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The preparation and antitubercular properties of a series of phthalimido- and naphthalimido-linked phenazines are described. Some of these new compounds inhibited the growth of Mycobacterium tuberculosis ATCC 27294, Mycobacterium avium ATCC 49601, Mycobacterium intracellulare ATCC 13950 and some clinical isolates.
To respond to emerging and re-emerging infections, it is necessary to understand the interactions between microbial pathogens and their hosts and the impact of environmental and social factors on these interactions. The importance of understanding host-pathogen interactions is underscored by the emergence of virulent H5N1 avian influenza viruses and their transmission to humans, and the potential pandemic threat they pose.
Little is known about the functions of two different beta5 integrins: repeated-FNK (FNKFNK764-769) and single-FNK (FNK764-766) amino acid sequences in the cytoplasmic domain. We examined whether they occurred as germ line mutations or somatic mutations associated with neoplastic transformation, and whether there were functional alterations. Out of six cultured cell lines, only KATO-III cells had the single-FNK beta5 sequence. The single-FNK beta5 was found in 9 out of 79 patients with colon carcinoma, but no somatic mutations were detected in cancerous tissues. CHO cells were transformed with expression vectors containing single-FNK or repeated-FNK beta5 cDNA, which were derived from KATO-III cells. CHO cells transfected with single-FNK and repeated-FNK showed similar adhesiveness to, and proliferative activity on, vitronectin substrates.
Two-dimensional gel electrophoresis practitioners have long waited for a fully automated system. This article presents an integrated platform that is capable of complete automation from sample introduction to spots detection. The strip gel for the first dimensional separation is fixed on the edge of a discrete planar stage before separation. A pair of platinum pin electrodes for isoelectric focusing (IEF) makes contact from underneath the stage. IEF is performed directly after rehydration and protein loading. After the first dimensional separation, sodium dodecyl sulfate (SDS) equilibration is done on the same stage without moving the gel. The IEF stage is then moved horizontally to couple with a precast second dimensional gel. The <0.5 mm gap between the two gels is filled with poly (ethylene oxide) solution. After SDS-polyacrylamide gel electrohporesis separation, a charge-coupled device camera is used to detect spots via protein native fluorescence excited by a Hg (Xe) lamp with the gel inside the running cell. Potential for full automation is demonstrated with 0.5 microg of Escherichia coli proteins on this miniaturized platform. More than 240 spots are detected in a total experiment time of <2.5 h.
Bioregulators are naturally occurring organic compounds that regulate a multitude of biologic processes. Under natural circumstances, bioregulators are synthesized in minute quantities in a variety of living organisms and are essential for physiologic homeostasis. In the wrong hands, these compounds have the capability to be used as nontraditional threat agents that are covered by the prohibitions of the Chemical Weapons Convention and the Biological and Toxin Weapons Convention. Unlike traditional biowarfare/bioterrorism agents that have a latency period of hours to days,the onset of action of bioregulators may occur within minutes after host exposure. Concerns regarding the potential misuse of bioregulators for nefarious purposes relate to the ability of these nontraditional agents to induce profound physiologic effects.
The innate immune system is comprised of a sophisticated network of recognition and effector molecules that act together to protect the host in the first minutes or hours of exposure to an infectious challenge. The mannose-binding lectin (MBL) is an evolutionary conserved circulating host defense protein that acts as a broad-spectrum recognition molecule against a wide variety of infectious agents. Target binding triggers the MBL pathway of complement activation. MBL can be considered conceptually as an 'ante-antibody' because it has a role in mammals during the lag period that is required to develop an antibody response against infectious agents. Additionally, there are MBL-like homologues in animals that lack adaptive immunity that activate a primitive complement system, and under these circumstances these MBL-like molecules play an analogous role to antibodies in higher animals. These molecules might be considered to be functional antecedents of antibodies. Recent work also indicates that MBL recognizes altered self-antigens, and as such MBL has a role that extends beyond a traditional role in first line host defense as it appears to play a role as a modulator of inflammation.
Colloidal semiconductor nanocrystals have attracted considerable attention as a novel biological luminescent label. The bioinorganic conjugates of luminescent CdTe nanocrystals and protein, including CdTe/BSA (bovine serum albumin) and CdTe/MAB (mouse monoclonal antibody against hepatitis B surface antigen), were formed via electrostatic/coordination self-assembly. Pure CdTe nanocrystals, CdTe/BSA and CdTe/MAB were used in the immunochromatographic assay experiments, respectively. And the results indicated that CdTe nanocrystals could be used and developed as a novel label with good stability, high sensitivity and facile determination of several analytes in immunochromatographic assay strips.
Synthetic biology combines knowledge from various disciplines including molecular biology, engineering, mathematics and physics to design and build novel proteins, genetic circuits and metabolic networks. Early efforts aimed at altering the behavior of individual elements have now evolved to focus on the construction of complex networks in single-cell and multicellular systems. Recent achievements include the development of sophisticated non-native behaviors such as bi-stability, oscillations, proteins customized for biosensing, optimized drug synthesis and programmed spatial pattern formation. The de novo construction of such systems offers valuable quantitative insight into naturally occurring information processing activities. Furthermore, as the techniques for system design, synthesis and optimization mature, we will witness a rapid growth in the capabilities of synthetic systems with a wide-range of applications.
Analysis of the chicken genome has shown that the chicken has a different repertoire of chemokines and chemokine receptors to those of mammals and other species. In this study, we report the sequencing and analysis of a bacterial artificial chromosome containing the entire chicken MIP family CC chemokine cluster. The gene duplication and divergence events that have taken place in mammals do not appear to have occurred as extensively in the avian lineage, as chickens possess fewer MIP family chemokine genes than humans or mice. We previously proposed that the four chicken MIP family members be named chicken (ch) CCLi1-4, according to their position on chicken chromosome 19, until such time as further analysis could determine if any of them were direct orthologues of mammalian MIP family members. Our analysis herein, combined with that of others, suggests that chCCLi4 is the orthologue of mammalian CCL5, and that chCCLi3 (K203) may be an orthologue of human CCL16. The other two chemokines do not have obvious orthologues, and thus we propose that they should still be called chCCLi1 and chCCLi2, until their biological function is further characterised. A similar pattern applies to the MIP family chemokine receptors, with only three receptor genes present at the relevant locus in the chicken genome, compared to four in man and mouse (CCR1, CCR2, CCR3 and CCR5). Of the three chicken receptor genes, only two look likely to be receptors for the MIP family chemokines, the third grouping with human, mouse and chicken CCR8 in phylogenetic analysis. The two chicken MIP CC receptors (CCRs) are not direct orthologues of the mammalian MIP CCRs.
OBJECTIVES: The goals of this study were to investigate the phase transformation and microstructure of dental porcelain bodies densified via a moving laser beam and to develop an understanding of how the microstructure of the dental porcelain varies with the laser processing condition and the position relative to the center of the laser beam. METHODS: A moving laser beam was used to scan and densify a commercial dental porcelain powder bed. The porcelain powder compact was also sintered using a furnace at different temperatures. The phase transformation and microstructure of these dental porcelain bodies were compared and investigated using a host of analytical instruments including scanning electron microscopy, X-ray diffraction, thermogravimetric analysis, and quantitative image analysis. RESULTS: Based on the temperature dependence of the leucite content in the dental porcelain derived from the furnace-sintered samples, the temperature distribution in the dental porcelain body during laser densification was established. The microstructure of the laser-densified porcelain body was found to be dependent of the location relative to the center of the laser beam and the average laser densification temperature. SIGNIFICANCE: The understanding of how the microstructure of dental porcelain bodies varies with the laser processing condition and the location with respect to the center of the laser beam was developed. Based on this understanding, the laser processing condition has been optimized to achieve the desired microstructure and densification of dental porcelain bodies simultaneously.
Macrophages are versatile, plastic cells which respond to micro-environmental signals with distinct functional programmes. In the tumour microenvironment, tumour-associated macrophages (TAM) polarise towards a type II phenotype, oriented to the promotion of tissue remodelling and repair. As polarised type II macrophages, TAM are a key component of the inflammatory circuits that promote tumour progression.
OBJECTIVE: Terminologia anatomica is the new standard in anatomical terminology. This terminology is available only in Latin and English and its worldwide adoption is subject to the addition of terms from others languages. On the other hand, Nomina anatomica, the previous standard, has been widely translated. Aim of this work was to append foreign terms to Terminologia by using similarity-matching algorithm between its Latin terms and those from Nomina. METHODS: A semi-automatic matching of Latin terms from Terminologia with those of Nomina was performed using a string-to-string distance algorithm and manual assessment. We used a French-Latin version of Nomina together with Terminologia and we suggested French terms for Terminologia. Coverage was evaluated by the number of exact and approximate matches. A target of 78% was set due to the higher number of terms in Terminologia compared to Nomina. Relevance was estimated by manually comparing the meanings of the English and French terms related to the same Latin term. The question was whether they refer to the same anatomical structure. RESULTS: Exact or approximate matches were found for 5982 terms (76.5%) of Terminologia. Our results indicated that more than 75% of the terms from Terminologia came from Nomina, most of them were left unchanged and all were used with the same meaning. CONCLUSION: This method produces relevant results, reaching our 78% target. The method is based only on Latin terms and can be used for other languages. We consider this work as a starting point for adding terms to other knowledge sources, such as the foundational model of anatomy or the Unified Medical Language System (UMLS).
A maxillofacial simulator can support education and training. In the present study, cutting, separation, and quantitative rearrangement of bone during orthognathic surgery were simulated by means of a haptic device with virtual tactile perception. Computed tomographic (CT) images of two patients with severe jaw deformity, one women and one man, were input into the device. In the woman, Le Fort I osteotomy of the maxilla and sagittal splitting ramus osteotomy of the mandible were initially simulated. During surgery with the haptic device, separation and rearrangement of the maxilla and the ramus of the mandible were initially processed. However, there was discrepancy and overlapping of the ramus with the mandible. Intraoral vertical osteotomy of the right ramus was then performed, with satisfactory results and less discrepancy and interference. The simulation was referred to at surgery, and satisfactory surgical assistance was postoperatively confirmed on CT images. The male patient had severe jaw deformity due to unequal growth between the ramuses, resulting in anterior crossbite. Sagittal splitting ramus osteotomy with rotation of the mandible was successfully simulated. Because of its versatility and functions, the present device was found to be useful for simulating various procedures for orthognathic surgery and thereby three-dimensionally determine surgical movements.
Celiac disease is a disorder of the small intestine characterized by chronic inflammation of the mucosa and protean clinical manifestations caused by loss of tolerance to dietary antigens. Two strongly associated cofactors have been identified: the presence of HLA-DQ2 or HLA-DQ8 in the host and specific antigenic peptides in the diet that are present in wheat, rye, and barley. Most patients have complete remission after dietary elimination of these foods. Crohn's disease is characterized by chronic, relapsing, recurrent, focal, transmural inflammation of the gastrointestinal tract that can lead to multiple serious problems requiring chronic medical and surgical therapy. Crohn's disease is associated with multiple genetic mutations, at least one of which has been clearly implicated in innate immunity. Multiple lines of evidence suggest that the disease involves abnormal immune responses to gut microbial flora.
EBV was the first candidate human tumor virus. It is found in several human cancers, particularly lymphomas and carcinomas, and has potent transforming activity in vitro. Yet the virus persists benignly for the lifetime of more than 90% of the human population. Thus it seems that EBV has the potential to be highly pathogenic yet rarely manifests this potential. Studies over the last several years show this is because the virus actually persists in resting memory B cells and not proliferating cells. EBV needs its growth-promoting ability to gain access to the memory compartment but has evolved to minimize its oncogenic potential. These studies also reveal that the different EBV-associated tumors apparently arise from different and discrete stages in the life cycle of B cells latently infected with EBV. This raises the question of how actively EBV participates in the development of human tumors. Does the virus cause the disease, or is it simply a passenger? In the case of immunoblastic lymphoma in the immunosuppressed patient, the virus almost certainly plays a causative role, but in other cases, such as Burkitt's lymphoma, the contribution of EBV remains less clear.
Expanding on the possible protein interaction partners in a biochemical pathway is one key molecular goal in the post-genomic era. Phage peptide display is a versatile in vitro tool for mapping novel protein-protein interfaces and the advantage of this technique in expanding protein interaction maps is that in vitro manipulation of the bait protein conformational integrity can be controlled carefully. Phage peptide display was used to expand on the possible types of binding proteins for the conformationally responsive protein MDM2. Peptides enriched differ depending upon whether MDM2 is ligand-free, zinc-bound, or RNA-bound, suggesting that MDM2 conformational changes alter the type of peptide ligands enriched. Classes of putative/established MDM2-binding proteins identified by this technique included ubiquitin-modifying enzymes (F-box proteins, UB-ligases, UBC-E1) and apoptotic modifiers (HSP90, GAS1, APAF1, p53). Of the many putative MDM2 proteins that could be examined, the impact of HSP90 on MDM2 activity was studied, since HSP90 has been linked with p53 protein unfolding in human cancers. Zinc ions were required to reconstitute a stable MDM2-HSP90 protein complex. Zinc binding converted MDM2 from a monomer to an oligomer, and activated MDM2 binding to its internal RING finger domain, providing evidence for a conformational change in MDM2 protein when it binds zinc. Reconstitution of an HSP90-MDM2 protein complex in vitro stimulated the unfolding of the p53 tetramer. A p53 DNA-binding inhibitor purified from human cells that is capable of unfolding p53 at ambient temperature in vitro contains co-purifying pools of HSP90 and MDM2. These data highlight the utility of phage peptide display as a powerful in vitro method to identify regulatory proteins that bind to a conformationally flexible protein like MDM2.
This study describes the three-dimensional crystal structure of a non-specific lipid transport protein (ns-LTP) from Rosaceae. Whilst ns-LTPs from species other than Rosaceae, such as nuts, cereals, grape, oranges and vegetables are also responsible for plant food allergies, this is less frequent compared with ns-LTPs from Rosaceae in the Mediterranean area. In this heterologously expressed peach Pru p3, a ligand is present inside the central cavity of the protein, presumably a fatty acid that was present or produced in the culture medium of the expression organism Escherichia coli. Moreover, the two molecules of ns-LTP present in the asymmetric unit bind this ligand in a different way, suggesting a significant degree of plasticity for the peach ns-LTP binding cavity, despite the presence of four disulphide bridges. Two molecules are present in the asymmetric unit: molecule A is a fully liganded protein, while molecule B apparently represents a partially liganded state. Also, molecular dynamics simulation, along with other evidence, suggests that these two molecular conformations represent different states in solution. Comparison of the 3D models of different ns-LTPs justifies the evidence of a high degree of conservation of the putative IgE binding epitopes among proteins of the Rosaceae family and the presence of significant amino acid replacements in correspondence of the same regions in ns-LTPs of botanical species unrelated to Rosaceae.
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