Hydrogel-based molecular tension fluorescence microscopy for investigating receptor-mediated rigidity sensing.

Extracellular matrix (ECM) rigidity serves as a crucial mechanical cue impacting diverse biological processes. However, understanding the molecular mechanisms of rigidity sensing has been limited by the spatial resolution and force sensitivity of current cellular force measurement techniques. Here we developed a method to functionalize DNA tension probes on soft hydrogel surfaces in a controllable and reliable manner, enabling molecular tension fluorescence microscopy for rigidity sensing studies. Our findings showed that fibroblasts respond to substrate rigidity by recruiting more force-bearing integrins and modulating integrin sampling frequency of the ECM, rather than simply overloading the existing integrin-ligand bonds, to promote focal adhesion maturation. We also demonstrated that ECM rigidity positively regulates the pN force of T cell receptor-ligand bond and T cell receptor mechanical sampling frequency, promoting T cell activation. Thus, hydrogel-based molecular tension fluorescence microscopy implemented on a standard confocal microscope provides a simple and effective means to explore detailed molecular force information for rigidity-dependent biological processes.

Design, synthesis and biological evaluation of quinazoline and pyrrolo[3,2-d]pyrimidine derivatives as TLR7 agonists for antiviral agents.

Pattern recognition receptors (PRRs) play a critical role in the innate immune response, and toll-like receptor 7 (TLR7) is an important member of PRRs. Although several TLR7 agonists are available, most of them are being tested clinically, with only one available on the market. Thus, it is imperative to develop new TLR7 agonists. In this study, we designed and synthesized three kinds of quinazoline derivatives and five kinds of pyrrolo[3,2-d]pyrimidine derivatives targeting TLR7. The antiviral efficacy of these compounds was evaluated in vitro and in vivo. Our findings indicated that four kinds of compounds showed exceptional antiviral activity. Furthermore, molecular docking studies confirmed that compound 11 successfully positioned itself in the pocket of the TLR7 guanosine loading site with a binding energy of -4.45 kcal mol-1. These results suggested that these compounds might be potential antiviral agents.

Ultra-mechanosensitive Chloride Ion Transport through Bioinspired High-Density Elastomeric Nanochannels.

Mechanosensitive ion channels play crucial roles in physiological activities, where small mechanical stimuli induce the membrane tension, trigger the ion channels' deformation, and are further transformed into significant electrochemical signals. Artificial ion channels with stiff moduli have been developed to mimic mechanosensory behaviors, exhibiting an electrochemical response by the high-pressure-induced flow. However, fabricating flexible mechanosensitive channels capable of regulating specific ion transporting upon dramatic deformation has remained a challenge. Here, we demonstrate bioinspired high-density elastomeric channels self-assembled by polyisoprene-b-poly4-vinylpyridine, which exhibit ultra-mechanosensitive chloride ion transport resulting from nanochannel deformation. The PI-formed continuous elastic matrix can transmit external forces into internal tensions, while P4VP forms transmembrane chloride channels that undergo dramatic deformation and respond to mechanical stimuli. The integrated and flexible chloride channels present a dramatic and stable electrochemical signal toward a low pressure of 0.2 mbar. This research first demonstrates the artificial mechanosensory chloride channels, which could provide a promising avenue for designing flexible and responsive channel systems.

Output characteristics of 3-8 µm mid-infrared source based on BaGa4Se7 crystal.

An optical parametric oscillator based on B a G a 4 S e 7 crystal is constructed for use as a 3-8 µm mid-infrared source. The output characteristics of the light source, including wavelength tuning, beam quality, and energy stability, are studied, which are usually concerned differently in spectral analysis, imaging, and laser processing. When the light source operates far from the threshold, the mid-infrared output is poor in beam quality and good in energy stability, and the contradiction should be addressed in practice. The results provide guidance on the selection of operating parameters and performance optimization for the application of the B a G a 4 S e 7 based mid-infrared source in various settings.

One Porphyrin Per Chain Self-Assembled Helical Ion-Exchange Channels for Ultrahigh Osmotic Energy Conversion.

Ion-exchange membranes (IEMs) convert osmotic energy into electricity when embedded in a reverse electrodialysis cell. IEMs with both high permselectivity and ionic conductivity are highly needed to increase the energy conversion efficiency. The ionic conductivity can be improved by increasing the content of immobile charge carriers, but it is always accompanied by undesirable permselectivity decrease due to excess swelling. Until now, breaking the permselectivity-conductivity tradeoff still has remained a challenge. Here, we demonstrate a membrane with the least ion-exchange capacity (∼10-2 mequiv g-1), generating an ultrahigh power density of 19.3 W m-2 at a 50-fold concentration ratio. The membrane is made of a porphyrin-core four-star block copolymer (p-BCP), forming the high-density helical porphyrin channels (∼1011 cm-2) under the synergistic effect of BCP self-assembly and porphyrin π-π stacking. The porphyrin channel shows high Cl- selectivity and high conductivity, benefiting high-performance osmotic energy conversion. This economic and facile membrane design strategy provides a promising approach to developing a new generation of IEMs.

Cascaded effect in a high-peak-power terahertz-wave parametric generator.

We demonstrate megawatt-level terahertz (THz)-wave generation via a Stokes-seed-injected THz-wave parametric generator and study the cascaded effect. The optical-to-THz conversion efficiency was 1.72 × 10-3, and the peak power was conservatively estimated to be 1.09 MW using the pulse width of the pump. More than 80% of the THz-wave energy came from primary parametric generation, with the rest coming from high-order parametric amplification. Clear cascaded Stokes spots of second to fourth order were observed, and the factors affecting the high-order parametric process are discussed. The cascaded parametric effect is beneficial for achieving a higher optical-to-THz conversion efficiency, thereby improving the performance of high-peak-power THz-wave parametric sources.

Widely tunable long-wave infrared difference frequency generation with a BaGa4Se7 crystal.

We report an experimental study of long-wave infrared difference frequency generation based on BaGa4Se7 crystal. The sources of two input wavelengths were the fundamental output of a Nd:YAG laser and its second-harmonic pumped ∼1.2µmKTiOPO4 optical parametric oscillator. A wide tuning range of 7.9-17.5 µm (>1.14 octave) was achieved, which reached the upper limit of the BaGa4Se7 transparency region. The spectra and pulse widths, input-output relationship, beam profile, wavelength tolerance, and angular acceptance of the phase-matching were characterized in detail. This presented coherent source can potentially be applied in multiple gas analyses and spectral imaging.

Cascaded difference frequency generation in organic crystal 4'-dimethylamino-N-methyl-4-stilbazolium tosylate.

In this Letter, we verified, for the first time to the best of our knowledge, an efficient cascaded difference frequency generation (DFG) with multi-order red shift. The experiment was performed with homemade organic crystals pumped by an optical parametric oscillator. The characteristics of energy conversion during DFG were investigated comprehensively at different frequencies and crystal thicknesses. Theoretical explanations were provided, based on the coupled-wave equations. The calculations predicted that the cascading effect contributed to a sustained growth of the DFG output (free from the saturation and shrinkage), especially in thick crystals. By measuring the optical spectrum, remarkable cascading processes of at least seven orders were observed. This effect shows the potential to overcome the quantum defect of the terahertz-wave DFG and fundamentally improve the conversion efficiency.

Efficient phase-matching for difference frequency generation with pump of Bessel laser beams.

A type of phase matching for difference frequency generation with Bessel-type pump beams is proposed. In this geometry, the phase matching is achieved in a cone around the laser path by properly controlling the beam profile. An experimental case that 1.5THz generation with ~2µm lasers pumped bulk GaAs crystal is considered. Calculations of the energy conversion characteristics are performed based on a semi-analytical model. The results indicate that this configuration could relax the phase matching condition in a wide range of nonlinear crystals and pump wavelengths.

SrTiO3 Nanotube-Based "Pneumatic Nanocannon" for On-Demand Delivery of Antibacterial and Sustained Osseointegration Enhancement.

Infection and aseptic loosening caused by bacteria and poor osseointegration remain serious challenges for orthopedic implants. The advanced surface modification of implants is an effective strategy for addressing these challenges. This study presents a "pneumatic nanocannon" coating for titanium orthopedic implants to achieve on-demand release of antibacterial and sustained release of osteogenic agents. SrTiO3 nanotubes (SrNT) were constructed on the surface of Ti implants as "cannon barrel," the "cannonball" (antibiotic) and "propellant" (NH4HCO3) were codeposited into SrNT with assistance of mussel-inspired copolymerization of dopamine and subsequently sealed by a layer of polydopamine. The encapsulated NH4HCO3 within the nanotubes could be thermally decomposed into gases under near-infrared irradiation, propelling the on-demand delivery of antibiotics. This coating demonstrated significant efficacy in eliminating typical pathogenic bacteria both in planktonic and biofilm forms. Additionally, this coating exhibited a continuous release of strontium ions, which significantly enhanced the osteogenic differentiation of preosteoblasts. In an implant-associated infection rat model, this coating demonstrated substantial antibacterial efficiency (>99%) and significant promotion of osseointegration, along with alleviated postoperative inflammation. This pneumatic nanocannon coating presents a promising approach to achieving on-demand infection inhibition and sustained osseointegration enhancement for titanium orthopedic implants.

Bioinspired light-driven chloride pump with helical porphyrin channels.

Halorhodopsin, a light-driven chloride pump, utilizes photonic energy to drive chloride ions across biological membranes, regulating the ion balance and conveying biological information. In the light-driven chloride pump process, the chloride-binding chromophore (protonated Schiff base) is crucial, able to form the active center by absorbing light and triggering the transport cycle. Inspired by halorhodopsin, we demonstrate an artificial light-driven chloride pump using a helical porphyrin channel array with excellent photoactivity and specific chloride selectivity. The helical porphyrin channels are formed by a porphyrin-core star block copolymer, and the defects along the channels can be effectively repaired by doping a small number of porphyrins. The well-repaired porphyrin channel exhibits the light-driven Cl- migration against a 3-fold concentration gradient, showing the ion pumping behavior. The bio-inspired artificial light-driven chloride pump provides a prospect for designing bioinspired responsive ion channel systems and high-performance optogenetics.

pH-Responsive antibacterial metal-phenolic network coating on hernia meshes.

Polypropylene (PP) mesh is widely used in hernioplasty, but it is prone to contamination by pathogenic bacteria. Here, we present an infection microenvironment-responsive metal-phenolic network (MPN) coating, which is made up of Cu2+ and tannic acid (TA) (referred to as CT coating), and is fabricated on PP meshes by layer-by-layer (LbL) assembly. The CT coating provided a robust protection for the PP mesh from pathogenic bacterial infection in a pH-responsive manner due to the pH-responsive disassembly kinetics of MPN complexes. Moreover, the PP meshes with ten CT coating cycles (PP-CT(10)) exhibited excellent stability in a physiological environment, with the killing ratio against "superbug" methicillin-resistant Staphylococcus aureus (MRSA) at pH 5.5 exceeding 99% even after 28 days of PBS (pH 7.4) immersion. In addition, the PP-CT(10) exhibited excellent in vivo anti-infective ability in a rodent subcutaneous implant MRSA infection model, and the results of histological and immunohistochemical analyses demonstrated that the reduced bacterial number alleviated the inflammatory response at implant sites. This study revealed that MPN coating is a promising strategy, which could provide a self-defensive ability for various implants to combat post-surgical infections in a pH-responsive manner.

Infection Microenvironment-Responsive Coating on Titanium Surfaces for On-Demand Release of Therapeutic Gas and Antibiotic.

Aseptic loosening and bacterial infection pose significant challenges in the clinical application of titanium (Ti) orthopedic implants, which are primarily caused by insufficient osseointegration and bacterial contamination. To address these issues, a responsive coating on Ti surface is constructed, which achieves enhanced osseointegration and infection elimination by on-demand release of therapeutic gas hydrogen sulfide (H2S) and antibiotic. TiO2 nanotubes (TNT) are anodized on the Ti surface to enhance its bioactivity and serve as reservoirs for the antibiotic. An infection microenvironment-responsive macromolecular H2S donor layer is coated on top of TNT to inhibit premature leakage of antibiotic. This layer exhibits a sustained release of low-dosage H2S, which is capable of promoting the osteogenic differentiation and migration of cells. Moreover, the compactness of the macromolecular H2S donor layer could be broken by bacterial invasion, leading to rapid antibiotic release thus preventing infection. In vitro antibacterial experiments validates significant antibacterial activity of the coating against both Gram-negative (Escherichia coli) and Gram-positive bacteria (Staphylococcus aureus). Crucially, this coating effectively suppresses implant-associated infection with 98.7% antibacterial efficiency in a rat femoral bone defect model, mitigates inflammation at the defect site and promotes osseointegration of the Ti orthopedic implant.

Synthesis of benzo[f][1,2]thiazepine 1,1-dioxides based on the visible-light-mediated aza Paternò-Büchi reaction of benzo[d]isothiazole 1,1-dioxides with alkenes.

A new two-step, one-pot synthesis of benzo[f][1,2]thiazepine 1,1-dioxides was developed, which contains a visible-light mediated aza Paternò-Büchi reaction of benzo[d]isothiazole 1,1-dioxides with alkenes and a Lewis acid catalyzed ring-expansion of azetidine. In this work, the mechanism of the aza Paternò-Büchi reaction was also investigated.

The hepatitis B virus promotes the progression of non-alcoholic fatty liver disease through incomplete autophagy.

Hepatitis B virus (HBV) infection is still a serious public health problem. In recent years, with the increasing incidence of chronic hepatitis B (CHB) combined with nonalcoholic fatty liver disease (NAFLD), a more in-depth exploration of the pathogenesis of CHB combined with NAFLD is required. HBV can induce autophagy and use to increase replication. The removal of fat by autophagy, also known as lipophagy, is also currently considered an alternative pathway for lipid metabolism in liver cells. This degradation of autophagy prevents hepatotoxicity and steatosis. However, it is not known whether there is a correlation between HBV-related autophagy and the progression of NAFLD. We explored how HBV affects disease progression in NAFLD should be " and determined whether it is associated with HBV-associated autophagy. In this study, we constructed HBV-TG mouse high-fat diet (HFD) models and controls, and the results showed that the presence of HBV promoted the occurrence of NAFLD. We also demonstrated that HBV promotes lipid droplet accumulation in hepatocytes using HBV-stable expression cell lines HepG2.2.15 and AML12-HBV. In addition, this study also found that exogenous OA supplementation reduced HBV replication. We further studied the mechanism and found that HBV-related autophagy can promote the absorption of liver cells to lipid droplets. It can reduce the decomposition of lipid droplets by inhibiting the function of autophagolysosome, and eventually lead to the accumulation of lipid droplets in hepatocytes. In a word, HBV promotes the progression of NAFLD by increasing lipid accumulation in hepatocytes through incomplete autophagy.

Recent advances in recurrent hepatocellular carcinoma therapy.

Hepatocellular carcinoma (HCC) is the most prevalent form of primary liver cancer, accounting for 75%-85% of cases. Although treatments are given to cure early-stage HCC, up to 50%-70% of individuals may experience a relapse of the illness in the liver after 5 years. Research on the fundamental treatment modalities for recurrent HCC is moving significantly further. The precise selection of individuals for therapy strategies with established survival advantages is crucial to ensuring better outcomes. These strategies aim to minimize substantial morbidity, support good life quality, and enhance survival for patients with recurrent HCC. For individuals with recurring HCC after curative treatment, no approved therapeutic regimen is currently available. A recent study presented novel approaches, like immunotherapy and antiviral medication, to improve the prognosis of patients with recurring HCC with the apparent lack of data to guide the clinical treatment. The data supporting several neoadjuvant and adjuvant therapies for patients with recurring HCC are outlined in this review. We also discuss the potential for future clinical and translational investigations.

The influence of early adoption of nonenhanced computed tomography on management of patients with pyogenic liver abscess.

Background and Aim: A pyogenic liver abscess (PLA) is an infectious disease with high in-hospital mortality. It has no specific symptoms and is difficult to be diagnosed early in the emergency department. Ultrasound is commonly used to detect PLA lesions of PLA, but its sensitivity can be affected by lesion size, location, and clinician experience. Therefore, early diagnosis and prompt treatment (especially abscess drainage) are crucial for better patient outcomes and should be prioritized by clinical physicians. Methods: We conducted a retrospective study to compare the effect of early and late (i.e., receiving CT scanning within 48 h and >48 h after admission) adoption of nonenhanced computed tomography (CT) scanning regarding the hospitalization days and interval between admission and drainage of patients with PLA. Results: This study included 76 hospitalized patients with PLA in the Department of Digestive Disease of Xiamen Chang Gung Hospital in China who underwent CT examinations from 2014 to 2021. We conducted CT scans on 56 patients within 48 h of admission and on 20 patients more than 48 h after admission. The early CT group had a significantly shorter hospitalization length compared with the late CT group (15.0 days vs. 20.5 days; P = 0.035). Besides, the median time to initiate drainage after admission was also significantly shorter in the early CT group than in the late CT group (1.0 days vs. 4.5 days; P < 0.001). Conclusion: Early CT scanning within 48 h of admission may aid in early PLA diagnosis and benefit disease recovery, as revealed by our findings.

Unconventional Dual Ion Selectivity Determined by the Forward Side of a Bipolar Channel toward Ion Flux.

Ion selectivity is an essential property of ion-selective membranes (ISMs). To date, all of the artificial ISMs have been reported to exhibit sole ion selectivity (SIS), either cation or anion selectivity. Here, we first demonstrate unconventional dual ion selectivity (DIS) in a bipolar channel membrane determined by the forward side toward ion flux. When the bipolar membrane meets the conditions of opposite ion selectivities and comparable resistance for both constructive layers, no matter which layer faces the ion flux, it functions as a selective layer and determines the selectivity of the whole membrane. The exploration of the unconventional DIS property inspires us to fabricate a new generation of ISMs, as well as other membranes for separation.

Analysis of the neural mechanism of spectra decrease in MCI by a thalamo-cortical coupled neural mass model.

Objective.In order to deeply understand the neurophysiological mechanism of the spectra decrease in mild cognitive impairment (MCI), this paper studies a new neural mass model, which can simulate various intracerebral electrophysiological activities.Approach. In this study, a thalamo-cortical coupled neural mass model (TCC-NMM) is proposed. The influences of the coupling coefficients and other key parameters on the model spectra are simulated. Then, the unscented Kalman filter (UKF) algorithm is used to reversely identify the parameters in the TCC-NMM. Furthermore, the TCC-NMM and UKF are combined to analyze the spectra reduction mechanism of electroencephalogram (EEG) signals in MCI patients. The independent sample t-test is carried out to statistical analyze the differences of the identified parameters between MCI and normal controls. The Pearson correlation analysis is used to analyze the intrinsic relationship between parameters and the scores of the comprehensive competence assessment scale.Main results.The simulation results show that the decreased cortical synaptic connectivity constantsC1can result in spectra decrease of the TCC-NMM outputs. The real EEG analysis results show that the identified values of parameterC1are significant lower in the MCI group than in control group in frontal and occipital areas and the parametersC1are positively correlated with the Montreal Cognitive Assessment (MoCA) scores in the two areas. This consistency suggests that the cortical synaptic connectivity loss from pyramidal cells to excitatory interneurons (eIN) may be one of the neural mechanisms of EEG spectra decrease in MCI.Significance. (a) In this study, a new mathematical model TCCNMM based on anatomy and neurophysiology is proposed. (b) All key parameters in TCC-NMM are studied in detail through the forward and reverse analysis and the influence of these parameters on the output spectra of the model is pointed out. (c) The possible neural mechanism of the decreased spectra in MCI patients is pointed out by the joint analysis of simulation in forward with TCC-NMM and analysis of the actual EEG signals in reverse with UKF identification algorithm. (d) We find that the identified parameter C1 of MCI patients is significantly lower than that of the control group, which is consistent with the simulation analysis of TCC-NMM. So, we suggest that the decreased MCI alpha power spectrum is likely related to the cortical synaptic connection loss from pyramidal cells to eIN.

A reversible shearing DNA probe for visualizing mechanically strong receptors in living cells.

In the last decade, DNA-based tension sensors have made significant contributions to the study of the importance of mechanical forces in many biological systems. Albeit successful, one shortcoming of these techniques is their inability to reversibly measure receptor forces in a higher regime (that is, >20 pN), which limits our understanding of the molecular details of mechanochemical transduction in living cells. Here, we developed a reversible shearing DNA-based tension probe (RSDTP) for probing molecular piconewton-scale forces between 4 and 60 pN transmitted by cells. Using these probes, we can easily distinguish the differences in force-bearing integrins without perturbing adhesion biology and reveal that a strong force-bearing integrin cluster can serve as a 'mechanical pivot' to maintain focal adhesion architecture and facilitate its maturation. The benefits of the RSDTP include a high dynamic range, reversibility and single-molecule sensitivity, all of which will facilitate a better understanding of the molecular mechanisms of mechanobiology.