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.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The lateral parabrachial nucleus (LPBN) is known to relay noxious information to the amygdala for processing affective responses. However, it is unclear whether the LPBN actively processes ...neuropathic pain characterized by persistent hyperalgesia with aversive emotional responses. Here we report that neuropathic pain-like hypersensitivity induced by common peroneal nerve (CPN) ligation increases nociceptive stimulation-induced responses in glutamatergic LPBN neurons. Optogenetic activation of GABAergic LPBN neurons does not affect basal nociception, but alleviates neuropathic pain-like behavior. Optogenetic activation of glutamatergic or inhibition of GABAergic LPBN neurons induces neuropathic pain-like behavior in naïve mice. Inhibition of glutamatergic LPBN neurons alleviates both basal nociception and neuropathic pain-like hypersensitivity. Repetitive pharmacogenetic activation of glutamatergic or GABAergic LPBN neurons respectively mimics or prevents the development of CPN ligation-induced neuropathic pain-like hypersensitivity. These findings indicate that a delicate balance between excitatory and inhibitory LPBN neuronal activity governs the development and maintenance of neuropathic pain.
Zona incerta (ZI) is a functionally mysterious subthalamic nucleus containing mostly inhibitory neurons. Here, we discover that GABAergic neurons in the rostral sector of ZI (ZIr) directly innervate ...excitatory but not inhibitory neurons in the dorsolateral and ventrolateral compartments of periaqueductal gray (PAG), which can drive flight and freezing behaviors respectively. Optogenetic activation of ZIr neurons or their projections to PAG reduces both sound-induced innate flight response and conditioned freezing response, while optogenetic suppression of these neurons enhances these defensive behaviors, likely through a mechanism of gain modulation. ZIr activity progressively increases during extinction of conditioned freezing response, and suppressing ZIr activity impairs the expression of fear extinction. Furthermore, ZIr is innervated by the medial prefrontal cortex (mPFC), and silencing mPFC prevents the increase of ZIr activity during extinction and the expression of fear extinction. Together, our results suggest that ZIr is engaged in modulating defense behaviors.
Chiral nematic liquid crystals--otherwise referred to as cholesteric liquid crystals (CLCs)--are self-organized helical superstructures that find practical application in, for example, thermography, ...reflective displays, tuneable colour filters and mirrorless lasing. Dynamic, remote and three-dimensional control over the helical axis of CLCs is desirable, but challenging. For example, the orientation of the helical axis relative to the substrate can be changed from perpendicular to parallel by applying an alternating-current electric field, by changing the anchoring conditions of the substrate, or by altering the topography of the substrate's surface; separately, in-plane rotation of the helical axis parallel to the substrate can be driven by a direct-current field. Here we report three-dimensional manipulation of the helical axis of a CLC, together with inversion of its handedness, achieved solely with a light stimulus. We use this technique to carry out light-activated, wide-area, reversible two-dimensional beam steering--previously accomplished using complex integrated systems and optical phased arrays. During the three-dimensional manipulation by light, the helical axis undergoes, in sequence, a reversible transition from perpendicular to parallel, followed by in-plane rotation on the substrate surface. Such reversible manipulation depends on experimental parameters such as cell thickness, surface anchoring condition, and pitch length. Because there is no thermal relaxation, the system can be driven either forwards or backwards from any light-activated intermediate state. We also describe reversible photocontrol between a two-dimensional diffraction state, a one-dimensional diffraction state and a diffraction 'off' state in a bilayer cell.
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IJS, KISLJ, NUK, SBMB, UL, UM, UPUK
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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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The presence of DNA in the cytoplasm is normally a sign of microbial infections and is quickly detected by cyclic GMP-AMP synthase (cGAS) to elicit anti-infection immune responses. However, chronic ...activation of cGAS by self-DNA leads to severe autoimmune diseases for which no effective treatment is available yet. Here we report that acetylation inhibits cGAS activation and that the enforced acetylation of cGAS by aspirin robustly suppresses self-DNA-induced autoimmunity. We find that cGAS acetylation on either Lys384, Lys394, or Lys414 contributes to keeping cGAS inactive. cGAS is deacetylated in response to DNA challenges. Importantly, we show that aspirin can directly acetylate cGAS and efficiently inhibit cGAS-mediated immune responses. Finally, we demonstrate that aspirin can effectively suppress self-DNA-induced autoimmunity in Aicardi-Goutières syndrome (AGS) patient cells and in an AGS mouse model. Thus, our study reveals that acetylation contributes to cGAS activity regulation and provides a potential therapy for treating DNA-mediated autoimmune diseases.
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•Acetylation suppresses cGAS activity•Aspirin directly acetylates cGAS•Aspirin inhibits cGAS-mediated interferon production•Aspirin alleviates DNA-induced autoimmunity in AGS mouse models and patient cells
Activation of the DNA sensor cGAS requires a deacetylation step, and its aspirin-induced acetylation can limit innate immune responses.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Tumor necrosis factor (TNF) is an important inflammatory cytokine and induces many cellular responses, including inflammation, cell proliferation, apoptosis, and necrosis. It is known that receptor ...interacting protein (RIP) kinases, RIP1 and RIP3, are key effectors of TNF-induced necrosis, but little is known about how these two RIP kinases mediate this process, although reactive oxygen species (ROS) generation and JNK activation have been suggested to be two downstream events of RIP kinases. Here we report the identification of mixed lineage kinase domain-like, MLKL, as a key RIP3 downstream component of TNF-induced necrosis. Through screening a kinase/phosphatase shRNA library in human colon adenocarcinoma HT-29 cells, we found that knockdown of MLKL blocked TNF-induced necrosis. Our data suggest that MLKL functions downstream of RIP1 and RIP3 and is recruited to the necrosome through its interaction with RIP3. Finally, we found that MLKL is required for the generation of ROS and the late-phase activation of JNK during TNF-induced necrosis. However, because these two events are not involved in TNF-induced necrosis in HT-29 cells, the target of MLKL during TNF-induced necrosis remains elusive. Taken together, our study suggests that MLKL is a key RIP3 downstream component of TNF-induced necrotic cell death.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
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.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Aggravated behaviors of hepatocellular carcinoma (HCC) will occur after inadequate thermal ablation. However, its underlying mechanisms are not fully understood. Here, we assessed whether the ...increased matrix stiffness after thermal ablation could promote the progression of residual HCC. Heat‐treated residual HCC cells were cultured on tailorable 3D gel with different matrix stiffness, simulating the changed physical environment after thermal ablation, and then the mechanical alterations of matrix stiffness on cell phenotypes were explored. Increased stiffness was found to significantly promote the proliferation of the heat‐treated residual HCC cells when the cells were cultured on stiffer versus soft supports, which was associated with stiffness‐dependent regulation of ERK phosphorylation. Heat‐exposed HCC cells cultured on stiffer supports showed enhanced motility. More importantly, vitamin K1 reduced stiffness‐dependent residual HCC cell proliferation by inhibiting ERK phosphorylation and suppressed the in vivo tumor growth, which was further enhanced by combining with sorafenib. Increased matrix stiffness promotes the progression of heat‐treated residual HCC cells, proposing a new mechanism of an altered biomechanical environment after thermal ablation accelerates HCC development. Vitamin K1 plus sorafenib can reverse this protumor effect.
Increased matrix stiffness after thermal ablation accelerates the progression of heat‐exposed residual HCC cells. Vitamin K1 and sorafenib disrupt the stiffness‐induced ERK activation to reverse the pro‐tumor effect as the potential therapeutic drugs. This new finding will help design strategy to treat the local tumor progression and prevent its rapid progression after RFA in the treatment of medium or large HCC.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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