Stability of a general adaptive immunity virus dynamics model with multistages of infected cells and two routes of infection

This paper studies an (n+4)-dimensional nonlinear virus dynamics model that characterizes the interactions of the viruses, susceptible host cells, n-stages of infected cells, B cells and cytotoxic T lymphocyte (CTL) cells. Both viral and cellular infections have been incorporated into the model. The infected-susceptible and virus-susceptible infection rates as well as the generation and removal rates of all compartments are described by general nonlinear functions. Five threshold parameters are computed, which insure the existence of the equilibria of the model under consideration. A set of conditions on the general functions has been established, which is sufficient to investigate the global dynamics of the model. The global asymptotic stability of all equilibria is proven by utilizing Lyapunov function and LaSalle's invariance principle. The theoretical results are illustrated by numerical simulations of the model with specific forms of the general functions.     

Membranes,peptides, and disease: Unraveling the mechanisms of viral proteins with solid state nuclear magnetic resonance spectroscopy

The interplay between peptides and lipid bilayers drives crucial biological processes. For example, a critical step in the replication cycle of enveloped viruses is the fusion of the viral membrane and host cell endosomal membrane, and these fusion events are controlled by viral fusion peptides. Thus such membrane-interacting peptides are of considerable interest as potential pharmacological targets. Deeper insight is needed into the mechanisms by which fusion peptides and other viral peptides modulate their surrounding membrane environment, and also how the particular membrane environment modulates the structure and activity of these peptides. An important step toward understanding these processes is to characterize the structure of viral peptides in environments that are as biologically relevant as possible. Solid state nuclear magnetic resonance (ssNMR) is uniquely well suited to provide atomic level information on the structure and dynamics of both membrane-associated peptides as well as the lipid bilayer itself; further ssNMR can delineate the contribution of specific membrane components, such as cholesterol, or changing cellular conditions, such as a decrease in pH on membrane-associating peptides. This paper highlights recent advances in the study of three types of membrane associated viral peptides by ssNMR to illustrate the more general power of ssNMR in addressing important biological questions involving membrane proteins.     

Structural and Dynamic Characterization of the Molecular Hub Early Region 1A (E1A) from Human Adenovirus

The small‐DNA human adenovirus encodes one of the most versatile molecular hubs, the E1A protein. This protein is essential for productive viral infection in human cells and a vast amount of biologically relevant data are available on its interactions with host proteins. Up to now, however, no high‐resolution structural and dynamic information on E1A is available despite its important biological role. Among the different spliced variants of E1A, two are expressed at high level in the early stage of infection. These are 243 and 289 residues isoforms. Herein, we present their NMR characterization, showing that they are both highly disordered, but also demonstrate a certain heterogeneous behavior in terms of structural and dynamic properties. Furthermore, we present the characterization of the isolated domain of the longer variant, known as CR3. This study opens the way to understanding at the molecular level how E1A functions.     

Molecular approach to human leukemia: Isolation and characterization of the first human retrovirus HTLV-1 and its impact on tumorigenesis in Adult T-cell Leukemia

Molecular biology of mouse and chicken retroviruses had identified oncogenes and provided a revolutionary concept in understanding of cancers. A human retrovirus was established during 1980–1982 in linkage with a unique human leukemia, concurrently in Japan and USA. This review covers our efforts on the discovery of new retrovirus, Human T-cell Leukemia Virus Type 1 (HTLV-1), first introducing to a new class of retroviruses with a unique regulatory factors, Tax and Rex. Then it is followed by analyses of molecular interaction of the vial Tax with cellular machineries involved in the pathogenesis of Adult T-cell Leukemia (ATL). And then a probable mechanism of pathogenesis of ATL is proposed including recent findings on HBZ after our efforts.     

天文/卫星组合点校捷联惯性导航系统算法研究

捷联式惯性导航系统通常采用卫星导航系统的位置、速度信息对惯导解算误差进行校正,但对于水下载体惯性导航系统而言,由于只能获得点位置信息,对惯导的校正精度以及校正参量有限。针对上述问题,提出了基于天文/卫星组合校正捷联式惯导技术,通过卫星精确定位信息和天文快速观测信息,全面修正惯导系统误差、提高导航精度。仿真结果表明,基于天文/卫星组合校正算法对惯导进行校正,相对于传统校正算法精度可提高约50%。     

NO in Viral Infections: Role and Development of Antiviral Therapies

Nitric oxide is a ubiquitous signaling radical that influences critical body functions. Its importance in the cardiovascular system and the innate immune response to bacterial and viral infections has been extensively investigated. The overproduction of NO is an early component of viral infections, including those affecting the respiratory tract. The production of high levels of NO is due to the overexpression of NO biosynthesis by inducible NO synthase (iNOS), which is involved in viral clearance. The development of NO-based antiviral therapies, particularly gaseous NO inhalation and NO-donors, has proven to be an excellent antiviral therapeutic strategy. The aim of this review is to systematically examine the multiple research studies that have been carried out to elucidate the role of NO in viral infections and to comprehensively describe the NO-based antiviral strategies that have been developed thus far. Particular attention has been paid to the potential mechanisms of NO and its clinical use in the prevention and therapy of COVID-19.     

Protein and Peptide Substances in the Treatment of Respiratory Syncytial Infection: Current State

Respiratory syncytial virus infection (RSVI) is an acute medical and social problem in many countries globally. Infection is most dangerous for infants under one year old and the elderly. Despite its epidemiological relevance, only two drugs are registered for clinical use against RSVI: ribavirin (approved in a limited number of countries due to side effects) and palivizumab (Synagis), which is intended only for the prevention, but not the treatment, of infection. Currently, various research groups are searching for new drugs against RSV, with three main areas of research: small molecules, polymeric drugs (proteins and peptides), and plant extracts. This review is devoted to currently developed protein and peptide anti-RSV drugs.     

Molecular Dynamics Simulation of HIV-1 Integrase Dimer Complexed with Viral DNA

The biological function of HIV‐1 integrase (IN) is to integrate viral DNA into the host cell chromosome, and the specific binding of IN with viral DNA is a precondition for IN to function correctly. Beforehand, the binding mode of IN dimer (IN₂) with the 27 bp segment of viral DNA before 3′ processing (3′‐P) was obtained via a molecular docking method. Based on the binding mode, the aim of this article was to explore the changes of motive mode and correlative motion for the IN₂ and DNA systems after their binding through dynamical cross‐correlation map (DCCM) and principal component analysis (PCA). Finally, solvent effect during the association was analyzed briefly. The results show that there is a significantly increased positive correlation in the interface region between IN₂ and viral DNA, and some obvious motive mode changes of the two systems (IN₂ and DNA) were also observed after their binding. It was found that water molecules played an important role in the recognition between IN₂ and viral DNA through analyzing the water‐mediated hydrogen bonds.     

Applications of rule-induction in the derivation of quantitative structure-activity relationships

Summary Recently, methods have been developed in the field of Artificial Intelligence (AI), specifically in the expert systems area using rule-induction, designed to extract rules from data. We have applied these methods to the analysis of molecular series with the objective of generating rules which are predictive and reliable.The input to rule-induction consists of a number of examples with known outcomes (a training set) and the output is a tree-structured series of rules. Unlike most other analysis methods, the results of the analysis are in the form of simple statements which can be easily interpreted. These are readily applied to new data giving both a classification and a probability of correctness.Rule-induction has been applied to in-house generated and published QSAR datasets and the methodology, application and results of these analyses are discussed.The results imply that in some cases it would be advantageous to use rule-induction as a complementary technique in addition to conventional statistical and pattern-recognition methods.     

Mesoporous Silica Nanoparticles Decorated with Carbosilane Dendrons as New Non‐viral Oligonucleotide Delivery Carriers

A novel nanosystem based on mesoporous silica nanoparticles covered with carbosilane dendrons grafted on the external surface of the nanoparticles is reported. This system is able to transport single‐stranded oligonucleotide into cells, avoiding an electrostatic repulsion between the cell membrane and the negatively charged nucleic acids thanks to the cationic charge provided by the dendron coating under physiological conditions. Moreover, the presence of the highly ordered pore network inside the silica matrix would make possible to allocate other therapeutic agents within the mesopores with the aim of achieving a double delivery. First, carbosilane dendrons of second and third generation possessing ammonium or tertiary amine groups as peripheral functional groups were prepared. Hence, different strategies were tested in order to obtain their suitable grafting on the outer surface of the nanoparticles. As nucleic acid model, a single‐stranded DNA oligonucleotide tagged with a fluorescent Cy3 moiety was used to evaluate the DNA adsorption capacity. The hybrid material functionalised with the third generation of a neutral dendron showed excellent DNA binding properties. Finally, the cytotoxicity as well as the capability to deliver DNA into cells, was tested in vitro by using a human osteoblast‐like cell line, achieving good levels of internalisation of the vector DNA/carbosilane dendron‐functionalised material without affecting the cellular viability.