Role of NaV1.7 in postganglionic sympathetic nerve function in human and guinea-pig arteries.

NaV1.7 plays a crucial role in inducing and conducting action potentials in pain-transducing sensory nociceptor fibres, suggesting that NaV1.7 blockers could be effective non-opioid analgesics. While SCN9A is expressed in both sensory and autonomic neurons, its functional role in the autonomic system remains less established. Our single neuron rt-PCR analysis revealed that 82% of sympathetic neurons isolated from guinea-pig stellate ganglia expressed NaV1.7 mRNA, with NaV1.3 being the only other tetrodotoxin-sensitive channel expressed in approximately 50% of neurons. We investigated the role of NaV1.7 in conducting action potentials in postganglionic sympathetic nerves and in the sympathetic adrenergic contractions of blood vessels using selective NaV1.7 inhibitors. Two highly selective NaV1.7 blockers, GNE8493 and PF 05089771, significantly inhibited postganglionic compound action potentials by approximately 70% (P < 0.01), with residual activity being blocked by the NaV1.3 inhibitor, ICA 121431. Electrical field stimulation (EFS) induced rapid contractions in guinea-pig isolated aorta, pulmonary arteries, and human isolated pulmonary arteries via stimulation of intrinsic nerves, which were inhibited by prazosin or the NaV1 blocker tetrodotoxin. Our results demonstrated that blocking NaV1.7 with GNE8493, PF 05089771, or ST2262 abolished or strongly inhibited sympathetic adrenergic responses in guinea-pigs and human vascular smooth muscle. These findings support the hypothesis that pharmacologically inhibiting NaV1.7 could potentially reduce sympathetic and parasympathetic function in specific vascular beds and airways. KEY POINTS: 82% of sympathetic neurons isolated from the stellate ganglion predominantly express NaV1.7 mRNA. NaV1.7 blockers inhibit action potential conduction in postganglionic sympathetic nerves. NaV1.7 blockade substantially inhibits sympathetic nerve-mediated adrenergic contractions in human and guinea-pig blood vessels. Pharmacologically blocking NaV1.7 profoundly affects sympathetic and parasympathetic responses in addition to sensory fibres, prompting exploration into the broader physiological consequences of NaV1.7 mutations on autonomic nerve activity.

Direct activation of airway sensory C-fibers by SARS-CoV-2 S1 spike protein.

Respiratory viral infection can lead to activation of sensory afferent nerves as indicated by the consequential sore throat, sneezing, coughing, and reflex secretions. In addition to causing troubling symptoms, sensory nerve activation likely accelerates viral spreading. The mechanism how viruses activate sensory nerve terminals during infection is unknown. In this study, we investigate whether coronavirus spike protein activates sensory nerves terminating in the airways. We used isolated vagally-innervated mouse trachea-lung preparation for two-photon microscopy and extracellular electrophysiological recordings. Using two-photon Ca2+ imaging, we evaluated a total number of 786 vagal bronchopulmonary nerves in six experiments. Approximately 49% of the sensory fibers were activated by S1 protein (4 µg/mL intratracheally). Extracellular nerve recording showed the S1 protein evoked action potential discharge in sensory C-fibers; of 39 airway C-fibers (one fiber per mouse), 17 were activated. Additionally, Fura-2 Ca2+ imaging was performed on neurons dissociated from vagal sensory ganglia (n = 254 from 22 mice). The result showed that 63% of neurons responded to S1 protein. SARS-CoV-2 S1 protein can lead to direct activation of sensory C-fiber nerve terminals in the bronchopulmonary tract. Direct activation of C-fibers may contribute to coronavirus symptoms, and amplify viral spreading in a population.

Single-Layer GaInSe3: Promising Water-Splitting Photocatalyst with Solar Conversion Efficiency over 30% from Theoretical Calculations.

Hydrogen energy from solar water-splitting is known as an ideal method with which to address the energy crisis and global environmental pollution. Herein, the first-principles calculations are carried out to study the photocatalytic water-splitting performance of single-layer GaInSe3 under biaxial strains from -2% to +2%. Calculations reveal that single-layer GaInSe3 under various biaxial strains has electronic bandgaps ranging from 1.11 to 1.28 eV under biaxial strain from -2% to +2%, as well as a completely separated valence band maximum and conduction band minimum. Meanwhile, the appropriate band edges for water-splitting and visible optical absorption up to ~3 × 105 cm-1 are obtained under biaxial strains from -2% to 0%. More impressively, the solar conversion efficiency of single-layer GaInSe3 under biaxial strains from -2% to 0% reaches over 30%. The OER of unstrained single-layer GaInSe3 can proceed without co-catalysts. These demonstrate that single-layer GaInSe3 is a viable material for solar water-splitting.

Advances in Low-Temperature Dual-Ion Batteries.

Fabricating rechargeable batteries for low-temperature (LT) applications is highly desired at high altitudes/latitudes, aerospace/subsea exploration, and defense. Lithium-ion batteries (LIBs) suffer from severe loss of capacity and energy/power density at sub-zero temperatures caused by the sluggish kinetics. By utilizing both cations and anions as charge carriers, dual-ion batteries (DIBs) become a nascent battery system for LT tolerance by overcoming ion-desolvation during discharge. Here, we summarize recent advances in LT DIBs. To begin with, distinctive advantages of DIBs at LTs are highlighted compared to LIBs, with a special attention to anion (de-)intercalation, and the in-depth understanding of key challenges for LT operation is discussed. The next major section deals with the exciting progress on the advanced strategies to improve the LT performance of DIBs, including alternative electrode materials, reliable electrolyte formulations, and construction of interphase protective layers. Finally, prospects and future developments in this exciting field of LT DIBs are suggested.

Case report: Myocarditis following COVID-19 protein subunit vaccination.

We report findings in a 34-year-old female patient who presented with fulminant myocarditis 8 days after receiving the first dose of the ZF2001 RBD-subunit vaccine against coronavirus disease 2019 (COVID-19). Autopsy showed severe interstitial myocarditis, including multiple patchy infiltrations of lymphocytes and monocytes in the myocardium of the left and right ventricular walls associated with myocyte degeneration and necrosis. This report highlights the details of clinical presentations and autopsy findings of myocarditis after ZF2001 (RBD-subunit vaccine) vaccination. The correlation between vaccination and death due to myocarditis is discussed.

Early pregnancy exposure to beta-cypermethrin compromises endometrial decidualisation in mice via downregulation of cyclin D3, CDK4/6, and p21.

Beta-cypermethrin (ß-CYP) is a highly effective broad-spectrum insecticide that can potentially affect female reproduction. However, little is known about the effect of ß-CYP on uterine decidualisation, which is a vital process by which the uterus provides a suitable microenvironment for pregnancy maintenance. Therefore, we focused on the effect and mechanism of ß-CYP on endometrial decidualisation during early pregnancy in mice. The results indicated that the expression levels of HOXA10, BMP2, and IGFBP1 was significantly downregulated in the decidual tissue and primary endometrial stromal cells of pregnant and pseudopregnant mice following ß-CYP treatment. Serum E2 concentration was significantly increased, whereas P4 concentration and oestrogen receptor (ERα) and progesterone receptor (PRA) expression were significantly downregulated following ß-CYP exposure. The number of polyploid decidual cells was lower in the ß-CYP-treated group. Furthermore, ß-CYP significantly downregulated the protein expression levels of CDK4 and CDK6, and the mRNA expression levels of cyclin D3 and p21. The number of foetuses per female in the first litter was markedly reduced following exposure to ß-CYP. In summary, early pregnancy exposure to ß-CYP may result in defective endometrial decidualisation via compromised proliferation of uterine stromal cells and reduced expressions of cyclin D3, CDK4/6, and p21 in mice.

The dynamics of chemically propelled dimer motors on a pinning substrate.

The dynamics of self-propelled micro-motors, in a thin fluid film containing an attractive substrate, is investigated by means of a particle-based simulation. A chemically powered sphere dimer, consisting of a catalytic and a noncatalytic sphere, may be captured by a trap on the substrate and consequently rotates around the trap center. A pair of trapped dimers spontaneously forms various configurations, including anti-parallel aligned doublets and head-to-tail rotating doublets. Small traps randomly distributed on the substrate are capable of pinning the dimers. The diffusion coefficient decreases with increasing pinning force or the pinning density, and it falls quickly at a certain critical pinning force beyond which the dimer motor is pinned completely. It is found that the pin array on the substrate gives rise to the formation of clusters of dimers and the underlying mechanism is discussed.

KV 1/D-type potassium channels inhibit the excitability of bronchopulmonary vagal afferent nerves.

The KV 1/D-type potassium current (ID ) is an important determinant of neuronal excitability. This study explored whether and how ID channels regulate the activation of bronchopulmonary vagal afferent nerves. The single-neuron RT-PCR assay revealed that nearly all mouse bronchopulmonary nodose neurons expressed the transcripts of α-dendrotoxin (α-DTX)-sensitive, ID channel-forming KV 1.1, KV 1.2 and/or KV 1.6 α-subunits, with the expression of KV 1.6 being most prevalent. Patch-clamp recordings showed that ID , defined as the α-DTX-sensitive K+ current, activated at voltages slightly more negative than the resting membrane potential in lung-specific nodose neurons and displayed little inactivation at subthreshold voltages. Inhibition of ID channels by α-DTX depolarized the lung-specific nodose neurons and caused an increase in input resistance, decrease in rheobase, as well as increase in action potential number and firing frequency in response to suprathreshold current steps. Application of α-DTX to the lungs via trachea in the mouse ex vivo vagally innervated trachea-lungs preparation led to action potential discharges in nearly half of bronchopulmonary nodose afferent nerve fibres, including nodose C-fibres, as detected by the two-photon microscopic Ca2+ imaging technique and extracellular electrophysiological recordings. In conclusion, ID channels act as a critical brake on the activation of bronchopulmonary vagal afferent nerves by stabilizing the membrane potential, counterbalancing the subthreshold depolarization and promoting the adaptation of action potential firings. Down-regulation of ID channels, as occurs in various inflammatory diseases, may contribute to the enhanced C-fibre activity in airway diseases that are associated with excessive coughing, dyspnoea, and reflex bronchospasm and secretions. KEY POINTS: The α-dendrotoxin (α-DTX)-sensitive D-type K+ current (ID ) is an important determinant of neuronal excitability. Nearly all bronchopulmonary nodose afferent neurons in the mouse express ID and the transcripts of α-DTX-sensitive, ID channel-forming KV 1.1, KV 1.2 and/or KV 1.6 α-subunits. Inhibition of ID channels by α-DTX depolarizes the bronchopulmonary nodose neurons, reduces the minimal depolarizing current needed to evoke an action potential (AP) and increases AP number and AP firing frequency in response to suprathreshold stimulations. Application of α-DTX to the lungs ex vivo elicits AP discharges in about half of bronchopulmonary nodose C-fibre terminals. Our novel finding that ID channels act as a critical brake on the activation of bronchopulmonary vagal afferent nerves suggests that their down-regulation, as occurs in various inflammatory diseases, may contribute to the enhanced C-fibre activity in airway inflammation associated with excessive respiratory symptoms.

The expression of lincRNA AC027700.1 in mouse decidualization.

Long non-coding RNAs (lncRNAs), which belong to the non-protein-coding RNAs, are greater than 200 nt in length. Although they have been found to play crucial roles in the regulation of cell growth and development, cell metabolism and the development of diseases, they are rarely reported in decidualization. The objective of our study is to explore the expression of lincRNA AC027700.1 in the endometrium of early pregnant mice and its role in decidualization. The expression of AC027700.1 in uterine tissues at implantation sites and inter implantation sites on the 6th day of pregnancy were detected by qRT-PCR. The relative expression of AC027700.1 in an in vivo model of induced decidualization in pseudopregnant mice and in in vitro model of induced decidualization in primary stromal cells and nucleus/cytoplasmic fractions were detected by qRT-PCR. GO and KEGG analysis of downstream target genes were performed by GOseq and KOBAS, respectively. The results show that AC027700.1 expression is significantly increased in tissues at implantation sites on the 6th day of pregnancy and in decidualized endometrial tissues and stromal cells. Furthermore, AC027700.1 localizes in the nuclear fraction and the downstream targeted genes are mainly involved in autophagy, cell cycle and RNA transport pathways. This study revealed that lincRNA AC027700.1 may be involved in decidualization of endometrium in early pregnancy, but the specific role and regulatory mechanism remain to be further studied.

MrMYB44-Like Negatively Regulates Anthocyanin Biosynthesis and Causes Spring Leaf Color of Malus 'Radiant' to Fade From Red to Green.

The "Spring-red-leaf" crabapple cultivar has young red leaves and mature green leaves. However, the mechanism of anthocyanin biosynthesis in crabapple leaves in spring remains unknown. In this study, Illumina RNA sequencing (RNA-Seq) was performed on Malus 'Radiant' leaf tissues in different stages of development. Twenty-two genes in the anthocyanin biosynthesis pathway and 44 MYB transcription factors (TFs) were significantly enriched among differentially expressed genes (DEGs). Three R2R3-MYB TFs in subgroup 22 of the MYB TF family, MrMYB44-like1, MrMYB44-like2, and MrMYB44-like3, were highly expressed in green leaves according to RNA-Seq and quantitative real-time quantitative PCR results. Their expression levels were negatively correlated with anthocyanin content. In transient assays, overexpression of MrMYB44-like1, MrMYB44-like2, or MrMYB44-like3 inhibited anthocyanin accumulation and reduced pigment in leaf disks of M. 'Radiant' and fruit peels of M. domestica 'Fuji.' When the conserved region of the three MrMYB44-likes was silenced, the anthocyanin biosynthesis pathway was activated and pigments increased in both tissues. Moreover, bimolecular fluorescence complementation assays showed MrMYB44-likes interacted with MrWRKY6 to form protein complexes that regulated anthocyanin biosynthesis.

Role of NaV 1.7 in action potential conduction along human bronchial vagal afferent C-fibres.

BACKGROUND AND PURPOSE: The purpose of this study was to determine the role of NaV 1.7 in action potential conduction in C-fibres in the bronchial branches of the human vagus nerve. EXPERIMENTAL APPROACH: Bronchial branches of the vagus nerve were dissected from human donor tissue. The C-wave of the electrically evoked compound action potential was quantified in the absence and presence of increasing concentrations of the selective NaV 1.7 blocking drugs, PF-05089771 and ST-2262, as well as the NaV 1.1, 1.2, and 1.3 blocking drug ICA121-431. The efficacy and potency of these inhibitors were compared to the standard NaV 1 blocker, tetrodotoxin. We then compared the relative potencies of the NaV 1 blockers in inhibiting the C-wave of the compound action potential, with their ability to inhibit parasympathetic cholinergic contraction of human isolated bronchi, a response previously shown to be strictly dependent on NaV 1.7 channels. KEY RESULTS: The selective NaV 1.7 blockers inhibited the C-wave of the compound action potential with potencies similar to that observed in the NaV 1.7 bronchial contractions assay. Using rt-PCR, we noted that NaV 1.7 mRNA was strongly expressed and transported down the vagus nerve bundles. CONCLUSIONS AND IMPLICATIONS: NaV 1.7 blockers can prevent action potential conduction in the majority of vagal C-fibres arising from human bronchi. Blockers of NaV 1.7 channels may therefore have value in inhibiting the responses to excessive airway C-fibre activation in inflammatory airway disease, responses that include coughing as well as reflex bronchoconstriction and secretions.

Analysis on cancer incidence and mortality attributed to human papillomavirus infection in China, 2016 / 中华流行病学杂志

Objective: We aim to evaluate the morbidity and mortality of cancer attributable to human papillomavirus (HPV) infection in China in 2016. Methods: Based on the cancer incidence and mortality rates, national population data, and population attributable fraction (PAF) in China, we calculated the number of incidence and death cases attributed to HPV infection in different areas, age groups, and gender in China in 2016. The standardized incidence and mortality rates for cancer attributed to HPV infection were calculated by using Segi's population. Results: In 2016, a total of 124 772 new cancer cases (6.32 per 100 000) were attributed to HPV infection in China, including 117 118 cases in women and 7 654 cases in men. Of these cancers, cervical cancer was the most common one, followed by anal cancer, oropharyngeal cancer, penile cancer, vaginal cancer, laryngeal cancer, oral cancer, and vulvar cancer. A total of 41 282 (2.03 per 100 000) deaths were attributed to HPV infection, of which 37 417 occurred in women and 3 865 in men. Most deaths were caused by cervical cancer, followed by anal cancer, oropharyngeal cancer, penile cancer, laryngeal cancer, vaginal cancer, oral cancer, and vulvar cancer. The incidence and mortality rates of cervical cancer increased rapidly with age, peaked in age group 50-54 years, then decreased obviously. The morbidity and mortality rates of non-cervical cancer increased with age. The cancer case and death numbers in rural areas (57 089 cases and 19 485 deaths) were lower than those in urban areas (67 683 cases and 21 797 deaths). However, the age-standardized incidence rate (ASIR) and age-standardized mortality rate (ASMR) of cervical cancer were higher in rural areas than in urban areas. There were no significant differences in ASIR and ASMR of non-cervical cancers between urban areas and rural areas. Conclusions: The incidence of cancers attributed to HPV infection in China was lower than the global average, but the number of incidences accounted largely, furthermore there is an increasing trend of morbidity and mortality. The preventions and controls of cervical cancer and male anal cancer are essential to contain the increases in cancer cases and deaths attributed to HPV infection.

Midterm outcomes of penetrating keratoplasty following allogeneic cultivated limbal epithelial transplantation in patients with bilateral limbal stem cell deficiency.

AIM: To evaluate the midterm outcomes of penetrating keratoplasty (PK) following allogeneic cultivated limbal epithelial transplantation (CLET) for bilateral total limbal stem cell deficiency (LSCD). METHODS: Ten patients (10 eyes) with bilateral LSCD were enrolled in this prospective noncomparative case series study. Each participant underwent PK approximately 6mo after a CLET. Topical tacrolimus, topical and systemic steroids, and oral ciclosporin were administered postoperatively. Best-corrected visual acuity (BCVA), intraocular pressure (IOP), ocular surface grading scores (OSS), corneal graft epithelial rehabilitation, persistent epithelial defect (PED), immunological rejection, and graft survival rate were assessed. RESULTS: The time interval between PK and allogeneic CLET was 6.90±1.29 (6-10)mo. BCVA improved from 2.46±0.32 logMAR preoperatively to 0.77±0.55 logMAR post-PK (P<0.001). Kaplan-Meier analysis of mean graft survival revealed graft survival rates of 100% at 12 and 24mo and 80.0% at 36mo. PEDs appeared in 5 eyes at different periods post-PK, and graft rejection occurred in 4 eyes. The total OSS decreased from 12.4±4.4 before allogeneic CLET to 1.4±1.51 after PK. CONCLUSION: A sequential therapy design of PK following allogeneic CLET can maintain a stable ocular surface with improved BCVA despite the relatively high graft rejection rate.

miR-21a inhibits decidual cell apoptosis by targeting Pdcd4.

Decidualization of endometrial stromal cells (ESCs) accompanied with embryo implantation is a key process in mammalian reproduction. Evidence suggests that maintenance of decidual cells function is essential. As a critical part in post-transcriptional gene regulation, microRNAs (miRNAs/miR) have been confirmed to be involved in decidualization. However, whether microRNAs regulate decidual cells function has not been reported. Aiming to clarify the role and potential mechanism of miRNAs in decidual cells, artificial induced decidualization model in mice was established. There are 94 differentially expressed miRNAs (≥two-fold change) between decidualized and non-decidualized tissues, including 60 upregulated and 34 downregulated miRNAs. Of the differentially expressed miRNAs, mmu-miR-21a is up-regulated. RT-qPCR also confirmed the up-regulation of mmu-miR-21a following decidualization in vivo and in vitro, and bioinformatic analysis and luciferase activity assay revealed Pdcd4 to be the target gene of mmu-miR-21a. Inhibition of mmu-miR-21a restrained secretory function of decidual cells induced by mESCs, accompanied with increase of Pdcd4 expression and resulted in the increase of cell apoptosis. In addition, we also determined the expression of hsa-miR-21 and Pdcd4 in human proliferative endometrial tissues and decidua tissues. hsa-miR-21 showed higher expression in human decidua tissues compared with proliferative endometrial tissues, while expression of Pdcd4 was contrary to that of hsa-miR-21. Similarly, cell apoptosis increased significantly in human endometrial stromal cell line in response to inhibition of hsa-miR-21. Collectively, we conclude that mmu-miR-21a/hsa-miR-21 may play a key role in regulating the function of decidual cells by inhibiting cell apoptosis through targeting Pdcd4.

Acute activation of bronchopulmonary vagal nociceptors by type I interferons.

KEY POINTS: Type I interferon receptors are expressed by the majority of vagal C-fibre neurons innervating the respiratory tract Interferon alpha and beta acutely and directly activate vagal C-fibers in the airways. The interferon-induced activation of C-fibers occurs secondary to stimulation of type 1 interferon receptors Type 1 interferons may contribute to the symptoms as well as the spread of respiratory viral infections by causing coughing and other defensive reflexes associated with vagal C-fibre activation ABSTRACT: We evaluated the ability of type I interferons to acutely activate airway vagal afferent nerve terminals in mouse lungs. Using single cell RT-PCR of lung-specific vagal neurons we found that IFNAR1 and IFNAR2 were expressed in 70% of the TRPV1-positive neurons (a marker for vagal C-fibre neurons) and 44% of TRPV1-negative neurons. We employed an ex vivo vagal innervated mouse trachea-lung preparation to evaluate the effect of interferons in directly activating airway nerves. Utilizing 2-photon microscopy of the nodose ganglion neurons from Pirt-Cre;R26-GCaMP6s mice we found that applying IFNα or IFNß to the lungs acutely activated the majority of vagal afferent nerve terminals. When the type 1 interferon receptor, IFNAR1, was blocked with a blocking antibody the response to IFNß was largely inhibited. The type 2 interferon, IFNγ, also activated airway nerves and this was not inhibited by the IFNAR1 blocking antibody. The Janus kinase inhibitor GLPG0634 (1 µm) virtually abolished the nerve activation caused by IFNß. Consistent with the activation of vagal afferent C-fibers, infusing IFNß into the mouse trachea led to defensive breathing reflexes including apneas and gasping. These reflexes were prevented by pretreatment with an IFN type-1 receptor blocking antibody. Finally, using whole cell patch-clamp electrophysiology of lung-specific neurons we found that IFNß (1000 U ml-1 ) directly depolarized the membrane potential of isolated nodose neurons, in some cases beyond to action potential threshold. This acute non-genomic activation of vagal sensory nerve terminals by interferons may contribute to the incessant coughing that is a hallmark of respiratory viral infections.

Stimulus intensity-dependent recruitment of NaV1 subunits in action potential initiation in nerve terminals of vagal C-fibers innervating the esophagus.

We investigated voltage-gated sodium channel (NaV1) subunits that regulate action potential initiation in the nerve terminals of vagal nodose C-fibers innervating the esophagus. Extracellular single fiber recordings were made from the nodose C-fibers, with mechanically sensitive nerve terminals in the isolated innervated guinea pig esophagus. NaV1 inhibitors were selectively delivered to the tissue-containing nerve terminals. Graded esophageal distention was used for mechanical stimulation. The NaV1.7 inhibitor PF-05089771 nearly abolished action potential initiation in response to low levels of esophageal distention but only partially inhibited the response to higher levels of esophageal distention. The PF-05089771-insensitive component of the response progressively increased (up to ≈50%) with increasing esophageal distention and was abolished by tetrodotoxin (TTX). In addition to NaV1.7, nodose C-fiber [transient receptor potential channel-vanilloid subfamily member 1 (TRPV1)-positive] neurons retrogradely labeled from the esophagus expressed mRNA for multiple TTX-sensitive NaV1s. The group NaV1.1, NaV1.2, and NaV1.3 inhibitor ICA-121431 inhibited but did not abolish the PF-05089771-insensitive component of the response to high level of esophageal distention. However, combination of ICA-121431 with compound 801, which also inhibits NaV1.7 and NaV1.6, nearly abolished the response to the high level of esophageal distention. Our data indicate that the action potential initiation in esophageal nodose C-fibers evoked by low (innocuous) levels of esophageal distention is mediated by NaV1.7. However, the response evoked by higher (noxious) levels of esophageal distention has a progressively increasing NaV1.7-independent component that involves multiple TTX-sensitive NaV1s. The stimulus intensity-dependent recruitment of NaV1s may offer novel opportunities for strategic targeting of NaV1 subunits for inhibition of nociceptive signaling in visceral C-fibers.NEW & NOTEWORTHY We report that pharmacologically distinguishable voltage-gated sodium channels (NaV1) mediate action potential initiation at low (innocuous) versus high (noxious) intensity of esophageal distention in nerve terminals of vagal nodose C-fibers. Action potential initiation at low intensity is entirely dependent on NaV1.7; however, additional tetrodotoxin (TTX)-sensitive NaV1s are recruited at higher intensity of distention. This is the first demonstration that NaV1s underlying action potential initiation in visceral C-fibers depend on the intensity of the stimulus.

Separation of nanoparticles via surfing on chemical wavefronts.

The separation of micro and nanoscale colloids is a necessary step in most biological microassay techniques, and is a common practice in microchemical processing. Chemical waves are frequently encountered in biochemical systems driven far from equilibrium. Here, we put forward a strategy for separating small suspending colloids by means of their surfing on substrate chemical wavefronts. The colloids with catalytic activities sensitive to the substrates are activated to show self-propulsion and consequently exhibit a chemotactic response to the traveling wavefronts, which results in their spontaneous separation from the multicomponent complex mixture via self-diffusiophoresis. The dynamics of the process is analyzed through a particle-based simulation. In addition, it is found that separation can be carried out according to particle size. The mechanisms underpinning the chemical and physical separation processes are discussed, and the dependencies on the reaction rate constant and particle size are presented. The results may prove relevant for further experimental and theoretical studies of separation in complex active environments.

Endometrial autophagy is essential for embryo implantation during early pregnancy.

Embryo implantation is an essential and complex process in mammalian reproduction. However, little evidence has indicated the involvement of autophagy during embryo implantation. To determine the possible role of autophagy in uterine of pregnant mice during the peri-implantation stage, we first examined the expression of autophagy-related markers ATG5 and LC3 on day 4, 5, and 6 of pregnancy (D4, D5, and D6, respectively). Compared with expression on D4, downregulation of the autophagy-related markers was observed on D5 and D6, the days after the embryo attached to the receptivity endometrium. Further examination showed that autophagy-related markers ATG5, ATG12, LC3, cathepsin B, and P62 at the implantation site were significantly decreased when comparing with the inter-implantation site. Fewer number of autophagosomes at the implantation site were also observed by transmission electron microscopy. To confirm the functional role of autophagy during embryo implantation in mice, we administered the autophagy inhibitor 3-methyladenine and chloroquine to mice. After treated with 3-methyladenine, the expression of decidual markers HOXA10 and progesterone receptor were significantly reduced. Furthermore, a reduction in implantation sites and increase in the HOXA10 and PR protein levels were observed in response to chloroquine treatment. In addition, impaired uterine decidualization and dysregulation of the PR and HOXA10 protein levels was observed after autophagy inhibited by 3-methyladenine and chloroquine in in vivo artificial decidualization mouse model. In the last, LC3 and P62 were also observed in normal human proliferative, secretory, and decidua tissues. In conclusion, endometrial autophagy may be essential for embryo implantation, and it may be associated with endometrial decidualization during early pregnancy. KEY MESSAGE: • Autophagy-related markers were significantly decreased at implantation site. • Autophagy inhibition results in abnormal decidualization. • Autophagy is essential for embryo implantation.

Allergen-induced histaminergic and non-histaminergic activation of itch C-fiber nerve terminals in mouse skin.

Acute cutaneous exposure to allergen often leads to itch, but seldom pain. The effect of mast cell activation on cutaneous C-fibers was studied using innervated isolated mouse skin preparation that allows for intra-arterial delivery of chemicals to the nerve terminals in the skin. Allergen (ovalbumin) injection into the isolated skin of actively sensitized mice strongly stimulated chloroquine (CQ)-sensitive C-fibers (also referred to as "itch" nerves); on the other hand, CQ-insensitive C-fibers were activated only modestly, if at all. The histamine H1 receptor antagonist pyrilamine abolished itch C-fibers response to histamine, but failed to significantly reduce the response to ovalbumin. Ovalbumin also strongly activated itch C-fibers in skin isolated from Mrgpr-cluster Δ-/- mice. When pyrilamine was studied in the Mrgpr-cluster Δ-/- mice thereby eliminating the influence of both histamine H1 and Mrgpr receptors (MrgprA3 and C11 are selectively expressed by itch nerves), the ovalbumin response was very nearly eliminated. The data indicate that the acute activation of itch C-fibers in mouse skin is largely secondary to the combined effect of activation of histamine H1 and Mrpgr receptors.

Targeting C-fibers for peripheral acting anti-tussive drugs.

Activation of vagal C-fibers is likely involved in some types of pathological coughing, especially coughing that is associated with airway inflammation. This is because stimulation of vagal C-fibers leads to strong urge to cough sensations, and because C-fiber terminals can be strongly activated by mediators associated with airway inflammation. The most direct manner in which a given mediator can activate a C-fiber terminal is through interacting with its receptor expressed in the terminal membrane. The agonist-receptor interaction then must lead to the opening (or potentially closing) of ion channels that lead to a membrane depolarization. This depolarization is referred to as a generator potential. If, and only if, the generator potential reaches the voltage necessary to activate voltage-gated sodium channels, action potentials are initiated and conducted to the central terminals within the CNS. Therefore, there are three target areas to block the inflammatory mediator induced activation of C-fiber terminals. First, at the level of the mediator-receptor interaction, secondly at the level of the generator potential, and third at the level of the voltage-gated sodium channels. Here we provide a brief overview of each of these therapeutic strategies.