Charge dependent substrate activity of C3' and N3 functionalized, organometallic technetium and rhenium-labeled thymidine derivatives toward human thymidine kinase 1.

Human cytosolic thymidine kinase (hTK1) has proven to be a suitable target for the noninvasive imaging of cancer cell proliferation using radiolabeled thymidine analogues such as [(18)F]3'-fluoro-3'-deoxythymidine ([(18)F]FLT). A thymidine analogue for single photon emission computed tomography (SPECT), which incorporates the readily available and inexpensive nuclide technetium-99m, would be of considerable practical interest. hTK1 is known to accommodate modification of the structure of the natural substrate thymidine at the positions N3 and C3' and, to a lesser extent, C5. In this work, we used the copper-catalyzed azide-alkyne cycloaddition to synthesize two series of derivatives in which thymidine is functionalized at either the C3' or N3 position with chelating systems suitable for the M(CO)(3) core (M = (99m)Tc, Re). The click chemistry approach enabled complexes with different structures and overall charges to be synthesized from a common precursor. Using this strategy, the first organometallic hTK1 substrates in which thymidine is modified at the C3' position were identified. Phosphorylation of the organometallic derivatives was measured relative to thymidine. We have shown that the influence of the overall charge of the derivatives is dependent on the position of functionalization. In the case of the C3'-functionalized derivatives, neutral and anionic substrates were most readily phosphorylated (20-28% of the value for the parent ligand thymidine), whereas for the N3-functionalized derivatives, cationic and neutral complexes were apparently better substrates for the enzyme (14-18%) than anionic derivatives (9%).

Neutralization of Macrophage Migration Inhibitory Factor (MIF) by Fully Human Antibodies Correlates with Their Specificity for the β-Sheet Structure of MIF.

The macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that recently emerged as an attractive therapeutic target for a variety of diseases. A diverse panel of fully human anti-MIF antibodies was generated by selection from a phage display library and extensively analyzed in vitro. Epitope mapping studies identified antibodies specific for linear as well as structural epitopes. Experimental animal studies revealed that only those antibodies binding epitopes within amino acids 50-68 or 86-102 of the MIF molecule exerted protective effects in models of sepsis or contact hypersensitivity. Within the MIF protein, these two binding regions form a β-sheet structure that includes the MIF oxidoreductase motif. We therefore conclude that this β-sheet structure is a crucial region for MIF activity and a promising target for anti-MIF antibody therapy.

O acervo de mosquitos (Diptera, Culicidae) de Nelson L. Cerqueira na Coleção de Invertebrados do Instituto Nacional de Pesquisas da Amazônia, Manaus, Brasil

Registra-se a descoberta de espécimes de mosquitos que pertenciam a Nelson L. Cerqueira, e estão sendo depositados na coleção de Invertebrados do Instituto Nacional de Pesquisas da Amazônia. A coleção contém 2.046 espécimes adultos e 387 lâminas representando 261 espécies, 22 gêneros, incluindo 51 parátipos de 34 espécies. Mais de 90% dos espécimes foram coletados no Brasil dos quais metade são do Estado do Amazonas. As espécies representadas neste acervo são listadas indicando o número de espécimes para cada tipo de preparação e as localidades de coleta. O material tipo também é listado, incluindo os dados dos rótulos de identificação e de procedência, bem como outras informações pertinentes.

FBXW7α attenuates inflammatory signalling by downregulating C/EBPδ and its target gene Tlr4.

Toll-like receptor 4 (Tlr4) has a pivotal role in innate immune responses, and the transcription factor CCAAT/enhancer binding protein delta (C/EBPδ, Cebpd) is a Tlr4-induced gene. Here we identify a positive feedback loop in which C/EBPδ activates Tlr4 gene expression in macrophages and tumour cells. In addition, we discovered a negative feedback loop whereby the tumour suppressor FBXW7α (FBW7, Cdc4), whose gene expression is inhibited by C/EBPδ, targets C/EBPδ for degradation when C/EBPδ is phosphorylated by GSK-3β. Consequently, FBXW7α suppresses Tlr4 expression and responses to the ligand lipopolysaccharide. FBXW7α depletion alone is sufficient to augment pro-inflammatory signalling in vivo. Moreover, as inflammatory pathways are known to modulate tumour biology, Cebpd null mammary tumours, which have reduced metastatic potential, show altered expression of inflammation-associated genes. Together, these findings reveal a role for C/EBPδ upstream of Tlr4 signalling and uncover a function for FBXW7α as an attenuator of inflammatory signalling.

Protection from lethal gram-negative bacterial sepsis by targeting Toll-like receptor 4.

Toll-like receptor 4 (TLR4), the signal-transducing molecule of the LPS receptor complex, plays a fundamental role in the sensing of LPS from gram-negative bacteria. Activation of TLR4 signaling pathways by LPS is a critical upstream event in the pathogenesis of gram-negative sepsis, making TLR4 an attractive target for novel antisepsis therapy. To validate the concept of TLR4-targeted treatment strategies in gram-negative sepsis, we first showed that TLR4(-/-) and myeloid differentiation primary response gene 88 (MyD88)(-/-) mice were fully resistant to Escherichia coli-induced septic shock, whereas TLR2(-/-) and wild-type mice rapidly died of fulminant sepsis. Neutralizing anti-TLR4 antibodies were then generated using a soluble chimeric fusion protein composed of the N-terminal domain of mouse TLR4 (amino acids 1-334) and the Fc portion of human IgG1. Anti-TLR4 antibodies inhibited intracellular signaling, markedly reduced cytokine production, and protected mice from lethal endotoxic shock and E. coli sepsis when administered in a prophylactic and therapeutic manner up to 13 h after the onset of bacterial sepsis. These experimental data provide strong support for the concept of TLR4-targeted therapy for gram-negative sepsis.

Molecular and functional characterization of a novel cardiac-specific human tropomyosin isoform.

BACKGROUND: Tropomyosin (TM), an essential actin-binding protein, is central to the control of calcium-regulated striated muscle contraction. Although TPM1alpha (also called alpha-TM) is the predominant TM isoform in human hearts, the precise TM isoform composition remains unclear. METHODS AND RESULTS: In this study, we quantified for the first time the levels of striated muscle TM isoforms in human heart, including a novel isoform called TPM1kappa. By developing a TPM1kappa-specific antibody, we found that the TPM1kappa protein is expressed and incorporated into organized myofibrils in hearts and that its level is increased in human dilated cardiomyopathy and heart failure. To investigate the role of TPM1kappa in sarcomeric function, we generated transgenic mice overexpressing cardiac-specific TPM1kappa. Incorporation of increased levels of TPM1kappa protein in myofilaments leads to dilated cardiomyopathy. Physiological alterations include decreased fractional shortening, systolic and diastolic dysfunction, and decreased myofilament calcium sensitivity with no change in maximum developed tension. Additional biophysical studies demonstrate less structural stability and weaker actin-binding affinity of TPM1kappa compared with TPM1alpha. CONCLUSIONS: This functional analysis of TPM1kappa provides a possible mechanism for the consequences of the TM isoform switch observed in dilated cardiomyopathy and heart failure patients.

Optimal information transmission in organizations: Search and congestion

We propose a stylized model of a problem-solving organization whoseinternal communication structure is given by a fixed network. Problemsarrive randomly anywhere in this network and must find their way to theirrespective specialized solvers by relying on local information alone.The organization handles multiple problems simultaneously. For this reason,the process may be subject to congestion. We provide a characterization ofthe threshold of collapse of the network and of the stock of foatingproblems (or average delay) that prevails below that threshold. We buildupon this characterization to address a design problem: the determinationof what kind of network architecture optimizes performance for any givenproblem arrival rate. We conclude that, for low arrival rates, the optimalnetwork is very polarized (i.e. star-like or centralized ), whereas it islargely homogenous (or decentralized ) for high arrival rates. We also showthat, if an auxiliary assumption holds, the transition between these twoopposite structures is sharp and they are the only ones to ever qualify asoptimal.

Culicidae (Diptera, Culicomorpha) from the western Brazilian Amazon: Juami-Japurá Ecological Station

With 312 trap-hours of sampling effort, 1554 specimens of Culicidae (Diptera) were collected, using CDC and Malaise traps, in nine different locations along the Juami River, within the Juami-Japurá Ecological Station, Amazonas State, Brazil. A list of mosquito species with 54 taxa is presented, which includes three new distributional records for the state of Amazonas. The species found belong to the genera Anopheles, Aedeomyia, Aedes, Psorophora, Culex, Coquillettidia, Sabethes, Wyeomyia and Uranotaenia.

Variance reduction methods for simulation of densities on Wiener space

We develop a general error analysis framework for the Monte Carlo simulationof densities for functionals in Wiener space. We also study variancereduction methods with the help of Malliavin derivatives. For this, wegive some general heuristic principles which are applied to diffusionprocesses. A comparison with kernel density estimates is made.

Organic matter in upwelling off northern Peru, november 1977

Analiza la cantidad de carbon organico y nitrogeno en las costas del norte del Perú en noviembre de 1977

Hesperioidea e Papilionoidea (Lepidoptera) coligidos em expedição aos Rios Nhamundá e Abacaxis, Amazonas, Brasil: novos subsídios para o conhecimento da biodiversidade da Amazônia Brasileira

Hesperioidea e Papilionoidea (Lepidoptera) coligidos em expedição aos Rios Nhamundá e Abacaxis, Amazonas, Brasil: novos subsídios para o conhecimento da biodiversidade da Amazônia Brasileira. Objetivando um aprimoramento do conhecimento da lepidopterofauna diurna da Amazônia brasileira, este estudo lista 180 taxa coligidos em cinco pontos distintos de dois afluentes do Rio Amazonas, envolvendo as áreas de endemismo Guiana e Rondônia. As coletas foram passivas e ativas e as diferentes localidades comparadas através de análise de Escalonamento Multidimensional Não-Métrico (NMDS).

Sarcophagidae and Calliphoridae related to Rhinella schneideri (Anura, Bufonidae), Bothrops moojeni (Reptilia, Serpentes) and Mabuya frenata (Reptilia, Lacertilia) carcasses in Brasília, Brazil

Sarcophagidae and Calliphoridae related to Rhinella schneideri (Anura, Bufonidae), Bothrops moojeni (Reptilia, Serpentes) and Mabuya frenata (Reptilia, Lacertilia) carcasses in Brasília, Brazil. This paper presents a list of necrophagous insects associated with small size carrions of two reptiles and one amphibian, found in areas of riparian forests and Cerrado sensu stricto physiognomies in a Conservation Unit located in Brasilia, Distrito Federal. We found seven species of insects related to these carcasses, being five Sarcophagidae, one Calliphoridae and one Braconidae parasitoid wasp. Lucilia eximia and Peckia (Pattonella) intermutans were the most abundant species in the study, corroborating with other studies that suggests that these species have specializations for colonization of small size animal carcasses.