抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

http://experimentationlab.berkeley.edu/sites/default/files/AFMImages/butt_AFM.pdf

Force measurements with the atomic force microscope: Technique, interpretation and applications

Contractile myocytes provide a test of the hypothesis that cells sense their mechanical as well as molecular microenvironment, altering expression, organization, and/or morphology accordingly. Here, myoblasts were cultured on collagen strips attached to glass or polymer gels of varied elasticity. Subsequent fusion into myotubes occurs independent of substrate flexibility. However, myosin/actin striations emerge later only on gels with stiffness typical of normal muscle (passive Young's modulus, E approximately 12 kPa). On glass and much softer or stiffer gels, including gels emulating stiff dystrophic muscle, cells do not striate. In addition, myotubes grown on top of a compliant bottom layer of glass-attached myotubes (but not softer fibroblasts) will striate, whereas the bottom cells will only assemble stress fibers and vinculin-rich adhesions. Unlike sarcomere formation, adhesion strength increases monotonically versus substrate stiffness with strongest adhesion on glass. These findings have major implications for in vivo introduction of stem cells into diseased or damaged striated muscle of altered mechanical composition.

/pdf/myotubes-differentiate-optimally-on-substrates-with-tissue-2s499cqco3.pdf

Myotubes differentiate optimally on substrates with tissue-like stiffness: pathological implications for soft or stiff microenvironments

Guided Lamb waves for identification of damage in composite structures: A review

Cell migration through 3D tissue depends on a physicochemical balance between cell deformability and physical tissue constraints. Migration rates are further governed by the capacity to degrade ECM by proteolytic enzymes, particularly matrix metalloproteinases (MMPs), and integrin- and actomyosin-mediated mechanocoupling. Yet, how these parameters cooperate when space is confined remains unclear. Using MMP-degradable collagen lattices or nondegradable substrates of varying porosity, we quantitatively identify the limits of cell migration by physical arrest. MMP-independent migration declined as linear function of pore size and with deformation of the nucleus, with arrest reached at 10% of the nuclear cross section (tumor cells, 7 µm2; T cells, 4 µm2; neutrophils, 2 µm2). Residual migration under space restriction strongly depended upon MMP-dependent ECM cleavage by enlarging matrix pore diameters, and integrin- and actomyosin-dependent force generation, which jointly propelled the nucleus. The limits of interstitial cell migration thus depend upon scaffold porosity and deformation of the nucleus, with pericellular collagenolysis and mechanocoupling as modulators.

/pdf/physical-limits-of-cell-migration-control-by-ecm-space-and-52gk5w0erg.pdf

Physical limits of cell migration: Control by ECM space and nuclear deformation and tuning by proteolysis and traction force

Repeated extragenic palindromes ( REP s) in the enterobacterial genomes are usually composed of individual palindromic units separated by linker sequences. A total of 355 annotated REP s are distributed along the Escherichia coli genome. RNA sequence (RNAseq) analysis showed that almost 80% of the REP s in E. coli are transcribed. The DNA sequence of REP 325 showed that it is a cluster of six repeats, each with two palindromic units capable of forming cruciform structures in supercoiled DNA. Here, we report that components of the REP 325 element and at least one of its RNA products play a role in bacterial nucleoid DNA condensation. These RNA not only are present in the purified nucleoid but bind to the bacterial nucleoid-associated HU protein as revealed by RNA IP followed by microarray analysis (RIP-Chip) assays. Deletion of REP 325 resulted in a dramatic increase of the nucleoid size as observed using transmission electron microscopy (TEM), and expression of one of the REP 325 RNAs, nucleoid-associated noncoding RNA 4 (naRNA4), from a plasmid restored the wild-type condensed structure. Independently, chromosome conformation capture (3C) analysis demonstrated physical connections among various REP elements around the chromosome. These connections are dependent in some way upon the presence of HU and the REP 325 element; deletion of HU genes and/or the REP 325 element removed the connections. Finally, naRNA4 together with HU condensed DNA in vitro by connecting REP 325 or other DNA sequences that contain cruciform structures in a pairwise manner as observed by atomic force microscopy (AFM). On the basis of our results, we propose molecular models to explain connections of remote cruciform structures mediated by HU and naRNA4. IMPORTANCE Nucleoid organization in bacteria is being studied extensively, and several models have been proposed. However, the molecular nature of the structural organization is not well understood. Here we characterized the role of a novel nucleoid-associated noncoding RNA, naRNA4, in nucleoid structures both in vivo and in vitro . We propose models to explain how naRNA4 together with nucleoid-associated protein HU connects remote DNA elements for nucleoid condensation. We present the first evidence of a noncoding RNA together with a nucleoid-associated protein directly condensing nucleoid DNA.

https://mbio.asm.org/content/mbio/6/4/e00998-15.full.pdf

A New Noncoding RNA Arranges Bacterial Chromosome Organization

Active control of structurally radiated noise using multiple piezoelectric actuators

The extraordinary fine-tuning characteristic of normal mammalian hearing is attributed to physiological mechanisms collectively known as the cochlear amplifier (CA), which amplifies and sharpens the basilar membrane (BM) vibration response to incoming acoustic pressure oscillations. Electromechanical properties of outer hair cells (OHCs) are believed to be the critical component of the CA, but its “circuitry” as yet remains unknown. Here, the required frequency-space response characteristics of the CA are computationally determined when typical in vivo tuning data are introduced as input to a linear hydroelastic cochlear model whose cross-sectional dynamics are represented by two coupled vibrational degrees of freedom. It is assumed that the CA senses motion at the tectorial membrane (TM) reticular lamina (RL) and applies proportional, equal, and opposite forces to the BM and the RL. The results show the CA to be tonotopically tuned, meaning it conforms to a space-frequency similarity principle like other cochlear dynamical responses. This requires that the active mechanism use information distributed along the cochlear partition. The physiological mechanism responsible for such behavior remains unknown, but here the computed CA characteristics can be qualitatively reproduced by a circuit spanning the length of the cochlea. This does not preclude other mechanisms, but is intended to motivate closer experimental investigation of extracellular and intercellular ionic flow pathways.

Solution of the inverse problem for a linear cochlear model: a tonotopic cochlear amplifier.

Cartilage is composed of cells and an extracellular matrix, the latter being a composite of a collagen mesh interpenetrated by proteoglycans responsible for tissue osmotic swelling. The matrix composition and structure vary through the tissue depth. Mapping such variability requires tissue sectioning to gain access. The resulting surface roughness, and concomitant proteoglycan loss contribute to large uncertainties in elastic modulus estimates. To extract elasticity values for the bulk matrix which are not obfuscated by the indeterminate surface layer, we developed a novel experimental and data analysis methodology. We analyzed the surface roughness to optimize the probe size, and performed high-resolution (1 μm) elasticity mapping on thin (∼12 μm), epiphyseal newborn mouse cartilage sections cut parallel to the bone longitudinal axis or normal to the articular surface. Mild fixation prevented the major proteoglycan loss observed in unfixed specimens but not the stress release that resulted in thickness changes in the sectioned matrix. Our novel data analysis method introduces a virtual contact point as a fitting parameter for the Hertz model, to minimize the effects of surface roughness and corrects for the finite section thickness. Our estimates of cartilage elasticity converge with increasing indentation depth and, unlike previous data interpretations, are consistent with linearly elastic material. A high cell density that leaves narrow matrix septa between cells may cause the underestimation of elastic moduli, whereas fixation probably causes an overestimation. The proposed methodology has broader relevance to nano- and micro-indentation of soft materials with multiple length scales of organization and whenever surface effects (including roughness, electrostatics, van der Waals forces, etc.) become significant.

/pdf/microscale-mapping-of-extracellular-matrix-elasticity-of-1igyli1f1j.pdf

Microscale mapping of extracellular matrix elasticity of mouse joint cartilage: an approach to extracting bulk elasticity of soft matter with surface roughness.

Plasma volume (PV) is an important determinant of cardiovascular function and organ perfusion, and it is the target of infusion and diuretic therapies in daily clinical practice. Despite its fundamental importance PV is not commonly measured because available methods of tracer dilution are reliant on dye substances that suffer from numerous drawbacks including binding plasma proteins, spectral changes, and clearance kinetics that complicate analysis and interpretation. To address these issues, we have tested the utility of fluorescent nanoparticles comprised of a dye-rich silica core and polyethylene glycol-coated shell. Photophysical and visual analysis showed discrete size-gradated nanoparticle populations could be synthesized within a distribution tolerance of ±4 nm, which were optically unaffected in the presence of plasma/albumin. In normal mice, the cutoff for renal filtration of nanoparticles from blood into urine was ≤11 nm. A linear relationship between body weight and PV was readily determined in mice administered far red fluorescent nanoparticles sized either 20 or 30 nm. PV measurements using nanoparticles were correlated to values obtained with Evans blue dye. Induced expansion or contraction of PV was demonstrated with albumin or furosemide administration, respectively, in mice. Longitudinal experiments >30 min required matched untreated control mice to correct for nanoparticle loss (≈30%) putatively to the reticuloendothelial/phagocyte system. Collectively, the findings support a nanotechnology-based solution to methodological problems in measure of PV, notably in clinical settings where information on hemodynamic changes may improve treatment of injury and disease.

https://www.physiology.org/doi/pdf/10.1152/japplphysiol.01068.2011

Emilios K. Dimitriadis

Papers

A New Noncoding RNA Arranges Bacterial Chromosome Organization

Active control of structurally radiated noise using multiple piezoelectric actuators

Solution of the inverse problem for a linear cochlear model: a tonotopic cochlear amplifier.

Microscale mapping of extracellular matrix elasticity of mouse joint cartilage: an approach to extracting bulk elasticity of soft matter with surface roughness.

Measurement of plasma volume using fluorescent silica-based nanoparticles