Brain endothelial cyclic GMP-AMP synthase(cGAS)-stimulator of interferon genes(STING)signaling pathway in aging and neurodegeneration

The cyclic GMP-AMP synthase(cGAS)-stimulator of interferon genes(STING)signaling pathway has emerged as a key mediator of neuroinflammation.While current studies primarily attribute its effects to neurons and glial cells,emerging research suggests that cGAS-STING signaling may play a critical role in cerebral vasculature,particularly in brain endothelial cells.Therefore,studying the role 7of inflammation caused by the cGAS-STING pathway in brain endothelial cells could provide a more comprehensive understanding of neuroinflammatory disease and new avenues for therapeutic interventions.Here,we review the multifaceted role of global cGAS-STING signaling in various neurological and neuroinflammatory diseases and the potential contribution of cGAS-STING in brain endothelial cells.

Pain Efficacy of a Home-Based Low-Intensity Continuous Ultrasound Stimulator for Knee Arthritis: A Single-Arm, Open-Label, Prospective Clinical Trial

1) Background: Osteoarthritis (OA) is defined as a degenerative joint disease that mainly affects the bone. This study aims to evaluate the effect of low-intensity continuous ultrasound (LICUS) treatment on the knee of osteoarthritis patients through home-based intervention using the LICUS medical device. 2) Methods: The clinical trials were designed in a single-arm, open-label, and intervention study. Thirty-five participants, including those who dropped out (12%), were screened and enrolled. The patients received LICUS (1.1 MHz, 1.5 W/cm2, collimated beams) on the knee by the instructions of the investigator at home (5 min/session, 3 times/day, for four-weeks). Outcome measures were assessed using the Visual Analog Scale (VAS) as a primary endpoint and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) as a secondary endpoint to evaluate pain relief and functional recovery of the knee between pre-treatment (baseline) and post-treatment (four-weeks). 3) Results: Knee pain scores measured using the VAS and WOMAC indices were significantly reduced after a four-week treatment with LICUS compared to baseline. Knee stiffness and functional capacity were significantly reduced after the LICUS application. In addition, there were no reports of adverse effects during the study period. 4) Conclusion: Long-term and home-based application of LICUS can be recommended as an alternative option for the treatment of OA patients, as evidenced by the effect of pain relief and knee function recovery.

Outcomes and efficacy of magnetic resonance imaging-compatible sacral nerve stimulator for management of fecal incontinence: A multi-institutional study

BACKGROUND Fecal incontinence(FI)is an involuntary passage of fecal matter which can have a significant impact on a patient’s quality of life.Many modalities of treatment exist for FI.Sacral nerve stimulation is a well-established treatment for FI.Given the increased need of magnetic resonance imaging(MRI)for diagnostics,the In-terStim which was previously used in sacral nerve stimulation was limited by MRI incompatibility.Medtronic MRI-compatible InterStim was approved by the United States Food and Drug Administration in August 2020 and has been widely used.AIM To evaluate the efficacy,outcomes and complications of the MRI-compatible InterStim.METHODS Data of patients who underwent MRI-compatible Medtronic InterStim placement at UPMC Williamsport,University of Minnesota,Advocate Lutheran General Hospital,and University of Wisconsin-Madison was pooled and analyzed.Patient demographics,clinical features,surgical techniques,complications,and outcomes were analyzed.Strengthening the Reporting of Observational studies in Epidemiology(STROBE)cross-sectional reporting guidelines were used.RESULTS Seventy-three patients had the InterStim implanted.The mean age was 63.29±12.2 years.Fifty-seven(78.1%)patients were females and forty-two(57.5%)patients had diabetes.In addition to incontinence,overlapping symptoms included diarrhea(23.3%),fecal urgency(58.9%),and urinary incontinence(28.8%).Fifteen(20.5%)patients underwent Peripheral Nerve Evaluation before proceeding to definite implant placement.Thirty-two(43.8%)patients underwent rechargeable InterStim placement.Three(4.1%)patients needed removal of the implant.Migration of the external lead connection was observed in 7(9.6%)patients after the stage I procedure.The explanation for one patient was due to infection.Seven(9.6%)patients had other complications like nerve pain,hematoma,infection,lead fracture,and bleeding.The mean follow-up was 6.62±3.5 mo.Sixty-eight(93.2%)patients reported significant improvement of symptoms on follow-up evaluation.CONCLUSION This study shows promising results with significant symptom improvement,good efficacy and good patient outcomes with low complication rates while using MRI compatible InterStim for FI.Further long-term follow-up and future studies with a larger patient population is recommended.

GTCS-Vagus Nerve Stimulator Automation Using Private IoT-Blockchain Smartcontract

Generalized Tonic Clonic Seizure(GTCS)is a form of epileptic seizure in which a patient loses control over their entire body,ultimately leading to loss of consciousness.The Vagus Nerve Stimulator(VNS)is a tool/method for treating epileptic episodes that sends counter-electrical stimulations to the Vagus Nerve in order to mitigate epileptic signals from the brain.The machine is a stand-alone device that depends on human decision-making.The proposed framework uses an IoT and Blockchain oversight mechanism to augment the device's transparency.The system counteracts against false-activation by monitoring the patient's vitals through a smart watch and allows only legitimate use.The nominal operating threshold is determined by preprocessing inferences that include an 18-year-old GTCS epileptic patient and a data set of 281 non-GTCS epileptic patients.The proposed system functions as a dual control lock where the IoT system and the manually activation system work in tandem to activate the device.Based on the values sensed by the IoT device,the deployed system is able to make deci-sions and regulate the use of the VNS.The IoT-Blockchain framework is able to fully eradicate false activation by increasing accuracy and transparency,ensur-ing the device is used correctly and safely.

Purification and Characterization of Hepatocyte Regeneration Stimulatory Factor from Shark Liver

Aim To purify hepatocyte regeneration stimulatory factor from shark liver and research its molecular feature and activity. Methods and Results Hepatocyte regeneration stimulatory factor (sHRSF) was isolated from healthy shark livers and separated by homogenization, freezing melting, heat treating, centrifugation, and ultrafiltration. HRSF activity was found mainly in the subfraction of molecular weight less than 30 000 daltons. This crude ultrafiltrate was further purified successively by DEAE Sepharose fast flow chromatography, FPLC Resource 30Q, Resource Q and Mono Q chromatography. A single band was displayed on sodium dodecyl sulfate polyacrylamide gel electrophoresis, which corresponds to molecular weight of 14 600 daltons. The characteristic absorption was obtained at the wavelength 276 nm. The isoelectric point was about 5 1. It contained 18 amino acids and the 15 N terminal amino acid residues were LVGPIGAVGPAGKDG. It had a significant activity in stimulating liver to regenerate. Conclusion We obtained an unknown new active protein, that is hepatocyte regeneration stimulatory factor from shark liver (sHRSF).

Growth induction of hepatic stimulator substance in hepatocytes through its regulation on EGF receptors

The cytosolic liver-specific growth factor-hepatic stimulator substance (HSS) has been shown to be able to amplify the rat hepatocyte proliferation responded to EGF. In order to get more insight into the mechanism, the regulatory effect of HSS on EGF-receptor(EGF-R) and the receptor phosphorylation at molecular level was studied. HSS partially purified from weanling rat liver was given to cultured hepatocytes and its influence on EGF-R specific binding and internalization as well as mRNA expression were investigated. The results showed that preincubation of hepatocytes with HSS could lead to an increase in [125I]-EGF binding to its receptors and inhibit EGFinduced receptor down-regulation. Furthermore, the overexpression of EGF-R mRNA stimulated by HSS was seen during 2-12 h after the incubation. Additionally, it was demonstrated with human hepatoma sMMC-7721 cells in Western blot that the EGF-R expression and the receptor autophosphorylation were increased with dose/timedependency after HSS treatment. These results strongly suggest that the mechanism of HSS action on hepatocyte growth might be related to its modulation on EGF-R and receptor-mediated signaling transduction.

Safety and efficacy of soluble guanylate cyclase stimulators in patients with heart failure: A systematic review and meta-analysis

BACKGROUND The utility of novel oral soluble guanylate cyclase(sGC)stimulators(vericiguat and riociguat),in patients with reduced or preserved ejection fraction heart failure(HFrEF/HFpEF)is currently unclear.AIM To determine the efficacy and safety of sGC stimulators in HF patients.METHODS Multiple databases were searched to identify relevant randomized controlled trials(RCTs).Data on the safety and efficacy of sGC stimulators were compared using relative risk ratio(RR)on a random effect model.RESULTS Six RCTs,comprising 5604 patients(2801 in sGC stimulator group and 2803 placebo group)were included.The primary endpoint(a composite of cardiovascular mortality and first HF-related hospitalization)was significantly reduced in patients receiving sGC stimulators compared to placebo[RR 0.92,95%confidence interval(CI):0.85-0.99,P=0.02].The incidence of total HF-related hospitalizations were also lower in sGC group(RR 0.91,95%CI:0.86-0.96,P=0.0009),however,sGC stimulators had no impact on all-cause mortality(RR 0.96,95%CI:0.86-1.07,P=0.45)or cardiovascular mortality(RR 0.94,95%CI:0.83-1.06,P=0.29).The overall safety endpoint(a composite of hypotension and syncope)was also similar between the two groups(RR 1.50,95%CI:0.93-2.42,P=0.10).By contrast,a stratified subgroup analysis adjusted by type of sGC stimulator and HF(vericiguat vs riociguat and HFrEF vs HFpEF)showed near identical rates for all safety and efficacy endpoints between the two groups at a mean follow-up of 19 wk.For the primary composite endpoint,the number needed to treat was 35,the number needed to harm was 44.CONCLUSION The use of vericiguat and riociguat in conjunction with standard HF therapy,shows no benefit in terms of decreasing HF-related hospitalizations or mortality.

Partial isolation and identification of hepatic stimulator substance mRNA extracted from human fetal liver

IM To partially isolate and identify hepatic stimulator substance mRNA from human fetal liver tissues.METHODS The poly (A)mRNA was extracted from human fetal liver tissues of 4-5 month gestation, fractionated by size on sucrose gradient centrifugation, translated into protein from each fraction in vitro and then its products were tested for HSS activity.RESULTS Twentytwo 500μg total RNA was obtained from human fetal liver tissues and pooled. mRNA of 420μg was yielded, processed by oligo(dT)cellulose column chromatography, then was sizefractionated by ultracentrifution on a continuous sucrose density gradient (5%-25%), and separated into 18 fractions. Translated products of mRNA in fraction 8 and 9 could produce a twofold increase in the incorporation of 3HTdR into DNA of SMMC7721 hepatoma cells and in a heatresistant and organspecific way.CONCLUSION The partially purified HSS mRNA was obtained and this would facilitate the cloning of HSS using expression vectors.

Pain management using Han’s acupoint nerve stimulator combined with patient-controlled analgesia following neurosurgery A randomized case control study

BACKGROUND： Han＇s acupoint nerve stimulator （HANS） has been frequently used to relieve pain by promoting the central nerve system＇s release of endogenous opioid peptides through electric stimulation to the body surface. OBJECTIVE： To investigate the pain-relieving effects of HANS, combined with patient-controlled analgesia, following neurosurgery, and to observe adverse reactions and effects. DESIGN, TIME AND SETTING： A randomized control observation was performed at the Department of Neurology in the First Affiliated Hospital of Gannan Medical College （Ganzhou, Jiangxi Province, China） from January 2005 to February 2006. PARTICIPANTS： Forty patients, who were selected for craniotomy and required pain relief following surgery at the Department of Neurology in the First Affiliated Hospital of Gannan Medical College （China）, were included in this study. METHODS： Forty patients underwent neurosurgery and were randomly divided into two groups： patient-controlled analgesia plus HANS （＋HANS, n = 20） and patient-controlled analgesia （-HANS, n = 20）. Both groups were well matched in baseline data. Automatic syringe infusion pump ZZB-150 was the product of Nantong Aipeng Medical Instruments Co., Ltd. （China）. Patient-controlled analgesia consisted of 100 mL 0.02% lappaconitine/0.02% metoclopramide. LH-402 HANS instrument was produced in Beijing （China）, with a serial number of 402183. The HANS instrumentation was used to stimulate the Hegu-Laogong acupoint on one side and Jiaogan, Shenmen penetrating Shen, Waifei, Naogan penetrating Pizhixia ear acupoints on the affected side for one hour, with 2-hour intervals. The disperse-dense wave was alternating, with a 2/100 Hz frequency of electrical stimulation. MAIN OUTCOME MEASURE： The scores of visual analogue scale and incidence of adverse reaction were observed in two groups following surgery. RESULTS： Compared with the HANS group, the visual analogue scale scores were remarkably lower in the ＋HANS group six hours after surgery （P 〈 0.01）, and the incidence rate of adverse reactions, such as nausea and vomiting, was also decreased （P 〈 0.05）.CONCLUSION： The application of HANS to induce body surface stimulation can enhance the effect of pain relief and reduce adverse reactions when used in combination with patient-controlled analgesia following neurosurgery. The effect of combined therapy is superior to patient-controlled analgesia alone.

Allelochemicals as Growth Stimulators for Drought Stressed Maize

Sorgaab, an aqueous extract of sorghum leaves was applied to probe the modulation in growth and physiological attributes of maize under drought in lab and greenhouse studies. Sorgaab soaked seeds (10 dilutions) were germinated to assess drought tolerance at germination and seedling growth stages. More concentrated Sorgaab solutions (2 mL·L-1) were damaging, while lower concentration in the range of 0.75 to 1.5 mL·L-1 improved the root and shoot growth of maize under drought. Applied drought stress decreased chlorophyll b greater than chlorophyll a that improved the chl a/b ratio. Application of Sorgaab also improved the internal CO2 assimilation, which increased the net photosynthesis and A/E ratio of drought affected plants. Soluble phenolics and anthocyanins were also more increased in plant receiving Sorgaab under drought than control. Although greater concentrations of phenolic acids inhibit the uptake of ions, but its lower concentrations stimulate the uptake of K+, Ca2+, NO3, PO4. In conclusion, although high concentrations of Sorgaab reduced the growth of plants, it might alleviate the adverse effects of drought, if applied at the low concentration. Dilute concentrations of Sorgaab can be utilized as a natural source for improving drought resistance in maize both at germination and later growth stages.

Change in Impedance with Change in Posture during Spinal Cord Stimulator Placement

In this article we discuss the effect of posture on impedance during the placement of a spinal cord stimulator. Although, according to several studies, there appears not to be a specific and consistent change in impedance with change in posture, we noticed on multiple occasions that if the impedance remains very high during spinal cord stimulator (SCS) lead placement, asking the patient to sit up from the prone position may drop the impedance down. This could be explained by having air around the lead, from using loss of resistance to air technique in finding the epidural space, which moves up when sitting the patient up, or having the lead immersed in epidural fat. Sitting the patient up from the prone position should be tried if the impedance remains very high before aborting the procedure and taking the lead out.

Effect of natural and synthetic growth stimulators on <i>in vitro</i>rooting and acclimatization of common ash (<i>Fraxinus excelsior</i>L.) microplants

Application of growth stimulators can be especially effective on plantlets in vitro of tree species which are usually worse rooted and adapted in comparison with annual plants. In our work we evaluate effects of natural (dihydroquercetin, Zircon) and synthetic growth stimulators (Melafen, Fumar, Epin-Extra) on rooting and acclimatization of common ash (Fraxinus excelsior L.) microplants. The 0.05% -?0.2% Zircon and 10-5%?Melafen enhanced in vitro rooting by 29% -?37% and 31%, respectively. Melafen also stimulated root formation faster compared to control plants. The dihydroquercetin concentration of 0.01% increased rooting by 24% and root number per shoot by 1.8 times. In vitro plants rooted on media supplemented with Melafen, Fumar and Zircon demonstrated enhanced ability to adapt to non-sterile conditions and accelerated growth. Two months after planting to the greenhouse, plants rooted on 0.01% dihydroquercetin were 45% taller than the control. Weekly spraying of plantlets with 0.02% Epin-Extra containing 24-epibrassinolid stimulated growth of uniform plants with large leaves. The obtained results support the use of growth stimulators for application in clonal micropropagation of common ash both for large-scale production of planting stock and for conservation of rare and valuable genotypes.

Effect of nerve stimulator-guided nerve block on the pain mediator secretion and stress degree after lower extremity operation

Objective: To study the effect of nerve stimulator-guided nerve block on the pain mediator secretion and stress degree after lower extremity operation. Methods: Patients who received lower extremity operation in Mianyang Orthopaedic Hospital between March 2015 and August 2017 were selected, and the analgesia methods within the medical records were reviewed and used to divide the patients into nerve block group, spinal analgesia group and intravenous analgesia group. The secretion of pain mediators, stress hormones, stress products and inflammatory factors in serum was measured 24 h after surgery. Results: CGRP, β-EP, 5-HT, HA, ACTH, Cor, PRL, GH, TSH, sTNFR-1, IL-2, IL-10 and TGF-β1 secretion as well as CRP, MPO, MDA and ROS generation in serum of nerve block group were significantly lower than those of spinal analgesia group and intravenous analgesia group, and the differences in serum pain mediators, stress hormones, stress products and inflammatory factors were statistically significant between nerve block group and spinal analgesia group as well as between nerve block group and intravenous analgesia group. Conclusion: The nerve stimulator-guided nerve block can be more effective than spinal analgesia and intravenous analgesia to reduce the secretion of pain mediators and relieve the degree of stress after lower extremity operation.

Novel T-cell co-stimulators in cancer gene therapy and immunotherapy

Optimal activation of T cells requires at least 2signals. Signal one is generated by interactionsbetween T cell receptor and antigenic peptide-majorhistocompatibility complex on antigen-presentingcells. Signal two is delivered by co-stimulatory ligandson antigen-presenting cells to their receptors on

Pulse electrical arc stimulator based on single-electrode for active exercise in tail-suspension rat

To make rat do active exercise to counteract bone loss in the rat tail-suspension model, a pulse electrical stimulator based on single-electrode with a low-current and a high-voltage was designed. The stimulator was controlled by SCM (single chip micyoco) that could accurately control the stimulation duration and the interval between stimulations, and cease the operation after the recorded number of stimulation had reached the value set by the program. With the help of posture estimation part, the device would operate intelligently by determining whether to stimulate or not, depending on the posture of rat's limb. Software was developed to make operator control the stimulator using computer, save the experiment data and print the report. In practical experiment, the voltaic arc is generated by the stimulator, and impacted on the rat's thenar. This induced pain to the rat and the rat would actively contract its hindlimb to evade the pain, so active exercise was carried out. The tail-suspension rats were trained twice every day for 14 d. At the 0 and 14th day, bone mineral density of rat femurs was determined by dual energy X-ray absorptiometry (DXA). The results show that the active exercise stimulated by the pulse electrical arc stimulator can attenuate weightlessness-induced bone loss, and this device is a convenient steady performance electrical stimulator that can surely induce rat's hindlimb to do active exercise.

Topographical Anatomical Neuropathic-Pain Guided (TANG) Mapping: A Tool Derived from a Patient Perspective to Facilitate the Transition from Spinal Cord Stimulator Trial to Potential Permanent Implantation

Introduction: Collecting a patient’s pain scores and the analgesic effect achieved during spinal cord stimulation (SCS) trials can be difficult, and no standard exists for doing so. We propose a topographical mapping tool that was derived from a patient’s perspective. Case: A 60-year-old man with postherpetic neuralgia (PHN) underwent a SCS trial after conservative treatment failed to relieve his pain. During the SCS trial, with the SCS off and on in five different settings, he recorded pain levels in each of the six different painful zones he identified. The data collected were transferred to a topographical and anatomical map, which helped the physicians to better understand the effects of the SCS at different settings. Ultimately, the data collected by the patient helped the physicians to implant a permanent SCS successfully. Conclusions: Patient pain diaries have been used in pain medicine for years. This particular patient’s collection of pain scores and SCS effects inspired the construction of a more standardized tool for collecting such data during SCS trials. We propose that use of our Topographical Anatomical Neuropathic-pain Guided (TANG) mapping tool will enable physicians to choose SCS lead positions more precisely than is currently possible.

The Design and Application of Nerve Stimulator

To apply electrical stimulation to the specific phase position of electroencephalogram （EEG） waveform, a nervous electrical stimulation system was developed using general data acquisition card and LabVIEW virtual instrument environment. The hippocampal field potential signal in the brain of rat was sampled using the acquisition card＇ s A/D channel, and the amplitude and cycle characteristics were analyzed and the wave peak or trough of the coming field potential （ 0 ） rhythm was predicted using LabVIEW program. Meanwhile, the needed stimulus signal was output at the specified phase position via the digital port or D/A channel of the acquisition card, so as to implement the nerve stimulation. The experimental result showed that the prediction accuracies of 0 -rhythm wave peak and trough were up to 92% and 86%, respectively. The electrical stimulation system can be applied to predicting a variety of nervous rhythm wave phases and other signal characteristics because of its universality and flexibility. Thus, a new loop control stimulation method is provided for the nerve electrophysiology study and the electrical stimulation treatment of brain diseases.

Electrogastrogram Recovery for Correction of Gastric Disorders Using Gastric Stimulator

Gastric disorders play an important role in digestive system of a human subject. Gastric disorder is due to the gastric dysmotility due to delayed gastric emptying and other motor dysfunctions like impaired fundic distention. Nowadays invasive technique like laparoscopy procedure, endoscopy procedure and surgery procedure plays a vital role in investigation of gastric disorders. Electrogastrogram is a noninvasive technique for analyzing digestive system disorders. In this proposed work, stimulation is delivered with the electrode package with camera, which travels through an esophagus to reach stomach and stimulate the interstitial cajal cells. Due to this stimulation the stomach starts, its activity a potential is provided that is recorded with electrode setup, which is called electrogastrogram. It is verified with its normal range 3 cpm. The stimulation includes pulses mode and continuous mode. Stomach function is recovered and its frequency is measured and the same is compared with normal range value. Depending upon the subject condition, the gastric activity is improved by setting different values of duty cycle. By this procedure the subject avoid painful procedure, stay in hospital, frequently and the cost is minimum.

Electroacupuncture alleviates postoperative pain through inhibiting neuroinflammation via stimulator of interferon genes/type-1 interferon pathway

Objective This work explores the impact of electroacupuncture(EA)on acute postoperative pain(APP)and the role of stimulator of interferon genes/type-1 interferon(STING/IFN-1)signaling pathway modulation in the analgesic effect of EA in APP rats.Methods The APP rat model was initiated through abdominal surgery and the animals received two 30 min sessions of EA at bilateral ST36(Zusanli)and SP6(Sanyinjiao)acupoints.Mechanical,thermal and cold sensitivity tests were performed to measure the pain threshold,and electroencephalograms were recorded in the primary somatosensory cortex to identify the effects of EA treatment on APP.Western blotting and immunofluorescence were used to examine the expression and distribution of proteins in the STING/IFN-1 pathway as well as neuroinflammation.A STING inhibitor(C-176)was administered intrathecally to verify its role in EA.Results APP rats displayed mechanical and thermal hypersensitivities compared to the control group(P<0.05).APP significantly reduced the amplitude ofθ,αandγoscillations compared to their baseline values(P<0.05).Interestingly,expression levels of proteins in the STING/IFN-1 pathway were downregulated after inducing APP(P<0.05).Further,APP increased pro-inflammatory factors,including interleukin-6,tumor necrosis factor-αand inducible nitric oxide synthase,and downregulated anti-inflammatory factors,including interleukin-10 and arginase-1(P<0.05).EA effectively attenuated APP-induced painful hypersensitivities(P<0.05)and restored theθ,αandγpower in APP rats(P<0.05).Meanwhile,EA distinctly activated the STING/IFN-1 pathway and mitigated the neuroinflammatory response(P<0.05).Furthermore,STING/IFN-1 was predominantly expressed in isolectin-B4-or calcitonin-gene-related-peptide-labeled dorsal root ganglion neurons and superficial laminae of the spinal dorsal horn.Inhibition of the STING/IFN-1 pathway by intrathecal injection of C-176 weakened the analgesic and anti-inflammatory effects of EA on APP(P<0.05).Conclusion EA can generate robust analgesic and anti-inflammatory effects on APP,and these effects may be linked to activating the STING/IFN-1 pathway,suggesting that STING/IFN-1 may be a target for relieving APP.

Live birth following an innovative artificial oocyte activation protocol using double calcium stimulators

Intracytoplasmic sperm injection(ICSI)is an effective method for human-assisted reproductive technology,especially for male-factor infertility.However,the average fertilization rate of ICSI is 70%,and total fertilization failure occurs in 3%of cycles.[1]Oocyte activation deficiency is the primary cause of fertilization failure.