Potassium and calcium channels in different nerve cells act as therapeutic targets in neurological disorders

The central nervous system, information integration center of the body, is mainly composed of neurons and glial cells. The neuron is one of the most basic and important structural and functional units of the central nervous system, with sensory stimulation and excitation conduction functions. Astrocytes and microglia belong to the glial cell family, which is the main source of cytokines and represents the main defense system of the central nervous system. Nerve cells undergo neurotransmission or gliotransmission, which regulates neuronal activity via the ion channels, receptors, or transporters expressed on nerve cell membranes. Ion channels, composed of large transmembrane proteins, play crucial roles in maintaining nerve cell homeostasis. These channels are also important for control of the membrane potential and in the secretion of neurotransmitters. A variety of cellular functions and life activities, including functional regulation of the central nervous system, the generation and conduction of nerve excitation, the occurrence of receptor potential, heart pulsation, smooth muscle peristalsis, skeletal muscle contraction, and hormone secretion, are closely related to ion channels associated with passive transmembrane transport. Two types of ion channels in the central nervous system, potassium channels and calcium channels, are closely related to various neurological disorders, including Alzheimer's disease, Parkinson's disease, and epilepsy. Accordingly, various drugs that can affect these ion channels have been explored deeply to provide new directions for the treatment of these neurological disorders. In this review, we focus on the functions of potassium and calcium ion channels in different nerve cells and their involvement in neurological disorders such as Parkinson's disease, Alzheimer's disease, depression, epilepsy, autism, and rare disorders. We also describe several clinical drugs that target potassium or calcium channels in nerve cells and could be used to treat these disorders. We concluded that there are few clinical drugs that can improve the pathology these diseases by acting on potassium or calcium ions. Although a few novel ion-channelspecific modulators have been discovered, meaningful therapies have largely not yet been realized. The lack of target-specific drugs, their requirement to cross the blood–brain barrier, and their exact underlying mechanisms all need further attention. This review aims to explain the urgent problems that need research progress and provide comprehensive information aiming to arouse the research community's interest in the development of ion channel-targeting drugs and the identification of new therapeutic targets for that can increase the cure rate of nervous system diseases and reduce the occurrence of adverse reactions in other systems.

Lithium-Ion Charged Polymer Channels Flattening Lithium Metal Anode

The concentration difference in the near-surface region of lithium metal is the main cause of lithium dendrite growth.Resolving this issue will be key to achieving high-performance lithium metal batteries(LMBs).Herein,we construct a lithium nitrate(LiNO_(3))-implanted electroactiveβphase polyvinylidene fluoride-co-hexafluoropropylene(PVDF-HFP)crystalline polymorph layer(PHL).The electronegatively charged polymer chains attain lithium ions on the surface to form lithium-ion charged channels.These channels act as reservoirs to sustainably release Li ions to recompense the ionic flux of electrolytes,decreasing the growth of lithium dendrites.The stretched molecular channels can also accelerate the transport of Li ions.The combined effects enable a high Coulombic efficiency of 97.0%for 250 cycles in lithium(Li)||copper(Cu)cell and a stable symmetric plating/stripping behavior over 2000 h at 3 mA cm^(-2)with ultrahigh Li utilization of 50%.Furthermore,the full cell coupled with PHL-Cu@Li anode and Li Fe PO_(4) cathode exhibits long-term cycle stability with high-capacity retention of 95.9%after 900 cycles.Impressively,the full cell paired with LiNi_(0.87)Co_(0.1)Mn_(0.03)O_(2)maintains a discharge capacity of 170.0 mAh g^(-1)with a capacity retention of 84.3%after 100 cycles even under harsh condition of ultralow N/P ratio of 0.83.This facile strategy will widen the potential application of LiNO_(3)in ester-based electrolyte for practical high-voltage LMBs.

Transient receptor potential channels as predictive marker and potential indicator of chemoresistance in colon cancer

Transient receptor potential(TRP)channels are strongly associated with colon cancer development and progression.This study leveraged a multivariate Cox regression model on publicly available datasets to construct a TRP channels-associated gene signature,with further validation of signature in real world samples from our hospital treated patient samples.Kaplan-Meier(K-M)survival analysis and receiver operating characteristic(ROC)curves were employed to evaluate this gene signature’s predictive accuracy and robustness in both training and testing cohorts,respectively.Additionally,the study utilized the CIBERSORT algorithm and single-sample gene set enrichment analysis to explore the signature’s immune infiltration landscape and underlying functional implications.The support vector machine algorithm was applied to evaluate the signature’s potential in predicting chemotherapy outcomes.The findings unveiled a novel three TRP channels-related gene signature(MCOLN1,TRPM5,and TRPV4)in colon adenocarcinoma(COAD).The ROC and K-M survival curves in the training dataset(AUC=0.761;p=1.58e-05)and testing dataset(AUC=0.699;p=0.004)showed the signature’s robust predictive capability for the overall survival of COAD patients.Analysis of the immune infiltration landscape associated with the signature revealed higher immune infiltration,especially an increased presence of M2 macrophages,in high-risk group patients compared to their low-risk counterparts.High-risk score patients also exhibited potential responsiveness to immune checkpoint inhibitor therapy,evident through increased CD86 and PD-1 expression profiles.Moreover,the TRPM5 gene within the signature was highly expressed in the chemoresistance group(p=0.00095)and associated with poor prognosis(p=0.036)in COAD patients,highlighting its role as a hub gene of chemoresistance.Ultimately,this signature emerged as an independent prognosis factor for COAD patients(p=6.48e-06)and expression of model gene are validated by public data and real-world patients.Overall,this bioinformatics study provides valuable insights into the prognostic implications and potential chemotherapy resistance mechanisms associated with TRPs-related genes in colon cancer.

Influence of pore structure heterogeneity on channeling channels during hot water flooding in heavy oil reservoir based on CT scanning

Hot water flooding is an effective way to develop heavy oil reservoirs.However,local channeling channels may form,possibly leading to a low thermal utilization efficiency and high water cut in the reservoir.The pore structure heterogeneity is an important factor in forming these channels.This study proposes a method that mixes quartz sand with different particle sizes to prepare weakly heterogeneous and strongly heterogeneous models through which hot water flooding experiments are conducted.During the experiments,computer tomography(CT)scanning identifies the pore structure and micro remaining oil saturation distribution to analyze the influence of the pore structure heterogeneity on the channeling channels.The oil saturation reduction and average pore size are divided into three levels to quantitatively describe the relationship between the channeling channel distribution and pore structure heterogeneity.The zone where oil saturation reduction exceeds 20%is defined as a channeling channel.The scanning area is divided into 180 equally sized zones based on the CT scanning images,and threedimensional(3D)distributions of the channeling channels are developed.Four micro remaining oil distribution patterns are proposed,and the morphology characteristics of micro remaining oil inside and outside the channeling channels are analyzed.The results show that hot water flooding is more balanced in the weakly heterogeneous model,and the oil saturation decreases by more than 20%in most zones without narrow channeling channels forming.In the strongly heterogeneous model,hot water flooding is unbalanced,and three narrow channeling channels of different lengths form.In the weakly heterogeneous model,the oil saturation reduction is greater in zones with larger pores.The distribution range of the average pore size is larger in the strongly heterogeneous model.The network remaining oil inside the channeling channels is less than outside the channeling channels,and the hot water converts the network remaining oil into cluster,film,and droplet remaining oil.

Multi-User Semantic Fusion for Semantic Communications over Degraded Broadcast Channels

Degraded broadcast channels(DBC) are a typical multiuser communication scenario, Semantic communications over DBC still lack in-depth research. In this paper, we design a semantic communications approach based on multi-user semantic fusion for wireless image transmission over DBC. The transmitter extracts semantic features for two users separately and then effectively fuses them for broadcasting by leveraging semantic similarity. Unlike traditional allocation of time, power, or bandwidth, the semantic fusion scheme can dynamically control the weight of the semantic features of the two users to balance their performance. Considering the different channel state information(CSI) of both users over DBC,a DBC-Aware method is developed that embeds the CSI of both users into the joint source-channel coding encoder and fusion module to adapt to the channel.Experimental results show that the proposed system outperforms the traditional broadcasting schemes.

Dilation,discrimination and Uhlmann's theorem of link products of quantum channels

We establish the Stinespring dilation theorem of the link product of quantum channels in two different ways,discuss the discrimination of quantum channels,and show that the distinguishability can be improved by self-linking each quantum channel n times as n grows.We also find that the maximum value of Uhlmann's theorem can be achieved for diagonal channels.

Effective Capacity of URLLC over Parallel Fading Channels with Imperfect Channel State Information

This paper investigates the effective capacity of a point-to-point ultra-reliable low latency communication(URLLC)transmission over multiple parallel sub-channels at finite blocklength(FBL)with imperfect channel state information(CSI).Based on reasonable assumptions and approximations,we derive the effective capacity as a function of the pilot length,decoding error probability,transmit power and the sub-channel number.Then we reveal significant impact of the above parameters on the effective capacity.A closed-form lower bound of the effective capacity is derived and an alternating optimization based algorithm is proposed to find the optimal pilot length and decoding error probability.Simulation results validate our theoretical analysis and show that the closedform lower bound is very tight.In addition,through the simulations of the optimized effective capacity,insights for pilot length and decoding error probability optimization are provided to evaluate the optimal parameters in realistic systems.

Cooperative Covert Communication in Multi-Antenna Broadcast Channels

With the gradual popularization of 5G communications,the application of multi-antenna broadcasting technology has become widespread.Therefore,this study aims to investigate the wireless covert communication in the two-user cooperative multi-antenna broadcast channel.We focus on the issue that the deteriorated reliability and undetectability are mainly affected by the transmission power.To tackle this issue,we design a scheme based on beamforming to increase the reliability and undetectability of wireless covert communication in the multi-antenna broadcast channel.We first modeled and analyzed the cooperative multi-antenna broadcasting system,and put forward the target question.Then we use the SCA(successive convex approximation)algorithm to transform the target problem into a series of convex subproblems.Then the convex problems are solved and the covert channel capacity is calculated.In order to verify the effectiveness of the scheme,we conducted simulation verification.The simulation results show that the proposed beamforming scheme can effectively improve the reliability and undetectability of covert communication in multi-antenna broadcast channels.

A Deep Learning Based Broadcast Approach for Image Semantic Communication over Fading Channels

We consider an image semantic communication system in a time-varying fading Gaussian MIMO channel,with a finite number of channel states.A deep learning-aided broadcast approach scheme is proposed to benefit the adaptive semantic transmission in terms of different channel states.We combine the classic broadcast approach with the image transformer to implement this adaptive joint source and channel coding(JSCC)scheme.Specifically,we utilize the neural network(NN)to jointly optimize the hierarchical image compression and superposition code mapping within this scheme.The learned transformers and codebooks allow recovering of the image with an adaptive quality and low error rate at the receiver side,in each channel state.The simulation results exhibit our proposed scheme can dynamically adapt the coding to the current channel state and outperform some existing intelligent schemes with the fixed coding block.

Cooperative activation of sodium channels for downgrading the energy efficiency in neuronal information processing

The Hodgkin–Huxley model assumes independent ion channel activation,although mutual interactions are common in biological systems.This raises the problem why neurons would favor independent over cooperative channel activation.In this study,we evaluate how cooperative activation of sodium channels affects the neuron’s information processing and energy consumption.Simulations of the stochastic Hodgkin–Huxley model with cooperative activation of sodium channels show that,while cooperative activation enhances neuronal information processing capacity,it greatly increases the neuron’s energy consumption.As a result,cooperative activation of sodium channel degrades the energy efficiency for neuronal information processing.This discovery improves our understanding of the design principles for neural systems,and may provide insights into future designs of the neuromorphic computing devices as well as systematic understanding of pathological mechanisms for neural diseases.

The variation in basal channels and basal melt rates of Pine Island Ice Shelf

In recent years,there has been a significant acceleration in the thinning,calving and retreat of the Pine Island Ice Shelf(PIIS).The basal channels,results of enhanced basal melting,have the potential to significantly impact the stability of the PIIS.In this study,we used a variety of remote sensing data,including Landsat,REMA DEM,ICESat-1 and ICESat-2 satellite altimetry observations,and Ice Bridge airborne measurements,to study the spatiotemporal changes in the basal channels from 2003 to 2020 and basal melt rate from 2010 to 2017 of the PIIS under the Eulerian framework.We found that the basal channels are highly developed in the PIIS,with a total length exceeding 450 km.Most of the basal channels are ocean-sourced or groundingline-sourced basal channels,caused by the rapid melting under the ice shelf or near the groundingline.A raised seabed prevented warm water intrusion into the eastern branch of the PIIS,resulting in a lower basal melt rate in that area.In contrast,a deepsea trough facilitates warm seawater into the mainstream and the western branch of the PIIS,resulting in a higher basal melt rate in the main-stream,and the surface elevation changes above the basal channels of the mainstream and western branch are more significant.The El Ni?o event in 2015–2016 possibly slowed down the basal melting of the PIIS by modulating wind field,surface sea temperature and depth seawater temperature.Ocean and atmospheric changes were driven by El Ni?o,which can further explain and confirm the changes in the basal melting of the PIIS.

Assessment of the Recent Hydromorphological Features of Nokoue Lake and Its Channels (South-East Benin)

Based on 2022 and 2023 hydrometric data and satellite images (Sentinel 2022, SPOT 2010), this study aims to present the Nokoué Lake and its channels’ re-cent hydromorphological characteristics. Integrating flow, tributary morphology, and topography data determined specific power values along the axes studied. The values obtained range from 2.69 to 12.92 W/m2 for Ouémé River and 2.46 to 10.99 W/m2 for Sô River. The resulting water erosion on banks and bottoms is of linear, areolar, or gully and claw types. Lake bathymetry varies from -0.5 to -2.6 m (low flow period) and -1 to -4 m;in the Ouémé, Sô, and Totchè rivers, it varies from -5 m to -7 m, reaching -10 m at the Cotonou channel entrance (flood period). Bathymetric profiles reveal varied “U”, “V” and “Intermediate” bottom morphologies, influenced by erosion/sedimentation processes and human activities. The flow facies identified are lentic in the northern tributaries and lotic in the Cotonou and Totchè canals. Spatial analysis identified nine (09) thematic classes. In 2022, the surface area of the water body has increased from 274 km2 at low water to 280 km2 at high water, whereas in 2010 (a recent year of exceptional flooding), the surface area was 270 km2 at low water and 277 km2 at high water. Significant changes in land use are observed between 2010 and 2022. The floodplain area decreased slightly, from 421 km2 in 2010 (year of exceptional flooding) to 419 km2 in 2022. The evolution of land use shows a progressive expansion of the urban environment to the detriment of the natural environment. In the medium to long term, this trend could threaten the hydromorphological balance and even the existence of this important lagoon ecosystem.

Temperature Drop of Molten Metals in Open Channels

The temperature drop of molten metal flowing in open channels is numerically determined. Rectangular, trapezoidal and triangular geometries are considered. The overall heat transfer coefficients for the bottom, side walls and free surface of the channel have been taken from the literature. For each geometry, the volumetric flow rate, mean residence time and temperature drop as a function of the channel inclination angle were determined. The rectangular and trapezoidal geometries present the smallest temperature drops, while the triangular geometry presents the greatest temperature drop. The factors that most affect this drop are the value of the free surface area of the channel, and the average residence time of the molten metal in the channel.

Treatment of Domestic Sewage by Channels Constructed Wetland in New Countryside

[Objection] The aim was to study application of channels constructed wetland in treatment of domestic sewages in new countryside. [Method] Supported by construction of new rural areas project in China, we surveyed on new rural areas in Gannan, Jiangxi Province, summarized source, characteristics and treatment of domestic sewage in countryside, and designed channels constructed wetland for sewage treatment. [Result] The technique is proven effective in sewage treatment. After the technique was conducted for a trial run for four months, removal rates of COD, TP and TN averaged 73.07%, 73.25% and 72.36%, respectively. After contin- uous sampling for six times, effluent COD was analyzed 20-35 mg/L, TP was 0.60- 1.19 mg/L and TN was 6.88-11.21 mg/L, better than that of Standard 1B ruled by Discharge Standard of Pollutants for Municipal Wastewater Treatment Plant. [Conclusion] Thanks for low investment, channels constructed wetland can be built by trans- formation of bottom land, proving a good way for treatment of diffuse pollution source and control of water non-point pollution.

Brain-derived neurotrophic factor signaling in the neuromuscular junction during developmental axonal competition and synapse elimination

During the development of the nervous system,there is an overproduction of neurons and synapses.Hebbian competition between neighboring nerve endings and synapses performing different activity levels leads to their elimination or strengthening.We have extensively studied the involvement of the brain-derived neurotrophic factor-Tropomyosin-related kinase B receptor neurotrophic retrograde pathway,at the neuromuscular junction,in the axonal development and synapse elimination process versus the synapse consolidation.The purpose of this review is to describe the neurotrophic influence on developmental synapse elimination,in relation to other molecular pathways that we and others have found to regulate this process.In particular,we summarize our published results based on transmitter release analysis and axonal counts to show the different involvement of the presynaptic acetylcholine muscarinic autoreceptors,coupled to downstream serine-threonine protein kinases A and C(PKA and PKC)and voltage-gated calcium channels,at different nerve endings in developmental competition.The dynamic changes that occur simultaneously in several nerve terminals and synapses converge across a postsynaptic site,influence each other,and require careful studies to individualize the mechanisms of specific endings.We describe an activity-dependent balance(related to the extent of transmitter release)between the presynaptic muscarinic subtypes and the neurotrophin-mediated TrkB/p75NTR pathways that can influence the timing and fate of the competitive interactions between the different axon terminals.The downstream displacement of the PKA/PKC activity ratio to lower values,both in competing nerve terminals and at postsynaptic sites,plays a relevant role in controlling the elimination of supernumerary synapses.Finally,calcium entry through L-and P/Q-subtypes of voltage-gated calcium channels(both channels are present,together with the N-type channel in developing nerve terminals)contributes to reduce transmitter release and promote withdrawal of the most unfavorable nerve terminals during elimination(the weakest in acetylcholine release and those that have already become silent).The main findings contribute to a better understanding of punishment-rewarding interactions between nerve endings during development.Identifying the molecular targets and signaling pathways that allow synapse consolidation or withdrawal of synapses in different situations is important for potential therapies in neurodegenerative diseases.

MixerKT:A Knowledge Tracing Model Based on Pure MLP Architecture

In the field of intelligent education,the integration of artificial intelligence,especially deep learning technologies,has garnered significant attention.Knowledge tracing(KT)plays a pivotal role in this field by predicting students’future performance through the analysis of historical interaction data,thereby assisting educators in evaluating knowledgemastery and tailoring instructional strategies.Traditional knowledge tracingmethods,largely based on Recurrent Neural Networks(RNNs)and Transformer models,primarily focus on capturing long-term interaction patterns in sequential data.However,these models may neglect crucial short-term dynamics and other relevant features.This paper introduces a novel approach to knowledge tracing by leveraging a pure Multilayer Perceptron(MLP)architecture.We proposeMixerKT,a knowledge tracing model based on theHyperMixer framework,which uniquely integrates global and localMixer feature extractors.This architecture enables more effective extraction of both long-terminteraction trends and recent learning behaviors,addressing limitations in currentmodels thatmay overlook these key aspects.Empirical evaluations on twowidely-used datasets,ASSIS Tments2009 and Algebra2005,demonstrate that MixerKT consistently outperforms several state-of-the-art models,including DKT,SAKT,and Separated Self-Attentive Neural Knowledge Tracing(SAINT).Specifically,MixerKT achieves higher prediction accuracy,highlighting its effectiveness in capturing the nuances of learners’knowledge states.These results indicate that our model provides a more comprehensive representation of student learning patterns,enhancing the ability to predict future performance with greater precision.

Engine Misfire Fault Detection Based on the Channel Attention Convolutional Model

To accurately diagnosemisfire faults in automotive engines,we propose a Channel Attention Convolutional Model,specifically the Squeeze-and-Excitation Networks(SENET),for classifying engine vibration signals and precisely pinpointing misfire faults.In the experiment,we established a total of 11 distinct states,encompassing the engine’s normal state,single-cylinder misfire faults,and dual-cylinder misfire faults for different cylinders.Data collection was facilitated by a highly sensitive acceleration signal collector with a high sampling rate of 20,840Hz.The collected data were methodically divided into training and testing sets based on different experimental groups to ensure generalization and prevent overlap between the two sets.The results revealed that,with a vibration acceleration sequence of 1000 time steps(approximately 50 ms)as input,the SENET model achieved a misfire fault detection accuracy of 99.8%.For comparison,we also trained and tested several commonly used models,including Long Short-Term Memory(LSTM),Transformer,and Multi-Scale Residual Networks(MSRESNET),yielding accuracy rates of 84%,79%,and 95%,respectively.This underscores the superior accuracy of the SENET model in detecting engine misfire faults compared to other models.Furthermore,the F1 scores for each type of recognition in the SENET model surpassed 0.98,outperforming the baseline models.Our analysis indicated that the misclassified samples in the LSTM and Transformer models’predictions were primarily due to intra-class misidentifications between single-cylinder and dual-cylinder misfire scenarios.To delve deeper,we conducted a visual analysis of the features extracted by the LSTM and SENET models using T-distributed Stochastic Neighbor Embedding(T-SNE)technology.The findings revealed that,in the LSTMmodel,data points of the same type tended to cluster together with significant overlap.Conversely,in the SENET model,data points of various types were more widely and evenly dispersed,demonstrating its effectiveness in distinguishing between different fault types.

Secure Channel Estimation Using Norm Estimation Model for 5G Next Generation Wireless Networks

The emergence of next generation networks(NextG),including 5G and beyond,is reshaping the technological landscape of cellular and mobile networks.These networks are sufficiently scaled to interconnect billions of users and devices.Researchers in academia and industry are focusing on technological advancements to achieve highspeed transmission,cell planning,and latency reduction to facilitate emerging applications such as virtual reality,the metaverse,smart cities,smart health,and autonomous vehicles.NextG continuously improves its network functionality to support these applications.Multiple input multiple output(MIMO)technology offers spectral efficiency,dependability,and overall performance in conjunctionwithNextG.This article proposes a secure channel estimation technique in MIMO topology using a norm-estimation model to provide comprehensive insights into protecting NextG network components against adversarial attacks.The technique aims to create long-lasting and secure NextG networks using this extended approach.The viability of MIMO applications and modern AI-driven methodologies to combat cybersecurity threats are explored in this research.Moreover,the proposed model demonstrates high performance in terms of reliability and accuracy,with a 20%reduction in the MalOut-RealOut-Diff metric compared to existing state-of-the-art techniques.

Effects of Rhynchophylline on L type Calcium Channels in Isolated Rat Cortical Neurons During Acute Hypoxia

Aim: To study the effects of rhynchophylline (Rhy) on the L type calcium channels in freshly dissociated cortical neurons of Wistar rats during acute hypoxia. Methods: Cell attached configuration of patch clamp technique. L type calcium channel was activated by stepping from 40 mV to 0 mV. Results: The results showed that the L type calcium channels of cortical neurons were activated by acute hypoxia. The mean open time of the channel was increased, the mean close time decreased and the open state probability raised during acute hypoxia. Rhy (15 and 30μmol·L -1 ) in concentration dependent manner blocked activity of the channels. The drug shortened the mean open time of the channels from 8 87 ms to 3 03 ms and 2 23 ms ( P 【0 001), prolonged the mean close time from 9 23 ms to 38 84 ms and 54 43 ms ( P 【0 001), and decreased the open state probability from 0 142 to 0 031 and 0 025 ( P 【0 001) under the hypoxia condition, respectively. The effects of Rhy were similar to but weaker than those of verapamil (15 μmol·L -1 ). Conclusion: The study confirmed that Rhy has the blockade effects on L type calcium channels in cortical neurons of rats during hypoxia, by which it protects the brain from hypoxic injury.

Phoneutria Spider Toxins Target Channels Involved in Cardiac Arrhythmias, Ischemia and Pain

Toxins isolated from the venom of the spider Phoneutria nigriventer either inhibit or activate a vast number of targets, such as ion channels, with high selectivity and affinity. PhTx3-1 toxin is a selective blocker of IA currents of K^＋ channels, and PhTx3-3 and PhTx3-4 are calcium channel blockers of the P/Q-type calcium channels. The spider neurotoxin PhTx3-6 reversibly and non-specifically inhibits high-voltage-activated Ca^2＋ channels with varying potency （N 〉 R 〉 P/Q 〉 L） in heterologous and native systems. There has been a huge increase in the range of medical disorders involving ionic channels, and blockers of these channels have potential as therapeutic agents. The mechanism of action of each toxin family is different; thus, each needs to be evaluated for its therapeutic potential. This review will focus on peptide toxins purified from the venom of the spider Phoneutria nigriventer that are currently being evaluated in preclinical tests as possible drugs for the treatment of pain, cardiac arrhythmias and ischemia.