Model-based closed-loop control of thalamic deep brain stimulation.

Introduction: Closed-loop control of deep brain stimulation (DBS) is beneficial for effective and automatic treatment of various neurological disorders like Parkinson's disease (PD) and essential tremor (ET). Manual (open-loop) DBS programming solely based on clinical observations relies on neurologists' expertise and patients' experience. Continuous stimulation in open-loop DBS may decrease battery life and cause side effects. On the contrary, a closed-loop DBS system uses a feedback biomarker/signal to track worsening (or improving) of patients' symptoms and offers several advantages compared to the open-loop DBS system. Existing closed-loop DBS control systems do not incorporate physiological mechanisms underlying DBS or symptoms, e.g., how DBS modulates dynamics of synaptic plasticity. Methods: In this work, we propose a computational framework for development of a model-based DBS controller where a neural model can describe the relationship between DBS and neural activity and a polynomial-based approximation can estimate the relationship between neural and behavioral activities. A controller is used in our model in a quasi-real-time manner to find DBS patterns that significantly reduce the worsening of symptoms. By using the proposed computational framework, these DBS patterns can be tested clinically by predicting the effect of DBS before delivering it to the patient. We applied this framework to the problem of finding optimal DBS frequencies for essential tremor given electromyography (EMG) recordings solely. Building on our recent network model of ventral intermediate nuclei (Vim), the main surgical target of the tremor, in response to DBS, we developed neural model simulation in which physiological mechanisms underlying Vim-DBS are linked to symptomatic changes in EMG signals. By using a proportional-integral-derivative (PID) controller, we showed that a closed-loop system can track EMG signals and adjust the stimulation frequency of Vim-DBS so that the power of EMG reaches a desired control target. Results and discussion: We demonstrated that the model-based DBS frequency aligns well with that used in clinical studies. Our model-based closed-loop system is adaptable to different control targets and can potentially be used for different diseases and personalized systems.

Nanoscale myelinogenesis image in developing brain via super-resolution nanoscopy by near-infrared emissive curcumin-BODIPY derivatives.

Understanding the intricate nanoscale architecture of neuronal myelin during central nervous system development is of utmost importance. However, current visualization methods heavily rely on electron microscopy or indirect fluorescent method, lacking direct and real-time imaging capabilities. Here, we introduce a breakthrough near-infrared emissive curcumin-BODIPY derivative (MyL-1) that enables direct visualization of myelin structure in brain tissues. The remarkable compatibility of MyL-1 with stimulated emission depletion nanoscopy allows for unprecedented super-resolution imaging of myelin ultrastructure. Through this innovative approach, we comprehensively characterize the nanoscale myelinogenesis in three dimensions over the course of brain development, spanning from infancy to adulthood in mouse models. Moreover, we investigate the correlation between myelin substances and Myelin Basic Protein (MBP), shedding light on the essential role of MBP in facilitating myelinogenesis during vertebral development. This novel material, MyL-1, opens up new avenues for studying and understanding the intricate process of myelinogenesis in a direct and non-invasive manner, paving the way for further advancements in the field of nanoscale neuroimaging.

Visualizing intracellular membrane interactions and cell type-specific differentiation in ferroptosis and apoptosis with Boranil-Carbazole derivative.

Intracellular lipid systems play essential roles in various physiological functions and cell growth processes. However, our understanding of the intricate interactions within this system, especially between mitochondria and lipid droplets, is limited, particularly in the context of cancer cells' altered lipid metabolism. To address this, our study introduces an N-B-O BODIPY-hexylcarbazole derivative, named Cz-Boranil, that sets a new benchmark in visualizing these critical interactions. Cz-Boranil's unique capability lies in its ability to display distinct intracellular distribution patterns in both normal and cancer cells, offering nuanced cell type-specific differentiation. More impressively, this probe tracks the coordinated interactions of lipid droplets and mitochondria during the critical processes of ferroptosis and apoptosis. We believe that the innovative capabilities of Cz-Boranil will revolutionize our understanding of intracellular lipid interactions and prove pivotal in identifying and studying cancerous cells.

Restriction of intramolecular rotation for functionalizing metal nanoclusters.

The restriction of intramolecular rotation has been extensively exploited to trigger the property enhancement of nanocluster-based materials. However, such a restriction is induced mainly by intermolecular aggregation. The direct restriction of intramolecular rotation of metal nanoclusters, which could boost their properties at the single molecular level, remains rarely explored. Here, ligand engineering was applied to activate intramolecular interactions at the interface between peripheral ligands and metallic kernels of metal nanoclusters. For the newly reported Au4Ag13(SPhCl2)9(DPPM)3 nanocluster, the molecule-level interactions between the Cl terminals on thiol ligands and the Ag atoms on the cluster kernel remarkably restricted the intramolecular rotation, endowing this robust nanocluster with superior thermal stability, emission intensity, and non-linear optical properties over its cluster analogue. This work presents a novel case of the restriction of intramolecular rotation (i.e., intramolecular interaction-induced property enhancement) for functionalizing metal clusters at the single molecular level.

Boosting activity of γ-alumina-supported vanadium catalyst for isobutane non-oxidative dehydrogenation via pure V3.

The vanadium-based dehydrogenation (DH) catalyst is becoming a promise alternative to the industrial used Pt- and Cr-based catalysts, due to lower cost and less environmental threat. However, the low DH activity hampered the industrial application of vanadium-based catalysts. Herein, for the first time, we introduce a method to prepare high-efficiency vanadium-based catalyst by constructing pure V3+ species on γ-Al2O3 through treatment of as-prepared thiovanadate. The V3+ species contributes to not only enhancing the DH activity, but also fabricating the V3+-O/S acid-base pair with ideal strength and stability. The isobutene yield can reach as high as 56.9 wt%. Only Lewis acid is recognized on V3+/Al2O3 catalyst, while no Brønsted acid remains. The side-reactions are consequently inhibited, and the selectivity to isobutene is improved. Besides, with the increase of vanadium loadings, the Lewis acid content increases at first and then decreases, and the content of acid sites in middle strength keeps decreasing. Though the deposited coke on V3+/Al2O3 was just 2.5 wt% during 8.5 h consecutive DH reaction, the valence state of vanadium was still influenced and the fraction of inert V4+ species increased steadily. This study will improve the potential for industrial application of vanadium-based DH catalyst, and offer theoretical guidance for optimization of ideal DH catalysts.

Revealing the amyloid ß-protein with zinc finger protein of micronucleus during Alzheimer's disease progress by a quaternary ammonium terpyridine probe.

Micronucleus (MN) is regarded as an abnormal structure in eukaryotic cells which can be used as a biomarker for genetic instability. However, direct observation of MN in living cells is rarely achieved due to the lack of probes that are capable of distinguishing nuclear- and MN-DNA. Herein, a water-soluble terpyridine organic small molecule (ABT) was designed and employed to recognize Zinc-finger protein (ZF) for imaging intracellular MN. The in vitro experiments suggested ABT has a high affinity towards ZF. Further live cell staining showed that ABT could selectively target MN in HeLa and NSC34 cells when combined with ZF. Importantly, we use ABT to uncover the correlation between neurotoxic amyloid ß-protein (Aß) and MN during Alzheimer's disease (AD) progression. Thus, this study provides profound insight into the relationship between Aß and genomic disorders, offering a deeper understanding for the diagnosis and treatment of AD.

Modeling Instantaneous Firing Rate of Deep Brain Stimulation Target Neuronal Ensembles in the Basal Ganglia and Thalamus.

OBJECTIVE: Deep brain stimulation (DBS) is an effective treatment for movement disorders, including Parkinson disease and essential tremor. However, the underlying mechanisms of DBS remain elusive. Despite the capability of existing models in interpreting experimental data qualitatively, there are very few unified computational models that quantitatively capture the dynamics of the neuronal activity of varying stimulated nuclei-including subthalamic nucleus (STN), substantia nigra pars reticulata (SNr), and ventral intermediate nucleus (Vim)-across different DBS frequencies. MATERIALS AND METHODS: Both synthetic and experimental data were used in the model fitting; the synthetic data were generated by an established spiking neuron model that was reported in our previous work, and the experimental data were provided using single-unit microelectrode recordings (MERs) during DBS (microelectrode stimulation). Based on these data, we developed a novel mathematical model to represent the firing rate of neurons receiving DBS, including neurons in STN, SNr, and Vim-across different DBS frequencies. In our model, the DBS pulses were filtered through a synapse model and a nonlinear transfer function to formulate the firing rate variability. For each DBS-targeted nucleus, we fitted a single set of optimal model parameters consistent across varying DBS frequencies. RESULTS: Our model accurately reproduced the firing rates observed and calculated from both synthetic and experimental data. The optimal model parameters were consistent across different DBS frequencies. CONCLUSIONS: The result of our model fitting was in agreement with experimental single-unit MER data during DBS. Reproducing neuronal firing rates of different nuclei of the basal ganglia and thalamus during DBS can be helpful to further understand the mechanisms of DBS and to potentially optimize stimulation parameters based on their actual effects on neuronal activity.

Lighting up RNA-specific multi-photon and super-resolution imaging using a novel zinc complex.

Ribonucleic acid (RNA) probes are critical for understanding the role of RNA dynamics in cellular function but are in short supply due to the lack of optimized imaging systems and excellent fluorescence emission performance. Here, the terpyridine Zn(II) complex (Zn-T) with D-π-A configuration and bright aggregation-induced fluorescence emission (AIE) has been fabricated for the selective detection and real-time monitoring of RNA. Impressively, Zn-T exhibits a large Stokes shift and three-photon absorption (3PA) activity and responds specifically through hydrophobic interactions with an RNA pocket. The combination of AIE-assisted two-photon fluorescence and stimulated emission depletion (STED) microscopy of Zn-T for imaging nuclear RNA has higher spatial resolution and brightness, thus providing an imaging platform for studying RNA-related physiological or pathological processes.

Four-Photon Absorption Iron Complex for Magnetic Resonance/Photoacoustic Dual-Model Imaging and an Enhanced Ferroptosis Process.

Four-photon absorption (4PA) multimodal therapeutic agent applied to tumor ferroptosis process tracking is rarely reported. In this paper, two functionalized terpyridine iron complexes (TD-FeCl3, TD-Fe-TD) with four-photon absorption properties were designed and synthesized. The four-photon absorption cross sections of TD-FeCl3 reached 6.87 × 10-74cm8·s3·photon-3. Due to its strong near-infrared absorption, TD-FeCl3 has excellent photoacoustic imaging (PAI) capability for accurate PA imaging. TD-FeCl3 has an efficient longitudinal electron relaxation rate (r1 = 2.26 mM-1 s-1) and high spatial resolution, which can be applied as T1-weighted magnetic resonance imaging (MRI) contrast agent for tumor imaging in vivo. In addition, Fe3+ as a natural ferroptosis tracer, TD-FeCl3, is able to deplete glutathione (GSH) effectively, which can further enhance the ferroptosis process. We found that the series of cheap transition metal complexes has four-photon absorption activity and can be used as multimodal (MRI/PAI) diagnostic agents for tumor tracing processes.

A tumor microenvironment-activated metal-organic framework-based nanoplatform for amplified oxidative stress-induced enhanced chemotherapy.

Engineering a highly tumor microenvironment-responsive nanoplatform toward effective chemotherapy has always been a challenge in targeted cancer treatment. Metal-organic frameworks are a promising delivery system to reformulate previously approved drugs for enhanced chemotherapy, such as disulfiram (DSF). Herein, a tumor microenvironment-activated metal-organic framework-based nanoplatform DSF@MOF-199@FA has been fabricated to realize amplified oxidative stress-induced enhanced chemotherapy. Our results unveil that the copper ions and DSF released by DSF@MOF-199@FA in an acidic environment can be converted into toxic bis(N, N-diethyl dithiocarbamate) copper and then induce cell apoptosis. Simultaneously, we determined that the apoptosis outcome is further promoted by amplified oxidative stress through effective generation of reactive oxygen species and GSH elimination. In conclusion, this work provides a promising platform for effective anticancer treatment.

Nanoscopic evaluation on mitochondrial ultrastructures by regulating reactive oxygen species productivity within terpyridyl Zn(II) complexes with different alkyl chain lengths.

Mitochondria targeting complexes are widely utilized as photosensitizers in photodynamic therapy. However, the mechanisms by which they regulate reactive oxygen species (ROS) production at the molecular level and their influence on intracellular mitochondrial signaling and ultrastructures remain rarely studied. Herein, we present two terpyridyl Zn(II) complexes with different side alkyl chain lengths (Zn-2C and Zn-6C) that lead to low and high ROS productivities in vitro, respectively. Both complexes could enter live cells effectively with minimal dark toxicity and accumulate preferably in the mitochondria. We also demonstrated that Zn-6C, with more efficient ROS productivity, could significantly downregulate the caspase signaling pathway but showed no evident influence on mitochondrial membrane proteins. We also highlighted and compared the mitochondrial ultrastructural variations during such a process by stimulated emission depletion (STED) super-resolution nanoscopy.

Novel two-photon absorption compounds with different organic cations: facile synthesis, photophysical properties, detection of viscosity, and selective imaging of the endoplasmic reticulum in living cells.

Three novel imidazole-based two-photon absorption compounds bearing different organic cations (1PIPy, 2PIQu, and 3PIIm) were facilely synthesized and fully characterized by 1H NMR, 13C NMR, FT-IR, and HRMS. The linear and nonlinear photophysical properties of the target compounds were systematically investigated in various solvents, supplemented with the density functional theory calculations to shed light on their structure-property relationships. The maximum two-photon action cross-sections (Φ × Î´max) were determined to be 22.4-98.2 (CH2Cl2), 9.6-41.3 (DMF), and 3.9-11.8 (H2O) GM. It is found that 3PIIm shows significant viscosity sensitivity with a sharp 27-fold increase in fluorescence intensity. Its fluorescence intensity also exhibits a linear relationship with the viscosity of the media in a logarithmic plot. The Φ × Î´max value of 3PIIm in highly viscous glycerol was found to be 107.5 GM. Cytotoxicity tests indicate that these compounds have relatively low cytotoxicity. All the target compounds were successfully characterized by one- and two-photon fluorescence imaging in living cells. The colocalization experiments reveal that 1PIPy and 3PIIm are specially located in the endoplasmic reticulum (ER) with the Pearson's coefficients above 0.90. 3PIIm can also monitor the fluctuation of ER viscosity during etoposide-induced apoptosis.

In Situ Coordination and Confinement of Two-Photon Active Unit Within Metal-Organic Frameworks for High-Order Multiphoton-Excited Fluorescent Performance.

Exploration of high-order multiphoton-excited fluorescent (H-MPEF) material for bioimaging with deeper tissue penetration and higher spatial resolution has attracted great interest but remains a challenge. Herein, a H-MPEF-responsive metal-organic framework-based material, ZLPH, was rationally fabricated by the pore confinement of a two-photon active unit (ZL) using the "ship-in-bottle" strategy. It demonstrated that the judicious selection effectively avoided the annoying weakened/quenched H-MPEF behavior due to the instability of ZL in the molecular state. Moreover, the obtained material, ZLPH, exhibited bright four-photon-excited fluorescence (4PEF) under the excitation of a 1550 nm femtosecond laser. In view of deep-tissue biological applications, it is envisioned that this work provides a promising platform for bright H-MPEF imaging.

Effect of Temperature on Asphaltene Precipitation in Crude Oils from Xinjiang Oilfield.

During the production of crude oil, asphaltenes are prone to precipitate due to the changes of external conditions (temperature, pressure, etc.). Therefore, a series of research studies were designed to investigate the effect of temperature on asphaltene precipitation for two Xinjiang crude oils (S1, S2) so as to reveal the mechanism of asphaltene dissolution. First, the changes of asphaltene precipitation were intuitively observed by using a microscope. The results demonstrated that the asphaltene solubility increased with the increase of temperature and the dispersion rate of asphaltene particles increased with the decrease of particle size. Second, the variation of asphaltene precipitation with temperature was quantified by a gravimetric method. The results suggested that the different asphaltenes showed different sensitivity to temperature within the temperature range 25-120 °C. Third, a hypothesis was proposed to explain these results and proved that the asphaltene aggregate structure was an important factor for asphaltene stability. The crystallite parameters of asphaltenes were obtained by X-ray diffraction (XRD) to describe the structural characteristics. The results revealed that the layer distance between aromatic sheets (d m ) of asphaltenes derived from S1 oil and S2 oil were 0.378 and 0.408 nm, respectively, which implied that the asphaltene aggregates derived from S2 oil were looser than those of S1 oil. Therefore, high temperature could facilitate the penetration of resins into asphaltene aggregates and ultimately improve the dispersion of asphaltenes. Finally, molecular dynamics (MD) simulation was used to verify the conclusions. Based on the molecular dynamics method, asphaltene aggregate models were developed. The compactness and internal energy of each model were calculated. The results showed that the asphaltene dispersion capability was proportional to the porosity and internal energy.

Ligand-regulated three-photon AIE properties of manganese(II) complexes for photodynamic therapy.

Owing to the advantages of deeper penetration depth and lower biological damage, multi-photon AIE probes are widely used in the field of multi-photon therapy. We have developed a series of carbazole terpyridine manganese(II) complexes (MD1-MD3) that are promising as aggregation-induced emission (AIE) photosensitizers (PSs). MD1-MD3 exhibit excellent three-photon AIE properties in DMSO/H2O solution. We modulated the AIE properties of the Mn(II) complexes by introducing halogen atoms (Br/I). The three-photon fluorescence intensity of the complexes upon introducing halogen atoms is strong under the conditions of fw = 99% and 60%, respectively. Based on halogen-substituted carbazole ligands, MD3 can be applied as a multi-photon absorption photosensitizer which can produce 1O2 and O2˙-. MD3 damages the mitochondrial morphology, leads to a decrease in mitochondrial membrane potential, and then triggers the apoptosis of cancer cells. Furthermore, MD3 is successfully applied as a photosensitizer in tumor theranostics in vivo. This work provides a new idea for ligand modulation of multiphoton AIE ground state transition metal complexes to make them multiphoton therapeutic agents.

Control the Single-, Two-, and Three-Photon Excited Fluorescence of Atomically Precise Metal Nanoclusters.

It remains challenging to control the single-, two-, and three-photon excited fluorescence of metal nanoclusters. In this work, the control over the non-linear optics of metal nanoclusters as single-, two-, and three-photon excited fluorescence has been accomplished via exploiting the solvent effect. An emissive nanocluster, Au9 Ag6 (SPht OMe)4 (DPPOE)3 Cl3 , was synthesized and structurally determined. The solvent effect can not only control the fluorescence of this nanocluster, but more significantly, it can also regulate the photoluminescence nature of the cluster as single-, two-, and three-photon excited fluorescence. We concluded that the increased solution polarity, improved dipole moment, enlarged HOMO-LUMO energy gap, and reduced solution viscosity of the cluster in solutions endow them with excellent high-order multiphoton excited fluorescence. The results provide an intriguing cluster template that enables us to manipulate the linear and nonlinear optics at the atomic level.

Three-Photon AIE Pt(II) Complexes as Cysteine-Targeting Theranostic Agents for Tumor Imaging and Chemotherapy.

Herein, we have synthesized a series of three-photon fluorescent Pt(II) complexes targeting a tumor-associated biothiol, cysteine (Cys), which allows it to be detected without any interference from other intracellular proteins. We focused on how to significantly improve the fluorescence response of Cys via regulating the recognition units in probes. The reaction of K2PtCl4 with L-CH3 or L-COOEt in DMSO solution gave Lyso-Pt-CH3 and Lyso-Pt-COOEt, respectively, which present four-coordinated square-planar geometries in mononuclear structures. Lyso-Pt-CH3 consists of a Cys aptamer labeled with typical aggregation-induced emission (AIE) characteristics, which shows strong three-photon absorption cross section (3PA) only in the presence of Cys. It was found that Lyso-Pt-CH3 displayed a perfect signal-to-noise ratio for imaging lysosomes and for rapid detection of Cys. Using Lyso-Pt-CH3, Cys-related cellular mechanisms were proposed. We confirm that cystine (Cyss) could be absorbed in cells through cystine/glutamate antiporters (system xc-) and is then converted to Cys under the effect of enzymes. All of these suggest that Lyso-Pt-CH3 might be a potential candidate as a simple and straightforward biomarker of lysosome-related Cys in vitro. Lyso-Pt-CH3 can effectively identify tumor tissues with excessive levels of Cys. Lyso-Pt-CH3 also showed excellent antitumor activity than cisplatin. This work provides a novel strategy for the rational design of controllably activated and Cys-targeted Pt(II) anticancer prodrugs for clinical diagnosis and treatment.

Coordination-Regulated Terpyridine-Mn(II) Complexes for Photodynamic Therapy Guided by Multiphoton Fluorescence/Magnetic Resonance Imaging.

The synergy of multiphoton fluorescence imaging (MP-FI) and magnetic resonance imaging (MRI) provides an imaging platform with high resolution and unlimited penetration depth for early disease detection. Herein, two kinds of terpyridine-Mn(II) complexes (FD-Mn-O2NO and FD-Mn-FD) possessing seven and six coordination modes, respectively, were designed rationally for photodynamic therapy (PDT) guided by MP-FI/MRI. The complexes obtain different multiphoton fluorescence/magnetic resonance properties by adjusting the number of terpyridine ligands. Among them, FD-Mn-FD exhibits the following superiorities: (1) The optimal three-photon excitation wavelength of FD-Mn-FD falls at 1450 nm (NIR-II), which brings high sensitivity and deep tissue penetration in MP-FI. (2) FD-Mn-FD has effective longitudinal relaxation efficiency (r1 = 2.6 m M-1 s-1), which can be used for T1-weighted MRI, overcoming the problems of limited tissue penetration depth and low spatial resolution. (3) FD-Mn-FD generates endogenous 1O2 under irradiation by 808 nm light, thereby enhancing the PDT effect in vitro and in vivo. To the best of our knowledge, the complex FD-Mn-FD is the first complex to guide PDT through MP-FI/MRI, providing a blueprint for accurate and effective early detection and timely treatment of the complex in the early stages of cancer.

Novel red light-emitting two-photon absorption compounds with large Stokes shifts for living cell imaging.

Three novel donor-π-acceptor two-photon absorption compounds (1PZPy, 2PZIm, 3CZPy) bearing the 10-butyl-10H-phenothiazine (9-butyl-9H-carbazole) donor, the pyridinium (benzimidazolium) acceptor, and the 2,5-divinylthiophene π-bridge were synthesized and fully characterized by 1H NMR, 13C NMR, FT-IR, and HRMS. The linear and nonlinear photophysical properties were systematically investigated. Their absorption properties show a strong solvent dependence, while the emission properties are nearly independent of solvent polarity. All of them possess large Stokes shifts (Δλ=149-190 nm in H2O). 1PZPy and 3CZPy exhibit red fluorescence emission centered at about 635 and 660 nm, respectively. The two-photon absorption cross-sections measured by the open aperture Z-scan technique are determined to be 486 (1PZPy), 601 (2PZIm), and 753 GM (3CZPy) in DMF. The density functional theory calculations were further carried out to reveal their electronic structures. All the target compounds are verified to have low cytotoxicity in the working solution and good capability for one- and two-photon excitation fluorescence imaging, suggesting their potential application in bioimaging. Moreover, they show the organelle targeting ability in living cells with the high Pearson's coefficients above 0.94 for the endoplasmic reticulum.

A cyclometallated iridium(III) complex with multi-photon absorption properties as an imaging-guided photosensitizer.

Conventional photosensitizers (PSs) often have shorter excitation wavelengths and poor cancer cell targeting, resulting in a limited tissue penetration depth and increased biotoxicity, which are significant barriers to ensuring effective photodynamic therapy (PDT) in vivo. In this work, a cyclometallated iridium(III) complex (Ir-Biotin) with a long excitation wavelength and effective cancer cell targeting was designed and synthesized. The initial in vitro assessment indicated that Ir-Biotin shows excellent PDT activity with a high singlet-oxygen (1O2) generation yield (0.19) due to the facilitated intersystem crossing process. Further study shows that Ir-Biotin shows good biocompatibility, has specific selectivity for cancer cells, and can induce apoptosis under laser irradiation. Furthermore, Ir-Biotin can be applied for imaging-guided PDT using an in vivo imaging system, and showed significant anti-tumour effects (tumour growth inhibition value: 87.66%). These results reveal the importance of long excitation wavelengths of photosensitizers for efficient PDT and suggest a promising strategy for developing effective photosensitizers.