Roles of Remote and Contact Forces in Epithelial Cell Structure Formation.

Cancer cells collectively form a large-scale structure for their growth. In this article, we report that HeLa cells, epithelial-like human cervical cancer cells, aggressively migrate on Matrigel and form a large-scale structure in a cell-density-dependent manner. To explain the experimental results, we develop a simple model in which cells interact and migrate using the two fundamentally different types of force, remote and contact forces, and show how cells form a large-scale structure. We demonstrate that the simple model reproduces experimental observations, suggesting that the remote and contact forces considered in this work play a major role in large-scale structure formation of HeLa cells. This article provides important evidence that cancer cells form a large-scale structure and develops an understanding into the poorly understood mechanisms of their structure formation.

A CTL-based liposomal vaccine capable of inducing protection against heterosubtypic influenza viruses in HLA-A*0201 transgenic mice.

The current vaccination strategy against influenza is to induce the production of antibodies directed against surface antigens of viruses. However, the frequent changes in the surface antigens of influenza viruses allow the viruses to avoid antibody-mediated immunity. On the other hand, it is known that cytotoxic T-lymphocyte (CTL) populations directed against internal antigens of influenza A virus are broadly cross-reactive to influenza virus subtypes. In the present study, liposomal conjugates with CTL epitope peptides derived from highly conserved internal antigens of influenza viruses were evaluated for their ability to protect against infection with influenza viruses. Liposomal conjugates with peptide M1 58-66, an HLA-A*0201-binding CTL epitope present within the amino-acid sequence of the M1 coding region, successfully induced antigen-specific CD8(+) T-cells and CTLs in HLA-A*0201-transgenic mice. Moreover, after nasal infection with either the H1N1 or H3N2 virus, viral replication in the lung was significantly inhibited in the immunized mice. These protective activities lasted at least 6months after the immunization. Thus, these results suggest that liposome-coupled CTL epitope peptides derived from highly conserved internal antigens of influenza viruses might be applicable to the development of vaccines that induce protection against infection with heterosubtypic influenza viruses.

A nanosensory device fabricated on a liposome for detection of chemical signals.

This paper describes construction of a nanosensory device for amplified detection of biologically important amines as chemical signals. The device was inspired by a biological signal transduction system, and was fabricated on an artificial cell membrane through self-organization of the molecular components, such as a synthetic receptor and a natural enzyme. Selective recognition of biologically important amines was achieved by a synthetic receptor with a pyridoxal moiety, as evaluated by means of electronic absorption spectroscopy. The selectivity in detecting amines as chemical signals mainly depends on hydrophobicity of the amines. The event upon detecting the chemical signals was transmitted to an enzyme by a metal ion acting as a mediator species, and then the enzyme amplified the event by the catalytic reaction to obtain signal output. This paper is realization of a biomimetic signal transduction system using amines as chemical signals and may provide a useful guidepost for designing integrated nanosystems.

Molecular Communication: A Personal Perspective.

The authors of this paper have been involved in molecular communication since its conception. They describe their decade-and-a-half long personal journey of the molecular communication research and share their observations and thoughts on how the molecular communication research started and expanded to flourish. The authors also share their thoughts on research challenges that they hope the molecular communication research community addresses in the coming decade.

Self-organizing network services with evolutionary adaptation.

This paper proposes a novel framework for developing adaptive and scalable network services. In the proposed framework, a network service is implemented as a group of autonomous agents that interact in the network environment. Agents in the proposed framework are autonomous and capable of simple behaviors (e.g., replication, migration, and death). In this paper, an evolutionary adaptation mechanism is designed using genetic algorithms (GAs) for agents to evolve their behaviors and improve their fitness values (e.g., response time to a service request) to the environment. The proposed framework is evaluated through simulations, and the simulation results demonstrate the ability of autonomous agents to adapt to the network environment. The proposed framework may be suitable for disseminating network services in dynamic and large-scale networks where a large number of data and services need to be replicated, moved, and deleted in a decentralized manner.

Molecular communication among biological nanomachines: a layered architecture and research issues.

Molecular communication is an emerging communication paradigm for biological nanomachines. It allows biological nanomachines to communicate through exchanging molecules in an aqueous environment and to perform collaborative tasks through integrating functionalities of individual biological nanomachines. This paper develops the layered architecture of molecular communication and describes research issues that molecular communication faces at each layer of the architecture. Specifically, this paper applies a layered architecture approach, traditionally used in communication networks, to molecular communication, decomposes complex molecular communication functionality into a set of manageable layers, identifies basic functionalities of each layer, and develops a descriptive model consisting of key components of the layer for each layer. This paper also discusses open research issues that need to be addressed at each layer. In addition, this paper provides an example design of targeted drug delivery, a nanomedical application, to illustrate how the layered architecture helps design an application of molecular communication. The primary contribution of this paper is to provide an in-depth architectural view of molecular communication. Establishing a layered architecture of molecular communication helps organize various research issues and design concerns into layers that are relatively independent of each other, and thus accelerates research in each layer and facilitates the design and development of applications of molecular communication.

Chimeric SV40 virus-like particles induce specific cytotoxicity and protective immunity against influenza A virus without the need of adjuvants.

Virus-like particles (VLPs) are a promising vaccine platform due to the safety and efficiency. However, it is still unclear whether polyomavirus-based VLPs are useful for this purpose. Here, we attempted to evaluate the potential of polyomavirus VLPs for the antiviral vaccine using simian virus 40 (SV40). We constructed chimeric SV40-VLPs carrying an HLA-A*02:01-restricted, cytotoxic T lymphocyte (CTL) epitope derived from influenza A virus. HLA-A*02:01-transgenic mice were then immunized with the chimeric SV40-VLPs. The chimeric SV40-VLPs effectively induced influenza-specific CTLs and heterosubtypic protection against influenza A viruses without the need of adjuvants. Because DNase I treatment of the chimeric SV40-VLPs did not disrupt CTL induction, the intrinsic adjuvant property may not result from DNA contaminants in the VLP preparation. In addition, immunization with the chimeric SV40-VLPs generated long-lasting memory CTLs. We here propose that the chimeric SV40-VLPs harboring an epitope may be a promising CTL-based vaccine platform with self-adjuvant properties.

The route of immunization with adenoviral vaccine influences the recruitment of cytotoxic T lymphocytes in the lung that provide potent protection from influenza A virus.

Virus-specific cytotoxic T lymphocytes (CTLs) in the lung are considered to confer protection from respiratory viruses. Several groups demonstrated that the route of priming was likely to have an implication for the trafficking of antigen-specific CTLs. Therefore, we investigated whether the route of immunization with adenoviral vaccine influenced the recruitment of virus-specific CTLs in the lung that should provide potent protection from influenza A virus. Mice were immunized with recombinant adenovirus expressing the matrix (M1) protein of influenza A virus via various immunization routes involving intraperitoneal, intranasal, intramuscular, or intravenous administration as well as subcutaneous administration in the hind hock. We found that the immunization route dramatically impacted the recruitment of M1-specific IFN-γ(+) CD8(+) T cells both in the lung and the spleen. Surprisingly, hock immunization was most effective for the accumulation in the lung of IFN-γ-producing CD8(+) T cells that possessed M1-specific cytolytic activity. Further, antigen-driven IFN-γ(+) CD8(+) T cells in the lung, but not in the spleen, were likely to be correlated with the resistance to challenge with influenza A virus. These results may improve our ability to design vaccines that target virus-specific CTL responses to respiratory viruses such as influenza A virus.

Molecular communication: modeling noise effects on information rate.

Molecular communication is a new paradigm for communication between biological nanomachines over a nano- and microscale range. As biological nanomachines (or nanomachines in short) are too small and simple to communicate through traditional communication mechanisms (e.g., through sending and receiving of radio or infrared signals), molecular communication provides a mechanism for a nanomachine (i.e., a sender) to communicate information by propagating molecules (i.e., information molecules) that represent the information to a nanomachine (i.e., a receiver). This paper describes the design of an in vitro molecular communication system and evaluates various approaches to maximize the probability of information molecules reaching a receiver(s) and the rate of information reaching the receiver(s). The approaches considered in this paper include propagating information molecules (diffusion or directional transport along protein filaments), removing excessive information molecules (natural decay or receiver removal of excessive information molecules), and encoding and decoding approaches (redundant information molecules to represent information and to decode information). Two types of molecular communication systems are considered: a unicast system in which a sender communicates with a single receiver and a broadcast system in which a sender communicates with multiple receivers. Through exploring tradeoffs among the various approaches on the two types of molecular communication systems, this paper identifies promising approaches and shows the feasibility of an in vitro molecular communication system.

A locally-induced increase in intracellular Ca2+ propagates cell-to-cell in the presence of plasma membrane Ca2+ ATPase inhibitors in non-excitable cells.

Intercellular Ca(2+) waves are commonly observed in many cell types. In non-excitable cells, intercellular Ca(2+) waves are mediated by gap junctional diffusion of a Ca(2+) mobilizing messenger such as IP(3). Since Ca(2+) is heavily buffered in the cytosolic environment, it has been hypothesized that the contribution of the diffusion of Ca(2+) to intercellular Ca(2+) waves is limited. Here, we report that in the presence of plasma membrane Ca(2+) ATPase inhibitors, locally-released Ca(2+) from the flash-photolysis of caged-Ca(2+) appeared to induce further Ca(2+) release and were propagated from one cell to another, indicating that Ca(2+) was self-amplified to mediate intercellular Ca(2+) waves. Our findings support the notion that non-excitable cells can establish a highly excitable medium to communicate local responses with distant cells.

Efficient induction of cytotoxic T lymphocytes specific for severe acute respiratory syndrome (SARS)-associated coronavirus by immunization with surface-linked liposomal peptides derived from a non-structural polyprotein 1a.

Spike and nucleocapsid are structural proteins of severe acute respiratory syndrome (SARS)-associated coronavirus (SARS-CoV) and major targets for cytotoxic T lymphocytes (CTLs). In contrast, non-structural proteins encoded by two-thirds of viral genome are poorly characterized for cell-mediated immunity. We previously demonstrated that nucleocapsid-derived peptides chemically coupled to the surface of liposomes effectively elicited SARS-CoV-specific CTLs in mice. Here, we attempted to identify HLA-A*0201-restricted CTL epitopes derived from a non-structural polyprotein 1a (pp1a) of SARS-CoV, and investigated whether liposomal peptides derived from pp1a were effective for CTL induction. Out of 30 peptides predicted on computational algorithms, nine peptides could significantly induce interferon gamma (IFN-gamma)-producing CD8(+) T cells in mice. These peptides were coupled to the surface of liposomes, and inoculated into mice. Six liposomal peptides effectively induced IFN-gamma-producing CD8(+) T cells and seven liposomal peptides including the six peptides primed CTLs showing in vivo killing activities. Further, CTLs induced by the seven liposomal peptides lysed an HLA-A*0201 positive cell line expressing naturally processed, pp1a-derived peptides. Of note, one of the liposomal peptides induced high numbers of long-lasting memory CTLs. These data suggest that surface-linked liposomal peptides derived from pp1a might offer an efficient CTL-based vaccine against SARS.