Mechanistic and Statistical Models to Understand CXCL12/CXCR4/CXCR7 in Breast Cancer.

Signaling via the CXCL12/CXCR4 axis is instrumental to the metastasis of more than 20 cancers, yet blocking the pathway alone has not been effective as cancer therapy. Since cancer progression results from a complex network of interdependent biological events, preventing metastasis cannot be understood by studying only one gene or protein at a time. In this thesis, we employed mathematical and statistical models to examine complexity in the CXCL12/CXCR4/CXCR7 signaling axis. First, we performed a comprehensive analysis of CXCL12 isoform expression in breast cancer. This is the first study to correlate the expression levels of all six CXCL12 isoforms to cancer survival outcomes. Second, to understand mechanisms of physiological gradient formation, we built a hybrid agent-based model of cancer cell chemotaxis that links molecular scale events to chemokine gradient shaping and sensing. Third, to understand how co-expression of CXCR7 may alter CXCR4 signaling, we constructed a mechanistic model of CXCR4/CXCR7 receptor dynamics and signaling with an emphasis on shared signaling components. Themes arising from this work include the importance of non-specific binding of ligand to surfaces, receptor desensitization, gradient sensing, and compensatory effects resulting from the competition of shared signaling components.PhDChemical EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/111458/1/seiwon_1.pd

A rare schizophrenia risk variant of CACNA1I disrupts CaV3.3 channel activity

CACNA1I is a candidate schizophrenia risk gene. It encodes the pore-forming human CaV3.3 α1 subunit, a subtype of voltage-gated calcium channel that contributes to T-type currents. Recently, two de novo missense variations, T797M and R1346H, of hCaV3.3 were identified in individuals with schizophrenia. Here we show that R1346H, but not T797M, is associated with lower hCaV3.3 protein levels, reduced glycosylation, and lower membrane surface levels of hCaV3.3 when expressed in human cell lines compared to wild-type. Consistent with our biochemical analyses, whole-cell hCaV3.3 currents in cells expressing the R1346H variant were ~50% of those in cells expressing WT hCaV3.3, and neither R1346H nor T797M altered channel biophysical properties. Employing the NEURON simulation environment, we found that reducing hCaV3.3 current densities by 22% or more eliminates rebound bursting in model thalamic reticular nucleus (TRN) neurons. Our analyses suggest that a single copy of Chr22: 39665939G > A CACNA1I has the capacity to disrupt CaV3.3 channel-dependent functions, including rebound bursting in TRN neurons, with potential implications for schizophrenia pathophysiology

RESEARCH PROGRESS IN THE SPLICING AND RESTORATION OF ARTIFACT FRAGMENTS BASED ON POINT CLOUD

Due to environmental reasons, most of the artifacts are fragmented, and the surface information of the artifacts is also blurred. The traditional method of repairing artifacts mainly relies on archaeologists to manually repair them, using fragment features to compare each fragment one by one, this method will cause secondary damage to the fragments. Based on computer technology, virtual restoration of artifacts fragments can obtain the latest unearthed data of artifacts quickly, preserve digital information of artifacts, achieve permanent preservation, and provide prior knowledge for subsequent artifacts restoration. Point cloud data is widely used in artifacts virtual restoration technology due to its good depth of information. This paper takes ceramics, bronzes, Terra-cotta Warriors, and other individual artifacts fragments as the main research object, and the point cloud data obtained by 3D laser scanner as the main research data. It comprehensively classifies and summarizes the work of computer artifacts splicing in recent years

Lighting and Optical Tools for Image Forensics

We present new forensic tools that are capable of detecting traces of tampering in digital images without the use of watermarks or specialized hardware. These tools operate under the assumption that images contain natural properties from a variety of sources, including the world, the lens, and the sensor. These properties may be disturbed by digital tampering and by measuring them we can expose the forgery. In this context, we present the following forensic tools: (1) illuminant direction, (2) specularity, (3) lighting environment, and (4) chromatic aberration. The common theme of these tools is that they exploit lighting or optical properties of images. Although each tool is not applicable to every image, they add to a growing set of image forensic tools that together will complicate the process of making a convincing forgery

Targeting protein kinases to manage or prevent Alzheimer’s disease

Due to the pressing need for new disease-modifying drugs for Alzheimer’s disease (AD), new treatment strategies and alternative drug targets are currently being heavily researched. One such strategy is to modulate protein kinases such as cyclin-dependent kinase 1 (CDK1), cyclin-dependent kinase 5 (CDK5), glycogen synthase kinase-3 (GSK-3α and GSK-3β), and the protein kinase RNA-like endoplasmic reticulum kinase (PERK). AD intervention by reduction of amyloid beta (Aβ) levels is also possible through development of protein kinase C-epsilon (PKC-ϵ) activators to recover α-secretase levels and decrease toxic Aβ levels, thereby restoring synaptogenesis and cognitive function. In this way, we aim to develop new AD drugs by targeting kinases that participate in AD pathophysiology. In our studies, comparative modeling was performed to construct 3D models for kinases whose crystal structures have not yet been identified. The information from structurally similar proteins was used to define the amino acid residues in the ATP binding site as well as other important sites and motifs. We searched for the comstructural motifs and domains of GSK-3β, CDK5 and PERK. Further, we identified the conserved water molecules in GSK-3β, CDK5 and PERK through calculation of the degree of water conservation. We investigated the protein-ligand interaction profiles of CDK1, CDK5, GSK-3α, GSK-3β and PERK based on molecular dynamics (MD) simulations, which provided a time-dependent demonstration of the interactions and contacts for each ligand. In addition, we explored the protein-protein interactions between CDK5 and p25. Small molecules which target this interaction may offer a prospective therapeutic benefit for AD. In order to identify new modulators for protein kinase targets in AD, we implemented three virtual screening protocols. The first protocol was a combined ligand- and protein structure-based approach to find new PERK inhibitors. In the second protocol, protein structure-based virtual screening was applied to find multiple-kinase inhibitors through parallel docking simulations into validated models of CDK1, CDK5 and GSK-3 kinases. In the third protocol, we searched for potential activators of PKC-ϵ based on the structure of its C1B domain

ICASE/LaRC Workshop on Adaptive Grid Methods

Solution-adaptive grid techniques are essential to the attainment of practical, user friendly, computational fluid dynamics (CFD) applications. In this three-day workshop, experts gathered together to describe state-of-the-art methods in solution-adaptive grid refinement, analysis, and implementation; to assess the current practice; and to discuss future needs and directions for research. This was accomplished through a series of invited and contributed papers. The workshop focused on a set of two-dimensional test cases designed by the organizers to aid in assessing the current state of development of adaptive grid technology. In addition, a panel of experts from universities, industry, and government research laboratories discussed their views of needs and future directions in this field

Monomeric and dimeric states of human ZO1-PDZ2 are functional partners of the SARS-CoV-2 E protein

: The Envelope (E) protein of SARS-CoV-2 plays a key role in virus maturation, assembly, and virulence mechanisms. The E protein is characterized by the presence of a PDZ-binding motif (PBM) at its C-terminus that allows it to interact with several PDZ-containing proteins in the intracellular environment. One of the main binding partners of the SARS-CoV-2 E protein is the PDZ2 domain of ZO1, a protein with a crucial role in the formation of epithelial and endothelial tight junctions (TJs). In this work, through a combination of analytical ultracentrifugation analysis and equilibrium and kinetic folding experiments, we show that ZO1-PDZ2 domain is able to fold in a monomeric state, an alternative form to the dimeric conformation that is reported to be functional in the cell for TJs assembly. Importantly, surface plasmon resonance (SPR) data indicate that the PDZ2 monomer is fully functional and capable of binding the C-terminal portion of the E protein of SARS-CoV-2, with a measured affinity in the micromolar range. Moreover, we present a detailed computational analysis of the complex between the C-terminal portion of E protein with ZO1-PDZ2, both in its monomeric conformation (computed as a high confidence AlphaFold2 model) and dimeric conformation (obtained from the Protein Data Bank), by using both polarizable and nonpolarizable simulations. Together, our results indicate both the monomeric and dimeric states of PDZ2 to be functional partners of the E protein, with similar binding mechanisms, and provide mechanistic and structural information about a fundamental interaction required for the replication of SARS-CoV-2

Fibre optic pressure sensors in healthcare applications

This PhD thesis provides an extensive description of the development of two fibre optic pressure sensors for applications in health care: (i) a miniature fibre optic Fabry–Perot pressure sensor for fluid pressure measurements in invasive blood pressure monitoring and; (ii) a highly sensitive fibre Bragg grating sensor for contact/interface pressure measurement. The fibre optic Fabry-Perot pressure sensor has a diameter of 125 μm and is created by forming a cavity at the tip of a single-mode optical fibre. Parylene films were used as the pressure-sensitive diaphragm. The performance of three sensors with different aspect ratios has been investigated. The pressure sensing range of ~10 kPa (diastolic pressure)- ~15 kPa (systolic pressure) was targeted; sensor with the cavity of 70 μm in diameter and cavity length of 87 μm is able to sense within a range of 0- 18 kPa with an average sensitivity of 0.12 nm/kPa and response time of 3 seconds. The temperature sensitivity of 0.084 nm/°C was observed. Hysteresis and wavelength drift were observed for the sensors, which may be due to the permeability of the Parylene film to the air. Solutions for reducing hysteresis, wavelength drift and temperature cross-sensitivity are discussed in detail. Fibre Bragg grating (FBG) sensor technology is an ideal candidate for contact pressure measurement in compression therapy, pressure ulcer or prosthetics due to its many advantages such as conforming to body parts, small size, biocompatibility and multiplexing capabilities. A successful mathematical model for an FBG contact pressure sensor for healthcare applications has been presented and experimentally validated. The model has been compared with previous studies reported in the literature and takes into account birefringence. The highest sensitivity was achieved for the disc shape with a sensitivity of 0.8719 nm/MPa for a diameter of 5.5 mm, thickness of 1 mm and Young’s modulus of 20 MPa. This sensor was comprised of a 3 mm long FBG 6 centrally located in the patch. This is a pressure sensitivity of ~270 times increase when compared with a bare FBG reported in the literature. Birefringence effect was observed for the disk patch for pressures larger than 2.6 MPa. Even though FBGs provide high sensitivity in contact pressure sensing in healthcare, the potential applications are limited by the size and cost of commercially available FBG interrogators. A successful first attempt towards the development of a single channel compact FBG interrogation was accomplished. The system consists of a three-section distributed Bragg Reflector (DBR) tuneable laser, microcontroller unit, precision 5 channel current driver IC, photodiode circuit and a temperature controller IC. The tuneable laser was calibrated within 1535-1544 nm wavelength range to produce three current–wavelength lookup tables for wavelength resolution of 1 nm, 0.1 nm, 0.01 nm which is dependent on the current resolution. Futureworkincludesaddingpowercircuitry, a photodiode circuit and a feedback circuit to minimize power fluctuations. The system was tested compared to the commercial Smartscope FBG interrogator

A Survey of Developable Surfaces: From Shape Modeling to Manufacturing

Developable surfaces are commonly observed in various applications such as architecture, product design, manufacturing, and mechanical materials, as well as in the development of tangible interaction and deformable robots, with the characteristics of easy-to-product, low-cost, transport-friendly, and deformable. Transforming shapes into developable surfaces is a complex and comprehensive task, which forms a variety of methods of segmentation, unfolding, and manufacturing for shapes with different geometry and topology, resulting in the complexity of developable surfaces. In this paper, we reviewed relevant methods and techniques for the study of developable surfaces, characterize them with our proposed pipeline, and categorize them based on digital modeling, physical modeling, interaction, and application. Through the analysis to the relevant literature, we also discussed some of the research challenges and future research opportunities.Comment: 20 pages, 24 figures, Author submitted manuscrip