Tunnel Barrier Research Articles

Information processing capabilities of two parallel gold-nanoparticle reservoirs dependent on operation temperatures

Abstract We demonstrate the fabrication and performance evaluation of physical reservoir computing (PRC) using a random network of gold-nanoparticles (GNPs). We fabricated two random arrays of GNPs with six electrodes on one sample. Electrical measurements for each array and two parallelized arrays were conducted at temperatures of 4.2 K, 77 K, and 294 K. The random connections of GNPs brought varied tunneling resistances, resulting in various output voltages. The computational performance was assessed using the second-order nonlinear autoregression moving average task. The parallelized reservoir configuration achieved the normalized mean square error as small as 0.03 at 294 K. This higher performance was evaluated through information processing capability and was attributed to the increased second-order capacity at 294 K. Although PRC with GNPs was traditionally regarded to rely on the Coulomb-blockade-induced nonlinearity, nonlinear dynamics possibly due to thermal noise and non-uniform tunnel barriers were effective in reservoir calculations even at room temperature.

Identifying natural inhibitors against FUS protein in dementia through machine learning, molecular docking, and dynamics simulation

Dementia, a complex and debilitating spectrum of neurodegenerative diseases, presents a profound challenge in the quest for effective treatments. The FUS protein is well at the center of this problem, as it is frequently dysregulated in the various disorders. We chose a route of computational work that involves targeting natural inhibitors of the FUS protein, offering a novel treatment strategy. We first reviewed the FUS protein's framework; early forecasting models using the AlphaFold2 and SwissModel algorithms indicated a loop-rich protein—a structure component correlating with flexibility. However, these models showed limitations, as reflected by inadequate ERRAT and Verify3D scores. Seeking enhanced accuracy, we turned to the I-TASSER suite, which delivered a refined structural model affirmed by robust validation metrics. With a reliable model in hand, our study utilized machine learning techniques, particularly the Random Forest algorithm, to navigate through a vast dataset of phytochemicals. This led to the identification of nimbinin, dehydroxymethylflazine, and several other compounds as potential FUS inhibitors. Notably, dehydroxymethylflazine and cleroindicin C identified during molecular docking analyses—facilitated by AutoDock Vina—for their high binding affinities and stability in interaction with the FUS protein, as corroborated by extensive molecular dynamics simulations. Originating from medicinal plants, these compounds are not only structurally compatible with the target protein but also adhere to pharmacokinetic profiles suitable for drug development, including optimal molecular weight and LogP values conducive to blood-brain barrier penetration. This computational exploration paves the way for subsequent experimental validation and highlights the potential of these natural compounds as innovative agents in the treatment of dementia.

Tunneling photo-thermoelectric effect in monolayer graphene/bilayer hexagonal boron nitride/bilayer graphene asymmetric van der Waals tunnel junctions

Graphene exhibits a pronounced photo-thermoelectric effect (PTE) in its in-plane carrier transport and has attracted attention toward various optoelectronic applications. In this study, we demonstrate an out-of-plane PTE by utilizing electron tunneling across a barrier, namely, the tunneling photo-thermoelectric effect (TPTE). This was achieved in a monolayer graphene (MLG)/bilayer hexagonal boron nitride (h-BN)/bilayer graphene (BLG) asymmetric tunnel junction. MLG and BLG exhibit different cyclotron resonance (CR) optical absorption energies when their energies are Landau quantized under an out-of-plane magnetic field. We tuned the magnetic field under mid-infrared irradiation to bring MLG into CR conditions, whereas BLG was not in CR. The CR absorption in the MLG generates an electron temperature difference between the MLG and BLG and induces an out-of-plane TPTE voltage across the h-BN tunnel barrier. The TPTE exhibited a unique dependence on the Fermi energy of the MLG, which differed from that of the in-plane PTE of the MLG. The TPTE signal was large when the Fermi energy of the MLG was tuned near the transition between the quantum Hall state (QHS) and non-QHS. The TPTE allows one to measure the PTE on vertically stacked tunnel junctions, thus providing another degree of freedom for probing the electronic and optoelectronic properties of two-dimensional material heterostructures.

Controlled Cooperativity of Proton Tunneling in a Water Trimer.

Proton tunneling through a hydrogen bond is a significant quantum phenomenon in proton-mediated processes. Hydrogen bonds strengthen each other through cooperative interactions, enhancing proton tunneling. Controlling cooperativity of the hydrogen-bond network is required to understand the role of cooperativity in proton tunneling; however, engineering hydrogen bonds is difficult due to the stable structure of hydrogen-bonded cluster. Here, we demonstrate that collective proton tunneling can be controlled inside a cyclic water trimer simply by assigning an asymmetry in the adsorption structure. Asymmetric configuration of water trimers in registry with the NaCl(001) surface perturbs the strength of hydrogen bonds, destroying cooperativity. We reveal two pathways that facilitate proton tunneling in the interfacial trimer: vibration-excited and rotation-mediated processes. The vibrationally excited states lead to lowering the tunneling barrier, and the intermolecular rotation increases the cooperativity by modifying the adsorption configuration. Our results highlight the atomic-scale control of hydrogen bonds, which is crucial in proton-involved reactions.

Synergistic Anti-Ferroptosis with a Minimalistic, Peroxide-Triggered Carbon Monoxide Donor for Parkinson's Disease.

Parkinson's disease (PD) is a debilitating neurodegenerative disease, with current treatments primarily focusing on improving dopaminergic activity, providing symptomatic relief but failing to halt disease progression. Ferroptosis drives PD pathogenesis and is a potential therapeutic target. Herein, we introduce a novel peroxide-activated carbon monoxide (CO) donor, PCOD, featuring a streamlined structure designed to potentially enhance blood-brain barrier (BBB) penetration and optimize therapeutic outcomes. PCOD releases CO upon activation by nucleophilic peroxides, e.g., ONOO- and H2O2. This mechanism provides a potent strategy against ferroptosis: first, scavenging peroxides that generate oxidative radicals involved in ferroptosis, and second, CO is proposed to inhibit Fenton chemistry through coordination to Fe2+. In MPTP-treated mice, PCOD prevents dopaminergic neuron loss in the substantia nigra and alleviates PD symptoms. This peroxide-triggered CO release offers a promising and innovative strategy to combat ferroptosis and neurodegeneration in PD.

Lipid nanoparticles and transcranial focused ultrasound enhance the delivery of SOD1 antisense oligonucleotides to murine brain

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease with extremely limited therapeutic options. One key pathological feature of ALS is the abnormal accumulation of misfolded proteins within motor neurons. Hence, reducing the burden of misfolded protein has emerged as a promising therapeutic approach. Antisense oligonucleotides (ASOs) have the potential to effectively silence proteins with gain-of-function mutations, such as superoxide dismutase 1 (SOD1). However, ASO delivery to the central nervous system (CNS) is hindered by poor blood-brain barrier (BBB) penetration and the invasiveness of intrathecal administration. In the current study, we demonstrate effective systemic delivery of a next-generation SOD1 ASO (Tofersen) into the brain of wildtype and G93A-SOD1 transgenic C57BL/6 mice using calcium phosphate lipid nanoparticles (CaP lipid NPs). We show that transcranial focused ultrasound (FUS) with intravenously administered microbubbles can significantly enhance ASO-loaded nanoparticle delivery into the mouse brain. Magnetic resonance imaging (MRI) and immunohistological analysis showed reduced SOD1 expression in the FUS-exposed brain regions and increased motor neuron count in the spinal cord of treated mice suggesting decreased motor neuron degeneration. Importantly, the BBB opening was transient without evidence of structural changes, neuroinflammation or damage to the brain tissue, indicating that the treatment is well tolerated. Overall, our results highlight FUS-assisted nanoparticle delivery of ASOs as a promising non-invasive therapeutic strategy for the treatment of ALS and CNS diseases more broadly.

Dynole‐Based Dynamin Inhibitors as Novel Cytotoxic Agents

AbstractDynamin plays a crucial role in mitosis, and dynamin inhibition broadly correlates with cytotoxicity. Dynole 34–2, dynamin inhibitor, is highly cytotoxic, but its poor drug‐like properties limit its in vivo development. Three focused libraries of dynole‐based dynamin inhibitors were synthesized enhance their druglike properties while maintaining their dynamin inhibition and cytotoxicity. Iterative modifications were undertaken to probe the effects of changes to the cyanoacrylamide linker amide, alkyl chain moieties, the N‐propyl‐N,N‐dimethylamino moiety and the indole core. These compounds were screened against: HT29 and SW480 (colon), SMA (spontaneous murine astrocytoma), MCF‐7 (breast), BE2‐C (glioblastoma), SJ‐G2 (neuroblastoma), MIA (pancreas), A2780 (ovarian), A431 (skin), H460 (lung), U87 (glioblastoma) and DU145 (prostate) cell lines to reveal a good correlation between dynamin inhibition and cytotoxicity. High potency against brain cancer cell lines was observed. The most dynamin active compounds returned average GI50 values of 2.26 and 1.5 µM across the cell lines examined. The most active compound against 4 brain cancer cell lines averaged a GI50 value of 4.7 µM; 10‐fold improved over the gold standard for glioblastoma treatment; temozolomide. Importantly, this maintained a tPSA of 24.8Å2 and cLogP of 4.11; appropriate for blood brain barrier penetration. This active analogue in this series was (Z)‐2‐(3,4‐dichlorophenyl)‐3‐(1‐(3‐(dimethylamino)propyl)‐1H‐pyrrol‐3‐yl)acrylonitrile (34).

Improving blood-brain barrier penetration in Hurler syndrome using an IDUA-ApoE fusion enzyme delivered via the PS Gene Editing System

Improving blood-brain barrier penetration in Hurler syndrome using an IDUA-ApoE fusion enzyme delivered via the PS Gene Editing System

Universal Behavior of Tunneling Time and Barrier Time-Delay Decoupling in Attoclock Measurements

Abstract The measurement of the tunneling time-delay is hotly debated and remains controversial. 
 In previous works, we showed that a model that accurately describes the time-delay measured by the attoclock experiment in adiabatic and nonadiabatic field calibrations.
 In the present work, we show that the tunneling time reveals a universal behavior with disentangled contributions. 
 Even more remarkable is that the barrier tunneling time-delay can be convincingly defined and determined from the difference between the time-delay of adiabatic and nonadiabatic tunnel-ionization, which also show good agreement with experimental results.
 Furthermore, we illustrate that in the weak measurement limit, the barrier time-delay corresponds to the Larmor-clock time and the interaction time within the barrier.

Two Birds with One Stone: Eco‐Friendly Nano‐Formulation Endows a Commercial Fungicide with Excellent Insecticidal Activity

AbstractThe development of multi‐action pesticides presents significant advantages, including cost‐effectiveness, reduced application frequency, enhanced resistance management, and minimized environmental impact. Despite its efficacy in targeting chitin synthase in both fungi and insects, the insecticidal performance of polyoxin B remains limited. To overcome this limitation, a novel nano‐formulation, polyoxin B@ZTS is developed, utilizing agricultural byproducts, tea saponin, and zein. This formulation features a small particle size, high leaf deposition efficiency, and excellent dispersion properties. Leveraging a disulfide bond system, polyoxin B@ZTS is designed to respond to the intracellular reducing environment, enabling controlled release of polyoxin B. Remarkably, the nano‐formulation facilitates the penetration of physiological barriers, achieving equivalent insecticidal and fungicidal efficacy to polyoxin B at only one‐fifth of the dosage. This work highlights the potential of eco‐friendly, cost‐effective, and multifunctional nano‐pesticides, providing a compelling solution for sustainable agricultural practices and demonstrating broad applicability in integrated pest and disease management.

Inelastic resonant tunnelling through adjacent localised electronic states in van der Waals heterostructures

Van der Waals heterostructures offer unprecedented opportunities to design next stage functional electronic 2D devices. Most architectures of those devices incorporate large bandgap insulator – hBN as an encapsulating or tunnel barrier layers. Here, we use an architecture of gated vertical tunnelling transistors to study a generic phenomenon of electron resonant tunnelling through adjacent localised electronic states in hBN barriers. We demonstrate that in the case of two localised electronic states, the tunnelling can be of inelastic nature giving rise to explicitly strong resonant features. It allows accurate tunnelling spectroscopy of delicate features of emitting and collecting layer electronic density of states, such as second neutrality point bandgap of moiré monolayer and electric field induced bandgap of Bernal bilayer graphene. Our findings enrich the perception of interaction mechanisms among the localised electronic states in hBN barriers paving the way for future explorations into their applications.

Development and Blood–Brain Barrier Penetration of Nanovesicles Loaded with Cannabidiol

Background: Cannabidiol (CBD) is a highly lipophilic compound with potential therapeutic applications in neurological disorders. However, its poor aqueous solubility and bioavailability, coupled with instability in physiological conditions, significantly limit its clinical use. Objectives: This study aimed to develop and characterize nanovesicles incorporating Tween 20 to enhance CBD encapsulation, stability, and the performance across the blood–brain barrier (BBB). Methods: Nanovesicles were prepared via thin-film hydration followed by sonication and optimized for size, polydispersity index, and zeta potential. Stability studies were conducted under physiological conditions and during storage at 4 °C. In vitro release studies employed the dialysis bag method, while permeability across the BBB was assessed using PAMPA-BBB and the hCMEC/D3-BBB cell line, characterized for brain endothelial phenotype and largely employed as a model of human blood–brain barrier (BBB) function. Cytotoxicity was evaluated via MTT and LDH assays. Results: The quantification of CBD was carried out by HPLC-DAD and HPLC-MS/MS. Nanovesicles with Tween 20 (VS-CBD) exhibited smaller size (65.27 ± 1.27 nm vs. 90.7 ± 0.2), lower polydispersity (0.230 ± 0.005 vs. 0.295 ± 0.003), and higher stability compared to conventional liposomes (L-CBD). VS-CBD achieved high encapsulation efficiency (96.80 ± 0.96%) and recovery (99.89 ± 0.52%). Release studies showed sustained CBD release with Higuchi model fitting (R2 = 0.9901). Both PAMPA-BBB and hCMEC/D3-BBB cell lines demonstrated an improved controlled permeability of the formulation compared to free CBD. Cytotoxicity tests confirmed the good biocompatibility of VS-CBD formulations. The addition of Tween 20 to nanovesicles enhanced CBD encapsulation, stability, and controlled release. Conclusions: These nanovesicles represent a promising strategy to improve CBD delivery to the brain, offering sustained therapeutic effects and reduced dosing frequency, potentially benefiting the treatment of neurological disorders.

Synthesis and Biological Evaluation of Peripheral HTR2A Antagonists for Colorectal Cancer.

Colorectal cancer is a prevalent and prominent contributor to global cancer-related fatalities with challenges in drug resistance and metastasis. Recent research highlights the potential relationship between serotonin and cancer. 5-Hydroxytryptamine receptor 2A (HTR2A) mRNA expression in colorectal cancer cells was found to be notably elevated compared to that in normal colon cells. We therefore attempted to synthesize and evaluate HTR2A antagonists to find peripherally acting anticancer agents. Among them, 15f showed good in vitro activity (IC50: 42.79 nM). 15f revealed good liver microsomal stability, without significant CYP inhibition and limited blood-brain barrier penetration. 15f also exerted selective cytotoxic effects against various colorectal cancer cells but not normal cells. 15f induced sub-G1 cell cycle arrest and apoptosis in colorectal cancer cells via the activation of p53/p21/caspase 3 signaling. In vivo treatment with 15f led to a marked delay in tumor growth in a colorectal cancer model in a dose-dependent manner.

Double-sided van der Waals epitaxy of topological insulators across an atomically thin membrane.

Atomically thin van der Waals (vdW) films provide a material platform for the epitaxial growth of quantum heterostructures. However, unlike the remote epitaxial growth of three-dimensional bulk crystals, the growth of two-dimensional material heterostructures across atomic layers has been limited due to the weak vdW interaction. Here we report the double-sided epitaxy of vdW layered materials through atomic membranes. We grow vdW topological insulators Sb2Te3 and Bi2Se3 by molecular-beam epitaxy on both surfaces of atomically thin graphene or hexagonal boron nitride, which serve as suspended two-dimensional vdW substrate layers. Both homo- and hetero-double-sided vdW topological insulator tunnel junctions are fabricated, with the atomically thin hexagonal boron nitride acting as a crystal-momentum-conserving tunnelling barrier with abrupt and epitaxial interfaces. By performing field-angle-dependent magneto-tunnelling spectroscopy on these devices, we reveal the energy-momentum-spin resonance of massless Dirac electrons tunnelling between helical Landau levels developed in the topological surface states at the interfaces.

Repurposing Linezolid in Conjunction with Histone Deacetylase Inhibitor Access in the Realm of Glioblastoma Therapies.

Since decades after temozolomide was approved, no effective drugs have been developed. Undoubtedly, blood-brain barrier (BBB) penetration is a severe issue that should be overcome in glioblastoma multiforme (GBM) drug development. In this research, we were inspired by linezolid through structural modification with several bioactive moieties to achieve the desired brain delivery. The results indicated that the histone deacetylase modification, referred to as compound 1, demonstrated promising cytotoxic effects in various brain tumor cell lines. Further comprehensive mechanism studies indicated that compound 1 induced acetylation, leading to DNA double-strand breaks, and induced the ubiquitination of RAD51, disrupting the DNA repair process. Furthermore, compound 1 also exhibited dramatic improvement in the orthotopic GBM mouse model, demonstrating its efficacy and satisfying BBB penetration. Therefore, the reported compound 1, provided with an independent therapeutic pathway, satisfying elongation in survival and tumor size reduction, and the ability to penetrate the BBB, was potent to achieve further development.

Development of Off-On Near-Infrared Fluorescent Probes for Sensitive In Vivo Imaging of Amyloid-β Species with Enhanced Pharmacokinetics.

The fluorescent imaging of pathologically accumulated β-amyloid (Aβ) proteins is of significant importance to the diagnosis of Alzheimer's disease (AD). In the paper, we prepare two new NIR probes, NIR-1 and NIR-2, through hydrophilic modification of introducing water-soluble bioactive groups such as polyethylene glycol (PEG) and morpholine to tune in vivo pharmacokinetics for specific detection of soluble and insoluble Aβ species. The in vitro assessments confirm that both NIR-1 and NIR-2 display strong near-infrared (NIR) fluorescence (FL) enhancement upon interaction with Aβ42 monomers, oligomers or aggregates (λem>670 nm) and show highly sensitive, rapid and selective response towards Aβ42 species. After i. v. injection, each probe showed fast blood-brain barrier (BBB) penetration and immediately produced intense FL signals in the brain of APP/PS1 AD model mice at 10 min. Moreover, compared with NIR-2, NIR-1 bearing a hydrophilic PEG chain displayed not only more rapid clearance but also lower background signal to efficiently distinguish APP/PS1 mice and wild-type mice with higher signal-to-background ratio, which was further validated by ex vivo histological staining of brain tissues. Therefore, due to its excellent pharmacokinetics, NIR-1 shows great promise as an effective NIR probe for specific detection of Aβ species.

Prolonged complete response to adjuvant tepotinib in a patient with newly diagnosed disseminated glioblastoma harboring mesenchymal-epithelial transition fusion.

The prognosis of patients with glioblastoma (GBM) remains poor despite current treatments. Targeted therapy in GBM has been the subject of intense investigation but has not been successful in clinical trials. The reasons for the failure of targeted therapy in GBM are multifold and include a lack of patient selection in trials, the failure to identify driver mutations, and poor blood-brain barrier penetration of investigational drugs. Here, we describe a case of a durable complete response in a newly diagnosed patient with GBM with leptomeningeal dissemination and PTPRZ1-MET fusion who was treated with tepotinib, a brain-penetrant MET inhibitor. This case of successful targeted therapy in a patient with GBM demonstrates that early molecular testing, identification of driver molecular alterations, and treatment with brain-penetrant small molecule inhibitors have the potential to change the outcome in select patients with GBM.

Hybrid Membrane Biomimetic Photothermal Nanorobots for Enhanced Chemodynamic-Chemotherapy-Immunotherapy.

Glioblastoma multiforme (GBM) is a highly invasive and fatal brain tumor with a grim prognosis, where current treatment modalities, including postoperative radiotherapy and temozolomide chemotherapy, yield a median survival of only 15 months. The challenges of tumor heterogeneity, drug resistance, and the blood-brain barrier necessitate innovative therapeutic approaches. This study introduces a strategy employing biomimetic magnetic nanorobots encapsulated with hybrid membranes derived from platelets and M1 macrophages to enhance blood-brain barrier penetration and target GBM. The nanorobots encapsulate a polypyrrole/Fe3O4 nanocomplex (PPy@F) for photothermal therapy (PTT) and promote the Fenton reaction of Fe3O4 to generate chemodynamic therapy (CDT). Additionally, temozolomide and PD-L1 antibody (SNTSESF) act as chemotherapy drug and immune checkpoint inhibitor, respectively. The biomimetic design leverages the functional properties of cell membranes to improve the blood residence time and tumor targeting. The integration of PTT and CDT aims to transform "cold" tumors into "hot" tumors, thereby enhancing immunotherapeutic efficacy. This multifaceted approach, PTT, CT, CDT, and immune checkpoint blockade therapy, offers a promising strategy for the treatment of GBM.

Targeting Soluble Amyloid Oligomers in Alzheimer's Disease: A Hypothetical Model Study Comparing Intrathecal Pseudodelivery of mAbs Against Intravenous Administration.

Neurotoxic soluble amyloid-β (Aβ) oligomers are key drivers of Alzheimer's pathology, with evidence suggesting that early targeting of these soluble forms may slow disease progression. Traditional intravenous (IV) monoclonal antibodies (mAbs) face challenges, including limited brain penetration and risks such as amyloid-related imaging abnormalities (ARIA). This hypothetical study aimed to model amyloid dynamics in early-to-moderate Alzheimer's disease (AD) and compare the efficacy of IV mAn with intrathecal pseudodelivery, a novel method that confines mAbs in a subcutaneous reservoir for selective amyloid clearance in cerebrospinal fluid (CSF) without systemic exposure. A mathematical framework was employed to simulate Aβ dynamics in patients with early-to-moderate AD. Two therapeutic approaches were compared: IV mAb and intrathecal pseudodelivery of mAb. The model incorporated amyloid kinetics, mAb affinity, protofibril size, and therapy-induced clearance rates to evaluate the impact of both methods on amyloid reduction, PET negativity timelines, and the risk of ARIA. Intrathecal pseudodelivery significantly accelerated Aβ clearance compared to IV administration, achieving amyloid PET scan negativity by month 132, as opposed to month 150 with IV mAb. This method demonstrated no ARIA risk and reduced amyloid reaccumulation. By targeting soluble Aβ species more effectively, intrathecal pseudodelivery emerged as a safer and more efficient strategy for early AD intervention. Intrathecal pseudodelivery offers a promising alternative to IV mAbs, overcoming challenges associated with blood-brain barrier penetration and systemic side effects. Further research should focus on optimizing this approach and exploring combination therapies to enhance clinical outcomes in AD.

Size effect-based improved antioxidant activity of selenium nanoparticles regulating Anti-PI3K-mTOR and Ras-MEK pathways for treating spinal cord injury to avoid hormone shock-induced immunosuppression

Spinal cord injury (SCI) is a critical condition affecting the central nervous system that often has permanent and debilitating consequences, including secondary injuries. Oxidative damage and inflammation are critical factors in secondary pathological processes. Selenium nanoparticles have demonstrated significant antioxidative and anti-inflammatory properties via a non-immunosuppressive pathway; however, their clinical application has been limited by their inadequate stability and functionality to cross the blood-spinal cord barrier (BSCB). This study proposed a synthesis method for ultra-small-diameter lentinan Se nanoparticles (LNT-UsSeNPs) with significantly superior reactive oxygen species (ROS) scavenging capabilities compared to conventional lentinan Se nanoparticles (LNT-SeNPs). These compounds effectively protected PC-12 cells from oxidative stress-induced cytotoxicity, alleviated mitochondrial dysfunction, reduced apoptosis. In vivo studies indicated that LNT-UsSeNPs efficiently penetrated the BSCB and effectively inhibited the apoptosis of spinal neurons. Ultimately, LNT-UsSeNPs directly regulated the PI3K-AKT-mTOR and Ras-Raf-MEK-ERK signaling pathways by regulating selenoproteins to achieve non-immunosuppressive anti-inflammatory therapy. Owing to their ultra-small size, LNT-UsSeNPs exhibited strong spinal barrier penetration and potent antioxidative and anti-inflammatory effects without compromising immune function. These findings suggest that LNT-UsSeNPs are promising candidates for further development in nanomedicine for the effective treatment of SCI.Graphical abstract