bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of an Optimal Cut-off for Drain Fluid Amylase on Postoperative Day 1 for Predicting Clinically Relevant Fistula After Distal Pancreatectomy
Authors: Maggino Laura , Malleo Giuseppe , Bassi Claudio , Allegrini Valentina , Beane Joal D. , Beckman Ross M. , Chen Bofeng , Dickson Euan J. , Drebin Jeffrey A. , Ecker Brett L. , Fraker Douglas L. , House Michael G. , Jamieson Nigel B. , Javed Ammar A. , Kowalsky Stacy J. , Lee Major K. , McMillan Matthew T. , Roses Robert E. , Salvia Roberto , Valero Vicente , Velu Lavanniya K. P. , Wolfgang Christopher L. , Zureikat Amer H. , Vollmer Charles M. 
Published: September 2017

Objective:
The aim of this study was to investigate the relationship between drain fluid amylase value on the first postoperative day (DFA1) and clinically relevant fistula (CR-POPF) after distal pancreatectomy (DP), and to identify the cut-off of DFA1 that optimizes CR-POPF prediction.

Background:
DFA1 is a well-recognized predictor of CR-POPF after pancreatoduodenectomy, but its role in DP is largely unexplored.

Methods:
DFA1 levels were correlated with CR-POPF in 2 independent multi-institutional sets of DP patients: developmental (n = 338; years 2012 to 2017) and validation cohort (n = 166; years 2006 to 2016). Cut-off choice was based on Youden index calculation, and its ability to predict CR-POPF occurrence was tested in a multivariable regression model adjusted for clinical, demographic, operative, and pathological variables.

Results:
In the developmental set, median DFA1 was 1745 U/L and the CR-POPF rate was 21.9%. DFA1 correlated with CR-POPF with an area under the curve of 0.737 (P < 0.001). A DFA1 of 2000 U/L had the highest Youden index, with 74.3% sensitivity and 62.1% specificity. Patients in the validation cohort displayed different demographic and operative characteristics, lower values of DFA1 (784.5 U/L, P < 0.001), and reduced CR-POPF rate (10.2%, P < 0.001). However, a DFA1 of 2000 U/L had the highest Youden index in this cohort as well, with 64.7% sensitivity and 75.8% specificity. At multivariable analysis, DFA1 ≥2000 U/L was the only factor significantly associated with CR-POPF in both cohorts.

Conclusion:
A DFA1 of 2000 U/L optimizes CR-POPF prediction after DP. These results provide the substrate to define best practices and improve outcomes for patients receiving DP.
A molecular model of the mitochondrial genome segregation machinery inTrypanosoma brucei
Authors: Hoffmann Anneliese , Käser Sandro , Jakob Martin , Amodeo Simona , Peitsch Camille , Týč Jiří , Vaughan Sue , Zuber Benoît , Schneider André , Ochsenreiter Torsten 
Published: September 2017

AbstractIn almost all eukaryotes mitochondria maintain their own genome. Despite the discovery more than 50 years ago still very little is known about how the genome is properly segregated during cell division. The protozoan parasiteTrypanosoma bruceicontains a single mitochondrion with a singular genome the kinetoplast DNA (kDNA). Electron microscopy studies revealed the tripartite attachment complex (TAC) to physically connect the kDNA to the basal body of the flagellum and to ensure proper segregation of the mitochondrial genome via the basal bodies movement, during cell cycle. Using super-resolution microscopy we precisely localize each of the currently known unique TAC components. We demonstrate that the TAC is assembled in a hierarchical order from the base of the flagellum towards the mitochondrial genome and that the assembly is not dependent on the kDNA itself. Based on biochemical analysis the TAC consists of several non-overlapping subcomplexes suggesting an overall size of the TAC exceeding 2.8 mDa. We furthermore demonstrate that the TAC has an impact on mitochondrial organelle positioning however is not required for proper organelle biogenesis or segregation.Significance StatementMitochondrial genome replication and segregation are essential processes in most eukaryotic cells. While replication has been studied in some detail much less is known about the molecular machinery required distribute the replicated genomes. Using super-resolution microscopy in combination with molecular biology and biochemistry we show for the first time in which order the segregation machinery is assembled and that it is assembledde novorather than in a semi conservative fashion in the single celled parasiteTrypanosoma brucei. Furthermore, we demonstrate that the mitochondrial genome itself is not required for assembly to occur. It seems that the physical connection of the mitochondrial genome to cytoskeletal elements is a conserved feature in most eukaryotes, however the molecular components are highly diverse.Abbreviation(EZF)Exclusion zone filaments(ULF)Unilateral filament(TAC)tripartite attachment complex(OM)outer mitochondrial(IM)inner mitochondrial(BSF)bloodstream form(PCF)procyclic form(kDNA)kinetoplast DNA(gRNA)guide RNA(SBFSEM)Serial block face-scanning electron microscopy(Tet)tetracyclin(STED)Stimulated Emission Depletion
Pharmacodynamic Considerations of Collateral Sensitivity in Design of Antibiotic Treatment Regimen
Authors: Udekwu Klas I. , Weiss Howie 
Published: September 2017

ABSTRACTAntibiotics have greatly reduced the morbidity and mortality due to infectious diseases. Although antibiotic resistance is not a new problem, its breadth now constitutes a significant threat to human health. One strategy to help combat resistance is to find novel ways to use existing drugs, even those that display high rates of resistance. For the pathogensEscherichia coliandPseudomonas aeruginosa, pairs of antibiotics have been identified for which evolution of resistance to drug A increases sensitivity to drug B and vice versa. These research groups have proposed cycling such pairs to treat infections, similar treatment strategies are being investigated for various cancer forms as well.While an exciting treatment prospect, no cycling experiments have yet been performed with consideration of pharmacokinetics (PK) and pharmacodynamics (PD). To test the plausibility of this scheme and search for ways to optimize it, we create a mathematical model with explicit PK-PD considerations. We study several possible treatment protocols using pairs of such antibiotics, and investigate the speed of ascent of multiply resistant mutants. Our analyses show that for low concentrations of antibiotics, treatment failure will always occur due to the rapid ascent and fixation of resistant mutants. However, at moderate to high concentrations of some types of bacteriostatic antibiotics with multiday cycling, resistance is prevented from developing and treatment succeeds. This calls for guarded optimism of such treatment protocols whose development can be directed by these types of models.
The whole-genome panorama of cancer drivers
Authors: Sabarinathan Radhakrishnan , Pich Oriol , Martincorena Iñigo , Rubio-Perez Carlota , Juul Malene , Wala Jeremiah , Schumacher Steven , Shapira Ofer , Sidiropoulos Nikos , Waszak Sebastian M. , Tamborero David , Mularoni Loris , Rheinbay Esther , Hornshøj Henrik , Deu-Pons Jordi , Muiños Ferran , Bertl Johanna , Guo Qianyun , Creighton Chad J. , Weischenfeldt Joachim , Korbel Jan O. , Getz Gad , Campbell Peter J. , Pedersen Jakob S. , Beroukhim Rameen , Gonzalez-Perez Abel , López-Bigas Núria ,   on behalf of the PCAWG Drivers and Functional Interpretation Group and the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Network
Published: September 2017

SUMMARYThe advance of personalized cancer medicine requires the accurate identification of the mutations driving each patient’s tumor. However, to date, we have only been able to obtain partial insights into the contribution of genomic events to tumor development. Here, we design a comprehensive approach to identify the driver mutations in each patient’s tumor and obtain a whole-genome panorama of driver events across more than 2,500 tumors from 37 types of cancer. This panorama includes coding and non-coding point mutations, copy number alterations and other genomic rearrangements of somatic origin, and potentially predisposing germline variants. We demonstrate that genomic events are at the root of virtually all tumors, with each carrying on average 4.6 driver events. Most individual tumors harbor a unique combination of drivers, and we uncover the most frequent co-occurring driver events. Half of all cancer genes are affected by several types of driver mutations. In summary, the panorama described here provides answers to fundamental questions in cancer genomics and bridges the gap between cancer genomics and personalized cancer medicine.
Forecasting biodiversity in breeding birds using best practices
Authors: Harris David J. , Taylor Shawn D. , White Ethan P 
Published: September 2017

AbstractBiodiversity forecasts are important for conservation, management, and evaluating how well current models characterize natural systems. While the number of forecasts for biodiversity is increasing, there is little information available on how well these forecasts work. Most biodiversity forecasts are not evaluated to determine how well they predict future diversity, fail to account for uncertainty, and do not use time-series data that captures the actual dynamics being studied. We addressed these limitations by using best practices to explore our ability to forecast the species richness of breeding birds in North America. We used hindcasting to evaluate six different modeling approaches for predicting richness. Hindcasts for each method were evaluated annually for a decade at 1,237 sites distributed throughout the continental United States. All models explained more than 50% of the variance in richness, but none of them consistently outperformed a baseline model that predicted constant richness at each site. The best practices implemented in this study directly influenced the forecasts and evaluations. Stacked species distribution models and “naive” forecasts produced poor estimates of uncertainty and accounting for this resulted in these models dropping in the relative performance compared to other models. Accounting for observer effects improved model performance overall, but also changed the rank ordering of models because it did not improve the accuracy of the “naive” model. Considering the forecast horizon revealed that the prediction accuracy decreased across all models as the time horizon of the forecast increased. To facilitate the rapid improvement of biodiversity forecasts, we emphasize the value of specific best practices in making forecasts and evaluating forecasting methods.
Competing effects of indirect protection and clustering on the power of cluster-randomized controlled vaccine trials
Authors: Hitchings Matt D.T. , Lipsitch Marc , Wang Rui , Bellan Steven E. 
Published: September 2017

AbstractPower considerations for trials evaluating vaccines against infectious diseases are complicated by indirect protective effects of vaccination. While cluster-randomized trials (cRCTs) are less statistically efficient than individually randomized trials (iRCT), a cRCT’s ability to measure direct and indirect vaccine effects may mitigate the loss of efficiency due to clustering. Within cRCTs, the number and size of clusters affects three determinants of power: the effect size being measured, disease incidence, and intra-cluster correlation. We simulate trials conducted in a collection of small communities to assess how indirect protection and clustering affect the power of cRCTs and iRCTs during an emerging epidemic. Across diverse parameters, we find that within the same trial population, cRCTs are never more powerful than iRCTs, although the difference can be small. We also identify two effects that attenuate the loss of cRCT power traditionally associated with increased cluster size. First, if enrollment of fewer, larger clusters is performed to achieve higher vaccine coverage within vaccinated communities, this increases the effect to be measured and, consequently, power. Second, the greater rate of imported transmission in larger communities may increase the attack rate and similarly mitigate loss of power relative to a trial in many, smaller communities.
High Peak Density Artifacts in Fourier Transform Mass Spectra and their Effects on Data Analysis
Authors: Mitchell Joshua M. , Flight Robert M. , Wang Qing Jun , Kang Woo-Young , Higashi Richard M , Fan Teresa W-M , Lane Andrew N. , Moseley Hunter N.B. 
Published: September 2017

AbstractFourier-transform mass spectrometry (FT-MS) allows for the high-throughput and high-resolution detection of thousands of metabolites. Observed spectral features (peaks) that are not isotopologues do not directly correspond to known compounds and cannot be placed into existing metabolic networks. Spectral artifacts account for many of these unidentified peaks, and misassignments made to these artifact peaks can create large interpretative errors. Without accurate identification of artifactual features and correct assignment of real features, discerning their roles within living systems is effectively impossible.We have observed three types of artifacts unique to FT-MS that often result in regions of abnormally high peak density (HPD), which we collectively refer to as HPD artifacts: i) fuzzy sites representing small regions of m/z space with a ‘fuzzy’ appearance due to the extremely high number of peaks present; ii) ringing due to a very intense peak producing side bands of decreasing intensity that are symmetrically distributed around the main peak; and iii) partial ringing where only a subset of the side bands are observed for an intense peak. Fuzzy sites and partial ringing appear to be novel artifacts previously unreported in the literature and we hypothesize that all three artifact types derive from Fourier transformation-based issues. In some spectra, these artifacts account for roughly a third of the peaks present in the given spectrum. We have developed a set of tools to detect these artifacts and approaches to mitigate their effects on downstream analyses.
Neuronal rhythms orchestrate cell assembles to distinguish perceptual categories
Authors: Goudarzi Morteza Moazami , Cromer Jason , Roy Jefferson , Miller Earl K. 
Published: September 2017

AbstractCategories are reflected in the spiking activity of neurons. However, how neurons form ensembles for categories is unclear. To address this, we simultaneously recorded spiking and local field potential (LFP) activity in the lateral prefrontal cortex (lPFC) of monkeys performing a delayed match to category task with two independent category sets (Animals: Cats vs Dogs; Cars: Sports Cars vs Sedans). We found stimulus and category information in alpha and beta band oscillations. Different category distinctions engaged different frequencies. There was greater spike field coherence (SFC) in alpha (∼8-14 Hz) for Cats and in beta (∼16-22 Hz) for Dogs. Cars showed similar differences, albeit less pronounced: greater alpha SFC for Sedans and greater beta SFC for Sports Cars. Thus, oscillatory rhythms can help coordinate neurons into different ensembles. Engagement of different frequencies may help differentiate the categories.
Controlling striatal function via anterior frontal cortex stimulation
Authors: Holstein Mieke van , Froböse Monja I. , O’Shea Jacinta , Aarts Esther , Cools Roshan 
Published: September 2017

AbstractMotivational, cognitive and action goals are processed by distinct, topographically organized, corticostriatal circuits. We aimed to test whether processing in the striatum is und er causal control by cortical regions in the human brain by investigating the effects of offline transcranial magnetic stimulation (TMS) over distinct frontal regions associated with motivational, cognitive and action goal processing. Using a three-session counterbalanced within-subject crossover design, continuous theta burst stimulation was applied over the anterior prefrontal cortex (aPFC), dorsolateral prefrontal cortex, or premotor cortex, immediately after which participants (N=27) performed a paradigm assessing reward anticipation (motivation), task (cognitive) switching, and response (action) switching. Using task-related functional magnetic resonance imaging (fMRI), we assessed the effects of stimulation on processing in distinct regions of the striatum. To account for non-specific effects, each session consisted of a baseline (no-TMS) and a stimulation (post-TMS) fMRI run. Stimulation of the aPFC tended to decrease reward-related processing in the caudate nucleus, while stimulation of the other sites was unsuccessful. A follow-up analysis revealed that aPFC stimulation also decreased processing in the putamen as a function of the interaction between all factors (reward, cognition and action), suggesting stimulation modulated the transfer of motivational information to cortico-striatal circuitry associated with action control.
Proteomic identification of Axc, a novel beta-lactamase with carbapenemase activity in a meropenem-resistant clinical isolate ofAchromobacter xylosoxidans
Authors: Fleurbaaij Frank , Henneman Alex A. , Corver Jeroen , Knetsch Cornelis W. , Smits Wiep Klaas , Nauta Sjoerd T. , Giera Martin , Dragan Irina , Kumar Nitin , Lawley Trevor D. , Verhoeven Aswin , van Leeuwen Hans C. , Kuijper Ed J. , Hensbergen Paul J. 
Published: September 2017

AbstractThe development of antibiotic resistance during treatment is a threat to patients and their environment. Insight in the mechanisms of resistance development is important for appropriate therapy and infection control. Here, we describe how through the application of mass spectrometry-based proteomics, a novel beta-lactamase Axc was identified as an indicator of acquired carbapenem resistance in a clinical isolate ofAchromobacter xylosoxidans.Comparative proteomic analysis of consecutively collected susceptible and a resistant isolates from the same patient revealed that high Axc protein levels were only observed in the resistant isolate. Heterologous expression of Axc inEscherichia colisignificantly increased the resistance towards carbapenems. Importantly, direct Axc mediated hydrolysis of imipenem was demonstrated using pH shift assays and1H-NMR, confirming Axc as a legitimate carbapenemase. Whole genome sequencing revealed that the susceptible and resistant isolates were remarkably similar.Together these findings provide a molecular context for the fast development of meropenem resistance inA. xylosoxidansduring treatment and demonstrate the use of mass spectrometric techniques in identifying novel resistance determinants.
Cyclin A2 localises in the cytoplasm at the S/G2 transition to activate PLK1
Authors: Cascales Helena Silva , Burdova Kamila , Middleton Anna , Kuzin Vladislav , Müllers Erik , Stoy Henriette , Baranello Laura , Macurek Libor , Lindqvist Arne 
Published: September 2017

AbstractCyclin A2 is a key regulator of the cell cycle, implicated both in DNA replication and mitotic entry. Cyclin A2 participates in feedback loops that activate mitotic kinases in G2-phase, but why active Cyclin A2-CDK2 during S phase does not trigger mitotic kinase activation remains unclear. Here we describe a change in localisation of Cyclin A2 from being only nuclear to both nuclear and cytoplasmic at the S/G2 border. We find that Cyclin A2-CDK2 can activate the mitotic kinase PLK1 through phosphorylation of Bora, and that only cytoplasmic Cyclin A2 interacts with Bora and PLK1. Expression of predominately cytoplasmic Cyclin A2 or phospho-mimicking PLK1 T210D can partially rescue a G2 arrest caused by Cyclin A2 depletion. Cytoplasmic presence of Cyclin A2 is restricted by p21, in particular after DNA damage. Cyclin A2 chromatin association during DNA replication and additional mechanisms contribute to Cyclin A2 localisation change in G2 phase. We find no evidence that such mechanisms involve G2 feedback loops and suggest that cytoplasmic appearance of Cyclin A2 at the S/G2 transition functions as a trigger for mitotic kinase activation.SynopsisMain mitotic kinases as PLK1 are activated at the S/G2 transition. A change in Cyclin A2 localisation at the S/G2 transition enables activation of PLK1.Main points-Cyclin A2 appears in the cytoplasm at the S/G2 transition-Association with replicating chromatin and p21 restricts Cyclin A2 to the nucleus-DNA damage ensures nuclear Cyclin A2 through p21-Cytoplasmic Cyclin A2 initiates PLK1 activationGraphical abstract
Genetic Identification of Novel Separase regulators inCaenorhabditis elegans
Authors: Melesse Michael , Sloan Dillon E. , Benthal Joseph T. , Caylor Quincey , Gosine Krishen , Bai Xiaofei , Bembenek Joshua N. 
Published: September 2017

ABSTRACTSeparase is a highly conserved protease required for chromosome segregation. Although observations that separase also regulates membrane trafficking events have been made, it is still not clear how separase achieves this function. Here we present an extensive ENU mutagenesis suppressor screen aimed at identifying suppressors ofsep-1(e2406), a temperature sensitive maternal effect embryonic lethal separase mutant. We screened nearly a million haploid genomes, and isolated sixty-eight suppressed lines. We identified fourteen independent intragenicsep-1(e2406)suppressed lines. These intragenic alleles map to seven SEP-1 residues within the N-terminus, compensating for the original mutation within the poorly conserved N-terminal domain. Interestingly, 47 of the suppressed lines have novel mutations throughout the entire coding region of thepph-5phosphatase, indicating that this is an important regulator of separase. We also found that a mutation near the MEEVD motif of HSP-90, which binds and activates PPH-5, also rescuessep-1(e2406)mutants. Finally, we identified six potentially novel suppressor lines that fall into five complementation groups. These new alleles provide the opportunity to more exhaustively investigate the regulation and function of separase.
Nano-scale size holes in ER sheets provide an alternative to tubules for highly-curved membranes
Authors: Schroeder Lena K. , Barentine Andrew E. S. , Schweighofer Sarah , Baddeley David , Bewersdorf Joerg , Bahmanyar Shirin 
Published: September 2017

AbstractThe endoplasmic reticulum (ER) is composed of interconnected membrane sheets and tubules. Super-resolution microscopy recently revealed densely packed, rapidly moving ER tubules, highlighting the importance of revisiting classical views of ER structure with high spatial resolution in living cells. Using live-cell Stimulated Emission Depletion (STED) microscopy, we show highly dynamic, subdiffraction-sized holes in ER sheets. Holes coexist with uniform sheet regions and are distinct from tubular ER structures. The curvature-stabilizing reticulon protein Rtn4 localizes to these holes and the ER luminal tether Climp63 controls their diameter and mobility. Analytical modeling demonstrates that holes in ER sheets can serve as reservoirs for curvature-stabilizing proteins to support ER tubule extension and retraction, thus providing an explanation for how the ER locally alters its morphology on fast time-scales.One Sentence SummaryDynamic nano-scale sized holes are prominent features of ER sheets that serve as reservoirs for curvature-stabilizing proteins to support ER tubule extension and retraction.