Delirium and Alzheimer's Disease: A Proposed Model for Shared Pathophysiology.

Int J Geriatr Psychiatry. 2019 Feb 17;:

Authors: Fong TG, Vasunilashorn SM, Libermann T, Marcantonio ER, Inouye SK

PMID: 30773695 [PubMed - as supplied by publisher]

Delivering blended bioinformatics training in resource-limited settings: a case study on the University of Khartoum H3ABioNet node.

Brief Bioinform. 2019 Feb 15;:

Authors: Ahmed AE, Awadallah AA, Tagelsir M, Suliman MA, Eltigani A, Elsafi H, Hamdelnile BD, Mukhtar MA, Fadlelmola FM

Abstract
MOTIVATION: Delivering high-quality distance-based courses in resource-limited settings is a challenging task. Besides the needed infrastructure and expertise, effective delivery of a bioinformatics course could benefit from hands-on sessions, interactivity and problem-based learning approaches.
RESULTS: In this article, we discuss the challenges and best practices in delivering bioinformatics training in resource-limited settings taking the example of hosting and running a multiple-delivery online course, Introduction to Bioinformatics, that was developed by the H3ABioNet Education and Training working group and delivered in 27 remote classrooms across Africa in 2017. We take the case of the University of Khartoum classrooms. Believing that our local setting is similar to others in less-developed countries, we also reflect upon aspects like classroom environment and recruitment of students to maximize outcomes.

PMID: 30773584 [PubMed - as supplied by publisher]

Rho Flares Repair Local Tight Junction Leaks.

Dev Cell. 2019 Feb 11;:

Authors: Stephenson RE, Higashi T, Erofeev IS, Arnold TR, Leda M, Goryachev AB, Miller AL

Abstract
Tight junctions contribute to epithelial barrier function by selectively regulating the quantity and type of molecules that cross the paracellular barrier. Experimental approaches to evaluate the effectiveness of tight junctions are typically global, tissue-scale measures. Here, we introduce Zinc-based Ultrasensitive Microscopic Barrier Assay (ZnUMBA), which we used in Xenopus laevis embryos to visualize short-lived, local breaches in epithelial barrier function. These breaches, or leaks, occur as cell boundaries elongate, correspond to visible breaks in the tight junction, and are followed by transient localized Rho activation, or Rho flares. We discovered that Rho flares restore barrier function by driving concentration of tight junction proteins through actin polymerization and ROCK-mediated localized contraction of the cell boundary. We conclude that Rho flares constitute a damage control mechanism that reinstates barrier function when tight junctions become locally compromised because of normally occurring changes in cell shape and tissue tension.

PMID: 30773490 [PubMed - as supplied by publisher]

The Root Cap Cuticle: A Cell Wall Structure for Seedling Establishment and Lateral Root Formation.

Cell. 2019 Feb 08;:

Authors: Berhin A, de Bellis D, Franke RB, Buono RA, Nowack MK, Nawrath C

Abstract
The root cap surrounding the tip of plant roots is thought to protect the delicate stem cells in the root meristem. We discovered that the first layer of root cap cells is covered by an electron-opaque cell wall modification resembling a plant cuticle. Cuticles are polyester-based protective structures considered exclusive to aerial plant organs. Mutations in cutin biosynthesis genes affect the composition and ultrastructure of this cuticular structure, confirming its cutin-like characteristics. Strikingly, targeted degradation of the root cap cuticle causes a hypersensitivity to abiotic stresses during seedling establishment. Furthermore, lateral root primordia also display a cuticle that, when defective, causes delayed outgrowth and organ deformations, suggesting that it facilitates lateral root emergence. Our results show that the previously unrecognized root cap cuticle protects the root meristem during the critical phase of seedling establishment and promotes the efficient formation of lateral roots.

PMID: 30773319 [PubMed - as supplied by publisher]

Genome-Scale Transcriptional Regulatory Network Models of Psychiatric and Neurodegenerative Disorders.

Cell Syst. 2019 Jan 31;:

Authors: Pearl JR, Colantuoni C, Bergey DE, Funk CC, Shannon P, Basu B, Casella AM, Oshone RT, Hood L, Price ND, Ament SA

Abstract
Transcriptional regulatory changes in the developing and adult brain are prominent features of brain diseases, but the involvement of specific transcription factors (TFs) remains poorly understood. We integrated brain-specific DNase footprinting and TF-gene co-expression to reconstruct a transcriptional regulatory network (TRN) model for the human brain. We identified key regulator TFs whose predicted target genes were enriched for differentially expressed genes in the prefrontal cortex of individuals with psychiatric and neurodegenerative diseases. Many of these TFs were further implicated in the same diseases through disruption of their binding sites by disease-associated SNPs and associations of TF loci with disease risk. Using primary human neural stem cells, we validated network predictions that link the TF POU3F2 to schizophrenia and bipolar disorder via both cis- and trans-acting mechanisms. Our models of brain-specific TF binding sites and target genes provide a resource for network analysis of brain diseases.

PMID: 30772379 [PubMed - as supplied by publisher]

Single-Cell Analysis of Diverse Pathogen Responses Defines a Molecular Roadmap for Generating Antigen-Specific Immunity.

Cell Syst. 2019 Feb 01;:

Authors: Blecher-Gonen R, Bost P, Hilligan KL, David E, Salame TM, Roussel E, Connor LM, Mayer JU, Bahar Halpern K, Tóth B, Itzkovitz S, Schwikowski B, Ronchese F, Amit I

Abstract
The immune system generates pathogen-tailored responses. The precise innate immune cell types and pathways that direct robust adaptive immune responses have not been fully characterized. By using fluorescent pathogens combined with massively parallel single-cell RNA-seq, we comprehensively characterized the initial 48 h of the innate immune response to diverse pathogens. We found that across all pathogens tested, most of the lymph node cell types and states showed little pathogen specificity. In contrast, the rare antigen-positive cells displayed pathogen-specific transcriptional programs as early as 24 h after immunization. In addition, mycobacteria activated a specific NK-driven IFNγ response. Depletion of NK cells and IFNγ showed that IFNγ initiated a monocyte-specific signaling cascade, leading to the production of major chemokines and cytokines that promote Th1 development. Our systems immunology approach sheds light on early events in innate immune responses and may help further development of safe and efficient vaccines.

PMID: 30772378 [PubMed - as supplied by publisher]

A Two-Amino Acid Mutation in Murine IgA Enables Downstream Processing and Purification on Staphylococcal Superantigen-Like Protein 7.

J Biotechnol. 2019 Feb 13;:

Authors: Bakshi S, Depicker A, Schepens B, Saelens X, Juarez P

Abstract
With few exceptions, all currently marketed antibody therapeutics are IgG molecules. One of the reasons that other antibody isotypes are less developed are the difficulties associated with their purification. While commercial chromatography affinity resins like staphylococcal superantigen-like 7 (SSL7) protein containing resin, allow purification of IgAs from many animal species, these are not useful for murine IgAs. Because the mouse model is predominantly used for preclinical evaluation of IgA-based therapeutics, there is a need to develop an effective purification method for mouse IgA. Here, we adapted the sequence of a mouse IgA by mutating two amino acid residues in the fragment crystallizable (Fc) sequence to facilitate its purification on SSL7 resin. The mutated IgA Fc (hereafter referred to as IgA*) was then genetically fused with the variable domain of a llama heavy chain-only antibody (VHH) directed against the fusion protein of human respiratory syncytial virus (HRSV) resulting in VHH-IgA*, and transiently produced in infiltrated N. benthamiana leaves. These plant-produced mouse VHH-IgA* fusions were enriched by SSL7 affinity chromatography and were found to be functional in ELISA and could neutralize RSV in vitro, suggesting no detrimental effect of the mutation on their antigen-binding properties. This approach for the purification of murine IgA will facilitate downstream processing steps when designing innovative murine IgA-based fusions.

PMID: 30771443 [PubMed - as supplied by publisher]

ASPP proteins discriminate between PP1 catalytic subunits through their SH3 domain and the PP1 C-tail.

Nat Commun. 2019 Feb 15;10(1):771

Authors: Bertran MT, Mouilleron S, Zhou Y, Bajaj R, Uliana F, Kumar GS, van Drogen A, Lee R, Banerjee JJ, Hauri S, O'Reilly N, Gstaiger M, Page R, Peti W, Tapon N

Abstract
Serine/threonine phosphatases such as PP1 lack substrate specificity and associate with a large array of targeting subunits to achieve the requisite selectivity. The tumour suppressor ASPP (apoptosis-stimulating protein of p53) proteins associate with PP1 catalytic subunits and are implicated in multiple functions from transcriptional regulation to cell junction remodelling. Here we show that Drosophila ASPP is part of a multiprotein PP1 complex and that PP1 association is necessary for several in vivo functions of Drosophila ASPP. We solve the crystal structure of the human ASPP2/PP1 complex and show that ASPP2 recruits PP1 using both its canonical RVxF motif, which binds the PP1 catalytic domain, and its SH3 domain, which engages the PP1 C-terminal tail. The ASPP2 SH3 domain can discriminate between PP1 isoforms using an acidic specificity pocket in the n-Src domain, providing an exquisite mechanism where multiple motifs are used combinatorially to tune binding affinity to PP1.

PMID: 30770806 [PubMed - in process]

Fhit-Fdxr interaction in the mitochondria: modulation of reactive oxygen species generation and apoptosis in cancer cells.

Cell Death Dis. 2019 Feb 15;10(3):147

Authors: Druck T, Cheung DG, Park D, Trapasso F, Pichiorri F, Gaspari M, Palumbo T, Aqeilan RI, Gaudio E, Okumura H, Iuliano R, Raso C, Green K, Huebner K, Croce CM

Abstract
Fhit protein is lost in cancers of most, perhaps all, cancer types; when restored, it can induce apoptosis and suppress tumorigenicity, as shown in vitro and in mouse tumor models in vivo. Following protein cross-linking and proteomics analyses, we characterized a Fhit protein complex involved in triggering Fhit-mediated apoptosis. The complex includes the heat-shock chaperonin pair, HSP60/10, which is likely involved in importing Fhit into the mitochondria, where it interacts with ferredoxin reductase, responsible for transferring electrons from NADPH to cytochrome P450 via ferredoxin, in electron transport chain complex III. Overexpression of Fhit protein in Fhit-deficient cancer cells modulates the production of intracellular reactive oxygen species, causing increased ROS, following peroxide treatment, with subsequent increased apoptosis of lung cancer cells under oxidative stress conditions; conversely, Fhit-negative cells escape ROS overproduction and ROS-induced apoptosis, likely carrying oxidative damage. Thus, characterization of Fhit-interacting proteins has identified direct effectors of a Fhit-mediated apoptotic signal pathway that is lost in many cancers. This is of translational interest considering the very recent emphasis in a number of high-profile publications, concerning the role of oxidative phosphorylation in the treatment of human cancers, and especially cancer stem cells that rely upon oxidative phosphorylation for survival. Additionally, we have shown that cells from a Fhit-deficient lung cancer cell line, are sensitive to killing by exposure to atovaquone, thought to act as a selective oxidative phosphorylation inhibitor by targeting the CoQ10 dependence of the mitochondrial complex III, while the Fhit-expressing sister clone is resistant to this treatment.

PMID: 30770797 [PubMed - in process]

Parameter estimation in models of biological oscillators: an automated regularised estimation approach.

BMC Bioinformatics. 2019 Feb 15;20(1):82

Authors: Pitt JA, Banga JR

Abstract
BACKGROUND: Dynamic modelling is a core element in the systems biology approach to understanding complex biosystems. Here, we consider the problem of parameter estimation in models of biological oscillators described by deterministic nonlinear differential equations. These problems can be extremely challenging due to several common pitfalls: (i) a lack of prior knowledge about parameters (i.e. massive search spaces), (ii) convergence to local optima (due to multimodality of the cost function), (iii) overfitting (fitting the noise instead of the signal) and (iv) a lack of identifiability. As a consequence, the use of standard estimation methods (such as gradient-based local ones) will often result in wrong solutions. Overfitting can be particularly problematic, since it produces very good calibrations, giving the impression of an excellent result. However, overfitted models exhibit poor predictive power. Here, we present a novel automated approach to overcome these pitfalls. Its workflow makes use of two sequential optimisation steps incorporating three key algorithms: (1) sampling strategies to systematically tighten the parameter bounds reducing the search space, (2) efficient global optimisation to avoid convergence to local solutions, (3) an advanced regularisation technique to fight overfitting. In addition, this workflow incorporates tests for structural and practical identifiability.
RESULTS: We successfully evaluate this novel approach considering four difficult case studies regarding the calibration of well-known biological oscillators (Goodwin, FitzHugh-Nagumo, Repressilator and a metabolic oscillator). In contrast, we show how local gradient-based approaches, even if used in multi-start fashion, are unable to avoid the above-mentioned pitfalls.
CONCLUSIONS: Our approach results in more efficient estimations (thanks to the bounding strategy) which are able to escape convergence to local optima (thanks to the global optimisation approach). Further, the use of regularisation allows us to avoid overfitting, resulting in more generalisable calibrated models (i.e. models with greater predictive power).

PMID: 30770736 [PubMed - in process]

Functional Heatmap: an automated and interactive pattern recognition tool to integrate time with multi-omics assays.

BMC Bioinformatics. 2019 Feb 15;20(1):81

Authors: Williams JR, Yang R, Clifford JL, Watson D, Campbell R, Getnet D, Kumar R, Hammamieh R, Jett M

Abstract
BACKGROUND: Life science research is moving quickly towards large-scale experimental designs that are comprised of multiple tissues, time points, and samples. Omic time-series experiments offer answers to three big questions: what collective patterns do most analytes follow, which analytes follow an identical pattern or synchronize across multiple cohorts, and how do biological functions evolve over time. Existing tools fall short of robustly answering and visualizing all three questions in a unified interface.
RESULTS: Functional Heatmap offers time-series data visualization through a Master Panel page, and Combined page to answer each of the three time-series questions. It dissects the complex multi-omics time-series readouts into patterned clusters with associated biological functions. It allows users to identify a cascade of functional changes over a time variable. Inversely, Functional Heatmap can compare a pattern with specific biology respond to multiple experimental conditions. All analyses are interactive, searchable, and exportable in a form of heatmap, line-chart, or text, and the results are easy to share, maintain, and reproduce on the web platform.
CONCLUSIONS: Functional Heatmap is an automated and interactive tool that enables pattern recognition in time-series multi-omics assays. It significantly reduces the manual labour of pattern discovery and comparison by transferring statistical models into visual clues. The new pattern recognition feature will help researchers identify hidden trends driven by functional changes using multi-tissues/conditions on a time-series fashion from omic assays.

PMID: 30770734 [PubMed - in process]

Longitudinal active sampling for respiratory viral infections across age groups.

Influenza Other Respir Viruses. 2019 Feb 15;:

Authors: Galanti M, Birger R, Ud-Dean M, Filip I, Morita H, Comito D, Anthony S, Freyer GA, Ibrahim S, Lane B, Ligon C, Rabadan R, Shittu A, Tagne E, Shaman J

Abstract
BACKGROUND: Respiratory viral infections are a major cause of morbidity and mortality worldwide. However, their characterization is incomplete because prevalence estimates are based on syndromic surveillance data. Here, we address this shortcoming through the analysis of infection rates among individuals tested regularly for respiratory viral infections, irrespective of their symptoms.
METHODS: We carried out longitudinal sampling and analysis among 214 individuals enrolled at multiple New York City locations from fall 2016 to spring 2018. We combined personal information with weekly nasal swab collection to investigate the prevalence of 18 respiratory viruses among different age groups and to assess risk factors associated with infection susceptibility.
RESULTS: 17.5% of samples were positive for respiratory viruses. Some viruses circulated predominantly during winter, whereas others were found year round. Rhinovirus and coronavirus were most frequently detected. Children registered the highest positivity rates, and adults with daily contacts with children experienced significantly more infections than their counterparts without children.
CONCLUSION: Respiratory viral infections are widespread among the general population with the majority of individuals presenting multiple infections per year. The observations identify children as the principal source of respiratory infections. These findings motivate further active surveillance and analysis of differences in pathogenicity among respiratory viruses.

PMID: 30770641 [PubMed - as supplied by publisher]

Reactive oxygen species modulate macrophage immunosuppressive phenotype through the up-regulation of PD-L1.

Proc Natl Acad Sci U S A. 2019 Feb 15;:

Authors: Roux C, Jafari SM, Shinde R, Duncan G, Cescon DW, Silvester J, Chu MF, Hodgson K, Berger T, Wakeham A, Palomero L, Garcia-Valero M, Pujana MA, Mak TW, McGaha TL, Cappello P, Gorrini C

Abstract
The combination of immune checkpoint blockade with chemotherapy is currently under investigation as a promising strategy for the treatment of triple negative breast cancer (TNBC). Tumor-associated macrophages (TAMs) are the most prominent component of the breast cancer microenvironment because they influence tumor progression and the response to therapies. Here we show that macrophages acquire an immunosuppressive phenotype and increase the expression of programmed death ligand-1 (PD-L1) when treated with reactive oxygen species (ROS) inducers such as the glutathione synthesis inhibitor, buthionine sulphoximine (BSO), and paclitaxel. Mechanistically, these agents cause accumulation of ROS that in turn activate NF-κB signaling to promote PD-L1 transcription and the release of immunosuppressive chemokines. Systemic in vivo administration of paclitaxel promotes PD-L1 accumulation on the surface of TAMS in a mouse model of TNBC, consistent with in vitro results. Combinatorial treatment with paclitaxel and an anti-mouse PD-L1 blocking antibody significantly improved the therapeutic efficacy of paclitaxel by reducing tumor burden and increasing the number of tumor-associated cytotoxic T cells. Our results provide a strong rationale for the use of anti-PD-L1 blockade in the treatment of TNBC patients. Furthermore, interrogation of chemotherapy-induced PD-L1 expression in TAMs is warranted to define appropriate patient selection in the use of PD-L1 blockade.

PMID: 30770442 [PubMed - as supplied by publisher]

Inactivation of Apoptosis Antagonizing Transcription Factor in tubular epithelial cells induces accumulation of DNA damage and nephronophthisis.

Kidney Int. 2019 Feb 12;:

Authors: Jain M, Kaiser RWJ, Bohl K, Hoehne M, Göbel H, Bartram MP, Habbig S, Müller RU, Fogo AB, Benzing T, Schermer B, Höpker K, Slaats GG

Abstract
Recent human genetic studies have suggested an intriguing link between ciliary signaling defects and altered DNA damage responses in nephronophthisis (NPH) and related ciliopathies. However, the molecular mechanism and the role of altered DNA damage response in kidney degeneration and fibrosis have remained elusive. We recently identified the kinase-regulated DNA damage response target Apoptosis Antagonizing Transcription Factor (AATF) as a master regulator of the p53 response. Here, we characterized the phenotype of mice with genetic deletion of Aatf in tubular epithelial cells. Mice were born without an overt phenotype, but gradually developed progressive kidney disease. Histology was notable for severe tubular atrophy and interstitial fibrosis as well as cysts at the corticomedullary junction, hallmarks of human nephronophthisis. Aatf deficiency caused ciliary defects as well as an accumulation of DNA double strand breaks. In addition to its role as a p53 effector, we found that AATF suppressed RNA:DNA hybrid (R loop) formation, a known cause of DNA double strand breaks, and enabled DNA double strand break repair in vitro. Genome-wide transcriptomic analysis of Aatf deficient tubular epithelial cells revealed several deregulated pathways that could contribute to the nephronophthisis phenotype, including alterations in the inflammatory response and anion transport. These results suggest that AATF is a regulator of primary cilia and a modulator of the DNA damage response, connecting two pathogenetic mechanisms in nephronophthisis and related ciliopathies.

PMID: 30770218 [PubMed - as supplied by publisher]

Investigating Common Pathogenic Mechanisms between Homo sapiens and Different Strains of Candida albicans for Drug Design: Systems Biology Approach via Two-Sided NGS Data Identification.

Toxins (Basel). 2019 Feb 15;11(2):

Authors: Yeh SJ, Yeh CC, Lan CY, Chen BS

Abstract
Candida albicans (C. albicans) is the most prevalent fungal species. Although it is a healthy microbiota, genetic and epigenetic alterations in host and pathogen, and microenvironment changes would lead to thrush, vaginal yeast infection, and even hematogenously disseminated infection. Despite the fact that cytotoxicity is well-characterized, few studies discuss the genome-wide genetic and epigenetic molecular mechanisms between host and C. albicans. The aim of this study is to identify drug targets and design a multiple-molecule drug to prevent the infection from C. albicans. To investigate the common and specific pathogenic mechanisms in human oral epithelial OKF6/TERT-2 cells during the C. albicans infection in different strains, systems modeling and big databases mining were used to construct candidate host⁻pathogen genetic and epigenetic interspecies network (GEIN). System identification and system order detection are applied on two-sided next generation sequencing (NGS) data to build real host⁻pathogen cross-talk GEINs. Core host⁻pathogen cross-talk networks (HPCNs) are extracted by principal network projection (PNP) method. By comparing with core HPCNs in different strains of C. albicans, common pathogenic mechanisms were investigated and several drug targets were suggested as follows: orf19.5034 (YBP1) with the ability of anti-ROS; orf19.939 (NAM7), orf19.2087 (SAS2), orf19.1093 (FLO8) and orf19.1854 (HHF22) with high correlation to the hyphae growth and pathogen protein interaction; orf19.5585 (SAP5), orf19.5542 (SAP6) and orf19.4519 (SUV3) with the cause of biofilm formation. Eventually, five corresponding compounds-Tunicamycin, Terbinafine, Cerulenin, Tetracycline and Tetrandrine-with three known drugs could be considered as a potential multiple-molecule drug for therapeutic treatment of C. albicans.

PMID: 30769958 [PubMed - in process]

Analysis of Topological Parameters of Complex Disease Genes Reveals the Importance of Location in a Biomolecular Network.

Genes (Basel). 2019 Feb 14;10(2):

Authors: Zhao X, Liu ZP

Abstract
Network biology and medicine provide unprecedented opportunities and challenges for deciphering disease mechanisms from integrative viewpoints. The disease genes and their products perform their dysfunctions via physical and biochemical interactions in the form of a molecular network. The topological parameters of these disease genes in the interactome are of prominent interest to the understanding of their functionality from a systematic perspective. In this work, we provide a systems biology analysis of the topological features of complex disease genes in an integrated biomolecular network. Firstly, we identify the characteristics of four network parameters in the ten most frequently studied disease genes and identify several specific patterns of their topologies. Then, we confirm our findings in the other disease genes of three complex disorders (i.e., Alzheimer's disease, diabetes mellitus, and hepatocellular carcinoma). The results reveal that the disease genes tend to have a higher betweenness centrality, a smaller average shortest path length, and a smaller clustering coefficient when compared to normal genes, whereas they have no significant degree prominence. The features highlight the importance of gene location in the integrated functional linkages.

PMID: 30769902 [PubMed]

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