Recurrent Inhibition Research Articles

Activation of arginine vasopressin receptor 1a reduces inhibitory synaptic currents at reciprocal synapses in the mouse accessory olfactory bulb.

Central arginine vasopressin (AVP) facilitates social recognition and modulates many complex social behaviors in mammals that, in many cases, recognize each other based on olfactory and/or pheromonal signals. AVP neurons are present in the accessory olfactory bulb (AOB), which is the first relay in the vomeronasal system and has been demonstrated to be a critical site for mating-induced mate recognition (olfactory memory) in female mice. The transmission of information from the AOB to higher centers is controlled by the dendrodendritic recurrent inhibition, i.e., inhibitory postsynaptic currents (IPSCs) generated in mitral cells by recurrent dendrodendritic inhibitory inputs from granule cells. These reports suggest that AVP might play an important role in regulating dendrodendritic inhibition in the AOB. To test this hypothesis, we examined the effects of extracellularly applied AVP on synaptic responses measured from mitral and granule cells in slice preparations from 23--36-day-old Balb/c mice. To evoke dendrodendritic inhibition in a mitral cell, depolarizing voltages of -70 to 0 mV (10 ms duration) were applied to a mitral cell using a conventional whole-cell configuration. We found that AVP significantly reduced the IPSCs. The suppressive effects of AVP on the IPSCs was diminished by an antagonist for vasopressin receptor 1a (V1aR) (Manning compound), but not by an antagonist for vasopressin receptor 1b (SSR149415). An agonist for V1aRs [(Phe2)OVT] mimicked the action of AVP on IPSCs. Additionally, AVP significantly suppressed voltage-activated currents in granule cells without affecting the magnitude of the response of mitral cells to gamma-aminobutyric acid (GABA). The present results suggest that V1aRs play a role in reciprocal transmission between mitral cells and granule cells in the mouse AOB by reducing GABAergic transmission through a presynaptic mechanism in granule cells.

Full-course NIR-II imaging-navigated fractionated photodynamic therapy of bladder tumours with X-ray-activated nanotransducers

The poor 5-year survival rate for bladder cancers is associated with the lack of efficient diagnostic and treatment techniques. Despite cystoscopy-assisted photomedicine and external radiation being promising modalities to supplement or replace surgery, they remain invasive or fail to provide real-time navigation. Here, we report non-invasive fractionated photodynamic therapy of bladder cancer with full-course real-time near-infrared-II imaging based on engineered X-ray-activated nanotransducers that contain lanthanide-doped nanoscintillators with concurrent emissions in visible and the second near-infrared regions and conjugated photosensitizers. Following intravesical instillation in mice with carcinogen-induced autochthonous bladder tumours, tumour-homing peptide-labelled nanotransducers realize enhanced tumour regression, robust recurrence inhibition, improved survival rates, and restored immune homeostasis under X-ray irradiation with accompanied near-infrared-II imaging. On-demand fractionated photodynamic therapy with customized doses is further achieved based on quantifiable near-infrared-II imaging signal-to-background ratios. Our study presents a promising non-invasive strategy to confront the current bladder cancer dilemma from diagnosis to treatment and prognosis.

Cell-type-specific origins of locomotor rhythmicity at different speeds in larval zebrafish

Different speeds of locomotion require heterogeneous spinal populations, but a common mode of rhythm generation is presumed to exist. Here, we explore the cellular versus synaptic origins of spinal rhythmicity at different speeds by performing electrophysiological recordings from premotor excitatory interneurons in larval zebrafish. Chx10-labeled V2a neurons are divided into at least two morphological subtypes proposed to play distinct roles in timing and intensity control. Consistent with distinct rhythm generating and output patterning functions within the spinal V2a population, we find that descending subtypes are recruited exclusively at slow or fast speeds and exhibit intrinsic cellular properties suitable for rhythmogenesis at those speeds, while bifurcating subtypes are recruited more reliably at all speeds and lack appropriate rhythmogenic cellular properties. Unexpectedly, however, phasic firing patterns during locomotion in rhythmogenic and non-rhythmogenic V2a neurons alike are best explained by distinct modes of synaptic inhibition linked to cell type and speed. At fast speeds reciprocal inhibition in descending V2a neurons supports phasic firing, while recurrent inhibition in bifurcating V2a neurons helps pattern motor output. In contrast, at slow speeds recurrent inhibition in descending V2a neurons supports phasic firing, while bifurcating V2a neurons rely on reciprocal inhibition alone to pattern output. Our findings suggest cell-type-specific, not common, modes of rhythmogenesis generate and coordinate different speeds of locomotion.

Cell-type-specific origins of locomotor rhythmicity at different speeds in larval zebrafish.

Different speeds of locomotion require heterogeneous spinal populations, but a common mode of rhythm generation is presumed to exist. Here, we explore the cellular versus synaptic origins of spinal rhythmicity at different speeds by performing electrophysiological recordings from premotor excitatory interneurons in larval zebrafish. Chx10-labeled V2a neurons are divided into at least two morphological subtypes proposed to play distinct roles in timing and intensity control. Consistent with distinct rhythm generating and output patterning functions within the spinal V2a population, we find that descending subtypes are recruited exclusively at slow or fast speeds and exhibit intrinsic cellular properties suitable for rhythmogenesis at those speeds, while bifurcating subtypes are recruited more reliably at all speeds and lack appropriate rhythmogenic cellular properties. Unexpectedly, however, phasic firing patterns during locomotion in rhythmogenic and non-rhythmogenic V2a neurons alike are best explained by distinct modes of synaptic inhibition linked to cell type and speed. At fast speeds reciprocal inhibition in descending V2a neurons supports phasic firing, while recurrent inhibition in bifurcating V2a neurons helps pattern motor output. In contrast, at slow speeds recurrent inhibition in descending V2a neurons supports phasic firing, while bifurcating V2a neurons rely on reciprocal inhibition alone to pattern output. Our findings suggest cell-type-specific, not common, modes of rhythmogenesis generate and coordinate different speeds of locomotion.

Intraoperative Cavity Local Delivery System with NETs-Specific Drug Release for Post-Breast Cancer Surgery Recurrence Correction.

Postoperative breast cancer recurrence is tricky due to the limited therapeutic options. Transforming growth factors-β (TGF-β) is vital in promoting postoperative tumor recurrence. However, conventional blocking strategies fail to satisfy both bio-safety and sufficient relapse correction. Neutrophil extracellular traps (NETs) are essential for the spatiotemporal dynamics of TGF-β at tumor-resection sites, whose unique mechanism for local TGF-β amplification could remarkably increase the risk of relapse after surgery. Herein, the principle of NETs formation is ingeniously utilized to construct a surgical residual cavity hydrogel that mimics NETs formation. The hydrogel is prepared based on the electrostatic interaction between histidine (His) and sodium alginate (Alg). Then, arginine deiminase 4 (PAD4) protein is released during NETs formation. Simultaneously, the electrical property of His in hydrogel changes automatically, which further lead to promising localized release of anti-TGF-β. The hydrogel system can realize specific and selective drug release at targeted NETs site over a prolonged period while exhibiting excellent biocompatibility. Superior breast cancer recurrence inhibition is achieved by suppressing TGF-β and related indicators, impeding epithelial-mesenchymal transition (EMT) progression, and rectifying the locally exacerbated immunosuppressive environment within NETs. The novel NETs local microenvironment drug release functional hydrogel will provide inspiration for postoperative recurrence correction strategies.

Fast-spiking interneuron detonation drives high-fidelity inhibition in the olfactory bulb.

Inhibitory circuits in the mammalian olfactory bulb (OB) dynamically reformat olfactory information as it propagates from peripheral receptors to downstream cortex. To gain mechanistic insight into how specific OB interneuron types support this sensory processing, we examine unitary synaptic interactions between excitatory mitral and tufted cells (MTCs), the OB projection neurons, and a conserved population of anaxonic external plexiform layer interneurons (EPL-INs) using pair and quartet whole-cell recordings in acute mouse brain slices. Physiological, morphological, neurochemical, and synaptic analyses divide EPL-INs into distinct subtypes and reveal that parvalbumin-expressing fast-spiking EPL-INs (FSIs) perisomatically innervate MTCs with release-competent dendrites and synaptically detonate to mediate fast, short-latency recurrent and lateral inhibition. Sparse MTC synchronization supralinearly increases this high-fidelity inhibition, while sensory afferent activation combined with single-cell silencing reveals that individual FSIs account for a substantial fraction of total network-driven MTC lateral inhibition. OB output is thus powerfully shaped by detonation-driven high-fidelity perisomatic inhibition.

Recurrent inhibition refines mental templates to optimize perceptual decisions.

Translating sensory inputs to perceptual decisions relies on building internal representations of features critical for solving complex tasks. Yet, we still lack a mechanistic account of how the brain forms these mental templates of task-relevant features to optimize decision-making. Here, we provide evidence for recurrent inhibition: an experience-dependent plasticity mechanism that refines mental templates by enhancing γ-aminobutyric acid (GABA)-mediated (GABAergic) inhibition and recurrent processing in superficial visual cortex layers. We combine ultrahigh-field (7 T) functional magnetic resonance imaging at submillimeter resolution with magnetic resonance spectroscopy to investigate the fine-scale functional and neurochemical plasticity mechanisms for optimized perceptual decisions. We demonstrate that GABAergic inhibition increases following training on a visual (i.e., fine orientation) discrimination task, enhancing the discriminability of orientation representations in superficial visual cortex layers that are known to support recurrent processing. Modeling functional and neurochemical plasticity interactions reveals that recurrent inhibitory processing optimizes brain computations for perpetual decisions and adaptive behavior.

Engineering Cells for Cancer Therapy.

ConspectusCells, particularly living cells, serve as natural carriers of bioactive substances. Their inherent low immunogenicity and multifunctionality have garnered significant attention in the realm of disease treatment applications, specifically within the domains of cancer immunotherapy and regenerative tissue repair. Nevertheless, several prominent challenges impede their swift translation into clinical applications, including obstacles related to large-scale production feasibility and high utilization costs. To address these issues comprehensively, researchers have proposed the notion of bionic cells that are synthetically generated through chemical or biosynthetic means to emulate cellular functions and behaviors. However, artificial cell strategies encounter difficulties in fully replicating the intricate functionalities exhibited by living cells while also grappling with the complexities associated with design implementation for clinical translation purposes. The convergence of disciplines has facilitated the reform of living cells through a range of approaches, including chemical-, biological-, genetic-, and materials-based methods. These techniques can be employed to impart specific functions to cells or enhance the efficacy of therapy. For example, cells are engineered through gene transduction, surface modifications, endocytosis of drugs as delivery systems, and membrane fusion. The concept of engineered cells presents a promising avenue for enhancing control over living cells, thereby enhancing therapeutic efficacy while concurrently mitigating toxic side effects and ultimately facilitating the realization of precision medicine.In this Account, we present a comprehensive overview of our recent research advancements in the field of engineered cells. Our work involves the application of biological or chemical engineering techniques to manipulate endogenous cells for therapeutics or drug delivery purposes. For instance, to avoid the laborious process of isolating, modifying, and expanding engineered cells in vitro, we proposed the concept of in situ engineered cells. By applying a hydrogel loaded with nanoparticles carrying edited chimeric antigen receptor (CAR) plasmids within the postoperative cavity of glioma, we successfully targeted tumor-associated macrophages for gene editing, leading to effective tumor recurrence inhibition. Furthermore, leveraging platelet's ability to release microparticles upon activation at injury sites, we modified antiprogrammed death 1 (PD-1) antibodies on their surface to suppress postoperative tumor recurrence and provide immunotherapy for inoperable tumors. Similarly, by exploiting bacteria's active tropism toward sites of inflammation and hypoxia, we delivered protein drugs by engineered bacteria to induce cancer cell death through pyroptosis initiation and immunotherapy strategies. In the final section, we summarize our aforementioned research progress while providing an outlook on cancer therapy and the hurdles for clinical translation with potential solutions or future directions based on the concept of engineered cells.

Stimuli-Responsive Hydrogels Potentiating Photothermal Therapy against Cancer Stem Cell-Induced Breast Cancer Metastasis.

The self-renewal and differentiation properties of cancer stem cells (CSCs) result in chemoresistance in breast cancer. Even though numerous drugs have been developed to target CSCs, they have suffered from inefficient delivery and accumulation at the focal site. Here, a thermoresponsive hydrogel is developed by coencapsulating aggregation-induced emission (AIE)-active photothermal agent and thioridazine (THZ), demonstrating a controllable delivery system triggered by the AIE agent to augment THZ-mediated CSC ablation. Upon near-infrared laser stimuli, the photothermal effect from the AIE agent induces hydrogel deformation for burst drug release. The precise in situ tumor administration of the hydrogel accelerates drug diffusion and accumulation in deep breast cancer lesions. Thus, THZ can invade tumors and provoke massive CSC apoptosis via dopamine receptor blockage and oxidative stress induction. Consequently, effective CSC inhibition and significant suppression of tumor recurrence and metastasis are demonstrated in mice with breast cancer. We believe that this intelligent hydrogel-based delivery system represents a promising treatment strategy for metastatic breast cancer with clinical potential.

Modeling the impact of neuromorphological alterations in Down syndrome on fast neural oscillations.

Cognitive disorders, including Down syndrome (DS), present significant morphological alterations in neuron architectural complexity. However, the relationship between neuromorphological alterations and impaired brain function is not fully understood. To address this gap, we propose a novel computational model that accounts for the observed cell deformations in DS. The model consists of a cross-sectional layer of the mouse motor cortex, composed of 3000 neurons. The network connectivity is obtained by accounting explicitly for two single-neuron morphological parameters: the mean dendritic tree radius and the spine density in excitatory pyramidal cells. We obtained these values by fitting reconstructed neuron data corresponding to three mouse models: wild-type (WT), transgenic (TgDyrk1A), and trisomic (Ts65Dn). Our findings reveal a dynamic interplay between pyramidal and fast-spiking interneurons leading to the emergence of gamma activity (∼40 Hz). In the DS models this gamma activity is diminished, corroborating experimental observations and validating our computational methodology. We further explore the impact of disrupted excitation-inhibition balance by mimicking the reduction recurrent inhibition present in DS. In this case, gamma power exhibits variable responses as a function of the external input to the network. Finally, we perform a numerical exploration of the morphological parameter space, unveiling the direct influence of each structural parameter on gamma frequency and power. Our research demonstrates a clear link between changes in morphology and the disruption of gamma oscillations in DS. This work underscores the potential of computational modeling to elucidate the relationship between neuron architecture and brain function, and ultimately improve our understanding of cognitive disorders.

Injectable Therapeutic Hydrogel with H2O2 Self-Supplying and GSH Consumption for Synergistic Chemodynamic/Low-Temperature Photothermal Inhibition of Postoperative Tumor Recurrence and Wound Infection.

Postoperative tumor recurrence and wound infection remain significant clinical challenges in surgery, often requiring adjuvant therapies. The combination treatment of photothermal therapy (PTT) and chemodynamic therapy (CDT) has proven to be effective in cancer treatment and wound infection. However, the hyperthermia during PTT increases the risk of normal tissue damage, severely impeding its application. Moreover, the efficacy of CDT is limited by insufficient hydrogen peroxide (H2O2) and excessive glutathione (GSH) levels at tumor or infection sites. Herein, an injectable and multifunctional CuO2@Au hydrogel system (CuO2@Au Gel) is developed for synergistic CDT and low-temperature PTT (LTPTT) to prevent tumor recurrence and bacterial wound infections. CuO2@Au Gel is constructed by embedding therapeutic CuO2@Au into low-melting point agarose hydrogel. In vitro and in vivo experiments confirm that the CuO2@Au in CuO2@Au Gel is capable of self-supplying H2O2 and depleting GSH, exhibiting effective CDT effect in acidic tumor or bacterial infected microenvironment. Additionally, it exhibits favorable photothermal conversion ability, inducing localized temperature elevation and synergistically enhancing CDT efficiency. The prepared CuO2@Au Gel demonstrates efficient tumor ablation capability in post-surgery recurrence mouse models and exhibits promising anti-infective efficiency in bacterial infection wound models, indicating significant potential in adjuvant therapy for post-surgical treatment and recovery.

Biomimetic Hydrogel-Mediated Mechano-Immunometabolic Therapy for Inhibition of ccRCC Recurrence After Surgery.

The unique physical tumor microenvironment (TME) and aberrant immune metabolic status are two obstacles that must be overcome in cancer immunotherapy to improve clinical outcomes. Here, an in situ mechano-immunometabolic therapy involving the injection of a biomimetic hydrogel is presented with sequential release of the anti-fibrotic agent pirfenidone, which softens the stiff extracellular matrix, and small interfering RNA IDO1, which disrupts kynurenine-mediated immunosuppressive metabolic pathways, together with the multi-kinase inhibitor sorafenib, which induces immunogenic cell death. This combination synergistically augmented tumor immunogenicity and induced anti-tumor immunity. In mouse models of clear cell renal cell carcinoma, a single-dose peritumoral injection of a biomimetic hydrogel facilitated the perioperative TME toward a more immunostimulatory landscape, which prevented tumor relapse post-surgery and prolonged mouse survival. Additionally, the systemic anti-tumor surveillance effect induced by local treatment decreased lung metastasis by inhibiting epithelial-mesenchymal transition conversion. The versatile localized mechano-immunometabolic therapy can serve as a universal strategy for conferring efficient tumoricidal immunity in "cold" tumor postoperative interventions.

Reduced inhibition from quadriceps onto soleus after acute quadriceps fatigue suggests Golgi tendon organ contribution to heteronymous inhibition.

Heteronymous inhibition between lower limb muscles is primarily attributed to recurrent inhibitory circuits in humans but could also arise from Golgi tendon organs (GTOs). Distinguishing between recurrent inhibition and mechanical activation of GTOs is challenging because their heteronymous effects are both elicited by stimulation of nerves or a muscle above motor threshold. Here, the unique influence of mechanically activated GTOs was examined by comparing the magnitude of heteronymous inhibition from quadriceps (Q) muscle stimulation onto ongoing soleus electromyographic at five Q stimulation intensities (1.5-2.5× motor threshold) before and after an acute bout of stimulation-induced Q fatigue. Fatigue was used to decrease Q stimulation evoked force (i.e., decreased GTO activation) despite using the same pre-fatigue stimulation currents (i.e., same antidromic recurrent inhibition input). Thus, a decrease in heteronymous inhibition after Q fatigue and a linear relation between stimulation-evoked torque and inhibition both before and after fatigue would support mechanical activation of GTOs as a source of inhibition. A reduction in evoked torque but no change in inhibition would support recurrent inhibition. After fatigue, Q stimulation-evoked knee torque, heteronymous inhibition magnitude and inhibition duration were significantly decreased for all stimulation intensities. In addition, heteronymous inhibition magnitude was linearly related to twitch-evoked knee torque before and after fatigue. These findings support mechanical activation of GTOs as a source of heteronymous inhibition along with recurrent inhibition. The unique patterns of heteronymous inhibition before and after fatigue across participants suggest the relative contribution of GTOs, and recurrent inhibition may vary across persons.

A dual-enzyme-like photosensitive nanozyme for remodeling the tumor immunosuppressive microenvironment to enhance immunotherapy

In “immune-cold” tumors, the upregulation of immunosuppressive cells and insufficient infiltration of lymphocytes contribute to the resistance against immune therapy. Herein, we have developed a dual-enzyme-like photosensitive nanozyme (PBAF) to remodel the tumor immunosuppressive microenvironment (TIME) and induce the tumor infiltration of cytotoxic T lymphocytes (CTLs). Specifically, PBAF exhibits peroxidase (POD)-like activity and glutathione oxidase (GSHOx)-like activity and can be stimulated by 750 nm laser, promoting oxidative stress at the tumor site. Consequently, this process further leads to the reconstruction of TIME in animal experiments, inducing tumor-associated macrophages (TAMs) toward the immunostimulatory M1 phenotype, eliminating myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs). Simultaneously, PBAF also promotes dendritic cells (DCs) maturation to enhance CTLs infiltration into the tumor. The remodeled TIME and enhanced immune responses by PBAF demonstrate significant post-administration inhibition of recurrence and metastasis in the treatment of malignant tumors.

Personalized Nanovaccines Enhance Lymph Node Accumulation and Reprogram the Tumor Microenvironment for Improved Photodynamic Immunotherapy.

Tumor immunotherapy has emerged as an efficacious therapeutic approach that mobilizes the patient's immune system to achieve durable tumor suppression. Here, we design a photodynamic therapy-motivated nanovaccine (Dex-HDL/ALA-Fe3O4) co-delivering 5-aminolevulinic acid and Fe3O4 nanozyme that demonstrate a long-term durable immunotherapy strategy. After vaccination, the nanovaccine exhibits obvious tumor site accumulation, lymph node homing, and specific and memory antitumor immunity evocation. Upon laser irradiation, Dex-HDL/ALA-Fe3O4 effectively generates reactive oxygen species at the tumor site not only to induce the immunogenic cell death-cascade but also to trigger the on-demand release of full types of tumor antigens. Intriguingly, Fe3O4 nanozyme-catalyzed hydrogen peroxide generated oxygen for alleviating tumor hypoxia and modifying the inhibitory tumor microenvironment, thereby exhibiting remarkable potential as a sensitizer. The intravenous administration of nanovaccines in diverse preclinical cancer models has demonstrated remarkable tumor regression and inhibition of postoperative tumor recurrence and metastasis, thereby enabling personalized treatment strategies against highly heterogeneous tumors.

Stimuli-sensitive biomimetic nanoparticles for the inhibition of breast cancer recurrence and pulmonary metastasis

Biomimetic nanoparticles represent a promising avenue for mitigating rapid clearance by the reticuloendothelial system (RES); however, current challenges include insufficient tumour targeting, suboptimal adhesion, and inadequate localized drug release within tumour regions. These shortcomings contribute to persistent contests, such as recurrence and pulmonary metastasis, even with advanced breast cancer therapies. Stimuli-sensitive drug release can furbish the membrane coated nanoparticles for their efficiency against the stated problems. To enhance the efficacy of biomimetic nanoparticles in addressing these issues, we proposed a versatile, stimuli-responsive drug delivery system by encapsulating doxorubicin (Dox) and perfluorohexane (PFH) within poly (lactic-co-glycolic acid) (PLGA) nanoparticles, subsequently coated with macrophage-derived cell membranes. Within this framework, PFH serves as the mediator for ultrasonic (US)-irradiation-triggered drug release specifically within tumour microenvironment, while the macrophage-derived cell membrane coating enhances cell adhesion, enables immune evasion, and natural tumour-homing ability. The characterization assays and in vitro evaluations yielded encouraging results, indicating enhanced targeting and release efficiencies. In vivo studies demonstrated marked inhibitory effects on both breast cancer recurrence and pulmonary metastasis. The resulting data indicate that these engineered nanoparticles have notable potential for targeted delivery and controlled release upon US irradiation, thereby offering significant therapeutic efficacy against primary breast cancer, pulmonary metastasis, and recurrent malignancies. Our findings lay the groundwork for a novel clinical approach, representing an intriguing direction for ongoing investigation by oncologists.

Modeling circuit mechanisms of opposing cortical responses to visual flow perturbations.

In an ever-changing visual world, animals' survival depends on their ability to perceive and respond to rapidly changing motion cues. The primary visual cortex (V1) is at the forefront of this sensory processing, orchestrating neural responses to perturbations in visual flow. However, the underlying neural mechanisms that lead to distinct cortical responses to such perturbations remain enigmatic. In this study, our objective was to uncover the neural dynamics that govern V1 neurons' responses to visual flow perturbations using a biologically realistic computational model. By subjecting the model to sudden changes in visual input, we observed opposing cortical responses in excitatory layer 2/3 (L2/3) neurons, namely, depolarizing and hyperpolarizing responses. We found that this segregation was primarily driven by the competition between external visual input and recurrent inhibition, particularly within L2/3 and L4. This division was not observed in excitatory L5/6 neurons, suggesting a more prominent role for inhibitory mechanisms in the visual processing of the upper cortical layers. Our findings share similarities with recent experimental studies focusing on the opposing influence of top-down and bottom-up inputs in the mouse primary visual cortex during visual flow perturbations.

Controlled Refolding of Denatured IL-12 Using In Situ Antigen-Capturing Nanochaperone Remarkably Reduces the Systemic Toxicity and Enhances Cancer Immunotherapy.

Cytokines are powerful in cancer immunotherapy, however, their therapeutic potential is limited by the severe systemic toxicity. Here a potent strategy to reduce the toxicity of systemic cytokine therapy by delivering its denatured form using a finely designed nanochaperone, is described. It is demonstrated that even if the denatured protein cargos are occasionally released under normal physiological conditions they are still misfolded, while can effectively refold into native states and release to function in tumor microenvironment. Consequently, the systemic toxicity of cytokines is nearly completely overcome. Moreover, an immunogenic cell death (ICD)-inducing chemotherapeutic is further loaded and delivered to tumor using this nanochaperone to trigger the release of tumor-associated antigens (TAAs) that are subsequently captured in situ by nanochaperone and then reflows into lymph nodes (LNs) to promote antigen cross-presentation. This optimized personalized nanochaperone-vaccine demonstrates unprecedented suppressive effects against large, advanced tumors, and in combination with immune checkpoint blockade (ICB) therapy results in a significant abscopal effect and inhibition of postoperative tumor recurrence and metastasis. Hence, this approach provides a simple and universal delivery strategy to reduce the systemic toxicities of cytokines, as well as provides a robust personalized cancer vaccination platform, which may find wide applications in cancer immunotherapy.

Integrated network pharmacology and experimental verification to explore the potential mechanism of San Ying decoction for treating triple-negative breast cancer.

Traditional Chinese medicine (TCM) has been used to treat triple-negative breast cancer (TNBC), a breast cancer subtype with poor prognosis. Clinical studies have verified that the Sanyingfang formula (SYF), a TCM prescription, has obvious effects on inhibiting breast cancer recurrence and metastasis, prolonging patient survival, and reducing clinical symptoms. However, its active ingredients and molecular mechanisms are still unclear. In this study, the active ingredients of each herbal medicine composing SYF and their target proteins are obtained from the Traditional Chinese Medicine Systems Pharmacology database. Breast cancer-related genes are obtained from the GeneCards database. Major targets and pathways related to SYF treatment in breast cancer are identified by analyzing the above data. By conducting molecular docking analysis, we find that the active ingredients quercetin and luteolin bind well to the key targets KDR1, PPARG, SOD1, and VCAM1. In vitro experiments verify that SYF can reduce the proliferation, migration, and invasion ability of TNBC cells. Using a TNBC xenograft mouse model, we show that SYF could delay tumor growth and effectively inhibit the occurrence of breast cancer lung metastasis in vivo. PPARG, SOD1, KDR1, and VCAM1 are all regulated by SYF and may play important roles in SYF-mediated inhibition of TNBC recurrence and metastasis.

Synchrony in Networks of Type 2 Interneurons Is More Robust to Noise with Hyperpolarizing Inhibition Compared to Shunting Inhibition in Both the Stochastic Population Oscillator and the Coupled Oscillator Regimes.

Synchronization in the gamma band (25-150 Hz) is mediated by PV+ inhibitory interneurons, and evidence is accumulating for the essential role of gamma oscillations in cognition. Oscillations can arise in inhibitory networks via synaptic interactions between individual oscillatory neurons (mean-driven) or via strong recurrent inhibition that destabilizes the stationary background firing rate in the fluctuation-driven balanced state, causing an oscillation in the population firing rate. Previous theoretical work focused on model neurons with Hodgkin's Type 1 excitability (integrators) connected by current-based synapses. Here we show that networks comprised of simple Type 2 oscillators (resonators) exhibit a supercritical Hopf bifurcation between synchrony and asynchrony and a gradual transition via cycle skipping from coupled oscillators to stochastic population oscillator (SPO), as previously shown for Type 1. We extended our analysis to homogeneous networks with conductance rather than current based synapses and found that networks with hyperpolarizing inhibitory synapses were more robust to noise than those with shunting synapses, both in the coupled oscillator and SPO regime. Assuming that reversal potentials are uniformly distributed between shunting and hyperpolarized values, as observed in one experimental study, converting synapses to purely hyperpolarizing favored synchrony in all cases, whereas conversion to purely shunting synapses made synchrony less robust except at very high conductance strengths. In mature neurons the synaptic reversal potential is controlled by chloride cotransporters that control the intracellular concentrations of chloride and bicarbonate ions, suggesting these transporters as a potential therapeutic target to enhance gamma synchrony and cognition.