bluuebunny/crossref_metadata_2025 huggingface dataset:
Risk Factors and Outcomes Associated with Prolonged Subtherapeutic Anticoagulation with Bivalirudin: A Retrospective Cohort Study
Authors: Orzel Libby A. , Abel Erik E. , Blais Danielle M. , Wang Tzu‐Fei , Porter Kyle A. , Burcham Pamela K.
Published: October 2019

Background

Bivalirudin, a direct thrombin inhibitor, is a treatment option for the management of heparin‐induced thrombocytopenia (HIT) and other coagulation disorders. To date, no published studies have identified patients at risk for or the consequence of subtherapeutic bivalirudin therapy.

Objectives

The primary objective was to identify factors associated with failure to achieve early therapeutic anticoagulation (ETA) with bivalirudin, defined as achievement of two consecutive therapeutic activated partial thromboplastin times (aPTTs) within 24 hours. Secondary objectives included evaluating whether failure to achieve ETA was a risk factor for clinical outcomes of interest including thromboembolism, hemorrhage, and mortality.

Patients/Methods

This was a retrospective cohort study. Patients between the ages of 18 and 89 years treated with bivalirudin for 24 hours or longer were identified and classified as either achieving or failing to achieve ETA.

Results

Nonadherence to the dosing protocol (odds ratio [OR] 1.7, 95% confidence interval [CI] 1.07‐2.71) and creatinine clearance (CrCl) of 60 ml/min or greater (OR 2.99, 95% CI 1.12‐7.97) were significantly associated with failure to achieve ETA in univariate analyses. Conversely, increasing age (OR 0.98, 95% CI 0.97‐0.99) was significantly associated with achievement of ETA. Failure to achieve ETA was associated with a 4‐fold increase in the odds of thromboembolism.

Conclusions

Younger age, normal renal function, and nonadherence to the dosing protocol when targeting therapeutic anticoagulation is associated with increased risk of failure to achieve ETA. This confers an elevated risk of thromboembolism when using bivalirudin for the management of HIT or other coagulation disorders.
Paramagnetic relaxation enhancement‐assisted structural characterization of a partially disordered conformation of ubiquitin
Authors: Wakamoto Takuro , Ikeya Teppei , Kitazawa Soichiro , Baxter Nicola J. , Williamson Mike P. , Kitahara Ryo
Published: October 2019

Nuclear magnetic resonance (NMR) is a powerful tool to study three‐dimensional structures as well as protein conformational fluctuations in solution, but it is compromised by increases in peak widths and missing signals. We previously reported that ubiquitin has two folded conformations, N1 and N2 and plus another folded conformation, I, in which some amide group signals of residues 33–41 almost disappeared above 3 kbar at pH 4.5 and 273 K. Thus, well‐converged structural models could not be obtained for this region owing to the absence of distance restraints. Here, we reexamine the problem using the ubiquitin Q41N variant as a model for this locally disordered conformation, I. We demonstrate that the variant shows pressure‐induced loss of backbone amide group signals at residues 28, 33, 36, and 39–41 like the wild‐type, with a similar but smaller effect on CαH and CβH signals. In order to characterize this I structure, we measured paramagnetic relaxation enhancement (PRE) under high pressure to obtain distance restraints, and calculated the structure assisted by Bayesian inference. We conclude that the more disordered I conformation observed at pH 4.0, 278 K, and 2.5 kbar largely retained the N2 conformation, although the amide groups at residues 33–41 have more heterogeneous conformations and more contact with water, which differ from the N1 and N2 states. The PRE‐assisted strategy has the potential to improve structural characterization of proteins that lack NMR signals, especially for relatively more open and hydrated protein conformations.
Pre‐planting weed detection based on ground field spectral data
Authors: Pott Luan P , Amado Telmo JC , Schwalbert Raí A , Sebem Elodio , Jugulam Mithila , Ciampitti Ignacio A
Published: October 2019

BACKGROUND

Site‐specific weed management (SSWM) demands higher resolution data for mapping weeds in fields, but the success of this tool relies on the efficiency of optical sensors to discriminate weeds relative to other targets (soils and residues) before cash crop establishment. The objectives of this study were to (i) evaluate the accuracy of spectral bands to differentiate weeds (target) and other non‐targets, (ii) access vegetation indices (VIs) to assist in the discrimination process, and (iii) evaluate the accuracy of the thresholds to distinguish weeds relative to non‐targets for each VI using training and validation data sets.

RESULTS

The main outcomes of this study for effectively distinguishing weeds from other non‐targets are (i) training and validation data exhibited similar spectral curves, (ii) red and near‐infrared spectral bands presented greater accuracy relative to the other bands, and (iii) the tested VIs increased the discrimination accuracy related to single bands, with an overall accuracy above 95% and a kappa above 0.93.

CONCLUSION

This study provided a novel approach to distinguish weeds from other non‐targets utilizing a ground‐level sensor before cash crop planting based on field spectral data. However, the limitations of this study are related to the spatial resolution to distinguish weeds that might be closer to the one this study presented, and also related to the soil and crop residues conditions at the time of collecting the readings. Overall the results presented contribute to an improved understanding of spectral signatures from different targets (weeds, soils, and residues) before planting time supporting SSWM. © 2019 Society of Chemical Industry
Small Wavevector–Dependent Spin Susceptibility in Weyl Semimetals
Authors: Okvátovity Z. , Simon F. , Dóra B.
Published: October 2019

A detailed derivation of the off‐diagonal spin–spin correlation functions of 3D Weyl semimetals in the static ω = 0 limit for small wavevectors at zero temperature is presented. The real part of the spin correlation function is evaluated analytically and follows behavior, with W and μ being the high‐energy cutoff and chemical potential, respectively. Its imaginary part grows linearly with μ. These quantities are also evaluated using brute force numerical integration, and the numerical data agree convincingly with the analytical result. This work provides the starting point to determine the Knight shift of Weyl semimetals from the hyperfine coupling through the wavevector‐dependent susceptibility.
Detection of Nonradiative Recombination Centers in GaPN (N:0.105%) by Below‐Gap Excitation Light
Authors: Ferdous Sanjida , Kamata Norihiko , Yagi Shuhei , Yaguchi Hiroyuki
Published: October 2019

Investigation on cascade photo‐excitation via intermediate band (IB) is promising for improving the efficiency of IB‐type solar cells (IBSCs). Increasing nitrogen (N) concentration in GaP changes an ensemble of discrete N–N pair levels to form the IB as well as introducing defect levels acting as nonradiative recombination (NRR) centers. In continuation of detecting NRR centers in GaP1−xNx (x > 0.5%), a study is made for the lower N concentration region of 0.105% to understand an original formation of defect levels and their properties. Elimination of temperature quenching by immersing the sample into liquid nitrogen reveals a distribution of NRR centers inside the forbidden energy gap and the shift of Fermi energy depending on above‐gap excitation (AGE) density. Profound understanding of IB and defects of GaP1−xNx leads to a proper optimization of IBSCs.
A note on non‐negativity correction for a multimoment finite‐volume transport model with WENO limiter
Authors: Li Xingliang , Shen Xueshun , Chen Chungang , Tang Jie , Xiao Feng
Published: October 2019

An oscillation‐less multimoment global transport model was proposed by Tang et al. in 2018 by introducing a slope limiter based on the weighted essentially non‐oscillatory (WENO) concept. The spurious oscillations around the discontinuities and strong gradients can be effectively removed and the model preserves the fourth‐order accuracy in spherical geometry for smooth solutions. However, the WENO limiter does not strictly guarantee the non‐negativity of numerical solution and the resulting model will violate the physical principle due to the existence of the nonphysical negative undershoots. As the numerical fluxes, which determine the time tendency of the volume‐integrated average, are evaluated by the point values (PVs) defined along the cell boundaries in the multimoment finite‐volume schemes, the non‐negativity preserving model can be accomplished by modifying those PVs to implement the corrections on the numerical fluxes proposed in the positive definite flux‐corrected transport (FCT) method by Smolarkiewicz in 1989. In this study, a non‐negativity correction algorithm is proposed for a global transport model using the MM‐FVM_WENO scheme and verified by simulating the widely used benchmark tests.
Benzyl isothiocyanate promotes miR‐99a expression through ERK/AP‐1‐dependent pathway in bladder cancer cells
Authors: Tsai Te‐Fu , Chen Po‐Chun , Lin Yi‐Chia , Chou Kuang‐Yu , Chen Hung‐En , Ho Chao‐Yen , Lin Ji‐Fan , Hwang Thomas I‐S.
Published: October 2019

Benzyl isothiocyanate (BITC), a bioactive natural product present in cruciferous vegetables, has been proved to prevent cancer progression through various mechanisms. In our previous report, we proved that BITC exhibits antitumor effects in bladder cancer by suppressing IGF1R, FGFR3, and mTOR, which is mediated by miR‐99a expression. In this study, we identified the signal pathway involved in regulating miR‐99a expression after BITC exposure in bladder cancer. Treatment with different BITC concentrations resulted in induction of miR‐99a expression in bladder cancer cell lines. Activation of extracellular signal‐regulated protein kinase (ERK) and c‐jun N‐terminal kinase was observed in bladder cancer after BITC treatment for 24 hours. Interestingly, by using a chemical inhibitor of candidate pathways, we found that only the ERK signal pathway is required for miR‐99a expression. Furthermore, we evaluated the transcription factor that may contribute to miR‐99a expression in response to BITC treatment. The results indicated that c‐Jun/AP‐1 was activated after BITC treatment. Moreover, we confirmed c‐Jun/AP‐1 activation through immunofluorescence and the luciferase reporter assay. The results showed that BITC treatment markedly improved nuclear translocation of c‐Jun/AP‐1 and luciferase activity dose dependently. Finally, pretreatment with the ERK inhibitor U0126 diminished c‐Jun phosphorylation and transcriptional activation, suggesting that BITC elicits ERK/c‐Jun signal transduction, which is responsible for miR‐99a expression in bladder cancer. The present work identifies the mechanism involved in upregulation miR‐99a after BITC treatment, which provides an explanation for BITC biological function in our previous work.
Prevalence of Antiphospholipid Antibodies Negativisation in Patients with Antiphospholipid Syndrome: A Long-Term Follow-Up Multicentre Study
Authors: Radin Massimo , Schreiber Karen , Sciascia Savino , Roccatello Dario , Cecchi Irene , Aguirre Zamorano María Ángeles , Cuadrado Maria Jose
Published: October 2019

Objective This article aims to analyse the rate of antiphospholipid antibodies (aPL) negativisation in patients with antiphospholipid syndrome (APS), and to evaluate potential new clinical manifestations after negativisation and/or aPL fluctuations in a long-term follow-up.

Methods Inclusion criteria are (1) any patients with an APS diagnosis according to the current Sydney criteria and (2) patients in whom aPL negativisation occurred. aPL negativisation was defined as repeated aPL measurements on at least two consecutive occasions at least 12 weeks apart, with a follow-up of at least 1 year since aPL first turned negative.

Results Out of 259 APS patients, a total of 23 patients (8.9%) met the inclusion criteria for persistent aPL negativisation. Patients were followed-up for 14.4 ± 8.1 years, experienced aPL negativisation after a mean of 5.3 ± 3.5 years and were followed-up after experiencing the aPL negativisation for a mean of 7.6 ± 5.8 years. Seventeen patients (73.9%) presented with thrombotic APS, 2 with pregnancy morbidity (8.7%) and 4 (17.4%) with both. Most of the patients (18; 78.3%) had a single aPL positivity, 5 (21.7%) double, while no triple aPL positivity was observed. At the time of data collection, after aPL negativisation, anticoagulation was stopped in 8 patients with previous thrombotic venous event (8/21, 38%) according to the treating physicians' judgements. None of the patients experienced any recurrent thrombotic event during the follow-up period after their aPL negativisation.

Conclusion In our patient cohort consisting of 259 patients with definitive APS, we observed over a mean observation period of > 5 years, that aPL negativisation occurred in approximately 9% of patients. Negativisation occurred most often in patients who were previously found to be positive for only one aPL.
Evaluation of a New, Rapid, Fully Automated Assay for the Measurement of ADAMTS13 Activity
Authors: Valsecchi Carla , Mirabet Maribel , Mancini Ilaria , Biganzoli Marina , Schiavone Lucia , Faraudo Susanna , Mane-Padros Daniel , Giles David , Serra-Domenech Josep , Blanch Silvia , Trisolini Silvia Maria , Facchini Luca , Rinaldi Erminia , Peyvandi Flora
Published: October 2019

Thrombotic thrombocytopenic purpura (TTP) is a rare thrombotic microangiopathy (TMA) characterized by the severe deficiency of a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) activity (< 10%). Rapid ADAMTS13 testing is crucial for an early diagnosis and optimal management of acute TTP. We evaluated the performance of the HemosIL AcuStar ADAMTS13 activity assay (Instrumentation Laboratory, Bedford, Massachusetts, United States), a fully automated chemiluminescent immunoassay with an analytical time of 33 minutes. A method comparison study was performed on 176 samples from 49 healthy donors and 127 TMA patients (109 TTP, 7 atypical hemolytic uremic syndrome, 11 other TMAs), comparing this new assay with an in-house FRETS-VWF73 assay and a commercial enzyme-linked immunosorbent assay (ELISA) (TECHNOZYM ADAMTS-13 Activity, Technoclone GmbH, Vienna, Austria). Agreement between methods was assessed with focus on ADAMTS13 activity less than 10%, the medical decision level relevant for TTP diagnosis. The HemosIL AcuStar ADAMTS13 Activity showed good correlation with both the FRETS-VWF73 (r = 0.96) and ELISA (r = 0.96) methods. Slope of the Passing–Bablok regression was 1.05 for FRETS-VWF73 and 1.02 for ELISA, and absolute bias at the medical decision level was +0.1 and +0.3%, respectively. The study also revealed high agreement with FRETS-VWF73 (kappa 0.97) and ELISA (kappa 0.98) methods in classifying TTP patients with a severe deficiency of ADAMTS13 activity. Because of its short turnaround time and full automation, the HemosIL AcuStar ADAMTS13 activity assay might become the assay of choice to rapidly test ADAMTS13 activity in plasma and thus establish the diagnosis of acute TTP in emergency settings.
Spiritual formation and workplace engagement: prosocial workplace behaviors
Authors: Baker Bruce D. , Lee Donghun Don
Published: October 2019

This paper presents a study of prosocial workplace behaviors indicative of spiritual formation. This research aims to provide practical guidance to managers interested in fostering workplace spirituality and engagement. We present a theoretical model of prosocial workplace behaviors analogous to some classical disciplines of spiritual formation found in Christian tradition (e.g. confession, guidance, celebration, study, service, fellowship, and submission). These behaviors align well with organizational citizenship behaviors (OCB). We developed the Spiritual Formation Inventory (SFI) for the empirical study of these prosocial behaviors in workplace communities. The SFI survey is non-religious, focused on observable behaviors, and suitable for general use in secular workplace settings. In order to test for the association of these prosocial behaviors with workplace engagement, our study adopts the Utrecht Workplace Engagement Study (UWES) as dependent variables. Data were collected in 40 organizations, with a total of 398 participants. Factor analysis confirms three factors (honoring individuals, nurturing relationships, and serving with integrity) that are significantly and positively associated with workplace engagement. Moderating effects are also analyzed. In conclusion, we offer guidance for how these results can be interpreted and applied to foster workplace spirituality and engagement in businesses and a wide variety of organizations.Abbreviations: OCB: Organizational Citizenship Behaviors; SFI: Spiritual Formation Inventory; SOC: Sense of Community; UWES: Utrecht Work Engagement Scale
Parental Education May Differentially Impact Pediatric Inflammatory Bowel Disease Phenotype Risk
Authors: Krishna Mahesh , Salako Aziza , Fofanova Tatiana , Kellermayer Richard
Published: October 2019

Background

The incidence of pediatric inflammatory bowel diseases (PIBDs: Crohn’s disease [CD], ulcerative colitis [UC]) is on the rise around the world. Yet, the critical risk factors for this rising incidence are not well understood. Demographic characteristics of PIBD may improve our understanding of their developmental origins and aid in prevention.

Methods

Four hundred eighty-eight consecutive PIBD patients diagnosed at Texas Children’s Hospital from 13 counties around Houston were studied. An annual incidence map was created by ZIP code of residence at diagnosis by using ArcGIS and the American Community Survey from the US Census Bureau. Correlation between demographic variables and PIBD incidence was examined. A model to explain incidence from different health factors was created in R.

Results

Hispanic children were more likely to be diagnosed with UC (P < 0.01) and unclassified IBD (IBD-U) (P < 0.03) compared with other races/ethnicities. A significant positive correlation (r = 0.35, P < 0.0001) between median household income and PIBD incidence was observed (UC: r = 0.23, P < 0.0001; CD: r = 0.22, P = 0.0004). ZIP codes with majority college-educated adults had a higher incidence of PIBD than ZIP codes with majority high school–educated adults (P < 0.0001). Pediatric cases with CD were more common in ZIP codes where the majority of adults were college educated (P < 0.0001). Pediatric cases with UC, however, were more common in ZIP codes where the majority of adults were high school educated (P = 0.0036).

Conclusions

Hispanic children more commonly present with UC and IBD-U in southern USA. Household income and/or adult education–related environmental/dietary differences may be important in the developmental origins of PIBD in large metro areas, such as Houston.
Re: Parental Education May Differentially Modulate Pediatric Inflammatory Bowel Disease Phenotype Risk
Authors: Day Andrew S
Published: October 2019

The article by Krishna and colleagues provides further support for the purported association between higher socioeconomic status and increased risk of developing inflammatory bowel disease. Although there is other support for this link, the reasons contributing to this relationship are not elucidated.
Detection of Fluorescent Powders and Their Effect on Survival and Recapture of Aedes aegypti (Diptera: Culicidae)
Authors: Rojas-Araya Diana , Alto Barry W , Burkett-Cadena Nathan , Cummings Derek At
Published: October 2019

The use of insect markers, such as fluorescent powders, is a useful tool for studying ecological and epidemiological questions. Evaluating their effect on vectors of human disease agents, such as the invasive mosquito vector Aedes aegypti (Linnaeus), is crucial for their practical and reliable use, especially in parameters linked to the risk of disease transmission such as adult survival, dispersal, and host-seeking. Seven fluorescent powders (Hercules Radiant, DayGlo (DG), Risk Reactor (RR), and Angstrom Technologies), applied externally on cohorts of Ae. aegypti female mosquitoes, were tested to determine their impact on survival and recapture by baited mosquito traps, and their detectability after being exposed to controlled laboratory and semifield environments. There were no significant differences in survival among marked and unmarked females across all powders. Marked females were significantly less likely to be captured in baited traps relative to unmarked females, except for one of the DG powders. All females remained visibly marked on five parts of their body for 30 d (under both environments), except for one of the RR powders. The tested powders and application method are suitable for tracking mosquitoes throughout most of their lives under different environments, without significantly affecting their survival, but with potential impact on recapture by baited traps, possibly due to effects on senses or other physiological traits.
DateLife: leveraging databases and analytical tools to reveal the dated Tree of Life
Authors: Reyes Luna L. Sánchez , McTavish Emily Jane , O’Meara Brian
Published: October 2019

Achieving a high-quality reconstruction of a phylogenetic tree with branch lengths proportional to absolute time (chronogram) is a difficult and time-consuming task. But the increased availability of fossil and molecular data, and time-efficient analytical techniques has resulted in many recent publications of large chronograms for a large number and wide diversity of organisms. Knowledge of the evolutionary time frame of organisms is key for research in the natural sciences. It also represent valuable information for education, science communication, and policy decisions. When chronograms are shared in public and open databases, this wealth of expertly-curated and peer-reviewed data on evolutionary timeframe is exposed in a programatic and reusable way, as intensive and localized efforts have improved data sharing practices, as well as incentivizited open science in biology. Here we present DateLife, a service implemented as an R package and an R Shiny website application available at www.datelife.org, that provides functionalities for efficient and easy finding, summary, reuse, and reanalysis of expert, peer-reviewed, public data on time frame of evolution. The main DateLife workflow constructs a chronogram for any given combination of taxon names by searching a local chronogram database constructed and curated from the Open Tree of Life Phylesystem phylogenetic database, which incorporates phylogenetic data from the TreeBASE database as well. We implement and test methods for summarizing time data from multiple source chronograms using supertree and congruification algorithms, and using age data extracted from source chronograms as secondary calibration points to add branch lengths proportional to absolute time to a tree topology. DateLife will be useful to increase awareness of the existing variation in alternative hypothesis of evolutionary time for the same organisms, and can foster exploration of the effect of alternative evolutionary timing hypotheses on the results of downstream analyses, providing a framework for a more informed interpretation of evolutionary results.
Human GBP1 differentially targetsSalmonellaandToxoplasmato license recognition of microbial ligands and caspase-mediated death
Authors: Fisch Daniel , Clough Barbara , Domart Marie-Charlotte , Encheva Vesela , Bando Hironori , Snijders Ambrosius P , Collinson Lucy M , Yamamoto Masahiro , Shenoy Avinash R , Frickel Eva-Maria
Published: October 2019

Guanylate binding proteins (GBPs), a family of interferon (IFN)-inducible GTPases, can promote cell-intrinsic defense by removal of intracellular microbial replicative niches through host cell death. GBPs target pathogen-containing vacuoles or the pathogen itself, and assist in membrane-disruption and release of microbial molecules that trigger cell death by activating the inflammasomes. We previously showed that GBP1 mediates atypical apoptosis or pyroptosis of human macrophages infected withToxoplasma gondii(Tg) orSalmonella entericaTyphimurium (STm), respectively. In mice, the p47 Immunity-related GTPases (IRGs) control the recruitment of GBPs to microbe-containing vacuoles and subsequent cell death. However, humans are devoid of functional IRGs, and the pathogen-proximal immune detection mechanisms by GBP1 are poorly understood. Here, we describe two novel single-cell assays which show that GBP1 promotes the lysis ofTg-containing vacuoles andTgplasma membrane, resulting in the cytosolic detection ofTg-DNA. In contrast, we show GBP1 only targets cytosolic STm and does not contribute to bacterial escape into the cytosol of human macrophages. GBP1 interacts with caspase-4 and recruits it directly to the bacterial surface, where caspase-4 can be activated by LPS. During STm infection, caspase-1 cleaves and inactivates GBP1 at Asp192, a site conserved in related mammalian GBP1 proteins but not in murine Gbps. STm-infected human macrophages expressing a cleavage-deficient GBP1 mutant exhibit higher pyroptosis due to the absence of caspase-1-mediated feedback inhibition of the GBP1-caspase-4 pathway. Our comparative studies elucidate microbe-specific spatiotemporal roles of GBP1 in detecting infection and the assembly and regulation of divergent caspase signaling platforms.
Integration of Contours Defined by Second-Order Contrast-Modulation of Texture
Authors: Baldwin Alex S , Kenwood Madeleine , Hess Robert F
Published: October 2019

ABSTRACT

Boundaries in the visual world can be defined by changes in luminance and texture in the input image. A “contour integration” process joins together local changes into percepts of lines or edges. A previous study tested the integration of contours defined by second-order contrast-modulation. Their contours were placed in a background of random wavelets. Subjects performed near chance. We re-visited second-order contour integration with a different task. Subjects distinguished contours with “good continuation” from distractors. We measured thresholds in different amounts of external orientation or position noise. This gave two noise-masking functions. We also measured thresholds for contours with a baseline curvature to assess performance with more curvy targets. Our subjects were able to discriminate the good continuation of second-order contours. Thresholds were higher than for first-order contours. In our modelling, we found this was due to multiple factors. There was a doubling of equivalent internal noise between first- and second-order contour integration. There was also a reduction in efficiency. The efficiency difference was only significant in our orientation noise condition. For both first- and second-order stimuli, subjects were also able to perform our task with more curved contours. We conclude that humans can integrate second-order contours, even when they are curved. There is however reduced performance compared to first-order contours. We find both an impaired input to the integrating mechanism, and reduced efficiency seem responsible. Second-order contour integration may be more affected by the noise background used in the previous study. Difficulty segregating that background may explain their result.
Gouania willdenowi is a teleost fish without immunoglobulin genes
Authors: Mirete-Bachiller Serafin , Olivieri David N. , Gambón-Deza Francisco
Published: October 2019

In the study of immunoglobulin V genes in fish genomes, we found that the species Gouania willdenowi does not possess any such regions, neither for the heavy chain nor for the light chains. Also, genes that code for the immunoglobulin constant regions were also not found. A detailed analysis of the chromosomal region of these genes revealed a deletion in the entire locus for regions of the heavy and light chains. These studies provide evidence that this species does not possess genes coding for immunoglobulins. Additionally, we found the genes that code for CD79a and CD79b protein molecules have also been deleted. Regions for the Tα/β lymphocyte receptors are present but the T γ/δ receptors were not found. In transcripts of two other Gobiesocidae species, Acystus sp. and Tomicodon sp., no antibody sequences could be detected, possibly indicating the absence of immunoglobulins in all species of this family.
Dose-controlled tDCS reduces electric field intensity variability at a cortical target site
Authors: Evans Carys , Bachmann Clarissa , Lee Jenny , Gregoriou Evridiki , Ward Nick , Bestmann Sven
Published: October 2019

Background

Variable effects limit the efficacy of transcranial direct current stimulation (tDCS) as a research and therapeutic tool. Conventional application of a fixed-dose of tDCS does not account for inter-individual differences in anatomy (e.g. skull thickness), which varies the amount of current reaching the brain. Individualised dose-control may reduce the variable effects of tDCS by reducing variability in electric field intensities at a cortical target site.

Objective

To characterise the variability in electric field intensity at a cortical site (left primary motor cortex; M1) and throughout the brain for conventional fixed-dose tDCS, and individualised dose-controlled tDCS.

Methods

The intensity and distribution of the electric field during tDCS was estimated using Realistic Volumetric Approach to Simulate Transcranial Electric Stimulation (ROAST) in 50 individual brain scans taken from the Human Connectome Project, for fixed-dose tDCS (1mA & 2mA) and individualised dose-controlled tDCS targeting left M1.

Results

With a fixed-dose (1mA & 2mA), E-field intensity in left M1 varied by more than 100% across individuals, with substantial variation observed throughout the brain as well. Individualised dose-controlled ensured the same E-field intensity was delivered to left M1 in all individuals. Its variance in other regions of interest (right M1 and area underneath the electrodes) was comparable with fixed- and individualised-dose.

Conclusions

Individualized dose-control can eliminate the variance in electric field intensities at a cortical target site. Assuming that the current delivered to the brain directly determines its physiological and behavioural consequences, this approach may allow for reducing the known variability of tDCS effects.
Muscle-derived Myoglianin regulatesDrosophilaimaginal disc growth
Authors: Upadhyay Ambuj , Peterson Aidan J. , Kim Myung-Jun , O’Connor Michael B.
Published: October 2019

Organ growth and size are finely tuned by intrinsic and extrinsic signaling molecules. InDrosophila, the BMP family member Dpp is produced in a limited set of imaginal disc cells and functions as a classic morphogen to regulate pattern and growth by diffusing throughout imaginal discs. However, the role of TGFβ/Activin-like ligands in disc growth control remains ill-defined. Here we demonstrate that Myoglianin (Myo), an Activin family member, and a close homolog of mammalian Myostatin (Mstn), is a muscle-derived extrinsic factor that uses canonical dSmad2 mediated signaling to regulate wing size. We propose that Myo is a myokine that helps mediate an allometric relationship between muscles and their associated appendages.
Diagnostic value of circulating tumor DNA as an effective biomarker in cervical cancer: a meta-analysis
Authors: Gu Yulan , Wan Chuandan , Qiu Jiaming , Cui Yanhong , Jiang Tingwang
Published: October 2019

The applications of liquid biopsy have attracted much attention in biomedical research in recent years. Circulating cell-free DNA (cfDNA) in the serum may serve as a unique tumor marker in various types of cancer. Circulating tumor DNA (ctDNA) is a type of serum cfDNA found in patients with cancer and contains abundant information regarding tumor characteristics, highlighting its potential diagnostic value in the clinical setting. However, the diagnostic value of cfDNA as a biomarker in cervical cancer remains unclear. Here, we performed a meta-analysis to evaluate the applications of ctDNA as a biomarker in cervical cancer. A systematic literature search was performed using PubMed, Embase, and WANFANG MED ONLINE databases up to March 18, 2019. All literature was analyzed using Meta Disc 1.4 and STATA 14.0 software. Diagnostic measures of accuracy of ctDNA in cervical cancer were pooled and investigated. Fifteen studies comprising 1109 patients with cervical cancer met our inclusion criteria and were subjected to analysis. The pooled sensitivity and specificity were 0.52 (95% confidence interval [CI], 0.33–0.71) and 0.97 (95% CI, 0.91–0.99), respectively. The pooled positive likelihood ratio and negative likelihood ratio were 16.0 (95% CI, 5.5–46.4) and 0.50 (95% CI, 0.33–0.75), respectively. The diagnostic odds ratio was 32 (95% CI, 10–108), and the area under the summary receiver operating characteristic curve was 0.92 (95% CI, 0.90– 0.94). There was no significant publication bias observed. In the included studies, ctDNA showed clear diagnostic value for diagnosing and monitoring cervical cancer. Our meta-analysis suggested that detection of human papilloma virus ctDNA in patients with cervical cancer could be used as a noninvasive early dynamic biomarker of tumors, with high specificity and moderate sensitivity. Further large-scale prospective studies are required to validate the factors that may influence the accuracy of cervical cancer diagnosis and monitoring.
Energy landscape steering mediates dynamic coupling in ATP-driven protein translocation by the bacterial Sec machinery
Authors: Crossley Joel A. , Allen William J. , Watkins Daniel W. , Sabir Tara , Radford Sheena E. , Tuma Roman , Collinson Ian , Fessl Tomas
Published: October 2019

The Sec translocon is a highly conserved membrane complex for transport of polypeptides across, or into, lipid bilayers. In bacteria, the core protein-channel SecYEG resides in the inner-membrane, through which secretion is powered by the cytosolic ATPase SecA. Here, we use single-molecule fluorescence to interrogate the dynamic state of SecYEG throughout the hydrolytic cycle of SecA. We show that the SecYEG channel fluctuates between open and closed states faster (∼20-fold during transport) than ATP turnover; while the nucleotide status of SecA modulates the rates of opening and closure. Interestingly, a SecY variant (PrlA4), exhibiting faster protein transport, but unaffected ATPase rates, increases the dwell time in the open state, facilitating pre-protein diffusion through the pore; thereby improving the efficiency of translocation. Thus, contrary to prevailing structure-based models, SecYEG plays an integral part in the translocation mechanism through dynamic allosteric coupling in which SecA ‘steers’ the energy landscape of the protein-channel.
Mitigating Temozolomide Resistance in Glioblastoma via DNA Damage-Repair Inhibition
Authors: Sorribes Inmaculada C. , Handelman Samuel K. , Jain Harsh V.
Published: October 2019

Glioblastomas are among the most lethal cancers, with a five year survival rate below 25%. Temozolomide is typically used in glioblastoma treatment; however, the enzymes APNG and MGMT efficiently mediate the repair of DNA damage caused by temozolomide, reducing treatment efficacy. Consequently, APNG and MGMT inhibition has been proposed as a way of overcoming chemotherapy resistance. Here, we develop a mechanistic mathematical model that explicitly incorporates the effect of chemotherapy on tumor cells, including the processes of DNA damage induction, cell arrest and DNA repair. Our model is carefully parameterized and validated, and then used to virtually recreate the response of heteroclonal glioblastoma to dual treatment with TMZ and inhibitors of APNG/MGMT. Using our mechanistic model, we identify four combination treatment strategies optimized by tumor cell phenotype, and isolate the strategy most likely to succeed in a pre-clinical and clinical setting. If confirmed in clinical trials, these strategies have the potential to offset chemotherapy resistance in glioblastoma patients, and improve overall survival.
Imaging FCS Delineates Subtle Heterogeneity in Plasma Membranes of Resting Mast Cells
Authors: Bag Nirmalya , Holowka David A. , Baird Barbara A.
Published: October 2019

A myriad of transient, nanoscopic lipid- and protein-based interactions confer a steady-state organization of plasma membrane in resting cells that is poised to orchestrate assembly of key signaling components upon reception of an extracellular stimulus. Although difficult to observe directly in live cells, these subtle interactions can be discerned by their impact on the diffusion of membrane constituents. Herein, we quantified the diffusion properties of a panel of structurally distinct lipid-anchored and transmembrane (TM) probes in RBL mast cells by multiplexed Imaging Fluorescence Correlation Spectroscopy. We developed a statistical analysis of data combined from many pixels over multiple cells to characterize differences as small as 10% in diffusion coefficients, which reflect differences in underlying interactions. We found that the distinctive diffusion properties of lipid-anchored probes can be explained by their dynamic partitioning into ordered proteo-lipid nanodomains, which encompass a major fraction of the membrane and whose physical properties are influenced by actin polymerization. Effects on diffusion by functional protein modules in both lipid-anchored and TM probes reflect additional complexity in steady-state membrane organization. The contrast we observe between different probes diffusing through the same membrane milieu represent the dynamic resting steady-state, which serves as a baseline for monitoring plasma membrane remodeling that occurs upon stimulation.
Light activates the translational regulatory GCN2 kinase via reactive oxygen species emanating from the chloroplast
Authors: Lokdarshi Ansul , Guan Ju , Urquidi Camacho Ricardo A , Cho Sung Ki , Morgan Philip , Leonard Madison , Shimono Masaki , Day Brad , von Arnim Albrecht G
Published: October 2019

Cytosolic mRNA translation is subject to global and mRNA-specific controls. Phosphorylation of translation initiation factor eIF2α anchors a reversible switch that represses translation globally. The stress-responsive GCN2 kinase is the only known kinase for eIF2α inArabidopsis. Here we show that conditions that generate reactive oxygen species (ROS) in the chloroplast, such as dark-light transitions, high light, and the herbicide methyl viologen all rapidly activated the GCN2 kinase, whereas mitochondrial and ER stress did not. In addition, GCN2 activation was light dependent and mitigated by photosynthesis inhibitors and ROS quenchers. Accordingly, seedling growth of multiplegcn2mutant alleles was retarded under conditions of excess light, implicating the GCN2-eIF2α pathway in responses to light and associated ROS. Once activated, the GCN2 kinase preferentially suppressed the ribosome loading of mRNAs for functions such as mitochondrial ATP synthesis, the chloroplast thylakoids, vesicle trafficking, and translation. The transcriptome ofgcn2mutants was sensitized to abiotic stress, including oxidative stress, as well as innate immune responses. Accordingly,gcn2displayed defects in immune priming by the fungal elicitor, chitin. In conclusion, we provide evidence that reactive oxygen species produced by the photosynthetic apparatus help to activate the highly conserved GCN2 kinase, leading to eIF2α phosphorylation and thus affecting the status of the cytosolic protein synthesis apparatus.
Multispectral Imaging Differentiates Unique Macrophage Profiles in Patients with Distinct Chronic Liver Diseases
Authors: Saldarriaga Omar A. , Booth Adam L. , Freiberg Benjamin , Burks Jared , Krishnan Santhoshi , Rao Arvind , Utay Netanya , Ferguson Monique , Yi Minkyung , Beretta Laura , Stevenson Heather L.
Published: October 2019

Intrahepatic macrophages influence the composition of the microenvironment, host immune response to liver injury, and development of fibrosis. Compared to stellate cells, the role of intrahepatic macrophages in the development of fibrosis remains ill defined. Multispectral imaging allows detection of multiple markersin situin human formalin-fixed, paraffin-embedded tissue. This cutting-edge technology is ideal for analyzing human liver tissues since it allows spectral unmixing of fluorophore signals, subtraction of auto-fluorescence, and preserves architecture and thein vivohepatic milieu. We analyzed resident Kupffer cells (CD68+), monocyte-derived macrophages (Mac387+), pro-fibrogenic macrophages (CD163+), and co-expression of pro-inflammatory (CD14) and anti-inflammatory (CD16) markers in liver biopsies from patients with hepatitis C virus (HCV) and different stages of fibrosis. Liver biopsies with advanced fibrosis showed increased accumulation of CD163+, MAC387+ and CD68+ macrophages in the portal tracts when compared to those with minimal fibrosis. Imaging software generated t-distributed stochastic neighbor embedding (t-SNE) plots and phenotype matrices that facilitated comparison of macrophage profiles. These included monocyte-derived (CD68+/Mac387+) and pro-fibrotic/anti-inflammatory (CD163+/CD16+) phenotypes. We established that the utility of this platform could be extended to liver biopsies from patients with other chronic liver diseases including nonalcoholic steatohepatitis and autoimmune hepatitis. Each disease exhibited a unique profile after spectral imaging analysis and this platform holds the potential to identify patients predisposed to progressive liver disease based on the macrophage composition. In summary, spectral imaging is a powerful tool that enables analysis of macrophage profiles in different types of chronic liver diseases and has potential to change the manner in which we evaluate liver biopsies leading to more personalized treatment strategies.
Novel functional insights revealed by distinct protein-protein interactions of the residual SWI/SNF complex in SMARCA4-deficient small cell carcinoma of the ovary, hypercalcemic type
Authors: Raupach Elizabeth A. , Garcia-Mansfield Krystine , Sharma Ritin , Hegde Apurva M. , David-Dirgo Victoria , Wang Yemin , Shin Chae Young , Tao Lan V. , Facista Salvatore J. , Moore Rayvon , Lang Jessica D. , Zismann Victoria L. , Orlando Krystal A. , Spillman Monique , Karnezis Anthony N. , Bennett Lynda B. , Huntsman David G. , Trent Jeffrey M. , Hendricks William P. D. , Weissman Bernard E. , Pirrotte Patrick
Published: October 2019

Chromatin remodeling plays a critical role in tumor suppression as demonstrated by 20% of human cancers bearing inactivating mutations in SWI/SNF chromatin remodeling complex members. Mutations in different SWI/SNF subunits drive a variety of adult and pediatric tumor types, including non-small cell lung cancers, rhabdoid tumors, medulloblastomas, and ovarian cancers. Small cell carcinoma of the ovary hypercalcemic type (SCCOHT) is an aggressive subtype of ovarian cancer occurring in young women. Nearly all (>98%) SCCOHTs have inactivating mutations inSMARCA4, which encodes 1 of 2 mutually exclusive catalytic subunits of the SWI/SNF complex. Less than half of SCCOHT patients survive 5 years despite aggressive surgery and multimodal chemotherapy. Empirical support for effective SCCOHT treatments is scarce, in part because of the poor understanding of SCCOHT tumorigenesis. To gain insight into the functional consequences of SWI/SNF subunit loss, we defined SWI/SNF composition and its protein-protein interactions (PPIs) by immunoprecipitation and mass spectrometry (IP-MS) of SWI/SNF subunits in 3 SCCOHT cell lines. Comparing these results to a cell line containing a wild-type SWI/SNF complex, the interaction of most canonical core SWI/SNF subunits was observed in all SCCOHT cell lines at a lower abundance. The SCCOHT SWI/SNF also lacked ATPase module subunits and showed a drastic reduction in PBAF-specific subunit interactions. The wild-type and SCCOHT SWI/SNF subunits immunoprecipitated a shared set of 26 proteins, including core SWI/SNF subunits and RNA processing proteins. We observed 131 proteins exclusively interacting with the wild-type SWI/SNF complex including isoform-specific SWI/SNF subunits, members of the NuRD complex, and members of the MLL3/4 complex. We observed 60 PPIs exclusive to the SCCOHT residual SWI/SNF shared in at least 2 of the 3 SCCOHT cell lines, including many proteins involved in RNA processing. Differential interactions with the residual SWI/SNF complex in SCCOHT may further elucidate altered functional consequences of SMARCA4 mutations in these tumors as well as identify synthetic lethal targets that translate to other SWI/SNF-deficient tumors.
Range expansion shifts clonal interference patterns in evolving populations
Authors: Krishnan Nikhil , Fusco Diana , Scott Jacob G.
Published: October 2019

Increasingly, predicting and even controlling evolutionary processes is a sought after goal in fields ranging from agriculture, artificial intelligence, astrobiology, oncology, and infectious diseases. However, our ability to predict evolution and plan such interventions in real populations is limited in part by our understanding of how spatial structure modulates evolutionary dynamics. Among current clinical assays applied to predict drug response in infectious diseases, for instance, many do not explicitly consider spatial structure and its influence on phenotypic heterogeneity, despite it being an inextricable characteristic of real populations. As spatially structured populations are subject to increased interference of beneficial mutants compared to their well-mixed counter-parts, among other effects, this population heterogeneity and structure may non-trivially impact drug response. In spatially-structured populations, the extent of this mutant interference is density dependent and thus varies with relative position within a meta-population in a manner modulated by mutant frequency, selection strength, migration speed, and habitat length, among other factors. In this study, we examine beneficial mutant fixation dynamics along the front of an asexual population expanding its range. We observe that multiple distinct evolutionary regimes of beneficial mutant origin-fixation dynamics are maintained at characteristic length scales along the front of the population expansion. Using an agent-based simulation of range expansion with mutation and selection in one dimension, we measure these length scales across a range of population sizes, selection strengths, and mutation rates. Furthermore, using simple scaling arguments to adapt theory from well-mixed populations, we find that the length scale at the tip of the front within which ‘local’ mutant fixation occurs in a successive mode decreases with increasing mutation rate, as well as population size in a manner predicted by our derived analytic expression. Finally, we discuss the relevance of our findings to real cellular populations, arguing that this conserved region of successive mutant fixation dynamics at the wave tip can be exploited by emerging evolutionary control strategies.