Cancer remains as one of the most significant health problems, with approximately 19 million people diagnosed worldwide each year. Chemotherapy is a routinely used method to treat cancer patients. ...However, current treatment options lack the appropriate selectivity for cancer cells, are prone to resistance mechanisms, and are plagued with dose-limiting toxicities. As such, researchers have devoted their attention to developing prodrug-based strategies that have the potential to overcome these limitations. This tutorial review highlights recently developed prodrug strategies for cancer therapy. Prodrug examples that provide an integrated diagnostic (fluorescent, photoacoustic, and magnetic resonance imaging) response, which are referred to as theranostics, are also discussed. Owing to the non-invasive nature of light (and X-rays), we have discussed external excitation prodrug strategies as well as examples of activatable photosensitizers that enhance the precision of photodynamic therapy/photothermal therapy. Activatable photosensitizers/photothermal agents can be seen as analogous to prodrugs, with their phototherapeutic properties at a specific wavelength activated in the presence of disease-related biomarkers. We discuss each design strategy and illustrate the importance of targeting biomarkers specific to the tumour microenvironment and biomarkers that are known to be overexpressed within cancer cells. Moreover, we discuss the advantages of each approach and highlight their inherent limitations. We hope in doing so, the reader will appreciate the current challenges and available opportunities in the field and inspire subsequent generations to pursue this crucial area of cancer research.
This tutorial review provides a general overview for the design of prodrugs and activatable phototherapeutics which enables the development of improved therapies.
Amino acids are required for activation of the mammalian target of rapamycin (mTOR) kinase, which regulates protein translation, cell size, and autophagy. However, the amino acid sensor that directly ...couples intracellular amino acid-mediated signaling to mTORC1 is unknown. Here we show that leucyl-tRNA synthetase (LRS) plays a critical role in amino acid-induced mTORC1 activation by sensing intracellular leucine concentration and initiating molecular events leading to mTORC1 activation. Mutation of LRS amino acid residues important for leucine binding renders the mTORC1 pathway insensitive to intracellular levels of amino acids. We show that LRS directly binds to Rag GTPase, the mediator of amino acid signaling to mTORC1, in an amino acid-dependent manner and functions as a GTPase-activating protein (GAP) for Rag GTPase to activate mTORC1. This work demonstrates that LRS is a key mediator for amino acid signaling to mTORC1.
Display omitted
► Leucyl-tRNA synthetase (LRS) senses leucine for mTORC1 signaling ► mTORC1 activity, lysosomal localization, cell size, and autophagy are regulated by LRS ► LRS acts as GTPase-activating protein (GAP) for RagD GTPase, an mTORC1 regulator ► The interaction between LRS and RagD GTPase is amino acid dependent
In response to leucine, leucyl-tRNA synthetase activates the mTORC1 pathway by acting as a GTPase-activating protein for a component of mTORC1. The findings reveal a mechanism for transducing amino acid availability to TOR signaling.
Color is everything: Hg2+ in aqueous media is detected by the formation of thymidine–Hg2+–thymidine coordination complexes, which raises the melting temperature of the DNA‐hybridized gold ...nanoparticle probes and thus the temperature at which the probes disperse and effect a purple‐to‐red color change. The method has very high sensitivity and selectivity, and it provides a simple and fast colorimetric readout (see picture).
Phenotypic plasticity is a crucial adaptive mechanism that enables organisms to modify their traits in response to changes in their environment. Predator-induced defenses are an example of phenotypic ...plasticity observed across a wide range of organisms, from single-celled organisms to vertebrates. In addition to morphology and behavior, these responses also affect life-history traits. The crustacean Daphnia galeata is a suitable model organism for studying predator-induced defenses, as it exhibits life-history traits changes under predation risk. To get a better overview of their phenotypic plasticity under predation stress, we conducted RNA sequencing on the transcriptomes of two Korean Daphnia galeata genotypes, KE1, and KB11, collected in the same environment. When exposed to fish kairomones, the two genotypes exhibited phenotypic variations related to reproduction and growth, with opposite patterns in growth-related phenotypic variation. From both genotypes, a total of 135,611 unigenes were analyzed, of which 194 differentially expressed transcripts (DETs) were shared among the two genotypes under predation stress, which showed consistent, or inconsistent expression patterns in both genotypes. Prominent DETs were related to digestion and reproduction and consistently up-regulated in both genotypes, thus associated with changes in life-history traits. Among the inconsistent DETs, transcripts encode vinculin (VINC) and protein obstructor-E (OBST-E), which are associated with growth; these may explain the differences in life-history traits between the two genotypes. In addition, genotype-specific DETs could explain the variation in growth-related life-history traits between genotypes, and could be associated with the increased body length of genotype KE1. The current study allows for a better understanding of the adaptation mechanisms related to reproduction and growth of two Korean D. galeata genotypes induced by predation stress. However, further research is necessary to better understand the specific mechanisms by which the uncovered DETs are related with the observed phenotypic variation in each genotype. In the future, we aim to unravel the precise adaptive mechanisms underlying predator-induced responses.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Ferroelectric field-effect transistor (FeFET) is a promising nonvolatile memory device because of its CMOS compatibility, scalability, and energy efficiency. However, the device physics has not been ...studied well, which hinders FeFET development and process design kit (PDK) construction. In this article, we report a comprehensive understanding of the n/p-FeFET operation mechanism as a nonvolatile memory device, for the first time, based on quasi-static split CV measurement. We also suggest a new methodology to examine the device and show the existence of excess trapped charge and the true nonvolatile polarization. Furthermore, we found that charge trapping is necessary to switch polarization in FeFET. Finally, based on our physical findings and insights, we propose a new erase mode that leads to a wider memory window and higher write endurance (> 10 10 cycles), even without optimizing the device fabrication process.
•We propose a virtual sensing procedure for real-time strain field estimation.•Strain field is estimated with high accuracy using several strain gauges attached to the structure.•The effectiveness of ...the proposed procedure is assessed through experimental tests under water waves.
This study aims to achieve real-time estimation of the full-field strain distribution in a structure by signals measured from several strain gauges attached to the structure. Our virtual sensing procedure is developed based on finite element formulation and employs the mode superposition approach. To verify the feasibility of the proposed procedure, numerical and experimental tests are conducted on a laboratory-scale offshore jacket structure subjected to water waves. Key aspects addressed in this study include the selection of displacement modes and the division of strain signals. The experiments are performed in an ocean basin, and comprehensive explanations are provided for the jacket prototype design, implementations, experimental setup, and wave loading conditions. The performance of the proposed virtual sensing procedure is thoroughly assessed through various evaluation measures, enhancing the understanding of its capabilities and limitations in practical applications.
In this study, a draping simulation technique that can reflect the mechanical behavior of uncured woven fabric prepregs, including bending characteristics, was implemented using non-orthogonal ...constitutive VUMAT code and a lay-up shell model. The basic mechanical properties of uncured woven fabric prepregs were accurately obtained through uniaxial tensile, picture frame shear, and cantilever bending tests for the draping simulation. The major moduli of the uncured fabric prepregs were derived from semi-empirical formulae, and the mechanical properties of the lay-up shell element were estimated by using the rule of mixture for all layers. Using the proposed simulation technique, the drapability and wrinkle generation qualities of a fabric composite structure with a complex geometry, i.e., an egg-box panel, were estimated according to the initial draping orientation (30° and 45°), and the simulation results were experimentally validated.
Purpose
Many conventional ex vivo magnetic resonance imaging (MRI) setups utilize cylindrical or other nonspherical tissue containers which can cause static field (B0) inhomogeneity affecting the ...accuracy of the measurements in an orientation‐dependent manner. In this work we demonstrate an experimental method to obtain MRI of ex vivo tissue samples held in a spherical container in order to minimize bulk susceptibility‐induced B0 inhomogeneity in arbitrary orientations.
Methods
B0 inhomogeneity caused by tissue‐air susceptibility mismatch can be theoretically eliminated if the surface of susceptibility discontinuity is spherical. This situation can be approximated by putting a tissue sample in a spherical shell filled with materials with tissue‐like magnetic susceptibility. We achieved this on an intact monkey brain by (a) holding the brain with a three‐dimensional (3D)‐printed holder with tissue‐like (within 0.5 ppm) susceptibility, and (b) enclosing the brain and the holder in an acrylic spherical shell filled with diamagnetic liquid. Furthermore, the sphere and the radio‐frequency coil for MRI were mounted on a 3D‐printed frame designed to reduce B0 inhomogeneity contributions. The sphere could be rotated freely without disturbing the RF coil to facilitate multi‐orientation imaging. We verified our setup by mapping B0 in the monkey brain at 13 different orientations in a human 7T scanner, and measuring orientation‐dependent
R2∗ relaxation rates in the white and gray matters of the brain. The results were then compared with a setup where the brain was held inside a cylindrical container.
Results
In all orientations, the B0 standard deviation in the brain in the spherical setup (converted to Larmor frequency offset) was less than about 10 Hz. This corresponds to two‐sigma deviation of B0 of <0.07 ppm. The B0 gradient was <9 Hz/mm in 95 % of the brain voxels in all orientations. In high‐resolution imaging with e.g. voxel size <0.4 mm, this corresponds to voxel line broadening of <4 Hz (0.013 ppm).
R2∗ in the corpus callosum showed distinctly different orientation dependence compared to the gray matter. The B0 uniformity and
R2∗ reliability were much reduced in the cylindrical container setup.
Conclusions
We have demonstrated an experimental method to effectively minimize bulk susceptibility‐induced B0 perturbation in multi‐orientation ex vivo MRI. The method promises to benefit a range of tissue orientation‐dependent MR property studies.
Biodegradable composites of unidirectionally reinforced 50-Mg/PLA (50% Mg wire by volume) were investigated to replace conventional non-degradable metallic implants for fixing long-bone fractures. ...This study presents the advantages of fluoride-coated magnesium alloy AZ31 wires in unidirectionally reinforced Mg/PLA biodegradable composites. The samples were also evaluated for degradation over a duration of 56 days by immersion in phosphate buffered saline solution at the human body temperature of 37 °C; variations in wet mass, dry mass, and pH were used as the indicators for degradation. The 50-C-Mg/PLA composite (with coated wires) suppressed mass loss, controlled the pH, and promoted the deposition of Ca and P compounds. Further, the retention of tensile and flexural properties significantly improved for the immersion period as the interface was better protected by the coating. The results indicate that the 50-C-Mg/PLA composite has good potential as a biodegradable implant for load-bearing bone fractures.
In recent years, biodegradable materials have garnered increasing attention from researchers for use as orthopedic implants. In this study, the fabrication of unidirectional magnesium alloy (AZ31) ...wire-reinforced poly(lactic acid) (PLA) composites by lamina stacking is presented for bone fracture healing. The tensile and flexural properties of unidirectional composites with wire volume contents of 20%, 30%, 40%, and 50% were measured. Under the simulated human body temperature of 37 °C and accelerated environment of 50 °C, the degradation behaviors of 50-Mg/PLA composite (50% Mg wires by volume) and pure PLA were evaluated by testing water uptake, mass loss, and pH variation. Scanning electron microscopy helped to understand the fracture mode and degradation of magnesium wires inside the composites. Moreover, energy-dispersive spectroscopy confirmed the formation of an apatite layer that mainly consisted of a Ca-P phase deposited on the composite surface and wires, which is essential for bone healing.
PDF
