A human MAP kinase interactome.

Mitogen-activated protein kinase (MAPK) pathways form the backbone of signal transduction in the mammalian cell. Here we applied a systematic experimental and computational approach to map 2,269 interactions between human MAPK-related proteins and other cellular machinery and to assemble these data into functional modules. Multiple lines of evidence including conservation with yeast supported a core network of 641 interactions. Using small interfering RNA knockdowns, we observed that approximately one-third of MAPK-interacting proteins modulated MAPK-mediated signaling. We uncovered the Na-H exchanger NHE1 as a potential MAPK scaffold, found links between HSP90 chaperones and MAPK pathways and identified MUC12 as the human analog to the yeast signaling mucin Msb2. This study makes available a large resource of MAPK interactions and clone libraries, and it illustrates a methodology for probing signaling networks based on functional refinement of experimentally derived protein-interaction maps

Airships: A New Horizon for Science

The "Airships: A New Horizon for Science" study at the Keck Institute for Space Studies investigated the potential of a variety of airships currently operable or under development to serve as observatories and science instrumentation platforms for a range of space, atmospheric, and Earth science. The participants represent a diverse cross-section of the aerospace sector, NASA, and academia. Over the last two decades, there has been wide interest in developing a high altitude, stratospheric lighter-than-air (LTA) airship that could maneuver and remain in a desired geographic position (i.e., "station-keeping") for weeks, months or even years. Our study found considerable scientific value in both low altitude (< 40 kft) and high altitude (> 60 kft) airships across a wide spectrum of space, atmospheric, and Earth science programs. Over the course of the study period, we identified stratospheric tethered aerostats as a viable alternative to airships where station-keeping was valued over maneuverability. By opening up the sky and Earth's stratospheric horizon in affordable ways with long-term flexibility, airships allow us to push technology and science forward in a project-rich environment that complements existing space observatories as well as aircraft and high-altitude balloon missions.Comment: This low resolution version of the report is 8.6 MB. For the high resolution version see: http://kiss.caltech.edu/study/airship

BigBOSS: The Ground-Based Stage IV BAO Experiment

The BigBOSS experiment is a proposed DOE-NSF Stage IV ground-based dark energy experiment to study baryon acoustic oscillations (BAO) and the growth of structure with an all-sky galaxy redshift survey. The project is designed to unlock the mystery of dark energy using existing ground-based facilities operated by NOAO. A new 4000-fiber R=5000 spectrograph covering a 3-degree diameter field will measure BAO and redshift space distortions in the distribution of galaxies and hydrogen gas spanning redshifts from 0.2&lt; z&lt; 3.5. The Dark Energy Task Force figure of merit (DETF FoM) for this experiment is expected to be equal to that of a JDEM mission for BAO with the lower risk and cost typical of a ground-based experiment

Antimicrobial Resistance Incidence and Risk Factors among Helicobacter pylori–Infected Persons, United States

Helicobacter pylori is the primary cause of peptic ulcer disease and an etiologic agent in the development of gastric cancer. H. pylori infection is curable with regimens of multiple antimicrobial agents, and antimicrobial resistance is a leading cause of treatment failure. The Helicobacter pylori Antimicrobial Resistance Monitoring Program (HARP) is a prospective, multicenter U.S. network that tracks national prevalence rates of H. pylori antimicrobial resistance. Of 347 clinical H. pylori isolates collected from December 1998 through 2002, 101 (29.1%) were resistant to one antimicrobial agent, and 17 (4.8%) were resistant to two or more antimicrobial agents. Eighty-seven (25.1%) isolates were resistant to metronidazole, 45 (12.9%) to clarithromycin, and 3 (0.9%) to amoxicillin. On multivariate analysis, black race was the only significant risk factor (p < 0.01, hazard ratio 2.04) for infection with a resistant H. pylori strain. Formulating pretreatment screening strategies or providing alternative therapeutic regimens for high-risk populations may be important for future clinical practice

A small molecule MST1/2 inhibitor accelerates murine liver regeneration with improved survival in models of steatohepatitis

Dysfunctional liver regeneration following surgical resection remains a major cause of postoperative mortality and has no therapeutic options. Without targeted therapies, the current treatment paradigm relies on supportive therapy until homeostasis can be achieved. Pharmacologic acceleration of regeneration represents an alternative therapeutic avenue. Therefore, we aimed to generate a small molecule inhibitor that could accelerate liver regeneration with an emphasis on diseased models, which represent a significant portion of patients who require surgical resection and are often not studied. Utilizing a clinically approved small molecule inhibitor as a parent compound, standard medicinal chemistry approaches were utilized to generate a small molecule inhibitor targeting serine/threonine kinase 4/3 (MST1/2) with reduced off-target effects. This compound, mCLC846, was then applied to preclinical models of murine partial hepatectomy, which included models of diet-induced metabolic dysfunction-associated steatohepatitis (MASH). mCLC846 demonstrated on target inhibition of MST1/2 and reduced epidermal growth factor receptor inhibition. The inhibitory effects resulted in restored pancreatic beta-cell function and survival under diabetogenic conditions. Liver-specific cell-line exposure resulted in Yes-associated protein activation. Oral delivery of mCLC846 perioperatively resulted in accelerated murine liver regeneration and improved survival in diet-induced MASH models. Bulk transcriptional analysis of regenerating liver remnants suggested that mCLC846 enhanced the normal regenerative pathways and induced them following liver resection. Overall, pharmacological acceleration of liver regeneration with mCLC846 was feasible, had an acceptable therapeutic index, and provided a survival benefit in models of diet-induced MASH

Streptococcus iniae M-Like Protein Contributes to Virulence in Fish and Is a Target for Live Attenuated Vaccine Development

Streptococcus iniae is a significant pathogen in finfish aquaculture, though knowledge of virulence determinants is lacking. Through pyrosequencing of the S. iniae genome we have identified two gene homologues to classical surface-anchored streptococcal virulence factors: M-like protein (simA) and C5a peptidase (scpI).S. iniae possesses a Mga-like locus containing simA and a divergently transcribed putative mga-like regulatory gene, mgx. In contrast to the Mga locus of group A Streptococcus (GAS, S. pyogenes), scpI is located distally in the chromosome. Comparative sequence analysis of the Mgx locus revealed only one significant variant, a strain with an insertion frameshift mutation in simA and a deletion mutation in a region downstream of mgx, generating an ORF which may encode a second putative mga-like gene, mgx2. Allelic exchange mutagenesis of simA and scpI was employed to investigate the potential role of these genes in S. iniae virulence. Our hybrid striped bass (HSB) and zebrafish models of infection revealed that M-like protein contributes significantly to S. iniae pathogenesis whereas C5a peptidase-like protein does not. Further, in vitro cell-based analyses indicate that SiMA, like other M family proteins, contributes to cellular adherence and invasion and provides resistance to phagocytic killing. Attenuation in our virulence models was also observed in the S. iniae isolate possessing a natural simA mutation. Vaccination of HSB with the Delta simA mutant provided 100% protection against subsequent challenge with a lethal dose of wild-type (WT) S. iniae after 1,400 degree days, and shows promise as a target for live attenuated vaccine development.Analysis of M-like protein and C5a peptidase through allelic replacement revealed that M-like protein plays a significant role in S. iniae virulence, and the Mga-like locus, which may regulate expression of this gene, has an unusual arrangement. The M-like protein mutant created in this research holds promise as live-attenuated vaccine

Gene expression variability across cells and species shapes innate immunity.

As the first line of defence against pathogens, cells mount an innate immune response, which varies widely from cell to cell. The response must be potent but carefully controlled to avoid self-damage. How these constraints have shaped the evolution of innate immunity remains poorly understood. Here we characterize the innate immune response's transcriptional divergence between species and variability in expression among cells. Using bulk and single-cell transcriptomics in fibroblasts and mononuclear phagocytes from different species, challenged with immune stimuli, we map the architecture of the innate immune response. Transcriptionally diverging genes, including those that encode cytokines and chemokines, vary across cells and have distinct promoter structures. Conversely, genes that are involved in the regulation of this response, such as those that encode transcription factors and kinases, are conserved between species and display low cell-to-cell variability in expression. We suggest that this expression pattern, which is observed across species and conditions, has evolved as a mechanism for fine-tuned regulation to achieve an effective but balanced response

BIOINFORMATICS APPLICATIONS NOTE doi:10.1093/bioinformatics/btm630 Systems biology NetworkBLAST: comparative analysis of protein networks

Summary: The identification of protein complexes is a fundamental challenge in interpreting protein–protein interaction data. Crossspecies analysis allows coping with the high levels of noise that are typical to these data. The NetworkBLAST web-server provides a platform for identifying protein complexes in protein-protein interaction networks. It can analyze a single network or two networks from different species. In the latter case, NetworkBLAST outputs a set of putative complexes that are evolutionarily conserved across the two networks. Availability: NetworkBLAST is available as web-server at: www.cs.tau.ac.il / roded/networkblast.ht