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Transforming growth factor β-1 (TGFβ-1) is a secreted signalling protein that directs many cellular processes and is an attractive target for the treatment of several diseases. The primary endogenous activity regulatory mechanism for TGFβ-1 is sequestration by its pro-peptide, latency-associated peptide (LAP), which sterically prohibits receptor binding by caging TGFβ-1. As such, recombinant LAP is promising as a protein-based therapeutic for modulating TGFβ-1 activity; however, the mechanism of binding is incompletely understood. Comparison of the crystal structure of unbound LAP (solved here to 3.5 Å resolution) with that of the bound complex shows that LAP is in a more open and extended conformation when unbound to TGFβ-1. Analysis suggests a mechanism of binding TGFβ-1 through a large-scale conformational change that includes contraction of the inter-monomer interface and caging by the `straight-jacket' domain that may occur in partnership through a loop-to-helix transition in the core jelly-roll fold. This conformational change does not appear to include a repositioning of the integrin-binding motif as previously proposed. X-ray scattering-based modelling supports this mechanism and reveals possible orientations and ensembles in solution. Although native LAP is heavily glycosylated, solution scattering experiments show that the overall folding and flexibility of unbound LAP are not influenced by glycan modification. The combination of crystallography, solution scattering and biochemical experiments reported here provide insight into the mechanism of LAP sequestration of TGFβ-1 that is of fundamental importance for therapeutic development.
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Anomalous mass dependence of phonon thermal transport in lanthanum monopnictides and its origin in the nature of chemical bonding
Metavalent descriptors of LaP exhibit a stronger pressure dependence than those of LaBi. Strong anharmonicity in LaP bonds come from its antibonding π* valence bands. These features in LaP make its thermal conductivity lower than LaBi.
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- Award ID(s):
- 2103989
- PAR ID:
- 10539252
- Publisher / Repository:
- ACS
- Date Published:
- Journal Name:
- Journal of Materials Chemistry A
- ISSN:
- 2050-7488
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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Taxol, a formulation of paclitaxel (PTX), is one of the most widely used anticancer drugs, particularly for treating recurring ovarian carcinomas following surgery. Clinically, PTX is used in combination with other drugs such as lapatinib (LAP) to increase treatment efficacy. Delivering drug combinations with nanoparticles has the potential to improve chemotherapy outcomes. In this study, we use Flash NanoPrecipitation, a rapid, scalable process to encapsulate weakly hydrophobic drugs (logP < 6) PTX and LAP into polymer nanoparticles with a coordination complex of tannic acid and iron formed during the mixing process. We determine the formulation parameters required to achieve uniform nanoparticles and evaluate the drug release in vitro. The size of the resulting nanoparticles was stable at pH 7.4, facilitating sustained drug release via first-order Fickian diffusion. Encapsulating either PTX or LAP into nanoparticles increases drug potency (as indicated by the decrease in IC-50 concentration); we observe a 1500-fold increase in PTX potency and a six-fold increase in LAP potency. When PTX and LAP are co-loaded in the same nanoparticle, they have a synergistic effect that is greater than treating with two single-drug-loaded nanoparticles as the combination index is 0.23 compared to 0.40, respectively.more » « less
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UV radiation (UVR) has significant physiological effects on organisms living at or near the Earth’s surface, yet the full suite of genes required for fitness of a photosynthetic organism in a UVR-rich environment remains unknown. This study reports a genome-wide fitness assessment of the genes that affect UVR tolerance under environmentally relevant UVR dosages in the model cyanobacterium Synechococcus elongatus PCC 7942. Our results highlight the importance of specific genes that encode proteins involved in DNA repair, glutathione synthesis, and the assembly and maintenance of photosystem II, as well as genes that encode hypothetical proteins and others without an obvious connection to canonical methods of UVR tolerance. Disruption of a gene that encodes a leucyl aminopeptidase (LAP) conferred the greatest UVR-specific decrease in fitness. Enzymatic assays demonstrated a strong pH-dependent affinity of the LAP for the dipeptide cysteinyl-glycine, suggesting an involvement in glutathione catabolism as a function of night-time cytosolic pH level. A low differential expression of the LAP gene under acute UVR exposure suggests that its relative importance would be overlooked in transcript-dependent screens. Subsequent experiments revealed a similar UVR-sensitivity phenotype in LAP knockouts of other organisms, indicating conservation of the functional role of LAPs in UVR tolerance.more » « less
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null (Ed.)Many inverse problems involve two or more sets of variables that represent different physical quantities but are tightly coupled with each other. For example, image super-resolution requires joint estimation of the image and motion parameters from noisy measurements. Exploiting this structure is key for efficiently solving these large-scale optimization problems, which are often ill-conditioned. In this paper, we present a new method called Linearize And Project (LAP) that offers a flexible framework for solving inverse problems with coupled variables. LAP is most promising for cases when the subproblem corresponding to one of the variables is considerably easier to solve than the other. LAP is based on a Gauss–Newton method, and thus after linearizing the residual, it eliminates one block of variables through projection. Due to the linearization, this block can be chosen freely. Further, LAP supports direct, iterative, and hybrid regularization as well as constraints. Therefore LAP is attractive, e.g., for ill-posed imaging problems. These traits differentiate LAP from common alternatives for this type of problem such as variable projection (VarPro) and block coordinate descent (BCD). Our numerical experiments compare the performance of LAP to BCD and VarPro using three coupled problems whose forward operators are linear with respect to one block and nonlinear for the other set of variables.more » « less
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- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1039/d4ta04146a
