4 research outputs found
Unraveling the Mechanical Property Decrease of Electrospun Spider Silk: A Molecular Dynamics Simulation Study
This
study investigated the impact of electric fields on Nephila
clavipes spider silk using molecular dynamics modeling.
Electric fields with varying amplitudes and directions were observed
to disrupt the β sheet structure of spider silk and reduce its
mechanical properties. However, a notable exception was observed when
a 0.1 V/nm electric field was applied in the antiparallel direction,
resulting in improvements in Young’s modulus and ultimate tensile
strength. The antiparallel direction was observed to be particularly
sensitive to electric fields, causing disruptions in beta sheets and
hydrogen bonds, which significantly influence the mechanical properties.
This study demonstrates that spider silk maintains its structural
integrity at 0.1 V/nm. Possibly, lowering the power levels of typical
electrospinning machines can prevent secondary structural disruption.
These findings provide valuable insights for enhancing silk fiber
production and applications using natural silk proteins while shedding
light on the impact of electric fields on other silk proteins. Finally,
this study opens up possibilities for optimizing electrospinning processes
to enhance performance in various silk electrospinning applications
Discovery and Design of First Benzylamine-Based Ligands Binding to an Unlocked Conformation of the Complement Factor D
Complement
Factor D, a serine protease of the S1 family and key
component of the alternative pathway amplification loop, represents
a promising target for the treatment of several prevalent and rare
diseases linked to the innate immune system. Previously reported FD
inhibitors have been shown to bind to the FD active site in its self-inhibited
conformation characterized by the presence of a salt bridge at the
bottom of the S1 pocket between Asp189 and Arg218. We report herein
a new set of small-molecule FD ligands that harbor a basic S1 binding
moiety directly binding to the carboxylate of Asp189, thereby displacing
the Asp189-Arg218 ionic interaction and significantly changing the
conformation of the self-inhibitory loop
MerTK mediates STAT3–KRAS/SRC-signaling axis for glioma stem cell maintenance
<p>Receptor tyrosine kinase Mer (MerTK) has been shown to be highly expressed in Glioblastoma multiforme (GBM) in comparison to its healthy counterpart and is implicated in brain tumorigenesis. Clarifying the underlying mechanism of MerTK induced invasiveness would result in novel strategies to improve patient’s response to chemotherapeutics. <i>In vitro</i> and <i>in vivo</i> assays were performed to examine the functional role of cancer stem sell (CSC) maintenance in MerTK associated invasiveness. In this article, we demonstrate that apart from GBM cells, MerTK is also upregulated in GBM stem-like cells and associated with an increased infiltrative potential of brain tumors <i>in vivo</i>. Silencing of MerTK suppressed the self-renewal of patient-derived GBM stem-like cells. The signaling mechanisms by which MerTK contributes to CSC maintenance have largely been obscure. Molecular analyses revealed that high expression of the signal transducer and activator of transcription 3 (STAT3)- Kirsten rat sarcoma viral oncogene homolog (KRAS) and proto-oncogene tyrosine-protein kinase SRC axis supports MerTK-induced CSC maintenance in GBM spheroids. Furthermore, a short-hairpin RNA-mediated MerTK knockdown effectively blocked invasiveness and N-cadherin expression in mouse xenografts. Collectively, our results uncover a critical function of MerTK in CSC maintenance. Considering the low basal level of MerTK expression in healthy brain cells, evaluation of MerTK as a therapeutic target should advance the research into better therapeutics for GBM.</p
Intestinally Targeted Diacylglycerol Acyltransferase 1 (DGAT1) Inhibitors Robustly Suppress Postprandial Triglycerides
High DGAT1 expression levels in the small intestine highlight
the
critical role this enzyme plays in nutrient absorption. Identification
of inhibitors which predominantly inhibit DGAT1 in the gut is an attractive
drug discovery strategy with anticipated benefits of reduced systemic
toxicity. In this report we describe our discovery and optimization
of DGAT1 inhibitors whose plasma exposure is minimized by the action
of transporters, including the P-glycoprotein transporter. The impact
of this unique absorption profile on efficacy in rat and dog efficacy
models is presented