bluuebunny/crossref_metadata_2025 huggingface dataset:
Functional organization of the human 4D Nucleome
Authors: Chen Haiming , Chen Jie , Muir Lindsey A. , Ronquist Scott , Meixner Walter , Ljungman Mats , Ried Thomas , Smale Stephen , Rajapakse Indika
Published: June 2015

Significance

We explored the human genome as a dynamical system. Using a data-guided mathematical framework and genome-wide assays, we interrogated the dynamical relationship between genome architecture (structure) and gene expression (function) and its impact on phenotype, which defines the 4D Nucleome. Structure and function entrained with remarkable persistence in genes that underlie wound healing processes and circadian rhythms. Using genome-wide intragene and intergene contact maps, we identified gene networks with high potential for coregulation and colocalization, consistent with expression via transcription factories. In an intriguing example, we found periodic movements of circadian genes in three dimensions that entrained with expression. This work can be broadly applied to identifying genomic signatures that define critical cell states during differentiation, reprogramming, and cancer.
PRUNE2 is a human prostate cancer suppressor regulated by the intronic long noncoding RNA
PCA3
Authors: Salameh Ahmad , Lee Alessandro K. , Cardó-Vila Marina , Nunes Diana N. , Efstathiou Eleni , Staquicini Fernanda I. , Dobroff Andrey S. , Marchiò Serena , Navone Nora M. , Hosoya Hitomi , Lauer Richard C. , Wen Sijin , Salmeron Carolina C. , Hoang Anh , Newsham Irene , Lima Leandro A. , Carraro Dirce M. , Oliviero Salvatore , Kolonin Mikhail G. , Sidman Richard L. , Do Kim-Anh , Troncoso Patricia , Logothetis Christopher J. , Brentani Ricardo R. , Calin George A. , Cavenee Webster K. , Dias-Neto Emmanuel , Pasqualini Renata , Arap Wadih
Published: June 2015

Significance

Prostate cancer has an unpredictable natural history: While most tumors are clinically indolent, some patients display lethal phenotypes. Serum prostate-specific antigen is the most often used test in prostate cancer but screening is controversial. Treatment options are limited for metastatic disease, hence the need for early diagnosis. Prostate cancer antigen 3 (
PCA3
), a long noncoding RNA, is the most specific biomarker identified and approved as a diagnostic test. However, its inherent biological function (if any) has remained elusive. We uncovered a negative transdominant oncogenic role for
PCA3
that down-regulates an unrecognized tumor suppressor gene,
PRUNE2
(a human homolog of the
Drosophila
prune gene) thereby promoting malignant cell growth. This work defines a unique biological function for
PCA3
in prostate cancer.
CRISPR-based screening of genomic island excision events in bacteria
Authors: Selle Kurt , Klaenhammer Todd R. , Barrangou Rodolphe
Published: June 2015

Significance

The development of Clustered regularly interspaced short palindromic repeats (CRISPR)–CRISPR-associated genes (CAS)–based technology for targeted genome editing has revolutionized molecular biology approaches, but significant and outstanding gaps exist for applications in bacteria, the native hosts of these adaptive immune systems. This study shows that CRISPR-Cas systems can be directed to target and delete genomic islands that are flanked by insertion-sequence elements and devoid of essential genes. Naturally occurring minor subpopulations harboring deletions in genomic islands were identified and readily isolated using CRISPR-Cas screening. Promising applications of this approach can define minimal bacterial genomes, determine essential genes, and characterize genetically heterogeneous bacterial populations.
Next-generation libraries for robust RNA interference-based genome-wide screens
Authors: Kampmann Martin , Horlbeck Max A. , Chen Yuwen , Tsai Jordan C. , Bassik Michael C. , Gilbert Luke A. , Villalta Jacqueline E. , Kwon S. Chul , Chang Hyeshik , Kim V. Narry , Weissman Jonathan S.
Published: June 2015

Significance

Genetic screening is a classic approach to identify genes acting in a biological process of interest. In mammalian cells, screens are commonly based on RNA interference (RNAi), in which a short interfering RNA (siRNA) or short-hairpin RNA (shRNA) triggers degradation of cellular messenger RNAs. RNAi approaches are prone to false-positive results because of siRNA/shRNA off-target effects and false-negative results because of siRNAs/shRNAs lacking activity. We previously established that these problems can be minimized with ultracomplex shRNA libraries. Here, we present next-generation shRNA libraries targeting the human and mouse genomes, for which we improved several features to increase shRNA activity. In a pilot screen, the new library yields complementary results to clustered regularly interspaced short palindromic repeats interference (CRISPRi), an orthogonal approach we developed recently.
Muscarinic regulation of dopamine and glutamate transmission in the nucleus accumbens
Authors: Shin Jung Hoon , Adrover Martín F. , Wess Jürgen , Alvarez Veronica A.
Published: June 2015

Significance

Increases in dopamine (DA) concentration in the nucleus accumbens (NAc) are required for reward seeking, motivation, and motor control. In this article, we describe how release of another neurotransmitter, acetylcholine (ACh), affects DA transmission and concentration in the NAc. Specifically, we observed that activation of muscarinic M
2
and M
4
ACh receptors depressed, whereas activation of muscarinic M
5
ACh receptors potentiated, DA transmission in the NAc. These findings reconcile a long-standing controversy on the roles of muscarinic receptors on DA transmission in the NAc and are highly relevant for the development of novel muscarinic drugs aimed at modulating dopaminergic signaling for therapeutic purposes.
Inflammation induces dermal Vγ4
+
γδT17 memory-like cells that travel to distant skin and accelerate secondary IL-17–driven responses
Authors: Ramírez-Valle Francisco , Gray Elizabeth E. , Cyster Jason G.
Published: June 2015

Significance

An attribute of adaptive immunity is the generation of memory cells that mount enhanced responses after rechallenge. While memory is best understood for αβT cell receptor-bearing lymphocytes, the properties of γδT cells in the context of a secondary challenge have been less examined. After murine skin inflammation with imiquimod, IL-17–secreting γδT cells expand in lymph nodes and traffic to skin where they persist as memory-like cells capable of rapid activation upon rechallenge. This enhanced secondary response is in part mediated by increased IL-1R1 expression. Expansion of potentially pathogenic memory cells in lymph nodes and redistribution throughout normal and inflamed skin may help explain the generalized worsening of psoriasis reported in patients undergoing localized skin treatment with imiquimod.
Osborne Reynolds pipe flow: Direct simulation from laminar through gradual transition to fully developed turbulence
Authors: Wu Xiaohua , Moin Parviz , Adrian Ronald J. , Baltzer Jon R.
Published: June 2015

Significance

The precise dynamics of disturbance energy growth and breakdown in pipe transition is a century-old unresolved problem in fluid mechanics. In this paper, we demonstrate that the mystery attributed to the breakdown process of the Osborne Reynolds pipe transition can be partially resolved with a direct, spatially evolving simulation that carries weakly but finitely perturbed laminar inflow through gradual rather than abrupt transition arriving at the fully developed turbulent state. Some of the previously attributed abruptness and mysteriousness was perhaps due to the inability to study the process accurately with very fine spatial and temporal resolution. The energy norm was found to grow exponentially rather than algebraically. The sensitivity of the transition process to pipe entrance conditions is demonstrated.
Diel Resource Partitioning among Juvenile Atlantic Salmon, Brown Trout, and Rainbow Trout during Summer
Authors: Johnson James H. , McKenna James E.
Published: June 2015

Interspecific partitioning of food and habitat resources has been widely studied in stream salmonids. Most studies have examined resource partitioning between two native species or between a native species and one that has been introduced. In this study we examine the diel feeding ecology and habitat use of three species of juvenile salmonids (i.e., Atlantic Salmon Salmo salar, Brown Trout Salmo trutta, and Rainbow Trout Oncorhynchus mykiss) in a tributary of Skaneateles Lake, New York. Subyearling Brown Trout and Rainbow Trout fed more heavily from the drift than the benthos, whereas subyearling Atlantic Salmon fed more from the benthos than either species of trout. Feeding activity of Atlantic Salmon and Rainbow Trout was similar, with both species increasing feeding at dusk, whereas Brown Trout had no discernable feeding peak or trough. Habitat availability was important in determining site-specific habitat use by juvenile salmonids. Habitat selection was greater during the day than at night. The intrastream, diel, intraspecific, and interspecific variation we observed in salmonid habitat use in Grout Brook illustrates the difficulty of acquiring habitat use information for widespread management applications.

Received June 13, 2014; accepted January 28, 2015
Selection and evaluation of reference genes for expression analysis of Cassi
Authors: Liu Zubi , Zhu Qiankun , Li Juanjuan , Yu Jihua , Li Yangyang , Huang Xinhe , Wang Wanjun , Tan Rui , Zhou Jiayu , Liao Hai
Published: June 2015

Cassia obtusifolia, belonging to legume family, is important in many fields with high pharmaceutical, economic, and ecological values. These interests of C. obtusifolia triggered in-depth and fundamental genetic and molecular research. Therefore, the stable reference gene is necessary for normalization of the gene expression studies. In this study, 10 candidate reference genes were subjected to expression analysis in 12 different tissues and under different stresses by qRT-PCR. The expression stability was evaluated using geNorm, NormFinder, and BestKeeper software. In conclusion, different suitable reference genes were selected in different tissues and under different stress. CYP1, EF1α2, ACT2, UBQ1 were the most stable reference genes in all samples. The relative expression levels of WRKY gene were detected to confirm the reliability of the selected reference genes. These results provided suitable reference genes that could be used for normalization in C. obtusifolia tissues and under different stress.
Kar1 binding to Sfi1 C-terminal regions anchors the SPB bridge to the nuclear envelope
Authors: Seybold Christian , Elserafy Menattallah , Rüthnick Diana , Ozboyaci Musa , Neuner Annett , Flottmann Benjamin , Heilemann Mike , Wade Rebecca C. , Schiebel Elmar
Published: June 2015

The yeast spindle pole body (SPB) is the functional equivalent of the mammalian centrosome. The half bridge is a SPB substructure on the nuclear envelope (NE), playing a key role in SPB duplication. Its cytoplasmic components are the membrane-anchored Kar1, the yeast centrin Cdc31, and the Cdc31-binding protein Sfi1. In G1, the half bridge expands into the bridge through Sfi1 C-terminal (Sfi1-CT) dimerization, the licensing step for SPB duplication. We exploited photo-activated localization microscopy (PALM) to show that Kar1 localizes in the bridge center. Binding assays revealed direct interaction between Kar1 and C-terminal Sfi1 fragments. kar1Δ cells whose viability was maintained by the dominant CDC31-16 showed an arched bridge, indicating Kar1’s function in tethering Sfi1 to the NE. Cdc31-16 enhanced Cdc31–Cdc31 interactions between Sfi1–Cdc31 layers, as suggested by binding free energy calculations. In our model, Kar1 binding is restricted to Sfi1-CT and Sfi1 C-terminal centrin-binding repeats, and centrin and Kar1 provide cross-links, while Sfi1-CT stabilizes the bridge and ensures timely SPB separation.
A cell-free CENP-A assembly system defines the chromatin requirements for centromere maintenance
Authors: Westhorpe Frederick G. , Fuller Colin J. , Straight Aaron F.
Published: June 2015

Centromeres are defined by the presence of CENP-A nucleosomes in chromatin and are essential for accurate chromosome segregation. Centromeric chromatin epigenetically seeds new CENP-A nucleosome formation, thereby maintaining functional centromeres as cells divide. The features within centromeric chromatin that direct new CENP-A assembly remain unclear. Here, we developed a cell-free CENP-A assembly system that enabled the study of chromatin-bound CENP-A and soluble CENP-A separately. We show that two distinct domains of CENP-A within existing CENP-A nucleosomes are required for new CENP-A assembly and that CENP-A nucleosomes recruit the CENP-A assembly factors CENP-C and M18BP1 independently. Furthermore, we demonstrate that the mechanism of CENP-C recruitment to centromeres is dependent on the density of underlying CENP-A nucleosomes.
The lysophosphatidylserine receptor GPR174 constrains regulatory T cell development and function
Authors: Barnes Michael J. , Li Chien-Ming , Xu Ying , An Jinping , Huang Yong , Cyster Jason G.
Published: June 2015

Regulatory T cell (T reg cell) numbers and activities are tightly calibrated to maintain immune homeostasis, but the mechanisms involved are incompletely defined. Here, we report that the lysophosphatidylserine (LysoPS) receptor GPR174 is abundantly expressed in developing and mature T reg cells. In mice that lacked this X-linked gene, T reg cell generation in the thymus was intrinsically favored, and a higher fraction of peripheral T reg cells expressed CD103. LysoPS could act in vitro via GPR174 to suppress T cell proliferation and T reg cell generation. In vivo, LysoPS was detected in lymphoid organ and spinal cord tissues and was abundant in the colon. Gpr174−/Y mice were less susceptible to experimental autoimmune encephalomyelitis than wild-type mice, and GPR174 deficiency in T reg cells contributed to this phenotype. This study provides evidence that a bioactive lipid, LysoPS, negatively influences T reg cell accumulation and activity through GPR174. As such, GPR174 antagonists might have therapeutic potential for promoting immune regulation in the context of autoimmune disease.
Comparative sequence analysis suggests a conserved gating mechanism for TRP channels
Authors: Palovcak Eugene , Delemotte Lucie , Klein Michael L. , Carnevale Vincenzo
Published: June 2015

The transient receptor potential (TRP) channel superfamily plays a central role in transducing diverse sensory stimuli in eukaryotes. Although dissimilar in sequence and domain organization, all known TRP channels act as polymodal cellular sensors and form tetrameric assemblies similar to those of their distant relatives, the voltage-gated potassium (Kv) channels. Here, we investigated the related questions of whether the allosteric mechanism underlying polymodal gating is common to all TRP channels, and how this mechanism differs from that underpinning Kv channel voltage sensitivity. To provide insight into these questions, we performed comparative sequence analysis on large, comprehensive ensembles of TRP and Kv channel sequences, contextualizing the patterns of conservation and correlation observed in the TRP channel sequences in light of the well-studied Kv channels. We report sequence features that are specific to TRP channels and, based on insight from recent TRPV1 structures, we suggest a model of TRP channel gating that differs substantially from the one mediating voltage sensitivity in Kv channels. The common mechanism underlying polymodal gating involves the displacement of a defect in the H-bond network of S6 that changes the orientation of the pore-lining residues at the hydrophobic gate.
MetaPathways v2.5: quantitative functional, taxonomic and usability improvements
Authors: Konwar Kishori M. , Hanson Niels W. , Bhatia Maya P. , Kim Dongjae , Wu Shang-Ju , Hahn Aria S. , Morgan-Lang Connor , Cheung Hiu Kan , Hallam Steven J.
Published: June 2015

Summary: Next-generation sequencing is producing vast amounts of sequence information from natural and engineered ecosystems. Although this data deluge has an enormous potential to transform our lives, knowledge creation and translation need software applications that scale with increasing data processing and analysis requirements. Here, we present improvements to MetaPathways, an annotation and analysis pipeline for environmental sequence information that expedites this transformation. We specifically address pathway prediction hazards through integration of a weighted taxonomic distance and enable quantitative comparison of assembled annotations through a normalized read-mapping measure. Additionally, we improve LAST homology searches through BLAST-equivalent E-values and output formats that are natively compatible with prevailing software applications. Finally, an updated graphical user interface allows for keyword annotation query and projection onto user-defined functional gene hierarchies, including the Carbohydrate-Active Enzyme database.

Availability and implementation: MetaPathways v2.5 is available on GitHub: http://github.com/hallamlab/metapathways2.

Contact:  shallam@mail.ubc.ca

Supplementary information:  Supplementary data are available at Bioinformatics online.
REDEMPTION: reduced dimension ensemble modeling and parameter estimation
Authors: Liu Yang , Manesso Erica , Gunawan Rudiyanto
Published: June 2015

Summary: Here, we present REDEMPTION (Reduced Dimension Ensemble Modeling and Parameter estimation), a toolbox for parameter estimation and ensemble modeling of ordinary differential equations (ODEs) using time-series data. For models with more reactions than measured species, a common scenario in biological modeling, the parameter estimation is formulated as a nested optimization problem based on incremental parameter estimation strategy. REDEMPTION also includes a tool for the identification of an ensemble of parameter combinations that provide satisfactory goodness-of-fit to the data. The functionalities of REDEMPTION are accessible through a MATLAB user interface (UI), as well as through programming script. For computational speed-up, REDEMPTION provides a numerical parallelization option using MATLAB Parallel Computing toolbox.

Availability and implementation: REDEMPTION can be downloaded from http://www.cabsel.ethz.ch/tools/redemption.

Contact:  rudi.gunawan@chem.ethz.ch
An algorithm to identify medication nonpersistence using electronic pharmacy databases
Authors: Parker Melissa M , Moffet Howard H , Adams Alyce , Karter Andrew J
Published: June 2015

Objective Identifying patients who are medication nonpersistent (fail to refill in a timely manner) is important for healthcare operations and research. However, consistent methods to detect nonpersistence using electronic pharmacy records are presently lacking. We developed and validated a nonpersistence algorithm for chronically used medications.

Materials and Methods Refill patterns of adult diabetes patients (n = 14,349) prescribed cardiometabolic therapies were studied. We evaluated various grace periods (30-300 days) to identify medication nonpersistence, which is defined as a gap between refills that exceeds a threshold equal to the last days’ supply dispensed plus a grace period plus days of stockpiled medication. Since data on medication stockpiles are typically unavailable for ongoing users, we compared nonpersistence to rates calculated using algorithms that ignored stockpiles.

Results When using grace periods equal to or greater than the number of days’ supply dispensed (i.e., at least 100 days), this novel algorithm for medication nonpersistence gave consistent results whether or not it accounted for days of stockpiled medication. The agreement (Kappa coefficients) between nonpersistence rates using algorithms with versus without stockpiling improved with longer grace periods and ranged from 0.63 (for 30 days) to 0.98 (for a 300-day grace period).

Conclusions Our method has utility for health care operations and research in prevalent (ongoing) and new user cohorts. The algorithm detects a subset of patients with inadequate medication-taking behavior not identified as primary nonadherent or secondary nonadherent. Healthcare systems can most comprehensively identify patients with short- or long-term medication underutilization by identifying primary nonadherence, secondary nonadherence, and nonpersistence.
The effect of tablet computers with a mobile patient portal application on hospitalized patients’ knowledge and activation
Authors: O’Leary Kevin J , Lohman Mary E , Culver Eckford , Killarney Audrey , Randy Smith G , Liebovitz David M
Published: June 2015

Objective To assess the effect of tablet computers with a mobile patient portal application on hospitalized patients’ knowledge and activation.

Methods We developed a mobile patient portal application including pictures, names, and role descriptions of team members, scheduled tests and procedures, and a list of active medications. We evaluated the effect of the application using a controlled trial involving 2 similar units in a large teaching hospital. Patients on the intervention unit were offered use of tablet computers with the portal application during their hospitalization. We assessed patients’ ability to correctly name their nurse, primary service physicians, physician roles, planned tests and procedures, medications started, and medications stopped since admission. We also administered the Short Form of the Patient Activation Measure.

Results Overall, 100 intervention- and 102 control-unit patients participated. A higher percentage of intervention-unit patients correctly named ≥1 physician (56% vs 29.4%; P < .001) and ≥1 physician role (47% vs 15.7%; P < .001). Knowledge of nurses’ names, planned tests, planned procedures, and medication changes was generally low and not significantly different between the study units. The Short Form of the Patient Activation Measure mean (SD) score was also not significantly different at 64.1 (13.4) vs 62.7 (12.8); P = .46.

Conclusions Additional research is needed to identify optimal methods to engage and inform patients during their hospitalization, which will improve preparation for self- management after discharge.
Mycobacterium avium Complex Osteomyelitis in Persons With Human Immunodeficiency Virus: Case Series and Literature Review
Authors: Wood Brian R. , Buitrago Martha O. , Patel Sugat , Hachey David H. , Haneuse Sebastien , Harrington Robert D.
Published: June 2015

In persons with advanced immunosuppression, Mycobacterium avium complex (MAC) typically causes disseminated disease with systemic symptoms. We report 2 cases in which MAC caused localized osteomyelitis in human immunodeficiency virus (HIV)-infected individuals on antiretroviral therapy with rising CD4 counts. We summarize 17 additional cases of HIV-associated MAC osteomyelitis from the literature and compare CD4 count at presentation for vertebral cases versus nonvertebral cases, which reveals a significantly higher CD4 at presentation for vertebral cases (median 251 cells/µL vs 50 cells/µL; P = .043; Mann–Whitney U test). The literature review demonstrates that the majority of cases of MAC osteomyelitis, especially vertebral, occurs in individuals with CD4 counts that have increased to above 100 cells/µL on antiretroviral therapy. Among HIV-infected individuals with osteomyelitis, MAC should be considered a possible etiology, particularly in the setting of immune reconstitution.
Revisiting the Role of the Myofibroblast in Socket Surgery: An Immunohistochemical Study
Authors: Tawfik Hatem A. , Abdulhafez Mohamed H. , Fouad Yousef A. , Rashed Hazem O. , Osman Wesam M.
Published: June 2015

Purpose:

To determine the impact of a single injection of various anti-inflammatory, antimitotic, and antiangiogenic agents on the cell count of myofibroblasts in an eviscerated socket.

Methods:

One eye from 15 skeletally mature New Zealand white rabbits was eviscerated, and the rabbits were divided into 5 groups. Each group of 3 rabbits received a 0.1 ml subconjunctival injection of a different agent. Group I received bevacizumab 25 mg/ml, group II received triamcinolone 40 mg/ml, group III received 5-fluorouracil 50 mg/ml, group IV received mitomycin-C 0.4 mg/ml, while group V was the control group and received no injections. The animals were euthanized 19 days after evisceration and conjunctival samples were submitted for histopathological examination. Monoclonal α-smooth muscle actin antibody was applied, and the mean of 5 readings of the number of myofibroblasts was recorded in each slide.

Results:

The mean count of myofibroblasts was highest for the control group and all groups achieved a statistically significant reduction in myofibroblast count compared with the control group. Sorting the means showed that Group IV (mitomycin-C) achieved the lowest mean value (p = 0.000006) followed by triamcinolone (p = 0.00048), while group I (bevacizumab) achieved the least reduction in myofibroblast count (p = 0.00148).

Conclusion:

Until newer antimyofibroblast medications and antibodies are commercially available, a single injection of mitomycin-C or triamcinolone during surgery achieves the highest mean reduction of myofibroblast count.
Photothermal raster image correlation spectroscopy of gold nanoparticles in solution and on live cells
Authors: Nieves D. J. , Li Y. , Fernig D. G. , Lévy R.
Published: June 2015

Raster image correlation spectroscopy (RICS) measures the diffusion of fluorescently labelled molecules from stacks of confocal microscopy images by analysing correlations within the image. RICS enables the observation of a greater and, thus, more representative area of a biological system as compared to other single molecule approaches. Photothermal microscopy of gold nanoparticles allows long-term imaging of the same labelled molecules without photobleaching. Here, we implement RICS analysis on a photothermal microscope. The imaging of single gold nanoparticles at pixel dwell times short enough for RICS (60 μs) with a piezo-driven photothermal heterodyne microscope is demonstrated (photothermal raster image correlation spectroscopy, PhRICS). As a proof of principle, PhRICS is used to measure the diffusion coefficient of gold nanoparticles in glycerol : water solutions. The diffusion coefficients of the nanoparticles measured by PhRICS are consistent with their size, determined by transmission electron microscopy. PhRICS was then used to probe the diffusion speed of gold nanoparticle-labelled fibroblast growth factor 2 (FGF2) bound to heparan sulfate in the pericellular matrix of live fibroblast cells. The data are consistent with previous single nanoparticle tracking studies of the diffusion of FGF2 on these cells. Importantly, the data reveal faster FGF2 movement, previously inaccessible by photothermal tracking, and suggest that inhomogeneity in the distribution of bound FGF2 is dynamic.
RNA-directed epigenetic silencing of Periostin inhibits cell motility
Authors: Lister Nicholas C. , Clemson Matthew , Morris Kevin V.
Published: June 2015

The over-expression of Periostin, a member of the fasciclin family of proteins, has been reported in a number of cancers and, in particular, in metastatic tumours. These include breast, ovarian, lung, colon, head and neck, pancreatic, prostate, neuroblastoma and thyroid cancers. It is thought that Periostin plays a major role in the development of metastases owing to its apparent involvement in restructuring of the extracellular matrix to create a microenvironment favouring invasion and metastases, angiogenesis, independent proliferation, avoidance of apoptosis and the ability for cells to re-enter the cell cycle. As such we reasoned that targeted suppression of Periostin at the promoter and epigenetic level could result in the stable inhibition of cell motility. We find here that promoter-directed small antisense non-coding RNAs can induce transcriptional gene silencing of Periostin that results ultimately in a loss of cellular motility. The observations presented here suggest that cell motility and possibly metastasis can be controlled by transcriptional and epigenetic regulation of Periostin, offering a potentially new and novel manner to control the spread of cancerous cells.
Intrinsic universality and the computational power of self-assembly
Authors: Woods Damien
Published: June 2015

Molecular self-assembly, the formation of large structures by small pieces of matter sticking together according to simple local interactions, is a ubiquitous phenomenon. A challenging engineering goal is to design a few molecules so that large numbers of them can self-assemble into desired complicated target objects. Indeed, we would like to understand the ultimate capabilities and limitations of this bottom-up fabrication process. We look to theoretical models of algorithmic self-assembly, where small square tiles stick together according to simple local rules in order to carry out a crystal growth process. In this survey, we focus on the use of simulation between such models to classify and separate their computational and expressive powers. Roughly speaking, one model simulates another if they grow the same structures, via the same dynamical growth processes. Our journey begins with the result that there is a single intrinsically universal tile set that, with appropriate initialization and spatial scaling, simulates any instance of Winfree's abstract Tile Assembly Model. This universal tile set exhibits something stronger than Turing universality: it captures the geometry and dynamics of any simulated system in a very direct way. From there we find that there is no such tile set in the more restrictive non-cooperative model, proving it weaker than the full Tile Assembly Model. In the two-handed model, where large structures can bind together in one step, we encounter an infinite set of infinite hierarchies of strictly increasing simulation power. Towards the end of our trip, we find one tile to rule them all: a single rotatable flipable polygonal tile that simulates any tile assembly system. We find another tile that aperiodically tiles the plane (but with small gaps). These and other recent results show that simulation is giving rise to a kind of computational complexity theory for self-assembly. It seems this could be the beginning of a much longer journey, so directions for future work are suggested.
Space–time programming
Authors: Beal Jacob , Viroli Mirko
Published: June 2015

Computation increasingly takes place not on an individual device, but distributed throughout a material or environment, whether it be a silicon surface, a network of wireless devices, a collection of biological cells or a programmable material. Emerging programming models embrace this reality and provide abstractions inspired by physics, such as computational fields, that allow such systems to be programmed holistically, rather than in terms of individual devices. This paper aims to provide a unified approach for the investigation and engineering of computations programmed with the aid of space–time abstractions, by bringing together a number of recent results, as well as to identify critical open problems.
Towards heterotic computing with droplets in a fully automated droplet-maker platform
Authors: Henson Alon , Gutierrez Juan Manuel Parrilla , Hinkley Trevor , Tsuda Soichiro , Cronin Leroy
Published: June 2015

The control and prediction of complex chemical systems is a difficult problem due to the nature of the interactions, transformations and processes occurring. From self-assembly to catalysis and self-organization, complex chemical systems are often heterogeneous mixtures that at the most extreme exhibit system-level functions, such as those that could be observed in a living cell. In this paper, we outline an approach to understand and explore complex chemical systems using an automated droplet maker to control the composition, size and position of the droplets in a predefined chemical environment. By investigating the spatio-temporal dynamics of the droplets, the aim is to understand how to control system-level emergence of complex chemical behaviour and even view the system-level behaviour as a programmable entity capable of information processing. Herein, we explore how our automated droplet-maker platform could be viewed as a prototype chemical heterotic computer with some initial data and example problems that may be viewed as potential chemically embodied computations.
Symmetry structure in discrete models of biochemical systems: natural subsystems and the weak control hierarchy in a new model of computation driven by interactions
Authors: Nehaniv Chrystopher L. , Rhodes John , Egri-Nagy Attila , Dini Paolo , Morris Eric Rothstein , Horváth Gábor , Karimi Fariba , Schreckling Daniel , Schilstra Maria J.
Published: June 2015

Interaction computing is inspired by the observation that cell metabolic/regulatory systems construct order dynamically, through constrained interactions between their components and based on a wide range of possible inputs and environmental conditions. The goals of this work are to (i) identify and understand mathematically the natural subsystems and hierarchical relations in natural systems enabling this and (ii) use the resulting insights to define a new model of computation based on interactions that is useful for both biology and computation. The dynamical characteristics of the cellular pathways studied in systems biology relate, mathematically, to the computational characteristics of automata derived from them, and their internal symmetry structures to computational power. Finite discrete automata models of biological systems such as the lac operon, the Krebs cycle and p53–mdm2 genetic regulation constructed from systems biology models have canonically associated algebraic structures (their transformation semigroups). These contain permutation groups (local substructures exhibiting symmetry) that correspond to ‘pools of reversibility’. Thesenatural subsystemsare related to one another in a hierarchical manner by the notion of ‘weak control’. We present natural subsystems arising from several biological examples and their weak control hierarchies in detail. Finite simple non-Abelian groups are found in biological examples and can be harnessed to realizefinitary universal computation. This allows ensembles of cells to achieve any desired finitary computational transformation, depending on external inputs, via suitably constrained interactions. Based on this,interaction machinesthat grow and change their structure recursively are introduced and applied, providing a natural model of computation driven by interactions.
Heterotic computing: past, present and future
Authors: Kendon Viv , Sebald Angelika , Stepney Susan
Published: June 2015

We introduce and define ‘heterotic computing’ as a combination of two or more computational systems such that they provide an advantage over either substrate used separately. This first requires a definition of physical computation. We take the framework in Horsman
et al.
(Horsman
et al.
2014
Proc. R. Soc. A
470, 20140182. (
doi:10.1098/rspa.2014.0182
)), now known as abstract-representation theory, then outline how to compose such computational systems. We use examples to illustrate the ubiquity of heterotic computing, and to discuss the issues raised when one or more of the substrates is not a conventional silicon-based computer. We briefly outline the requirements for a proper theoretical treatment of heterotic computational systems, and the advantages such a theory would provide.
Systematic identification of significantly mutated regions reveals a rich landscape of functional molecular alterations across cancer genomes
Authors: Araya Carlos L. , Cenik Can , Reuter Jason A. , Kiss Gert , Pande Vijay S. , Snyder Michael P. , Greenleaf William J.
Published: June 2015

Cancer genome sequencing studies have identified cancer-driver genes from the increased accumulation of protein-altering mutations. However, the positional distributions of coding mutations, and the 79% of somatic variants in exome data that do not alter protein sequence or RNA splicing, remain largely unstudied. We employed density-based clustering methods on ~4,700 exomes from 21 tumor types to detect variably-sized significantly mutated regions (SMRs). SMRs reveal recurrent alterations across a diverse spectrum of coding and non-coding elements, including microRNAs, transcription factor binding sites, and untranslated regions that are individually mutated in up to ~15% of samples in specific cancer types. SMRs often associated with changes in gene expression and signaling. Mapping SMRs to protein structures revealed spatial clustering of somatic mutations at known and novel cancer-driver domains and molecular interfaces. Mutation frequencies in SMRs demonstrate that distinct protein regions are differentially mutated among tumor types. The functional diversity of SMRs underscores both the varied mechanisms of oncogenic misregulation and the advantage of unbiased driver identification.
Engineering Modular Viral Scaffolds for Targeted Bacterial Population Editing
Authors: Ando Hiroki , Lemire Sebastien , Pires Diana P. , Lu Timothy K.
Published: June 2015

Bacteria are central to human health and disease, but the tools available for modulating and editing bacterial communities are limited. New technologies for tuning microbial populations would facilitate the targeted manipulation of the human microbiome and treatment of bacterial infections. For example, antibiotics are often broad spectrum in nature and cannot be used to accurately manipulate bacterial communities. Bacteriophages can provide highly specific targeting of bacteria, but relying solely on natural phage isolation strategies to assemble well-defined and uniform phage cocktails that are amenable to engineering can be a time-consuming and labor-intensive process. Here, we present a synthetic-biology strategy to modulate phage host ranges by manipulating phage genomes inSaccharomyces cerevisiae. We used this technology to swap multiple modular phage tail components and demonstrated thatEscherichia coliphage scaffolds can be redirected to target pathogenicYersiniaandKlebsiellabacteria, and conversely,Klebsiellaphage scaffolds can be redirected to targetE. coli. The synthetic phages achieved multiple orders-of-magnitude killing of their new target bacteria and were used to selectively remove specific bacteria from multi-species bacterial communities. We envision that this approach will accelerate the study of phage biology, facilitate the tuning of phage host ranges, and enable new tools for microbiome engineering and the treatment of infectious diseases.
Tools and pipelines for BioNano data: molecule assembly pipeline and FASTA super scaffolding tool
Authors: Shelton Jennifer Marie , Coleman Michelle C , Herndon Nic , Lu Nanyan , Lam Ernest T , Anantharaman Thomas , Sheth Palak , Brown Susan J
Published: June 2015

Background: Genome assembly remains an unsolved problem. Assembly projects face a range of hurdles that confound assembly. Thus a variety of tools and approaches are needed to improve draft genomes. Results: We used a custom assembly workflow to optimize consensus genome map assembly, resulting in an assembly equal to the estimated length of the Tribolium castaneum genome and with an N50 of more than 1 Mb. We used this map for super scaffolding the T. castaneum sequence assembly, more than tripling its N50 with the program Stitch. Conclusions: In this article we present software that leverages consensus genome maps assembled from extremely long single molecule maps to increase the contiguity of sequence assemblies. We report the results of applying these tools to validate and improve a 7x Sanger draft of the T. castaneum genome.
Identification of Slco1a6 as a candidate gene that broadly affects gene expression in mouse pancreatic islets
Authors: Tian Jianan , Keller Mark P. , Oler Angie T. , Rabaglia Mary E. , Schueler Kathryn L. , Stapleton Donald S. , Broman Aimee Teo , Zhao Wen , Kendziorski Christina , Yandell Brian S. , Hagenbuch Bruno , Broman Karl W , Attie Alan D.
Published: June 2015

We surveyed gene expression in six tissues in an F2 intercross between mouse strains C57BL/6J (abbreviated B6) and BTBR T+ tf /J (abbreviated BTBR) made genetically obese with the Leptin(ob) mutation. We identified a number of expression quantitative trait loci (eQTL) affecting the expression of numerous genes distal to the locus, called trans-eQTL hotspots. Some of these trans-eQTL hotspots showed effects in multiple tissues, whereas some were specific to a single tissue. An unusually large number of transcripts (7% of genes) mapped in trans to a hotspot on chromosome 6, specifically in pancreatic islets. By considering the first two principal components of the expression of genes mapping to this region, we were able to convert the multivariate phenotype into a simple Mendelian trait. Fine-mapping the locus by traditional methods reduced the QTL interval to a 298 kb region containing only three genes, including Slco1a6, one member of a large family of organic anion transporters. Direct genomic sequencing of all Slco1a6 exons identified a non-synonymous coding SNP that converts a highly conserved proline residue at amino acid position 564 to serine. Molecular modeling suggests that Pro564 faces an aqueous pore within this 12-transmembrane domain-spanning protein. When transiently overexpressed in HEK293 cells, BTBR OATP1A6-mediated cellular uptake of the bile acid taurocholic acid (TCA) was enhanced compared to B6 OATP1A6. Our results suggest that genetic variation in Slco1a6 leads to altered transport of TCA (and potentially other bile acids) by pancreatic islets, resulting in broad gene regulation.
Inhibition of glycogen synthase kinase-3β enhances cognitive recovery after stroke: the role of TAK1
Authors: Venna Venugopal Reddy , Benashski Sharon E. , Chauhan Anjali , McCullough Louise D.
Published: June 2015

Memory deficits are common among stroke survivors. Identifying neuroprotective agents that can prevent memory impairment or improve memory recovery is a vital area of research. Glycogen synthase kinase-3β (GSK-3β) is involved in several essential intracellular signaling pathways. Unlike many other kinases, GSK-3β is active only when dephosphorylated and activation promotes inflammation and apoptosis. In contrast, increased phosphorylation leads to reduced GSK-3β (pGSK-3β) activity. GSK-3β inhibition has beneficial effects on memory in other disease models. GSK-3β regulates both the 5′AMP-activated kinase (AMPK) and transforming growth factor-β-activated kinase (TAK1) pathways. In this work, we examined the effect of GSK-3β inhibition, both independently, in conjunction with a TAK inhibitor, and in AMPK-α2 deficient mice, after stroke to investigate mechanistic interactions between these pathways. GSK-3β inhibition was neuroprotective and ameliorated stroke-induced cognitive impairments. This was independent of AMPK signaling as the protective effects of GSK-3β inhibition were seen in AMPK deficient mice. However, GSK-3β inhibition provided no additive protection in mice treated with a TAK inhibitor suggesting that TAK1 is an upstream regulator of GSK-3β. Targeting GSK-3β could be a novel therapeutic strategy for post-stroke cognitive deficits.
Atypical PKCs in memory maintenance: the roles of feedback and redundancy
Authors: Jalil Sajiya J. , Sacktor Todd Charlton , Shouval Harel Z.
Published: June 2015

Memories that last a lifetime are thought to be stored, at least in part, as persistent enhancement of the strength of particular synapses. The synaptic mechanism of these persistent changes, late long-term potentiation (L-LTP), depends on the state and number of specific synaptic proteins. Synaptic proteins, however, have limited dwell times due to molecular turnover and diffusion, leading to a fundamental question: how can this transient molecular machinery store memories lasting a lifetime? Because the persistent changes in efficacy are synapse-specific, the underlying molecular mechanisms must to a degree reside locally in synapses. Extensive experimental evidence points to atypical protein kinase C (aPKC) isoforms as key components involved in memory maintenance. Furthermore, it is evident that establishing long-term memory requires new protein synthesis. However, a comprehensive model has not been developed describing how these components work to preserve synaptic efficacies over time. We propose a molecular model that can account for key empirical properties of L-LTP, including its protein synthesis dependence, dependence on aPKCs, and synapse-specificity. Simulations and empirical data suggest that either of the two aPKC subtypes in hippocampal neurons, PKMζ and PKCι/λ, can maintain L-LTP, making the system more robust. Given genetic compensation at the level of synthesis of these PKC subtypes as in knockout mice, this system is able to maintain L-LTP and memory when one of the pathways is eliminated.
Crystal structure of a mixed-ligand dinuclear Ba—Zn complex with 2-methoxyethanol having triphenylacetate and chloride bridges
Authors: Utko Józef , Sobocińska Maria , Dobrzyńska Danuta , Lis Tadeusz
Published: June 2015

The dinuclear barium–zinc complex, μ-chlorido-1:2κ2Cl:Cl-chlorido-2κCl-bis(2-methoxyethanol-1κO)bis(2-methoxyethanol-1κ2O,O′)bis(μ-triphenylacetato-1:2κ2O:O′)bariumzinc, [BaZn(C20H15O2)2Cl2(C3H8O2)4], has been synthesized by the reaction of barium triphenylacetate, anhydrous zinc chloride and 2-methoxyethanol in the presence of toluene. The barium and zinc metal cations in the dinuclear complex are linkedviaone chloride anion and carboxylate O atoms of the triphenylacetate ligands, giving a Ba...Zn separation of 3.9335 (11) Å. The irregular nine-coordinate BaO8Cl coordination centres comprise eight O-atom donors, six of them from 2-methoxyethanol ligands (four from two bidentateO,O′-chelate interactions and two from monodentate interactions), two from bridging triphenylacetate ligands and one from a bridging Cl donor. The distorted tetrahedral coordination sphere of zinc comprises two O-atom donors from the triphenylacetate ligands and two Cl donors (one bridging and one terminal). In the crystal, O—H...Cl, O—H...O and C—H...Cl intermolecular interactions form a layered structure, lying parallel to (001).
Crystal structure of 5-(1-benzofuran-2-yl)-3-(4-methylphenyl)-4,5-dihydro-1,2-oxazol-5-ol
Authors: Ravi A. J. , Vinayaka A. C. , Jeyaseelan S. , Sadashiva M. P. , Devarajegowda H. C.
Published: June 2015

In the title compound, C18H15NO3, the isoxazole moiety adopts a shallow envelope conformation, with the C atom bearing the OH group displaced by 0.148 (1) Å from the mean plane through the other four atoms. The mean plane of this ring (all atoms) subtends dihedral angles of 87.19 (6) and 15.51 (7)° with the benzofuran ring system (r.m.s. deviation = 0.007 Å) and the 4-methylphenyl ring, respectively. In the crystal, molecules are linked by O—H...N hydrogen bonds, generating [001]C(5) chains, with adjacent molecules in the chain related byc-glide symmetry. Weak C—H...O interactions link the chains into a three-dimensional network.