bluuebunny/crossref_metadata_2025_split huggingface dataset:
Thermal and Chemical Unfolding of a recombinant monoclonal IgG1 antibody: Application of the Multi-State Zimm-Bragg Theory
Authors: Garidel P. , Eiperle A. , Blech M. , Seelig J. 
Published: July 2019

AbstractThe thermal unfolding of a recombinant monoclonal antibody IgG1 (mAb) was measured with differential scanning calorimetry (DSC). The DSC thermograms reveal a pre-transition at 72°C with an unfolding enthalpy of ΔHcal∼ 200-300 kcal/mol and a main transition at 85 °C with an enthalpy of ∼900 - 1000 kcal/mol. In contrast to single-domain molecules, mAb unfolding is a complex reaction that is analysed with the multi-state Zimm-Bragg theory. For the investigated mAb, unfolding is characterised by a cooperativity parameter σ ∼10−4and a Gibbs free energy of unfolding of gnu∼100 cal/mol per amino acid. The enthalpy of unfolding provides the number of amino acid residuesvparticipating in the unfolding reaction. On average,v∼220±50 amino acids are involved in the pre-transition andv∼850±30 in the main transition, accounting for ∼90% of all amino acids. Thermal unfolding was further studied in the presence of guanidineHCl. The chemical denaturant reduces the unfolding enthalpy ΔHcaland lowers the midpoint temperature T0. Both parameters depend linearly on the concentration of denaturant. The guanidineHCl concentrations needed to unfold mAb at 25 °C are predicted to be 2-3 M for the pre-transition and 5-7 M for the main transition, varying with pH. GuanidineHCl binds to mAb with an exothermic binding enthalpy, which partially compensates the endothermic mAb unfolding enthalpy. The number of guanidineHCL molecules bound upon unfolding is deduced from the DSC thermograms. The bound guanidineHCl-to-unfolded amino acid ratio is 0.79 for the pre-transition and 0.55 for the main transition. The pre-transition binds more denaturant molecules and is more easily destabilised than the main transition.Overall, the current study shows the strength of the Zimm-Bragg model for the quantitative description of unfolding events of large, therapeutic proteins, such as a monoclonal antibody.Statement of significanceFirst quantitative thermodynamic study of an antibody with differential scanning calorimetry and analyzed with the multi-state Zimm-Bragg theory.
Colicin E1 opens its hinge to plug TolC
Authors: Budiardjo S. Jimmy , Stevens Jacqueline J. , Calkins Anna L. , Ikujuni Ayotunde P. , Wimalasena Virangika K. , Firlar Emre , Case David A. , Biteen Julie S. , Kaelber Jason T. , Slusky Joanna S.G. 
Published: July 2019

AbstractThe double membrane architecture of Gram-negative bacteria forms a barrier that is effectively impermeable to extracellular threats. Bacteriocin proteins evolved to exploit the accessible, surface-exposed proteins embedded in the outer membrane to deliver cytotoxic cargo. Colicin E1 is a bacteriocin produced by, and lethal to, Escherichia coli that hijacks the outer membrane proteins TolC and BtuB to enter the cell. Here we capture the colicin E1 translocation domain inside its membrane receptor, TolC, by high-resolution cryoEM, the first reported structure of a bacteriocin bound to TolC. Colicin E1 binds stably to TolC as an open hinge through the TolC pore—an architectural rearrangement from colicin E1’s unbound conformation. This binding is stable in live E. coli cells as indicated by single-molecule fluorescence microscopy. Finally, colicin E1 fragments binding to TolC plugs the channel, inhibiting its native efflux function as an antibiotic efflux pump and heightening susceptibility to three antibiotic classes. In addition to demonstrating that these protein fragments are useful starting points for developing novel antibiotic potentiators, this method could be expanded to other colicins to inhibit other outer membrane protein functions.
Cancer Type-Dependent Correlations betweenTP53Mutations and Antitumor Immunity
Authors: Li Lin , Li Mengyuan , Wang Xiaosheng 
Published: July 2019

AbstractMany studies have shown thatTP53mutations play a negative role in antitumor immunity. However, a few studies reported thatTP53mutations could promote antitumor immunity. To explain these contradictory findings, we analyzed five cancer cohorts from The Cancer Genome Atlas (TCGA) project. We found thatTP53-mutated cancers had significantly higher levels of antitumor immune signatures thanTP53-wildtype cancers in breast invasive carcinoma (BRCA) and lung adenocarcinoma (LUAD). In contrast,TP53-mutated cancers had significantly lower antitumor immune signature levels thanTP53-wildtype cancers in stomach adenocarcinoma (STAD), colon adenocarcinoma (COAD), and head and neck squamous cell carcinoma (HNSC). Moreover,TP53-mutated cancers likely had higher tumor mutation burden (TMB) and tumor aneuploidy level (TAL) thanTP53-wildtype cancers. However, the TMB differences were more marked betweenTP53-mutated andTP53-wildtype cancers than the TAL differences in BRCA and LUAD, and the TAL differences were more significant in STAD and COAD. Furthermore, we showed that TMB and TAL had a positive and a negative correlation with antitumor immunity and that TMB affected antitumor immunity more greatly than TAL did in BRCA and LUAD while TAL affected antitumor immunity more strongly than TMB in STAD and HNSC. These findings indicate that the distinct correlations betweenTP53mutations and antitumor immunity in different cancer types are a consequence of the joint effect of the altered TMB and TAL caused byTP53mutations on tumor immunity. Our data suggest that theTP53mutation status could be a useful biomarker for cancer immunotherapy response depending on cancer types.
GSDB: a database of 3D chromosome and genome structures reconstructed from Hi-C data
Authors: Oluwadare Oluwatosin , Highsmith Max , Cheng Jianlin 
Published: July 2019

ABSTRACTAdvances in the study of chromosome conformation capture (3C) technologies, such as Hi-C technique - capable of capturing chromosomal interactions in a genome-wide scale - have led to the development of three-dimensional (3D) chromosome and genome structure reconstruction methods from Hi-C data. The 3D genome structure is important because it plays a role in a variety of important biological activities such as DNA replication, gene regulation, genome interaction, and gene expression. In recent years, numerous Hi-C datasets have been generated, and likewise, a number of genome structure construction algorithms have been developed. However, until now, there has been no freely available repository for 3D chromosome structures. In this work, we outline the construction of a novel Genome Structure Database (GSDB) to create a comprehensive repository that contains 3D structures for Hi-C datasets constructed by a variety of 3D structure reconstruction tools. GSDB contains over 50,000 structures constructed by 12 state-of-the-art chromosome and genome structure prediction methods for publicly used Hi-C datasets with varying resolution. The database is useful for the community to study the function of genome from a 3D perspective. GSDB is accessible at http://sysbio.rnet.missouri.edu/3dgenome/GSDB
Vaccination against antibiotic resistant gonorrhoea for men who have sex with men in England: a modelling study
Authors: Whittles Lilith K , White Peter J. , Didelot Xavier 
Published: July 2019

SUMMARYBackgroundGonorrhoea incidence is increasing rapidly: diagnoses in men who have sex with men (MSM) in England increased eight-fold 2008-2017. Concurrently, antibiotic resistance is making treatment more difficult, leading to renewed interest in a gonococcal vaccine. The MeNZB meningococcal B vaccine is partially protective, and several other candidates are in development. We modelled realistic vaccination strategies under various scenarios of antibiotic resistance and vaccine protection level and duration, to assess the impact of vaccination and examine the feasibility of the WHO’s target of reducing gonorrhoea incidence by 90% between 2016 and 2030.MethodsWe fitted a stochastic transmission-dynamic model, incorporating asymptomatic and symptomatic infection and heterogeneous sexual behaviour, to gonorrhoea incidence in MSM in England, 2008-17, using particle Markov Chain Monte Carlo methods. Bayesian forecasting was used to examine future scenarios, including emergence of extensively antibiotic-resistant (ABR) gonorrhoea.FindingsEven in the worst-case scenario of untreatable infection emerging, the WHO target could be met by vaccinating all MSM attending sexual health clinics with a 53%-protective vaccine lasting for >6 years, or a 70%-protective vaccine lasting >3 years. A vaccine like MeNZB, conferring 30% protection for 2-4 years, could reduce incidence in 2030 by 45% in the worst-case scenario, and by 75% if >70% of ABR gonorrhoea is treatable.InterpretationOur statistically-rigorous assessment shows that even a partially-protective vaccine, delivered through a practical targeting strategy, could have substantial benefit in reducing gonorrhoea incidence in the context of an epidemic with rising antibiotic resistance.
The codon frustration index as a new metric for mRNA stability, translation efficiency, and rates of protein synthesis
Authors: Forcelloni Sergio , Giansanti Andrea 
Published: July 2019

AbstractTaking the human genome as a case of study, we propose a new classification of codons based only on two genomic information. We use the relative synonymous codon usage (RSCU) as a measure of non-uniform usage of synonymous codons. Similarly, we introduce here the relative gene frequencies of cognate tRNAs (RGFCt) to quantify the non-uniform availability of cognate tRNAs in each family of synonymous codons. Using these two quantities, we define two general groups of codons: non-frustrated codons, whose usage in the coding sequences is in proportion to the expected cognate tRNA levels, and frustrated codons, which do not satisfy this proportionality. With this decoding for every codon, we defined the Codon Frustration Index (CFI) as the net frustration of a gene, normalized for its length. Notably, we find that CFI correlates very well with other independent measures of CUB and a high content of non-frustrated codons increases both translation efficiency and mRNA stability. Finally, we show that genes with either a high content of frustrated or of non-frustrated codons are differentially enriched in specific functional classes that typically comprise nucleic acid binding proteins, mRNA processing factors, RNA helicase, and in several transcription factors.
Evolutionary dynamics of abundant 7 bp satellites in the genome ofDrosophila virilis
Authors: Flynn Jullien M. , Long Manyuan , Wing Rod A. , Clark Andrew G. 
Published: July 2019

AbstractThe factors that drive the rapid changes in satellite DNA genomic composition we see in eukaryotes are not well understood.Drosophila virilishas one of the highest relative amounts of simple satellites of any organism that has been studied, with an estimated >40% of its genome composed of a few related 7 bp satellites. Here we useD. virilisas a model to understand technical biases affecting satellite sequencing and the evolutionary processes that drive satellite composition. By analyzing sequencing data from Illumina, PacBio, and Nanopore platforms, we identify platform-specific biases and suggest best practices for accurate characterization of satellites by sequencing. We use comparative genomics and cytogenetics to demonstrate that the highly abundant satellite family arose from a related satellite in the branch leading to the virilis phylad 4.5 - 11 million years ago before exploding in abundance in some species of the clade. The most abundant satellite is conserved in sequence and location in the pericentromeric region but has diverged widely in abundance among species, whereas the satellites nearest the centromere are rapidly turning over in sequence composition. By analyzing multiple strains ofD. virilis, we saw that one centromere-proximal satellite is increasing in abundance along a geographical gradient while the other is contracting in an anti-correlated manner, suggesting ongoing conflicts at the centromere. In conclusion, we illuminate several key attributes of satellite evolutionary dynamics that we hypothesize to be driven by processes like selection, meiotic drive, and constraints on satellite sequence and abundance.
High-Resolution Cryo-EM Reveals Dynamics in the Murine Norovirus Capsid
Authors: Snowden Joseph S. , Hurdiss Daniel L. , Adeyemi Oluwapelumi O. , Ranson Neil A. , Herod Morgan R. , Stonehouse Nicola J. 
Published: July 2019

AbstractRather than acting as rigid symmetrical shells to protect and transmit their genomes, the capsids of non-enveloped, icosahedral viruses co-ordinate multiple, essential processes during the viral life-cycle, and undergo extensive conformational rearrangements to deliver these functions. Capturing conformational flexibility has been challenging, yet could be key in understanding and combating infections that viruses cause. Noroviruses are non-enveloped, icosahedral viruses of global importance to human health. They are a common cause of acute non-bacterial gastroenteritis, yet no vaccines or antiviral agents specific to norovirus are available. Here, we use cryo-electron microscopy to study the high-resolution solution structures of infectious, inactivated and mutant virions of murine norovirus (MNV) as a model for human noroviruses. Together with genetic studies, we show that the viral capsid is highly dynamic. While there is little change to the shell domain of the capsid, the protruding domains that radiate from this are flexible and adopt distinct states both independently and synchronously. In doing so the viral capsid is able to sample a defined range of conformational space, with implications for the maintenance of virion stability and infectivity. These data will aid in developing the first generation of effective control measures against this virus.
An adaptive algorithm for fast and reliable online saccade detection
Authors: Schweitzer Richard , Rolfs Martin 
Published: July 2019

AbstractTo investigate visual perception around the time of eye movements, vision scientists manipulate stimuli contingent upon the onset of a saccade. For these experimental paradigms, timing is especially crucial, as saccade offset imposes a deadline on the display change. Although efficient online saccade detection can greatly improve timing, most algorithms rely on spatial-boundary techniques or absolute-velocity thresholds, which both suffer from their respective weaknesses: late detections and false alarms. We propose an adaptive, velocity-based algorithm for online saccade detection that surpasses both standard techniques in speed and accuracy and allows the user to freely define detection criteria. Inspired by the Engbert-Kliegl-algorithm for microsaccade detection, our algorithm computes two-dimensional velocity thresholds from variance in preceding fixation samples, while compensating for noisy or missing data samples. An optional direction criterion limits detection to the instructed saccade direction, further increasing robustness. We validated the algorithm by simulating its performance on a large saccade dataset and found that high detection accuracy (false-alarm rates of <1%) could be achieved with detection latencies of only 3 milliseconds. High accuracy was maintained even under simulated high-noise conditions. To demonstrate that purely intra-saccadic presentations are technically feasible, we devised an experimental test, in which a Gabor patch drifted at saccadic peak velocities. While this stimulus was invisible when presented during fixation, observers reliably detected it during saccades. Photodiode measurements verified that – including all system delays – stimuli were physically displayed on average 20 ms after saccade onset. Thus, the proposed algorithm provides valuable tool for gaze-contingent paradigms.
CX3CL1 and CX3CR1 Expressing Tendon Cells – A novel Immune Cell Population in the Tendon Core
Authors: Lehner Christine , Spitzer Gabriel , Gehwolf Renate , Wagner Andrea , Weissenbacher Nadja , Deininger Christian , Emmanuel Katja , Wichlas Florian , Tempfer Herbert , Traweger Andreas 
Published: July 2019

AbstractTendon disorders frequently occur and recent evidence has clearly implicated the presence of immune cells and inflammatory events during early tendinopathy. However, the origin and properties of these cells remain poorly defined. Therefore, the aim of this study was to determine the presence of myleoid cells in healthy rodent and human tendon tissue and to characterize them. Using various transgenic reporter mouse models, we demonstrate the presence of tendon cells in the dense matrix of the tendon core expressing the fractalkine (Fkn) receptor CX3CR1 and its cognate ligand CX3CL1/Fkn. Pro-inflammatory stimulation of 3D tendon-like constructsin vitroresulted in a significant increase in the expression of IL-1β, IL-6, Mmp3, Mmp9, Cx3cl1, and epiregulin which has been reported to contribute to inflammation, wound healing, and tissue repair. Furthermore, we demonstrate that inhibition of the fractalkine receptor blocked tendon cell migrationin vitroand show the presence of CX3CR1/CX3CL1/EREG expressing cells in healthy human tendons. Taken together, we demonstrate the presence of CX3CL1+/CX3CR1+ “tenophages” within the healthy tendon proper potentially fulfilling surveillance functions in tendons.Summary StatementHere, we demonstrate the presence of a macrophage-like, CX3CL1/CX3CR1-expressing cell population within the healthy tendon proper potentially fulfilling a surveillance function.
Investigating the Effects of Osmolytes and Environmental pH on Bacterial Persisters
Authors: Karki Prashant , Orman Mehmet A. 
Published: July 2019

ABSTRACTBacterial persisters are phenotypic variants that temporarily demonstrate an extraordinary tolerance towards antibiotics. Persisters have been linked to the recalcitrance of biofilm related infections; hence, a complete understanding of the physiology of persisters can lead to improvement of therapeutic strategies associated with such infections. Mechanisms pertaining to persister formation are known to be related to stress response pathways triggered from intra- or extra-cellular stress factors. Unfortunately, studies demonstrating the effects of osmolyte- and/or pH- induced stresses on bacterial persistence are largely missing. To fill this knowledge gap within the field, here we studied the effects of various osmolytes and pH conditions onEscherichia colipersistence with the use of phenotype microarrays and antibiotic tolerance assays. Although we found that a number of chemicals and pH environments, including urea, sodium nitrite and acidic pH, significantly reduced persister formation inE. colicompared to no-osmolyte/no-buffer controls, this reduction in persister levels was lessened in late-stationary-phase cultures. Our results further demonstrated a positive correlation between cell growth and persister formation, which challenges the general notion in the field that slow-growing cultures have more persister cells than fast-growing cultures.
Perifolliculitis capitis abscedens et suffodiens treatment with tumor necrosis factor inhibitors: A case report and review of published cases
Authors: Takahashi Toshiya , Yamasaki Kenshi , Terui Hitoshi , Omori Ryoko , Tsuchiyama Kenichiro , Fujimura Taku , Aiba Setsuya 
Published: July 2019

AbstractPerifolliculitis capitis abscedens et suffodiens (PCAS) or dissecting cellulitis is a rare condition presenting deep follicular occlusions, follicular ruptures and follicular infections in the scalp area with unknown etiology, which consequently cause primary neutrophilic cicatricial alopecia by the repeated follicular inflammation. PCAS is categorized as one of the “follicular occlusion tetrad” along with hidradenitis suppurativa, acne conglobata and pilonidal cyst. In the pathogenesis of the follicular occlusion tetrad, the involvement of neutrophils and its activator tumor necrosis factor (TNF) have been discussed. Here, we report a case of PCAS that was successfully treated with adalimumab, a human anti‐TNF monoclonal antibody. This is the first Asian case of PCAS that was improved by a TNF inhibitor.
Circulating miR‐99b‐5p as a novel predictor of erosion progression on high‐resolution peripheral quantitative computed tomography in early rheumatoid arthritis: A prospective cohort study
Authors: Yue Jiang , Lau Terrence C. K. , Griffith James F. , Xu Jiankun , Xiao Fan , Shi Lin , Wang Defeng , Wong Priscilla C. H. , Li Edmund K. , Tam Lydia P. , Li Martin , Li Tena K. , Mak Wah Yan , Hung Vivian , Qin Ling , Tam Lai‐Shan 
Published: July 2019

AbstractObjectivesTo compare micro RNA (miRNA) expression: (a) between healthy individuals and early rheumatoid arthritis (ERA) patients with and without erosion on high‐resolution peripheral quantitative computed tomography (HR‐pQCT) at baseline; and (b) to explore whether these miRNAs could inform a signature predictive of erosion progression despite treatment with conventional synthetic disease‐modifying antirheumatic drugs (csDMARDs).MethodsThe second metacarpophalangeal head (MCP2) was scanned by HR‐pQCT at baseline and 1 year in 117 ERA patients. We performed global profiling of 377 miRNAs in 10 ERA patients with and without erosion on HR‐pQCT at baseline and six healthy controls. Validation of the miRNAs of interest were conducted using TaqMan® quantitative real‐time polymerase chain reaction in the validation ERA cohort (n = 117) at baseline. Correlation between the candidate miRNAs and erosion progression over 1 year were also assessed.ResultsIn the 377 screened miRNAs, 94 (60.6%) miRNAs were upregulated in patients with erosions, with 13 (8.4%) upregulated more than 2‐fold. Sixty‐one (39.4%) miRNAs were downregulated in patients with erosions, with 6 (3.9%) downregulated more than 2‐fold. Expression of miR‐143‐3p, miR‐145‐5p and miR‐99b‐5p were significantly higher in the plasma of ERA patients with erosions compared with those without erosions. Logistic regression analysis revealed that the baseline expression of miR‐99b‐5p was an independent predictor of erosion progression at month 12 (Exp [B] = 4.257, 95% CI 1.178‐15.386, P = 0.027).ConclusionsDifferential expressions of circulating miR‐143‐3p, miR‐145‐5p and miR‐99b‐5p in the plasma of ERA patients may characterize a severe form of the disease. MiR‐99b‐5p, in particular, may serve as a possible predictor for erosion progression.
Market response to dividend change announcements: unregulated versus regulated US firms
Authors: Khokhar Abdul‐Rahman , Sarkar Sudipto 
Published: July 2019

AbstractThis paper attempts to determine whether there is a significant difference in how the stock market responds to dividend change announcements of regulated (both utilities and financials) versus unregulated firms and, if so, which factors cause this difference. An analysis of dividend change announcements of US firms over the period 1962–2016 shows that the market response is larger for unregulated than for regulated firms, but this difference is statistically significant only for dividend increases (not for dividend decreases). Further, cross‐sectional analysis indicates that, for dividend increases, the difference between regulated and unregulated firms increases with diffused ownership and informational asymmetry. When both these factors are controlled for, the difference between regulated and unregulated firms becomes statistically insignificant. Thus, the evidence suggests that the significant difference in market response to dividend increases of regulated versus unregulated firms can be explained by differences in diffused ownership and informational asymmetry. There seems to be no intrinsic difference between regulated and unregulated firms in the market response to dividend decreases.