Antibody Repertoire Analysis of Hepatitis C Virus Infections Identifies Immune Signatures Associated With Spontaneous Clearance.

Hepatitis C virus (HCV) is a major public health concern, with over 70 million people infected worldwide, who are at risk for developing life-threatening liver disease. No vaccine is available, and immunity against the virus is not well-understood. Following the acute stage, HCV usually causes chronic infections. However, ~30% of infected individuals spontaneously clear the virus. Therefore, using HCV as a model for comparing immune responses between spontaneous clearer (SC) and chronically infected (CI) individuals may empower the identification of mechanisms governing viral infection outcomes. Here, we provide the first in-depth analysis of adaptive immune receptor repertoires in individuals with current or past HCV infection. We demonstrate that SC individuals, in contrast to CI patients, develop clusters of antibodies with distinct properties. These antibodies' characteristics were used in a machine learning framework to accurately predict infection outcome. Using combinatorial antibody phage display library technology, we identified HCV-specific antibody sequences. By integrating these data with the repertoire analysis, we constructed two antibodies characterized by high neutralization breadth, which are associated with clearance. This study provides insight into the nature of effective immune response against HCV and demonstrates an innovative approach for constructing antibodies correlating with successful infection clearance. It may have clinical implications for prognosis of the future status of infection, and the design of effective immunotherapies and a vaccine for HCV.

PEG-Phospholipids Coated Quantum Rods as Amplifiers of the Photosensitization Process by FRET.

Singlet oxygen ((1)O2) generated upon photostimulation of photosensitizer molecules is a highly reactive specie which is utilized in photodynamic therapy. Recent studies have shown that semiconductor nanoparticles can be used as donors in fluorescence resonance energy transfer (FRET) process to excite attached photosensitizer molecules. In these studies, their unique properties, such as low nanoscale size, long-term photostability, wide broad absorbance band, large absorption cross section, and narrow and tunable emission bands were used to provide advantages over the traditional methods to produce singlet oxygen. Previous studies that achieved this goal, however, showed some limitations, such as low FRET efficiency, poor colloidal stability, nonspecific interactions, and/or complex preparation procedure. In this work, we developed and characterized a novel system of semiconductor quantum rods (QRs) and the photosensitizer meso-tetra(hydroxyphenyl) chlorin (mTHPC), as a model system that produces singlet oxygen without these limitations. A simple two-step preparation method is shown; Hydrophobic CdSe/CdS QRs are solubilized in aqueous solutions by encapsulation with lecithin and PEGylated phospholipid (PEG-PL) of two lipid lengths: PEG350 or PEG2000. Then, the hydrophobic photosensitizer mTHPC, was intercalated into the new amphiphilic PEG-PL coating of the QR, providing a strong attachment to the nanoparticle without covalent linkage. These PEGylated QR (eQR)-mTHPC nanocomposites show efficient FRET processes upon light stimulation of the QR component which results in efficient production of singlet oxygen. The results demonstrate the potential for future use of this concept in photodynamic therapy schemes.

Synchronization by elastic neuronal latencies.

Psychological and physiological considerations entail that formation and functionality of neuronal cell assemblies depend upon synchronized repeated activation such as zero-lag synchronization. Several mechanisms for the emergence of this phenomenon have been suggested, including the global network quantity, the greatest common divisor of neuronal circuit delay loops. However, they require strict biological prerequisites such as precisely matched delays and connectivity, and synchronization is represented as a stationary mode of activity instead of a transient phenomenon. Here we show that the unavoidable increase in neuronal response latency to ongoing stimulation serves as a nonuniform gradual stretching of neuronal circuit delay loops. This apparent nuisance is revealed to be an essential mechanism in various types of neuronal time controllers, where synchronization emerges as a transient phenomenon and without predefined precisely matched synaptic delays. These findings are described in an experimental procedure where conditioned stimulations were enforced on a circuit of neurons embedded within a large-scale network of cortical cells in vitro, and are corroborated and extended by simulations of circuits composed of Hodgkin-Huxley neurons with time-dependent latencies. These findings announce a cortical time scale for time controllers based on tens of microseconds stretching of neuronal circuit delay loops per spike. They call for a reexamination of the role of the temporal periodic mode in brain functionality using advanced in vitro and in vivo experiments.