bluuebunny/crossref_metadata_2025_split huggingface dataset:
Proteomics of broad deubiquitylase inhibition unmasks redundant enzyme function to reveal substrates
Authors: Rossio Valentina , Paulo Joao A. , Chick Joel , Brasher Bradley , Gygi Steven P. , King Randall W. 
Published: November 2019

AbstractDeubiquitylating enzymes (DUBs) counteract ubiquitylation to control stability or activity of substrates. Identification of DUB substrates is challenging because multiple DUBs act on the same substrates, thwarting genetic approaches. Here, we circumvented redundancy by broadly inhibiting DUBs inXenopusegg extract. DUB inhibition increases ubiquitylation of hundreds of proteins, depleting free ubiquitin without inducing widespread degradation. Restoring available ubiquitin led to proteasomal degradation of over thirty proteins, indicating that deubiquitylation is essential to maintain their stability. We confirmed their DUB-dependent stability with recombinant human proteins, demonstrating evolutionary conservation. We profiled the ability of DUBs to rescue protein stability, and found that USP7 has a unique ability to broadly antagonize proteasomal degradation. Together, we provide a comprehensive characterization of ubiquitin dynamics in theXenopussystem, identify new DUB substrates, and present a new approach to characterize physiological DUB specificity that overcomes challenges posed by DUB redundancy
Evaluation of Dose Fractionated Polymyxin B on Acute Kidney Injury: A Translational In Vivo Model
Authors: Liu Jiajun , Pais Gwendolyn M. , Avedissian Sean N. , Gilchrist Annette , Lee Andrew , Rhodes Nathaniel J. , Hauser Alan R. , Scheetz Marc H. 
Published: November 2019

AbstractThe polymyxins are last-line defense for highly resistant infections. Nephrotoxicity, however, is a dose-limiting factor. Yet, approaches to mitigate nephrotoxicity are poorly defined. This study aimed to investigate the impact of dose fractionated (once, twice and thrice daily) polymyxin B (PB) on acute kidney injury (AKI) in a pre-clinical model. Secondarily, we aimed to describe the pharmacokinetic (PK) profile of PB. Sprague-Dawley rats were assigned to experimental groups with different dosing intervals but constant total daily exposure (12 mg/kg/day into single, twice daily, and thrice daily doses) and controls received normal saline subcutaneously over 3 days. Blood and urine samples were collected, and kidneys were harvested at necropsy. A three-compartment model best described the data and Bayesian observed vs. predicted concentration demonstrated bias, imprecision, and R2 of 0.129 mg/L, 0.729 mg2/L2 and 0.652, respectively. PB exposure (i.e. AUC24h) were similar across treatment groups over time (p=0.87). As a representative, urinary KIM-1 were elevated on days 1 and 2 for experimental groups compared to controls, and thrice daily group experienced the most KIM-1 increase [mean increase (95% CI) day 1 from day −1, 4.44 (0.89, 8.00) ng/mL; p=0.018] as compared to control [mean increase (95% CI) day 1 from day −1, 0.03 (−0.42, 0.49) ng/mL; p=0.99]. Correspondingly, significant histopathological damage was observed with the same group (p=0.013) (controls as a referent). Our findings suggested that fractionating the PB dose thrice daily resulted in the most injury in a rat model.
Improvement of cryo-EM maps by density modification
Authors: Terwilliger Thomas C. , Ludtke Steven J. , Read Randy J. , Adams Paul D. , Afonine Pavel V. 
Published: November 2019

AbstractA density modification procedure for improving maps produced by single-particle electron cryo-microscopy is presented. The theoretical basis of the method is identical to that of maximum-likelihood density modification, previously used to improve maps from macromolecular X-ray crystallography. Two key differences from applications in crystallography are that the errors in Fourier coefficients are largely in the phases in crystallography but in both phases and amplitudes in electron cryo-microscopy, and that half-maps with independent errors are available in electron cryo-microscopy. These differences lead to a distinct approach for combination of information from starting maps with information obtained in the density modification process. The applicability of density modification theory to electron cryo-microscopy was evaluated using half-maps for apoferritin at a resolution of 3.1 Å and a matched 1.8 Å reference map. Error estimates for the map obtained by density modification were found to closely agree with true errors as estimated by comparison with the reference map. The density modification procedure was applied to a set of 104 datasets where half-maps, a full map and a model all had been deposited. The procedure improved map-model correlation and increased the visibility of details in the maps. The procedure requires two unmasked half-maps and a sequence file or other source of information on the volume of the macromolecule that has been imaged.
Real time structural search of the Protein Data Bank
Authors: Guzenko Dmytro , Burley Stephen K. , Duarte Jose M. 
Published: November 2019

AbstractDetection of protein structure similarity is a central challenge in structural bioinformatics. Comparisons are usually performed at the polypeptide chain level, however the functional form of a protein within the cell is often an oligomer. This fact, together with recent growth of oligomeric structures in the Protein Data Bank (PDB), demands more efficient approaches to oligomeric assembly alignment/retrieval. Traditional methods use atom level information, which can be complicated by the presence of topological permutations within a polypeptide chain and/or subunit rearrangements. These challenges can be overcome by comparing electron density volumes directly. But, brute force alignment of 3D data is a compute intensive search problem. We developed a 3D Zernike moment normalization procedure to orient electron density volumes and assess similarity with unprecedented speed. Similarity searching with this approach enables real-time retrieval of proteins/protein assemblies resembling a target, from PDB or user input, together with resulting alignments (http://shape.rcsb.org).Author SummaryProtein structures possess wildly varied shapes, but patterns at different levels are frequently reused by nature. Finding and classifying these similarities is fundamental to understand evolution. Given the continued growth in the number of known protein structures in the Protein Data Bank, the task of comparing them to find the common patterns is becoming increasingly complicated. This is especially true when considering complete protein assemblies with several polypeptide chains, where the large sizes further complicate the issue. Here we present a novel method that can detect similarity between protein shapes and that works equally fast for any size of proteins or assemblies. The method looks at proteins as volumes of density distribution, departing from what is more usual in the field: similarity assessment based on atomic coordinates and chain connectivity. A volumetric function is amenable to be decomposed with a mathematical tool known as 3D Zernike polynomials, resulting in a compact description as vectors of Zernike moments. The tool was introduced in the 1990s, when it was suggested that the moments could be normalized to be invariant to rotations without losing information. Here we demonstrate that in fact this normalization is possible and that it offers a much more accurate method for assessing similarity between shapes, when compared to previous attempts.
TheLegionella pneumophilametaeffector Lpg2505 (SusF) regulates SidI-mediated translation inhibition and GDP-dependent glycosyltransferase activity
Authors: Joseph Ashley M. , Pohl Adrienne E. , Ball Theodore J. , Abram Troy G. , Johnson David K. , Geisbrecht Brian V. , Shames Stephanie R. 
Published: November 2019

AbstractLegionella pneumophila, the etiological agent of Legionnaires Disease, employs an arsenal of hundreds of Dot/Icm-translocated effector proteins to facilitate replication within eukaryotic phagocytes. Several effectors, called metaeffectors, function regulate the activity of other Dot/Icm-translocated effectors during infection. The metaeffector Lpg2505 is essential forL. pneumophilaintracellular replication only when its cognate effector, SidI, is present. SidI is a cytotoxic effector that interacts with the host translation factor eEF1A and potently inhibits eukaryotic protein translation by an unknown mechanism. Here, we evaluated the impact of Lpg2505 on SidI-mediated phenotypes and investigated the mechanism of SidI function. We determined that Lpg2505 binds with nanomolar affinity to SidI and suppresses SidI-mediated inhibition of protein translation. SidI binding to eEF1A and SusF is not mutually exclusive and these proteins bind distinct regions of SidI. We also discovered that SidI possesses GDP-dependent glycosyltransferase activity and that this activity is regulated by Lpg2505. We have therefore renamed Lpg2505, SusF (suppressor ofSidI function). This work reveals novel enzymatic activity for SidI and provides insight into how intracellular replication ofL. pneumophilais regulated by a metaeffector.
Adult Muscle Stem Cell Self-Renewal Induced by Endurance Exercise is Mediated by Inhibition of Mitochondrial Oxygen Consumption
Authors: Abreu Phablo , Kowaltowski Alicia J. 
Published: November 2019

AbstractSkeletal muscle stem cells (satellite cells) are well known to participate in regeneration and maintenance of the tissue over time. Studies have shown increases in the number of satellite cells after exercise, but their functional role in endurance training remains unexplored. Here, we found that injured muscles from endurance-exercised mice display improved regenerative capacity, demonstrated through higher densities of newly formed myofibers compared to controls, as well as lower inflammation and fibrosis. Enhanced myogenic function was accompanied by an increased fraction of satellite cells expressing self-renewal markers. Control satellite cells had morphologies suggestive of early differentiation, while endurance exercise enhanced myogenic colony formation. The beneficial effects of endurance exercise were associated with satellite cell metabolic reprogramming, including reduced mitochondrial respiration (O2consumption) under resting conditions (absence of muscle injury) and increased stemness. During proliferation or activated states (three days after injury), O2consumption was equal in control and exercised cells. Surprisingly, inhibition of mitochondrial O2consumption was sufficient to enhance muscle stem cell self-renewal characteristicsin vitro. Moreover, transplanted muscle satellite cells from exercised mice or cells with reduced mitochondrial respiration promoted a significant reduction in inflammation compared to controls. We propose that endurance exercise promotes self-renewal and inhibits differentiation in satellite cells, an effect promoted by metabolic reprogramming and respiratory inhibition, and which is associated with a more favorable muscular response to injury.
Advantages of acute brain slices prepared at physiological temperature in characterization of synaptic functions
Authors: Eguchi Kohgaku , Velicky Philipp , Hollergschwandtner Elena , Itakura Makoto , Fukazawa Yugo , Danzl Johann Georg , Shigemoto Ryuichi 
Published: November 2019

AbstractAcute brain slice preparation is a powerful experimental model for investigating the characteristics of synaptic function in the brain. Although brain tissue is usually cut at ice-cold temperature (CT) to facilitate slicing and avoid neuronal damage, exposure to CT causes molecular and architectural changes of synapses. To address these issues, we investigated ultrastructural and electrophysiological features of synapses in mouse acute cerebellar slices prepared at ice-cold and physiological temperature (PT). In the slices prepared at CT, we found significant spine loss and reconstruction, synaptic vesicle rearrangement and decrease in synaptic proteins, all of which were not detected in slices prepared at PT. Consistent with these structural findings, slices prepared at PT showed higher release probability and higher detectability of long-term depression after motor learning compared with slices prepared at CT. These results indicate substantial advantages of the slice preparation at PT for investigating synaptic functions in different physiological conditions.
SparK: A Publication-quality NGS Visualization Tool
Authors: Kurtenbach Stefan , William Harbour J. 
Published: November 2019

AbstractWhile there are sophisticated resources available for displaying NGS data, including the Integrative Genomics Viewer (IGV) and the UCSC genome browser, exporting regions and assembling figures for publication remains challenging. In particular, customizing track appearance and overlaying track replicates is a manual and time-consuming process. Here, we present SparK, a tool which auto-generates publication-ready, high-resolution, true vector graphic figures from any NGS-based tracks, including RNA-seq, ChIP-seq, and ATAC-seq. Novel functions of SparK include averaging of replicates, plotting standard deviation tracks, and highlighting significantly changed areas. SparK is written in Python 3, making it executable on any major OS platform. Using command line prompts to generate figures allows later changes to be made very easy. For instance, if the genomic region of the plot needs to be changed, or tracks need to be added or removed, the figure can easily be re-generated within seconds without the manual process of re-exporting and re-assembling everything. After plotting with SparK, changes to the output SVG vector graphic files are simple to make, including text, lines, and colors. SparK is publicly available on GitHub: https://github.com/harbourlab/SparK.
Unsupervised domain adaptation for the automated segmentation of neuroanatomy in MRI: a deep learning approach
Authors: Novosad Philip , Fonov Vladimir , Collins D. Louis 
Published: November 2019

AbstractNeuroanatomical segmentation in T1-weighted magnetic resonance imaging of the brain is a prerequisite for quantitative morphological measurements, as well as an essential element in general pre-processing pipelines. While recent fully automated segmentation methods based on convolutional neural networks have shown great potential, these methods nonetheless suffer from severe performance degradation when there are mismatches between training (source) and testing (target) domains (e.g. due to different scanner acquisition protocols or due to anatomical differences in the respective populations under study). This work introduces a new method for unsupervised domain adaptation which improves performance in challenging cross-domain applications without requiring any additional annotations on the target domain. Using a previously validated state-of-the-art segmentation method based on a context-augmented convolutional neural network, we first demonstrate that networks with better domain generalizability can be trained using extensive data augmentation with label-preserving transformations which mimic differences between domains. Second, we incorporate unlabelled target domain samples into training using a self-ensembling approach, demonstrating further performance gains, and further diminishing the performance gap in comparison to fully-supervised training on the target domain.
A Mechanism for Beam-Induced Motion in Cryo-Electron Microscopy
Authors: Thorne Robert E. 
Published: November 2019

AbstractEstimates of heat transfer rates during plunge cooling and patterns of ice observed in cryo-EM samples indicate that the grid bars cool much more slowly than do the support foil and sample near the middle of the grid openings. The resulting transient temperature differences generate transient tensile stresses in the support foil. Most of this foil stress develops while the sample is liquid and cooling toward its glass transition Tg, and so does not generate tensile sample stress. As the grid bars continue cooling toward the cryogen temperature and contracting, the tensile stress in the foil is released, placing the sample in compressive stress. Radiation-induced creep in the presence of this compressive stress should generate a doming of the sample in the foil openings, as is observed experimentally. Crude estimates of the magnitude of doming that may be generated by this mechanism are consistent with observation. Several approaches to reducing beam-induced motion are discussed.
GLP-1R is downregulated in beta cells of NOD mice and T1D patients
Authors: Recino Asha , Barkan Kerry , Schmidt-Christensen Anja , Nilsson Julia , Holmes Nick , Howie Duncan , Holmberg Dan , Larsson Pär , Flodström-Tullberg Malin , Laraia Luca , Spring David R , Hecksher-Sørensen Jacob , Cooke Anne , Ladds Graham , Wållberg Maja 
Published: November 2019

AbstractGlucagon-like peptide 1 (GLP-1) is produced by L cells in the small intestine in response to ingested glucose and increases insulin release from pancreatic beta cells by activation of its cognate receptor (GLP-1R). Stimulation of this receptor also contributes to increased beta cell survival and regeneration. We have found that pancreatic beta cells from Non Obese Diabetic (NOD) mice express significantly lower levels of GLP-1R than C57BL/6 mice, leaving the NOD beta cells with an impaired response to GLP-1 stimulation. The lower expression appears to be caused by accelerated degradation of GLP-1R in the beta cells, a process that can be reversed by inhibiting trafficking to the lysosome. Importantly, our results appear to translate to the human disease since we also observed significantly lower expression of the GLP-1R in pancreatic islets from donors with type 1 diabetes. These results suggest that beta cell physiology may play a role in susceptibility to autoimmune inflammation.
Analysis of regulatory element evolution between human and mouse reveals a lack ofcis-transcompensation
Authors: Mattioli Kaia , Oliveros Winona , Gerhardinger Chiara , Andergassen Daniel , Maass Philipp G. , Rinn John L. , Melé Marta 
Published: November 2019

ABSTRACTGene expression differences between species are driven by bothcisandtranseffects. Whereasciseffects are caused by genetic variants in close proximity to the target gene,transeffects are due to distal genetic variants that affect diffusible elements such as transcription factors. Previous studies have mostly assessed the impact ofcisandtranseffects at the gene level. However, howcisandtranseffects differentially impact regulatory elements such as enhancers and promoters remains poorly understood. Here, we used massively parallel reporter assays to directly measurecisandtranseffects between human and mouse embryonic stem cells at thousands of individual regulatory elements. Our approach revealed thatciseffects are widespread across regulatory elements, and the strongestciseffects are associated with the disruption of motifs recognized by strong transcriptional activators. Conversely, we found thattranseffects are rare but stronger in enhancers than promoters, and can be attributed to a subset of transcription factors that are differentially expressed between human and mouse. While previous studies have found extensive co-occurrence ofcisandtranseffects in opposite directions that stabilize gene expression throughout evolution, we find thatcis-transcompensation is uncommon within individual regulatory elements. Thus, our results are consistent with a model wherein compensatorycis-transeffects at the gene level are explained bycisandtranseffects that separately impact several regulatory elements rather thancis-transeffects that occur simultaneously within a single regulatory element. Together, these results indicate that studying the evolution of individual regulatory elements is pivotal to understand the tempo and mode of gene expression evolution.
Human origin and migration deciphered from a novel genomic footprints of mitochondrial sequences
Authors: Mahapatra Aritra , Mukherjee Jayanta 
Published: November 2019

AbstractThe origin of modern human and their migration across the world is one of the most debated topics for the decades. There exist two different hypotheses, recent African origin and multi-regional evolution, based on the genomic studies, haplogroups, archaeological records, cultural behaviors, palaeontology studies, etc. Various studies placed the modern humans in a phylogenetic tree to depict the relationships among them. The debate for determining those regions of Africa which witnessed the first origin of humans still exists. The conflicts between the results obtained from the molecular data and the archaeological and palaeontological reports still exist. We adopt a novel genomic feature derived from the whole mitochondrial sequence, and using a novel distance function the phylogenetic trees are constructed based on the feature which provide a new insight on human migration. We propose a new method to derive the bootstrap replica from the genome sequences by considering the genetic variance to demonstrate the robustness of the obtained trees. The results derived from the genomic feature are more consistent with the archaeological findings based on the time of origin of different communities. We find that west and central African communities are placed at the basal point with a very high bootstrap score. This study roughly estimates the existence of the archaic human at 800-900 kilo years ago and presence of human in Africa at 600-700 kilo years ago. This supports the presence of an ancestor in the west and central Africa much earlier than that of the fossils identified.
Trend and pattern of economic and financial crimes statutes in Nigeria
Authors: Aigbovo Osaretin 
Published: November 2019

Purpose
The purpose of this paper is to examine the general direction and pattern of modern economic and financial crimes statutes in Nigeria.

Design/methodology/approach
This paper examines Nigerian economic and financial crime statues.

Findings
This paper identifies the trend and features, which are common to all the statutes irrespective of economic and financial crime covered by them.

Originality/value
This paper shows that although Nigerian economic and financial crimes statutes have evolved gradually from Military era Decrees, and target different aspects of economic and financial crimes, there are certain features, which are common to all of them.