bluuebunny/crossref_metadata_2025_split huggingface dataset:
Insights into the Polyhexamethylene Biguanide (PHMB) Mechanism of Action on Bacterial Membrane and DNA: A Molecular Dynamics Study
Authors: Sowlati-Hashjin Shahin , Carbone Paola , Karttunen Mikko 
Published: March 2020

AbstractPolyhexamethylene biguanide (PHMB) is a cationic polymer with antimicrobial and antiviral properties. It has been commonly accepted that the antimicrobial activity is due the ability of PHMB to perforate the bacterial phospholipid membrane leading ultimately to its death. In this study we show by the means of atomistic molecular dynamics (MD) simulations that while the PHMB molecules attach to the surface of the phospholipid bilayer and partially penetrate it, they do not cause any pore formation at least within the microsecond simulation times. The polymers initially adsorb onto the membrane surface via the favourable electrostatic interactions between the phospholipid headgroups and the biguanide groups, and then partially penetrate the membrane slightly disrupting its structure. This, however, does not lead to the formation of any pores. The microsecond-scale simulations reveal that it is unlikely for PHMB to spontaneously pass through the phospholipid membrane. Our findings suggest that PHMB translocation across the bilayer may take place through binding to the phospholipids. Once inside the cell, the polymer can effectively ‘bind’ to DNA through extensive interactions with DNA phosphate backbone, which can potentially block the DNA replication process or activate DNA repair pathways.TOC Graphic
Conformational states of the cytoprotective protein Bcl-xL
Authors: Ryzhov P. , Tian Y. , Yao Y. , Bobkov A. A. , Im W. , Marassi F. M. 
Published: March 2020

ABSTRACTBcl-xL is a major inhibitor of apoptosis, a fundamental homeostatic process of programmed cell death that is highly conserved across evolution. Because it plays prominent roles in cancer, Bcl-xL is a major target for anti-cancer therapy and for studies aimed at understanding its structure and activity. While Bcl-xL is active primarily at intracellular membranes, most studies have focused on soluble forms of the protein lacking both the membrane-anchoring C-terminal tail and the intrinsically disordered loop, and this has resulted in a fragmented view of the protein’s biological activity. Here we describe how these segments affect the protein’s conformation and ligand binding activity in both its soluble and membrane-anchored states. The combined data from nuclear magnetic resonance (NMR) spectroscopy, molecular dynamics (MD) simulations, and isothermal titration calorimetry (ITC) provide information about the molecular basis for the protein’s functionality and a view of its complex molecular mechanisms.SIGNIFICANCEThe human protein Bcl-xL is a key regulator of programmed cell death in health and disease. Structural studies, important for understating the molecular basis for its functions, have advanced primarily by deleting both the long disordered loop that regulates its activity and the C-terminal tail that anchors the protein to intracellular membranes Here we describe the preparation and conformations of full-length Bcl-xL in both its water-soluble and membrane-anchored states. The study provides new biophysical insights about Bcl-xL and its greater Bcl-2 protein family.
Poisson poisoning as the mechanism of action of the microtubule-targeting agent colchicine
Authors: Hemmat M. , Braman M. , Escalante D. , Odde D.J. 
Published: March 2020

AbstractMicrotubule-directed anti-cancer drugs, such as paclitaxel, vinblastine, and colchicine, disrupt cell mitosis through suppression of microtubule dynamics (“kinetic stabilization”). However, while the molecular mechanisms of paclitaxel and vinblastine act as pseudo- and true-kinetic stabilizers, respectively, the molecular mechanism of colchicine has remained enigmatic since it requires explanation of both the slow kinetics of the drug and suppression of microtubule dynamics. In this work, we applied an integrated multi-scale modeling-experimental approach to systematically characterize the microtubule targeting agent (MTA) colchicine. We found that colchicine stabilizes microtubule dynamics significantly bothin vivoandin vitroin a time and concentration-dependent manner. Molecular modeling results suggest that tubulin’s binding pocket is accessible to the drug for only 15% of the simulation trajectory time in straight and 82% in curved conformation on average, confirming that colchicine mainly binds to free tubulin. Molecular dynamics simulations show that there are conformational changes at longitudinal and lateral residues of GTP-tubulin-colchicine compared to a lattice tubulin structure, explaining why further incorporation of tubulin dimers to a tubulin-colchicine complex at a protofilament tip is unfavorable. Thermokinetic modeling of microtubule assembly shows that colchicine bound at fractions as low as ∼0.008 to free tubulin can poison the ends of protofilaments with a Poisson distribution and thus, reduce the microtubule growth rate, while stabilizing the tubulin lateral bond and reducing the microtubule shortening rate, i.e. true kinetic stabilization. This study suggests new strategies for colchicine administration to improve the therapeutic window in the treatment of cancer and inflammatory diseases.Significance StatementColchicine is an ancient microtubule targeting agent (MTA) known to attenuate microtubule (MT) dynamics but its cancer treatment efficacy is often limited by lack of a detailed understanding of the drug’s mechanism of action. The primary goal of this study was to perform a multi-scale systematic analysis of molecular mechanism of action of colchicine. The analysis indicates that unlike paclitaxel and vinblastine, colchicine poisons the ends of protofilaments of MTs at low fractions bound to tubulin, in a time-dependent manner. Our results suggest new insights into improvement of the clinical administration of colchicine and new colchicine-site inhibitors.
Ion transport mechanisms for smoke inhalation injured airway epithelial barrier
Authors: Chang Jianjun , Chen Zaixing , Zhao Runzhen , Nie Hong-Guang , Ji Hong-Long 
Published: March 2020

AbstractSmoke inhalation injury is the leading cause of death in firefighters and victims. Inhaled hot air and toxic smoke are the predominant hazards to the respiratory epithelium. We aimed to analyze the effects of thermal stress and smoke aldehyde on the permeability of the airway epithelial barrier. Transepithelial resistance (RTE) and short-circuit current (ISC) of mouse tracheal epithelial monolayers were digitized by an Ussing chamber setup. Zonula occludens-1 tight junctions were visualized under confocal microscopy. A cell viability test and fluorescein isothiocyanate-dextran assay were performed. Thermal stress (40°C) decreased RTEin a two-phase manner. Meanwhile, thermal stress increased ISCfollowed by its decline. Na+depletion, amiloride (an inhibitor for epithelial Na+channels [ENaCs]), ouabain (a blocker for Na+/K+-ATPase) and CFTRinh-172 (a blocker of cystic fibrosis transmembrane regulator [CFTR]) altered the responses of RTEand ISCto thermal stress. Steady-state 40°C increased activity of ENaCs, Na+/K+-ATPase, and CFTR. Acrolein, one of the main oxidative unsaturated aldehydes in fire smoke, eliminated RTEand ISC. Na+depletion, amiloride, ouabain, and CFTRinh-172 suppressed acrolein-sensitive ISC, but showed activating effects on acrolein-sensitive RTE. Thermal stress or acrolein disrupted zonula occludens-1 tight junctions, increased fluorescein isothiocyanate-dextran permeability but did not cause cell death or detachment. The synergistic effects of thermal stress and acrolein exacerbated the damage to monolayers. In conclusion, the paracellular pathway mediated by the tight junctions and the transcellular pathway mediated by active and passive ion transport pathways contribute to impairment of the airway epithelial barrier caused by thermal stress and acrolein.Graphical HeadlightsThermal stress and acrolein are two essential determinants for smoke-inhalation injury, impairing airway epithelial barrier.Transcellular ion transport pathways via the ENaC, CFTR, and Na/K-ATPase are interrupted by both thermal stress and acrolein, one of the most potent smoke toxins.Heat and acrolein damage the integrity of the airway epithelium through suppressing and relocating the tight junctions.
A survey of rare epigenetic variation in 23,116 human genomes identifies disease-relevant epivariations and novel CGG expansions
Authors: Garg Paras , Jadhav Bharati , Rodriguez Oscar L. , Patel Nihir , Martin-Trujillo Alejandro , Jain Miten , Metsu Sofie , Olsen Hugh , Paten Benedict , Ritz Beate , Kooy R. Frank , Gecz Jozef , Sharp Andrew J. 
Published: March 2020

ABSTRACTThere is growing recognition that epivariations, most often recognized as promoter hypermethylation events that lead to gene silencing, are associated with a number of human diseases. However, little information exists on the prevalence and distribution of rare epigenetic variation in the human population. In order to address this, we performed a survey of methylation profiles from 23,116 individuals using the Illumina 450k array. Using a robust outlier approach, we identified 4,452 unique autosomal epivariations, including potentially inactivating promoter methylation events at 384 genes linked to human disease. For example, we observed promoter hypermethylation ofBRCA1andLDLRat population frequencies of ~1 in 3,000 and ~1 in 6,000 respectively, suggesting that epivariations may underlie a fraction of human disease which would be missed by purely sequence-based approaches. Using expression data, we confirmed that many epivariations are associated with outlier gene expression. Analysis of SNV data and monozygous twin pairs suggests that approximately two thirds of epivariations segregate in the population secondary to underlying sequence mutations, while one third are likely sproradic events that occur post-zygotically. We identified 25 loci where rare hypermethylation coincided with the presence of an unstable CGG tandem repeat, and validated the presence of novel CGG expansions at several of these, identifying the molecular defect underlying most of the known folate-sensitive fragile sites in the genome. Our study provides a catalog of rare epigenetic changes in the human genome, gives insight into the underlying origins and consequences of epivariations, and identifies many novel hypermethylated CGG repeat expansions.
Krüppel-Like Factor 14 Improves Cardiac Function After Myocardial Infarction
Authors: Wang Yating , Xu Danyan , Shen Li 
Published: March 2020

AbstractBackgroundReversal of heart failure after myocardial infarction (MI) remains a global challenge. The goal of a clinical physician is to prevent heart failure immediately following the infarct. Since traditional strategies are only partially helpful for improving cardiac function, there is an urgency to identify novel approaches to maintain cardiac function.ObjectivesThe aim of this study was to determine the role of Krüppel-Like Factor 14 (KLF14) in the heart post-MI.Methods and ResultsWild-type and KLF14 overexpression mice were subjected to MI. At four weeks following MI, the infarct size was significantly reduced, left ventricular fraction shortening was significantly preserved, and left ventricular chamber dilation was attenuated in the KLF14 overexpression group. Transmission electron microscopy studies revealed striking evidence of decreased mitochondrial damage in the KLF14 overexpression myocardium following MI. To gain insight into the underlying relationship between KLF14 and mitochondria, we examined a broad array of genes involved in mitochondrial function and found that KLF14 overexpression was involved in the decreased apoptosis of mitochondria induced by H2O2. This beneficial effect was associated with increased levels of PGC-1α.ConclusionsThese results demonstrate that KLF14 plays a critical protective role in the heart after MI by regulating mitochondrial function, which may be achieved by regulating PGC-1α.
A dynamic 6,000-year genetic history of Eurasia’s Eastern Steppe
Authors: Jeong Choongwon , Wang Ke , Wilkin Shevan , Taylor William Timothy Treal , Miller Bryan K. , Ulziibayar Sodnom , Stahl Raphaela , Chiovelli Chelsea , Bemmann Jan H. , Knolle Florian , Kradin Nikolay , Bazarov Bilikto A. , Miyagashev Denis A. , Konovalov Prokopiy B. , Zhambaltarova Elena , Miller Alicia Ventresca , Haak Wolfgang , Schiffels Stephan , Krause Johannes , Boivin Nicole , Myagmar Erdene , Hendy Jessica , Warinner Christina 
Published: March 2020

SummaryThe Eastern Eurasian Steppe was home to historic empires of nomadic pastoralists, including the Xiongnu and the Mongols. However, little is known about the region’s population history. Here we reveal its dynamic genetic history by analyzing new genome-wide data for 214 ancient individuals spanning 6,000 years. We identify a pastoralist expansion into Mongolia ca. 3000 BCE, and by the Late Bronze Age, Mongolian populations were biogeographically structured into three distinct groups, all practicing dairy pastoralism regardless of ancestry. The Xiongnu emerged from the mixing of these populations and those from surrounding regions. By comparison, the Mongols exhibit much higher Eastern Eurasian ancestry, resembling present-day Mongolic-speaking populations. Our results illuminate the complex interplay between genetic, sociopolitical, and cultural changes on the Eastern Steppe.
Chronic Interleukin-1 exposure triggers selective expansion ofCebpa-deficient multipotent hematopoietic progenitors
Authors: Higa Kelly C. , Goodspeed Andrew , Chavez James S. , Zaberezhnyy Vadym , Rabe Jennifer L. , Tenen Daniel G. , Pietras Eric M. , DeGregori James 
Published: March 2020

AbstractThe early events that drive hematologic disorders like clonal hematopoiesis, myelodysplastic syndrome, myeloproliferative neoplasm, and acute myeloid leukemia are not well understood. Most studies focus on the cell-intrinsic genetic changes that occur in these disorders and how they impact cell fate decisions. We consider how chronic exposure to the pro-inflammatory cytokine, interleukin-1β (IL-1β), impactsCebpa-deficient hematopoietic stem and progenitor cells (HSPC) in competitive settings. We surprisingly found thatCebpa-deficient HSPC did not have a hematopoietic cell intrinsic competitive advantage; rather chronic IL-1β exposure engendered potent selection forCebpaloss. Chronic IL-1β augments myeloid lineage output by activating differentiation and repressing stem cell gene expression programs in aCebpa-dependent manner. As a result,Cebpa-deficient HSPC are resistant to the pro-differentiative effects of chronic IL-1β, and competitively expand. These findings have important implications for the earliest events that drive hematologic disorders, suggesting that chronic inflammation could be an important driver of leukemogenesis and a potential target for intervention.SummaryHigaet al. show that chronic interleukin-1β exposure primes hematopoietic stem and progenitor cells for myelopoiesis by upregulating myeloid differentiation programs and repressing stem gene programs in aCebpa-dependent manner. Consequently, interleukin-1 potently selects forCebpaloss in hematopoietic stem and progenitor cells.
The environmental stress response causes ribosome loss in aneuploid yeast cells
Authors: Terhorst Allegra , Sandikci Arzu , Keller Abigail , Whittaker Charles A. , Dunham Maitreya J. , Amon Angelika 
Published: March 2020

AbstractAneuploidy, a condition characterized by whole chromosome gains and losses, is often associated with significant cellular stress and decreased fitness. However, how cells respond to the aneuploid state has remained controversial. In aneuploid budding yeast, two opposing gene expression patterns have been reported: the “environmental stress response” (ESR) and the “common aneuploidy gene-expression” (CAGE) signature, in which many ESR genes are oppositely regulated. Here, we investigate and bring clarity to this controversy. We show that the CAGE signature is not an aneuploidy-specific gene expression signature but the result of normalizing the gene expression profile of actively proliferating aneuploid cells to that of euploid cells grown into stationary phase. Because growth into stationary phase is amongst the strongest inducers of the ESR, the ESR in aneuploid cells was masked when stationary phase euploid cells were used for normalization in transcriptomic studies. When exponentially growing euploid cells are used in gene expression comparisons with aneuploid cells, the CAGE signature is no longer evident in aneuploid cells. Instead, aneuploid cells exhibit the ESR. We further show that the ESR causes selective ribosome loss in aneuploid cells, providing an explanation for the decreased cellular density of aneuploid cells. We conclude that aneuploid budding yeast cells mount the ESR, rather than the CAGE signature, in response to aneuploidy-induced cellular stresses, resulting in selective ribosome loss. We propose that the ESR serves two purposes in aneuploid cells: protecting cells from aneuploidy-induced cellular stresses and preventing excessive cellular enlargement during slowed cell cycles by downregulating translation capacity.
The anti-tumour effect of CD8+ infiltration is associated with Human Leukocyte Antigen Class I expression and tumour proliferation in colorectal cancer
Authors: Powell Arfon G M T , Richards Colin , Platt Jonathan J , Orange Clare , Bennett Lindsay , McMillan Donald C , Horgan Paul G , Edwards Joanne 
Published: March 2020

AbstractPurposeThe host inflammatory response is an important determinant of cancer outcome, however, the factor/s that regulate this response remains unclear. We aimed to determine if Human Leukocyte Antigen (HLA) class I and tumour cell proliferation are associated with CD8+ infiltration and survival in patients undergoing potentially curative resection for colorectal cancer.MethodsHLA class I expression (W6/32 and B2-microglobulin) and tumour proliferation index (Ki67) were quantified using immunohistochemistry on tissue micro arrays (TMA). The local inflammatory response at the invasive margin was assessed using the Klintrup-Makinen (K-M) score and CD8+ infiltration was assessed at the invasive margin (mCD8+), stroma (sCD8+) and cancer cell nests (cCD8+).ResultsPreserved HLA class I expression was associated with lower Dukes’ stage (p=0.032), lower T stage (p=0.040) and higher cCD8+ (p=0.003). High Ki67 was associated with a good K-M score (p<0.001), higher mCD8+ (p=0.033), higher sCD8+ (p=0.025) and higher cCD8+ (p<0.001). On binary logistical regression analysis both preserved HLA class I expression (HR 1.99 95%CI (1.13–3.51),p=0.012) and high Ki67 (HR 2.63 95%CI (1.08–6.38),p=0.033) were independently associated with higher CD8+ infiltration within the cancer cell nests. On multivariate survival analysis, preserved HLA class I expression was associated with disease free (HR 0.47 95%CI (0.25–0.89),p=0.020) and cancer specific survival (HR 0.52 95%CI (0.28–0.97),p=0.038).ConclusionThis study suggests that a pronounced local inflammatory response is independently associated with both, HLA class I expression and tumour proliferation.
An international comparison of the second derivative of COVID-19 deaths after implementation of social distancing measures
Authors: Pike W. T. , Saini V. 
Published: March 2020

AbstractThis work compares deaths for confirmed COVID-19 cases in China to eight other countries, Italy, Spain, France, USA, UK, Germany, Netherlands and South Korea. After implementing varying intensities and timing of social distancing measures, several appear to be converging onto the decline in the daily growth rate of deaths, or relative second derivative of total deaths, seen in China after the implementation an aggressive social distancing policy. By calculating future trajectories in these countries based on the observed Chinese fatality statistics, an estimate of the total deaths and maximum daily death rates over a defined period of time is made. Our lower bound estimate for the United Kingdom based on the real data approximates the lower bound estimate of the recent modelling study of Ferguson et al. [1]. These results suggest there may be a threshold of effective public health intervention. Our method of viewing the data may be helpful in monitoring the course of the epidemic, judging the effectiveness of implementation, and monitoring the relaxation of social distancing.
Coast-to-coast spread of SARS-CoV-2 in the United States revealed by genomic epidemiology
Authors: Fauver Joseph R. , Petrone Mary E. , Hodcroft Emma B. , Shioda Kayoko , Ehrlich Hanna Y. , Watts Alexander G. , Vogels Chantal B.F. , Brito Anderson F. , Alpert Tara , Muyombwe Anthony , Razeq Jafar , Downing Randy , Cheemarla Nagarjuna R. , Wyllie Anne L. , Kalinich Chaney C. , Ott Isabel , Quick Joshua , Loman Nicholas J. , Neugebauer Karla M. , Greninger Alexander L. , Jerome Keith R. , Roychoudhury Pavitra , Xie Hong , Shrestha Lasata , Huang Meei-Li , Pitzer Virginia E. , Iwasaki Akiko , Omer Saad B. , Khan Kamran , Bogoch Isaac I. , Martinello Richard A. , Foxman Ellen F. , Landry Marie L. , Neher Richard A. , Ko Albert I. , Grubaugh Nathan D. 
Published: March 2020

SummarySince its emergence and detection in Wuhan, China in late 2019, the novel coronavirus SARS-CoV-2 has spread to nearly every country around the world, resulting in hundreds of thousands of infections to date. The virus was first detected in the Pacific Northwest region of the United States in January, 2020, with subsequent COVID-19 outbreaks detected in all 50 states by early March. To uncover the sources of SARS-CoV-2 introductions and patterns of spread within the U.S., we sequenced nine viral genomes from early reported COVID-19 patients in Connecticut. Our phylogenetic analysis places the majority of these genomes with viruses sequenced from Washington state. By coupling our genomic data with domestic and international travel patterns, we show that early SARS-CoV-2 transmission in Connecticut was likely driven by domestic introductions. Moreover, the risk of domestic importation to Connecticut exceeded that of international importation by mid-March regardless of our estimated impacts of federal travel restrictions. This study provides evidence for widespread, sustained transmission of SARS-CoV-2 within the U.S. and highlights the critical need for local surveillance.