Herb-Nanoparticle Hybrid System for Improved Oral Delivery Efficiency to Alleviate Breast Cancer Lung Metastasis.

Background: Metastasis is a complex process involving multiple factors and stages, in which tumor cells and the tumor microenvironment (TME) play significant roles. A combination of orally bioavailable therapeutic agents that target both tumor cells and TME is conducive to prevent or impede the progression of metastasis, especially when undetectable. However, sequentially overcoming intestinal barriers, ensuring biodistribution in tumors and metastatic tissues, and enhancing therapeutic effects required for efficient therapy remain challenging. Methods: Inspired by the unique chemical features of natural herbs, we propose an oral herb-nanoparticle hybrid system (HNS) formed through the self-binding of Platycodon grandiflorum-Curcuma zedoaria (HG), a herb pair/group used in clinical practice to treat breast cancer metastasis, to lipid-polymer nanoparticles (LPNs) loaded with silibinin. The molecular structure responsible for HG association with LPNs was assessed using surface-enhanced Raman spectroscopy for HNS surface chemistry characterization. Moreover, the molecular class of HG was identified using UPLC-Orbitrap-MS/MS to further confirm the surface binding. Mucus diffusion and in vivo biodistribution were evaluated using in vitro multiple-particle tracking and environment-responsive fluorescence probe in 4T1 tumor-bearing mice, respectively. The alleviation of breast cancer metastasis was assessed in 4T1 tumor-bearing mice, and the underlying mechanism was investigated. Results: The HNS reduced particle-mucus interactions by altering hydrophilicity and surface characteristics compared to LPNs. The epithelium transportation of HNS and absorption through Peyer's patch in mice were improved, promoting their biodistribution in the lung and tumor tissues. Furthermore, the HNS alleviated lung metastasis by inducing cell apoptosis and regulating the expression of MMP-9 and TGF-ß1, which altered the TME in 4T1 tumor-bearing mice. Conclusion: HNS provides an appealing system with multi-component binding of herbal medicine to facilitate both oral nanoparticle delivery efficiency and the alleviation of lung metastasis. This strategy may potentially help improve treatment for patients with breast cancer.

Photovoltaic-driven Ni(ii)/Ni(iii) redox mediator for the valorization of PET plastic waste with hydrogen production.

Electrocatalytic valorization of PET plastic waste provides an appealing route by converting intermittent renewable energy into valuable chemicals and high-energy fuels. Normally, anodic PET hydrolysate oxidation and cathodic water reduction reactions occur simultaneously in the same time and space, which increases the challenges for product separation and operational conditions. Although these problems can be addressed by utilizing membranes or diaphragms, the parasitic cell resistance and high overall cost severely restrict their future application. Herein, we introduce a Ni(ii)/Ni(iii) redox mediator to decouple these reactions into two independent processes: an electrochemical process for water reduction to produce hydrogen fuel assisted by the oxidation of the Ni(OH)2 electrode into the NiOOH counterpart, followed subsequently by a spontaneous chemical process for the valorization of PET hydrolysate to produce formic acid with a high faradaic efficiency of ∼96% by the oxidized NiOOH electrode. This decoupling strategy enables the electrochemical valorization of PET plastic waste in a membrane-free system to produce high-value formic acid and high-purity hydrogen production. This study provides an appealing route to facilitate the transformation process of PET plastic waste into high-value products with high efficiency, low cost and high purity.

Ox-LDL-induced CD80+ macrophages expand pro-atherosclerotic NKT cells via CD1d in atherosclerotic mice and hyperlipidemic patients.

Atherosclerosis is an inflammatory disease of blood vessels involving the immune system. Natural killer T (NKT) cells, as crucial components of the innate and acquired immune systems, play critical roles in the development of atherosclerosis. However, the mechanism and clinical relevance of NKT cells in early atherosclerosis are largely unclear. The study investigated the mechanism influencing NKT cell function in apoE deficiency-induced early atherosclerosis. Our findings demonstrated that there were higher populations of NKT cells and interferon-gamma (IFN-γ)-producing NKT cells in the peripheral blood of patients with hyperlipidemia and in the aorta, blood, spleen, and bone marrow of early atherosclerotic mice compared with the control groups. Moreover, we discovered that the infiltration of CD80+ macrophages and CD1d expression on CD80+ macrophages in atherosclerotic mice climbed remarkably. CD1d expression increased in CD80+ macrophages stimulated by oxidized low-density lipoprotein (ox-LDL) ex vivo and in vitro. Ex vivo coculture of macrophages with NKT cells revealed that ox-LDL-induced CD80+ macrophages presented lipid antigen α-Galcer (alpha-galactosylceramide) to NKT cells via CD1d, enabling NKT cells to express more IFN-γ. Furthermore, a greater proportion of CD1d+ monocytes and CD1d+CD80+ monocytes were found in peripheral blood of hyperlipidemic patients compared with that of healthy donors. Positive correlations were found between CD1d+CD80+ monocytes and NKT cells or IFN-γ+ NKT cells in hyperlipidemic patients. Our findings illustrated that CD80+ macrophages stimulated NKT cells to secrete IFN-γ via CD1d-presenting α-Galcer, which may accelerate the progression of early atherosclerosis. Inhibiting lipid antigen presentation by CD80+ macrophages to NKT cells may be a promising immune target for the treatment of early atherosclerosis.NEW & NOTEWORTHY This work proposed the ox-LDL-CD80+ monocyte/macrophage-CD1d-NKT cell-IFN-γ axis in the progression of atherosclerosis. The proinflammatory IFN-γ+ NKT cells are closely related to CD1d+CD80+ monocytes in hyperlipidemic patients. Inhibiting CD80+ macrophages to present lipid antigens to NKT cells through CD1d blocking may be a new therapeutic target for atherosclerosis.

NMAAP1 regulated macrophage polarizion into M1 type through glycolysis stimulated with BCG.

Bacillus Calmette Guerin (BCG) perfusion is widely used as cancer adjuvant therapy, in which macrophages play an important role. Novel macrophage activated associated protein 1 (NMAAP1), upregulated after BCG's activation, was proved to promote macrophage polarization to the M1 type. We found that BCG could stimulate mice BMDM to the M1 type and kill tumor cells. After the deletion of NMAAP1, the tumor volume of mice became larger, and the number of M1 type macrophages in the tumor decreased significantly. When macrophages were induced into the M1 type, aerobic glycolysis, the Warburg effect manifested in the increased uptake of glucose and the conversion of pyruvate to lactic acid. NMAAP1 could bind with IP3R and regulate macrophage polarization to the M1 type. However, the specific mechanism of how NMAAP1 regulates macrophage polarization towards the M1 type and plays an antitumor role must be clarified. NMAAP1 could promote the release of lactic acid and pyruvate, enhance the glycolysis of macrophages, and affect the expression of HIF-1α. After inhibition of glycolysis by 2-DG and lactic acid generation by FX11, the effects of NMAAP1 promoting macrophage polarization to the antitumor M1 type were weakened. Furthermore, NMAAP1 upregulated the expression of HIF-1α, which is associated with glycolysis. Moreover, the Ca2+/NF-κB pathway regulated HIF-1α expression by NMAAP1 in the macrophages. NMAAP1 promotes the polarization of macrophages towards the M1 type by affecting the Warburg effect stimulated by BCG.

PDGFRA exhibits potential as an indicator of angiogenesis within the tumor microenvironment and is up-regulated in BLCA.

Bladder cancer (BLCA) is a common type of urogenital malignancy worldwide. The recurrence and metastasis of bladder cancer are closely related to angiogenesis, but the underlying mechanisms are unclear. In this study, we developed a method to predict survival outcomes among BLCA patients, which could be used to guide immunotherapy and chemotherapy. We obtained patient data from The Cancer Genome Atlas (TCGA) and identified angiogenesis-related genes from the GeneCards database. First, we used differential expression analysis and univariate Cox analysis to identify angiogenesis-related genes and used correlation analysis to generate molecular subtypes based on M2 macrophages. Next, we constructed a prognostic signature consisting of four genes (ECM1, EFEMP1, SLIT2, and PDGFRΑ), which was found to be an independent prognostic factor. Higher risk scores were associated with worse overall survival and higher expression of immune checkpoints. We also evaluated immune cell infiltration using the CIBERSORT and ssGSEA algorithms. Additionally, we performed stratification analyses, constructed a nomogram, and predicted chemotherapeutic responses based on the risk signature. Finally, we validated our findings by using qRT-PCR as well as IHC data to detect the expression levels of the four genes at mRNA and protein levels in BLCA patients and obtained results that were consistent with our predictions. Our study demonstrates the utility of a four-gene prognostic signature for prognostication in bladder cancer patients and designing personalized treatments, which could provide new avenues for personalized management of these patients.

Improving Spatial Resolution and Selectivity of Transcorneal Electrical Stimulation by Temporal Interference Technology.

Transcorneal electrical stimulation (TES) used in a therapeutic device has been demonstrated significant neuroprotective effect for rescuing retinal function. However, the diffuse electric field induced by conventional TES devices reduced their spatial resolution and selectivity, limiting their capability of actively stimulating a severely diseased retina. A cutting-edge neuromodulation approach named temporal interference stimulation (TIS) was reported to induce electric fields focalizing on local neuronal targets. Despite the competent feasibility of application in retinal TIS, the interpretation of characteristics of spatial resolution and selectivity under TIS remains rudimentary. In this study, we conduct in silico investigations to understand the characteristics of spatial selectivity and resolution using a finite element model of a multi-layered eyeball and multiple electrode configuration. By simulating different metrics of electric potentials envelope modulated by TIS, our model supports the possibility of achieving mini-invasive and spatially selective electrical stimulation using retinal TIS. These simulations provide theoretical evidence on the basis of which sophisticated devices for improved spatial selectivity can be designed.Clinical Relevance- This study provides a theoretical basis for understanding how the design of electrode configuration impacts transcorneal TIS performance. This model can guide future development of transcorneal TIS configurations and stimulation strategies that may benefit patients with inherited retinal diseases.

Double-single-atom MoCu-embedded porous carbons boost the electrocatalytic N2 reduction reaction.

NH3 is an essential ingredient of chemical, fertilizer, and energy storage products. Industrial nitrogen fixation consumes an enormous amount of energy, which is counter to the concept of carbon neutrality, hence eNRR ought to be implemented as a clean alternative. Herein, we propose a double-single-atom MoCu-embedded porous carbon material derived from uio-66 (MoCu@C) by plasma-enhanced chemical vapor deposition (PECVD) to boost eNRR capabilities, with an NH3 yield rate of 52.4 µg h-1 gcat.-1 and a faradaic efficiency (FE) of 27.4%. Advanced XANES shows that the Mo active site receives electrons from Cu, modifies the electronic structure of the Mo active site and enhances N2 adsorption activation. The invention of rational MoCu double-single-atom materials and the utilization of effective eNRR approaches furnish the necessary building blocks for the fundamental study and practical application of Mo-based materials.

Spatial Attention Modulates Neuronal Interactions between Simple and Complex Cells in V1.

Visual perception is profoundly modulated by spatial attention, which can selectively prioritize goal-related information. Previous studies found spatial attention facilitated the efficacy of neuronal communication between visual cortices with hierarchical organizations. In the primary visual cortex (V1), there is also a hierarchical connection between simple (S) and complex (C) cells. We wonder whether and how spatial attention modulates neuronal communication within V1, especially for neuronal pairs with heterogeneous visual input. We simultaneously recorded the pairs' activity from macaque monkeys when they performed a spatial-attention-involved task, then applied likelihood-based Granger causality analysis to explore attentional modulation of neuronal interactions. First, a significant attention-related decrease in Granger causality was found in S-C pairs, which primarily displayed in the S-to-C feedforward connection. Second, the interaction strength of the feedforward connection was significantly higher than that of the feedback under attend toward (AT) conditions. Although information flow did not alter as the attentional focus shifted, the strength of communications between target- and distractor-stimuli-covered neurons differed only when attending to complex cells' receptive fields (RFs). Furthermore, pairs' communications depended on the attentional modulation of neurons' firing rates. Our findings demonstrate spatial attention does not induce specific information flow but rather amplifies directed communication within V1.

An in-silicoanalysis of retinal electric field distribution induced by different electrode design of trans-corneal electrical stimulation.

Objective.Trans-corneal electrical stimulation (TcES) produces therapeutic effects on many ophthalmic diseases non-invasively. Existing clinical TcES devices use largely variable design of electrode distribution and stimulation parameters. Better understanding of how electrode configuration paradigms and stimulation parameters influence the electric field distribution on the retina, will be beneficial to the design of next-generation TcES devices.Approach.In this study, we constructed a realistic finite element human head model with fine eyeball structure. Commonly used DTL-Plus and ERG-Jet electrodes were simulated. We then conductedin silicoinvestigations of retina observation surface (ROS) electric field distributions induced by different return electrode configuration paradigms and different stimulus intensities.Main results.Our results suggested that the ROS electric field distribution could be modulated by re-designing TcES electrode settings and stimulus parameters. Under far return location paradigms, either DTL-Plus or ERG-Jet approach could induce almost identical ROS electric field distribution regardless where the far return was located. However, compared with the ERG-Jet mode, DTL-Plus stimulation induced stronger nasal lateralization. In contrast, ERG-Jet stimulation induced relatively stronger temporal lateralization. The ROS lateralization can be further tweaked by changing the DTL-Plus electrode length.Significance.These results may contribute to the understanding of the characteristics of DTL-Plus and ERG-Jet electrodes based electric field distribution on the retina, providing practical implications for the therapeutic application of TcES.

Spatial Attention Modulates Spike Count Correlations and Granger Causality in the Primary Visual Cortex.

The influence of spatial attention on neural interactions has been revealed even in early visual information processing stages. It resolves the process of competing for sensory information about objects perceived as targets and distractors. However, the attentional modulation of the interaction between pairs of neurons with non-overlapping receptive fields (RFs) is not well known. Here, we investigated the activity of anatomically distant neurons in two behaving monkeys' primary visual cortex (V1), when they performed a spatial attention task detecting color change. We compared attentional modulation from the perspective of spike count correlations and Granger causality among simple and complex cells. An attention-related increase in spike count correlations and a decrease in Granger causality were found. The results showed that spatial attention significantly influenced only the interactions between rather than within simple and complex cells. Furthermore, we found that the attentional modulation of neuronal interactions changed with neuronal pairs' preferred directions differences. Thus, we found that spatial attention increased the functional communications and competing connectivities when attending to the neurons' RFs, which impacts the interactions only between simple and complex cells. Our findings enrich the model of simple and complex cells and further understand the way that attention influences the neurons' activities.

Efficient Catalytic Conversion of 5-Hydroxymethylfurfural to 2,5-Furandicarboxylic Acid over Ruthenium Cluster-Embedded Ni(OH)2 Catalyst.

5-Hydroxymethylfurfural (HMF) can be oxidized to 2,5-furandicarboxylic acid (FDCA) for the production of biorenewable plastics to replace fossil resourced polyethylene terephthalate (PET). Development of a highly efficient electrocatalyst using renewable electricity as energy input is highly desired. In this work, Ru cluster-embedded Ni(OH)2 nanosheets [Ru/Ni(OH)2 ] were synthesized and exploited as electrochemical catalysts for the conversion of HMF to FDCA. Ru/Ni(OH)2 exhibited significantly improved current density (40 mA cm-2 at 1.41 V vs. reversible hydrogen electrode) of over 7.7 times in comparison with Ni(OH)2 , and nearly 100 % conversion degree for HMF and 98.5 % selectivity towards FDCA were obtained. Operando Raman experiments revealed the catalysis was facilitated by the interconversion between Ni3+ and Ni2+ . Density functional theory calculations further revealed the effect of Ru clusters of Ni(OH)2 , thereby promoting HMF adsorption capacity on Ni sites to boost HMF oxidation activity. This work provides a novel strategy using Ru clusters to modify earth abundant Ni based catalyst for HMF oxidation to obtain high-value biomass-derived products.

An infrared image-enhancement algorithm in simulated prosthetic vision: Enlarging working environment of future retinal prostheses.

BACKGROUND: Most existing retinal prostheses contain a built-in visible-light camera module that captures images of the surrounding environment. Thus, in case of insufficient or lack of visible light, the camera fails to work, and the retinal prostheses enter a dormant or "OFF" state. A simple and effective solution is replacing the visible-light camera with a dual-mode camera. The present research aimed to achieve two main purposes: (1) to explore whether the dual-mode camera in prosthesis recipients works under no visible-light conditions and (2) to assess its performance. METHODS: To accomplish these aims, we enrolled subjects in a psychophysical experiment under simulated prosthetic vision conditions. We found that the subjects could complete some simple visual tasks, but the recognition performance under the infrared mode was significantly inferior to that under the visible-light mode. These results inspired us to develop and propose a feasible infrared image-enhancement processing algorithm. Another psychophysical experiment was performed to verify the feasibility of the algorithm. RESULTS: The obtained results showed that the average efficiency of the subjects completing visual tasks using our enhancement algorithm (0.014 ± 0.001) was significantly higher (p < 0.001) than that of subjects using direct pixelization (0.007 ± 0.001). CONCLUSIONS: We concluded that a dual-mode camera could be a feasible solution to improving the performance of retinal prostheses as the camera adapted better to the specific existing ambient light conditions. Dual-mode cameras combined with this infrared image-enhancement algorithm could provide a promising direction for the design of future retinal prostheses.

Anin-silicoanalysis of electrically evoked responses of midget and parasol retinal ganglion cells in different retinal regions.

Objective. Visual outcomes provided by present retinal prostheses that primarily target retinal ganglion cells (RGCs) through epiretinal stimulation remain rudimentary, partly due to the limited knowledge of retinal responses under electrical stimulation. Better understanding of how different retinal regions can be quantitatively controlled with high spatial accuracy, will be beneficial to the design of micro-electrode arrays and stimulation strategies for next-generation wide-view, high-resolution epiretinal implants.Approach. A computational model was developed to assess neural activity at different eccentricities (2 mm and 5 mm) within the human retina. This model included midget and parasol RGCs with anatomically accurate cell distribution and cell-specific morphological information. We then performedin silicoinvestigations of region-specific RGC responses to epiretinal electrical stimulation using varied electrode sizes (5-210µm diameter), emulating both commercialized retinal implants and recently developed prototype devices.Main results. Our model of epiretinal stimulation predicted RGC population excitation analogous to the complex percepts reported in human subjects. Following this, our simulations suggest that midget and parasol RGCs have characteristic regional differences in excitation under preferred electrode sizes. Relatively central (2 mm) regions demonstrated higher number of excited RGCs but lower overall activated receptive field (RF) areas under the same stimulus amplitudes (two-way analysis of variance (ANOVA),p< 0.05). Furthermore, the activated RGC numbers per unit active RF area (number-RF ratio) were significantly higher in central than in peripheral regions, and higher in the midget than in the parasol population under all tested electrode sizes (two-way ANOVA,p< 0.05). Our simulations also suggested that smaller electrodes exhibit a higher range of controllable stimulation parameters to achieve pre-defined performance of RGC excitation. An empirical model:I=a· exp (b·D) +cof the stimulus amplitude (I)-electrode diameter (D) relationship was constructed to achieve the pre-defined objective function values in different retinal regions, indicating the ability of controlling retinal outputs by fine-tuning the stimulation amplitude with different electrode sizes. Finally, our multielectrode simulations predicted differential neural crosstalk between adjacent electrodes in central temporal and peripheral temporal regions, providing insights towards establishing a non-uniformly distributed multielectrode array geometry for wide-view retinal implants.Significance.Stimulus-response properties in central and peripheral retina can provide useful information to estimate electrode parameters for region-specific activation by retinal stimulation. Our findings support the possibility of improving the performance of epiretinal prostheses by exploring the influence of electrode array geometry on activation of different retinal regions.

The visual cortical responses to sinusoidal transcorneal electrical stimulation.

Retinal stimulation has become a widely utilized approach to restore visual function for individuals with retinal degenerative diseases. Although the rectangular electrical pulse is the primary stimulus waveform used in retinal neuromodulation, it remains unclear whether alternate waveforms may be more effective. Here, we used the optical intrinsic signal imaging system to assess the responses of cats' visual cortex to sinusoidal electrical stimulation through contact lens electrode, analyzing the response to various stimulus parameters (frequency, intensity, pulse width). A comparison between sinusoidal and rectangular stimulus waveform was also investigated. The results indicated that the optimal stimulation frequency for sinusoidal electrical stimulation was approximately 20 Hz, supporting the hypothesis that low-frequency electrostimulation induces more responsiveness in retinal neurons than high-frequency electrostimulation in case of sinusoidal stimulation. We also demonstrated that for low-frequency retinal neuromodulation, sinusoidal pulses are more effective than rectangular ones. In addition, we found that compared to current intensity, the effect of the sinusoidal pulse width on cortical responses was more prominent. These results suggested that sinusoidal electrical stimulation may provide a promising strategy for improved retinal neuromodulation in clinical settings.

Antigen-Presenting Cell-Like Neutrophils Foster T Cell Response in Hyperlipidemic Patients and Atherosclerotic Mice.

Neutrophils constitute abundant cellular components in atherosclerotic plaques. Most of the current studies are focused on the roles of granular proteins released by neutrophils in atherosclerosis. Here, we revealed a unique subset of neutrophils which exhibit the characteristics of antigen-presenting cell (APC) (which were called APC-like neutrophils afterwards) in atherosclerosis. The roles of APC-like neutrophils and relevant mechanisms were investigated in hyperlipidemic patients and atherosclerotic mice. Higher percentages of neutrophils and APC-like neutrophils were found in peripheral blood of hyperlipidemic patients than that of healthy donors. Meanwhile, we also identified higher infiltration of neutrophils and APC-like neutrophils in atherosclerotic mice. Ox-LDL induced Phorbol-12-myristate-13-acetate (PMA)-activated neutrophils to acquire the APC-like phenotype. Importantly, upon over-expression of APC-like markers, neutrophils acquired APC functions to promote the proliferation and interferon-γ production of CD3+ T cells via HLA-DR/CD80/CD86. In accordance with what found in vitro, positive correlation between neutrophils and CD3+ T cells was observed in hyperlipidemic patients. In conclusion, our work identifies a proinflammatory neutrophil subset in both hyperlipidemic patients and atherosclerotic mice. This unique phenotype of neutrophils could activate the adaptive immune response to promote atherosclerosis progression. Thus, this neutrophil subset may be a new target for immunotherapy of atherosclerosis.

Objective neuromodulation basis for intrafascicular artificial somatosensation through carbon nanotube yarn electrodes.

BACKGROUND: Intrafascicular electrical stimulation has been extensively adopted to achieve sensory feedback for limb amputees. Axon-like carbon nanotube yarn (CNTy) electrodes with both promising flexibility and spatial selectivity index (SSI) can be fascinating alternatives to generate artificial somatosensation. NEW METHOD: Here we systematically disclose objective neuromodulation basis for artificial somatosensation through intrafascicular CNTy electrodes. CNTy electrodes with different exposed lengths were utilized for electrically stimulating tibial nerves in twelve rats. Somatosensory evoked potentials (SEPs) were recorded synchronously using an epidural thirty-channel electrode array. Spatiotemporal characteristics of SEPs were analyzed as current pulse amplitude (PA), pulse width (PW) and pulse frequency (PF) varied. RESULTS: The current thresholds at 1 Hz exhibit the lowest means when compared with those at 4 and 8 Hz for most CNTy electrodes (20/28). For all the electrodes, amplitudes of SEPs and activated areas of perceptive fields increase with PWs and PAs rising, and decrease remarkably with PFs from 1 to 8 Hz. Latencies of P1 and N1 of SEP peaks gradually reduced with PWs and PAs advancing. Considering high SSIs, relatively stable current thresholds, wider variation ranges of sensory magnitudes and optimal stability of perceptive fields, the L-200 µm electrodes are preferable for neuromodulation with PFs of 1 - 8 Hz, PWs of 100 - 800 µs and PAs of 2 - 64 µA. COMPARISON WITH EXISTING METHODS: New-type CNTy electrodes possess both promising flexibility and SSI when compared with other neural interfaces. We systematically explore objective neuromodulation basis for artificial somatosensation through CNTy electrodes for the first time. CONCLUSIONS: Significantly higher SSIs, lower current and charge thresholds exist for CNTy electrodes in comparison with other peripheral-nerve interfaces. This study can, for the first time, lay a solid neuromodulation foundation for CNTy electrodes to achieve fine sensory feedback.

Modulation of Spike Count Correlations Between Macaque Primary Visual Cortex Neurons by Difficulty of Attentional Task.

Studies have shown that spatial attention remarkably affects the trial-to-trial response variability shared between neurons. Difficulty in the attentional task adjusts how much concentration we maintain on what is currently important and what is filtered as irrelevant sensory information. However, how task difficulty mediates the interactions between neurons with separated receptive fields (RFs) that are attended to or attended away is still not clear. We examined spike count correlations between single-unit activities recorded simultaneously in the primary visual cortex (V1) while monkeys performed a spatial attention task with two levels of difficulty. Moreover, the RFs of the two neurons recorded were non-overlapping to allow us to study fluctuations in the correlated responses between competing visual inputs when the focus of attention was allocated to the RF of one neuron. While increasing difficulty in the spatial attention task, spike count correlations were either decreased to become negative between neuronal pairs, implying competition among them, with one neuron (or none) exhibiting attentional enhancement of firing rate, or increased to become positive, suggesting inter-neuronal cooperation, with one of the pair showing attentional suppression of spiking responses. Besides, the modulation of spike count correlations by task difficulty was independent of the attended locations. These findings provide evidence that task difficulty affects the functional interactions between different neuronal pools in V1 when selective attention resolves the spatial competition.

Mesophyll conductance, photoprotective process and optimal N partitioning are essential to the maintenance of photosynthesis at N deficient condition in a wheat yellow-green mutant (Triticum aestivum L.).

The major effect of nitrogen (N) deficiency is the inhibition on CO2 assimilation regulated by light energy absorption, transport and conversion, as well as N allocation. In this study, a yellow-green wheat mutant (Jimai5265yg) and its wild type (Jimai5265, WT) were compared between 0 mM N (N0) and 14 mM N (N14) treatments using hydroponic experiments. The mutant exhibited higher photosynthetic efficiency (An) than WT despite low chlorophyll (Chl) content in non-stressed conditions. The photosynthetic advantages of the mutant were maintained under N deficient condition. The quantitative analysis of limitations to photosynthesis revealed that CO2 diffusion associated with mesophyll conductance (gm) was the dominant limitation. Relative easiness to gain CO2 in the chloroplast contributed to the higher An of Jimai5265yg. N deficiency induced the photoinhibition of PSII, but the cyclic electron transport and photochemical activity of PSI was higher in Jimai5265yg compared to Jimai5265, which was a protective mechanism to avoid photodamage. Because of the sharp drop of An, N deficient seedlings had much lower photosynthetic N use efficiency (PNUE). However, N deficiency increased the relative content of photosynthetic N (Npsn) and decreased the relative content of storage N (Nstore). The range of change in N partitioning induced by N deficiency was smaller for Jimai5265yg compared to WT. The less insensitive to N deficiency for the mutant in terms of photosynthetic property and N partitioning suggested that gm, cyclic electron transport around PSI and more optimal N partitioning pattern is necessary to sustain photosynthesis under N deficient condition.

Computational Modeling of Spatially Selective Retinal Stimulation With Temporally Interfering Electric Fields.

Retinal electrical stimulation is a widely utilized method to restore visual function for patients with retinal degenerative diseases. Transcorneal electrical stimulation (TES) represents an effective way to improve the visual function due to its potential neuroprotective effect. However, TES with single electrode fails to spatially and selectively stimulate retinal neurons. Herein, a computational modeling method was proposed to explore the feasibility of spatially selective retinal stimulation via temporally interfering electric fields. An eyeball model with multiple electrodes was constructed to simulate the interferential electric fields with various electrode montages and current ratios. The results demonstrated that the temporal interference (TI) stimulation would gradually generate an increasingly localized high-intensity region on retina as the return electrodes moved towards the posterior of the eyeball and got closer. Additionally, the position of the convergent region could be modulated by regulating the current ratio of different electrode channels. The TI strategy with multisite and steerable stimulation can stimulate local retinal region with certain convergence and a relatively large stimulation range, which would be a feasible approach for the spatially selective retinal neuromodulation.

Mediating different-diameter Aß nerve fibers using a biomimetic 3D TENS computational model.

BACKGROUND: Significant progress has been made over the last 50 years in the design, development and testing of transcutaneous electrical nerve stimulation (TENS) in mediating different levels of tactile sensations. However, without knowing how best to stimulate the nerve fibers, the elicited sensation quality will always remain poor and unnatural. NEW METHOD: A new biomimetic 3D TENS computational model is developed to quantify the neural activation mechanism with varied surface electrodes. This model includes seven-layered anatomical structure of the forearm and biophysically-detailed myelinated Aß fibers. The Aß-fiber diameters from 1.5 - 7.5 µm were randomly distributed beneath the skin to mimic the physiologically-realistic fiber population. The arithmetic averaging algorithm and Gaussian filter were adopted to identify the sensation center and to quantify sensation intensities under different stimulation conditions. RESULTS: Fibers larger than 4.5 µm can usually be activated producing tactile sensations such as light touch, pressure, buzz, and vibration. While, fibers with diameters of 3.5 and 3 µm can only be excited at uncomfortable numb and pain sensations. The resulted modelling predictions match the recent psychophysical experimental data. COMPARISON WITH EXISTING METHOD(S): The new TENS model is more physiologically-realistic by introducing a detailed morphological information and key ionic mechanisms in nerve fibers. CONCLUSIONS: Our results indicate that TENS may be a promising method to target functionally-distinct neural pathways in an effort to improve the elicited tactile sensations quality with electrical stimulation. This work provides a promising platform of discovering neural mechanisms under TENS.