Ex vivo Immune Profiling in Patient Blood enables Quantification of innate immune Effector Functions

The immune response towards infection is a dynamic system combating invading pathogens to maintain homeostasis and the integrity of the body. Unbalanced immune response profiles determine many clinical syndromes including sepsis and thus present a major challenge in management of life threatening infections. Consequently, there is a high demand to determine a patient’s immune status and identifying functional parameters for immune dysfunction.Here, we quantified the global functional status of human innate immune responses by using a human whole-blood model of infection combined with biomathematical modeling. By determining functional parameters of innate immune cell populations after ex vivo whole-blood bacterial (Staphylococcus aureus) and fungal (Candida albicans) infection, we examined cell-specific functional parameters including migration rates or phagocytosis rates in patients that underwent cardiac surgery with extracorporeal circulation. This intervention is known to pose a transient but strong inflammatory stimulus. In addition to a post-operative increase in white blood cell count mainly caused by mobilization of immature neutrophils we find that the surgery induced pro-inflammatory stimulus results in a mitigation of pathogen-specific response patterns that are characteristic for healthy people and baseline results in our patients. Moreover, our model revealed changing rates for pathogen immune evasion, indicating increased inter-pathogenic differences after surgery. This effect was specific for C. albicans and could not be observed for S. aureus. In summary, our model gives insight into immune functionality and might serve as a functional immune assay to record and evaluate innate response patterns towards infection.Author summaryAssessment of a patient’s immune function is critical in many clinical situations. One prominent example is sepsis, which results from a loss of immune homeostasis due to microbial infection. Sepsis is characterized by a plethora of pro- and anti-inflammatory simuli that may occur consecutively or simultaneously and thus any immunomodulatory therapy would require in depth knowledge of an individual patient’s immune status at a given time. Whereas lab-test based immune profiling often relies solely on quantification of cell numbers, we have used an ex vivo whole-blood infection model in combination with biomathematical modeling to quantify functional parameters of innate immune cells in patient blood. A small blood sample of patients undergoing cardiac surgery, which is known to constitute an inflammatory stimulus was infected ex vivo. Functional immune cell parameters were determined using a combination of experimental assays and biomathematical modeling. We show that these parameters change after an inflammatory insult triggered by cardiac surgery and extracorporeal circulation. This does not only interfere with pathogen elimination from blood but also selectively augments the escape of the fungal pathogen Candida albicans from phagocytosis.

Biomathematical model for gyrotactic free-forced bioconvection with oxygen diffusion in near-wall transport within a porous medium fuel cell

Bioconvection has shown significant promise for environmentally friendly, sustainable “green” fuel cell technologies. The improved design of such systems requires continuous refinements in biomathematical modeling in conjunction with laboratory and field testing. Motivated by exploring deeper the near-wall transport phenomena involved in bio-inspired fuel cells, in the present paper, we examine analytically and numerically the combined free-forced convective steady boundary layer flow from a solid vertical flat plate embedded in a Darcian porous medium containing gyrotactic microorganisms. Gyrotaxis is one of the many taxes exhibited in biological microscale transport, and other examples include magneto-taxis, photo-taxis, chemotaxis and geo-taxis (reflecting the response of microorganisms to magnetic field, light, chemical concentration or gravity, respectively). The bioconvection fuel cell also contains diffusing oxygen species which mimics the cathodic behavior in a proton exchange membrane (PEM) system. The vertical wall is maintained at iso-solutal (constant oxygen volume fraction and motile microorganism density) and iso-thermal conditions. Wall values of these quantities are sustained at higher values than the ambient temperature and concentration of oxygen and biological microorganism species. Similarity transformations are applied to render the governing partial differential equations for mass, momentum, energy, oxygen species and microorganism species density into a system of ordinary differential equations. The emerging eight order nonlinear coupled, ordinary differential boundary value problem features several important dimensionless control parameters, namely Lewis number (Le), buoyancy ratio parameter i.e. ratio of oxygen species buoyancy force to thermal buoyancy force (Nr), bioconvection Rayleigh number (Rb), bioconvection Lewis number (Lb), bioconvection Péclet number (Pe) and the mixed convection parameter ([Formula: see text] spanning the entire range of free and forced convection. The transformed nonlinear system of equations with boundary conditions is solved numerically by a finite difference method with central differencing, tridiagonal matrix manipulation and an iterative procedure. Computations are validated with the symbolic Maple 14.0 software. The influence of buoyancy and bioconvection parameters on the dimensionless temperature, velocity, oxygen concentration and motile microorganism density distribution, Nusselt, Sherwood and gradient of motile microorganism density are studied. The work clearly shows the benefit of utilizing biological organisms in fuel cell design and presents a logical biomathematical modeling framework for simulating such systems. In particular, the deployment of gyrotactic microorganisms is shown to stimulate improved transport characteristics in heat and momentum at the fuel cell wall.

The Effect of Proportion and Degree of Resistance of CD4+ Lymphocytes on in vivo HIV dynamics

For a disease like HIV(Human Immunodeficiency Virus) that infects 240 human beings each hour with the consequent increase in morbidity and mortality, a cure would be very welcome news. In order for this to happen, the true in vivo dynamics of transmission must be understood. Mathematical modelling and computational prowess have made it possible to convert large sets of data into easily analyzed and interpreted information with an amazing potential to change lives. In this paper, we explored the use of biomathematical modeling with computation in the dynamic changes resulting from HIV infection of CD4+(Cluster of differentiation 4) lymphocytes. This model is designed to simulate the in vivo dynamics of the proportion and degree of CD4+ lymphocyte resistance. Our results show that the degree of intrinsic CD4+resistance against the acquisition of HIV is more important than the proportion of resistant CD4+lymphocytes in vivo. Genetic determinants of resistance are postulated to be the backbone of development of intrinsic resistance. This work may serve as serve as a blueprint on how to use biomathematical modeling to tackle other infectious diseases. The findings of this work will be the basis of enthusiastic research to finally realize definitive control of HIV.

LOUDNESS OF SOUNDS OF DIFFERENT FREQUENCY AND INTENSITY: THE GENERALIZED WEBER LAW FOR HEARING

Aim - rigorous scientificand theoretical substantiation of the Weber law for determination of loudness of sounds of different frequency and intensity. Objects and methods. E.H. Weber's experimental results on subjective perception of objectively measured parameters of external irritants, their theoretical substantiation for sounds of the standard frequency 1 kHz, biophysical and biomathematical modeling of loudness of sounds with different parameters. Results. The Weber law by author for determination of loudness of sounds of different frequency and intensity is evidence based.