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Many studies have been conducted to demonstrate the survival processing advantage (SPA) as an evolutionary-oriented memory effect. But few studies were conducted to demonstrate this effect in real-life or simulated survival environments. This study tested whether the SPA could be replicated in a survival virtual reality environment (VRE). In Experiment 1, the SPAs were measured in VREs (survival grasslands, survival battlefield, nonsurvival moving) in which Experiment 1A used the standard long instructions and Experiment 1B used the modified short instructions. In Experiment 2, the SPAs were measured again with the scenarios corresponding to the VREs used in Experiment 1A. All experiments demonstrated typical SPAs, suggesting that the survival VRE is a reliable tool in designing and delivering a survival situation. The potential problems of applying survival VRE to survival processing research are discussed at the end.

Light-activable spatiotemporal control of PROTAC-induced protein degradation was achieved with novel arylazopyrazole photoswitchable PROTACs (AP-PROTACs). The use of a promiscuous kinase inhibitor in the design enables this unique photoswitchable PROTAC to selectively degrade four protein kinases together with on/off optical control using different wavelengths of light.

Millirobots that can be actuated and accurately steered by external magnetic fields, are highly desirable for bioengineering and wearable devices. However, existing designs of millirobots are limited by their specific material composition, hindering their wider application due to a lack of scalability. Here, we present a method for the generation of heterogeneous magnetic millirobots based on magnetic coatings. The coatings, composed of hard-magnetic CrO

Gating systems have been extensively researched in energy harvesting, lab-on-chip applications, and so forth. However, the controlled drug delivery system with artificial hydrogel-based porous gating systems (HPGSs) is rarely reported. Herein, a biomimetic HPGS with a pH-responsive hydrogel as the valve and polydimethylsiloxane as the frame is fabricated by in situ femtosecond laser microdrilling and subsequent ultraviolet exposure. The proposed HPGS loaded with doxorubicin hydrochloride (DOX) is stable under physiological conditions, has a low drug leakage rate, and can achieve sustained drug release in a low pH environment. The experimental results show that the drug release is mainly controlled by non-Fickian diffusion, which renders the dynamic speed control of molecular transport possible. Moreover, the HPGS can also be prepared into an antitumor microcapsule. The results of in vitro cell experiments demonstrate that DOX@HPGS can release drugs and achieve terrific therapeutic efficacy in the elimination of HeLa cells in the acidic environments around tumor cells. This functional HPGS is envisioned to be an ideal pH-response carrier for sustained drug release treatment of digestive diseases such as inflammatory bowel disease and gastrointestinal cancer.

Functional microdevices based on responsive hydrogel show great promise in targeted delivery and biomedical analysis. Among state-of-the-art techniques for manufacturing hydrogel-based microarchitectures, femtosecond laser two-photon polymerization distinguishes itself by high designability and precision, but the point-by-point writing scheme requires mechanical apparatuses to support focus scanning. In this work, by predesigning holograms combined with lens phase modulation, multiple femtosecond laser spots are holographically generated and shifted for prototyping of three-dimensional shape-morphing structures without any moving equipment in the construction process. The microcage array is rapidly fabricated for high-performance target capturing enabled by switching environmental pH. Moreover, the built scaffolds can serve as arrayed analytical platforms for observing cell behaviors in normal or changeable living spaces or revealing the anticancer effects of loaded drugs. The proposed approach opens a new path for facile and flexible manufacturing of hydrogel-based functional microstructures with great versatility in micro-object manipulation.

The mammalian membrane‐bound O‐acyltransferase (MBOAT) superfamily is involved in biological processes including growth, development and appetite sensing. MBOATs are attractive drug targets in cancer and obesity; however, information on the binding site and molecular mechanisms underlying small‐molecule inhibition is elusive. This study reports rational development of a photochemical probe to interrogate a novel small‐molecule inhibitor binding site in the human MBOAT Hedgehog acyltransferase (HHAT). Structure‐activity relationship investigation identified single enantiomer IMP‐1575, the most potent HHAT inhibitor reported to‐date, and guided design of photocrosslinking probes that maintained HHAT‐inhibitory potency. Photocrosslinking and proteomic sequencing of HHAT delivered identification of the first small‐molecule binding site in a mammalian MBOAT. Topology and homology data suggested a potential mechanism for HHAT inhibition which was confirmed by kinetic analysis. Our results provide an optimal HHAT tool inhibitor IMP‐1575 (K i=38 nM) and a strategy for mapping small molecule interaction sites in MBOATs., Structure‐activity relationship analysis of Hedgehog acyltransferase (HHAT) inhibitors allowed rational design of photochemical probes for HHAT. Probe photocrosslinking identified the first small‐molecule inhibitor binding site in HHAT and revealed the inhibitory mechanism, providing an optimal HHAT tool inhibitor IMP‐1575 (K i=38 nM) for future studies.

Airy beams, which propagate along a curved trajectory, have been widely utilized in optical tweezers, biomedical analysis, and material processing. However, the dynamic regulation of nonlinear Airy beams is still challenging. Here, we demonstrate directionally switchable nonlinear Airy beams via three-dimensional (3D) nonlinear photonic crystals (NPCs) fabricated by the femtosecond laser erasing technique. The 3D NPCs contain several sequential arrays of spatially modulated nonlinearities with different spatial frequencies and cubic coefficients. By tuning the wavelength of the fundamental beam, the quasi-phase-matching condition can be switched to modulate the acceleration direction and wavelength of the generated nonlinear Airy beam. This offers a versatile platform for dynamic nonlinear Airy beam generation, paving the way for applications in optical trapping, optical communication, and biomedical imaging.

Structural color (SC) has enormous potential for improving the visualization and identification of functional micro/nano structures for information encryption and intelligent sensing. Nevertheless, achieving the direct writing of SCs at the micro/nano scale and the change of color in response to external stimuli simultaneously is rather challenging. To this end, we directly printed woodpile structures (WSs) utilizing femtosecond laser two-photon polymerization (fs-TPP), which demonstrated obvious SCs under an optical microscope. After that, we achieved the change of SCs by transferring WSs between different mediums. Furthermore, the influence of laser power, structural parameters, and mediums on the SCs was systematically investigated, and the mechanism of SCs using the finite-difference time-domain (FDTD) method was further explored. Finally, we realized the reversible encryption and decryption of certain information. This finding holds broad application prospects in smart sensing, anti-counterfeiting tags, and advanced photonic devices.

In recent decades, magnetic shields have provided basic experimental environments for the measurements of extremely weak magnetic fields represented by the biological magnetic signal. Excellent shielding performances, including the low residual field and high shielding factor (SF), are necessary to ensure the quality of these weak magnetic signals and avoid the interference of external magnetic fields. The magnetic shielding performance of the same device can be affected by different degaussing and test conditions, which remains to be systematically studied. In this paper, experiments with variable magnetization conditions, including different degaussing orders, test fields and environmental fields, are established in a nearly zero-field space to simulate the different situations during measurement. The residual field and SF of the cubic shielding device are tested in these cases. Meanwhile, these shielding performances are analyzed from the perspective of the magnetization state and calculated based on the magnetic properties which are tested and fitted by the Jiles–Atherton model. The results show the influence of these different conditions on the shielding performances of the cubic device, consistent with the numerical calculation. Under the same environmental field, the different degaussing order and test field lead to completely different residual field and shielding performance, respectively. The influence of the Earth’s magnetic field on the SF can be ignored due to its tiny equivalent bias field determined by the anhysteretic magnetization curve.

The present study compared an immersive virtual reality-based attentional bias modification (immersive VR-ABM) with the desktop version of the VR-ABM and an immersive virtual reality-based game (immersive VR-game) to examine the possible effect of the immersive presence on self-reported emotional reactions to a stressful task. One hundred and twenty participants were randomly assigned into three groups, and each group received a three-turn induction-intervention training. Anxiety symptoms were assessed at pre-induction, post-induction, and post-training. Results showed that virtual reality-based anxiety was induced and alleviated successfully in all three groups, but only the immersive VR-ABM group showed an accumulated effect on self-reported anxiety across sessions. The attentional bias based on probe latencies indicated no significant change in either the immersive or desktop VR-ABM groups. The present findings support the hypothesized VR-ABM's effect on self-reported anxiety at the immersive presence. The practical implications of using immersive VR-ABM are discussed for obtaining ecological validity.

Atherosclerosis preferentially occurs in arterial regions exposed to disturbed blood flow (d-flow), while regions exposed to stable flow (s-flow) are protected. The proatherogenic and atheroprotective effects of d-flow and s-flow are mediated in part by the global changes in endothelial cell (EC) gene expression, which regulates endothelial dysfunction, inflammation, and atherosclerosis. Previously, we identified kallikrein-related peptidase 10 (Klk10, a secreted serine protease) as a flow-sensitive gene in mouse arterial ECs, but its role in endothelial biology and atherosclerosis was unknown. Here, we show that KLK10 is upregulated under s-flow conditions and downregulated under d-flow conditions using in vivo mouse models and in vitro studies with cultured ECs. Single-cell RNA sequencing (scRNAseq) and scATAC sequencing (scATACseq) study using the partial carotid ligation mouse model showed flow-regulated Klk10 expression at the epigenomic and transcription levels. Functionally, KLK10 protected against d-flow-induced permeability dysfunction and inflammation in human artery ECs, as determined by NFκB activation, expression of vascular cell adhesion molecule 1 and intracellular adhesion molecule 1, and monocyte adhesion. Furthermore, treatment of mice in vivo with rKLK10 decreased arterial endothelial inflammation in d-flow regions. Additionally, rKLK10 injection or ultrasound-mediated transfection of Klk10-expressing plasmids inhibited atherosclerosis in Apoe−/− mice. Moreover, KLK10 expression was significantly reduced in human coronary arteries with advanced atherosclerotic plaques compared to those with less severe plaques. KLK10 is a flow-sensitive endothelial protein that serves as an anti-inflammatory, barrier-protective, and anti-atherogenic factor.

Biomimetic stimuli-responsive structure colors (SCs) can improve the visualization and identification in the micro functional structure field such as information encryption/decryption and smart actuators. However, it is still challenging to develop the ability to 4D print arbitrary submerged colorful patterns with stimuli-responsive materials at the microscale. Herein, a hydrogel photoresist with feature resolution (98 nm) for the fabrication of 4D microscopic SCs by the femtosecond direct laser writing method is developed. The 4D printed woodpile SCs are grouped as pixel palettes with various laser parameters and they spanned almost the entire color space. The coloring mechanism of diffraction gratings is not only investigated by optics microscopy and spectroscopy but also supported by simulation. Moreover, the 4D printed hydrogel-integrated amphichromatic fish constructions and pixelated painting can visually discolor reversibly by regulating the solution pH. This finding promises an ideal coloring method for sensors, anti-counterfeiting labels, and transformable photonic devices.

IntroductionAtherosclerosis preferentially occurs in arterial regions exposed to disturbed blood flow (d-flow), while regions exposed to stable flow (s-flow) are protected. The proatherogenic and atheroprotective effects ofd-flowands-floware mediated in part by the global changes in endothelial cell gene expression, which regulates endothelial dysfunction, inflammation, and atherosclerosis. Previously, we identified Kallikrein-Related Peptidase 10 (KLK10, a secreted serine protease) as a flow-sensitive gene in arterial endothelial cells, but its role in endothelial biology and atherosclerosis was unknown.Methods and ResultsHere, we show that KLK10 is upregulated unders-flowconditions and downregulated underd-flowconditions usingin vivomouse models andin vitrostudies with cultured endothelial cells (ECs). Single-cell RNA sequencing (scRNAseq) and scATAC sequencing (scATACseq) study using the partial carotid ligation mouse model showed flow-regulated KLK10 expression at the epigenomic and transcription levels. Functionally, KLK10 protected againstd-flow-induced inflammation and permeability dysfunction in human artery ECs (HAECs). Further, treatment of micein vivowith rKLK10 decreased arterial endothelial inflammation ind-flowregions. Additionally, rKLK10 injection or ultrasound-mediated transfection of KLK10-expressing plasmids inhibited atherosclerosis inApoE-/-mice. Studies using pharmacological inhibitors and siRNAs revealed that the anti-inflammatory effects of KLK10 were mediated by a Protease Activated Receptors (PAR1/2)-dependent manner. However, unexpectedly, KLK10 did not cleave the PARs. Through a proteomics study, we identified HTRA1 (High-temperature requirement A serine peptidase 1), which bound and cleaved KLK10. Further, siRNA knockdown of HTRA1 prevented KLK10’s anti-inflammatory and barrier protective function in HAECs, suggesting that HTRA1 regulates KLK10 function. Moreover, KLK10 expression was significantly reduced in human coronary arteries with advanced atherosclerotic plaques compared to those with less severe plaques.ConclusionKLK10 is a flow-sensitive endothelial protein and, in collaboration with HTRA1, serves as an anti-inflammatory, barrier-protective, and anti-atherogenic factor.

In this issue of Cell Chemical Biology, Yoo et al. (2020) use chemical proteomics to identify target proteins for the potent antimalarial natural product Salinipostin A. Polypharmacology from targeting multiple parasite serine hydrolases and lipases limits resistance to the compound, making this a promising new approach for treating malaria.

The two-center three-electron (2c-3e) bonded species are important in chemical and biological science. Reported isolable 2c-3e σ-bonded species are usually constructed in homoatomic radicals. The one-electron oxidation of main-group heteronuclear species Nap(SPh)(P(Mes)2) (1), Nap(SePh)(P(Mes)2) (2), Nap(SPh)(As(Mes)2) (3) and Nap(SePh)(As(Mes)2) (4) produced persistent radical cations 1˙+-4˙+ in solution. Large couplings of heteroatoms in EPR spectra of 1˙+-4˙+, shorter bond distances and bigger Wiberg bond orders of Ch-Pn in 1˙+-4˙+ than those in 1-4 in DFT calculations indicate large amounts of spin densities over heteroatoms and the formation of 2c-3e σ-bonds between chalcogen and pnicogen atoms. This work provides evidence of 2c-3e σ-bonds constructed between main-group heteronuclears and rare examples of radical cations involving three-electron σ-bonds between S/Se and P/As atoms.

The mammalian membrane-bound O-acyltransferase (MBOAT) superfamily is involved in biological processes including growth, development and appetite sensing. MBOATs are attractive drug targets in cancer and obesity; however, information on the binding site and molecular mechanisms underlying small-molecule inhibition is elusive. This study reports development of a photochemical probe to interrogate the small-molecule binding site in the human MBOAT Hedgehog acyltransferase (HHAT) based on HHAT inhibitor RUSKI-201. Structure-activity relationship investigation identified the improved enantiomeric inhibitor IMP-1575, which is the most potent HHAT inhibitor reported to-date, and guided rational design of a photocrosslinking probe that maintained HHAT-inhibitory potency. Photocrosslinking and proteomic sequencing of HHAT delivered identification of the first small-molecule binding site in a mammalian MBOAT. Topology and homology data suggested a potential mechanism for HHAT inhibition which was confirmed via kinetic analysis. Our results provide an optimal HHAT inhibitor IMP-1575 (Ki = 38 nM) and a strategy for mapping of interaction sites in MBOATs.

The two-center three-electron (2c-3e) bonded species are important in chemical and biological science. Reported isolable 2c-3e σ-bonded species are usually constructed in homoatomic radicals. The one-electron oxidation of main-group heteronuclear species Nap(SPh)(P(Mes)2) (1), Nap(SePh)(P(Mes)2) (2), Nap(SPh)(As(Mes)2) (3) and Nap(SePh)(As(Mes)2) (4) produced persistent radical cations 1˙+–4˙+ in solution. Large couplings of heteroatoms in EPR spectra of 1˙+–4˙+, shorter bond distances and bigger Wiberg bond orders of Ch–Pn in 1˙+–4˙+ than those in 1–4 in DFT calculations indicate large amounts of spin densities over heteroatoms and the formation of 2c-3e σ-bonds between chalcogen and pnicogen atoms. This work provides evidence of 2c-3e σ-bonds constructed between main-group heteronuclears and rare examples of radical cations involving three-electron σ-bonds between S/Se and P/As atoms.

Soft pressure sensors based on liquid metals (LMs) may find broad applications, but it is challenging to fabricate such sensors that can achieve high stress resolution without additional parts. Herein, a method named laser-induced selective adhesion transfer (LISAT) is proposed. LISAT can pattern LM by selectively changing high adhesion of the poly(dimethylsiloxane) (PDMS) surface to LM into low adhesion with the aid of rough micro/nanostructures induced by a femtosecond laser. Based on this principle, LM microchannels with controllable shapes can be obtained by LM transfer and subsequent encapsulation. Since the smallest microchannel thickness is only ∼25 μm, sensor stress resolution can reach 0.0168 kPa without any additional parts to amplify the effect of pressure. As proof-of-concept demonstrations, the sensor is used for sensing the dynamic movement of a small sphere (∼0.16 g) and even an ant (∼0.025 g). LISAT provides a versatile platform for fabricating high-stress-resolution LM pressure sensors with controllable patterns and device structures to adapt to different application scenarios.

In this Letter, we propose a type of continuous phase vortex gratings (CPVGs), which are able to generate a series of vortex beams with equal or proportional diffracted energies and different topological charges (TCs). A set of CPVGs with dimensions (60 × 60 × 1.1 μm3) are directly designed by mathematical equations, which avoids the use of iterative algorithms. The CPVGs are fabricated by femtosecond laser direct writing (FsLDW) with photoresist, and the experimentally generated vortex beams are in good agreement with the theoretical designs, exhibiting high optical efficiencies. In addition, we realized a CPVG onto the tip of a composite fiber for integrated optical systems. Our work paves the way for applications in optical communications, optical manipulations, and high-performance integrated optics.

Flexible electrodes with good conductivity and stability during deformation are the key medical devices for thermal therapy. However, reconciling the contradiction between conductive stability and stretchability is still a challenging issue. In this study, biaxial stress field was generated by rotation extrusion technology and we successfully realized the concentric arrangement of 2D conductive graphene (GR) in the flexible tubular electrode. It is worth mentioning that this 2D stacked GR network can act as a confining space, which not only increases the contact probability of the one-dimensional filler carbon fiber (CF) in the hybrid system, reducing the percolation threshold, but also greatly improves the durability of the conductive network. The as-prepared polyethylene elastomer (POE)/g/CF electrode displayed a strain affordability of over 50%, tunable saturation temperature (Ts) of 41.8–62.3 °C with an input of 5–10 V and lower power consumption (8.0 mW/°C). Most impressively, after being compressed by 140 times (50% strain), the electrothermal performance of the flexible tubular electrode remained unchanged, which was promising in practical thermal therapy.

The proper-time resolution function for the measurement of D 0 time evolution in two-body hadronic decay at Belle is studied in detail. The determined resolution function for both signal and backgrounds are applied to D 0 - D ¯ 0 mixing parameter measurement.

Pancreatic cancer has the lowest survival rate of all common cancers due to late diagnosis and limited treatment options. Serine hydrolases are known to mediate cancer progression and metastasis through initiation of signaling cascades and cleavage of extracellular matrix proteins, and the kallikrein-related peptidase (KLK) family of secreted serine proteases have emerging roles in pancreatic ductal adenocarcinoma (PDAC). However, the lack of reliable activity-based probes (ABPs) to profile KLK activity has hindered progress in validation of these enzymes as potential targets or biomarkers. Here, we developed potent and selective ABPs for KLK6 by using a positional scanning combinatorial substrate library and characterized their binding mode and interactions by X-ray crystallography. The optimized KLK6 probe IMP-2352 (kobs/I = 11,000 M-1 s-1) enabled selective detection of KLK6 activity in a variety of PDAC cell lines, and we observed that KLK6 inhibition reduced the invasiveness of PDAC cells that secrete active KLK6. KLK6 inhibitors were combined with N-terminomics to identify potential secreted protein substrates of KLK6 in PDAC cells, providing insights into KLK6-mediated invasion pathways. These novel KLK6 ABPs offer a toolset to validate KLK6 and associated signaling partners as targets or biomarkers across a range of diseases.

Kallikrein-related peptidases (KLKs) are a family of secreted serine proteases, which form a network (the KLK activome) with an important role in proteolysis and signaling. In prostate cancer (PCa), increased KLK activity promotes tumor growth and metastasis through multiple biochemical pathways, and specific quantification and tracking of changes in the KLK activome could contribute to validation of KLKs as potential drug targets. Herein we report a technology platform based on novel activity-based probes (ABPs) and inhibitors enabling simultaneous orthogonal analysis of KLK2, KLK3, and KLK14 activity in hormone-responsive PCa cell lines and tumor homogenates. Importantly, we identifed a significant decoupling of KLK activity and abundance and suggest that KLK proteolysis should be considered as an additional parameter, along with the PSA blood test, for accurate PCa diagnosis and monitoring. Using selective inhibitors and multiplexed fluorescent activity-based protein profiling (ABPP), we dissect the KLK activome in PCa cells and show that increased KLK14 activity leads to a migratory phenotype. Furthermore, using biotinylated ABPs, we show that active KLK molecules are secreted into the bone microenvironment by PCa cells following stimulation by osteoblasts suggesting KLK-mediated signaling mechanisms could contribute to PCa metastasis to bone. Together our findings show that ABPP is a powerful approach to dissect dysregulation of the KLK activome as a promising and previously underappreciated therapeutic target in advanced PCa.