NMR assignment of a KlbA intein precursor from Methanococcus jannaschii

The backbone and side chain resonance assignments of a precursor of the KlbA intein from Methanococcus jannaschii have been determined, based on triple-resonance experiments with the uniformly [¹³C,¹⁵N]-labeled protein.     

HIV-1 coinfection and morphine coexposure severely dysregulate hepatitis C virus-induced hepatic proinflammatory cytokine release and free radical production: increased pathogenesis coincides with uncoordinated host defenses

Coinfection with human immunodeficiency virus type-1 (HIV-1) and hepatitis C virus (HCV) is a global problem that is more prevalent in injection drug users because they have a higher risk for acquiring both viruses. The roles of inflammatory cytokines and oxidative stress were examined in HIV-1- and HCV-coinfected human hepatic cells. Morphine (the bioactive product of heroin), HIV-1 Tat and the MN strain gp120 (gp120(MN)) proteins, and X4 HIV-1(LAI/IIIB) and R5 HIV-1(SF162) isolates were used to study the mechanisms of disease progression in HCV (JFH1)-infected Huh7.5.1 cell populations. HCV increased tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) release and augmented production of reactive oxygen species (ROS), nitric oxide (NO), and 3-nitrotyrosine (3-NT) in Huh7.5.1 cells. Morphine preferentially affected R5-tropic, but not X4-tropic, HIV-1 interactions with Huh7.5.1 cells. HIV-1 proteins or isolates increased cytokine release in HCV-infected cells, while adding morphine to coinfected cells caused complex imbalances, significantly disrupting cytokine secretion depending on the cytokine, morphine concentration, exposure duration, and particular pathogen involved. Production of ROS, NO, and 3-NT increased significantly in HCV- and HIV-1-coexposed cells while exposure to morphine further increased ROS. The proteasome inhibitor MG132 significantly decreased oxyradicals, cytokine levels, and HCV protein levels. Our findings indicate that hepatic inflammation is increased by combined exposure to HCV and HIV-1, that the ubiquitin-proteasome system and NF-κB contribute to key aspects of the response, and that morphine further exacerbates the disruption of host defenses. The results suggest that opioid abuse and HIV-1 coinfection each further accelerate HCV-mediated liver disease by dysregulating immune defenses.     

Landscape correlates of forest plant invasions: A high‐resolution analysis across the eastern United States

Aim

Invasive species occurrence is often related to the anthropogenic context of a given area. Quantifying the effects of roads is of particular interest as roads are a major vector for invasion. Our objective was to further quantify the effects of roads on forest plant invasion through a macroscale, high‐resolution investigation to assist effective invasion control and mitigation.

Location

Eastern United States.

Methods

Using invasive plant data from 23,039 forest inventory plots in 13 ecological provinces, we employed logistic regression to relate the odds of invasion to distance from a road, with adjustments for broadscale differences attributable to ecological provinces, and local scale differences in productivity, forest fragmentation and land use.

Results

The overall proportion (P) of invaded plots was 0.58 (0.65 for plots within 50 m of a road), and the highest odds (P/1 ? P) of invasion were found in relatively more productive, fragmented forest in landscapes with more than 10% agriculture or developed land cover. Wald chi‐square statistics indicated the best predictor of the odds of invasion was ecological province, followed by land use, productivity, forest fragmentation and distance from a road. Depending on the province, the adjusted odds of invasion decreased by up to 23% (typically 4%–10%) per 100 m distance from a road. The adjusted probability of invasion approached zero in only three provinces, for the least productive, least fragmented forest that was at least 2,000 m from a road in landscapes with less than 10% agricultural or developed land cover.

Main conclusions

In the eastern United States, the existence of a nearby road is less important than the landscape context associated with the road. A purely road‐mediated effect has little practical meaning because anthropogenic activities and roads are pervasive and confounded.

     

Physical and chemical properties determine zebra mussel invasion success in lakes

To address the question whether the abundance of an invasive species can be explained by physical and chemical properties of the invaded ecosystems, we gathered density data of invasive zebra mussels and the physical and chemical data of ecosystems they invaded. We assembled published data from 55 European and 13 North American lakes and developed a model for zebra mussel density using a generalized additive model (GAM) approach. Our model revealed that the joint effect of surface area, total phosphorus and calcium concentrations explained 62% of the variation in Dreissena density. Our study indicates that large and less productive North American lakes can support larger local populations of zebra mussels. Our results suggest that the proliferation of an exotic species in an area can partially be explained by physical and chemical properties of the recipient environment.     

Isosteric ramatroban analogs: selective and potent CRTH-2 antagonists

The chemoattractant receptor-homologous molecule expressed on T(H)2 cells (CRTH-2), also found on eosinophils and basophils, is a prostaglandin D2 receptor involved in the recruitment of these cell types during an inflammatory response. In this report, we describe the synthesis and optimization of a ramatroban isostere that is a selective and potent antagonist of CRTH-2 which may be useful in the treatment of certain diseases.     

Recommendations for the presentation of NMR structures of proteins and nucleic acids – IUPAC-IUBMB-IUPAB Inter-Union Task Group on the Standardization of Data Bases of Protein and Nucleic Acid Structures Determined by NMR Spectroscopy

The recommendations presented here are designed to support easier communication of NMR data and NMR structures of proteins and nucleic acids through unified nomenclature and reporting standards. Much of this document pertains to the reporting of data in journal articles; however, in the interest of the future development of structural biology, it is desirable that the bulk of the reported information be stored in computer-accessible form and be freely accessible to the scientific community in standardized formats for data exchange. These recommendations stem from an IUPAC-IUBMB-IUPAB inter-union venture with the direct involvement of ICSU and CODATA. The Task Group has reviewed previous formal recommendations and has extended them in the light of more recent developments in the field of biomolecular NMR spectroscopy. Drafts of the recommendations presented here have been examined critically by more than 50 specialists in the field and have gone through two rounds of extensive modification to incorporate suggestions and criticisms.     

High-Throughput miRNA and mRNA Sequencing of Paired Colorectal Normal,Tumor and Metastasis Tissues and Bioinformatic Modeling of miRNA-1 Therapeutic Applications

MiRNAs are discussed as diagnostic and therapeutic molecules. However, effective miRNA drug treatments with miRNAs are, so far, hampered by the complexity of the miRNA networks. To identify potential miRNA drugs in colorectal cancer, we profiled miRNA and mRNA expression in matching normal, tumor and metastasis tissues of eight patients by Illumina sequencing. We validated six miRNAs in a large tissue screen containing 16 additional tumor entities and identified miRNA-1, miRNA-129, miRNA-497 and miRNA-215 as constantly de-regulated within the majority of cancers. Of these, we investigated miRNA-1 as representative in a systems-biology simulation of cellular cancer models implemented in PyBioS and assessed the effects of depletion as well as overexpression in terms of miRNA-1 as a potential treatment option. In this system, miRNA-1 treatment reverted the disease phenotype with different effectiveness among the patients. Scoring the gene expression changes obtained through mRNA-Seq from the same patients we show that the combination of deep sequencing and systems biological modeling can help to identify patient-specific responses to miRNA treatments. We present this data as guideline for future pre-clinical assessments of new and personalized therapeutic options.     

A forward genetic screen identifies Dolk as a regulator of startle magnitude through the potassium channel subunit Kv1.1

The acoustic startle response is an evolutionarily conserved avoidance behavior. Disruptions in startle behavior, particularly startle magnitude, are a hallmark of several human neurological disorders. While the neural circuitry underlying startle behavior has been studied extensively, the repertoire of genes and genetic pathways that regulate this locomotor behavior has not been explored using an unbiased genetic approach. To identify such genes, we took advantage of the stereotypic startle behavior in zebrafish larvae and performed a forward genetic screen coupled with whole genome analysis. We uncovered mutations in eight genes critical for startle behavior, including two genes encoding proteins associated with human neurological disorders, Dolichol kinase (Dolk), a broadly expressed regulator of the glycoprotein biosynthesis pathway, and the potassium Shaker-like channel subunit Kv1.1. We demonstrate that Kv1.1 and Dolk play critical roles in the spinal cord to regulate movement magnitude during the startle response and spontaneous swim movements. Moreover, we show that Kv1.1 protein is mislocalized in dolk mutants, suggesting they act in a common genetic pathway. Combined, our results identify a diverse set of eight genes, all associated with human disorders, that regulate zebrafish startle behavior and reveal a previously unappreciated role for Dolk and Kv1.1 in regulating movement magnitude via a common genetic pathway.     

E,E,E-1-(4-Arylamino-4-oxo-2-butenoyl)-3,5-bis(arylidene)-4-piperidones: a topographical study of some novel potent cytotoxins

A series of E,E,E-3,5-bis(arylidene)-1-(4-arylamino-4-oxo-2-butenoyl)-4-piperidones 4 (phenylidene) and 5 (4-nitrophenylidene) were prepared in order to explore the structural features of the N-acyl group which affects the cytotoxic potency. Evaluation toward human Molt 4/C8 and CEM T-lymphocytes revealed that many of the IC(50) figures were submicromolar and lower than melphalan. Marked inhibitory potencies toward murine leukemia L1210 cells were also noted. When evaluated against a panel of human tumor cell lines, three representative compounds in series 4 displayed selective toxicity to leukemia and colon cancer cell lines and were significantly more potent than the reference drug melphalan. Molecular modeling of representative compounds in both series 4 and the analogs, in which the configuration of the olefinic double bond was changed from E to Z (series 3), revealed that the torsion angles of the arylidene aryl rings and locations of the terminal arylaminocarbonyl groups may have contributed to the greater cytotoxic properties displayed in 3. Compounds 4c (3,4-dichlorophenylamino), d (4-methylphenylamino) and 5c (3,4-dichlorophenylamino), d (4-methylphenylamino) inhibited the activity of human N-myristoyltransferase by approximately 50% at concentrations of 50-100 microM. The compounds in series 4 and 5 were well tolerated in a short-term toxicity study in mice.     

Rib lesions in skeletons from early neolithic sites in Central Germany: On the trail of tuberculosis at the onset of agriculture

As an infectious disease, tuberculosis (TB) is one of the major causes of death worldwide. Paleopathological and paleomicrobiological studies indicate a long standing association of the causative agent Mycobacterium tuberculosis and its human host. Since the occurrence and the epidemic spread of this pathogen seem to be closely linked to social and biological factors, it is of particular interest to understand better the role of TB during periods of social and nutritional change such as the Neolithic. In this study, 118 individuals from three sites in Saxony‐Anhalt (Germany) dating to the Linear Pottery Culture (5400–4800 BC) were examined macroscopically to identify TB related bone lesions. In two individuals, Pott's disease was detected. In addition, periosteal reactions of varying degrees and frequency were observed mainly along the neck of the ribs in 6.5% (2/31) of subadults and 35.1% (20/57) of adults, with one site standing out markedly. Rib lesions, however, are not specific indicators of TB as they can also be caused by other diseases; so additional investigations were undertaken using histology and micro‐CT scans to say more about the disease process. Supplementary molecular analyses indicate the presence of pathogens belonging to the Mycobacterium tuberculosis complex in individuals of all sites. Furthermore, we discuss the occurrence and spread of TB during the Neolithic with regard to nutritional aspects and possible risks of infection. The data presented provide important insights into the health status of Early Neolithic populations in Central Germany. Am J Phys Anthropol, 2012. © 2012 Wiley Periodicals, Inc.