Somatosensory neurons express specific sets of lincRNAs, and lincRNA CLAP promotes itch sensation in mice.

Somatosensory neurons are highly heterogeneous with distinct types of neural cells responding to specific stimuli. However, the distribution and roles of cell-type-specific long intergenic noncoding RNAs (lincRNAs) in somatosensory neurons remain largely unexplored. Here, by utilizing droplet-based single-cell RNA-seq (scRNA-seq) and full-length Smart-seq2, we show that lincRNAs, but not coding mRNAs, are enriched in specific types of mouse somatosensory neurons. Profiling of lincRNAs from single neurons located in dorsal root ganglia (DRG) identifies 200 lincRNAs localized in specific types or subtypes of somatosensory neurons. Among them, the conserved cell-type-specific lincRNA CLAP associates with pruritus and is abundantly expressed in somatostatin (SST)-positive neurons. CLAP knockdown reduces histamine-induced Ca2+ influx in cultured SST-positive neurons and in vivo reduces histamine-induced scratching in mice. In vivo knockdown of CLAP also decreases the expression of neuron-type-specific and itch-related genes in somatosensory neurons, and this partially depends on the RNA binding protein MSI2. Our data reveal a cell-type-specific landscape of lincRNAs and a function for CLAP in somatosensory neurons in sensory transmission.

Distinct neural networks derived from galanin-containing nociceptors and neurotensin-expressing pruriceptors.

Pain and itch are distinct sensations arousing evasion and compulsive desire for scratching, respectively. It's unclear whether they could invoke different neural networks in the brain. Here, we use the type 1 herpes simplex virus H129 strain to trace the neural networks derived from two types of dorsal root ganglia (DRG) neurons: one kind of polymodal nociceptors containing galanin (Gal) and one type of pruriceptors expressing neurotensin (Nts). The DRG microinjection and immunosuppression were performed in transgenic mice to achieve a successful tracing from specific types of DRG neurons to the primary sensory cortex. About one-third of nuclei in the brain were labeled. More than half of them were differentially labeled in two networks. For the ascending pathways, the spinothalamic tract was absent in the network derived from Nts-expressing pruriceptors, and the two networks shared the spinobulbar projections but occupied different subnuclei. As to the motor systems, more neurons in the primary motor cortex and red nucleus of the somatic motor system participated in the Gal-containing nociceptor-derived network, while more neurons in the nucleus of the solitary tract (NST) and the dorsal motor nucleus of vagus nerve (DMX) of the emotional motor system was found in the Nts-expressing pruriceptor-derived network. Functional validation of differentially labeled nuclei by c-Fos test and chemogenetic inhibition suggested the red nucleus in facilitating the response to noxious heat and the NST/DMX in regulating the histamine-induced scratching. Thus, we reveal the organization of neural networks in a DRG neuron type-dependent manner for processing pain and itch.

Phage-based delivery systems: engineering, applications, and challenges in nanomedicines.

Bacteriophages (phages) represent a unique category of viruses with a remarkable ability to selectively infect host bacteria, characterized by their assembly from proteins and nucleic acids. Leveraging their exceptional biological properties and modifiable characteristics, phages emerge as innovative, safe, and efficient delivery vectors. The potential drawbacks associated with conventional nanocarriers in the realms of drug and gene delivery include a lack of cell-specific targeting, cytotoxicity, and diminished in vivo transfection efficiency. In contrast, engineered phages, when employed as cargo delivery vectors, hold the promise to surmount these limitations and attain enhanced delivery efficacy. This review comprehensively outlines current strategies for the engineering of phages, delineates the principal types of phages utilized as nanocarriers in drug and gene delivery, and explores the application of phage-based delivery systems in disease therapy. Additionally, an incisive analysis is provided, critically examining the challenges confronted by phage-based delivery systems within the domain of nanotechnology. The primary objective of this article is to furnish a theoretical reference that contributes to the reasoned design and development of potent phage-based delivery systems.

Microfluidics-enabled fluorinated assembly of EGCG-ligands-siTOX nanoparticles for synergetic tumor cells and exhausted t cells regulation in cancer immunotherapy.

Immune checkpoint inhibitor (ICI)-derived evolution offers a versatile means of developing novel immunotherapies that targets programmed death-ligand 1 (PD-L1)/programmed death-1 (PD-1) axis. However, one major challenge is T cell exhaustion, which contributes to low response rates in "cold" tumors. Herein, we introduce a fluorinated assembly system of LFNPs/siTOX complexes consisting of fluorinated EGCG (FEGCG), fluorinated aminolauric acid (LA), and fluorinated polyethylene glycol (PEG) to efficiently deliver small interfering RNA anti-TOX (thymus high mobility group box protein, TOX) for synergistic tumor cells and exhausted T cells regulation. Using a microfluidic approach, a library of LFNPs/siTOX complexes were prepared by altering the placement of the hydrophobe (LA), the surface PEGylation density, and the siTOX ratio. Among the different formulations tested, the lead formulation, LFNPs3-3/siTOX complexes, demonstrated enhanced siRNA complexation, sensitive drug release, improved stability and delivery efficacy, and acceptable biosafety. Upon administration by the intravenous injection, this formulation was able to evoke a robust immune response by inhibiting PD-L1 expression and mitigating T cell exhaustion. Overall, this study provides valuable insights into the fluorinated assembly and concomitant optimization of the EGCG-based delivery system. Furthermore, it offers a promising strategy for cancer immunotherapy, highlighting its potential in improving response rates in ''cold'' tumors.

Fibroblastic SMOC2 Suppresses Mechanical Nociception by Inhibiting Coupled Activation of Primary Sensory Neurons.

Nociceptive information is detected and transmitted by neurons in the DRG. Recently, single-cell RNA sequencing has revealed the molecular profile of various cell types, including fibroblasts in the DRG. However, the role of molecules in fibroblasts needs to be elucidated in nociceptive regulation. Here, we found that secreted modular calcium-binding protein 2 (SMOC2) was secreted by fibroblasts to become a component of basement membrane and envelop the unit consisting of DRG neurons and attached satellite glial cells. KO of Smoc2 in both sexes of mice led to increased neuronal clusters and decreased mechanical threshold, but unchanged noxious thermal response. Knockdown of Smoc2 in the DRG phenocopied the behavioral performance by Smoc2 KO in both sexes of mice. In vivo calcium imaging showed that Smoc2 KO increased coupled activation of adjacent DRG neurons induced by nociceptive mechanical stimuli, which was reversed by DRG injection of SMOC2. Importantly, SMOC2 interacted with P2X7 receptor (P2X7R) and suppressed ATP-induced activation in HEK293 cells expressing this receptor. Injection of A740003, an antagonist of P2X7R, to the DRG reduced coupled activation of adjacent DRG neurons induced by nociceptive mechanical stimuli but did not further enhance the SMOC2-inhibited effect. Furthermore, peripheral inflammation resulted in a decreased SMOC2 and increased neuronal clusters. DRG injection of SMOC2 inhibited the neuronal coupling resulted from peripheral inflammation. This study reveals a specific role of fibroblastic SMOC2 in suppressing mechanical nociception through inhibiting the communication of adjacent DRG neurons, which provides an important mechanism of fibroblasts in nociceptive regulation.SIGNIFICANCE STATEMENT The function of fibroblastic molecules is rarely noticed in the regulation of nociceptive sensation. Here, we reveal that fibroblastic SMOC2 is secreted to be a component of basement membrane and surrounded the unit consisting of DRG neuron and attached satellite glial cells. SMOC2 is required for maintaining the basal mechanical nociceptive threshold in the DRG. Loss of SMOC2 leads to the increased coupled activation of adjacent DRG neurons induced by noxious mechanical stimuli. Peripheral inflammation causes decreased fibroblast cells and SMOC2, which may result in the increase of coupled activation of adjacent DRG neurons. Mechanistically, SMOC2 interacts with and suppresses satellite glial P2X7 receptor to inhibit the coupled activation of adjacent DRG neurons.

Simplified analysis and suppression of polarization aberration in planar symmetric optical systems.

Polarized remote sensing imaging has attracted more attention in recent years due to its wider detection information dimension compared to traditional imaging methods. However, the inherent instrument errors in optical systems can lead to errors in the polarization state of the incident and outgoing light, which is the polarization aberration of the optical system, resulting in a decrease in polarization detection accuracy. We propose a polarization aberration simplification calculation method for planar symmetric optical systems, by what only three ray samples are needed to obtain the distribution of polarization aberrations within the pupil. This method has a calculation accuracy close to traditional methods, and the sampling rate is 0.003 times that of traditional methods. Based on this, we designed a merit function that optimizes both wavefront and polarization aberrations simultaneously. It is found that diattenuation and retardance of the optical system are 62% and 58% of the original, and the polarization crosstalk term is reduced by 37% when the polarization weight factor takes an appropriate value. And at the same time, the wavefront aberration has also been well optimized.

Divergent Synthesis of Highly Substituted Tetrahydroquinolines and Cyclopentenes via Lewis Base Catalyzed Switchable [4 + 2] and [3 + 2] Annulations of MBH-Carbonates with Activated Olefins.

A highly selective and divergent synthesis which enabled access to various complex compounds is highly attractive in organic synthesis and medicinal chemistry. Herein, we developed an effective method for divergent synthesis of highly substituted tetrahydroquinolines via Lewis base catalyzed switchable annulations of Morita-Baylis-Hillman carbonates with activated olefins. The reaction displayed switchable [4 + 2] or [3 + 2] annulations via catalyst or substrate control, providing a diverse range of architectures which contained highly substituted tetrahydroquinolines or cyclopentenes with three contiguous stereocenters bearing a quaternary carbon center in high yields with excellent diastereoselectivities and regioselectivities. Furthermore, synthetic utility of this strategy was further highlighted by gram-scale experiments and simple transformations of the products.

Synergetic regulation of cancer cells and exhausted T cells to fight cold tumors with a fluorinated EGCG-based nanocomplex.

Immune therapy that targets PD-L1 (programmed cell death-ligand 1) is attractive to augment immune response by breaking the programmed cell death-1 (PD-1)/PD-L1 axis. However, T cell exhaustion associated with insufficient T cells infiltration may diminish the efficacy of cancer therapy. Here, we report a novel delivery system of FEGCG/FPEI@siTOX composed of fluorinated EGCG (FEGCG) and fluorinated polyethyleneimine (FPEI) for delivery of small interfering RNA anti-TOX (thymus high mobility group box protein, TOX) to treat tumor and metastasis. In this way, the reduction in PD-L1 expression by FEGCG can promote T-cell function, while inhibition of TOX expression with siTOX can alleviate T-cell exhaustion. FPEI are designed to deliver siRNA with high efficiency and low toxicity compared to classical PEI. Integrating FEGCG, FPEI and siTOX into such a novel system resulted in excellent anti-tumor and antimetastatic effects. It is a promising delivery system and potential strategy for the treatment of "cold" tumors.

Direction of arrival estimation method for ground source based on optimally polarized Rayleigh waves.

This paper points out a critical issue in the study of estimating the azimuth of ground sources by using the polarization characteristics of Rayleigh waves: even if the signal quality is good, the degree of polarization of Rayleigh waves varies across different frequency bands, and the band with the strongest energy is not the one with the lowest azimuth error. A direction of arrival estimation method for ground sources based on optimally polarized Rayleigh waves using a single three-component geophone is presented in this paper. First, the reciprocal ellipse rate, flatness coefficient, and the angle between the semi-minor axes and the horizontal plane are selected as the polarization parameters of this method according to two quantitative principles. Then the frequency band range of the optimal polarization Rayleigh wave is determined by analyzing the sum of the weights of the three polarization parameters in different frequency bands. After filtering and combining with the existing surface wave analysis method, the actual data bearing estimation result with an average error of only 4.95 degrees and a standard deviation of only 1.82 degrees is obtained. It is also found that the signal-to-noise ratio approximates the exponential decay of the direction of arrival error obtained by this method.

Advanced Computer Vision-Based Subsea Gas Leaks Monitoring: A Comparison of Two Approaches.

Recent years have witnessed the increasing risk of subsea gas leaks with the development of offshore gas exploration, which poses a potential threat to human life, corporate assets, and the environment. The optical imaging-based monitoring approach has become widespread in the field of monitoring underwater gas leakage, but the shortcomings of huge labor costs and severe false alarms exist due to related operators' operation and judgment. This study aimed to develop an advanced computer vision-based monitoring approach to achieve automatic and real-time monitoring of underwater gas leaks. A comparison analysis between the Faster Region Convolutional Neural Network (Faster R-CNN) and You Only Look Once version 4 (YOLOv4) was conducted. The results demonstrated that the Faster R-CNN model, developed with an image size of 1280 × 720 and no noise, was optimal for the automatic and real-time monitoring of underwater gas leakage. This optimal model could accurately classify small and large-shape leakage gas plumes from real-world datasets, and locate the area of these underwater gas plumes.

Substrate-Controlled Diversity-Oriented Synthesis of Novel Polycyclic Frameworks via [4 + 2] and [3 + 2] Annulations of Ninhydrin-Derived MBH Adducts with 3,4-Dihydroisoquinolines.

Substrate-controlled diversity-oriented synthesis of polycyclic frameworks via [4 + 2] and [3 + 2] annulations between ninhydrin-derived Morita-Baylis-Hillman (MBH) adducts and 3,4-dihydroisoquinolines under similar reaction conditions have been developed. The reaction provides diversity-oriented synthesis of a series of novel and structurally complex spiro multi heterocyclic skeletons in good yields (up to 87% and 90%, respectively) with excellent diastereoselectivities (up to >25:1 dr). In particular, the switchable [4 + 2] and [3 + 2] annulation reactions are controlled by tuning the hydroxyl protecting group on the ninhydrin-derived MBH adduct to deliver structural diverse spiro[indene-2,2'-[1,3]oxazino[2,3-a]isoquinoline] and spiro[indene-2,1'-pyrrolo[2,1-a]isoquinoline], respectively. Furthermore, the relative configuration and chemical structure of two kinds of cycloadducts were confirmed through X-ray diffraction analysis.

Effect of Perspective-Taking on Trust Between Doctors and Patients: A Randomized Controlled Trial.

Tension between doctors and patients as a social problem has existed for a long time; thus far, there is no good solution. From the perspective of trust between doctors and patients, this research studies the relieving effect of perspective-taking interventions on the tension between doctors and patients. This study used a randomized, single-blind online experiment. 133 participants were randomly divided into an intervention group (n = 67) and control group (n = 66). Participants were asked to complete writing tasks from the doctor's perspective. Patients' trust in doctors was measured at 3 time points: before intervention, immediately after intervention, and 10 days after the intervention. Findings showed a significant interaction effect between time measurement and group. In the intervention group, a pairwise comparison of time measurements showed a significant difference between T1 and T2. Perspective-taking interventions can improve patients' trust in doctors, but this effect diminishes over time.

TBAI-Catalyzed S-H and N-H Insertion Reactions of α-Diazoesters with Thiophenols and Amines under Metal-Free Conditions.

Mild, convenient, and effective TBAI-catalyzed S-H and N-H insertion reactions of α-diazoesters with thiophenols and aromatic amines under metal-free conditions have been described, furnishing a straightforward and general platform for the synthesis of various thioethers and 2-amino-2-oxoacetates in moderate to excellent yields. Moreover, this strategy features simple operation, mild conditions, broad substrate scope, and easy scale-up.

Copper-Catalyzed Regio- and Stereoselective Sulfonylation of Alkynyl Imines with Sulfonyl Hydrazides: Access to (E)-ß-Sulfonyl Enones.

A copper-catalyzed sulfonylation of alkynyl imines with sulfonyl hydrazides has been developed, which exhibited excellent regio- and stereoselectivity and furnished a series of (E)-ß-sulfonyl enones in moderate to good yields. Mechanistic studies suggest that this strategy goes through a radical process.

Substrate-Controlled Regioselectivity Switchable [3 + 2] Annulations To Access Spirooxindole Skeletons.

The additive-free [3 + 2] annulation from isatins, amino acids with 2-styrylbenzoxazoles, was described, providing a series of functional and structurally complex 3,3'-pyrrolidinyl-spirooxindole derivatives containing four contiguous and two quaternary stereogenic centers in high yields (up to 95%) and excellent diastereoselectivities (up to >25:1 dr). Interestingly, the reaction exhibits switchable regioselectivity depending on the substrate of amino acids. With proline or thioproline as the substrate, the reaction afforded α-regioselective spirooxindole skeletons. In contrast, when piperidine acid is the substrate, the reaction provided γ-regioselective spirooxindole skeletons.

Synthesis of 1,3,5-trisubstituted pyrazoles via 1,3-dipolar cycloaddition of nitrile imines with ninhydrin-derived Morita-Baylis-Hillman carbonates.

An effective synthetic method for 1,3,5-trisubstituted pyrazoles via 1,3-dipolar cycloaddition reaction has been developed. This reaction could smoothly proceed between ninhydrin-derived Morita-Baylis-Hillman carbonates and nitrilimines to provide a wide scope of differently substituted pyrazoles in high yields (up to 95%). In addition, the reaction mechanism was also proposed to explain its regioselectivity.

Polarization Super-Resolution Imaging Method Based on Deep Compressed Sensing.

The division of focal plane (DoFP) polarization imaging sensors, which can simultaneously acquire the target's two-dimensional spatial information and polarization information, improves the detection resolution and recognition capability by capturing the difference in polarization characteristics between the target and the background. In this paper, we propose a novel polarization imaging method based on deep compressed sensing (DCS) by adding digital micromirror devices (DMD) to an optical system and simulating the polarization transmission model of the optical system to reconstruct high-resolution images under low sampling rate conditions. By building a simulated dataset, training a polarization super-resolution imaging network, and showing excellent reconstructions on real shooting scenes, compared to current algorithms, our model has a higher peak signal-to-noise ratio (PSNR), which validates the feasibility of our approach.

Synergetic Fermentation of Glucose and Glycerol for High-Yield N-Acetylglucosamine Production in Escherichia coli.

N-acetylglucosamine (GlcNAc) is an amino sugar that has been widely used in the nutraceutical and pharmaceutical industries. Recently, microbial production of GlcNAc has been developed. One major challenge for efficient biosynthesis of GlcNAc is to achieve appropriate carbon flux distribution between growth and production. Here, a synergistic substrate co-utilization strategy was used to address this challenge. Specifically, glycerol was utilized to support cell growth and generate glutamine and acetyl-CoA, which are amino and acetyl donors, respectively, for GlcNAc biosynthesis, while glucose was retained for GlcNAc production. Thanks to deletion of the 6-phosphofructokinase (PfkA and PfkB) and glucose-6-phosphate dehydrogenase (ZWF) genes, the main glucose catabolism pathways of Escherichia coli were blocked. The resultant mutant showed a severe defect in glucose consumption. Then, the GlcNAc production module containing glucosamine-6-phosphate synthase (GlmS*), glucosamine-6-phosphate N-acetyltransferase (GNA1*) and GlcNAc-6-phosphate phosphatase (YqaB) expression cassettes was introduced into the mutant, to drive the carbon flux from glucose to GlcNAc. Furthermore, co-utilization of glucose and glycerol was achieved by overexpression of glycerol kinase (GlpK) gene. Using the optimized fermentation medium, the final strain produced GlcNAc with a high stoichiometric yield of 0.64 mol/mol glucose. This study offers a promising strategy to address the challenge of distributing carbon flux in GlcNAc production.

NIR-II AIEgens with Photodynamic Effect for Advanced Theranostics.

Phototheranostics that concurrently integrates accurate diagnosis (e.g., fluorescence and photoacoustic (PA) imaging) and in situ therapy (e.g., photodynamic therapy (PDT) and photothermal therapy (PTT)) into one platform represents an attractive approach for accelerating personalized and precision medicine. The second near-infrared window (NIR-II, 1000-1700 nm) has attracted considerable attention from both the scientific community and clinical doctors for improved penetration depth and excellent spatial resolution. NIR-II agents with a PDT property as well as other functions are recently emerging as a powerful tool for boosting the phototheranostic outcome. In this minireview, we summarize the recent advances of photodynamic NIR-II aggregation-induced emission luminogens (AIEgens) for biomedical applications. The molecular design strategies for tuning the electronic bandgaps and photophysical energy transformation processes are discussed. We also highlight the biomedical applications, such as image-guided therapy of both subcutaneous and orthotopic tumors, and multifunctional theranostics in combination with other treatment methods, including chemotherapy and immunotherapy; and the precise treatment of both tumor and bacterial infection. This review aims to provide guidance for PDT agents with long-wavelength emissions to improve the imaging precision and treatment efficacy. We hope it will provide a comprehensive understanding about the chemical structure-photophysical property-biomedical application relationship of NIR-II luminogens.

Facile Synthesis of Tricyclic 1,2,4-Oxadiazolines-Fused Tetrahydro-Isoquinolines from Oxime Chlorides with 3,4-Dihydroisoquinoline Imines.

A mild and efficient strategy for the synthesis of tricyclic 1,2,4-oxadiazolines-fused tetrahydro-isoquinolines derivatives via [3 + 2] cycloaddition reaction is reported. The reactions provided the functionalized tricyclic 1,2,4-oxadiazolines in high yields (up to 96%). This protocol is simple and easy to handle. Moreover, a gram-scale experiment further highlights the synthetic utility. The chemical structure of the product was determined by X-ray single-crystal structure analysis. A possible mechanism for this transformation is proposed to explain the reaction process.