Despite rapid advancements in the field of nanotechnology, there is mounting frustration in the scientific community regarding the translational impact of nanomedicine. Modest therapeutic performance ...of FDA-approved nanomedicines combined with multiple disappointing clinical trials (such as phase III HEAT trial) have raised questions about the future of nanomedicine. Encouraging breakthroughs, however, have been made in the last few years towards the development of new classes of nanoparticles that can respond to tumor microenvironmental conditions and successfully deliver therapeutic agents to cancer cells. Concurrently, a great deal of effort has also been devoted to alter various parameters of tumor pathophysiology to pre-treat tumors before nanoparticles are administered. Such ‘priming’ treatments improve access of the systemically administered agents to the tumor and promote drug penetration into the deeper layers of tumor tissue. This review will highlight recent advances in cancer nanomedicine exploiting both nanoparticle design and tumor microenvironment modification; and provide a critical perspective on the future development of nanomedicine delivery in oncology.
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Mesogenic soft materials, having single or multiple mesogen moieties per molecule, commonly exhibit typical self‐organization characteristics, which promotes the formation of elegant helical ...superstructures or supramolecular assemblies in chiral environments. Such helical superstructures play key roles in the propagation of circularly polarized light and display optical properties with prominent handedness, that is, chiro‐optical properties. The leveraging of light to program the chiro‐optical properties of such mesogenic helical soft materials by homogeneously dispersing photosensitive chiral material into an achiral soft system or covalently connecting photochromic moieties to the molecules has attracted considerable attention in terms of materials, properties, and potential applications and has been a thriving topic in both fundamental science and application engineering. State‐of‐the‐art technologies are described in terms of the material design, synthesis, properties, and modulation of photoprogrammable chiro‐optical mesogenic soft helical architectures. Additionally, the scientific issues and technical problems that hinder further development of these materials for use in various fields are outlined and discussed. Such photoprogrammable mesogenic soft helical materials are competitive candidates for use in stimulus‐controllable chiro‐optical devices with high optical efficiency, stable optical properties, and easy miniaturization, facilitating the future integration and systemization of chiro‐optical chips in photonics, photochemistry, biomedical engineering, chemical engineering, and beyond.
Photoprogrammable mesogenic helical soft materials with both photosensitive and mesogenic moieties in molecules possess typical chiro‐optical properties, showing handedness dependency on the transmission, reflection, and absorption of an incident circularly polarized light (photonic bandgap and circular dichroism). This can be modulated readily by light irradiation, thus paving the way toward future chiro‐optical devices and systems.
The vital role optical and phototonic technologies have played in medical advances is addresed, as are modern phototheranostic applications. Topics addressed include phototheranostic techniques ...involving singlet state radiative relaxation, phototheranostic techniques involving singlet state radiative relaxation and phototheranostic techniques involving vibrational relaxation.
The mixed lineage kinase domain-like protein (MLKL) has recently been identified as a key RIP3 (receptor interacting protein 3) downstream component of tumour necrosis factor (TNF)-induced ...necroptosis. MLKL is phosphorylated by RIP3 and is recruited to the necrosome through its interaction with RIP3. However, it is still unknown how MLKL mediates TNF-induced necroptosis. Here, we report that MLKL forms a homotrimer through its amino-terminal coiled-coil domain and locates to the cell plasma membrane during TNF-induced necroptosis. By generating different MLKL mutants, we demonstrated that the plasma membrane localization of trimerized MLKL is critical for mediating necroptosis. Importantly, we found that the membrane localization of MLKL is essential for Ca(2+) influx, which is an early event of TNF-induced necroptosis. Furthermore, we identified that TRPM7 (transient receptor potential melastatin related 7) is a MLKL downstream target for the mediation of Ca(2+) influx and TNF-induced necroptosis. Hence, our study reveals a crucial mechanism of MLKL-mediated TNF-induced necroptosis.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
In this paper, a sensorless output feedback controller is designed in order to drive the induction motor (IM) without the use of flux and speed sensors. First, a new sliding-mode observer that uses ...only the measured stator currents is synthesized to estimate the speed, flux, and load torque. Second, a current-based field-oriented sliding-mode control is developed so as to steer the estimated speed and flux magnitude to the desired references. A stability analysis based on the Lyapunov theory is also presented in order to guarantee the closed-loop stability of the proposed observer-control system. Two experimental results for a 1.5-kW IM are presented and analyzed by taking into account the unobservability phenomena of the sensorless IM.
Background and Purpose
Necroptosis is a form of programmed, caspase‐independent, cell death, mediated by receptor‐interacting protein kinases, RIPK1 and RIPK3, and the mixed lineage kinase ...domain‐like (MLKL). Necroptosis contributes to the pathophysiology of various inflammatory, infectious, and degenerative diseases. Thus, identification of low MW inhibitors for necroptosis has broad therapeutic relevance. Here, we identified that the pan‐Raf inhibitor TAK‐632 was also an inhibitor of necroptosis. We have further generated a more selective, highly potent analogue of TAK‐632 by targeting RIPK1 and RIPK3.
Experimental Approach
Cell viability was measured by MTT, propidium staining, or CellTiter‐Glo luminescent assays. Effects of TAK‐632 on necroptosis signalling pathways were investigated by western blotting, immunoprecipitation, and in vitro kinase assays. Downstream targets of TAK‐632 were identified by a drug affinity responsive target stability assay and a pull‐down assay with biotinylated TAK‐632. A mouse model of TNF‐α‐induced systemic inflammatory response syndrome (SIRS) was further used to explore the role of TAK‐632 in protecting against necroptosis‐associated inflammation in vivo.
Key Results
TAK‐632 protected against necroptosis in human and mouse cells but did not protect cells from apoptosis. TAK‐632 directly bound with RIPK1 and RIPK3 to inhibit kinase activities of both enzymes. In vivo, TAK‐632 alleviated TNF‐induced SIRS. Furthermore, we performed a structure–activity relationship analysis of TAK‐632 analogues and generated SZM594, a highly potent inhibitor of RIPK1/3.
Conclusions and Implications
TAK‐632 is an inhibitor of necroptosis and represents a new lead compound in the development of highly potent inhibitors of RIPK1 and RIPK3.
Differentiation to different types of macrophages determines their distinct functions. Tumor-associated mac- rophages （TAMs） promote tumorigenesis owing to their proangiogenic and immune-suppressive ...functions similar to those of alternatively activated （M2） macrophages. We report that reactive oxygen species （ROS） production is criti- cal for macrophage differentiation and that inhibition of superoxide （02-） production specifically blocks the differ- entiation of M2 macrophages. We found that when monocytes are triggered to differentiate, 02- is generated and is needed for the biphasic ERK activation, which is critical for macrophage differentiation. We demonstrated that ROS elimination by butylated hydroxyanisole （BHA） and other ROS inhibitors blocks macrophage differentiation. How- ever, the inhibitory effect of ROS elimination on macrophage differentiation is overcome when cells are polarized to classically activated （M1）, but not M2, macrophages. More importantly, the continuous administration of the ROS inhibitor BHA efficiently blocked the occurrence of TAMs and markedly suppressed tumorigenesis in mouse cancer models. Targeting TAMs by blocking ROS can be a potentially effective method for cancer treatment.
•Porphysome nanovesicles are generated by porphyrin-lipid bilayers.•Porphyrin-lipid imparts unprecedented photonic properties to lipid nanoparticles.•Metal chelation of porphyrin-lipid unlocks ...porphysomes’ potential for PET and MRI.•The simple yet intrinsic multimodal nature of porphysomes facilitates their clinical translation.•Porphyrin-lipid supramolecular assembly expands beyond porphysome nanotechnology.
The traditional role of lipids in the generation of lipid-based supramolecular structures has predominantly been to serve as building blocks to support the delivery or stabilization of a molecule or structure. With an introduction to the synthesis of porphyrin-lipid, a porphyrin conjugated to a phospholipid, and the discovery of porphysome nanovesicles, the role of phospholipids in supramolecular structures has shifted from a simple support to an intrinsic imaging and therapeutic agent. Here we provide an overview of recent developments in the generation of supramolecular structures using porphyrin-lipid and their applications in therapy and imaging, including photothermal therapy, photoacoustic imaging, multimodality imaging and activatable fluorescence imaging and photodynamic therapy. Furthermore, we introduce several new developments within the field of using organic nanoparticles for thermal-based biomedical applications using other organic nanomaterials.
To decipher neural circuits underlying brain functions, viral tracers are widely applied to map input and output connectivity of neuronal populations. Despite the successful application of retrograde ...transsynaptic viruses for identifying presynaptic neurons of transduced neurons, analogous anterograde transsynaptic tools for tagging postsynaptically targeted neurons remain under development. Here, we discovered that adeno-associated viruses (AAV1 and AAV9) exhibit anterograde transsynaptic spread properties. AAV1-Cre from transduced presynaptic neurons effectively and specifically drives Cre-dependent transgene expression in selected postsynaptic neuronal targets, thus allowing axonal tracing and functional manipulations of the latter input-defined neuronal population. Its application in superior colliculus (SC) reveals that SC neuron subpopulations receiving corticocollicular projections from auditory and visual cortex specifically drive flight and freezing, two different types of defense behavior, respectively. Together with an intersectional approach, AAV-mediated anterograde transsynaptic tagging can categorize neurons by their inputs and molecular identity, and allow forward screening of distinct functional neural pathways embedded in complex brain circuits.
•AAV1 and AAV9 exhibit anterograde transsynaptic spread properties•AAV1-Cre can transsynaptically tag input-defined postsynaptic neurons•Corticocollicular input-defined SC neurons mediate different defense behaviors•With an intersectional approach, the tagging can be postsynaptic cell-type specific
Zingg et al. revealed anterograde transsynaptic spread properties of adeno-associated viruses. This novel viral application is useful for tracing and manipulating neural circuits in a postsynaptic cell-type- and input-specific manner, thus facilitating dissection of neural circuits underlying different behaviors.
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