Salidroside inhibits the ferroptosis to alleviate lung ischemia reperfusion injury via the JAK2/STAT3 signalling pathway.

OBJECTIVE: The present study aims to investigate the protective potential of salidroside in both lung ischemia/reperfusion injury (LIRI) mice model and cell hypoxia/reoxygenation (H/R)model and the involvement of ferroptosis and JAK2/STAT3 pathway. MATERIALS AND METHODS: After we established the IR-induced lung injury model in mice, we administered salidroside and the ferroptosis inhibitor, ferrostatin-1, then assessed the lung tissue injury, ferroptosis (levels of reactive oxygen species level, malondialdehyde and glutathione), and inflammation in lung tissues. The levels of ferroptosis-related proteins (glutathione peroxidase 4, fibroblast-specific protein 1, solute carrier family 1 member 5 and glutaminase 2) in the lung tissue were measured with Western blotting. Next, BEAS-2B cells were used to establish an H/R cell model and treated with salidroside or ferrostatin-1 before the cell viability and the levels of lactate dehydrogenase (LDH), inflammatory factor, ferroptosis-related proteins were measured. The activation of the JAK2/STAT3 signaling pathway was measured with Western blotting, then its role was confirmed with STAT3 knockdown. RESULTS: Remarkably, salidroside was found to alleviate ferroptosis, inflammation, and lung injury in LIRI mice and the cell injury in H/R cell model. Severe ferroptosis were observed in LIRI mice models and H/R-induced BEAS-2B cells, which was alleviated by salidroside. Furthermore, salidroside could inhibit JAK2/STAT3 activation induced by LIRI. STAT3 knockdown could enhance the effect of salidroside treatment on H/R-induced cell damage and ferroptosis in vitro. CONCLUSIONS: Salidroside inhibits ferroptosis to alleviate lung ischemia reperfusion injury via the JAK2/STAT3 signaling pathway.

Detoxification of vancomycin fermentation residue by hydrothermal treatment and pyrolysis: Chemical analysis and toxicity tests.

Vancomycin fermentation residue (VFR) is a by-product of the pharmaceutical industry with high ecotoxicity caused by the residual antibiotics, antibiotic resistance genes (ARGs), and heavy metals (HMs). In this study, the detoxification effect of hydrothermal treatment (HT) and pyrolysis for VFR was assessed using chemical analysis and toxicity tests. When VFR was subjected to HT and pyrolysis at ≥400 °C, more than 99.70 % of the residual vancomycin and all ARGs were removed. The HMs contents in VFR followed the order of manganese (676.2 mg/kg) > zinc (148.6 mg/kg) > chromium (25.40 mg/kg) > copper (17.20 mg/kg), and they were highly bioavailable and easily leached. However, HT and pyrolysis (≥400 °C) substantially reduced the bioavailable fractions and leaching properties of the HMs. After HT and pyrolysis at ≥ 400 °C, the potential ecological risk of HMs in VFR was reduced from considerable to moderate/low levels. The elutriate acute toxicity test suggested that HT and pyrolysis at ≥ 400 °C effectively reduced the toxicity of VFR to an acceptable level (p < 0.05). This study demonstrates that HT and pyrolysis (≥400 °C) are promising methods for treating VFR and detoxifying it, and the treated products are safe for further reutilization.

Flotation recovery of barite from high-density waste drilling fluid using ß-cyclodextrin as a novel depressant and its mechanism.

High-density waste drilling fluid contains an abundance of recyclable weighting reagents, direct disposal can pollute the environment. In this paper, the primary mineral composition of a high-density waste drilling fluid from a well in the southwest oil and gas field was analyzed. This paper proposes ß-cyclodextrin (ß-CD) as a depressant for the recovery of barite from waste drilling fluid. The recovery process was investigated through inverse flotation experiments, and the mechanism was analyzed using zeta potential, contact angle analysis, and FTIR. The flotation experiments showed that under the SDS flotation system, when the pH was 9.0 and the amount of depressant ß-CD was 900 g/t, the barite recovery and density reached the highest values, which were 87.41% and 4.042 g/cm3, respectively. Zeta potential experiments, contact angle analysis, and FTIR analysis indicate that ß-CD adsorbed onto barite through enhancing the hydrophilicity of barite, electrostatic force adsorption, and strong adsorption, which could not be displayed by SDS through competitive adsorption. Furthermore, ß-CD exhibited a selective inhibitory effect on barite and enabled reverse flotation. The mechanism model of the flotation separation process was established.

Sensory Schwann cells set perceptual thresholds for touch and selectively regulate mechanical nociception.

Previous work identified nociceptive Schwann cells that can initiate pain. Consistent with the existence of inherently mechanosensitive sensory Schwann cells, we found that in mice, the mechanosensory function of almost all nociceptors, including those signaling fast pain, were dependent on sensory Schwann cells. In polymodal nociceptors, sensory Schwann cells signal mechanical, but not cold or heat pain. Terminal Schwann cells also surround mechanoreceptor nerve-endings within the Meissner's corpuscle and in hair follicle lanceolate endings that both signal vibrotactile touch. Within Meissner´s corpuscles, two molecularly and functionally distinct sensory Schwann cells positive for Sox10 and Sox2 differentially modulate rapidly adapting mechanoreceptor function. Using optogenetics we show that Meissner's corpuscle Schwann cells are necessary for the perception of low threshold vibrotactile stimuli. These results show that sensory Schwann cells within diverse glio-neural mechanosensory end-organs are sensors for mechanical pain as well as necessary for touch perception.

Novel Injectable, Self-Healing, Long-Effective Bacteriostatic, and Healed-Promoting Hydrogel Wound Dressing and Controlled Drug Delivery Mechanisms.

Multivalent ion cross-linking has been used to form hydrogels between sodium alginate (SA) and hyaluronic acid (HA) in previous studies. However, more stable and robust covalent cross-linking is rarely reported. Herein, we present a facile approach to fabricate a SA and HA hydrogel for wound dressings with injectable, good biocompatibility, and high ductility. HA was first reacted with ethylenediamine to graft an amino group. Then, it was cross-linked with oxidized SA with dialdehyde to form hydrogel networks. The dressing can effectively promote cell migration and wound healing. To increase the antibacterial property of the dressing, we successfully loaded tetracycline hydrochloride into the hydrogel as a model drug. The drug can be released slowly in the alkaline environment of chronic wounds, and the hydrogel releases drugs again in the more acidic environment with wound healing, achieving a long-term antibacterial effect. In addition, one-dimensional partial differential equations based on Fickian diffusion with time-varying diffusion coefficients and hydrogel thicknesses were used to model the entire complex drug release process and to predict drug release.

Surface functional groups on nanoplastics delay the recovery of gut microbiota after combined exposure to sulfamethazine in marine medaka (Oryzias melastigma).

Nanoplastics can interact with antibiotics, altering their bioavailability and the ensuing toxicity in marine organisms. It is reported that plain polystyrene (PS) nanoplastics decrease the bioavailability and adverse effects of sulfamethazine (SMZ) on the gut microbiota in Oryzias melastigma. However, the influence of surface functional groups on the combined effects with SMZ remains largely unknown. In this study, adult O. melastigma were fed diet amended with 4.62 mg/g SMZ and 3.65 mg/g nanoplastics (i.e., plain PS, PS-COOH and PS-NH2) for 30 days (F0-E), followed by a depuration period of 21 days (F0-D). In addition, the eggs produced on the last day of exposure were cultured under standard protocols without further exposure for 2 months (F1 fish). The results showed that the alpha diversity or the bacterial community of gut microbiota did not differ among the SMZ + PS, SMZ + PS-COOH, and SMZ + PS-NH2 groups in the F0-E and F1 fish. Interestingly, during the depuration, a clear recovery of gut microbiota (e.g., increases in the alpha diversity, beneficial bacteria abundances and network complexity) was found in the SMZ + PS group, but not for the SMZ + PS-COOH and SMZ + PS-NH2 groups, indicating that PS-COOH and PS-NH2 could prolong the toxic effect of SMZ and hinder the recovery of gut microbiota. Compared to plain PS, lower egestion rates of PS-COOH and PS-NH2 were observed in O. melastigma. In addition, under the simulated fish digest conditions, the SMZ-loaded PS-NH2 was found to desorb more SMZ than the loaded PS and PS-COOH. These results suggested that the surface -COOH and -NH2 groups on PS could influence their egestion efficiency and the adsorption/desorption behavior with SMZ, resulting in a long-lasting SMZ stress in the gut during the depuration phase. Our findings highlight the complexity of the carrier effect and ecological risk of surface-charged nanoplastics and the interactions between nanoplastics and antibiotics in natural environments.

Rapid and efficient removal of multiple heavy metals from diverse types of water using magnetic biochars derived from antibiotic fermentation residue.

Pyrolysis is a promising method to treat antibiotic fermentation residue (AFR), a hazardous waste in China, with the benefits of detoxification and resource recycling. However, the application of the AFR-derived biochar has been limited yet, restricting the use of pyrolysis to treat AFR. Herein, for the first time, we reported the use of magnetic biochars derived from vancomycin fermentation residue to rapidly and efficiently co-adsorb multiple heavy metals from diverse types of water with complex matrices. The biochar prepared at 700 °C (labeled as VBC700) exhibited high affinity and selectivity for multiple heavy metals, especially for Ag(I), Hg(II), Pb(II), and Cu(II). The kinetics for Ag(I), Hg(II), and Pb(II) were ultrafast with an equilibrium time of only 5 min, while those for Cu(II) were relatively slower. The maximum adsorption capacity calculated from the Langmuir model for Ag(I), Hg(II), Pb(II), and Cu(II) reached 177.4, 105.9, 387.1, 124.5 mg/g, respectively, which were superior to much previously reported adsorbents. Impressively, Na(I), K(I), Ca(II), Mg(II), and salinity did not affect the capture of these heavy metals, and thus >99% of Ag(I), Pb(II), and Cu(II) were concurrently removed from complex water matrices including seawater, which has rarely been reported before. Furthermore, VBC700 remained high adsorption performance at pH ≥ 3. The adsorption mechanisms included ion exchange, precipitation, and inner-sphere complexation. Overall, the results demonstrate that VBC700 would be an excellent adsorbent to co-capture multiple heavy metals from diverse types of water, highlighting the feasibility of using pyrolysis to achieve a win-win goal for AFR management and heavy metal pollution control.

Structural changes in Schwann cells and nerve fibres in type 1 diabetes: relationship with diabetic polyneuropathy.

AIMS/HYPOTHESIS: Our aim was to investigate structural changes of cutaneous Schwann cells (SCs), including nociceptive Schwann cells (nSCs) and axons, in individuals with diabetic polyneuropathy. We also aimed to investigate the relationship between these changes and peripheral neuropathic symptoms in type 1 diabetes. METHODS: Skin biopsies (3 mm) taken from carefully phenotyped participants with type 1 diabetes without polyneuropathy (T1D, n=25), type 1 diabetes with painless diabetic polyneuropathy (T1DPN, n=30) and type 1 diabetes with painful diabetic polyneuropathy (P-T1DPN, n=27), and from healthy control individuals (n=25) were immunostained with relevant antibodies to visualise SCs and nerve fibres. Stereological methods were used to quantify the expression of cutaneous SCs and nerve fibres. RESULTS: There was a difference in the number density of nSCs not abutting to nerve fibres between the groups (p=0.004) but not in the number density of nSCs abutting to nerve fibres, nor in solitary or total subepidermal SC soma number density. The overall dermal SC expression (measured by dermal SC area fraction and subepidermal SC process density) and peripheral nerve fibre expression (measured by intraepidermal nerve fibre density, dermal nerve fibre area fraction and subepidermal nerve fibre density) differed between the groups (all p<0.05): significant differences were seen in participants with T1DPN and P-T1DPN compared with those without diabetic polyneuropathy (healthy control and T1D groups) (all p<0.05). No difference was found between participants in the T1DPN and P-T1DPN group, nor between participants in the T1D and healthy control group (all p>0.05). Correlational analysis showed that cutaneous SC processes and nerve fibres were highly associated, and they were weakly negatively correlated with different neuropathy measures. CONCLUSIONS/INTERPRETATION: Cutaneous SC processes and nerves, but not SC soma, are degenerated and interdependent in individuals with diabetic polyneuropathy. However, an increase in structurally damaged nSCs was seen in individuals with diabetic polyneuropathy. Furthermore, dermal SC processes and nerve fibres correlate weakly with clinical measures of neuropathy and may play a partial role in the pathophysiology of diabetic polyneuropathy in type 1 diabetes.

Pyrolysis of Ca/Fe-rich antibiotic fermentation residues into biochars for efficient phosphate removal/recovery from wastewater: Turning hazardous waste to phosphorous fertilizer.

Ca/Fe-rich antibiotic fermentation residues (AFRs), a type of hazardous waste, can be regarded as recyclable biomass and metal resources. However, concurrent detoxification and reutilization of biomass and metals resources from AFRs have never been reported before. In this study, Ca/Fe-rich vancomycin fermentation residues were pyrolyzed into biochar to adsorb phosphate for the first time. The residual vancomycin and antibiotic resistance genes were completely decomposed during pyrolysis. The resultant Ca/Fe-rich biochar exhibited excellent performance at adsorbing phosphate without further modifications. The process had rapid kinetics and a maximum adsorption capacity of 102 mg P/g. Ca and Fe were the active sites, whereas different mechanisms were observed under acidic and alkaline conditions. Surprisingly, HCO3- enhanced phosphate adsorption with an increase of adsorption capacity from 43.9 to 71.0 mg/g when HCO3- concentration increased from 1 to 10 mM. Furthermore, actual wastewater could be effectively treated by the biochar. The phosphate-rich spent biochar significantly promoted seed germination (germination rate: 96.7 % vs. 80.0 % in control group, p < 0.01) and seedling growth (shoot length was increased by 57.9 %, p < 0.01) due to the slow release of bioavailable phosphate, and thus could be potentially used as a phosphorous fertilizer. Consequently, the hazardous waste was turned into phosphorous fertilizer, with the additional benefits of detoxifying AFRs, reutilizing biomass and metal resources from AFRs, controlling phosphate pollution, and recovering phosphate from wastewater.

EnConVis: A Unified Framework for Ensemble Contour Visualization.

Ensemble simulation is a crucial method to handle potential uncertainty in modern simulation and has been widely applied in many disciplines. Many ensemble contour visualization methods have been introduced to facilitate ensemble data analysis. On the basis of deep exploration and summarization of existing techniques and domain requirements, we propose a unified framework of ensemble contour visualization, EnConVis (Ensemble Contour Visualization), which systematically combines state-of-the-art methods. We model ensemble contour visualization as a four-step pipeline consisting of four essential procedures: member filtering, point-wise modeling, uncertainty band extraction, and visual mapping. For each of the four essential procedures, we compare different methods they use, analyze their pros and cons, highlight research gaps, and attempt to fill them. Specifically, we add Kernel Density Estimation in the point-wise modeling procedure and multi-layer extraction in the uncertainty band extraction procedure. This step shows the ensemble data's details accurately and provides abstract levels. We also analyze existing methods from a global perspective. We investigate their mechanisms and compare their effects, on the basis of which, we offer selection guidelines for them. From the overall perspective of this framework, we find choices and combinations that have not been tried before, which can be well compensated by our method. Synthetic data and real-world data are leveraged to verify the efficacy of our method. Domain experts' feedback suggests that our approach helps them better understand ensemble data analysis.

Identification of ocular refraction based on deep learning algorithm as a novel retinoscopy method.

BACKGROUND: The evaluation of refraction is indispensable in ophthalmic clinics, generally requiring a refractor or retinoscopy under cycloplegia. Retinal fundus photographs (RFPs) supply a wealth of information related to the human eye and might provide a promising approach that is more convenient and objective. Here, we aimed to develop and validate a fusion model-based deep learning system (FMDLS) to identify ocular refraction via RFPs and compare with the cycloplegic refraction. In this population-based comparative study, we retrospectively collected 11,973 RFPs from May 1, 2020 to November 20, 2021. The performance of the regression models for sphere and cylinder was evaluated using mean absolute error (MAE). The accuracy, sensitivity, specificity, area under the receiver operating characteristic curve, and F1-score were used to evaluate the classification model of the cylinder axis. RESULTS: Overall, 7873 RFPs were retained for analysis. For sphere and cylinder, the MAE values between the FMDLS and cycloplegic refraction were 0.50 D and 0.31 D, representing an increase of 29.41% and 26.67%, respectively, when compared with the single models. The correlation coefficients (r) were 0.949 and 0.807, respectively. For axis analysis, the accuracy, specificity, sensitivity, and area under the curve value of the classification model were 0.89, 0.941, 0.882, and 0.814, respectively, and the F1-score was 0.88. CONCLUSIONS: The FMDLS successfully identified the ocular refraction in sphere, cylinder, and axis, and showed good agreement with the cycloplegic refraction. The RFPs can provide not only comprehensive fundus information but also the refractive state of the eye, highlighting their potential clinical value.

Identification and quantification of nociceptive Schwann cells in mice with and without Streptozotocin-induced diabetes.

Specialized cutaneous Schwann cells (SCs), termed nociceptive SCs, were recently discovered. Their function is not fully understood, but they are believed not only to support peripheral axons in mouse skin by forming a mesh-like neural-glio networking structure in subepidermal area, but also contributing to transduction of mechanical sensation and neuropathic pain. Diabetic neuropathy (DPN) is one of the most common complication of diabetes, however, the mechanisms behind painful and painless DPN remain unclear. Using a mouse model of DPN, we want to investigate if there are quantitative differences in nociceptive SC density between the condition of hyperglycemia-induced sensory abnormalities and control condition and at which stage in the disease the damage occurs. Here, we developed a set of counting rules for nociceptive SCs based on immunofluorescent staining, and applied the method to quantify the density of nociceptive SCs in control mice (n = 10), mice with nociceptive hypersensitivity at early diabetic stage (n = 5), and mice with sensory hyposensitivity at late diabetic stage (n = 5) in the Streptozotocin (STZ) model of type 1 diabetes. Nociceptive SCs were identified as S100+/Sox10+/DAPI+ cells abutting to peripheral nerves, with the somas located within 25 µm depth in the subepidermal area and outside glands and large fiber bundles. Hypersensitive diabetic mice had decreased nociceptive SC density, despite having normal epidermal nerve fiber density, compared with age-matched control mice (P = 0.023). In contrast, there was a reduction in intraepidermal nerve fiber density but no difference in nociceptive SC density between hyposensitive diabetic mice and the age-matched control mice. This study provides a detailed description of how to identify and quantify nociceptive SC and demonstrates that nociceptive SC density declines before nerve fiber deterioration, which supports previous observations that nociceptive SCs are critical for maintenance of cutaneous sensory nerves.

Neural network learning defines glioblastoma features to be of neural crest perivascular or radial glia lineages.

Glioblastoma is believed to originate from nervous system cells; however, a putative origin from vessel-associated progenitor cells has not been considered. We deeply single-cell RNA-sequenced glioblastoma progenitor cells of 18 patients and integrated 710 bulk tumors and 73,495 glioma single cells of 100 patients to determine the relation of glioblastoma cells to normal brain cell types. A novel neural network-based projection of the developmental trajectory of normal brain cells uncovered two principal cell-lineage features of glioblastoma, neural crest perivascular and radial glia, carrying defining methylation patterns and survival differences. Consistently, introducing tumorigenic alterations in naïve human brain perivascular cells resulted in brain tumors. Thus, our results suggest that glioblastoma can arise from the brains' vasculature, and patients with such glioblastoma have a significantly poorer outcome.

Immediate effects of neuromuscular joint-facilitation bridging exercises on walking ability and balance function in stroke patients.

[Purpose] This study aimed to examine the immediate effects of a pelvic neuromuscular joint-facilitation intervention on the walking and balance ability of patients with hemiplegia caused by cerebrovascular accidents. [Participants and Methods] A total of 15 patients with hemiplegia caused by cerebrovascular accidents underwent a neuromuscular joint-facilitation lumbar-pattern intervention (intervention group), a bridge exercise (bridge intervention group), or a neuromuscular joint-facilitation bridge intervention (neuromuscular joint-facilitation bridge group). Each intervention was randomly administered at 7-day intervals. Measurement items included the timed up-and-go test, functional reach test, 10-m maximum walking speed test, and load in the standing position. Measurements were taken before and after the intervention in each group. [Results] The timed up-and-go test result was significantly shorter in the neuromuscular joint-facilitation intervention group. Timed up-and-go test results, functional reach, 10-m walking time, and standing load (non-paralyzed side) significantly improved in the neuromuscular joint-facilitation bridge group. [Conclusion] The neuromuscular joint-facilitation bridge intervention was immediately effective in patients with hemiplegia caused by cerebrovascular accidents and improved their walking and balance ability.

Feasible synthesis of a novel and low-cost seawater-modified biochar and its potential application in phosphate removal/recovery from wastewater.

In this study, a novel and low-cost seawater-modified biochar (SBC) was fabricated via the pyrolysis of fir wood waste followed by co-precipitation modification using seawater as the Ca/Mg source. The co-precipitation pH was a vital factor during modification, and the optimal pH was 10.50 according to calculations using PHREEQC 2.5 and experiments. The characterizations indicated that Ca and Mg were loaded on the SBC as irregular CaCO3 and nanoflake-like Mg(OH)2, respectively, with the latter dominating. The SBC exhibited a high maximum adsorption capacity of 181.07 mg/g for phosphate, calculated using the Langmuir model, excellent adsorption performance under acidic and neutral conditions (pH = 3.00-7.00), and remarkable selectivity against Cl-, NO3-, and SO42-. The presence of HCO3- promoted adsorption. The mechanisms behind phosphate adsorption involved electrostatic attraction, ligand exchange, precipitation, and inner-sphere complexation. Mg, rather than Ca, was served as the main adsorptive sites for phosphate. Additionally, the feasibility of treating real-world wastewater was tested in batch (using SBC powders) and fixed-bed column (using SBC granules) experiments. The results indicate that the SBC powders could reduce the phosphate concentration from 1.26 mg P/L to below 0.5 mg P/L at a low dose of 0.50 g/L, and the SBC granules exhibited a high removal efficiency with excellent recyclability; the capacity still remained at 78.92% of the initial capacity after five adsorption-desorption runs. Furthermore, the modification process almost did not increase the production cost of the SBC, which was estimated to be 0.41 $/kg. Our results demonstrate that seawater is a low-cost and efficient modifier for biochar modification, and the resultant SBC demonstrates great potential for treating actual phosphate-containing wastewater.

The reliability and effectiveness of shoulder joint evaluation by ultrasonography in stroke patients: deltoid muscle thickness, acromion-humeral distance, acromion-lesser tuberosity distance.

[Purpose] This study aimed to evaluate the reliability of the intraclass correlation coefficient (ICC) in measuring deltoid muscle thickness (DMT) at different angles, acromion-humeral distance (AHD), and acromion nodule tuberosity (ALT) distance in a resting position in stroke patients using ultrasonography. [Participants and Methods] We included 40 stroke patients. During the measurement of parameters by ultrasonography, we measured the deltoid muscle thickness on both sides at three test angles (0°, 30°, and 60° abduction) and AHD and ALT on both sides at 0° angle. The ICC was used to assess intra- and interrater reliability. The relationship between the hemiplegic and non-hemiplegic sides and each angle were analyzed using a two-way repeated-measure analysis of variance (ANOVA). [Results] When the shoulders were at three testing angles (0°, 30°, and 60° abduction), the deltoid muscle thickness of the hemiplegic and non-hemiplegic sides showed good reliability; the AHD and ALT of the shoulder joint at 0° angle equally showed good reliability. There was a significant difference in each abduction angle of the shoulder joint between the thickness of the hemiplegic and non-hemiplegic deltoid. [Conclusion] Measuring deltoid muscle thickness by ultrasonography showed excellent reliability and can be used in stroke patients.

Breaking of Henry's law for sulfide liquid-basaltic melt partitioning of Pt and Pd.

Platinum group elements are invaluable tracers for planetary accretion and differentiation and the formation of PGE sulfide deposits. Previous laboratory determinations of the sulfide liquid-basaltic melt partition coefficients of PGE ([Formula: see text]) yielded values of 102-109, and values of >105 have been accepted by the geochemical and cosmochemical society. Here we perform measurements of [Formula: see text] at 1 GPa and 1,400 °C, and find that [Formula: see text] increase respectively from 3,500 to 3.5 × 105 and 1,800 to 7 × 105, as the Pt and Pd concentration in the sulfide liquid increases from 60 to 21,000 ppm and 26 to 7,000 ppm, respectively, implying non-Henrian behavior of the Pt and Pd partitioning. The use of [Formula: see text] values of 2,000-6,000 well explains the Pt and Pd systematics of Earth's mantle peridotites and mid-ocean ridge basalts. Our findings suggest that the behavior of PGE needs to be reevaluated when using them to trace planetary magmatic processes.

Demise of nociceptive Schwann cells causes nerve retraction and pain hyperalgesia.

ABSTRACT: Recent findings indicate that nociceptive nerves are not "free", but similar to touch and pressure sensitive nerves, terminate in an end-organ in mice. This sensory structure consists of the nociceptive nerves and specialized nociceptive Schwann cells forming a mesh-like organ in subepidermis with pain transduction initiated at both these cellular constituents. The intimate relation of nociceptive nerves with nociceptive Schwann cells in mice raises the question whether defects in nociceptive Schwann cells can by itself contribute to pain hyperalgesia, nerve retraction, and peripheral neuropathy. We therefore examined the existence of nociceptive Schwann cells in human skin and their possible contribution to neuropathy and pain hyperalgesia in mouse models. Similar to mouse, human skin contains SOX10+/S100B+/AQP1+ Schwann cells in the subepidermal border that have extensive processes, which are intimately associated with nociceptive nerves projecting into epidermis. The ablation of nociceptive Schwann cells in mice resulted in nerve retraction and mechanical, cold, and heat hyperalgesia. Conversely, ablating the nociceptive nerves led to a retraction of epidermal Schwann cell processes, changes in nociceptive Schwann cell soma morphology, heat analgesia, and mechanical hyperalgesia. Our results provide evidence for a nociceptive sensory end-organ in the human skin and using animal models highlight the interdependence of the nerve and the nociceptive Schwann cell. Finally, we show that demise of nociceptive Schwann cells is sufficient to cause neuropathic-like pain in the mouse.

MicroRNA-96 is required to prevent allodynia by repressing voltage-gated sodium channels in spinal cord.

Voltage-gated sodium channels (Navs) 1.7, 1.8, and 1.9 are predominately expressed in peripheral sensory neurons and are critical for action potential propagation in nociceptors. Unexpectedly, we found that expression of SCN9A, SCN10A, SCN11A, and SCN2A, the alpha subunit of Nav1.7, Nav1.8, Nav1.9 and Nav1.2, respectively, are up-regulated in spinal dorsal horn (SDH) neurons of miR-96 knockout mice. These mice also have de-repression of CACNA2D1/2 in DRG and display thermal and mechanical allodynia that could be attenuated by intrathecal or intraperitoneal injection of Nav1.7 or Nav1.8 blockers or Gabapentin. Moreover, Gad2::CreERT2 conditional miR-96 knockout mice phenocopied global knockout mice, implicating inhibitory neurons; nerve injury induced significant loss of miR-96 in SDH GABAergic and Glutamatergic neurons in mice which negatively correlated to up-regulation of Nav1.7, Nav1.8, Nav1.9 and Scn2a, this dis-regulation of miR-96 and Navs in SDH neurons contributed to neuropathic pain which can be alleviated by intrathecal injection of Nav1.7 or Nav1.8 blockers. In conclusion, miR-96 is required to avoid allodynia through limiting the expression of VGCCs and Navs in DRG and Navs in SDH in naïve and nerve injury-induced neuropathic pain mice. Our findings suggest that central nervous system penetrating Nav1.7 and Nav1.8 blockers may be efficacious for pain relief.

Residual Learning Diagnosis Detection: An Advanced Residual Learning Diagnosis Detection System for COVID-19 in Industrial Internet of Things.

Due to the fast transmission speed and severe health damage, COVID-19 has attracted global attention. Early diagnosis and isolation are effective and imperative strategies for epidemic prevention and control. Most diagnostic methods for the COVID-19 is based on nucleic acid testing (NAT), which is expensive and time-consuming. To build an efficient and valid alternative of NAT, this article investigates the feasibility of employing computed tomography images of lungs as the diagnostic signals. Unlike normal lungs, parts of the lungs infected with the COVID-19 developed lesions, ground-glass opacity, and bronchiectasis became apparent. Through a public dataset, in this article, we propose an advanced residual learning diagnosis detection (RLDD) scheme for the COVID-19 technique, which is designed to distinguish positive COVID-19 cases from heterogeneous lung images. Besides the advantage of high diagnosis effectiveness, the designed residual-based COVID-19 detection network can efficiently extract the lung features through small COVID-19 samples, which removes the pretraining requirement on other medical datasets. In the test set, we achieve an accuracy of 91.33%, a precision of 91.30%, and a recall of 90%. For the batch of 150 samples, the assessment time is only 4.7 s. Therefore, RLDD can be integrated into the application programming interface and embedded into the medical instrument to improve the detection efficiency of COVID-19.