bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prospective Comparison of the Prognostic Relevance of Circulating Tumor Cells in Blood and Disseminated Tumor Cells in Bone Marrow of a Single Patient's Cohort With Esophageal Cancer
Authors: Konczalla Leonie , Ghadban Tarik , Effenberger Katharina E. , Wöstemeier Anna , Riethdorf Sabine , Uzunoglu Faik G. , Izbicki Jakob R. , Pantel Klaus , Bockhorn Maximilian , Reeh Matthias 
Published: June 2019

Objective:
Aim of this prospective study was to evaluate the prognostic significance of disseminated tumor cells (DTCs) and circulating tumor cells (CTCs) in 1 cohort of patients with esophageal cancer (EC).

Background:
Hematogenous tumor cell dissemination is a key event in tumor progression, and clinical significance of DTCs and CTCs are controversially discussed in the literature. However, evaluation of both biomarker in 1 patient's cohort has not been described before.

Methods:
In this prospective, single-center study, 76 patients with preoperatively nonmetastatic staged EC were included. The CellSearch system was used to enumerate CTCs. Bone marrow was aspirated from the iliac crest and cells were enriched by Ficoll density gradient centrifugation. DTCs were immunostained with the pan-keratin antibody A45-B/B3.

Results:
Fifteen of 76 patients (19.7%) harbored CTCs, whereas in 13 of 76 patients (17.1%), DTCs could be detected. In only 3 patients (3.9%), CTCs and DTCs were detected simultaneously, whereas concordant results (DTC/CTC negative and DTC/CTC positive) were found in 54 patients (71.1%). Surprisingly, only patients with CTCs showed significant shorter overall and relapse-free survival (P = 0.038 and P = 0.004, respectively). Multivariate analyses revealed that only the CTC status was an independent predictor of overall and relapse-free survival (P = 0.007 and P < 0.001, respectively).

Conclusions:
This is the first study analyzing CTC and DTC status in 1 cohort of nonmetastatic patients with EC. In this early disease stage, only the CTC status was an independent, prognostic marker suitable and easy to use for clinical staging of patients with EC.
Modeling missing cases and transmission links in networks of extensively drug-resistant tuberculosis in KwaZulu-Natal, South Africa
Authors: Nelson Kristin N. , Gandhi Neel R. , Mathema Barun , Lopman Benjamin A. , Brust James C.M. , Auld Sara C. , Ismail Nazir , Omar Shaheed Vally , Brown Tyler S. , Allana Salim , Campbell Angie , Moodley Pravi , Mlisana Koleka , Shah N. Sarita , Jenness Samuel M. 
Published: June 2019

ABSTRACTThe transmission patterns of drug-resistant tuberculosis (TB) remain poorly understood, despite over half a million incident cases in 2017. Modeling TB transmission networks can provide insight into the nature and drivers of transmission, but incomplete and non-random sampling of TB cases can pose challenges to making inferences from epidemiologic and molecular data. We conducted a quantitative bias analysis to assess the effect of missing cases on a transmission network inferred fromMtbsequencing data on extensively drug-resistant (XDR) TB cases in South Africa. We tested scenarios in which cases were missing at random, differentially by clinical characteristics, or differentially by transmission (i.e., cases with many links were under or over-sampled). Under the assumption cases were missing at random, cases in the complete, modeled network would have had a mean of 20 or more transmission links, which is far higher than expected, in order to reproduce the observed, partial network. Instead, we found that the most likely scenario involved undersampling of high-transmitting cases, and further models provided evidence for superspreading behavior. This is, to our knowledge, the first study to define and assess the support for different mechanisms of missingness in a study of TB transmission. Our findings should caution interpretation of results of future studies of TB transmission in high-incidence settings, given the potential for biased sampling, and should motivate further research aimed at identifying the specific host, pathogen, or environmental factors contributing to superspreading.
Hand Knob Area of Motor Cortex in People with Tetraplegia Represents the Whole Body in a Modular Way
Authors: Willett Francis R. , Deo Darrel R. , Avansino Donald T. , Rezaii Paymon , Hochberg Leigh , Henderson Jaimie , Shenoy Krishna 
Published: June 2019

AbstractDecades after the motor homunculus was first proposed, it is still unknown how different body parts are intermixed and interrelated in human motor cortex at single-neuron resolution. Using microelectrode arrays, we studied how face, head, arm and leg movements on both sides of the body are represented in hand knob area of precentral gyrus in people with tetraplegia. Contrary to the traditional somatotopy, we found strong representation of all movements. Probing further, we found that ipsilateral and contralateral movements, and homologous arm and leg movements (e.g. wrist and ankle), had a correlated representation. Additionally, there were neural dimensions where the limb was represented independently of the movement. Together, these patterns formed a “modular” code that might facilitate skill transfer across limbs. We also investigated dual-effector movement, finding that more strongly represented effectors suppressed the activity of weaker effectors. Finally, we leveraged these results to improve discrete brain-computer interfaces by spreading targets across all limbs.
Quantification of anticipation of excitement with three-axial model of emotion with EEG
Authors: Machizawa Maro G. , Lisi Giuseppe , Kanayama Noriaki , Mizuochi Ryohei , Makita Kai , Sasaoka Takafumi , Yamawaki Shigeto 
Published: June 2019

AbstractObjectivesMultiple facets of human emotions underlie diverse and sparse neural mechanisms. Amongst many models of emotions, the circumplex model of emotion is one of a significant theory. The use of the circumplex model allows us to model variable aspects of emotion; however, such momentary expression of one’s internal mental state still lacks to consider another, the third dimension of time. Here, we report an exploratory attempt to build a three-axial model of human emotion to model our sense of anticipatory excitement, “Waku-Waku (in Japanese),” when people are predictively coding upcoming emotional events.ApproachElectroencephalography (EEG) was recorded from 28 young adult participants while they mentalized upcoming emotional pictures. Three auditory tones were used as indicative cues, predicting the likelihood of valence of an upcoming picture, either positive, negative, or unknown. While seeing an image, participants judged its emotional valence during the task, and subsequently rated their subjective experiences on valence, arousal, expectation, and Waku-Waku immediately after the experiment. The collected EEG data were then analyzed to identify contributory neural signatures for each of the three axes.Main ResultsA three axial model was built to quantify Waku-Waku. As was expected, this model revealed considerable contribution of the third dimension over the classical two-dimension model. Distinctive EEG components were identified. Furthermore, a novel brain-emotion interface is proposed and validated within the scope of limitations.SignificanceThe proposed notion may shed new light on the theories of emotion and supports multiplex dimensions of emotion. With an introduction of the cognitive domain for a brain-computer-interface, we propose a novel brain-emotion-interface. Limitations and potential applications are discussed.
CLIJ: GPU-accelerated image processing for everyone
Authors: Haase Robert , Royer Loic A. , Steinbach Peter , Schmidt Deborah , Dibrov Alexandr , Schmidt Uwe , Weigert Martin , Maghelli Nicola , Tomancak Pavel , Jug Florian , Myers Eugene W. 
Published: June 2019

AbstractGraphics processing units (GPU) allow image processing at unprecedented speed. We present CLIJ, a Fiji plugin enabling end-users with entry level experience in programming to benefit from GPU-accelerated image processing. Freely programmable workflows can speed up image processing in Fiji by factor 10 and more using high-end GPU hardware and on affordable mobile computers with built-in GPUs.
A universal scaling method for biodiversity-ecosystem functioning relationships
Authors: Barry K.E. , Pinter G.A. , Strini J.W. , Yang K. , Lauko I.G. , Schnitzer S.A. , Clark A.T. , Cowles J. , Mori A.S. , Williams L. , Reich P.B. , Wright A.J. 
Published: June 2019

SummaryGlobal biodiversity is declining at rates faster than at any other point in human history. Experimental manipulations of biodiversity at small spatial scales have demonstrated that communities with fewer species consistently produce less biomass than higher diversity communities. However, understanding how the global extinction crisis is likely to impact global ecosystem functioning will require applying these local and largely experimental findings to natural systems at substantially larger spatial and temporal scales. Here we propose that we can use two simple macroecological patterns – the species area curve and the biomass-area curve – to upscale the species richness-biomass relationship. We demonstrate that at local spatial scales, each additional species will contribute more to biomass production with increasing area sampled because the species-area curve saturates and the biomass-area curve increases monotonically. We use species-area and biomass-area curves from a Minnesota grassland and a Panamanian tropical dry forest to examine the species richness – biomass relationship at three and ten sampling extents, respectively. In both datasets, the observed relationship between biodiversity and biomass production at every sampling extent was predicted from simple species-area and biomass-area relationships. These findings suggest that macroecological patterns like the species-area curve underpin the scaling of biodiversity-ecosystem functioning research and can be used to predict these relationships at the global scales where they are relevant for species loss.
Defining functional neuraminidase inhibitor drug resistance motifs in avian influenza viruses and the consequential impact on virus fitness in chicken cells
Authors: Bialy Dagmara , Shelton Holly 
Published: June 2019

ABSTRACTNeuraminidase inhibitors (NAIs) are antiviral agents recommended worldwide to treat or prevent influenza virus infections in humans. Mapping of functional resistance to currently licensed NAIs has been limited to human influenza viruses with only sporadic reports investigating avian influenza viruses (AIV). However past pandemics as well as the increasing number of humans infected with AIV have shown the importance of having information about avian NAs that could cross the species barrier. In this study we introduced four NAI resistance-associated mutations previously found in human strains into the NA of six prevalent AIV subtypes that threaten the poultry industry and human health: H7N9, H6N1, H4N6 and highly pathogenic H5N8, H5N6 and H5N2. Using the established MUNANA assay we show that R292K substitution significantly impaired NA activity in all strains, whereas E119V, H274Y and N294S have more variable effects on NA activity. The impact of these mutations on NAI susceptibility was drug- and strain-specific. We have shown that despite compromised NA activity drug-resistant H5N6 and H6N1 viruses replicated to comparable or significantly higher titres in primary chicken cells as compared to wild type. The replicative fitness of NAI-resistant H5N6 was also confirmedin ovo. Two drug resistant H5N6 viruses had single amino acid substitutions in their haemagglutinin (HA) which reduced receptor binding properties. Our results demonstrate that there are no universal NAI resistance determinants for all strains and although some are clearly deleterious for the virus, others can be rapidly compensated by acquiring concurrent changes in other gene segments.IMPORTANCEThe number of human infections caused by avian influenza viruses (AIV) keeps increasing. This together with the rapid emergence of influenza strains resistant to neuraminidase inhibitor drugs (NAIs) observed in the past raises a significant concern to public health. We studied the NAI resistance-associated molecular changes, previously reported in neuraminidase (NA) of human influenza, in AIV background. We found that single amino acid substitution can confer a multidrug resistance, or lead to a single-drug resistance across multiple virus subtypes. We also found that the drug-resistant viruses retained or showed enhanced fitness properties as compared to the corresponding wild-type, and this could be achieved by quick acquisition of concurrent mutations in haemagglutinin. Our study highlights the need for constant monitoring of NAI-resistance in AIV and understanding the molecular basis of antiviral resistance, as such information would be invaluable for pandemic preparedness and may facilitate the development of novel therapeutics.
Species-specific recognition of Sulfolobales mediated by UV-inducible pili and S-layer glycosylation patterns
Authors: van Wolferen Marleen , Shajahan Asif , Heinrich Kristina , Brenzinger Susanne , Black Ian M. , Wagner Alexander , Briegel Ariane , Azadi Parastoo , Albers Sonja-Verena 
Published: June 2019

AbstractThe UV-inducible pili system of Sulfolobales (Ups) mediates the formation of species-specific cellular aggregates. Within these aggregates, cells exchange DNA in order to repair DNA double strand breaks via homologous recombination. Substitution of theS. acidocaldariuspilin subunits UpsA and UpsB with their homologs fromSulfolobus tokodaiishowed that these subunits facilitate species-specific aggregation. A region of low conservation within the UpsA homologs is primarily important for this specificity. Aggregation assays in the presence of different sugars showed the importance ofN-glycosylation in the recognition process. In addition, theN-glycan decorating the S-layer ofS. tokodaiiis different from the one ofS. acidocaldarius. Therefore, eachSulfolobusspecies seems to have developed a unique UpsA binding pocket and uniqueN-glycan composition to ensure aggregation and consequently also DNA exchange with cells from only the same species, which is essential for DNA repair by homologous recombination.ImportanceType IV pili can be found on the cell surface of many archaea and bacteria where they play important roles in different processes. The Ups-pili from the crenarchaeal Sulfolobales species are essential in establishing species-specific mating partners, ensuring genome stability. With this work, we show that differentSulfolobusspecies have species-specific regions in their Ups-pilin subunits, which allow them to interact only with cells from the same species. Additionally, differentSulfolobusspecies all have unique S-layerN-glycosylation patterns. We propose that the unique features of each species allow the recognition of specific mating partners. This knowledge for the first time gives insights into the molecular basis of archaeal self-recognition.
A luciferase-based assay identifies niclosamide derivatives antagonizing Mcl-1 through post-translational down-regulation
Authors: Liu Qiang , Atkinson Jennifer M. , Gebru Melat T. , Clements Kristen , Moldovan George L. , Wang Hong-Gang 
Published: June 2019

AbstractThe up-regulation of Mcl-1 expression is a major mechanism of cancer cell survival and therapy resistance. However, the underlying molecular mechanism remains incompletely understood, limiting the number of druggable approaches to selectively inhibit Mcl-1 function. In this study, we designed and employed a novel mechanistic high-throughput screening system to selectively uncover post-translational modulators of Mcl-1. We generated a cell-based high-throughput screening assay in which myeloid leukemia K562 cells constitutively express Mcl-1 or Bcl-xL fused with luciferase (Luc-Mcl-1 or Luc-Bcl-xL, respectively) under a viral promoter. 1,650 bioactive compounds were screened for their ability to selectively induce Mcl-1 down-regulation in a 2-hour assay. A family of niclosamide derivatives were eventually identified for their remarkable ability to decrease Mcl-1 protein stability, exemplified by N007. These salicylate derivatives did not alter Mcl-1 mRNA levels, but selectively induced proteasome-dependent Mcl-1 down-regulation independent of Noxa, Mule, or GSK3β. We also demonstrate that N007 potently induced cell death in leukemia cell lines, including those resistant to Bcl-2 inhibitors. Our work highlights the versatility of the mechanistic high-throughput screening approach as a valuable tool in identifying novel agents with the ability to down-regulate proteins crucial to human diseases.
The NKCC1 Antagonist Bumetanide Mitigates Interneuronopathy Associated with Ethanol Exposure In Utero
Authors: Skorput Alexander G. J. , Lee Stephanie M. , Yeh Pamela W. L. , Yeh Hermes H. 
Published: June 2019

AbstractPrenatal exposure to ethanol induces aberrant tangential migration of corticopetal GABAergic interneurons, and long-term alterations in the form and function of the prefrontal cortex. We have hypothesized that interneuronopathy contributes significantly to the pathoetiology of fetal alcohol spectrum disorders (FASD). Activity-dependent tangential migration of GABAergic cortical neurons is driven by depolarizing responses to ambient GABA present in the cortical enclave. We found that ethanol exposure potentiates the depolarizing action of GABA in GABAergic cortical interneurons of the embryonic mouse brain. Pharmacological antagonism of the cotransporter NKCC1 mitigated ethanol-induced potentiation of GABA depolarization and prevented aberrant patterns of tangential migration induced by ethanol in vitro. In a model of FASD, maternal bumetanide treatment prevented interneuronopathy in the prefrontal cortex of ethanol exposed offspring, including deficits in behavioral flexibility. These findings position interneuronopathy as a mechanism of FASD symptomatology, and posit NKCC1 as a pharmacological target for the management of FASD.
Impaired Desynchronization of Beta Activity Underlies Memory Deficits in People with Parkinson’s Disease
Authors: MacDonald Hayley J. , Brittain John-Stuart , Spitzer Bernhard , Hanslmayr Simon , Jenkinson Ned 
Published: June 2019

AbstractThere is a pressing need to better understand the mechanisms underpinning the increasingly recognised non-motor deficits in Parkinson’s disease. Brain activity during Parkinson’s disease is excessively synchronized within the beta range (12–30Hz). However, relatively little is known about how the abnormal beta rhythms impact on non-motor symptoms. In healthy adults, beta desynchronization is necessary for successful episodic memory formation. We investigated whether there was a direct relationship between decreased beta modulation and memory formation in Parkinson’s disease. Electroencephalography recordings were made during an established memory-encoding paradigm. Parkinson’s participants showed impaired memory strength (P = 0.023) and reduced beta desynchronization (P = 0.014) relative to controls. Longer disease duration was correlated with a larger reduction in beta desynchronization, and a concomitant reduction in memory performance. These novel results extend the notion that pathological beta activity is causally implicated in the motor and (lesser appreciated) non-motor deficits inherent to Parkinson’s disease.
Non-uniform distribution of myosin-mediated forces governs red blood cell membrane curvature through tension modulation
Authors: Alimohamadi Haleh , Smith Alyson S. , Nowak Roberta B. , Fowler Velia M. , Rangamani Padmini 
Published: June 2019

AbstractThe biconcave disk shape of the mammalian red blood cell (RBC) is unique to the RBC and is vital for its circulatory function. Due to the absence of a transcellular cytoskeleton, RBC shape is determined by the membrane skeleton, a network of actin filaments cross-linked by spectrin and attached to membrane proteins. While the physical properties of a uniformly distributed actin network interacting with the lipid bilayer membrane have been assumed to control RBC shape, recent experiments reveal that RBC biconcave shape also depends on the contractile activity of nonmuscle myosin IIA (NMIIA) motor proteins. Here, we use the classical Helfrich-Canham model for the RBC membrane to test the role of heterogeneous force distributions along the membrane and mimic the contractile activity of sparsely distributed NMIIA filaments. By incorporating this additional contribution to the Helfrich-Canham energy, we find that the RBC biconcave shape depends on the ratio of forces per unit volume in the dimple and rim regions of the RBC. Experimental measurements of NMIIA densities at the dimple and rim validate our prediction that (a) membrane forces must be non-uniform along the RBC membrane and (b) the force density must be larger in the dimple than the rim to produce the observed membrane curvatures. Furthermore, we predict that RBC membrane tension and the orientation of the applied forces play important roles in regulating this force-shape landscape. Our findings of heterogeneous force distributions on the plasma membrane for RBC shape maintenance may also have implications for shape maintenance in different cell types.
A study on product assembly and disassembly time prediction methodology based on virtual maintenance
Authors: Cai Kaijun , Zhang Weiming , Chen Wenzhuo , Zhao Hongfei 
Published: June 2019

Purpose
Based on virtual maintenance, this paper aims to propose a time prediction method of assembly and disassembly (A&D) actions of product maintenance process to enhance existing methods’ prediction accuracy, applicability and efficiency.

Design/methodology/approach
First, a framework of A&D time prediction model is constructed, which describes the time prediction process in detail. Then, basic maintenance motions which can comprise a whole A&D process are classified into five categories: body movement, working posture change, upper limb movement, operation and grasp/placement. A standard posture library is developed based on the classification. Next, according to motion characteristics, different time prediction methods for each motion category are proposed based on virtual maintenance simulation, modular arrangement of predetermined time standard theory and the statistics acquired from motion experiment. Finally, time correction based on the quantitative evaluation method of motion time influence factors is studied so that A&D time could be predicted with more accuracy.

Findings
Case study of time prediction of products’ various A&D processes is conducted by implementing the proposed method. The prediction process of diesel cooling fan disassemble time is presented in detail. Through comparison, the advantages and effectiveness of the method are demonstrated.

Originality/value
This paper proposes a more accurate, efficient and applicable product A&D time prediction method. It can help designers predict A&D time of a product maintenance accurately in early design phases without a physical prototype. It can also provide basis for the verification of maintainability, the balance of the design of product structure and system layout.