chattopadhyay Krishnananda 
Published: August 2017

AbstractAggregation of alpha synuclein has strong implications in Parkinson’s disease. The heterogeneity of folding/aggregation landscape and transient nature of the early intermediates result in difficulty in developing a successful therapeutic intervention. Here we used fluorescence measurements at ensemble and single molecule resolution to study how the late and early events of alpha synuclein aggregation modulate each other. The in-vitro aggregation data was complemented using measurements inside live neuroblastoma cells by employing a small molecule labeling technique. An inhibitor molecule (arginine), which delayed the late event of amyloidosis, was found to bind to the protein, shifting the early conformational fluctuations towards a compact state. In contrast, a facilitator of late aggregation (glutamate), was found to be excluded from the protein surface. The presence of glutamate was found to speed up the oligomer formation at the early stage. We found that the effects of the inhibitor and facilitator were additive and as a result they maintained a ratio at which they cancelled each other’s influence on different stages of alpha synuclein aggregation.
Hydrogen peroxide formation by Nox4 limits malignant transformation
Authors: Helfinger Valeska , von Gall Florian Freiherr , Henke Nina , Kunze Michael M. , Schmid Tobias , Heidler Juliana , Wittig Ilka , Radeke Heinfried H. , Marschall Viola , Anderson Karen , Shah Ajay M. , Fulda Simone , Brüne Bernhard , Brandes Ralf P. , Schröder Katrin 
Published: August 2017

AbstractReactive oxygen species (ROS) can cause cellular damage and are thought to promote cancer-development. Nevertheless, under physiological conditions, all cells constantly produce ROS, either as chemical by-products or for signaling purpose. During differentiation cells induce the NADPH oxidase Nox4, which constitutively produces low amounts of H2O2. We infer that this constitutive H2O2is unlikely to be carcinogenic and may rather maintain basal activity of cellular surveillance systems.Utilizing two different murine tumor models we demonstrate that Nox4 prevents malignant transformation and facilitated the recognition of DNA-damage. Upon DNA-damage repair is initiated as consequence of phosphorylation of H2AX (γH2AX). Repair only occurs if nuclear activity of the γH2AX-dephosphorylating phosphatase PP2A is kept sufficiently low, a task fulfilled by Nox4: Nox4 continuously oxidizes AKT, and once oxidized AKT captures PP2A in the cytosol. Absence of Nox4 facilitates nuclear PP2A translocation and dephosphorylation of γH2AX. Simultaneously the proportion of active, phosphorylated AKT is increased. Thus, DNA-damage is not recognized and the increase in AKT activity promotes proliferation. The combination of both events resulted in genomic instability and tumor initiation.With the identification of the first cancer-protective source of reactive oxygen species, Nox4, the paradigm of reactive-oxygen species-induced initiation of malignancies should be revised.SignificanceThe stereotype of ROS produced by NADPH oxidases as cause of malignant diseases persists generalized since decades. We demonstrate that the NADPH oxidase Nox4, as constitutive source of ROS, prevents malignant transformation and that its pharmacological inhibition as currently aspired by several companies will potentially increase the risk of malignant cell transformation and eventually tumor formation.PrecisBy oxidizing AKT and keeping PP2A in the cytosol, the NADPH oxidase Nox4 allows proper DNA damage repair and averts cancer development.
PTE, a novel module to target Polycomb Repressive Complex 1 to theCyclin D2oncogene
Authors: Cameron Sarina R. , Nandi Soumyadeep , Kahn Tatyana G. , Barrasa Juan I. , Stenberg Per , Schwartz Yuri B. 
Published: August 2017

AbstractPolycomb Group proteins are essential epigenetic repressors. They form multiple protein complexes of which two kinds, PRC1 and PRC2, are indispensable for repression. Although much is known about their biochemical properties, how PRC1 and PRC2 are targeted to specific genes is poorly understood. Here we establish theCyclin D2(CCND2) oncogene as a simple model to address this question. We provide the evidence that coordinated recruitment of PRC1 and PRC2 complexes toCCND2involves a combination of a specialized PRC1 targeting element (PTE) and an adjacent CpG-island, which together act as a human Polycomb Response Element. Chromatin immunoprecipitation analysis ofCCND2in different transcriptional states indicates that histone modifications produced by PRC1 and PRC2 are not sufficient to recruit either of the complexes. However, catalytic activity of PRC2 helps to anchor PRC1 at the PTE. Our analyses suggest that coordinated targeting of PRC1 and PRC2 complexes by juxtaposed AT-rich PTEs and CpG-islands may be a general feature of Polycomb repression in mammals.
Simulating extracted connectomes
Authors: Gornet Jonathan , Scheffer Louis K. 
Published: August 2017

Connectomes derived from volume EM imaging of the brain can generate detailed physical models of every neuron, and simulators such as NEURON or GENESIS are designed to work with such models. In principal, combining these technologies, plus transmitter and channel models, should allow detailed and accurate simulation of real neural circuits. Here we experiment with this combination, using a well-studied system (motion detection inDrosophila). Since simulation requires both the physical geometry (which we have) and the models of the synapses (which are not currently available), we built approximate synapses corresponding to their known and estimated function. Once we did so, we reproduced direction selectivity in T4 cells, one of the main functions of this neural circuit. This verified the basic functionality of both extraction and simulations, and provided a biologically relevant computation we could use in further experiments. We then compared models with different degrees of physical realism, from full detailed models down to models consisting of a single node, to examine the tradeoff of simulation resources required versus accuracy achieved.Our results show that much simpler models may be adequate, at least in the case of medulla neurons inDrosophila. Such models can be easily derived from fully detailed models, and result in simulations that are much smaller, much faster, and accurate enough for many purposes. Biologically, we show that a lumped neuron model reproduces the main motion detector operation, confirming the result of Gruntman[1], that dendritic compution is not required for this function.
Gradual Cerebral Hypoperfusion Impair Fear Conditioning and Object Recognition Learning and Memory in Mice: Potential Roles of Neurodegeneration and Cholinergic Dysfunction
Authors: Mehla Jogender , Lacoursiere Sean , Stuart Emily , McDonald Robert J. , Mohajerani Majid H. 
Published: August 2017

AbstractIn the present study, male C57BL/6J mice were subjected to gradual cerebral hypoperfusion by implanting an ameroid constrictor (AC) on the left common carotid artery (CCA) and a stenosis on the right CCA. In the sham group, all surgical procedures were kept the same except no AC was implanted and stenosis was not performed. One month following the surgical procedures, fear conditioning and object recognition tests were conducted to evaluate learning and memory functions and motor functions were assessed using a balance beam test. At the experimental endpoint, mice were perfused and brains were collected for immunostaining and histology. Learning and memory as well as motor functions were significantly impaired in the hypoperfusion group. The immunoreactivity to choline acetyltransferase was decreased in dorsal striatum and basal forebrain of the hypoperfusion group indicating that cholinergic tone in these brain regions was compromised. In addition, an increased number of Fluoro-Jade positive neurons was also found in cerebral cortex, dorsal striatum and hippocampus indicating neurodegeneration in these brain regions. Based on this pattern of data, we argued that this mouse model would be a useful tool to investigate the therapeutic interventions for the treatment of vascular dementia. Additionally, this model could be employed to exploit the effect of microvascular occlusions on cognitive impairment in the absence and presence of Alzheimer pathology.
The Oyster River Protocol: A Multi Assembler and Kmer Approach Forde novoTranscriptome Assembly
Authors: MacManes Matthew D. 
Published: August 2017

AbstractCharacterizing transcriptomes in non-model organisms has resulted in a massive increase in our understanding of biological phenomena. This boon, largely made possible via high-throughput sequencing, means that studies of functional, evolutionary and population genomics are now being done by hundreds or even thousands of labs around the world. For many, these studies begin with ade novotranscriptome assembly, which is a technically complicated process involving several discrete steps. The Oyster River Protocol (ORP), described here, implements a standardized and benchmarked set of bioinformatic processes, resulting in an assembly with enhanced qualities over other standard assembly methods. Specifically, ORP produced assemblies have higherDetonateandTransRatescores and mapping rates, which is largely a product of the fact that it leverages a multi-assembler and kmer assembly process, thereby bypassing the shortcomings of any one approach. These improvements are important, as previously unassembled transcripts are included in ORP assemblies, resulting in a significant enhancement of the power of downstream analysis. Further, as part of this study, I show that assembly quality is unrelated with the number of reads generated, above 30 million reads.Code Availability:The version controlled open-source code is available athttps://github.com/macmanes-lab/Oyster_River_Protocol. Instructions for software installation and use, and other details are available athttp://oyster-river-protocol.rtfd.org/.