Absence Of Integration Research Articles

MANAGING URBAN DEVELOPMENT PROCESS BY USING SPATIAL INFORMATION SYSTEM: A Case Study of I-Space

The advancement in Information and Communication Technology (!CT), particularly in relation to Geographical Information System (GIS), Computer Aided Design (CAD), Database Management System (DBMS), and Facility Management System (FMS), has provided the opportunity for urban government to adopt innovative and effective technologies to aid and improve the management and decision-making in urban development process. Among the obstacles that hamper effective management and decision-making in urban development process are the absence of integration between the works of the professionals involve in such process and the unavailability of immediate and reliable data to form the basis for sound decision-making. Thus, this paper proposes that a city-wide spatial information system to be developed comprising two major elements: a common platform for integrating the works of the various built environment professionals and a city-wide built environment database. While the common platform will help to streamline the works of the professionals, the database will assists urban government in making sound and informed decision in relation to planning, management, maintenance, and monitoring of the urban built environment. This paper highlights the efforts of the International Islamic University Malaysia (IIUM) in developing its spatial information system. The system is designed to provide information on the IIUM property that covers buildings, infrastructure, facilities, and space to decision makers and managers to help them in making sound decision and in implementing effective property management scheme.

Nef expressed from human immunodeficiency virus type 1 extrachromosomal DNA downregulates CD4 on primary CD4+ T lymphocytes: implications for integrase inhibitors

Recently developed integrase inhibitors targeting the HIV-1 integrase (IN) protein block integration of HIV DNA in the target cell, preventing subsequent virus replication. In the absence of integration, viral DNA is shunted towards the formation of extrachromosomal DNA (E-DNA). Although HIV-1 E-DNA does not support productive replication, it is transcriptionally active and produces viral proteins. However, the significance of E-DNA in virus replication and pathogenesis is poorly understood. In this study, the functional activity of the HIV-1 Nef protein expressed in the absence of viral integration was analysed. Using both a recombinant HIV-1 IN defective virus and a diketo acid IN inhibitor, evidence was provided showing that Nef expressed from E-DNA downregulates CD4 surface expression on primary CD4(+) T lymphocytes. These results suggest that proteins expressed in the absence of integration may have potential clinical consequences, an issue that should be further explored with the introduction of IN inhibitors.

Mobile localization in nonlinear Schrödinger lattices

Using continuation methods from the integrable Ablowitz–Ladik lattice, we have studied the structure of numerically exact mobile discrete breathers in the standard discrete nonlinear Schrödinger equation. We show that, away from that integrable limit, the mobile pulse is dressed by a background of resonant plane waves with wavevectors given by a certain selection rule. This background is seen to be essential for supporting mobile localization in the absence of integrability. We show how the variations of the localized pulse energy during its motion are balanced by the interaction with this background, allowing the localization mobility along the lattice.

973. Efficient Transduction of Bone Marrow-Derived Mesenchymal Stem Cells for Cancer Gene Therapy Using a Tropism-Modified Adeno-Associated Virus (AAV) Vector

Top of pageAbstract Exogenously administered bone marrow-derived mesenchymal stem cells (MSCs) will preferentially engraft at tumor sites and contribute to the population of stromal fibroblasts. This has allowed the development of therapeutic strategies based on the local production of biological agents by gene-manipulated MSCs following transplantation. Adeno-associated virus (AAV) - based vectors are attractive for the introduction of therapeutic genes into MSCs due to their ability to promote stable gene expression in the absence of integration. While there are currently at least 8 naturally occurring serotypes of AAV, the AAV2 serotype has been associated with most gene therapy studies to date. Previously, our laboratory has generated a novel recombinant AAV vector based on AAV2 that contains an “RGD” polypeptide sequence (4C-RGD) inserted into the AAV capsid protein(s) following VP1 amino acid 588, “rAAV2(RGD)”. As with many of the available non-viral transfection methods, we found that AAV serotypes 1, 2, and 5 poorly infect human MSCs, even at very high multiplicities of infection (MOI). In contrast, rAAV2(RGD) is able to transduce greater than 80% of human MSCs in vitro. This represents a nearly three-order of magnitude enhancement in gene transfer efficiency compared to unmodified AAV2-based vectors. One potential obstacle to AAV-mediated gene therapy is the prolonged delay in transgene expression following AAV infection in vivo. Our ex vivo gene therapy approach circumvents this delay as demonstrated by rAAV2(RGD)-mediated transgene expression in as little as 72 hours post-infection in infected MSCs. Importantly, rapid onset of transgene expression was achieved in the absence of adenoviral help and in conjunction with increasing MOIs of rAAV2(RGD). Characterization of AAV-transduced MSCs for tri-lineage differentiation potential (adipogenic, chondrogenic, and osteogenic), duration of transgene expression, and maintenance of transgene expression levels in vitro following rAAV2(RGD) infection is ongoing. With the demonstration that human bone marrow-derived MSCs engraft into tumor microenvironments, AAV-transduced MSCs could provide an innovative delivery strategy for cancer gene therapies based on the local production of biological agents in the tumor microenvironment. Since such a treatment strategy will require safe and efficient ways of delivering and expressing therapeutic genes in human MSCs, the use of RGD-modified AAV vectors may provide the ideal platform to accomplish genetic manipulation of these cells.

Induction of potent human immunodeficiency virus type 1-specific T-cell-restricted immunity by genetically modified dendritic cells.

A novel technology combining replication- and integration-defective human immunodeficiency virus type 1 (HIV-1) vectors with genetically modified dendritic cells was developed in order to induce T-cell immunity. We introduced the vector into dendritic cells as a plasmid DNA using polyethylenimine as the gene delivery system, thereby circumventing the problem of obtaining viral vector expression in the absence of integration. Genetically modified dendritic cells (GMDC) presented viral epitopes efficiently, secreted interleukin 12, and primed both CD4(+) and CD8(+) HIV-specific T cells capable of producing gamma interferon and exerting potent HIV-1-specific cytotoxicity in vitro. In nonhuman primates, subcutaneously injected GMDC migrated into the draining lymph node at an unprecedentedly high rate and expressed the plasmid DNA. The animals presented a vigorous HIV-specific effector cytotoxic-T-lymphocyte (CTL) response as early as 3 weeks after a single immunization, which later developed into a memory CTL response. Interestingly, antibodies did not accompany these CTL responses, indicating that GMDC can induce a pure Th1 type of immune response. Successful induction of a broad and long-lasting HIV-specific cellular immunity is expected to control virus replication in infected individuals.

Neighborhood effects and genetic structure in a clonal grass: The role of the spatial structure of the environment

AbstractA dominant plant of temperate nutrient‐poor grasslands, Festuca rubra, has been used as a model species to assess biotic effects of fine‐scale environmental heterogeneity in the field and its genetic differentiation in response to this variation. Using experimental data, it is shown that this heterogeneity is partly due to interspecific variation in competitive abilities in the ‘matrix’ plants. Festuca rubra possesses remarkable intraspecific differentiation in its parameters of spatial spreading and competitive performance, and in their plasticity under cultured conditions. This morphological plastic response to the environment is weaker in the field. This indicates that in the field individuals use only a fraction of the full potential range of plasticity to respond to variation in competitive environments. A random amplified polymorphic DNA study has shown that populations of F. rubra consist of a high number of coexisting genets. The genet size distribution is strongly skewed, indicating high early stage mortality and lower larger genet mortality. There should be continuous seedling regeneration in order to maintain this genetic structure. The data presented here display major features that distinguish clonal expansion from vertical competition. These are: (i) absence of integration over the whole plant; (ii) potentially unlimited size; (iii) large and unpredictable environmental variation experienced by different parts of the genet; and (iv) absence of a size‐determined competition outcome at the genet level, and thus higher potential for species‐specific effects.

Will managed care ever deliver on its promises? Managed care, public policy, and consumers of mental health services.

Advocates of managed care have promised to greatly improve delivery of services to persons with serious mental illness by focusing on effectiveness and accountability. With the exception of a few beacons of success, experience shows that managed care has not delivered on its promises. This article examines several areas of the public mental health system that still have major flaws, hindering adequate provision of services. Such flaws include the absence of integration of Medicaid and the public mental health system; general lack of publicly documented performance measurements that demonstrate accountability; absence of meaningful and authentic consumer, family, and enrollee participation in service planning, implementation, and evaluation; among others. Are we ready to replicate the lessons from the few beacons of success, or will we just continue to fail persons with the most serious mental illnesses?

Streamlining the Drug Discovery Process by Integrating Miniaturization, High Throughput Screening, High Content Screening, and Automation on the CellChip™ System

A major bottleneck to the early stages of drug discovery is the absence of integration of high throughput screening (HTS) with smarter assays that screen “hits” from HTS to identify leads (High content screening, HCS). We propose a solution using novel fluorescent engineered protein biosensors integrated into a miniaturized live-cell-based screening platform (CellChip™ System) that markedly shortens the early drug discovery process. Microarrays of selectively localized living cells, containing engineered fluorescent biosensors, serve to integrate HTS and HCS onto a single platform. HTS “hits” are identified using one biosensor while reading the whole chip array of cells. The high-biological content information is then obtained from probing target activity at inter-cellular, sub-cellular and molecular levels in the “hit” wells. HCS assays yield temporal-spatial dynamic maps of the drug-target interaction within each living cell. We predict that a new platform incorporating HTS and HCS assays that are automated, miniaturized, and information-rich will dramatically improve the decision making process in the pharmaceutical industry and optimize lead compounds during the early part of the drug discovery process. There is an opportunity to establish a new paradigm for drug discovery based on integration of fluorescence technology, micropatterning of living cells, automated optical detection and data analysis, and a new generation of knowledge building bioinformatics approaches. The technology will have an expansive impact spanning the fields of drug discovery, biomedical research, environmental monitoring, life sciences, and clinical diagnostics. The integrated CellChip™ Platform with miniaturized tissue-specific microarrayed cells capable of providing inter-cellular and sub-cellular spatio-temporal information in response to drug-cell, toxin-cell, or pathogen-cell interactions will serve to enhance the decision making process in drug discovery, toxicology, and clinical diagnostics.

Computational decision support and the building delivery process: a necessary dialogue

The current critical discourse of computational design support systems (particularly building performance modeling tools) focuses more often than not on the ‘endogenous’ system problems, that is deficiencies in user communication, absence of integration, and the ‘black-box’ character of the underlying computational routines. As a result of this mostly valid criticism, work has been initiated in various quarters to improve modeling-based decision support environments. This paper argues that parallel efforts are needed to address other factors that go beyond the immediate technical realm of tool-making and involve matters pertaining to issues of building design and construction process at large. The building delivery process has traditionally been regarded as a discrete and sequential set of activities. This state of affairs is the result of a historical evolution driven by many factors, one of which might be the necessity to organize the activities for the purpose of establishing a professional fee structure that is commensurate with the scope of work and level of accountability or responsibility. However, within the context of rapidly changing building technologies, production processes, and knowledge transfer mechanisms, the existing procedural framework no longer seems capable of meeting the increasingly complex demands associated with the creation of the built environment. While the technical capabilities of decision support tools are expanding, they still fall short of challenging the very logic of the often nonintegrated processes they are designated to support. It may be understandable that, as compared to tools, processes tend to be more resilient to structural changes because of their inherent communicative nature, evolved over time through general acceptance and consensus. This paper argues, however, that careful study of the necessary conditions under which significant structural changes in the building delivery process would evolve, can effectively inform the developmental strategies in computational design support toward anticipation and encouragement of such changes.

Transgenic frogs and FGF signalling in early development

Time was, vertebrate developmental biologists worked on a particular species and stuck to the techniques appropriate to that species. If you worked on frogs you injected I~,tA into the eggs and did some dissections and grafts; if you worked on zehrafish you looked for mutations and followed the fates of transplanted cells; if you worked on cbickens you did grafts and followed the fates of cells; and if you .studied gastmlatinn in mice 1 think you must have been crazy, because the embryos are so small and inaccessible. With the realization that developmemal mechanisms are highly conserved, people began switching between species. It is much easier, for example, to overexpress a gene in a frog than in a mouse embryo, so why not do itt? And if you believe that regulatory elements are conserved, why not rake advantage of the small genome of Fugu and analyse promotets from thts species in transgenic mice2? This general approach has undoubtedly yielded important results hut it has the inevitable disadvantage of produdng a homogeneous view of vertebrate development in which all species are the same, and one is left wondering why we don't all look like a hybrid frog/monse/fish/chicken (or a fromtxshken, as Hazel Sive would put it3). Attempts are being made to overcome this problem. For example, Rossaot's and Sive's groups have cartied out frog-like in ~*t~o tissue recombinations in mouse'LS and zebrafish 6, and Beddington 7 and Shill and Fraser s,9, have earned out 'organizer grafts' in mouse and zebrafish, respectively. Indeed, Fl~¢er's work has revealed surprising differences between zebrafish and Xe~opus I0 I=.oth in the normal fate of the organizer and in its fate after transplantation. The latest advance reverses this trend of applying microsurgical techniques to species more usually respected for their contributions to genetics, for Amaya and Kroll have now introduced transgenesis to Xenoplt# 1.12. In the mouse, the ability to make transgenic animals has allowed detailed analysis of promoter and enhancer sequences 13, and, once suitable elements have been identified, it has also allowed investigators to overexpress a wild-type or mutant gene at the desired place and at the desired time 1~. Such experiments have proved very valuable in our understanding of the comrol of gene expression and of cell interactions in development. These approaches have been denied to the Xenopus embryologist, however, because injected DNA does not integrate into chromosomes during the early cell cycles of this species. As a result, the embryo expresses genes in a highly mosaic fashion and in the absence of integration it is likely that accurate temporal and tissue-specific control is lost. Although the cla.~sical Xenopusahemative, of injecting RNA, suffers only slightly from mosaieism, and one can inject into blasromeres wire known fates, there is no tempoml control of expression: translation occurs as soon as the RNA is iniected 15. It is possible to obtain effective temporal control by means of tricks, such as fusing one's protein of interest to the hormone-binding domain of a steroid receptor 16, but this only works for some genes. The importance of the correct timing of gene expression is illustrated by Xwm-8, where over-expression of this gene product by KNA injection causes dorsalization tT,rs, while more appropriate expression after the mid-blastula transition reveals that it is more likely to be involved in the specification of ventral mesoderm 19,

Self-Limiting, Cell Type-Dependent Replication of an Integrase-Defective Human Immunodeficiency Virus Type 1 in Human Primary Macrophages but Not T Lymphocytes

Integration of retroviral DNA into the host cell genome, catalyzed by the integrase (IN) protein, is thought to be required for replication. We show here that one IN-minus defective mutant of human immunodeficiency virus type 1 (HIV-1) is able to replicate in macrophages but not in peripheral blood lymphocytes (PBLs). Replication of the HIV-1 defective mutant, however, was inefficient and self-limiting. The absence of integration in the HIV-1 IN mutant in contrast to the wild-type implies that the replication of the IN mutant depends on the transcription of the extrachromosomal forms of viral DNA. In both PBLs and macrophages circular forms of DNA were detected at significant levels, indicating that the lack of a complete functional IN protein does not preclude nuclear import of HIV-1 DNA. Cell-associated p24 was absent in the IN-defectiveinfected PBLs, suggesting a transcriptional block of the extrachromosomal forms of HIV-1. These results show the existence of different strategies for HIV-1 replication depending upon the cell type, and indicate the necessity of integration of viral DNA for the self-maintained progression of the infection.

Brain death in the pediatric patient: historical, sociological, medical, religious, cultural, legal, and ethical considerations.

Objective To detail the origins of the definition of death, the development of the criterion of whole brain death as fulfilling the definition of death, and the tests used to fulfill that criterion. Data sources A review of the literature was performed. No Institutional Review Board approval was necessary. Data extraction In 1959, patients were described as being in "coma depasse" or beyond coma. In 1967, the first successful heart transplantation took place, with the organ coming from a brain-dead, beating-heart donor. However, anxiety over the definitions of death did not begin with the modern, technological era, and death itself has never been definable in objective terms. It has always been a subjective and value-based construct. During ancient times, most people agreed that death occurred when a person's heartbeat and breathing stopped. For the Greeks, the heart was the center of life; for the ancient Hebrews and Christians, the breath was the center of life. In the 12th century, Maimonides pointed toward the head, and the loss thereof, as the reason for lack of central guidance of the soul. Physicians neither diagnosed nor certified death. During the Enlightenment, the necessity of heartbeat, breath, and consciousness for the definition of life was questioned, leading to questioning regarding the definition of death. Tests to fulfill the criteria of death, and tests to determine the absence of integration between functions of respiration, circulation, and neurology were introduced. Sensorimotor potential was becoming recognized as defining life, rather than heartbeat and respiration. As new tests were devised to fulfill criteria of death, the physician developed a professional monopoly on meeting the criteria of brain death. In the modern era, the boundary between life and death has been blurred, but the intensive care unit straddles this boundary. We may have situations where the patient is alive but in a coma, without functioning heart, lungs, kidneys, or gastrointestinal tract, with a transplanted liver, a reversed coagulation system, a blocked immune system, and a paralyzed musculoskeletal system. Data synthesis A human being is a man, woman, or child who is a composite of two intricately related but conceptually distinguishable components: the biological entity and the person. Therefore, human beings can suffer more than one death: a biological death and decay, and another death. Biological death is a cessation of processes of biological synthesis and replication, and is an irreversible loss of integration of the biological units. The reasons for having criteria for death are to diagnose death and pronounce a person dead. Society can then begin to engage in grief, religious rites, funerals, and burials, and accept biological death. Wills can be read, property distributed, insurance claimed, individuals can remarry, succession can take place, and legal proceedings can begin. Also, organ donation can take place, which entails difficult ethical decisions. The Harvard criteria of 1968 were devised to set forth brain-death criteria with whole brain death in mind. Currently, there are several controversies regarding these criteria: a) whether they apply to infants and children; b) whether ancillary tests are necessary; c) what the intervals of observation and testing are; and d) are there exceptions to the whole brain death criteria. Concerning the use of the adult criteria for infants and children, most researchers now agree that the adult criteria apply to infants and children who are full term and > 7 days of age. Concerning ancillary tests, there has been, in our machine- and technology-oriented profession, a great deal of emphasis on the different tests and their ability to fulfill the criteria of whole brain death. However, clinical examination and the apnea test are usually sufficient to fulfill the criteria. Ancillary tests may be desired in some cases, and a variety of these tests is available. (ABSTRACT TR