If the Past Teaches, What Does the Future Learn? Ancient Urban Regions and the Durable Future

How can we transform urban environments to encourage durability and mediate the social price of myriad risks and vulnerability?Our work here is to build a bridge from archaeology to mainstream architectural and design theory. The study of places, landscapes, and regions links the two fields. Architecture can be shaped and enhanced by the long-term cultural and geographic perspective afforded by archaeology; architecture can offer archaeology a ride into the future. We hope that our efforts are novel enough to be inspiring and connected enough to allow existing concepts to be furthered. The bridge unites three domains: material, social, and aesthetic. We look to the past to find material technologies—new engineering and conceptual solutions to an array of problems—and the past obliges with many examples. However, these technologies in their material aspects are only part of the story. The archaeologist sees them as playing a role in a system. This system, while mechanically functional, is also profoundly social: it includes administrative structures, but also innumerable other kinds of relationships—kin groups, neighborhoods, genders—that mirror the embedded relations between humans and nature. As in architecture, systems include semantics and aesthetics: not only are these forms pleasing to the eye, but they also tell stories of history and place and give identity and meaning to the lives in which they are enmeshed. This multi-functionality and multi-vocality are inherent in past systems

If the Past Teaches, What Does the Future Learn? Ancient Urban Regions and the Durable Future

How can we transform urban environments to encourage durability and mediate the social price of myriad risks and vulnerability?Our work here is to build a bridge from archaeology to mainstream architectural and design theory. The study of places, landscapes, and regions links the two fields. Architecture can be shaped and enhanced by the long-term cultural and geographic perspective afforded by archaeology; architecture can offer archaeology a ride into the future. We hope that our efforts are novel enough to be inspiring and connected enough to allow existing concepts to be furthered. The bridge unites three domains: material, social, and aesthetic. We look to the past to find material technologies—new engineering and conceptual solutions to an array of problems—and the past obliges with many examples. However, these technologies in their material aspects are only part of the story. The archaeologist sees them as playing a role in a system. This system, while mechanically functional, is also profoundly social: it includes administrative structures, but also innumerable other kinds of relationships—kin groups, neighborhoods, genders—that mirror the embedded relations between humans and nature. As in architecture, systems include semantics and aesthetics: not only are these forms pleasing to the eye, but they also tell stories of history and place and give identity and meaning to the lives in which they are enmeshed. This multi-functionality and multi-vocality are inherent in past systems

If the Past Teaches, What Does the Future Learn? Ancient Urban Regions and the Durable Future

How can we transform urban environments to encourage durability and mediate the social price of myriad risks and vulnerability?Our work here is to build a bridge from archaeology to mainstream architectural and design theory. The study of places, landscapes, and regions links the two fields. Architecture can be shaped and enhanced by the long-term cultural and geographic perspective afforded by archaeology; architecture can offer archaeology a ride into the future. We hope that our efforts are novel enough to be inspiring and connected enough to allow existing concepts to be furthered. The bridge unites three domains: material, social, and aesthetic. We look to the past to find material technologies—new engineering and conceptual solutions to an array of problems—and the past obliges with many examples. However, these technologies in their material aspects are only part of the story. The archaeologist sees them as playing a role in a system. This system, while mechanically functional, is also profoundly social: it includes administrative structures, but also innumerable other kinds of relationships—kin groups, neighborhoods, genders—that mirror the embedded relations between humans and nature. As in architecture, systems include semantics and aesthetics: not only are these forms pleasing to the eye, but they also tell stories of history and place and give identity and meaning to the lives in which they are enmeshed. This multi-functionality and multi-vocality are inherent in past systems

Calculations of binding affinity between C8-substituted GTP analogs and the bacterial cell-division protein FtsZ

The FtsZ protein is a self-polymerizing GTPase that plays a central role in bacterial cell division. Several C8-substituted GTP analogs are known to inhibit the polymerization of FtsZ by competing for the same binding site as its endogenous activating ligand GTP. Free energy calculations of the relative binding affinities to FtsZ for a set of five C8-substituted GTP analogs were performed. The calculated values agree well with the available experimental data, and the main contribution to the free energy differences is determined to be the conformational restriction of the ligands. The dihedral angle distributions around the glycosidic bond of these compounds in water are known to vary considerably depending on the physicochemical properties of the substituent at C8. However, within the FtsZ protein, this substitution has a negligible influence on the dihedral angle distributions, which fall within the narrow range of −140° to −90° for all investigated compounds. The corresponding ensemble average of the coupling constants 3J(C4,H1′) is calculated to be 2.95 ± 0.1 Hz. The contribution of the conformational selection of the GTP analogs upon binding was quantified from the corresponding populations. The obtained restraining free energy values follow the same trend as the relative binding affinities to FtsZ, indicating their dominant contribution

Sequence and structural determinants of human APOBEC3H deaminase and anti-HIV-1 activities

Background: Human APOBEC3H (A3H) belongs to the A3 family of host restriction factors, which are cytidine deaminases that catalyze conversion of deoxycytidine to deoxyuridine in single-stranded DNA. A3 proteins contain either one (A3A, A3C, A3H) or two (A3B, A3D, A3F, A3G) Zn-binding domains. A3H has seven haplotypes (I-VII) that exhibit diverse biological phenotypes and geographical distribution in the human population. Its single Zn-coordinating deaminase domain belongs to a phylogenetic cluster (Z3) that is different from the Z1- and Z2-type domains in other human A3 proteins. A3H HapII, unlike A3A or A3C, has potent activity against HIV-1. Here, we sought to identify the determinants of A3H HapII deaminase and antiviral activities, using site-directed sequence- and structure-guided mutagenesis together with cell-based, biochemical, and HIV-1 infectivity assays. Results: We have constructed a homology model of A3H HapII, which is similar to the known structures of other A3 proteins. The model revealed a large cluster of basic residues (not present in A3A or A3C) that are likely to be involved in nucleic acid binding. Indeed, RNase A pretreatment of 293T cell lysates expressing A3H was shown to be required for detection of deaminase activity, indicating that interaction with cellular RNAs inhibits A3H catalytic function. Similar observations have been made with A3G. Analysis of A3H deaminase substrate specificity demonstrated that a 5" T adjacent to the catalytic C is preferred. Changing the putative nucleic acid binding residues identified by the model resulted in reduction or abrogation of enzymatic activity, while substituting Z3-specific residues in A3H to the corresponding residues in other A3 proteins did not affect enzyme function. As shown for A3G and A3F, some A3H mutants were defective in catalysis, but retained antiviral activity against HIV-1vif (-) virions. Furthermore, endogenous reverse transcription assays demonstrated that the E56A catalytic mutant inhibits HIV-1 DNA synthesis, although not as efficiently as wild type. Conclusions: The molecular and biological activities of A3H are more similar to those of the double-domain A3 proteins than to those of A3A or A3C. Importantly, A3H appears to use both deaminase-dependent and -independent mechanisms to target reverse transcription and restrict HIV-1 replication

Low bone mass in microscopic colitis

<p>Abstract</p> <p>Background</p> <p>Microscopic colitis presents with similar symptoms to classic inflammatory bowel diseases. Osteoporosis is a common complication of Crohn's disease but there are no data concerning bone metabolism in microscopic colitis.</p> <p>Aims</p> <p>The aim of the present study was to evaluate bone density and metabolism in patients with microscopic colitis.</p> <p>Methods</p> <p>Fourteen patients microscopic colitis were included in the study, and 28 healthy persons and 28 age and gender matched Crohn's disease patients were enrolled as controls. Bone mineral density was measured using dual x-ray absorptiometry at the lumbar spine, femoral neck and the radius. Serum bone formation and bone resorption markers (osteocalcin and beta-crosslaps, respectively) were measured using immunoassays.</p> <p>Results</p> <p>Low bone mass was measured in 57.14% patients with microscopic colitis. Bone mineral density at the femoral neck in patients suffering from microscopic colitis and Crohn's disease was lower than in healthy controls (0.852 ± 0.165 and 0.807 ± 0.136 vs. 1.056 ± 0.126 g/cm²; p < 0.01). Bone mineral density at the non-dominant radius was decreased in microscopic colitis patients (0.565 ± 0.093 vs. 0.667 ± 0.072 g/cm²; p < 0.05) but unaffected in Crohn's disease patients (0.672 ± 0.056 g/cm²). Mean beta-crosslaps concentration was higher in microscopic colitis and Crohn's disease patients than controls (417.714 ± 250.37 and 466.071 ± 249.96 vs. 264.75 ± 138.65 pg/ml; p < 0.05). A negative correlation between beta-crosslaps concentration and the femoral and radius t-scores was evident in microscopic colitis patients.</p> <p>Conclusions</p> <p>Low bone mass is frequent in microscopic colitis, and alterations to bone metabolism are similar to those present in Crohn's disease. Therefore, microscopic colitis-associated osteopenia could be a significant problem in such patients.</p

Tumor marker utility and prognostic relevance of cathepsin B, cathepsin L, urokinase-type plasminogen activator, plasminogen activator inhibitor type-1, CEA and CA 19-9 in colorectal cancer

<p>Abstract</p> <p>Background</p> <p>Cathepsin B and L (CATB, CATL), urokinase-type plasminogen activator (uPA) and its inhibitor PAI-1 play an important role in colorectal cancer invasion. The tumor marker utility and prognostic relevance of these proteases have not been evaluated in the same experimental setting and compared with that of CEA and CA-19-9.</p> <p>Methods</p> <p>Protease, CEA and CA 19-9 serum or plasma levels were determined in 56 patients with colorectal cancer, 25 patients with ulcerative colitis, 26 patients with colorectal adenomas and 35 tumor-free control patients. Protease, CEA, CA 19-9 levels have been determined by ELISA and electrochemiluminescence immunoassay, respectively; their sensitivity, specificity, diagnostic accuracy have been calculated and correlated with clinicopathological staging.</p> <p>Results</p> <p>The protease antigen levels were significantly higher in colorectal cancer compared with other groups. Sensitivity of PAI-1 (94%), CATB (82%), uPA (69%), CATL (41%) were higher than those of CEA or CA 19-9 (30% and 18%, respectively). PAI-1, CATB and uPA demonstrated a better accuracy than CEA or CA 19-9. A combination of PAI-1 with CATB or uPA exhibited the highest sensitivity value (98%). High CATB, PAI-1, CEA and CA 19-9 levels correlated with advanced Dukes stages. CATB (<it>P </it>= 0.0004), CATL (<it>P </it>= 0.02), PAI-1 (<it>P </it>= 0.01) and CA 19-9 (<it>P </it>= 0.004) had a significant prognostic impact. PAI-1 (<it>P </it>= 0.001), CATB (<it>P </it>= 0.04) and CA 19-9 (<it>P </it>= 0.02) proved as independent prognostic variables.</p> <p>Conclusion</p> <p>At the time of clinical detection proteases are more sensitive indicators for colorectal cancer than the commonly used tumor markers. Determinations of CATB, CATL and PAI-1 have a major prognostic impact in patients with colorectal cancer.</p

Free Energy Simulations of a GTPase: GTP and GDP Binding to Archaeal Initiation Factor 2

International audienceArchaeal initiation factor 2 (aIF2) is a protein involved in the initiation of protein biosynthesis. In its GTP-bound, "ON" conformation, aIF2 binds an initiator tRNA and carries it to the ribosome. In its GDP-bound, "OFF" conformation, it dissociates from tRNA. To understand the specific binding of GTP and GDP and its dependence on the ON or OFF conformational state of aIF2, molecular dynamics free energy simulations (MDFE) are a tool of choice. However, the validity of the computed free energies depends on the simulation model, including the force field and the boundary conditions, and on the extent of conformational sampling in the simulations. aIF2 and other GTPases present specific difficulties; in particular, the nucleotide ligand coordinates a divalent Mg(2+) ion, which can polarize the electronic distribution of its environment. Thus, a force field with an explicit treatment of electronic polarizability could be necessary, rather than a simpler, fixed charge force field. Here, we begin by comparing a fixed charge force field to quantum chemical calculations and experiment for Mg(2+):phosphate binding in solution, with the force field giving large errors. Next, we consider GTP and GDP bound to aIF2 and we compare two fixed charge force fields to the recent, polarizable, AMOEBA force field, extended here in a simple, approximate manner to include GTP. We focus on a quantity that approximates the free energy to change GTP into GDP. Despite the errors seen for Mg(2+):phosphate binding in solution, we observe a substantial cancellation of errors when we compare the free energy change in the protein to that in solution, or when we compare the protein ON and OFF states. Finally, we have used the fixed charge force field to perform MDFE simulations and alchemically transform GTP into GDP in the protein and in solution. With a total of about 200 ns of molecular dynamics, we obtain good convergence and a reasonable statistical uncertainty, comparable to the force field uncertainty, and somewhat lower than the predicted GTP/GDP binding free energy differences. The sign and magnitudes of the differences can thus be interpreted at a semiquantitative level, and are found to be consistent with the experimental binding preferences of ON- and OFF-aIF2

Usefulness of real time PCR for the differentiation and quantification of 652 and JP2 Actinobacillus actinomycetemcomitans genotypes in dental plaque and saliva

BACKGROUND: The aim of our study is to describe a fast molecular method, able to distinguish and quantize the two different genotypes (652 and JP2) of an important periodontal pathogen: Actinobacillus actinomycetemcomitans. The two genotypes show differences in the expression of an important pathogenic factor: the leukotoxin (ltx). In order to evidence this, we performed a real time PCR procedure on the ltx operon, able to recognize Aa clinical isolates with different leukotoxic potentials. METHODS: The specificity of the method was confirmed in subgingival plaque and saliva specimens collected from eighty-one Italian (Sardinian) subjects with a mean age of 43.9, fifty five (68 %) of whom had various clinical forms of periodontal disease. RESULTS: This procedure showed a good sensitivity and a high linear dynamic range of quantization (10(7)-10(2 )cells/ml) for all genotypes and a good correlation factor (R2 = 0.97–0.98). Compared with traditional cultural methods, this real time PCR procedure is more sensitive; in fact in two subgingival plaque and two positive saliva specimens Aa was only detected with the molecular method. CONCLUSION: A low number of Sardinian patients was found positive for Aa infections in the oral cavity, (just 10 positive periodontal cases out of 81 and two of these were also saliva positive). The highly leukotoxic JP2 strain was the most representative (60 % of the positive specimens); the samples from periodontal pockets and from saliva showed some ltx genotype for the same patient. Our experience suggests that this approach is suitable for a rapid and complete laboratory diagnosis for Aa infection