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Sensory neurons, also known as afferent neurons, perceive noxious stimuli from internal as well as external environments through nociceptive receptors and then transmit these signals to the central nervous system. Similarly, the innate immune system also recognizes external and internal danger signals from invading microbes or tissue injuries. The immune system and sensory neurons share mechanisms to respond to pathogen/damage-associated molecular patterns (PAMPs/DAMPs) through pattern recognition receptors. Recent studies have identified an inseparable bidirectional connection between sensory neurons and the immune system that is important for maintaining tissue homeostasis and regulating inflammatory states, as well as affecting the progression of inflammatory diseases. This review summarizes the recent findings on the crosstalk between sensory neurons and local immunity in peripheral tissues, including the skin, respiratory system, gastrointestinal tract, cornea, and joints. Understanding the mechanisms of this interaction can help in the development of therapeutic strategies to treat peripheral inflammatory diseases.

Abstract HIV subtypes convey important epidemiological information and possibly influence the rate of disease progression. In this study, HIV disease progression in patients infected with CRF01_AE, CRF07_BC, and subtype B was compared in the largest HIV molecular epidemiology study ever done in China. A national data set of HIV pol sequences was assembled by pooling sequences from public databases and the Beijing HIV laboratory network. Logistic regression was used to assess factors associated with the risk of AIDS at diagnosis ([AIDSAD], defined as a CD4 count

Pain signals are relayed to the brain via a nociceptive system, and in rare cases, this nociceptive system contains genetic variants that can limit the pain response. Here, we questioned whether a human transient receptor potential vanilloid 1 (TRPV1) missense variant causes a resistance to noxious stimuli and, further, whether we could target this region with a cell-permeable peptide as a pain therapeutic. Initially using a computational approach, we identified a human K710N TRPV1 missense variant in an otherwise highly conserved region of mammalian TRPV1. After generating a TRPV1K710N-knockin mouse using CRISPR/Cas9, we discovered that the K710N variant reduced capsaicin-induced calcium influx in dorsal root ganglion neurons. The TRPV1K710N rodents also had less acute behavioral responses to noxious chemical stimuli and less hypersensitivity to nerve injury, while their response to noxious heat remained intact. Furthermore, blocking this K710 region in WT rodents using a cell-penetrating peptide limited acute behavioral responses to noxious stimuli and returned pain hypersensitivity induced by nerve injury to baseline levels. These findings identify K710 TRPV1 as a discrete site that is crucial for the control of nociception and provide insights into how to leverage rare genetic variants in humans to uncover fresh strategies for developing pain therapeutics.

Background Heart failure with preserved ejection fraction (HFpEF) accounts for 50% of patients with heart failure. Clinically, HFpEF prevalence shows age and gender biases. Although the majority of patients with HFpEF are elderly, there is an emergence of young patients with HFpEF. A better understanding of the underlying pathogenic mechanism is urgently needed. Here, we aimed to determine the role of aging in the pathogenesis of HFpEF. Methods and Results HFpEF dietary regimen (high‐fat diet + Nω‐Nitro‐L‐arginine methyl ester hydrochloride) was used to induce HFpEF in wild type and telomerase RNA knockout mice (second‐generation and third‐generation telomerase RNA component knockout), an aging murine model. First, both male and female animals develop HFpEF equally. Second, cardiac wall thickening preceded diastolic dysfunction in all HFpEF animals. Third, accelerated HFpEF onset was observed in second‐generation telomerase RNA component knockout (at 6 weeks) and third‐generation telomerase RNA component knockout (at 4 weeks) compared with wild type (8 weeks). Fourth, we demonstrate that mitochondrial respiration transitioned from compensatory state (normal basal yet loss of maximal respiratory capacity) to dysfunction (loss of both basal and maximal respiratory capacity) in a p53 dosage dependent manner. Last, using myocardial‐specific p53 knockout animals, we demonstrate that loss of p53 activation delays the development of HFpEF. Conclusions Here we demonstrate that p53 activation plays a role in the pathogenesis of HFpEF. We show that short telomere animals exhibit a basal level of p53 activation, mitochondria upregulate mtDNA encoded genes as a mean to compensate for blocked mitochondrial biogenesis, and loss of myocardial p53 delays HFpEF onset in high fat diet + Nω‐Nitro‐L‐arginine methyl ester hydrochloride challenged murine model.

Abstract Extracellular vesicles (EVs) have been proved a promising small interfering RNA (siRNA) delivery vehicle to mediate gene‐silencing. Tumour‐derived extracellular vesicles (TDEVs) as genetic exchange vectors in the tumour microenvironment, enable intercellular communication for a wide range of endogenous cargo molecules, such as RNAs and proteins. However, the oncogenic cargo of TDEVs limits their application in siRNA delivery for cancer therapy. Herein, we isolated TDEVs from hepatocellular carcinoma (HCC) cells and derived TDEV membranes by abandoning their content. Innovative TDEV membrane hybrid lipid nanovesicles (LEVs) were then fabricated by fusion of TDEV membranes and phospholipids to realize precise delivery to tumours and highly efficient transfection of siRNA. The TDEV membranes endow LEVs with ‘homing’ targeting ability, facilitating specific internalisation into parent HCC cells primarily through heparan sulfate proteoglycan‐mediated pathways. Unlike conventional lipid‐based nanovesicles, LEVs can bypass the endosomal degradation pathway, boost the delivery of siRNA through the Golgi and endoplasmic reticulum (ER) intracellular ‘freeway’ transportation, achieving a 1.7‐fold improvement in siRNA transfection efficiency compared with liposomes. Additionally, siRNA loaded LEVs were demonstrated to enhance the antitumour efficacy in HCC bearing mice through effective gene silencing in the tumour sites. Our results highlight the potential application of the TDEV membrane‐derived nanovesicles as an advanced siRNA delivery strategy for cancer therapy.

Recently, liposomes have been widely used in cancer therapeutics, but their anti-tumor effects are suboptimal due to limited tumor penetration. To solve this problem, researchers have made significant efforts to optimize liposomal diameters and potentials, but little attention has been paid to liposomal membrane rigidity. Herein, we sought to demonstrate the effects of cholesterol-tuned liposomal membrane rigidity on tumor penetration and anti-tumor effects. In this study, liposomes composed of hydrogenated soybean phospholipids (HSPC), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (DSPE-PEG2000) and different concentrations of cholesterol were prepared. It was revealed that liposomal membrane rigidity decreased with the addition of cholesterol. Moderate cholesterol content conferred excellent diffusivity to liposomes in simulated diffusion medium, while excessive cholesterol limited the diffusion process. We concluded that the differences of the diffusion rates likely stemmed from the alterations in liposomal membrane rigidity, with moderate rigidity leading to improved diffusion. Next, the in vitro tumor penetration and the in vivo anti-tumor effects were analyzed. The results showed that liposomes with moderate rigidity gained excellent tumor penetration and enhanced anti-tumor effects. These findings illustrate a feasible and effective way to improve tumor penetration and therapeutic efficacy of liposomes by changing the cholesterol content, and highlight the importance of liposomal membrane rigidity. KEY WORDS: Cholesterol, Liposomal membrane rigidity, Tumor penetration, Anti-tumor effects

Elastic optical networks (EONs) can make service accommodation more flexible and precise by employing efficient routing and spectrum allocation (RSA) algorithms. In order to improve the efficiency of RSA algorithms, the advanced-reservation technique was introduced into designing RSA algorithms. However, few of these advanced-reservation-based RSA algorithms were focused on the unavailable spectrum resources in EONs. In this paper, we propose an Advanced-Reservation-based Invalid-Spectrum-Aware (AR-ISA) resource allocation algorithm to improve the networking performance and the resource alignment of EONs. By employing a new index, Invalid Spectrum Rate (ISR), to record the proportion of unavailable spectrum resources in EONs, the proposed AR-ISA algorithm set a network load threshold to trigger the postponement of an arriving service. Compared with the traditional slack-based AR mechanism, the proposed algorithm has more concerns about the current spectrum usage of the path designated by the service than the conflicts between AR services and other existing services. To further increase the networking performance, the proposed algorithm adopts defragmentation to increase the number of available spectrum resources when postponing a service. Theoretical analysis and simulation results show that the proposed AR-ISA algorithm has obvious effectiveness in reducing the service blocking rate and increasing the spectrum alignment rate.

In the luminance domain, studies show that perceived contrasts of plaids are a nonlinear summation of their components. In the disparity domain, perceived depth has been studied by using a depth adaptation paradigm with simple surfaces; however, the relationship between depth adaptation between plaids and their components has not been investigated. To clarify this, combinations of disparity-defined horizontal corrugation (marked as horizontal ) and disparity-defined plaids as adaptor-probe pairs were used. Three experiments were performed: The first two compared the aftereffects between horizontal-horizontal and plaid-horizontal pairs (Comparison 1) and between horizontal-plaid and plaid-plaid pairs (Comparison 2). Experiments 1 and 2 controlled the plaids to have the same and doubled peak-to-trough amplitudes as the horizontal corrugation, respectively. In Comparison 1, the horizontal or horizontally oriented component of the plaids was adapted. In Comparison 2, the plaid adaptor or horizontally oriented component of the plaid test stimuli was adapted. Thus, depth adaptation may be linked to cyclopean-oriented depth-from-disparity bandpass filters. The depth adaptation degree was determined by the adaptation of amplitudes of the similar oriented channels between the adaptation and test stimuli. Experiment 3 compared the aftereffects between noise-horizontal and horizontal-horizontal pairs. Since the noise adaptor contained multispatial frequency channels, only the channels with similar spatial frequencies as the horizontal corrugation were adapted, thus causing smaller depth aftereffects.

MicroRNAs (miRs) can affect the progression of cervical cancer (CC). The present study investigated the function of miR‑145‑5p in CC and demonstrated its association with fascin (FSCN1). The expression levels of miR‑145‑5p in CC tissues and cell lines were analyzed using reverse transcription‑quantitative PCR, and its direct targets were explored using a luciferase reporter assay. The viability, migration and invasion of HeLa cells transfected with small interfering FSCN1 or with miR‑145‑5p mimics and inhibitors were analyzed using Cell Counting Kit‑8 and Transwell assays. The expression levels of FSCN1 mRNA and protein were investigated using reverse transcription PCR and western blotting. miR‑145‑5p was downregulated in CC tissues and cell lines. Moreover, overexpression of miR‑145‑5p inhibited the migration, invasion and viability of HeLa cells. miR‑145‑5p directly targeted FSCN1, which regulated the suppressive functions of miR‑145‑5p in CC cells. Overall, miR‑145‑5p is a tumor suppressor gene and a promising target for CC treatment. [ABSTRACT FROM AUTHOR]

RNA interference (RNAi) technology has shown great promise for the treatment of cancer and other genetic disorders. Despite the efforts to increase the target tissue distribution, the safe and effective delivery of siRNA to the diseased cells with sufficient cytosolic transport is another critical factor for successful RNAi clinical application. Here, the constructed lipid-based liquid crystalline nanoparticles, called nano-Transformers, can transform thestructure in the intracellular acidic environment and perform high-efficient siRNA delivery for cancer treatment. The developed nano-Transformers have satisfactory siRNA loading efficiency and low cytotoxicity. Different from the traditional cationic nanocarriers, the endosomal membrane fusion induced by the conformational transition of lipids contributes to the easy dissociation of siRNA from nanocarriers and direct release of free siRNA into cytoplasm. We show that transfection with cyclin-dependent kinase 1 (CDK1)-siRNA-loaded nano-Transformers causes up to 95% reduction of relevant mRNA in vitro and greatly inhibits the tumor growth without causing any immunogenic response in vivo. This work highlights that the lipid-based nano-Transformers may become the next generation of siRNA delivery system with higher efficacy and improved safety profiles. [ABSTRACT FROM AUTHOR]

Background and Aims: Compound Astragalus and Salvia miltiorrhiza extract (CASE) is made up of astragalosides, astragalus polysaccharide and salvianolic acids extracted from Astragalus membranaceus Bunge (Leguminosae) and Salvia miltiorhiza Bunge (Lamiaceae) with a standard ratio. Previous reports showed that CASE inhibited hepatic fibrosis by mediating transforming growth factor (TGF)-β/Smad signaling. This study further investigated the effect of CASE on hepatoma HepG2 cells stimulated by TGF-β1 and its potential action mechanisms by TGF-β/Smad signaling. Methods: Cell proliferation was studied by MTT assay and cell invasion was evaluated by measuring cell migration through Matrigel. Protein expression in hepatoma HepG2 cells stimulated by TGF-β1 was analyzed by western blotting and plasminogen activator inhibitor type 1 (PAI-1) transcriptional activity in HepG2 cells was evaluated. Results: CASE (40 µg/mL) markedly suppressed cell invasion triggered by TGF-β1. Smad3 phosphorylation at the linker region (pSmad3L) and Samd2 phosphorylation at the C-terminal region (pSmad2C) were significantly reduced by CASE. Mild elevated Smad3 phosphorylation at C-terminal (pSmade3C) region was enhanced by CASE at 20 µg/mL. In addition, treatment of CASE decreased the level of Smad2/3/4 complex at 80 µg/mL, but upregulated the expression of Smad7 in a dose-dependent manner. CASE also showed inhibitory effect on PAI-1 transcriptional activity. Conclusion: All these results suggest that CASE exerts anti-HepG2 cell invasion effect by modulating TGF-β/Smad signaling. [ABSTRACT FROM AUTHOR]

We introduce our latest research of the computed tomography Fourier transform imaging spectrometer that combines the advantages of both the computed tomography imaging spectrometer and the Fourier transform imaging spectrometer. In our previous work, there were still some problems such as the optical aberration in the optical system. Therefore, some significant improvements are made on the optical configuration of our new system. In this paper, the computational simulation of our new system is introduced. Both the interferogram-projection cube and the spectrum-projection cube are generated in the simulation experiment, and the filtered back projection algorithm is adopted in the image reconstruction. The results of the simulation demonstrate the feasibility of our new system. [ABSTRACT FROM AUTHOR]