Smart stimuli-responsive drug delivery systems in spotlight of COVID-19

The world has been dealing with a novel severe acute respiratory syndrome(SARS-CoV-2)since the end of 2019,which threatens the lives of many peopleworldwide.COVID-19 causes respiratory infection with different symptoms,from sneezing and coughing to pneumonia and sometimes gastric symptoms.Researchers worldwide are actively developing novel drug delivery systems(DDSs),such as stimuli-responsive DDSs.The ability of these carriers to respond to external/internal and even multiple stimuli is essential in creating“smart”DDS that can effectively control dosage,sustained release,individual variations,and targeted delivery.To conduct a comprehensive literature survey for this article,the terms“Stimuli-responsive”,“COVID-19”and“Drug delivery”were searched on databases/search engines like“Google Scholar”,“NCBI”,“PubMed”,and“Science Direct”.Many different types of DDSs have been proposed,including those responsive to various exogenous(light,heat,ultrasound andmagnetic field)or endogenous(microenvironmental changes in pH,ROS and enzymes)stimuli.Despite significant progress in DDS research,several challenging issues must be addressed to fill the gaps in the literature.Therefore,this study reviews the drug release mechanisms and applications of endogenous/exogenous stimuli-responsive DDSs while also exploring their potential with respect to COVID-19.

Lycium barbarum polysaccharide-glycoprotein preventative treatment ameliorates aversive stimuli-induced depression

Previous studies have shown that Lycium barbarum polysaccharide,the main active component of Lycium barbarum,exhibits antiinflammatory and antioxidant effects in treating neurological diseases.However,the therapeutic action of Lycium barbarum polysaccharide on depression has not been studied.In this investigation,we established mouse models of depression using aversive stimuli including exposure to fox urine,air puff and foot shock and physical restraint.Concurrently,we administered 5 mg/kg per day Lycium barbarum polysaccharide-glycoprotein to each mouse intragastrically for the 28 days.Our results showed that long-term exposure to aversive stimuli significantly enhanced depressive-like behavior evaluated by the sucrose preference test and the forced swimming test and increased anxietylike behaviors evaluated using the open field test.In addition,aversive stimuli-induced depressed mice exhibited aberrant neuronal activity in the lateral habenula.Importantly,concurrent Lycium barbarum polysaccharide-glycoprotein treatment significantly reduced these changes.These findings suggest that Lycium barbarum polysaccharide-glycoprotein is a potential preventative intervention for depression and may act by preventing aberrant neuronal activity and microglial activation in the lateral habenula.The study was approved by the Jinan University Institutional Animal Care and Use Committee(approval No.20170301003)on March 1,2017.

Sensory Consciousness is Experienced through Amplification of Sensory Stimuli via Lateral Inhibition

At present, researchers are unclear about which activity within the brain is responsible for the emergence of consciousness—the subconscious or unconscious. Current literature suggests that consciousness is isolated in the brain;however, we suggest consciousness emerges from both—subconscious and unconscious activity, in addition to sensory consciousness. This article contends that sensory consciousness arises from neurophysiological brain activity, intrapersonal space, sensory information, and parallel processing of the external and internal environment through vision, olfaction, the integumentary system, gustation, and audition. Traditionally, lateral inhibition is defined as the ability for an excited neuron to laterally inhibit its neighbors, and is an integral part of neurophysiology in all senses. In this article, we are connecting the science behind the well-established physiological observations of gamma wave activity in the interneurons of peripheral receptors with what is currently unknown regarding the functional significance of seemingly unrelated gamma activity in the cortico-thalamic gamma oscillations. We suggest that this allows for instantaneous integration of the brain with sensory receptors. This article uses existing literature on lateral inhibition to investigate its role in sensory organs and various areas of the body. We explain how sensory consciousness is only one component of unified consciousness. We propose that lateral inhibition also plays a vital role in consciousness theory, and understanding this can help illustrate the dynamic interactions between the central and peripheral nervous systems within the body.

Comfort in observing stereoscopic images reduced by vibration stimuli

Numerous studies have been conducted to illuminate the effect of image factors to reduce unexpected influence of stereoscopic images on healthy visual experience. In this paper, we introduce changes in the psychological and physiological indexes of observers of a stereo- scopic image disturbed by vibration stimuli. Forty-four healthy university students participated in the experiment. A programmable vibration table generated two types of vibrations (5 Hz and 20 Hz) and provided intermittent vibration stimuli to a stereoscopic projector installed on a vibration table. Our results showed that the frequency of vibration stimuli has a strong impact in evaluating the local comfort of subjects. Our results also showed that the indexes of visual fatigue increased after observation independent of the frequency. The activity status of the autonomic nervous system as a physiological index significantly increased after observing 3D images with vibration stimuli although the vibrational frequency did not have a significant effect on the activity status.

Multifunctional stimuli responsive polymer-gated iron and gold-embedded silica nano golf balls:Nanoshuttles for targeted on-demand theranostics

Multi-functional nanoshuttles for remotely targeted and on-demand delivery of therapeutic molecules and imaging to defined tissues and organs hold great potentials in personalized medicine, including precise early diagnosis, efficient prevention and therapy without toxicity. Yet, in spite of 25 years of research, there are still no such shuttles available. To this end, we have designed magnetic and gold nanoparticles （NP）-embedded silica nanoshuttles （MGNSs） with nanopores on their surface. Fluorescently labeled Doxombicin （DOX）, a cancer drug, was loaded in the MGNSs as a payload. DOX loaded MGNSs were encapsulated in heat and pH sensitive polymer P（NIPAM-co- MAA） to enable controlled release of the payload. Magnetically-guided transport of MGNSs was examined in： （a） a glass capillary tube to simulate their delivery via blood vessels; and （b） porous hydrogels to simulate their transport in composite human tissues, including bone, cartilage, tendon, muscles and blood-brain barrier {BBB）. The viscoelastic properties of hydrogels were examined by atomic force microscopy （AFM）. Cellular uptake of DOX- loaded MGNSs and the subsequent pH and temperature-mediated release were demonstrated in differentiated human neurons derived from induced pluripotent stem cells （iPSCs） as well as epithelial HeLa cells. The presence of embedded iron and gold NPs in silica shells and polymer-coating are supported by SEM and TEM. Fluorescence spectroscopy and microscopy documented DOX loading in the MGNSs. Time-dependent transport of MGNSs guided by an external magnetic field was observed in both glass capillary tubes and in the porous hydrogel. AFM results affirmed that the stiffness of the hydrogels model the rigidity range from soft tissues to bone. pH and temperature-dependent drug release analysis showed stimuli responsive and gradual drug release. Cells＇ viability MTT assays showed that MGNSs are non-toxic. The cell death from on-demand DOX release was observed in both neurons and epithelial cells even though the drug release efficiency was higher in neurons. Therefore, development of smart nanoshuttles have significant translational potential for controlled delivery of theranostics＇ payloads and precisely guided transport in specified tissues and organs （for example, bone, cartilage, tendon, bone marrow, heart, lung, liver, kidney, and brain） for highly efficient personalized medicine applications.

Effects of different cue positions on evoked potentials in the cerebral cortex during global and local processing of compound stimuli A study of event-related potential

BACKGROUND： Previous studies of attentional control have focused primarily on pre-cue control of attentional cue and direction. OBJECTIVE： To measure the differences in electrical activity of brain cells while processing pre-cue and post-cue compound stimuli, and to explore brain electrical activity during global and local processing of compound stimuli according to electroencephalogram （EEG） recordings. DESIGN, TIME AND SETTING： A within-subject design study was performed at the School of Psychology, State Key Laboratory of Cognitive Neuroscience and Learning, Beijing Normal University, China from March to May 2006. PARTICIPANTS： A total of 30 healthy, undergraduate students, aged 17-24 years, comprising 12 males and 18 females, were voluntarily enrolled from Beijing Normal University. Subjects exhibited normal or corrected-to-normal visual acuity. No significant non signal wave drift was detected during testing. METHODS： A total of 30 subjects were subjected to pre-cue and post-cue compound stimulus processing using event-related potential and EEG recordings. MAIN OUTCOME MEASURES： Evoked potential was recorded in different brain regions utilizing event-related potential to observe hemispheric symmetry, cue consistency and global-local features. RESULTS： Pre-cue compound stimuli resulted in hemispheric asymmetry for early wave （N1） and late wave （P3） in anterior brain regions. Early- and late-wave induced hemispheric asymmetry for electrode points （O1, 02, P3, P4, Pz, F3, F4, F7, F8, Fz, FP1, FP2, T7, TS, C3, C4, and Cz） during processing of pre-cue compound stimuli （P 〈 0.05）. Post-cue compound stimuli did not induce hemispheric asymmetry of brain waves induced by the above-described electrode points. No significant differences in global and local responses were determined during processing of post-cue compound stimuli. Under pre-cue conditions, significant differences were observed in N1 and P3 in the above-mentioned electrode points （P 〈 0.05）. However, under post-cue conditions, no significant differences were observed in N1 and P3 using the above-mentioned electrode points. Significant differences in early waves （N1 and P1） using the above-mentioned electrode points were detected between anterior and posterior brain regions, regardless of consistent or inconsistent, large or small letters （P 〈 0.05）. CONCLUSION： Cue location effected mechanisms underlying global and local processing of compound stimuli. Pre- or post-cue conditions resulted in differences in hemispheric symmetry, cue consistency, and global and local features. Under pre-cue conditions, hemispheric dominance was detected in global and local processing following compound stimuli. Under post-cue conditions, hemispheric dominance was not determined.

Performance and Implementations of Vibrotactile Brain-Computer Interface with Ipsilateral and Bilateral Stimuli

The tactile P300 brain-computer interface( BCI) is related to the somatosensory perception and response of the human brain,and is different from visual or audio BCIs. Recently,several studies focused on the tactile stimuli delivered to different parts of the human body. Most of these stimuli were symmetrically bilateral.Only a fewstudies explored the influence of tactile stimuli laterality.In the current study,we extensively tested the performance of a vibrotactile BCI system using ipsilateral stimuli and bilateral stimuli.Two vibrotactile P300-based paradigms were tested. The target stimuli were located on the left and right forearms for the left forearm and right forearm( LFRF) paradigm,and on the left forearm and calf for the left forearm and left calf( LFLC)paradigm. Ten healthy subjects participated in this study. Our experiments and analysis showed that the bilateral paradigm( LFRF) elicited larger P300 amplitude and achieved significantly higher classification accuracy than the ipsilateral paradigm( LFLC). However, both paradigms achieved classification accuracies higher than 70% after the completion of several trials on average,which was usually regarded as the minimum accuracy level required for BCI system to be deemed useful.

The Effect of Humorous Stimuli on Alleviating Pain during Mammography: A Preliminary Study

Mammography is widely performed as a standardized procedure for breast cancer screening;however, women often feel some degree of pain during this procedure. Currently, there are limited options available for alleviating pain related to mammography. A non-medicinal approach to the alleviation of pain involves the effects of laughter on physical and psychological wellbeing. We therefore examined the possibility that humorous stimuli would alleviate the physical burden on women undergoing mammography. We assessed 29 women, 15 women received only conventional mammography (neutral group), while 14 women (humor group) watched a funny video during the same examination. The intensity of pain experienced during mammography was assessed by visual analogue scale (VAS) and the VAS results showed a statistically significant difference (P = 0.007) between the two groups, with the humor group experiencing less pain. In an additional experiment, 14 women in the humor group also underwent conventional mammography without exposure to the funny video and pain was assessed by VAS. We found that the pain experienced during conventional mammography without the funny video was significantly greater than the pain experienced during the same mammography but with the funny video (P = 0.047). These findings suggested the possibility of alleviating pain during mammography by humorous stimuli.

The Emotional Expression Response of a Patient Based on their Facial Expression—Focus on Music Stimuli

Objective: To determine whether patients with unresponsive wakefulness syndrome respond to auditory stimuli based on changes in facial expressions. Participants: Six patients diagnosed with disorders of consciousness due to brain injury with permission for participation from their doctor. Design: In this hypothesis-driven observational study, the facial expressions of patients with unresponsive wakefulness syndrome were video-recorded for 5 min before and during auditory stimulation in three consecutive weekly sessions. Main Measures: Facial muscle movement was quantified using FaceReader® software (Noldus, Wageningen, Netherlands). Valence/action unit values were plotted to detail facial expression changes. Heart rate values were also plotted. These parameters were compared before and after stimulation. Results: No significant differences in valence integral values or average heart rate were observed between the pre- and intra-stimulus conditions. However, valence signals increased in approximately half of the sessions, indicating that some patients with unresponsive wakefulness syndrome may exhibit emotional responses to auditory stimuli. Analysis of action unit integral values indicated that movement of the eyebrows and eyelids on the upper part of the face occurred during auditory stimulation. Furthermore, the types of auditory stimuli differed depending on the session for the 12 sessions of voice stimuli, whereas the changes in average heart rate differed in each of nine sessions of music stimuli. Because the changes in average heart rate were similar, it is possible that musical stimuli are more suitable than voice stimuli. Conclusion: Some patients with unresponsive wakefulness syndrome may have an emotional response to auditory stimuli. Our findings indicate that it may be possible to distinguish the emotional expression response of a patient based on their facial expression.

EEG Correlations during a Working Memory Task with Emotional Stimuli in Girls with Post-Traumatic Stress Disorder Secondary to Sexual Abuse

Survivors of Child Sexual Abuse (CSA) can develop Post-Traumatic Stress Disorder (PTSD), alterations in the prefrontal cortex, changes in electroencephalographic (EEG) activity, and lower performance on working memory tasks. The aim of this study was to characterize brain electrical correlations in girls with PTSD secondary to CSA during a working memory task based on recognizing emotional facial stimuli. Girls aged 8 - 16 years old were evaluated: 12 with PTSD secondary to CSA, and 12 healthy girls with no history of abuse. EEG activity during a working memory task with emotional stimuli was recorded, and the inter- and intra-hemispheric correlations that assessed the functional connectivity among different cortical regions were analyzed. The PTSD group showed lower performance than controls on the working memory task while watching happy faces, while the EEG of this group showed greater intrahemispheric correlation among frontal areas and between frontal and posterior cortical regions. Also, the PTSD group had lower interhemispheric correlations between posterior temporal areas. The higher intrahemispheric correlation in the PTSD group could indicate that those girls used more brain areas when performing the task, likely because it required greater effort. The lower inter-posterior temporal correlation could be attributed to a reduction of the corpus callosum.

Extracting Human Reaction Time from Observations in the Method of Constant Stimuli

We consider the psychophysical experiments in which the test subject’s binary reaction is determined by the prescribed exposure duration to a stimulus and a random variable subjective threshold. For example, when a subject is exposed to a millimeter wave beam for a prescribed duration, the occurrence of flight action is binary (yes or no). In experiments, in addition to the binary outcome, the actuation time of flight action is also recorded if it occurs;the delay from the initiation time to the actuation time of flight action is the human reaction time, which is not measurable. In this study, we model the random subjective threshold as a Weibull distribution and formulate an inference method for estimating the human reaction time, from data of prescribed exposure durations, binary outcomes and actuation times of flight action collected in a sequence of tests. Numerical simulations demonstrate that the inference of human reaction time based on the Weibull distribution converges to the correct value even when the underlying true model deviates from the inference model. This robustness of the inference method makes it applicable to real experimental data where the underlying true model is unknown.

The Short-Term Effect of Online Violent Stimuli on Aggression

The significance of this study was to find whether violent stimuli exposure could escalate the following levels of aggression in order to better cultivate aggression education among contemporary undergraduates in China. This study mainly tested the effects of violent stimuli on aggression by employing modified Stroop task. A total of 188 undergraduates participated in this study. Results showed that undergraduates exposing to violent stimuli exhibited high levels of aggression, whereas undergraduates who exposed to non-violent stimuli displayed low levels of aggression. Specifically, males, but not females, manifested high levels of aggression after exposure to violent stimuli. Moreover, viewers with high-aggressiveness (HA), but not with moderate-aggressiveness (MA) and low-aggressiveness (LA), showed high levels of aggression after exposure to violent stimuli via internet.

Correlation between MEG and BOLD fMRI signals induced by visual flicker stimuli

The goal of this work was to investigate how the MEG signal amplitude correlates with that of BOLD fMRI. To investigate the correlation between fMRI and macroscopic electrical activity, BOLD fMRI and MEG was performed on the same subjects (n=5). A visual flicker stimulus of varying temporal frequency was used to elicit neural responses in early visual areas. A strong similarity was observed in frequency tuning curves between both modalities. Although, averaged over subjects, the BOLD tuning curve was somewhat broader than MEG, both BOLD and MEG had maxima at a flicker frequency of 10 Hz. Also, we measured the first and second harmonic components as the stimuli frequency by MEG. In the low stimuli frequency (less than 6 Hz), the second harmonic has comparable amplitude with the first harmonic, which implies that neural frequency response is nonlinear and has more nonlinear components in low frequency than in high frequency.

A high-sensitive and self-selective humanoid mechanoreceptor for spatiotemporal tactile stimuli cognition

The cognition of spatiotemporal tactile stimuli,including fine spatial stimuli and static/dynamic temporal stimuli,is paramount for intelligent robots to feel their surroundings and complete manipulation tasks.However,current tactile sensors have restrictions on simultaneously demonstrating high sensitivity and performing selective responses to static/dynamic stimuli,making it a challenge to effectively cognize spatiotemporal tactile stimuli.Here,we report a high-sensitive and self-selective humanoid mechanoreceptor(HMR)that can precisely respond to spatiotemporal tactile stimuli.The HMR with PDMS/chitosan@CNTs(PDMS:polydimethylsiloxane;CNT:carbon nanotube)graded microstructures and polyurethane hierarchical porous spacer exhibits high sensitivity of 3790.8 kPa^(-1).The HMR demonstrates self-selective responses to static and dynamic stimuli with mono signal through the hybrid of piezoresistive and triboelectric mechanisms.Consequently,it can respond to spatiotemporal tactile stimuli and generate distinguishable and multi-type characteristic signals.With the assistance of the convolutional neural network,multiple target objects can be easily identified with a high accuracy of 99.1%.This work shows great potential in object precise identification and dexterous manipulation,which is the basis of intelligent robots and natural human-machine interactions.

Development of stimuli responsive polymeric nanomedicines modulating tumor microenvironment for improved cancer therapy

The complexity of the tumor microenvironment(TME)severely hinders the therapeutic effects of various cancer treatment modalities.The TME differs from normal tissues owing to the presence of hypoxia,lowpH,and immunesuppressive characteristics.Modulation of the TME to reverse tumor growth equilibrium is considered an effective way to treat tumors.Recently,polymeric nanomedicines have been widely used in cancer therapy,because their synthesis can be controlled and they are highly modifiable,and have demonstrated great potential to remodel the TME.In this review,we outline the application of various stimuli responsive polymeric nanomedicines to modulate the TME,aiming to provide insights for the design of the next generation of polymeric nanomedicines and promote the development of polymeric nanomedicines for cancer therapy.

基于天然多糖的刺激响应型药物控释系统研究进展

刺激响应型药物控释系统一般以天然多糖生物大分子或其衍生物作为载体,通过化学结合或物理吸附等方式负载药物分子。具有刺激响应功能的天然多糖生物大分子或其衍生物能够感知其所处环境的变化,并由于其物理或化学性质的变化而做出应激响应,因此可在不同环境或条件的刺激下,通过药物与载体之间化学键断裂或载体自身降解等方式将药物从载体中释放,从而实现药物的控制释放。结合课题组的研究工作,介绍了常用的刺激方式,包括单一刺激和多重刺激、外源性刺激和内源性刺激,为开发新型刺激响应型药物控释系统提供了思路。

刺激响应型玉米醇溶蛋白基纳米颗粒的制备及其应用研究进展

玉米醇溶蛋白是玉米淀粉加工的主要副产物,价格低廉且容易获取。基于其独特的自组装特性,玉米醇溶蛋白可通过多种方式构建成纳米颗粒,进而对生物活性物质进行荷载和输送。纳米颗粒的制备方法包括反溶剂沉淀、pH循环、电喷雾和微流控等。这些制备方法都可合成响应各种环境刺激且性质稳定的玉米醇溶蛋白基纳米颗粒。本文综述了刺激响应型玉米醇溶蛋白基纳米颗粒的制备方法、响应类型和应用最新进展。这些纳米载体可对内源性(pH、酶和氧化还原)和外源性环境刺激(磁和光)做出响应,已被用于食品智能包装、纳米农药和纳米医学中生物活性物质的包封递送。然而,仅依靠单一刺激响应很难实现活性物质的作用最大化,多重刺激(双重刺激、三重刺激等)响应的纳米颗粒已成为递送领域的新发展趋势。未来,更多的研究应该投入到多刺激响应纳米颗粒的研发,以及如何将纳米颗粒的多重响应特性和纳米颗粒的靶向递送结合还有待进一步探索。

骨细胞的力学感受器

骨细胞是骨骼中最丰富和寿命最长的细胞,是骨重建的调节器。骨细胞在内分泌调节和钙磷酸盐代谢中发挥重要作用,也是力学刺激的主要响应者,感知力学刺激以直接或间接的方式对刺激做出反应。骨细胞中的力学转导是一个复杂而精细的调节过程,涉及细胞与其周围环境、相邻细胞以及细胞内部不同功能的力学感受器之间的相互作用。目前已知的骨细胞主要力学感受器包括初级纤毛、Piezo离子通道、整合素、细胞外基质以及基于连接蛋白的细胞间连接。这些力学感受器在骨细胞中发挥着至关重要的作用,它们能够感知并转导力学信号,进而调节骨稳态。本文对5种力学感受器进行系统的介绍,以期为理解骨细胞如何响应力学刺激和维持骨组织稳态提供新的视角和认识。

社会信息加工对瞳孔大小的调节及其机制

瞳孔大小作为反映个体心理状态的窗口在社会互动中担任着重要的角色。除了非社会性信息(如刺激物理属性等因素)加工被发现影响瞳孔大小变化之外,越来越多的文献指出,瞳孔大小与个体社会信息加工之间也存在密切关系。基于此,本文系统综述了社会性刺激(如面孔和生物运动)本身以及社会性刺激含有的情绪信息对于瞳孔大小的影响,总结出瞳孔大小变化不仅可以反映个体对社会信息的感知,同样可以体现个体对更为复杂的社会互动情境的加工。这种社会性信息加工相关的瞳孔大小变化主要涉及个体的情绪唤醒和社会性注意过程。此外,对于自闭症谱系患者这一在社会互动中存在障碍的特殊群体,有关研究发现其对社会性刺激存在异常的瞳孔反应模式。这一特异性为进一步采用瞳孔指标对自闭症进行早期诊断提供了支持,具有重要的理论和实践意义。