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Biophysics
Neonatal infection leads to increased susceptibility to Aβ oligomer-induced brain inflammation, synapse loss and cognitive impairment in mice.
Apr 16, 2019   Cell Death & Disease
Frost PS, Barros-Aragão F, da Silva RT, Venancio A, Matias I, Lyra E Silva NM, Kincheski GC, Pimentel-Coelho PM, De Felice FG, Gomes FCA, Ferreira ST, Figueiredo CP, Clarke JR
Neonatal infection leads to increased susceptibility to Aβ oligomer-induced brain inflammation, synapse loss and cognitive impairment in mice.
Apr 16, 2019
Cell Death & Disease
Harmful environmental stimuli during critical stages of development can profoundly affect behavior and susceptibility to diseases. Alzheimer disease (AD) is the most frequent neurodegenerative disease, and evidence suggest that inflammatory conditions act cumulatively, contributing to disease onset. Here we investigated whether infection early in life can contribute to synapse damage and cognitive impairment induced by amyloid-β oligomers (AβOs), neurotoxins found in AD brains. To this end, wild-type mice were subjected to neonatal (post-natal day 4) infection by Escherichia coli (1 × 104 CFU/g), the main cause of infection in low-birth-weight premature infants in the US. E. coli infection caused a transient inflammatory response in the mouse brain starting shortly after infection. Although infected mice performed normally in behavioral tasks in adulthood, they showed increased susceptibility to synapse damage and memory impairment induced by low doses of AβOs (1 pmol; intracerebroventricular) in the novel object recognition paradigm. Using in vitro and in vivo approaches, we show that microglial cells from E. coli-infected mice undergo exacerbated activation when exposed to low doses of AβOs. In addition, treatment of infected pups with minocycline, an antibiotic that inhibits microglial pro-inflammatory polarization, normalized microglial response to AβOs and restored normal susceptibility of mice to oligomer-induced cognitive impairment. Interestingly, mice infected with by E. coli (1 × 104 CFU/g) during adolescence (post-natal day 21) or adulthood (post-natal day 60) showed normal cognitive performance even in the presence of AβOs (1 pmol), suggesting that only infections at critical stages of development may lead to increased susceptibility to amyloid-β-induced toxicity. Altogether, our findings suggest that neonatal infections can modulate microglial response to AβOs into adulthood, thus contributing to amyloid-β-induced synapse damage and cognitive impairment.
Caution Does Not Preclude Predictive and Testable Models of Cytoplasmic Incompatibility: A Reply to Shropshire et al.
Apr 17, 2019   Trends In Genetics : TIG
Beckmann JF, Bonneau M, Chen H, Hochstrasser M, Poinsot D, Merçot H, Weill M, Sicard M, Charlat S
Effect of plasma processing and storage on microparticle abundance, nitric oxide scavenging, and vasoactivity.
Apr 13, 2019   Transfusion
Rogers SC, Moynihan FT, McDonough R, Timm DD, Hovmand-Warner E, Frazier E, Thomas KA, Spinella PC, Doctor A
Effect of plasma processing and storage on microparticle abundance, nitric oxide scavenging, and vasoactivity.
Apr 13, 2019
Transfusion
BACKGROUND: We set out to define the impact of collection, processing, and storage on plasma product microparticle (MP) abundance, potential for nitric oxide (NO) scavenging, and vasoactivity. STUDY DESIGN AND METHODS: Three currently US licensed products were tested: liquid plasma (LP), fresh frozen plasma (FFP), and solvent detergent plasma (SDP), along with a product under development, spray-dried solvent detergent plasma (SD-SDP) with/without beads. Vasoactivity was assessed in vitro using rabbit aortic vascular rings; MP abundance was determined by flow cytometry; and NO scavenging capacity/rate was determined using a biochemical NO consumption assay. All samples were analyzed unprocessed and following centrifugation at two speeds (2,500× g to remove platelets, and 25,000× g to remove microparticles). RESULTS: Significant differences in vasoactivity were observed, with SD-SDP minus beads demonstrating the greatest constriction and FFP the lowest constriction response. All products exhibited the same total NO scavenging capacity; however, significant differences were observed in the maximal rate of scavenging, with SD-SDP minus beads and FFP reacting fastest and SDP the slowest. Across all products, platelet and microparticle depletion had no effect on vasoactivity or NO scavenging (total or rate). Microparticles (RBC derived) were found only in FFP and LP, with relative abundance (LP > FFP). Additionally, storage had no effect on total or RBC-derived MP abundance, NO scavenging, or vasoactivity. CONCLUSION: Although vasoactivity differed between plasma products, we did not find similar differences in either total or RBC-derived MP abundance or NO scavenging capacity/rate.
The Galaxy Platform for Reproducible Affinity Proteomic Mass Spectrometry Data Analysis.
Apr 13, 2019   Methods In Molecular Biology (Clifton, N.J.)
Stewart PA, Kuenzi BM, Mehta S, Kumar P, Johnson JE, Jagtap P, Griffin TJ, Haura EB
The Galaxy Platform for Reproducible Affinity Proteomic Mass Spectrometry Data Analysis.
Apr 13, 2019
Methods In Molecular Biology (Clifton, N.J.)
Affinity proteomics (AP-MS) is growing in importance for characterizing protein-protein interactions (PPIs) in the form of protein complexes and signaling networks. The AP-MS approach necessitates several different software tools, integrated into reproducible and accessible workflows. However, if the scientist (e.g., a bench biologist) lacks a computational background, then managing large AP-MS datasets can be challenging, manually formatting AP-MS data for input into analysis software can be error-prone, and data visualization involving dozens of variables can be laborious. One solution to address these issues is Galaxy, an open source and web-based platform for developing and deploying user-friendly computational pipelines or workflows. Here, we describe a Galaxy-based platform enabling AP-MS analysis. This platform enables researchers with no prior computational experience to begin with data from a mass spectrometer (e.g., peaklists in mzML format) and perform peak processing, database searching, assignment of interaction confidence scores, and data visualization with a few clicks of a mouse. We provide sample data and a sample workflow with step-by-step instructions to quickly acquaint users with the process.
Isotopic Labeling and Quantitative Proteomics of Acetylation on Histones and Beyond.
Apr 13, 2019   Methods In Molecular Biology (Clifton, N.J.)
Lund PJ, Kori Y, Zhao X, Sidoli S, Yuan ZF, Garcia BA
Isotopic Labeling and Quantitative Proteomics of Acetylation on Histones and Beyond.
Apr 13, 2019
Methods In Molecular Biology (Clifton, N.J.)
Lysine acetylation is an important posttranslational modification (PTM) that regulates the function of proteins by affecting their localization, stability, binding, and enzymatic activity. Aberrant acetylation patterns have been observed in numerous diseases, most notably cancer, which has spurred the development of potential therapeutics that target acetylation pathways. Mass spectrometry (MS) has become the most adopted tool not only for the qualitative identification of acetylation sites but also for their large-scale quantification. By using heavy isotope labeling in cell culture combined with MS, it is now possible to accurately quantify newly synthesized acetyl groups and other PTMs, allowing differentiation between dynamically regulated and steady-state modifications. Here, we describe MS-based protocols to identify acetylation sites and quantify acetylation rates on both proteins in general and in the special case of histones. In the experimental approach for the former, 13C-glucose and D3-acetate are used to metabolically label protein acetylation in cells with stable isotopes, thus allowing isotope incorporation to be tracked over time. After protein extraction and digestion, acetylated peptides are enriched via immunoprecipitation and then analyzed by MS. For histones, a similar metabolic labeling approach is performed, followed by acid extraction, derivatization with propionic anhydride, and trypsin digestion prior to MS analysis. The procedures presented may be adapted to investigate acetylation dynamics in a broad range of experimental contexts, including different cell types and stimulation conditions.
Structural bases of peptidoglycan recognition by lysostaphin SH3b domain.
Apr 13, 2019   Scientific Reports
Mitkowski P, Jagielska E, Nowak E, Bujnicki JM, Stefaniak F, Niedziałek D, Bochtler M, Sabała I
Structural bases of peptidoglycan recognition by lysostaphin SH3b domain.
Apr 13, 2019
Scientific Reports
Staphylococcus simulans lysostaphin cleaves pentaglycine cross-bridges between stem peptides in the peptidoglycan of susceptible staphylococci, including S. aureus. This enzyme consists of an N-terminal catalytic domain and a cell wall binding domain (SH3b), which anchors the protein to peptidoglycan. Although structures of SH3bs from lysostaphin are available, the binding modes of peptidoglycan to these domains are still unclear. We have solved the crystal structure of the lysostaphin SH3b domain in complex with a pentaglycine peptide representing the peptidoglycan cross-bridge. The structure identifies a groove between β1 and β2 strands as the pentaglycine binding site. The structure suggests that pentaglycine specificity of the SH3b arises partially directly by steric exclusion of Cβ atoms in the ligand and partially indirectly due to the selection of main chain conformations that are easily accessible for glycine, but not other amino acid residues. We have revealed further interactions of SH3b with the stem peptides with the support of bioinformatics tools. Based on the structural data we have attempted engineering of the domain specificity and have investigated the relevance of the introduced substitutions on the domain binding and specificity, also in the contexts of the mature lysostaphin and of its bacteriolytic activity.
Intrinsic molecular insights to enhancement of biogas production from kitchen refuse using alkaline-microwave pretreatment.
Apr 13, 2019   Scientific Reports
Singh PK, Verma SK, Ojha SK, Panda PK, Srichandan H, Jha E, Mishra S
Intrinsic molecular insights to enhancement of biogas production from kitchen refuse using alkaline-microwave pretreatment.
Apr 13, 2019
Scientific Reports
The current study analyzed and optimized the concentration of NaOH for alkaline pretreatment of kitchen refuse for biogas production. Also, the benefits of microwave assistance in enhanced biogasification of kitchen refuse were evaluated. The TS, VS and structural changes were compared using standard experimental techniques. Molecular dynamics was investigated for the molecular level changes leading to higher biogasification in NaOHmicrowave combined pretreatment. The methane and biogas yields were calculated to validate the benefits of microwave assistance in efficient biogasification. The NaOH-microwave combined pretreatment showed higher VS production. Microwave treatment degraded and removed lignin more efficiently. Molecular dynamics studies revealed the induction of configurational instability in lignin and cellulose molecules with variable temperatures. The methane and biogas production increased with 6% NaOH concentration, and decreased at higher NaOH concentration till 10%. Microwave assistance declined the required NaOH concentration further to 4%. Thus, as compared to 6% NaOH concentration required for an efficient pretreatment, the kitchen refuse was efficiently pretreated with 4% NaOH concentration when combined with a 30 min duration microwaving. The experimental and computational data provided a detailed analysis proposing an optimized, novel and promising method to pretreat kitchen refuse for efficient and enhanced biogas production.
Retrieving high-resolution information from disordered 2D crystals by single-particle cryo-EM.
Apr 16, 2019   Nature Communications
Righetto RD, Biyani N, Kowal J, Chami M, Stahlberg H
Retrieving high-resolution information from disordered 2D crystals by single-particle cryo-EM.
Apr 16, 2019
Nature Communications
Electron crystallography can reveal the structure of membrane proteins within 2D crystals under close-to-native conditions. High-resolution structural information can only be reached if crystals are perfectly flat and highly ordered. In practice, such crystals are difficult to obtain. Available image unbending algorithms correct for disorder, but only perform well on images of non-tilted, flat crystals, while out-of-plane distortions are not addressed. Here, we present an approach that employs single-particle refinement procedures to locally unbend crystals in 3D. With this method, density maps of the MloK1 potassium channel with a resolution of 4 Å were obtained from images of 2D crystals that do not diffract beyond 10 Å. Furthermore, 3D classification allowed multiple structures to be resolved, revealing a series of MloK1 conformations within a single 2D crystal. This conformational heterogeneity explains the poor diffraction observed and is related to channel function. The approach is implemented in the FOCUS package.
Direct observation of coordinated DNA movements on the nucleosome during chromatin remodelling.
Apr 17, 2019   Nature Communications
Sabantsev A, Levendosky RF, Zhuang X, Bowman GD, Deindl S
Direct observation of coordinated DNA movements on the nucleosome during chromatin remodelling.
Apr 17, 2019
Nature Communications
ATP-dependent chromatin remodelling enzymes (remodellers) regulate DNA accessibility in eukaryotic genomes. Many remodellers reposition (slide) nucleosomes, however, how DNA is propagated around the histone octamer during this process is unclear. Here we examine the real-time coordination of remodeller-induced DNA movements on both sides of the nucleosome using three-colour single-molecule FRET. During sliding by Chd1 and SNF2h remodellers, DNA is shifted discontinuously, with movement of entry-side DNA preceding that of exit-side DNA. The temporal delay between these movements implies a single rate-limiting step dependent on ATP binding and transient absorption or buffering of at least one base pair. High-resolution cross-linking experiments show that sliding can be achieved by buffering as few as 3 bp between entry and exit sides of the nucleosome. We propose that DNA buffering ensures nucleosome stability during ATP-dependent remodelling, and provides a means for communication between remodellers acting on opposite sides of the nucleosome.
Oscillatory cortical forces promote three dimensional cell intercalations that shape the murine mandibular arch.
Apr 16, 2019   Nature Communications
Tao H, Zhu M, Lau K, Whitley OKW, Samani M,   . . . . . .   , Ho HH, Atit R, Goyal S, Sun Y, Hopyan S
Oscillatory cortical forces promote three dimensional cell intercalations that shape the murine mandibular arch.
Apr 16, 2019
Nature Communications
Multiple vertebrate embryonic structures such as organ primordia are composed of confluent cells. Although mechanisms that shape tissue sheets are increasingly understood, those which shape a volume of cells remain obscure. Here we show that 3D mesenchymal cell intercalations are essential to shape the mandibular arch of the mouse embryo. Using a genetically encoded vinculin tension sensor that we knock-in to the mouse genome, we show that cortical force oscillations promote these intercalations. Genetic loss- and gain-of-function approaches show that Wnt5a functions as a spatial cue to coordinate cell polarity and cytoskeletal oscillation. These processes diminish tissue rigidity and help cells to overcome the energy barrier to intercalation. YAP/TAZ and PIEZO1 serve as downstream effectors of Wnt5a-mediated actomyosin polarity and cytosolic calcium transients that orient and drive mesenchymal cell intercalations. These findings advance our understanding of how developmental pathways regulate biophysical properties and forces to shape a solid organ primordium.
Precision Targeting with EZH2 and HDAC Inhibitors in Epigenetically Dysregulated Lymphomas.
Apr 13, 2019   Clinical Cancer Research : An Official Journal Of The American Association For Cancer Research
Lue JK, Prabhu SA, Liu Y, Gonzalez Y, Verma A,   . . . . . .   , Nandakumar R, Cremers S, Kelleher NL, Elemento O, Amengual JE
Precision Targeting with EZH2 and HDAC Inhibitors in Epigenetically Dysregulated Lymphomas.
Apr 13, 2019
Clinical Cancer Research : An Official Journal Of The American Association For Cancer Research
PURPOSE: Both gain-of-function EZH2 mutations and inactivating histone acetyltransferases mutations, such as CREBBP and EP300, have been implicated in the pathogenesis of germinal center (GC) derived lymphomas. We hypothesized that direct inhibition of EZH2 and HDAC would be synergistic in GC-derived lymphomas. EXPERIMENTAL DESIGN: Lymphoma cell lines (n=21) were exposed to GSK126, an EZH2 inhibitor, and romidepsin, a pan-HDAC inhibitor. Synergy was assessed by Excess over Bliss. Western blot, mass spectrometry and co-immunopreciptiation were performed. A SU-DHL-10 xenograft model was utilized to validate in vitro findings. Pre-treatment RNA-sequencing of cell lines was performed. MetaVIPER analysis was used to infer protein activity. RESULTS: Exposure to GSK126 and romidepsin demonstrated potent synergy in lymphoma cell lines with EZH2 dysregulation. Combination of romidepsin with other EZH2 inhibitors also demonstrated synergy suggesting a class effect of EZH2 inhibition with romidepsin. Dual inhibition of EZH2 and HDAC led to modulation of acetylation and methylation of H3K27. The synergistic effects of the combination was due to disruption of the PRC2 complex secondary to acetylation of RbAP 46/48. A common basal gene signature was shared among synergistic lymphoma cell lines and were characterized by upregulation in chromatin remodeling genes and transcriptional regulators. This finding was supported by metaVIPER analysis which also revealed that HDAC 1/2 and DNMT were associated with EZH2 activation. CONCLUSIONS: Inhibition of EZH2 and HDAC is synergistic and leads to the dissociation of PRC2 complex. Our findings support the clinical translation of the combination of EZH2 and HDAC inhibition in EZH2 dysregulated lymphomas.
Structural and Functional Insights into Host Death Domains Inactivation by the Bacterial Arginine GlcNAcyltransferase Effector.
Apr 13, 2019   Molecular Cell
Ding J, Pan X, Du L, Yao Q, Xue J, Yao H, Wang DC, Li S, Shao F
Structural and Functional Insights into Host Death Domains Inactivation by the Bacterial Arginine GlcNAcyltransferase Effector.
Apr 13, 2019
Molecular Cell
Enteropathogenic E. coli NleB and related type III effectors catalyze arginine GlcNAcylation of death domain (DD) proteins to block host defense, but the underlying mechanism is unknown. Here we solve crystal structures of NleB alone and in complex with FADD-DD, UDP, and Mn2+ as well as NleB-GlcNAcylated DDs of TRADD and RIPK1. NleB adopts a GT-A fold with a unique helix-pair insertion to hold FADD-DD; the interface contacts explain the selectivity of NleB for certain DDs. The acceptor arginine is fixed into a cleft, in which Glu253 serves as a base to activate the guanidinium. Analyses of the enzyme-substrate complex and the product structures reveal an inverting sugar-transfer reaction and a detailed catalytic mechanism. These structural insights are validated by mutagenesis analyses of NleB-mediated GlcNAcylation in vitro and its function in mouse infection. Our study builds a structural framework for understanding of NleB-catalyzed arginine GlcNAcylation of host death domain.
Characterization of Distinct Populations of Carcinoma-Associated Fibroblasts from Non-Small Cell Lung Carcinoma Reveals a Role for ST8SIA2 in Cancer Cell Invasion.
Apr 17, 2019   Neoplasia (New York, N.Y.)
Hao J, Zeltz C, Pintilie M, Li Q, Sakashita S,   . . . . . .   , Zhu CQ, Wang YH, Moghal N, Tsao MS, Navab R
Characterization of Distinct Populations of Carcinoma-Associated Fibroblasts from Non-Small Cell Lung Carcinoma Reveals a Role for ST8SIA2 in Cancer Cell Invasion.
Apr 17, 2019
Neoplasia (New York, N.Y.)
Carcinoma-associated fibroblasts (CAFs) are abundant stromal cells in tumor microenvironment that are critically involved in cancer progression. Contrasting reports have shown that CAFs can have either pro- or antitumorigenic roles, indicating that CAFs are functionally heterogeneous. Therefore, to precisely target the cancer-promoting CAF subsets, it is necessary to identify specific markers to define these subpopulations and understand their functions. We characterized two CAFs subsets from 28 non-small cell lung cancer (NSCLC) patient tumors that were scored and classified based on desmoplasia [mainly characterized by proliferating CAFs; high desmoplastic CAFs (HD-CAF; n = 15) and low desmoplastic CAFs (LD-CAF; n = 13)], which is an independent prognostic factor. Here, for the first time, we demonstrate that HD-CAFs and LD-CAFs show different tumor-promoting abilities. HD-CAFs showed higher rate of collagen matrix remodeling, invasion, and tumor growth compared to LD-CAFs. Transcriptomic analysis identified 13 genes that were differentially significant (fold ≥1.5; adjusted P value < .1) between HD-CAFs and LD-CAFs. The top upregulated differentially expressed gene, ST8SIA2 (11.3 fold; adjusted P value = .02), enhanced NSCLC tumor cell invasion in 3D culture compared to control when it was overexpressed in CAFs, suggesting an important role of ST8SIA2 in cancer cell invasion. We confirmed the protumorigenic role of ST8SIA2, showing that ST8SIA2 was significantly associated with the risk of relapse in three independent NSCLC clinical datasets. In summary, our studies show that functional heterogeneity in CAF plays key role in promoting cancer cell invasion in NSCLC.
Structural analyses of NudT16-ADP-ribose complexes direct rational design of mutants with improved processing of poly(ADP-ribosyl)ated proteins.
Apr 17, 2019   Scientific Reports
Thirawatananond P, McPherson RL, Malhi J, Nathan S, Lambrecht MJ, Brichacek M, Hergenrother PJ, Leung AKL, Gabelli SB
Structural analyses of NudT16-ADP-ribose complexes direct rational design of mutants with improved processing of poly(ADP-ribosyl)ated proteins.
Apr 17, 2019
Scientific Reports
ADP-ribosylation is a post-translational modification that occurs on chemically diverse amino acids, including aspartate, glutamate, lysine, arginine, serine and cysteine on proteins and is mediated by ADP-ribosyltransferases, including a subset commonly known as poly(ADP-ribose) polymerases. ADP-ribose can be conjugated to proteins singly as a monomer or in polymeric chains as poly(ADP-ribose). While ADP-ribosylation can be reversed by ADP-ribosylhydrolases, this protein modification can also be processed to phosphoribosylation by enzymes possessing phosphodiesterase activity, such as snake venom phosphodiesterase, mammalian ectonucleotide pyrophosphatase/phosphodiesterase 1, Escherichia coli RppH, Legionella pneumophila Sde and Homo sapiens NudT16 (HsNudT16). Our studies here sought to utilize X-ray crystallographic structures of HsNudT16 in complex with monomeric and dimeric ADP-ribose in identifying the active site for binding and processing free and protein-conjugated ADP-ribose into phosphoribose forms. These structural data guide rational design of mutants that widen the active site to better accommodate protein-conjugated ADP-ribose. We identified that several HsNudT16 mutants (Δ17, F36A, and F61S) have reduced activity for free ADP-ribose, similar processing ability against protein-conjugated mono(ADP-ribose), but improved catalytic efficiency for protein-conjugated poly(ADP-ribose). These HsNudT16 variants may, therefore, provide a novel tool to investigate different forms of ADP-ribose.
An investigation of racial/ethnic and sex differences in the association between experiences of everyday discrimination and leukocyte telomere length among patients with coronary artery disease.
Apr 17, 2019   Psychoneuroendocrinology
Sullivan S, Hammadah M, Al Mheid I, Shah A, Sun YV, Kutner M, Ward L, Blackburn E, Zhao J, Lin J, Bremner JD, Quyyumi AA, Vaccarino V, Lewis TT
An investigation of racial/ethnic and sex differences in the association between experiences of everyday discrimination and leukocyte telomere length among patients with coronary artery disease.
Apr 17, 2019
Psychoneuroendocrinology
Leukocyte telomere length (LTL) may be sensitive to psychosocial stressors such as discrimination. An inclusive examination of experiences of discrimination on LTL across racial/ethnic and sex groups is currently lacking. Baseline data were obtained from 369 White and African American patients with coronary artery disease (CAD) in the Mental Stress Ischemia Mechanisms and Prognosis Study. LTL was measured from peripheral blood leukocytes by quantitative polymerase chain reaction and calculated in kilobase pairs. Discrimination was measured using the 10-item Everyday Discrimination Scale (EDS). Responses were rated using 4-point Likert scales ranging from never = 1 to often = 4 and summed. Regression models were stratified by race/ethnicity and sex to estimate associations between discrimination and LTL. Each 10-unit increase in experiences of everyday discrimination was associated with an average of .20 fewer kilobase pairs (or 200 base pairs) among both African American women (β = -0.19; 95% CI: -0.35, -0.04; p-value: 0.02) and White women (β = -0.19; 95% CI: -0.37, -0.01; p-value: 0.04), after adjusting for basic demographic factors. Results were similar after further adjusting for behavioral, disease, and psychosocial risk factors (depression and stress). There were no significant associations between experiences of everyday discrimination and LTL for White men or African American men. Overall, experiences of discrimination were associated with shorter LTL among women and not in men. Discrimination may be a potential source of stress associated with shorter LTL among women with CAD. Future studies should explore longitudinal associations between everyday experiences of discrimination and telomere length and also with adverse cardiovascular outcomes.
The effect of cadmium exposition on the structure and mechanical properties of rat incisors.
Apr 12, 2019   PloS One
Świetlicka I, Tomaszewska E, Muszyński S, Valverde Piedra JL, Świetlicki M, Prószyński A, Cieślak K, Wiącek D, Szymańczyk S, Kamiński D
The effect of cadmium exposition on the structure and mechanical properties of rat incisors.
Apr 12, 2019
PloS One
Alterations in the structure and mechanical properties of teeth in adult Wistar rats exposed to cadmium were investigated. Analyses were conducted on two sets of incisors from female and male specimens, that were intoxicated with cadmium (n = 12) or belonged to the control (n = 12). The cadmium group was administered with CdCl2 dissolved in drinking water with a dose of 4mg/kgbw for 10 weeks. The oral intake of cadmium by adult rats led to the range of structural changes in enamel morphology and its mechanical features. A significant increase of cadmium levels in the teeth in comparison to the control, a slight shift in the colour and reduction of pigmented enamel length, higher surface irregularity, a decrease of hydroxyapatite crystals size in the c-axis and simultaneous increase in pigmented enamel hardness were observed. The extent of these changes was sex-dependent and was more pronounced in males.
Feasibility of a web-based neurocognitive battery for assessing cognitive function in critical illness survivors.
Apr 12, 2019   PloS One
Honarmand K, Malik S, Wild C, Gonzalez-Lara LE, McIntyre CW, Owen AM, Slessarev M
Feasibility of a web-based neurocognitive battery for assessing cognitive function in critical illness survivors.
Apr 12, 2019
PloS One
PURPOSE: To assess the feasibility of using a widely validated, web-based neurocognitive test battery (Cambridge Brain Sciences, CBS) in a cohort of critical illness survivors. METHODS: We conducted a prospective observational study in two intensive care units (ICUs) at two tertiary care hospitals. Twenty non-delirious ICU patients who were mechanically ventilated for a minimum of 24 hours underwent cognitive testing using the CBS battery. The CBS consists of 12 cognitive tests that assess a broad range of cognitive abilities that can be categorized into three cognitive domains: reasoning skills, short-term memory, and verbal processing. Patients underwent cognitive assessment while still in the ICU (n = 13) or shortly after discharge to ward (n = 7). Cognitive impairment on each test was defined as a raw score that was 1.5 or more standard deviations below age- and sex-matched norms from healthy controls. RESULTS: We found that all patients were impaired on at least two tests and 18 patients were impaired on at least three tests. ICU patients had poorer performance on all three cognitive domains relative to healthy controls. We identified testing related fatigue due to battery length as a feasibility issue of the CBS test battery. CONCLUSIONS: Use of a web-based patient-administered cognitive test battery is feasible and can be used in large-scale studies to identify domain-specific cognitive impairment in critical illness survivors and the temporal course of recovery over time.
The architecture of cell differentiation in choanoflagellates and sponge choanocytes.
Apr 12, 2019   PLoS Biology
Laundon D, Larson BT, McDonald K, King N, Burkhardt P
The architecture of cell differentiation in choanoflagellates and sponge choanocytes.
Apr 12, 2019
PLoS Biology
Although collar cells are conserved across animals and their closest relatives, the choanoflagellates, little is known about their ancestry, their subcellular architecture, or how they differentiate. The choanoflagellate Salpingoeca rosetta expresses genes necessary for animal development and can alternate between unicellular and multicellular states, making it a powerful model for investigating the origin of animal multicellularity and mechanisms underlying cell differentiation. To compare the subcellular architecture of solitary collar cells in S. rosetta with that of multicellular 'rosette' colonies and collar cells in sponges, we reconstructed entire cells in 3D through transmission electron microscopy on serial ultrathin sections. Structural analysis of our 3D reconstructions revealed important differences between single and colonial choanoflagellate cells, with colonial cells exhibiting a more amoeboid morphology consistent with higher levels of macropinocytotic activity. Comparison of multiple reconstructed rosette colonies highlighted the variable nature of cell sizes, cell-cell contact networks, and colony arrangement. Importantly, we uncovered the presence of elongated cells in some rosette colonies that likely represent a distinct and differentiated cell type, pointing toward spatial cell differentiation. Intercellular bridges within choanoflagellate colonies displayed a variety of morphologies and connected some but not all neighbouring cells. Reconstruction of sponge choanocytes revealed ultrastructural commonalities but also differences in major organelle composition in comparison to choanoflagellates. Together, our comparative reconstructions uncover the architecture of cell differentiation in choanoflagellates and sponge choanocytes and constitute an important step in reconstructing the cell biology of the last common ancestor of animals.
Microstimulation in a spiking neural network model of the midbrain superior colliculus.
Apr 12, 2019   PLoS Computational Biology
Kasap B, van Opstal AJ
Microstimulation in a spiking neural network model of the midbrain superior colliculus.
Apr 12, 2019
PLoS Computational Biology
The midbrain superior colliculus (SC) generates a rapid saccadic eye movement to a sensory stimulus by recruiting a population of cells in its topographically organized motor map. Supra-threshold electrical microstimulation in the SC reveals that the site of stimulation produces a normometric saccade vector with little effect of the stimulation parameters. Moreover, electrically evoked saccades (E-saccades) have kinematic properties that strongly resemble natural, visual-evoked saccades (V-saccades). These findings support models in which the saccade vector is determined by a center-of-gravity computation of activated neurons, while its trajectory and kinematics arise from downstream feedback circuits in the brainstem. Recent single-unit recordings, however, have indicated that the SC population also specifies instantaneous kinematics. These results support an alternative model, in which the desired saccade trajectory, including its kinematics, follows from instantaneous summation of movement effects of all SC spike trains. But how to reconcile this model with microstimulation results? Although it is thought that microstimulation activates a large population of SC neurons, the mechanism through which it arises is unknown. We developed a spiking neural network model of the SC, in which microstimulation directly activates a relatively small set of neurons around the electrode tip, which subsequently sets up a large population response through lateral synaptic interactions. We show that through this mechanism the population drives an E-saccade with near-normal kinematics that are largely independent of the stimulation parameters. Only at very low stimulus intensities the network recruits a population with low firing rates, resulting in abnormally slow saccades.
Combination of Searches for Higgs Boson Pair Production in Proton-Proton Collisions at sqrt[s]=13  TeV.
Apr 16, 2019   Physical Review Letters
Sirunyan AM, Tumasyan A, Adam W, Ambrogi F, Asilar E,   . . . . . .   , Sharma V, Smith N, Smith WH, Woods N, CMS Collaboration
Combination of Searches for Higgs Boson Pair Production in Proton-Proton Collisions at sqrt[s]=13  TeV.
Apr 16, 2019
Physical Review Letters
Sirunyan AM, Tumasyan A, Adam W, Ambrogi F, Asilar E, Bergauer T, Brandstetter J, Dragicevic M, Erö J, Escalante Del Valle A, Flechl M, Frühwirth R, Ghete VM, Hrubec J, Jeitler M, Krammer N, Krätschmer I, Liko D, Madlener T, Mikulec I, Rad N, Rohringer H, Schieck J, Schöfbeck R, Spanring M, Spitzbart D, Taurok A, Waltenberger W, Wittmann J, Wulz CE, Zarucki M, Chekhovsky V, Mossolov V, Suarez Gonzalez J, De Wolf EA, Di Croce D, Janssen X, Lauwers J, Pieters M, Van Haevermaet H, Van Mechelen P, Van Remortel N, Abu Zeid S, Blekman F, D'Hondt J, De Clercq J, Deroover K, Flouris G, Lontkovskyi D, Lowette S, Marchesini I, Moortgat S, Moreels L, Python Q, Skovpen K, Tavernier S, Van Doninck W, Van Mulders P, Van Parijs I, Beghin D, Bilin B, Brun H, Clerbaux B, De Lentdecker G, Delannoy H, Dorney B, Fasanella G, Favart L, Goldouzian R, Grebenyuk A, Kalsi AK, Lenzi T, Luetic J, Postiau N, Starling E, Thomas L, Vander Velde C, Vanlaer P, Vannerom D, Wang Q, Cornelis T, Dobur D, Fagot A, Gul M, Khvastunov I, Poyraz D, Roskas C, Trocino D, Tytgat M, Verbeke W, Vermassen B, Vit M, Zaganidis N, Bakhshiansohi H, Bondu O, Brochet S, Bruno G, Caputo C, David P, Delaere C, Delcourt M, Giammanco A, Krintiras G, Lemaitre V, Magitteri A, Piotrzkowski K, Saggio A, Vidal Marono M, Wertz S, Zobec J, Alves FL, Alves GA, Correa Martins Junior M, Correia Silva G, Hensel C, Moraes A, Pol ME, Rebello Teles P, Belchior Batista Das Chagas E, Carvalho W, Chinellato J, Coelho E, Da Costa EM, Da Silveira GG, De Jesus Damiao D, De Oliveira Martins C, Fonseca De Souza S, Malbouisson H, Matos Figueiredo D, Melo De Almeida M, Mora Herrera C, Mundim L, Nogima H, Prado Da Silva WL, Sanchez Rosas LJ, Santoro A, Sznajder A, Thiel M, Tonelli Manganote EJ, Torres Da Silva De Araujo F, Vilela Pereira A, Ahuja S, Bernardes CA, Calligaris L, Tomei TRFP, Gregores EM, Mercadante PG, Novaes SF, Padula SS, Aleksandrov A, Hadjiiska R, Iaydjiev P, Marinov A, Misheva M, Rodozov M, Shopova M, Sultanov G, Dimitrov A, Litov L, Pavlov B, Petkov P, Fang W, Gao X, Yuan L, Ahmad M, Bian JG, Chen GM, Chen HS, Chen M, Chen Y, Jiang CH, Leggat D, Liao H, Liu Z, Romeo F, Shaheen SM, Spiezia A, Tao J, Wang Z, Yazgan E, Zhang H, Zhang S, Zhao J, Ban Y, Chen G, Levin A, Li J, Li L, Li Q, Mao Y, Qian SJ, Wang D, Wang Y, Avila C, Cabrera A, Carrillo Montoya CA, Chaparro Sierra LF, Florez C, González Hernández CF, Segura Delgado MA, Courbon B, Godinovic N, Lelas D, Puljak I, Sculac T, Antunovic Z, Kovac M, Brigljevic V, Ferencek D, Kadija K, Mesic B, Starodumov A, Susa T, Ather MW, Attikis A, Kolosova M, Mavromanolakis G, Mousa J, Nicolaou C, Ptochos F, Razis PA, Rykaczewski H, Finger M, Finger M, Ayala E, Carrera Jarrin E, Abdalla H, Abdelalim AA, Mohamed A, Bhowmik S, Carvalho Antunes De Oliveira A, Dewanjee RK, Ehataht K, Kadastik M, Raidal M, Veelken C, Eerola P, Kirschenmann H, Pekkanen J, Voutilainen M, Havukainen J, Heikkilä JK, Järvinen T, Karimäki V, Kinnunen R, Lampén T, Lassila-Perini K, Laurila S, Lehti S, Lindén T, Luukka P, Mäenpää T, Siikonen H, Tuominen E, Tuominiemi J, Tuuva T, Besancon M, Couderc F, Dejardin M, Denegri D, Faure JL, Ferri F, Ganjour S, Givernaud A, Gras P, Hamel de Monchenault G, Jarry P, Leloup C, Locci E, Malcles J, Negro G, Rander J, Rosowsky A, Sahin MÖ, Titov M, Abdulsalam A, Amendola C, Antropov I, Beaudette F, Busson P, Charlot C, Granier de Cassagnac R, Kucher I, Lobanov A, Martin Blanco J, Martin Perez C, Nguyen M, Ochando C, Ortona G, Paganini P, Pigard P, Rembser J, Salerno R, Sauvan JB, Sirois Y, Stahl Leiton AG, Zabi A, Zghiche A, Agram JL, Andrea J, Bloch D, Brom JM, Chabert EC, Cherepanov V, Collard C, Conte E, Fontaine JC, Gelé D, Goerlach U, Jansová M, Le Bihan AC, Tonon N, Van Hove P, Gadrat S, Beauceron S, Bernet C, Boudoul G, Chanon N, Chierici R, Contardo D, Depasse P, El Mamouni H, Fay J, Finco L, Gascon S, Gouzevitch M, Grenier G, Ille B, Lagarde F, Laktineh IB, Lattaud H, Lethuillier M, Mirabito L, Perries S, Popov A, Sordini V, Touquet G, Vander Donckt M, Viret S, Khvedelidze A, Tsamalaidze Z, Autermann C, Feld L, Kiesel MK, Klein K, Lipinski M, Preuten M, Rauch MP, Schomakers C, Schulz J, Teroerde M, Wittmer B, Albert A, Duchardt D, Erdmann M, Erdweg S, Esch T, Fischer R, Ghosh S, Güth A, Hebbeker T, Heidemann C, Hoepfner K, Keller H, Mastrolorenzo L, Merschmeyer M, Meyer A, Millet P, Mukherjee S, Pook T, Radziej M, Reithler H, Rieger M, Schmidt A, Teyssier D, Thüer S, Flügge G, Hlushchenko O, Kress T, Müller T, Nehrkorn A, Nowack A, Pistone C, Pooth O, Roy D, Sert H, Stahl A, Aldaya Martin M, Arndt T, Asawatangtrakuldee C, Babounikau I, Beernaert K, Behnke O, Behrens U, Bermúdez Martínez A, Bertsche D, Bin Anuar AA, Borras K, Botta V, Campbell A, Connor P, Contreras-Campana C, Danilov V, De Wit A, Defranchis MM, Diez Pardos C, Domínguez Damiani D, Eckerlin G, Eichhorn T, Elwood A, Eren E, Gallo E, Geiser A, Grados Luyando JM, Grohsjean A, Guthoff M, Haranko M, Harb A, Hauk J, Jung H, Kasemann M, Keaveney J, Kleinwort C, Knolle J, Krücker D, Lange W, Lelek A, Lenz T, Leonard J, Lipka K, Lohmann W, Mankel R, Melzer-Pellmann IA, Meyer AB, Meyer M, Missiroli M, Mittag G, Mnich J, Myronenko V, Pflitsch SK, Pitzl D, Raspereza A, Savitskyi M, Saxena P, Schütze P, Schwanenberger C, Shevchenko R, Singh A, Tholen H, Turkot O, Vagnerini A, Van Onsem GP, Walsh R, Wen Y, Wichmann K, Wissing C, Zenaiev O, Aggleton R, Bein S, Benato L, Benecke A, Blobel V, Dreyer T, Ebrahimi A, Garutti E, Gonzalez D, Gunnellini P, Haller J, Hinzmann A, Karavdina A, Kasieczka G, Klanner R, Kogler R, Kovalchuk N, Kurz S, Kutzner V, Lange J, Marconi D, Multhaup J, Niedziela M, Niemeyer CEN, Nowatschin D, Perieanu A, Reimers A, Rieger O, Scharf C, Schleper P, Schumann S, Schwandt J, Sonneveld J, Stadie H, Steinbrück G, Stober FM, Stöver M, Vanhoefer A, Vormwald B, Zoi I, Akbiyik M, Barth C, Baselga M, Baur S, Butz E, Caspart R, Chwalek T, Colombo F, De Boer W, Dierlamm A, El Morabit K, Faltermann N, Freund B, Giffels M, Harrendorf MA, Hartmann F, Heindl SM, Husemann U, Katkov I, Kudella S, Mitra S, Mozer MU, Müller T, Musich M, Plagge M, Quast G, Rabbertz K, Schröder M, Shvetsov I, Simonis HJ, Ulrich R, Wayand S, Weber M, Weiler T, Wöhrmann C, Wolf R, Anagnostou G, Daskalakis G, Geralis T, Kyriakis A, Loukas D, Paspalaki G, Karathanasis G, Kontaxakis P, Panagiotou A, Papavergou I, Saoulidou N, Tziaferi E, Vellidis K, Kousouris K, Papakrivopoulos I, Tsipolitis G, Evangelou I, Foudas C, Gianneios P, Katsoulis P, Kokkas P, Mallios S, Manthos N, Papadopoulos I, Paradas E, Strologas J, Triantis FA, Tsitsonis D, Bartók M, Csanad M, Filipovic N, Major P, Nagy MI, Pasztor G, Surányi O, Veres GI, Bencze G, Hajdu C, Horvath D, Hunyadi Á, Sikler F, Vámi TÁ, Veszpremi V, Vesztergombi G, Beni N, Czellar S, Karancsi J, Makovec A, Molnar J, Szillasi Z, Raics P, Trocsanyi ZL, Ujvari B, Choudhury S, Komaragiri JR, Tiwari PC, Bahinipati S, Kar C, Mal P, Mandal K, Nayak A, Sahoo DK, Swain SK, Bansal S, Beri SB, Bhatnagar V, Chauhan S, Chawla R, Dhingra N, Gupta R, Kaur A, Kaur M, Kaur S, Kumari P, Lohan M, Mehta A, Sandeep K, Sharma S, Singh JB, Virdi AK, Walia G, Bhardwaj A, Choudhary BC, Garg RB, Gola M, Keshri S, Kumar A, Malhotra S, Naimuddin M, Priyanka P, Ranjan K, Shah A, Sharma R, Bhardwaj R, Bharti M, Bhattacharya R, Bhattacharya S, Bhawandeep U, Bhowmik D, Dey S, Dutt S, Dutta S, Ghosh S, Mondal K, Nandan S, Purohit A, Rout PK, Roy A, Roy Chowdhury S, Saha G, Sarkar S, Sharan M, Singh B, Thakur S, Behera PK, Chudasama R, Dutta D, Jha V, Kumar V, Netrakanti PK, Pant LM, Shukla P, Aziz T, Bhat MA, Dugad S, Mohanty GB, Sur N, Sutar B, Kumar Verma R, Banerjee S, Bhattacharya S, Chatterjee S, Das P, Guchait M, Jain S, Karmakar S, Kumar S, Maity M, Majumder G, Mazumdar K, Sahoo N, Sarkar T, Chauhan S, Dube S, Hegde V, Kapoor A, Kothekar K, Pandey S, Rane A, Rastogi A, Sharma S, Chenarani S, Eskandari Tadavani E, Etesami SM, Khakzad M, Mohammadi Najafabadi M, Naseri M, Rezaei Hosseinabadi F, Safarzadeh B, Zeinali M, Felcini M, Grunewald M, Abbrescia M, Calabria C, Colaleo A, Creanza D, Cristella L, De Filippis N, De Palma M, Di Florio A, Errico F, Fiore L, Gelmi A, Iaselli G, Ince M, Lezki S, Maggi G, Maggi M, Miniello G, My S, Nuzzo S, Pompili A, Pugliese G, Radogna R, Ranieri A, Selvaggi G, Sharma A, Silvestris L, Venditti R, Verwilligen P, Zito G, Abbiendi G, Battilana C, Bonacorsi D, Borgonovi L, Braibant-Giacomelli S, Campanini R, Capiluppi P, Castro A, Cavallo FR, Chhibra SS, Ciocca C, Codispoti G, Cuffiani M, Dallavalle GM, Fabbri F, Fanfani A, Fontanesi E, Giacomelli P, Grandi C, Guiducci L, Iemmi F, Lo Meo S, Marcellini S, Masetti G, Montanari A, Navarria FL, Perrotta A, Primavera F, Rovelli T, Siroli GP, Tosi N, Albergo S, Di Mattia A, Potenza R, Tricomi A, Tuve C, Barbagli G, Chatterjee K, Ciulli V, Civinini C, D'Alessandro R, Focardi E, Latino G, Lenzi P, Meschini M, Paoletti S, Russo L, Sguazzoni G, Strom D, Viliani L, Benussi L, Bianco S, Fabbri F, Piccolo D, Ferro F, Mulargia R, Ravera F, Robutti E, Tosi S, Benaglia A, Beschi A, Brivio F, Ciriolo V, Di Guida S, Dinardo ME, Fiorendi S, Gennai S, Ghezzi A, Govoni P, Malberti M, Malvezzi S, Massironi A, Menasce D, Monti F, Moroni L, Paganoni M, Pedrini D, Ragazzi S, Tabarelli de Fatis T, Zuolo D, Buontempo S, Cavallo N, De Iorio A, Di Crescenzo A, Fabozzi F, Fienga F, Galati G, Iorio AOM, Khan WA, Lista L, Meola S, Paolucci P, Sciacca C, Voevodina E, Azzi P, Bacchetta N, Boletti A, Bragagnolo A, Carlin R, Checchia P, Dall'Osso M, De Castro Manzano P, Dorigo T, Dosselli U, Gasparini F, Gasparini U, Hoh SY, Lacaprara S, Lujan P, Margoni M, Meneguzzo AT, Passaseo M, Pazzini J, Pozzobon N, Ronchese P, Rossin R, Simonetto F, Tiko A, Torassa E, Tosi M, Zanetti M, Zotto P, Zumerle G, Braghieri A, Magnani A, Montagna P, Ratti SP, Re V, Ressegotti M, Riccardi C, Salvini P, Vai I, Vitulo P, Biasini M, Bilei GM, Cecchi C, Ciangottini D, Fanò L, Lariccia P, Leonardi R, Manoni E, Mantovani G, Mariani V, Menichelli M, Rossi A, Santocchia A, Spiga D, Androsov K, Azzurri P, Bagliesi G, Bianchini L, Boccali T, Borrello L, Castaldi R, Ciocci MA, Dell'Orso R, Fedi G, Fiori F, Giannini L, Giassi A, Grippo MT, Ligabue F, Manca E, Mandorli G, Messineo A, Palla F, Rizzi A, Rolandi G, Spagnolo P, Tenchini R, Tonelli G, Venturi A, Verdini PG, Barone L, Cavallari F, Cipriani M, Del Re D, Di Marco E, Diemoz M, Gelli S, Longo E, Marzocchi B, Meridiani P, Organtini G, Pandolfi F, Paramatti R, Preiato F, Rahatlou S, Rovelli C, Santanastasio F, Amapane N, Arcidiacono R, Argiro S, Arneodo M, Bartosik N, Bellan R, Biino C, Cappati A, Cartiglia N, Cenna F, Cometti S, Costa M, Covarelli R, Demaria N, Kiani B, Mariotti C, Maselli S, Migliore E, Monaco V, Monteil E, Monteno M, Obertino MM, Pacher L, Pastrone N, Pelliccioni M, Pinna Angioni GL, Romero A, Ruspa M, Sacchi R, Salvatico R, Shchelina K, Sola V, Solano A, Soldi D, Staiano A, Belforte S, Candelise V, Casarsa M, Cossutti F, Da Rold A, Della Ricca G, Vazzoler F, Zanetti A, Kim DH, Kim GN, Kim MS, Lee J, Lee S, Lee SW, Moon CS, Oh YD, Pak SI, Sekmen S, Son DC, Yang YC, Kim H, Moon DH, Oh G, Francois B, Goh J, Kim TJ, Cho S, Choi S, Go Y, Gyun D, Ha S, Hong B, Jo Y, Lee K, Lee KS, Lee S, Lim J, Park SK, Roh Y, Kim HS, Almond J, Kim J, Kim JS, Lee H, Lee K, Nam K, Oh SB, Radburn-Smith BC, Seo SH, Yang UK, Yoo HD, Yu GB, Jeon D, Kim H, Kim JH, Lee JSH, Park IC, Choi Y, Hwang C, Lee J, Yu I, Dudenas V, Juodagalvis A, Vaitkus J, Ahmed I, Ibrahim ZA, Md Ali MAB, Mohamad Idris F, Wan Abdullah WAT, Yusli MN, Zolkapli Z, Benitez JF, Castaneda Hernandez A, Murillo Quijada JA, Castilla-Valdez H, De La Cruz-Burelo E, Duran-Osuna MC, Heredia-De La Cruz I, Lopez-Fernandez R, Mejia Guisao J, Rabadan-Trejo RI, Ramirez-Garcia M, Ramirez-Sanchez G, Reyes-Almanza R, Sanchez-Hernandez A, Carrillo Moreno S, Oropeza Barrera C, Vazquez Valencia F, Eysermans J, Pedraza I, Salazar Ibarguen HA, Uribe Estrada C, Morelos Pineda A, Krofcheck D, Bheesette S, Butler PH, Ahmad A, Ahmad M, Asghar MI, Hassan Q, Hoorani HR, Saddique A, Shah MA, Shoaib M, Waqas M, Bialkowska H, Bluj M, Boimska B, Frueboes T, Górski M, Kazana M, Szleper M, Traczyk P, Zalewski P, Bunkowski K, Byszuk A, Doroba K, Kalinowski A, Konecki M, Krolikowski J, Misiura M, Olszewski M, Pyskir A, Walczak M, Araujo M, Bargassa P, Beirão Da Cruz E Silva C, Di Francesco A, Faccioli P, Galinhas B, Gallinaro M, Hollar J, Leonardo N, Seixas J, Strong G, Toldaiev O, Varela J, Afanasiev S, Bunin P, Gavrilenko M, Golutvin I, Gorbunov I, Kamenev A, Karjavine V, Lanev A, Malakhov A, Matveev V, Moisenz P, Palichik V, Perelygin V, Shmatov S, Shulha S, Skatchkov N, Smirnov V, Voytishin N, Zarubin A, Golovtsov V, Ivanov Y, Kim V, Kuznetsova E, Levchenko P, Murzin V, Oreshkin V, Smirnov I, Sosnov D, Sulimov V, Uvarov L, Vavilov S, Vorobyev A, Andreev Y, Dermenev A, Gninenko S, Golubev N, Karneyeu A, Kirsanov M, Krasnikov N, Pashenkov A, Tlisov D, Toropin A, Epshteyn V, Gavrilov V, Lychkovskaya N, Popov V, Pozdnyakov I, Safronov G, Spiridonov A, Stepennov A, Stolin V, Toms M, Vlasov E, Zhokin A, Aushev T, Chadeeva M, Parygin P, Philippov D, Polikarpov S, Popova E, Rusinov V, Andreev V, Azarkin M, Dremin I, Kirakosyan M, Terkulov A, Baskakov A, Belyaev A, Boos E, Bunichev V, Dubinin M, Dudko L, Ershov A, Gribushin A, Klyukhin V, Kodolova O, Lokhtin I, Miagkov I, Obraztsov S, Petrushanko S, Savrin V, Barnyakov A, Blinov V, Dimova T, Kardapoltsev L, Skovpen Y, Azhgirey I, Bayshev I, Bitioukov S, Elumakhov D, Godizov A, Kachanov V, Kalinin A, Konstantinov D, Mandrik P, Petrov V, Ryutin R, Slabospitskii S, Sobol A, Troshin S, Tyurin N, Uzunian A, Volkov A, Babaev A, Baidali S, Okhotnikov V, Adzic P, Cirkovic P, Devetak D, Dordevic M, Milosevic J, Alcaraz Maestre J, Álvarez Fernández A, Bachiller I, Barrio Luna M, Brochero Cifuentes JA, Cerrada M, Colino N, De La Cruz B, Delgado Peris A, Fernandez Bedoya C, Fernández Ramos JP, Flix J, Fouz MC, Gonzalez Lopez O, Goy Lopez S, Hernandez JM, Josa MI, Moran D, Pérez-Calero Yzquierdo A, Puerta Pelayo J, Redondo I, Romero L, Soares MS, Triossi A, Albajar C, de Trocóniz JF, Cuevas J, Erice C, Fernandez Menendez J, Folgueras S, Gonzalez Caballero I, González Fernández JR, Palencia Cortezon E, Rodríguez Bouza V, Sanchez Cruz S, Vischia P, Vizan Garcia JM, Cabrillo IJ, Calderon A, Chazin Quero B, Duarte Campderros J, Fernandez M, Fernández Manteca PJ, García Alonso A, Garcia-Ferrero J, Gomez G, Lopez Virto A, Marco J, Martinez Rivero C, Martinez Ruiz Del Arbol P, Matorras F, Piedra Gomez J, Prieels C, Rodrigo T, Ruiz-Jimeno A, Scodellaro L, Trevisani N, Vila I, Vilar Cortabitarte R, Wickramage N, Abbaneo D, Akgun B, Auffray E, Auzinger G, Baillon P, Ball AH, Barney D, Bendavid J, Bianco M, Bocci A, Botta C, Brondolin E, Camporesi T, Cepeda M, Cerminara G, Chapon E, Chen Y, Cucciati G, d'Enterria D, Dabrowski A, Daci N, Daponte V, David A, De Roeck A, Deelen N, Dobson M, Dünser M, Dupont N, Elliott-Peisert A, Everaerts P, Fallavollita F, Fasanella D, Franzoni G, Fulcher J, Funk W, Gigi D, Gilbert A, Gill K, Glege F, Gruchala M, Guilbaud M, Gulhan D, Hegeman J, Heidegger C, Innocente V, Jafari A, Janot P, Karacheban O, Kieseler J, Kornmayer A, Krammer M, Lange C, Lecoq P, Lourenço C, Malgeri L, Mannelli M, Meijers F, Merlin JA, Mersi S, Meschi E, Milenovic P, Moortgat F, Mulders M, Ngadiuba J, Nourbakhsh S, Orfanelli S, Orsini L, Pantaleo F, Pape L, Perez E, Peruzzi M, Petrilli A, Petrucciani G, Pfeiffer A, Pierini M, Pitters FM, Rabady D, Racz A, Reis T, Rovere M, Sakulin H, Schäfer C, Schwick C, Seidel M, Selvaggi M, Sharma A, Silva P, Sphicas P, Stakia A, Steggemann J, Treille D, Tsirou A, Veckalns V, Verzetti M, Zeuner WD, Caminada L, Deiters K, Erdmann W, Horisberger R, Ingram Q, Kaestli HC, Kotlinski D, Langenegger U, Rohe T, Wiederkehr SA, Backhaus M, Bäni L, Berger P, Chernyavskaya N, Dissertori G, Dittmar M, Donegà M, Dorfer C, Gómez Espinosa TA, Grab C, Hits D, Klijnsma T, Lustermann W, Manzoni RA, Marionneau M, Meinhard MT, Micheli F, Musella P, Nessi-Tedaldi F, Pata J, Pauss F, Perrin G, Perrozzi L, Pigazzini S, Quittnat M, Reissel C, Ruini D, Sanz Becerra DA, Schönenberger M, Shchutska L, Tavolaro VR, Theofilatos K, Vesterbacka Olsson ML, Wallny R, Zhu DH, Aarrestad TK, Amsler C, Brzhechko D, Canelli MF, De Cosa A, Del Burgo R, Donato S, Galloni C, Hreus T, Kilminster B, Leontsinis S, Neutelings I, Rauco G, Robmann P, Salerno D, Schweiger K, Seitz C, Takahashi Y, Zucchetta A, Doan TH, Khurana R, Kuo CM, Lin W, Pozdnyakov A, Yu SS, Chang P, Chao Y, Chen KF, Chen PH, Hou WS, Kumar A, Liu YF, Lu RS, Paganis E, Psallidas A, Steen A, Asavapibhop B, Srimanobhas N, Suwonjandee N, Bat A, Boran F, Cerci S, Damarseckin S, Demiroglu ZS, Dolek F, Dozen C, Dumanoglu I, Eskut E, Girgis S, Gokbulut G, Guler Y, Gurpinar E, Hos I, Isik C, Kangal EE, Kara O, Kayis Topaksu A, Kiminsu U, Oglakci M, Onengut G, Ozdemir K, Ozturk S, Polatoz A, Tok UG, 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Mcdermott K, Mirman N, Patterson JR, Quach D, Rinkevicius A, Ryd A, Skinnari L, Soffi L, Tan SM, Tao Z, Thom J, Tucker J, Wittich P, Zientek M, Abdullin S, Albrow M, Alyari M, Apollinari G, Apresyan A, Apyan A, Banerjee S, Bauerdick LAT, Beretvas A, Berryhill J, Bhat PC, Burkett K, Butler JN, Canepa A, Cerati GB, Cheung HWK, Chlebana F, Cremonesi M, Duarte J, Elvira VD, Freeman J, Gecse Z, Gottschalk E, Gray L, Green D, Grünendahl S, Gutsche O, Hanlon J, Harris RM, Hasegawa S, Hirschauer J, Hu Z, Jayatilaka B, Jindariani S, Johnson M, Joshi U, Klima B, Kortelainen MJ, Kreis B, Lammel S, Lincoln D, Lipton R, Liu M, Liu T, Lykken J, Maeshima K, Marraffino JM, Mason D, McBride P, Merkel P, Mrenna S, Nahn S, O'Dell V, Pedro K, Pena C, Prokofyev O, Rakness G, Ristori L, Savoy-Navarro A, Schneider B, Sexton-Kennedy E, Soha A, Spalding WJ, Spiegel L, Stoynev S, Strait J, Strobbe N, Taylor L, Tkaczyk S, Tran NV, Uplegger L, Vaandering EW, Vernieri C, Verzocchi M, Vidal R, Wang M, Weber HA, Whitbeck A, Acosta D, Avery P, Bortignon P, Bourilkov D, Brinkerhoff A, Cadamuro L, Carnes A, Curry D, Field RD, Gleyzer SV, Joshi BM, Konigsberg J, Korytov A, Lo KH, Ma P, Matchev K, Mei H, Mitselmakher G, Rosenzweig D, Shi K, Sperka D, Wang J, Wang S, Zuo X, Joshi YR, Linn S, Ackert A, Adams T, Askew A, Hagopian S, Hagopian V, Johnson KF, Kolberg T, Martinez G, Perry T, Prosper H, Saha A, Schiber C, Yohay R, Baarmand MM, Bhopatkar V, Colafranceschi S, Hohlmann M, Noonan D, Rahmani M, Roy T, Yumiceva F, Adams MR, Apanasevich L, Berry D, Betts RR, Cavanaugh R, Chen X, Dittmer S, Evdokimov O, Gerber CE, Hangal DA, Hofman DJ, Jung K, Kamin J, Mills C, Sandoval Gonzalez ID, Tonjes MB, Trauger H, Varelas N, Wang H, Wang X, Wu Z, Zhang J, Alhusseini M, Bilki B, Clarida W, Dilsiz K, Durgut S, Gandrajula RP, Haytmyradov M, Khristenko V, Merlo JP, Mestvirishvili A, Moeller A, Nachtman J, Ogul H, Onel Y, Ozok F, Penzo A, Snyder C, Tiras E, Wetzel J, Blumenfeld B, Cocoros A, Eminizer N, 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Thomas S, Thomassen P, Walker M, Delannoy AG, Heideman J, Riley G, Spanier S, Bouhali O, Celik A, Dalchenko M, De Mattia M, Delgado A, Dildick S, Eusebi R, Gilmore J, Huang T, Kamon T, Luo S, Mueller R, Overton D, Perniè L, Rathjens D, Safonov A, Akchurin N, Damgov J, De Guio F, Dudero PR, Kunori S, Lamichhane K, Lee SW, Mengke T, Muthumuni S, Peltola T, Undleeb S, Volobouev I, Wang Z, Greene S, Gurrola A, Janjam R, Johns W, Maguire C, Melo A, Ni H, Padeken K, Ruiz Alvarez JD, Sheldon P, Tuo S, Velkovska J, Verweij M, Xu Q, Arenton MW, Barria P, Cox B, Hirosky R, Joyce M, Ledovskoy A, Li H, Neu C, Sinthuprasith T, Wang Y, Wolfe E, Xia F, Harr R, Karchin PE, Poudyal N, Sturdy J, Thapa P, Zaleski S, Brodski M, Buchanan J, Caillol C, Carlsmith D, Dasu S, De Bruyn I, Dodd L, Gomber B, Grothe M, Herndon M, Hervé A, Hussain U, Klabbers P, Lanaro A, Long K, Loveless R, Ruggles T, Savin A, Sharma V, Smith N, Smith WH, Woods N, CMS Collaboration
This Letter describes a search for Higgs boson pair production using the combined results from four final states: bbγγ, bbττ, bbbb, and bbVV, where V represents a W or Z boson. The search is performed using data collected in 2016 by the CMS experiment from LHC proton-proton collisions at sqrt[s]=13  TeV, corresponding to an integrated luminosity of 35.9  fb^{-1}. Limits are set on the Higgs boson pair production cross section. A 95% confidence level observed (expected) upper limit on the nonresonant production cross section is set at 22.2 (12.8) times the standard model value. A search for narrow resonances decaying to Higgs boson pairs is also performed in the mass range 250-3000 GeV. No evidence for a signal is observed, and upper limits are set on the resonance production cross section.
Highly Reproducible Physiological Asymmetric Membrane with Freely Diffusing Embedded Proteins in a 3D-Printed Microfluidic Setup.
Apr 12, 2019   Small (Weinheim An Der Bergstrasse, Germany)
Heo P, Ramakrishnan S, Coleman J, Rothman JE, Fleury JB, Pincet F
Highly Reproducible Physiological Asymmetric Membrane with Freely Diffusing Embedded Proteins in a 3D-Printed Microfluidic Setup.
Apr 12, 2019
Small (Weinheim An Der Bergstrasse, Germany)
Experimental setups to produce and to monitor model membranes have been successfully used for decades and brought invaluable insights into many areas of biology. However, they all have limitations that prevent the full in vitro mimicking and monitoring of most biological processes. Here, a suspended physiological bilayer-forming chip is designed from 3D-printing techniques. This chip can be simultaneously integrated to a confocal microscope and a path-clamp amplifier. It is composed of poly(dimethylsiloxane) and consists of a ≈100 µm hole, where the horizontal planar bilayer is formed, connecting two open crossed-channels, which allows for altering of each lipid monolayer separately. The bilayer, formed by the zipping of two lipid leaflets, is free-standing, horizontal, stable, fluid, solvent-free, and flat with the 14 types of physiologically relevant lipids, and the bilayer formation process is highly reproducible. Because of the two channels, asymmetric bilayers can be formed by making the two lipid leaflets of different composition. Furthermore, proteins, such as transmembrane, peripheral, and pore-forming proteins, can be added to the bilayer in controlled orientation and keep their native mobility and activity. These features allow in vitro recapitulation of membrane process close to physiological conditions.
Effect of Formulation Method, Lipid Composition, and PEGylation on Vesicle Lamellarity: A Small-Angle Neutron Scattering Study.
Apr 12, 2019   Langmuir : The ACS Journal Of Surfaces And Colloids
Nele V, Holme MN, Kauscher U, Thomas MR, Doutch JJ, Stevens MM
Effect of Formulation Method, Lipid Composition, and PEGylation on Vesicle Lamellarity: A Small-Angle Neutron Scattering Study.
Apr 12, 2019
Langmuir : The ACS Journal Of Surfaces And Colloids
Liposomes are well-established systems for drug delivery and biosensing applications. The design of a liposomal carrier requires careful choice of lipid composition and formulation method. These determine many vesicle properties including lamellarity, which can have a strong effect on both encapsulation efficiency and the efflux rate of encapsulated active compounds. Despite this, a comprehensive study on how the lipid composition and formulation method affect vesicle lamellarity is still lacking. Here, we combine small-angle neutron scattering and cryogenic transmission electron microscopy to study the effect of three different well-established formulation methods followed by extrusion through 100 nm polycarbonate membranes on the resulting vesicle membrane structure. Specifically, we examine vesicles formulated from the commonly used phospholipids 1-palmitoyl-2-oleoyl- sn-glycero-3-phosphocholine (POPC), 1,2-dipalmitoyl- sn-glycero-3-phosphocholine (DPPC) and 1,2-dioleoyl- sn-glycero-3-phosphocholine (DOPC) via film hydration followed by (i) agitation on a shaker or (ii) freeze-thawing, or (iii) the reverse-phase evaporation vesicle method. After extrusion, up to half of the total lipid content is still assembled into multilamellar structures. However, we achieved unilamellar vesicle populations when as little as 0.1 mol % PEG-modified lipid was included in the vesicle formulation. Interestingly, DPPC with 5 mol % PEGylated lipid produces a combination of cylindrical micelles and vesicles. In conclusion, our results provide important insights into the effect of the formulation method and lipid composition on producing liposomes with a defined membrane structure.
Role of hydrophobic residues for the gaseous formation of helical motifs.
Apr 12, 2019   Chemical Communications (Cambridge, England)
Liu L, Dong X, Liu Y, Österlund N, Gräslund A, Carloni P, Li J
Role of hydrophobic residues for the gaseous formation of helical motifs.
Apr 12, 2019
Chemical Communications (Cambridge, England)
The secondary structure content of proteins and their complexes may change significantly on passing from aqueous solution to the gas phase (as in mass spectrometry experiments). In this work, we investigate the impact of hydrophobic residues on the formation of the secondary structure of a real protein complex in the gas phase. We focus on a well-studied protein complex, the amyloid-β (1-40) dimer (2Aβ). Molecular dynamics simulations reproduce the results of ion mobility-mass spectrometry experiments. In addition, a helix (not present in the solution) is identified involving 19FFAED23, consistent with infrared spectroscopy data on an Aβ segment. Our simulations further point to the role of hydrophobic residues in the formation of helical motifs - hydrophobic sidechains "shield" helices from being approached by residues that carry hydrogen bond sites. In particular, two hydrophobic phenylalanine residues, F19 and F20, play an important role for the helix, which is induced in the gas phase in spite of the presence of two carboxyl-containing residues.
Author Correction: Inhibiting PD-L1 palmitoylation enhances T-cell immune responses against tumours.
Apr 12, 2019   Nature Biomedical Engineering
Yao H, Lan J, Li C, Shi H, Brosseau JP,   . . . . . .   , Zhou X, Wang C, Xue Y, Cui Y, Xu J
Author Correction: Inhibiting PD-L1 palmitoylation enhances T-cell immune responses against tumours.
Apr 12, 2019
Nature Biomedical Engineering
In the version of this Article originally published, 'palmitoyltransferase ZDHHC3 (DHHC3)' was incorrectly referred to as an 'acetyltransferase' rather than an as an 'acyltransferase'; this has now been corrected in five instances. In Fig. 3a, the label for the bottom row of the blots was mistakenly written as 'GAPHD'; it should have read 'GAPDH'. In the two right-most panels of Fig. 4j, the antibody labels 'α-PD-L1' for the reciprocal co-immunoprecipitation of DHHC3 were incorrect; they should have been 'α-DHHC3'. These errors have been corrected in all versions of the Article.
Molecular analysis of ampR and ampD to understand variability in inducible expression of "BlaB-like" cephalosporinase in Yersinia enterocolitica biotype 1A.
Apr 16, 2019   Gene
Singhal N, Pandey D, Kumar M, Virdi JS
Molecular analysis of ampR and ampD to understand variability in inducible expression of "BlaB-like" cephalosporinase in Yersinia enterocolitica biotype 1A.
Apr 16, 2019
Gene
Yersinia enterocolitica strains produce two chromosomal β‑lactamases, BlaA - a constitutively produced penicillinase, and BlaB - an inducible "AmpC-type" cephalosporinase. As in other members of Enterobacteriaceae, expression of ampC in Y. enterocolitica is regulated by the genes - ampR and ampD. The ampR encodes a transcriptional regulator which represses the expression of ampC and, ampD encodes a cytoplasmic N‑acetyl‑anhydromuramyl‑l‑alanine amidase which participates in recycling of peptidoglycan. Exposure of bacteria to antibiotics like imipenem and cefoxitin results in generation and accumulation of large quantities of muropeptides in cytoplasm which is beyond the recycling capability of AmpD. These muropeptides bind to AmpR, converting it into an activator of ampC expression (ampC de-repression). Earlier studies from our laboratory indicated that instead of BlaB, Y. enterocolitica biotype 1A strains produced a "BlaB-like" enzyme which was non-heterogeneous and showed a differential expression when induced with imipenem. The detection of "BlaB-like" cephalosporinase which was also induced differentially in Y. enterocolitica biotype 1A strains presented an opportunity to discern newer mechanisms, if any, which may underlie inducible expression of "AmpC-type" cephalosporinases. Thus, the objective of the present study was to understand the role of ampR and ampD in regulating differential expression of "BlaB-like" cephalosporinases in biotype 1A strains. Analysis of promoters and amino acid sequences of AmpR revealed that these were conserved in all strains of biotype 1A. Analysis of AmpD amino acid sequences revealed that five variants of AmpD were present which did not contribute to hyper-inducible production of "BlaB-like" enzyme. In-silico prediction of the mRNA secondary structures of ampD revealed significant differences, which might have affected the rate of translation of ampD and accumulation of un-recycled muropeptides inside the cell leading to hyper production of "BlaB-like" cephalosporinases in some Y. enterocolitica biotype 1A strains. The findings provide newer insights to our understanding of the mechanisms underlying regulation of expression of "AmpC-type" β‑lactamases.

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