Sympatho-Excitatory Response to Pulmonary Chemosensitive Spinal Afferent Activation in Anesthetized, Vagotomized Rats

The sensory innervation of the lung is well known to be innervated by nerve fibers of both vagal and sympathetic origin. Although the vagal afferent innervation of the lung has been well characterized, less is known about physiological effects mediated by spinal sympathetic afferent fibers. We hypothesized that activation of sympathetic spinal afferent nerve fibers of the lung would result in an excitatory pressor reflex, similar to that previously characterized in the heart. In this study, we evaluated changes in renal sympathetic nerve activity (RSNA) and hemodynamics in response to activation of TRPV1-sensitive pulmonary spinal sensory fibers by agonist application to the visceral pleura of the lung and by administration into the primary bronchus in anesthetized, bilaterally vagotomized, adult Sprague-Dawley rats. Application of bradykinin (BK) to the visceral pleura of the lung produced an increase in mean arterial pressure (MAP), heart rate (HR), and RSNA. This response was significantly greater when BK was applied to the ventral surface of the left lung compared to the dorsal surface. Conversely, topical application of capsaicin (Cap) onto the visceral pleura of the lung, produced a biphasic reflex change in MAP, coupled with increases in HR and RSNA which was very similar to the hemodynamic response to epicardial application of Cap. This reflex was also evoked in animals with intact pulmonary vagal innervation and when BK was applied to the distal airways of the lung via the left primary bronchus. In order to further confirm the origin of this reflex, epidural application of a selective afferent neurotoxin (resiniferatoxin, RTX) was used to chronically ablate thoracic TRPV1-expressing afferent soma at the level of T1-T4 dorsal root ganglia pleura. This treatment abolished all sympatho-excitatory responses to both cardiac and pulmonary application of BK and Cap in vagotomized rats 9-10 weeks post-RTX. These data suggest the presence of an excitatory pulmonary chemosensitive sympathetic afferent reflex. This finding may have important clinical implications in pulmonary conditions inducing sensory nerve activation such as pulmonary inflammation and inhalation of chemical stimuli

A Holistic Systems Approach to Characterize the Impact of Pre- and Post-natal Oxycodone Exposure on Neurodevelopment and Behavior

Background: Increased risk of oxycodone (oxy) dependency during pregnancy has been associated with altered behaviors and cognitive deficits in exposed offspring. However, a significant knowledge gap remains regarding the effect of in utero and postnatal exposure on neurodevelopment and subsequent behavioral outcomes. Methods: Using a preclinical rodent model that mimics oxy exposure in utero (IUO) and postnatally (PNO), we employed an integrative holistic systems biology approach encompassing proton magnetic resonance spectroscopy (1H-MRS), electrophysiology, RNA-sequencing, and Von Frey pain testing to elucidate molecular and behavioral changes in the exposed offspring during early neurodevelopment as well as adulthood. Results: 1H-MRS studies revealed significant changes in key brain metabolites in the exposed offspring that were corroborated with changes in synaptic currents. Transcriptomic analysis employing RNA-sequencing identified alterations in the expression of pivotal genes associated with synaptic transmission, neurodevelopment, mood disorders, and addiction in the treatment groups. Furthermore, Von Frey analysis revealed lower pain thresholds in both exposed groups. Conclusions: Given the increased use of opiates, understanding the persistent developmental effects of these drugs on children will delineate potential risks associated with opiate use beyond the direct effects in pregnant women

Cardio-Renal Syndrome Type 2: The Role of Cardiac Spinal Afferent Reflex

Cardio-renal syndrome type 2 (CRS type 2) is defined as a chronic cardiovascular disease, usually chronic heart failure (CHF), resulting in chronic kidney disease. We hypothesized that the cardiac spinal afferent reflex (CSAR), a cardiogenic sympatho-excitatory reflex mediated by cardiac spinal afferents plays a critical role in the development of CRS type 2. We examined the effects of acute activation and chronic ablation of the CSAR on renal blood flow (RBF), renal vascular resistance (RVR), central venous pressure (CVP), renal function and renal histology in sham and myocardial infarction (MI)-induced CHF rats. RNA sequencing analysis (RNA-Seq) and validation by real-time PCR in renal tissues were used to identify the potential molecular mechanisms underlying the effects of the CSAR on renal function in CHF. We found that acute CSAR activation increased RVR to a greater extent in CHF rats compared to sham rats. Chronic CSAR ablation with the epicardial application of a selective afferent neurotoxin resiniferatoxin (RTX) at the time of myocardial infarction (MI), in part, restored RBF and reduced RVR in CHF rats. Furthermore, epicardial RTX largely prevented the development of renal dysfunction 4-5 months post-MI. RNA-Seq analysis showed that renal injury, inflammatory, hypoxia, and apoptotic genes were significantly upregulated in the renal tissue of CHF rats, which was largely restored by RTX. Renal congestion as indexed by increased CVP in CHF+vehicle rats was significantly attenuated by epicardial RTX. These data suggest that CSAR ablation by epicardial RTX has a selective protective effect on renal proximal tubular damage in the setting of CHF by partially restoring renal cortical blood flow and ameliorating renal congestion. In addition, CSAR ablation by intra-stellate ganglia (SG) injection 4 weeks after MI had similar renal protective effects on renal tubular damage in CHF rats, suggesting a translational potential of CSAR ablation in the post-MI state. To examine whether renal denervation (RDN) mimics the beneficial effects of CSAR ablation in CHF, unilateral RDN was performed in CHF rats. We observed that unilateral RDN mitigated renal dysfunction, by preventing the deterioration of glomerular filtration rate (GFR) and by attenuation of the gene expression of kidney damage marker. Unilateral RDN also improved the cardiac function of CHF rats. On the other hand, we carried out a systematic analysis of clinical trials to assess the effectiveness and risks of bilateral RDN in patients with CHF with reduced ejection fraction. Our calculation showed that RDN significantly improved the symptoms of CHF as evidenced by decreases in New York Heart Association (NYHA) class and increased six-minute walk distances. This meta-analysis also showed echocardiographic improvements in left ventricular function and congestion after RDN, suggesting that these echocardiographic improvements could drive symptomatic improvement. Moreover, RDN decreased systolic and diastolic blood pressure (BP) as well as heart rate (HR) without affecting renal function. In summary, the current study suggests that both CSAR ablation and RDN may have translational potential in the treatment of patients with CRS type 2

Potential Neuromodulation of the Cardio-Renal Syndrome

The cardio-renal syndrome (CRS) type 2 is defined as a progressive loss of renal function following a primary insult to the myocardium that may be either acute or chronic but is accompanied by a decline in myocardial pump performance. The treatment of patients with CRS is difficult, and the disease often progresses to end-stage renal disease that is refractory to conventional therapy. While a good deal of information is known concerning renal injury in the CRS, less is understood about how reflex control of renal sympathetic nerve activity affects this syndrome. In this review, we provide insight into the role of the renal nerves, both from the afferent or sensory side and from the efferent side, in mediating renal dysfunction in CRS. We discuss how interventions such as renal denervation and abrogation of systemic reflexes may be used to alleviate renal dysfunction in the setting of chronic heart failure. We specifically focus on a novel cardiac sensory reflex that is sensitized in heart failure and activates the sympathetic nervous system, especially outflow to the kidney. This so-called Cardiac Sympathetic Afferent Reflex (CSAR) can be ablated using the potent neurotoxin resinferitoxin due to the high expression of Transient Receptor Potential Vanilloid 1 (TRPV1) receptors. Following ablation of the CSAR, several markers of renal dysfunction are reversed in the post-myocardial infarction heart failure state. This review puts forth the novel idea of neuromodulation at the cardiac level in the treatment of CRS Type 2

Increased Brain-Derived Neurotrophic Factor in Lumbar Dorsal Root Ganglia Contributes to the Enhanced Exercise Pressor Reflex in Heart Failure

An exaggerated exercise pressor reflex (EPR) is associated with excessive sympatho-excitation and exercise intolerance in the chronic heart failure (CHF) state. We hypothesized that brain-derived neurotrophic factor (BDNF) causes the exaggerated EPR via sensitizing muscle mechanosensitive afferents in CHF. Increased BDNF expression was observed in lumbar dorsal root ganglia (DRGs) from CHF rats compared to sham rats. Immunofluorescence data showed a greater increase in the number of BDNF-positive neurons in medium and large-sized DRG subpopulations from CHF rats. Patch clamp data showed that incubation with BDNF for 4–6 h, significantly decreased the current threshold-inducing action potential (AP), threshold potential and the number of APs during current injection in Dil-labeled isolectin B4 (IB4)-negative medium-sized DRG neurons (mainly mechano-sensitive) from sham rats. Compared to sham rats, CHF rats exhibited an increased number of APs during current injection in the same DRG subpopulation, which was significantly attenuated by 4-h incubation with anti-BDNF. Finally, chronic epidural delivery of anti-BDNF attenuated the exaggerated pressor response to either static contraction or passive stretch in CHF rats whereas this intervention had no effect on the pressor response to hindlimb arterial injection of capsaicin. These data suggest that increased BDNF in lumbar DRGs contributes to the exaggerated EPR in CHF

CWAN: Covert Watermarking Attack Network

Digital watermarking technology is widely used in today’s copyright protection, data monitoring, and data tracking. Digital watermarking attack techniques are designed to corrupt the watermark information contained in the watermarked image (WMI) so that the watermark information cannot be extracted effectively or correctly. While traditional digital watermarking attack technology is more mature, it is capable of attacking the watermark information embedded in the WMI. However, it is also more damaging to its own visual quality, which is detrimental to the protection of the original carrier and defeats the purpose of the covert attack on WMI. To advance watermarking attack technology, we propose a new covert watermarking attack network (CWAN) based on a convolutional neural network (CNN) for removing low-frequency watermark information from WMI and minimizing the damage caused by WMI through the use of deep learning. We import the preprocessed WMI into the CWAN, obtain the residual feature images (RFI), and subtract the RFI from the WMI to attack image watermarks. At this point, the WMI’s watermark information is effectively removed, allowing for an attack on the watermark information while retaining the highest degree of image detail and other features. The experimental results indicate that the attack method is capable of effectively removing the watermark information while retaining the original image’s texture and details and that its ability to attack the watermark information is superior to that of most traditional watermarking attack methods. Compared with the neural network watermarking attack methods, it has better performance, and the attack performance metrics are improved by tens to hundreds of percent in varying degrees, indicating that it is a new covert watermarking attack method

Mitochondrial DNA 4977 bp deletion is a common phenomenon in hair and increases with age

Mitochondrial DNA (mtDNA) is believed to be particularly susceptible to oxidative damage during aging, resulting in mtDNA point mutations, duplications, and deletions. Although mtDNA deletions have been reported in various human tissues, e.g., the brain, heart, and skeletal muscle, little is known about the occurrence in hair. Therefore, we screened for the presence of mtDNA 13162 bp, 10422 bp, 7663 bp, 7436 bp, 4989 bp, and 4977 bp deletions in 90 hair samples from subjects aged 5 days to 91 years by using polymerase chain reaction (PCR) and investigated the deletion load by TaqMan probe-based real-time PCR. We detected the mtDNA 4977 bp deletion in hair samples, but none of the other deletions that were screened for. The proportion of mtDNA 4977 deletion carriers was 98.3% (89/90) and the deletion loads increased from 0 to 1.436 ± 0.2086% of the total mtDNA with an exponential increase with age (r = 0.677,p < 0.05). These results suggest that mtDNA 4977 bp deletion is a common phenomenon in hair and increases with age. These findings expand our understanding of the tissue-specific distribution of mtDNA deletions

Local-Scale Horizontal CO₂ Flux Estimation Incorporating Differential Absorption Lidar and Coherent Doppler Wind Lidar

A micro-pulse lidar system incorporating differential absorption lidar (DIAL) and coherent Doppler wind lidar (CDWL) is proposed and demonstrated. Due to the high signal-to-noise ratio (SNR) of the superconducting nanowire single-photon detector (SNSPD), the DIAL channel achieves high sensitivity in CO2 measurement. Meanwhile, the CDWL channel is used to obtain the horizontal wind field. In the process of the optimization and calibration of the DIAL receiver, specifically, mode scrambling and temperature control of the connecting fiber between the telescope and the SNSPD enhance the stability and robustness of the system. Horizontal scanning of the CO2 concentration and the wind field is carried out in a 6 km range over a scanning span of 60° with a radial resolution of 150 m and 15 s. The results show that the hybrid lidar system captures the spatial distribution of CO2 concentration and the wind field simultaneously. The horizontal net CO2 flux in a radius of 6 km is estimated by integrating the CO2 concentration and the wind transport vector, indicating different characteristics of horizontal net CO2 fluxes in an industrial area, a university campus, and a park. During most of the experiment, CO2 flux remained positive in the industrial area, but balances fell to nearly zero on the campus and in the park. The horizontal net fluxes averaged over 24 h in the three areas are 3.5 × 105 ppm·m2·s−1, 0.7 × 105 ppm·m2·s−1, and 0.1 × 105 ppm·m2·s−1