Bioinspired Liquid Metal based Soft Humanoid Robots.

The pursuit of constructing humanoid robots to replicate the anatomical structures and capabilities of human beings has been a long-standing significant undertaking and especially garnered tremendous attention in recent years. However, despite the progress made over recent decades, humanoid robots have predominantly been confined to those rigid metallic structures, which however starkly contrast with the inherent flexibility observed in biological systems. To better innovate this area, the present article systematically explores the value and potential of liquid metals and their derivatives in facilitating a crucial transition towards soft humanoid robots. Through a comprehensive interpretation of bionics, we present an overview of liquid metals' multifaceted roles as essential components in constructing advanced humanoid robots - functioning as soft actuators, sensors, power sources, logical devices, circuit systems, and even transformable skeletal structures. We conceived that the integration of these components with flexible structures, facilitated by the unique properties of liquid metals, can create unexpected versatile functionalities and behaviors to better fulfill human needs. Finally, we envision a revolution in humanoid robots, transitioning from metallic frameworks to hybrid soft-rigid structures resembling that of biological tissues. This article is expected to provide fundamental guidance for the coming research, thereby advancing the area. This article is protected by copyright. All rights reserved.

Splicing factor hnRNPA1 regulates alternative splicing of LOXL2 to enhance production of LOXL2Δ13.

Lysyl oxidase-like 2 (LOXL2) is a member of the lysyl oxidase family and has the ability to catalyze the cross-linking of extracellular matrix collagen and elastin. High expression of LOXL2 is related to tumor cell proliferation, invasion and metastasis. LOXL2 contains 14 exons. Previous studies have found that LOXL2 has abnormal alternative splicing and exon skipping in a variety of tissues and cells, resulting in a new alternatively-spliced isoform denoted LOXL2Δ13. LOXL2Δ13 lacks LOXL2WT exon 13, but its encoded protein has greater ability to induce tumor cell proliferation, invasion and metastasis. However, the molecular events that produce LOXL2Δ13 are still unclear. In this study, we found that overexpression of the splicing factor hnRNPA1 in cells can regulate the alternative splicing of LOXL2 and increase the expression of LOXL2Δ13. The exonic splicing silencer (ESS) exists at the 3' splice site (3' SS) and 5' splice site (5' SS) of LOXL2 exon 13. HnRNPA1 can bind to the ESS and inhibit the inclusion of exon 13. The RRM domain of hnRNPA1 and phosphorylation of hnRNPA1 at S91 and S95 are important for the regulation of LOXL2 alternative splicing. These results show that hnRNPA1 is a splicing factor that enhances the production of LOXL2Δ13.

Single-Shot Solid-Phase Synthesis of Full-Length H2 Relaxin Disulfide Surrogates.

Chemical synthesis of insulin superfamily proteins (ISPs) has recently been widely studied to develop next-generation drugs. Separate synthesis of multiple peptide fragments and tedious chain-to-chain folding are usually encountered in these studies, limiting accessibility to ISP derivatives. Here we report the finding that insulin superfamily proteins (e.g. H2 relaxin, insulin itself, and H3 relaxin) incorporating a pre-made diaminodiacid bridge at A-B chain terminal disulfide can be easily and rapidly synthesized by a single-shot automated solid-phase synthesis and expedient one-step folding. Our new H2 relaxin analogues exhibit almost identical structures and activities when compared to their natural counterparts. This new synthetic strategy will expediate production of new ISP analogues for pharmaceutical studies.

Identification of ellagic acid and urolithins as natural inhibitors of Aß25-35-induced neurotoxicity and the mechanism predication using network pharmacology analysis and molecular docking.

Ellagic acid (EA) is a dietary polyphenol that widely exists in grapes, strawberries, and walnuts. It usually exerts multiple biological activities together with its in vivo metabolites called urolithins. EA and urolithins had been proposed as natural agents for applying on the early intervention of Alzheimer's disease (AD). However, the neuroprotective effects of those small molecules have not been confirmed, and the action mechanism is not clear. Deposition of beta-amyloid (Aß) protein is well documented as being involved in the initiation and pathological process of AD. In the present study, we investigated the attenuating effects of EA and several urolithins on Aß25-35-induced neuronal injury and its underlying molecular mechanism by constructing the in vitro AD cell model of PC12 cells and primary neurons. The results revealed that EA and urolithins especially the UM5 and UM6 exerted promising neuroprotective effects in improving the Aß25-35-induced cell damage and lactate dehydrogenase (LDH) leakage, reducing reactive oxygen species (ROS) production, inhibiting neuronal apoptosis, and promoting neurite outgrowth. These results provide new insights into the development of UM5 and UM6 as anti-AD candidates. A network pharmacology analysis combining molecular docking strategy was further adopted to predict the signaling pathway involved in the anti-AD action of EA and urolithins, and the activation of PI3K-Akt, as well as the inhibition of MAPK was found to be involved.

Promising Colloidal Rhenium Disulfide Nanosheets: Preparation and Applications for In Vivo Breast Cancer Therapy.

Photothermal therapy (PTT) has become an important therapeutic strategy in the treatment of cancer. However, exploring novel photothermal nanomaterials with satisfactory biocompatibility, high photothermal conversion efficiency, and efficient theranostic outcomes, remains a major challenge for satisfying clinical application. In this study, poly-ethylene glycol modified rhenium disulfide (PEG-ReS2) nanosheets are constructed by a simple-liquid phase exfoliation method. The PEG-ReS2 nanosheets were demonstrated to have good solubility, good biocompatibility, low toxicity, and strong capability of accumulating near-infrared (NIR) photons. Under 808 nm laser irradiation, the PEG-ReS2 nanosheets were found to have an excellent photothermal conversion efficiency (PTCE) of 42%. Moreover, the PEG-ReS2 nanosheets were demonstrated to be ideal photothermal transduction agents (PTAs), which promoted rapid cancer cell death in vitro and efficiently ablated tumors in vivo. Interestingly, the potential utility of up-regulation or down-regulation of miRNAs was proposed to evaluate the therapeutic outcomes of PEG-ReS2 nanosheets. The expression levels of a set of miRNAs in tumor-bearing mice were restored to normal levels after PTT therapy with PEG-ReS2 nanosheets. Both down-regulation miRNAs (miR-125a-5p, miR-34a-5p, miR-132-3p, and miR-148b-3p) and up-regulation miRNAs (miR-133a-3p, miR-200c-5p, miR-9-3p, and miR-150-3p) were suggested to be important clinical biomarkers for evaluating therapeutic outcomes of breast cancer-related PTT. This work highlights the great significance of PEG-ReS2 nanosheets as therapeutic nanoagents for cancer therapy.

Structural insights into the activation of somatostatin receptor 2 by cyclic SST analogues.

The endogenous cyclic tetradecapeptide SST14 was reported to stimulate all five somatostatin receptors (SSTR1-5) for hormone release, neurotransmission, cell growth arrest and cancer suppression. Two SST14-derived short cyclic SST analogues (lanreotide or octreotide) with improved stability and longer lifetime were developed as drugs to preferentially activate SSTR2 and treat acromegalia and neuroendocrine tumors. Here, cryo-EM structures of the human SSTR2-Gi complex bound with SST14, octreotide or lanreotide were determined at resolutions of 2.85 Å, 2.97 Å, and 2.87 Å, respectively. Structural and functional analysis revealed that interactions between ß-turn residues in SST analogues and transmembrane SSTR2 residues in the ligand-binding pocket are crucial for receptor binding and functional stimulation of the two SST14-derived cyclic octapeptides. Additionally, Q1022.63, N2766.55, and F2947.35 could be responsible for the selectivity of lanreotide or octreotide for SSTR2 over SSTR1 or SSTR4. These results provide valuable insights into further rational development of SST analogue drugs targeting SSTR2.

A Clinical Study on Microwave Ablation in Combination with Chemotherapy in Treating Peripheral IIIB-IV Non-Small Cell Lung Cancer.

Background: This study investigated the efficacy and complications of microwave ablation in combination with chemotherapy in treating peripheral IIIB-IV non-small cell lung cancer (NSCLC). Materials and Methods: A total of 100 patients with peripheral IIIB-IV NSCLC were randomly divided into two groups: combination group (n = 52) and chemotherapy group (n = 48). Patients in the combination group were treated with microwave ablation, radiotherapy, and chemotherapy, whereas the patients in the chemotherapy group were treated with pemetrexed disodium or gemcitabine hydrochloride, cisplatin chemotherapy, and conventional radiotherapy. Results: The effectiveness and disease control rates were significantly higher in the combination group than in the chemotherapy group (p < 0.05). The second- and third-year survival rates were significantly higher in the combination group than in the chemotherapy group (p < 0.05). However, patients in the combination group had no serious complications, and there were no intraoperative and perioperative deaths. Conclusions: Microwave ablation is safe and effective. Combination chemotherapy is superior to chemotherapy in treating peripheral IIIB-IV NSCLC in terms of effectiveness rate, disease control rate, and extended patient survival time.

Progress on intraoperative condylar positioning techniques in orthognathic surgery / 口腔疾病防治

@#Condylar displacement can lead to temporomandibular joint (TMJ) symptoms and relapse after orthognathic surgery. To minimize condylar displacement, numerous condylar positioning techniques have been applied in clinical practice. To verify the effectiveness of condylar positioning techniques in preventing postoperative TMJ symptoms and relapse, we reviewed the literature related to all types of intraoperative condylar positioning techniques in the past 20 years. According to a literature review, positioning techniques aim to seat the condyles at a preoperative position during surgery and are divided into noncomputer-aided and computer-aided condyle positioning methods. At present, computer-aided design/computer-aided manufacturing condylar positioning devices (CAD/CAM CPDs) are the most superior positioning methods and are composed of teeth-supported and bone-supported guidance. The sequence of the remaining technology positioning effect from high to low is as follows: CAD/CAM titanium plate positioning > manual positioning > computer-aided navigation system > image positioning system. Different techniques reach considerable accuracy within 1-2 mm and 1°-2° in locating the preoperative condylar position and preventing TMJ symptoms or disorders and surgical relapse to provide a clinical reference for different levels of surgeons and cases. However, this study lacks randomized controlled trials with large samples and long-term follow-up. Future studies should upgrade the current methods, improve the clinical utility, and develop new positioning techniques.

Structural mechanism of cooperative activation of the human calcium-sensing receptor by Ca2+ ions and L-tryptophan.

The human calcium-sensing receptor (CaSR) is a class C G protein-coupled receptor (GPCR) responsible for maintaining Ca2+ homeostasis in the blood. The general consensus is that extracellular Ca2+ is the principal agonist of CaSR. Aliphatic and aromatic L-amino acids, such as L-Phe and L-Trp, increase the sensitivity of CaSR towards Ca2+ and are considered allosteric activators. Crystal structures of the extracellular domain (ECD) of CaSR dimer have demonstrated Ca2+ and L-Trp binding sites and conformational changes of the ECD upon Ca2+/L-Trp binding. However, it remains to be understood at the structural level how Ca2+/L-Trp binding to the ECD leads to conformational changes in transmembrane domains (TMDs) and consequent CaSR activation. Here, we determined the structures of full-length human CaSR in the inactive state, Ca2+- or L-Trp-bound states, and Ca2+/L-Trp-bound active state using single-particle cryo-electron microscopy. Structural studies demonstrate that L-Trp binding induces the closure of the Venus flytrap (VFT) domain of CaSR, bringing the receptor into an intermediate active state. Ca2+ binding relays the conformational changes from the VFT domains to the TMDs, consequently inducing close contact between the two TMDs of dimeric CaSR, activating the receptor. Importantly, our structural and functional studies reveal that Ca2+ ions and L-Trp activate CaSR cooperatively. Amino acids are not able to activate CaSR alone, but can promote the receptor activation in the presence of Ca2+. Our data provide complementary insights into the activation of class C GPCRs and may aid in the development of novel drugs targeting CaSR.

Enhancement of Gas Barrier Properties of Graphene Oxide/Poly (Lactic Acid) Films Using a Solvent-free Method.

Graphene oxide(GO)/polylactic acid (PLA) nanocomposite, prepared using a solvent-free melt mixing processing, is investigated as a potential oxygen barrier packaging film in this work. In order to disperse GO homogeneously in PLA matrix, hydrophobic silane coupling agent, i.e., γ-(2,3-epoxypropoxy)propyltrimethoxysilane (KH560), is used to modify the graphene oxide sheets. The modified GO is able to be well bonded to the PLA due to the formation of covalent bonds between the epoxy groups of KH560 and the carboxyl and hydroxyl terminal groups of PLA. Furthermore, the thermal stability of GO is enhanced due to the long alkyl side chain of KH560, which could also increase the crystallinity of PLA. As a result, the crystallinity of PLA is significantly improved because of the linear KH560 chains, which can act as nucleating agents to improve the crystallization. The KH560-GO helps to reduce the O2 permeability of KH560-GO/PLA composite films via a dual-action mechanism: (1) providing physical barrier due to their native barrier properties, and (2) by resulting in higher degree of crystallinity. The as-prepared KH560-GO0.75/PLA is able to exhibit ca. 33% and ca. 13% decrease in the PO2 than the neat PLA and GO0.75/PLA film, respectively. Finally, the mechanical properties and impact fractured surfaces indicate that the increase in the tensile strength and elongation at break value of KH560-GO/PLA are due to the strong interfacial adhesion and the strong bonding between the epoxy group of KH560-GO and hydroxyl and carboxyl acid terminal groups of PLA matrix.

Ultrasensitive Surface Plasmon Resonance Biosensor Using Blue Phosphorus-Graphene Architecture.

This study theoretically proposed a novel surface plasmon resonance biosensor by incorporating emerging two dimensional material blue phosphorus and graphene layers with plasmonic gold film. The excellent performances employed for biosensing can be realized by accurately tuning the thickness of gold film and the number of blue phosphorus interlayer. Our proposed plasmonic biosensor architecture designed by phase modulation is much superior to angular modulation, providing 4 orders of magnitude sensitivity enhancement. In addition, the optimized stacked configuration is 42 nm Au film/2-layer blue phosphorus /4-layer graphene, which can produce the sharpest differential phase of 176.7661 degrees and darkest minimum reflectivity as low as 5.3787 × 10-6. For a tiny variation in local refractive index of 0.0012 RIU (RIU, refractive index unit) due to the binding interactions of aromatic biomolecules, our proposed biosensor can provide an ultrahigh detection sensitivity up to 1.4731 × 105 °/RIU, highly promising for performing ultrasensitive biosensing application.

Comparative clinical study on microwave ablation combined with gemcitabine and cisplatin or combined with pemetrexed and cisplatin in treatment of advanced NSCLC.

OBJECTIVE: Solving the limitations of single chemotherapy in the treatment of non-small cell lung cancer (NSCLC). METHODS: About 100 patients with NSCLC treated in First Hospital of Jiaxing, Zhejiang from June 2016 to June 2018 were selected and randomly divided into MPC group and MGC group, with 50 cases in each group. The patients in MPC group were treated with microwave ablation (MWA) combined with PC while patients in MGC group were given MWA combined with gemcitabine plus cisplatin (GC). The therapeutic effects of the two groups as well as the complications and adverse reactions (ADRs) were observed and recorded. RESULTS: There was no significant difference in disease response rate (MPC group 33.3% vs MGC group 32.0%), disease control rate (MPC group 86.4% vs MGC group 78.0%) and overall survival (1-, 2- and 3-year survival, MPC group 65%, 59%, 32.7% vs MGC group 58%, 46%, 30%) between the two groups. In addition, the ADR myelosuppression was slighter in MPC group. There were 12 cases (23%) developed myelosuppression in the MPC group and 20 cases (42%) in MGC group, with a significant difference between the two groups (P < 0.05). The treatment was interrupted for 0 case (0%) in MPC group because of myelosuppression while 4 cases (8.3%) in MGC group. CONCLUSION: The two therapeutic regimens have similar efficacy in treatment of advanced NSCLC, but MPC causes slighter myelosuppression and can be the first-line therapy for advanced NSCLC.

Monitoring the Cellular Delivery of Doxorubicin-Cu Complexes in Cells by Fluorescence Lifetime Imaging Microscopy.

In the prodrug research field, information obtained from traditional end point biochemical assays in drug effect studies could provide neither the dynamic processes nor heterogeneous responses of individual cells. In situ imaging microscopy techniques, especially fluorescence lifetime imaging microscopy (FLIM), could fulfill these requirements. In this work, we used FLIM techniques to observe the entry and release of doxorubicin (Dox)-Cu complexes in live KYSE150 cells. The Dox-Cu complex has weaker fluorescence signals but similar lifetime values as compared to the raw Dox, whose fluorescence could be released by the addition of biothiol compound (such as glutathione). The cell viability results indicated that the Dox-Cu compound has a satisfactory killing effect on KYSE150 cells. The FLIM data showed that free doxorubicin was released from Dox-Cu complexes in cytoplasm of KYSE150 cells and then accumulated in the nucleus. After 90 min administration, the fluorescence lifetime signals reached 1.21 and 1.46 ns in the cytoplasm and nucleus, respectively, reflecting the transformation and transportation of Dox-Cu complexes. In conclusion, this work provides a satisfactory example for the research of prodrug monitored by FLIM techniques, expanding the useful applications of FLIM technique in drug development.