Kv3.1 Interaction with UBR5 Is Required for Chronic Inflammatory Pain.

Chronic inflammatory pain caused by neuronal hyperactivity is a common and refractory disease. Kv3.1, a member of the Kv3 family of voltage-dependent K+ channels, is a major determinant of the ability of neurons to generate high-frequency action potentials. However, little is known about its role in chronic inflammatory pain. Here, we show that although Kv3.1 mRNA expression was unchanged, Kv3.1 protein expression was decreased in the dorsal spinal horn of mice after plantar injection of complete Freund's adjuvant (CFA), a mouse model of inflammatory pain. Upregulating Kv3.1 expression alleviated CFA-induced mechanical allodynia and heat hyperalgesia, whereas downregulating Kv3.1 induced nociception-like behaviors. Additionally, we found that ubiquitin protein ligase E3 component n-recognin 5 (UBR5), a key factor in the initiation of chronic pain, binds directly to Kv3.1 to drive its ubiquitin degradation. Intrathecal injection of the peptide TP-CH-401, a Kv3.1 ubiquitination motif sequence, rescued the decrease in Kv3.1 expression and Kv currents through competitive binding to UBR5, and consequently attenuated mechanical and thermal hypersensitivity. These findings demonstrate a previously unrecognized pathway of Kv3.1 abrogation by UBR5 and indicate that Kv3.1 is critically involved in the regulation of nociceptive behavior. Kv3.1 is thus a promising new target for treating inflammatory pain.

Topological oscillated edge states in trimer lattices.

We investigate a 1D trimer optical lattice model. Two kinds of topological oscillating optical transmission phenomena at edges are shown. The exact and the approximate solutions of the system's edge states are obtained with and without the inversion symmetry for this system respectively. Based on the solutions, the existence and the periods of the oscillations can be controlled arbitrarily. Moreover, in a system without inversion symmetry, controlling the incident beam can eliminate both types of oscillations, resulting in a more stable edge state compared to the one with inversion symmetry. This prompts us to reconsider topological systems under symmetry protection.

Denoising and Baseline Correction Methods for Raman Spectroscopy Based on Convolutional Autoencoder: A Unified Solution.

Preprocessing plays a key role in Raman spectral analysis. However, classical preprocessing algorithms often have issues with reducing Raman peak intensities and changing the peak shape when processing spectra. This paper introduces a unified solution for preprocessing based on a convolutional autoencoder to enhance Raman spectroscopy data. One is a denoising algorithm that uses a convolutional denoising autoencoder (CDAE model), and the other is a baseline correction algorithm based on a convolutional autoencoder (CAE+ model). The CDAE model incorporates two additional convolutional layers in its bottleneck layer for enhanced noise reduction. The CAE+ model not only adds convolutional layers at the bottleneck but also includes a comparison function after the decoding for effective baseline correction. The proposed models were validated using both simulated spectra and experimental spectra measured with a Raman spectrometer system. Comparing their performance with that of traditional signal processing techniques, the results of the CDAE-CAE+ model show improvements in noise reduction and Raman peak preservation.

[Medical emergency support for the snowboarding project during the Beijing Winter Olympics].

OBJECTIVE: To analyze and summarize the medical security situation of the snowmobile, sled, and steel frame snowmobile tracks at the National Sliding Centre, and to provide experience for future event hosting and medical security work for mass ice and snow sports. METHODS: Retrospective analysis of injuries and treatment of athletes participating in the International Training Week and World Cup for Ski, Sled, and Steel Frame Ski from October to November 2021(hereinafter referred to as "International Training Week"), as well as the Ski, Sled, and Steel Frame Ski events at the Beijing Winter Olympics in February 2022 (hereinafter referred to as the "Beijing Winter Olympics"). We referred to and drew on the "Medical Security Standards for Winter Snow Sports" to develop specific classification standards for analyzing injured areas, types of injuries, and accident locations. RESULTS: A total of 743 athletes participated in the International Training Week and the Beijing Winter Olympics. During the competition, there were 58 incidents of overturning, prying, and collision, of which 28 (28 athletes) were injured, accounting for 48.3% of the total accidents and 3.8% of the total number of athletes. Among them, there were 9 males (32.1%) and 19 females (67.9%), with an average age of (26.3 ± 4.7) years. Among the 28 injured athletes, 20 cases (71.4%) received on-site treatment for Class Ⅰ injuries, while 8 cases (28.6%) had more severe injuries, including Class Ⅱ injuries (7 cases) and Class Ⅲ injuries (1 case), which were referred to designated hospitals for further treatment. Among the 28 injured athletes, 3 cases (10.7%) experienced multiple injuries, including 2 cases of 2 injuries and 1 case of 3 injuries. The most common injuries were in the ankle and toes (10/32, 31.3%). Out of 28 injured athletes, one (3.6%) experienced two types of injuries simultaneously, with joint and/or ligament injuries being the most common (11/29, 37.9%). The most accident prone point on the track was the ninth curve (18/58, 31.0%). CONCLUSION: Through the analysis and summary of medical security work, it can provide better experience and reference for the future development of snowmobile, sled, and steel frame snowmobile sports in China, making the National Snowy and Ski Center truly a sustainable Olympic heritage.

Structure and mechanism of a neuropeptide-activated channel in the ENaC/DEG superfamily.

Phe-Met-Arg-Phe-amide (FMRFamide)-activated sodium channels (FaNaCs) are a family of channels activated by the neuropeptide FMRFamide, and, to date, the underlying ligand gating mechanism remains unknown. Here we present the high-resolution cryo-electron microscopy structures of Aplysia californica FaNaC in both apo and FMRFamide-bound states. AcFaNaC forms a chalice-shaped trimer and possesses several notable features, including two FaNaC-specific insertion regions, a distinct finger domain and non-domain-swapped transmembrane helix 2 in the transmembrane domain (TMD). One FMRFamide binds to each subunit in a cleft located in the top-most region of the extracellular domain, with participation of residues from the neighboring subunit. Bound FMRFamide adopts an extended conformation. FMRFamide binds tightly to A. californica FaNaC in an N terminus-in manner, which causes collapse of the binding cleft and induces large local conformational rearrangements. Such conformational changes are propagated downward toward the TMD via the palm domain, possibly resulting in outward movement of the TMD and dilation of the ion conduction pore.

Linear π-conjugated units of the D∞h point group as superior ultraviolet birefringent units.

At present, birefringent materials face a limited selection of large structural anisotropic functional modules (FMs). In this paper, we present a series of linear units which belong to the D∞h point group represented by (BO2)- proposed as novel birefringent active FMs. By analyzing the molecular orbital of the (BO2)- unit, it is found that there are relatively fewer non-bonding orbitals in (BO2)- than in (BO3)3- and the delocalized π bonds in (BO2)- appear in shallow energy levels, which are easily excited. Through first-principles modeling and simulation, it is found that the delocalized π bonds in (BO2)- can still show obvious transition processes, which produce a significant gain to the birefringence. Besides, a series of compounds containing linear anionic frameworks which also belong to the D∞h point group show excellent optical anisotropy in the same way. Therefore, the linear anionic basic units which belong to the D∞h point group have the great potential to become new birefringent FMs.

Three Polyborates with High-Symmetry [B12O24] Units Featuring Different Dimensions of Anion Groups.

Three polyborates, namely, LiNa11B28O48, Li1.45Na7.55B21O36, and Li2Na4Ca7Sr2B13O27F9, were synthesized via the high-temperature solution method. All of them feature high-symmetry [B12O24] units, yet their anion groups exhibit distinct dimensions. LiNa11B28O48 features a three-dimensional anionic structure of 3[B28O48]∞ framework, which is composed of three units: [B12O24], [B15O30], and [BO3]. Li1.45Na7.55B21O36 possesses a one-dimensional anionic structure of 1[B21O36]∞ chain consisting of [B12O24] and [B9O18] units. The anionic structure of Li2Na4Ca7Sr2B13O27F9 is composed of two zero-dimensional isolated units, namely, [B12O24] and [BO3]. The novel FBBs [B15O30] and [B21O39] are present in LiNa11B28O48 and Li1.45Na7.55B21O36, respectively. The anionic groups in these compounds exhibit a high degree of polymerization, thereby augmenting the structural diversity of borates. And the crystal structure, synthesis, thermal stability, and optical properties were meticulously discussed to guide the synthesis and characterization of novel polyborates.

Recent advances in transition-metal-catalyzed Büchner reaction of alkynes.

Medium-sized ring-containing organic molecules, especially seven-membered rings, are significant structural motifs. However, such frameworks are considered difficult structures to access owing to entropic effects and transannular interactions. Compared to the construction of five and six-membered rings, the synthesis of seven-membered rings can be more challenging through traditional cyclization pathways. Büchner reactions are particularly attractive and efficient synthetic strategies to construct functionalized seven-membered ring products from the benzenoid double bond with carbene. In recent years, the field of transition-metal-catalyzed Büchner ring expansion reactions of alkynes has experienced a speedy development and a diverse array of efficient synthetic procedures have been disclosed under mild experimental conditions, as the synthesis of synthetically challenging seven-membered rings is easily achieved. In this review, we will focus on the recent progress in the transition-metal-catalyzed Büchner reaction of alkynes and the mechanistic rationale is depicted where possible, with the reactions being sorted according to the type of catalyst.

Ultrasensitive Linear Capacitive Pressure Sensor with Wrinkled Microstructures for Tactile Perception.

Ultrasensitive flexible pressure sensors with excellent linearity are essential for achieving tactile perception. Although microstructured dielectrics have endowed capacitive sensors with ultrahigh sensitivity, the compromise of sensitivity with increasing pressure is an issue yet to be resolved. Herein, a spontaneously wrinkled MWCNT/PDMS dielectric layer is proposed to realize the excellent sensitivity and linearity of capacitive sensors for tactile perception. The synergistic effect of a high dielectric constant and wrinkled microstructures enables the sensor to exhibit linearity up to 21 kPa with a sensitivity of 1.448 kPa-1 and a detection limit of 0.2 Pa. Owing to these merits, the sensor monitors subtle physiological signals such as various arterial pulses and respiration. This sensor is further integrated into a fully multimaterial 3D-printed soft pneumatic finger to realize material hardness perception. Eight materials with different hardness values are successfully discriminated, and the capacitance of the sensor varies linearly (R2 > 0.975) with increasing hardness. Moreover, the sensitivity to the material hardness can be tuned by controlling the inflation pressure of the soft finger. As a proof of concept, the finger is used to discriminate pork fats with different hardness, paving the way for hardness discrimination in clinical palpation.

Molecular mechanism of substrate recognition by folate transporter SLC19A1.

Folate (vitamin B9) is the coenzyme involved in one-carbon transfer biochemical reactions essential for cell survival and proliferation, with its inadequacy causing developmental defects or severe diseases. Notably, mammalian cells lack the ability to de novo synthesize folate but instead rely on its intake from extracellular sources via specific transporters or receptors, among which SLC19A1 is the ubiquitously expressed one in tissues. However, the mechanism of substrate recognition by SLC19A1 remains unclear. Here we report the cryo-EM structures of human SLC19A1 and its complex with 5-methyltetrahydrofolate at 3.5-3.6 Å resolution and elucidate the critical residues for substrate recognition. In particular, we reveal that two variant residues among SLC19 subfamily members designate the specificity for folate. Moreover, we identify intracellular thiamine pyrophosphate as the favorite coupled substrate for folate transport by SLC19A1. Together, this work establishes the molecular basis of substrate recognition by this central folate transporter.

Rescuing Cardiac Cells and Improving Cardiac Function by Targeted Delivery of Oxygen-Releasing Nanoparticles after or Even before Acute Myocardial Infarction.

Myocardial infarction (MI) causes massive cell death due to restricted blood flow and oxygen deficiency. Rapid and sustained oxygen delivery following MI rescues cardiac cells and restores cardiac function. However, current oxygen-generating materials cannot be administered during acute MI stage without direct injection or suturing methods, both of which risk rupturing weakened heart tissue. Here, we present infarcted heart-targeting, oxygen-releasing nanoparticles capable of being delivered by intravenous injection at acute MI stage, and specifically accumulating in the infarcted heart. The nanoparticles can also be delivered before MI, then gather at the injured area after MI. We demonstrate that the nanoparticles, delivered either pre-MI or post-MI, enhance cardiac cell survival, stimulate angiogenesis, and suppress fibrosis without inducing substantial inflammation and reactive oxygen species overproduction. Our findings demonstrate that oxygen-delivering nanoparticles can provide a nonpharmacological solution to rescue the infarcted heart during acute MI and preserve heart function.

The Association of Folic Acid, Iron Nutrition during Pregnancy and Congenital Heart Disease in Northwestern China: A Matched Case-Control Study.

Background: The purpose of this study was to investigate the relationship between folic acid and iron nutrition during pregnancy and congenital heart disease (CHD) in the offspring. Methods: Conditional logistic regression models and nonlinear mixed-effects models were used to analyze the effects of folic acid and iron nutrition during pregnancy on CHD in offspring. Results: After adjusting for confounders, folic acid or iron supplementation during pregnancy reduced the risk for fetal CHD (OR = 0.60 (0.45, 0.82) or 0.36 (0.27, 0.48)). Similarly, dietary iron intake during pregnancy (≥29 mg/d) was associated with a reduced risk of fetal CHD (OR = 0.64 (0.46, 0.88)). Additionally, compared with women who only supplemented folic acid (OR = 0.59 (0.41, 0.84)) or iron (OR = 0.32 (0.16, 0.60)), women who supplemented both folic acid and iron had lower risk for newborns with CHD (OR = 0.22 (0.15, 0.34)). Similarly, compared with women who only supplemented folic acid (OR = 0.59 (0.41, 0.84)) or higher dietary iron intake (≥29 mg/d) (OR = 0.60 (0.33, 1.09)), women who supplemented both folic acid and higher dietary iron intake (≥29 mg/d) had lower risk for the newborn with CHD (OR = 0.41 (0.28, 0.62)). The combined effects were significant in the multiplication model (OR = 0.35 (0.26, 0.48) or 0.66 (0.50, 0.85)) but not in the additive model. Conclusions: Our study found that folic acid and iron nutrition during pregnancy were associated with a reduced risk of CHD in the offspring and confirmed a statistically significant multiplicative interaction between folic acid and iron nutrition on the reduced risk of CHD in offspring.

Imaginary coupling induced Dirac points and group velocity control in the non-reciprocal Hermitian lattice.

We propose a mechanism to achieve the group velocity control of bifurcation light via an imaginary coupling effect in the non-reciprocal lattice. The physical model is composed of two-layer photonic lattices with non-reciprocal coupling in each unit cell, which can support a real energy spectrum with a pair of Dirac points due to the hermicity. Furthermore, we show that the systems experience topological phase transition at the Dirac points, allowing the existence of topological edge states on the left or right boundaries of respective lattice layers. By adjusting the imaginary coupling and the wave number, the group velocity of the light wave can be manipulated, and bifurcation light transmission can be achieved both at the Dirac points and the condition without the group velocity dispersion. Our work might guide the design of photonic directional couplers with group velocity control functions.

NaB3O4F(OH): A Hydroxyfluorooxoborate with One-Dimensional Chain Featuring Large Birefringence and Short Ultraviolet Cutoff Edge.

A new sodium hydroxyfluorooxoborate, NaB3O4F(OH) (NBOFH), was discovered and synthesized. NBOFH features the unprecedented [B3O4F(OH)] infinite chain constructed by the novel fundamental building block (FBB) of [B3O5F(OH)]. NBOFH has a large birefringence of 0.097 at 1064 nm and short ultraviolet (UV) cutoff edge below 200 nm. First-principles calculations and response electron distribution anisotropy (REDA) were performed to explain the structure-property relationships. This work provides a novel strategy for the synthesis of deep-ultraviolet birefringent crystals and enriches the structural diversity of the emerging hydroxyfluorooxoborates.

Delivery of VEGF and delta-like 4 to synergistically regenerate capillaries and arterioles in ischemic limbs.

Vascularization of the poorly vascularized limbs affected by critical limb ischemia (CLI) is necessary to salvage the limbs and avoid amputation. Effective vascularization requires forming not only capillaries, but also arterioles and vessel branching. These processes rely on the survival, migration and morphogenesis of endothelial cells in the ischemic limbs. Yet endothelial cell functions are impaired by the upregulated TGFß. Herein, we developed an injectable hydrogel-based drug release system capable of delivering both VEGF and Dll4 to synergistically restore endothelial cellular functions, leading to accelerated formation of capillaries, arterioles and vessel branching. In vitro, the Dll4 and VEGF synergistically promoted the human arterial endothelial cell (HAEC) survival, migration, and formation of filopodial structure, lumens, and branches under the elevated TGFß1 condition mimicking that of the ischemic limbs. The synergistic effect was resulted from activating VEGFR2, Notch-1 and Erk1/2 signaling pathways. After delivering the Dll4 and VEGF via an injectable and thermosensitive hydrogel to the ischemic mouse hindlimbs, 95% of blood perfusion was restored at day 14, significantly higher than delivery of Dll4 or VEGF only. The released Dll4 and VEGF significantly increased density of capillaries and arterioles, vessel branching point density, and proliferating cell density. Besides, the delivery of Dll4 and VEGF stimulated skeletal muscle regeneration and improved muscle function. Overall, the developed hydrogel-based Dll4 and VEGF delivery system promoted ischemic limb vascularization and muscle regeneration. STATEMENT OF SIGNIFICANCE: Effective vascularization of the poorly vascularized limbs affected by critical limb ischemia (CLI) requires forming not only capillaries, but also arterioles and vessel branching. These processes rely on the survival, migration and morphogenesis of endothelial cells. Yet endothelial cell functions are impaired by the upregulated TGFß in the ischemic limbs. Herein, we developed an injectable hydrogel-based drug release system capable of delivering both VEGF and Dll4 to synergistically restore endothelial cell functions, leading to accelerated formation of capillaries, arterioles and vessel branching.

Circ_0026416 downregulation blocks the development of colorectal cancer through depleting MYO6 expression by enriching miR-545-3p.

BACKGROUND: Emerging evidence reveals that the initiation and development of human cancers, including colorectal cancer (CRC), are associated with the deregulation of circular RNAs (circRNAs). Our study intended to disclose the role of circ_0026416 in the malignant behaviors of CRC. METHODS: The detection for circ_0026416 expression, miR-545-3p expression, and myosin VI (MYO6) mRNA expression was performed using quantitative real-time PCR (qPCR). CCK-8 assay, colony formation assay, transwell assay, and flow cytometry assay were applied for functional analysis to monitor cell proliferation, migration, invasion, and apoptosis. The protein levels of MYO6 and epithelial mesenchymal-transition (EMT) markers were detected by western blot. Mouse models were used to determine the role of circ_0026416 in vivo. The potential relationship between miR-545-3p and circ_0026416 or MYO6 was verified by dual-luciferase reporter assay and RIP assay. RESULTS: The expression of circ_0026416 was increased in CRC tumor tissues and cell lines. Circ_0026416 downregulation inhibited CRC cell proliferation, colony formation, migration, invasion, and EMT but induced cell apoptosis in vitro, and circ_0026416 knockdown also blocked tumor growth in vivo. MiR-545-3p was a target of circ_0026416, and rescue experiments indicated that circ_0026416 knockdown blocked CRC development by enriching miR-545-3p. In addition, miR-545-3p targeted MYO6 and inhibited MYO6 expression. MiR-545-3p enrichment suppressed CRC cell malignant behaviors by sequestering MYO6. Importantly, circ_0026416 knockdown depleted MYO6 expression by enriching miR-545-3p. CONCLUSION: Circ_0026416 downregulation blocked the development of CRC through depleting MYO6 expression by enriching miR-545-3p. HIGHLIGHTS: 1. Circ_0026416 downregulation inhibits CRC development in vitro and in vivo. 2. Circ_0026416 regulates the expression of MYO6 by targeting miR-545-3p. 3. Circ_0026416 governs the miR-545-3p/MYO6 axis to regulate CRC progression.

Sustained oxygenation accelerates diabetic wound healing by promoting epithelialization and angiogenesis and decreasing inflammation.

Nonhealing diabetic wounds are common complications for diabetic patients. Because chronic hypoxia prominently delays wound healing, sustained oxygenation to alleviate hypoxia is hypothesized to promote diabetic wound healing. However, sustained oxygenation cannot be achieved by current clinical approaches, including hyperbaric oxygen therapy. Here, we present a sustained oxygenation system consisting of oxygen-release microspheres and a reactive oxygen species (ROS)-scavenging hydrogel. The hydrogel captures the naturally elevated ROS in diabetic wounds, which may be further elevated by the oxygen released from the administered microspheres. The sustained release of oxygen augmented the survival and migration of keratinocytes and dermal fibroblasts, promoted angiogenic growth factor expression and angiogenesis in diabetic wounds, and decreased the proinflammatory cytokine expression. These effects significantly increased the wound closure rate. Our findings demonstrate that sustained oxygenation alone, without using drugs, can heal diabetic wounds.