Presynaptic structural and functional plasticity are coupled by convergent Rap1 signaling.

Dynamic presynaptic actin remodeling drives structural and functional plasticity at synapses, but the underlying mechanisms remain largely unknown. Previous work has shown that actin regulation via Rac1 guanine exchange factor (GEF) Vav signaling restrains synaptic growth via bone morphogenetic protein (BMP)-induced receptor macropinocytosis and mediates synaptic potentiation via mobilization of reserve pool vesicles in presynaptic boutons. Here, we find that Gef26/PDZ-GEF and small GTPase Rap1 signaling couples the BMP-induced activation of Abelson kinase to this Vav-mediated macropinocytosis. Moreover, we find that adenylate cyclase Rutabaga (Rut) signaling via exchange protein activated by cAMP (Epac) drives the mobilization of reserve pool vesicles during post-tetanic potentiation (PTP). We discover that Rap1 couples activation of Rut-cAMP-Epac signaling to Vav-mediated synaptic potentiation. These findings indicate that Rap1 acts as an essential, convergent node for Abelson kinase and cAMP signaling to mediate BMP-induced structural plasticity and activity-induced functional plasticity via Vav-dependent regulation of the presynaptic actin cytoskeleton.

Exposure and risk assessment for agricultural workers during chlorothalonil and flubendiamide treatments in pepper fields.

Pesticides are indispensable tools in modern agriculture for enhancing crop productivity. However, the inherent toxicity of pesticides raises significant concerns regarding human exposure, particularly among agricultural workers. This study investigated the exposure and associated risks of two commonly used pesticides in open-field pepper cultivation, namely, chlorothalonil and flubendiamide, in the Republic of Korea. We used a comprehensive approach, encompassing dermal and inhalation exposure measurements in agricultural workers during two critical scenarios: mixing/loading and application. Results revealed that during mixing/loading, dermal exposure to chlorothalonil was 3.33 mg (0.0002% of the total active ingredient [a.i.]), while flubendiamide exposure amounted to 0.173 mg (0.0001% of the a.i.). Conversely, dermal exposure increased significantly during application to 648 mg (chlorothalonil) and 93.1 mg (flubendiamide), representing 0.037% and 0.065% of the total a.i., respectively. Inhalation exposure was also evident, with chlorothalonil and flubendiamide exposure levels varying across scenarios. Notably, the risk assessment using the Risk Index (RI) indicated acceptable risk of exposure during mixing/loading but raised concerns during application, where all RIs exceeded 1, signifying potential risk. We suggest implementing additional personal protective equipment (PPE) during pesticide application, such as gowns and lower-body PPE, to mitigate these risks.

Central Nervous System Dissemination of Solitary Sporadic Supratentorial Hemangioblastoma: A Case Report and Literature Review.

We report a patient with whole neuroaxis dissemination of a sporadic supratentorial hemangioblastoma (HB) for more than 15 years. A 68-year-old female patient presented with severe radiating pain in the right leg. Gadolinium-enhanced lumbar spine MRI showed an intradural mass (2.5 cm in diameter) at the L4 level. The patient had been severely disabled for 22 years after a previous intraventricular brain tumor resection. At that time, the diagnosis was angioblastic meningioma, which was thought to be incorrect. At 14 years after the brain surgery, gamma knife radiosurgery was performed three times for newly developed or recurred supratentorial and infratentorial tumors in the cerebrospinal fluid pathway. The patient underwent lumbar spinal surgery, and a gross total removal of the mass was performed, which confirmed the histopathological diagnosis of HB. We reexamined the old histopathological specimen of the intraventricular tumor from 20 years ago and changed the diagnosis from angioblastic meningioma to supratentorial HB. Six months after spinal surgery, the patient underwent a second spinal surgery and brain surgery, and the histopathological diagnosis was HB following both surgeries, which was the same following the first spinal surgery. Here, we report a sporadic supratentorial HB patient who showed cranial and spinal disseminations for more than two decades along with a literature review.

Two-Day Fraction Gamma Knife Radiosurgery for Large Brain Metastasis.

Objective: We investigated how treating large brain metastasis (LBM) using two-day fraction gamma knife radiosurgery (GKRS) affects tumor control and patient survival. A prescription dose of 10.3 Gy was applied for two consecutive days, with a biologically effective dose (BED) equivalent to a tumor single-fraction dose of 16.05 Gy and a brain single-fraction dose of 15.12 Gy. Methods: Between November 2017 and December 2021, 42 patients (mean age: 68.3 years, range: 50-84 years, male: 29 [69.1%], female: 13 [30.9%]) with 44 tumors underwent two-day fraction GKRS to treat large volume brain metastasis. The main cancer types were non-small cell lung cancer (NSCLC, N=16), small cell lung cancer (SCLC, N=7), colorectal cancer (N=7), breast cancer (N=3), gastric cancer (N=2), and other cancers (N=7). Twenty-one (50.0%) patients had a single LBM, nineteen (46.3%) had a single LBM and other metastasi(e)s, and two had two (4.7%) large brain metastases. At the time of the two-day fraction GKRS, the tumors had a mean volume of 23.1 cc (range: 12.5-67.4). on each day, radiation was administered at a dose of 10.3 Gy, mainly using a 50% isodose-line. Results: We obtained clinical and magnetic resonance imaging (MRI) follow-up data for 34 patients (81%) with 35 tumors, who had undergone two-day fraction GKRS. These patients did not experience acute or late radiation-induced complications during follow-up. The median and mean progression-free survival (PFS) periods were 188 and 194 days, respectively. The local control rates at 6, 9, and 12 months were 77%, 40%, and 34%, respectively. The prognostic factors related to PFS were prior radiotherapy (P = 0.019) and lung cancer origin (P = 0.041). Other factors such as tumor volumes, each isodose volumes, and peri-GKRS systemic treatment were not significantly related to PFS. The overall survival period of the 44 patients following repeat SRS ranged from 15-878 days (median: 263±38 days, mean: 174±43) after the two-day fraction GKRS. Eight patients (18.2%) were still alive. Conclusion: Considering the unsatisfactory tumor control, a higher prescription dose should be needed in this procedure as a salvage management. Moreover, in the treatment for LBM with fractionated SRS, using different isodoses and prescription doses at the treatment planning for LBMs should be important. However, this report might be a basic reference with the same fraction number and prescription dose in the treatment for LBMs with frame-based SRS.

Colloidal Synthesis of Ultrathin and Se-Rich V2Se9 Nanobelts as High-Performance Anode Materials for Li-Ion Batteries.

In this study, the one-dimensional (1D) material V2Se9 was successfully synthesized using a colloidal method with VO(acac)2 and Se powder as precursors in a 1-octadecene solvent. The obtained colloidally synthesized V2Se9 (C-V2Se9) has an ultrathin nanobelt shape and a 4.5 times higher surface area compared with the bulk V2Se9, which is synthesized in a solid-state reaction as previously reported. In addition, all surfaces of C-V2Se9 are exposed to Se atoms, which is advantageous for storing Li through the conversion reaction into the Li2Se phase. Herein, the electrochemical performance of the C-V2Se9 anode material is evaluated; thus, the novelty of C-V2Se9 as a Se-rich 1D anode material is verified. The C-V2Se9 electrode exhibits a reversible capacity of 893.21 mA h g-1 and a Coulombic efficiency of 97.82% at the 100th cycle and excellent structural stability. Compared with the bulk V2Se9 electrode, the outstanding electrochemical performance of C-V2Se9 is attributed to its ultrathin nanobelt shape, high surface area, shorter Li diffusion length, and more electrochemically active sites. This work indicates the great potential of the Se-rich 1D material, C-V2Se9, as a post-transition metal dichalcogenide material for high-performance LIBs.

From the perspective of pseudo-progression rather than treatment failure, how long should we wait before considering treatment failure if large cystic enlargement occurs after Gamma Knife radiosurgery for vestibular schwannoma?: insight into pseudoprogression based on two case reports.

Gamma knife radiosurgery (GKRS) has been accepted as a safe and effective treatment for vestibular schwannoma (VS). However, during follow-up, tumor expansion induced by irradiation can occur, and diagnosis of failure in radiosurgery for VS is still controversial. Tumor expansion with cystic enlargement causes some confusion regarding whether further treatment should be performed. We analyzed more than 10 years of clinical findings and imaging of patients with VS with cystic enlargement after GKRS. A 49-year-old male with hearing impairment was treated with GKRS (12 Gy; isodose, 50%) for a left VS with a preoperative tumor volume of 0.8 cc. The tumor size increased with cystic changes from the third year after GKRS, reaching a volume of 10.8 cc at 5 years after GKRS. At the 6th year of follow-up, the tumor volume started to decrease, up to 0.3 cc by the 14th year of follow-up. A 52-year-old female with hearing impairment and left facial numbness was treated with GKRS for a left VS (13 Gy; isodose, 50%). The preoperative tumor volume was 6.3 cc, which started to increase with cystic enlargement from the first year after GKRS, and reaching 18.2 cc by 5 years after GKRS. The tumor maintained a cystic pattern with slight changes in size, but no other neurologic symptoms developed during the follow-up period. After 6 years of GKRS, tumor regression was observed, eventually reaching a volume of 3.2 cc by the 13th year of follow-up. In both cases, persistent cystic enlargement in VS was observed at 5 years after GKRS, after which the tumors began to stabilize. After more than 10 years of GKRS, the tumor volume was less than that before GKRS. Enlargement with large cystic formation in the first 3-5 years after GKRS has been considered as treatment failure. However, our cases show that further treatment for cystic enlargement should be deferred for at least 10 years, especially in patients without neurological deterioration, as inadequate surgery can be prevented within that period.

Development of a High-SNR Stochastic sEMG Processor in a Multiple Muscle Elbow Joint.

In the robotics and rehabilitation engineering fields, surface electromyography (sEMG) signals have been widely studied to estimate muscle activation and utilized as control inputs for robotic devices because of their advantageous noninvasiveness. However, the stochastic property of sEMG results in a low signal-to-noise ratio (SNR) and impedes sEMG from being used as a stable and continuous control input for robotic devices. As a traditional method, time-average filters (e.g., low-pass filters) can improve the SNR of sEMG, but time-average filters suffer from latency problems, making real-time robot control difficult. In this study, we propose a stochastic myoprocessor using a rescaling method extended from a whitening method used in previous studies to enhance the SNR of sEMG without the latency problem that affects traditional time average filter-based myoprocessors. The developed stochastic myoprocessor uses 16 channel electrodes to use the ensemble average, 8 of which are used to measure and decompose deep muscle activation. To validate the performance of the developed myoprocessor, the elbow joint is selected, and the flexion torque is estimated. The experimental results indicate that the estimation results of the developed myoprocessor show an RMS error of 6.17[%], which is an improvement with respect to previous methods. Thus, the rescaling method with multichannel electrodes proposed in this study is promising and can be applied in robotic rehabilitation engineering to generate rapid and accurate control input for robotic devices.

Proteomic analysis of zebrafish (Danio rerio) embryos exposed to benzyl benzoate.

Benzyl benzoate (BB) is widely used in the food, cosmetics, agriculture, and pharmaceutical industries and is discharged into the aquatic environment via various water sources, including wastewater. Research on the bioaccumulation and possible toxicity of BB has been conducted, but the biochemical responses to BB toxicity are not fully understood, and the specific molecular pathways by which BB causes toxicity remain unknown. In this study, label-free quantitative proteomics based on mass spectrometry was applied to investigate protein profiles in zebrafish (Danio rerio) embryos exposed to BB (1 µg/mL) for 7 days. A total of 83 differentially expressed proteins (DEPs) were identified, including 49 up-regulated and 34 down-regulated proteins. The biological functions of proteins regulated by BB were grouped into functional categories and subcategories, including the biosynthesis of organonitrogen compound biosynthetic process, translation, amide biosynthetic process, lipid transport, stress response, and cytoskeletal activity. The results provide novel insight into the molecular basis of the ecotoxicity of BB in aquatic ecosystems.

Residue Behavior of Methoxyfenozide and Pymetrozine in Chinese Cabbage and Their Health Risk Assessment.

Methoxyfenozide and pymetrozine are used for pest control in the cultivation of Chinese cabbage. This has raised concerns in recent years due to health risks. Therefore, this study aimed to determine the residual concentrations of pesticides in the target crop and associated health risks. The dynamics and influence of environmental factors on the dissipation of methoxyfenozide and pymetrozine residues in Chinese cabbage were investigated. Analyses were performed using a modified QuEchERS (Quick, Easy, Cheap, Effective, Rugged, and Safe) and an optimized high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). The observed half-lives of methoxyfenozide and pymetrozine in cabbage samples ranged between two sampling seasons: in May−June, half-lives of methoxyfenozide and pymetrozine were 1.20 days and 1.89 days, respectively; during October−November, half-lives of methoxyfenozide and pymetrozine were 11.8 and 2.80 days, respectively. Meanwhile, a negative Spearman correlation was found between the residual concentrations and temperature (p < 0.01). This indicates that higher temperatures resulted in higher dissipation rates for methoxyfenozide and pymetrozine, suggesting that these pesticides degraded faster at higher temperatures. Additionally, higher pesticide residues in Chinese cabbage during low-temperature seasons resulted in higher risk quotients (RQ) (RQ > 1) for both analyzed compounds, which suggests that the effect of temperature on pesticide degradation needs to be considered as an essential factor while setting up the maximum residue limits (MRL).

Vav independently regulates synaptic growth and plasticity through distinct actin-based processes.

Modulation of presynaptic actin dynamics is fundamental to synaptic growth and functional plasticity; yet the underlying molecular and cellular mechanisms remain largely unknown. At Drosophila NMJs, the presynaptic Rac1-SCAR pathway mediates BMP-induced receptor macropinocytosis to inhibit BMP growth signaling. Here, we show that the Rho-type GEF Vav acts upstream of Rac1 to inhibit synaptic growth through macropinocytosis. We also present evidence that Vav-Rac1-SCAR signaling has additional roles in tetanus-induced synaptic plasticity. Presynaptic inactivation of Vav signaling pathway components, but not regulators of macropinocytosis, impairs post-tetanic potentiation (PTP) and enhances synaptic depression depending on external Ca2+ concentration. Interfering with the Vav-Rac1-SCAR pathway also impairs mobilization of reserve pool (RP) vesicles required for tetanus-induced synaptic plasticity. Finally, treatment with an F-actin-stabilizing drug completely restores RP mobilization and plasticity defects in Vav mutants. We propose that actin-regulatory Vav-Rac1-SCAR signaling independently regulates structural and functional presynaptic plasticity by driving macropinocytosis and RP mobilization, respectively.

Understanding the Structural Collapse during Activation of Metal-Organic Frameworks with Copper Paddlewheels.

Many metal-organic frameworks (MOFs) suffer from stability issues as they can be easily amorphized from various external stimuli. In particular, it is common to observe structural collapse during the activation process of removing the synthesis solvent. In this study, we conduct high-throughput computational analysis that focuses on the activation status of MOFs that possess copper paddlewheel metal nodes. From the analysis, various mechanical properties (e.g., bulk, Young's, and shear moduli) were found to be good predictors for collapse. Furthermore, we have identified anomaly MOFs with good mechanical stability that were previously reported to collapse. Accordingly, the activation process was reattempted with improved techniques, and one of these MOFs was successfully activated.

Elevation of phospholipase C-ß1 expression by amyloid-ß facilitates calcium overload in neuronal cells.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia. Amyloid-ß (Aß) has long been considered a key cause of neurodegeneration in the AD brain. Although the mechanisms underlying Aß-induced neurodegeneration are not fully understood, a number of recent studies have suggested that intracellular calcium overload mediates this process. In this study, we focused on the cellular function of phospholipase C-ß1 (PLCB1), which regulates calcium signaling by mediating hydrolysis of phosphatidylinositol 4,5-bisphosphate through G-protein coupled receptor pathways. First, we confirmed that acetylcholine-induced calcium release from intracellular stores of SH-SY5Y cells was significantly increased with Aß42 oligomer treatment. We further found that PLCB1 expression was upregulated in Aß42-treated cells, and PLCB1 overexpression in SH-SY5Y cells elicited the calcium overload observed in Aß-treated cells. In addition, Aß42 oligomer-induced calcium overload in SH-SY5Y cells was alleviated by knockdown of PLCB1, indicating that PLCB1 plays an essential role in the neurotoxic process initiated by Aß. The elevation of PLCB1 expression was confirmed in the brain tissues from the 5× familial AD (5×FAD) model mice. These findings suggest that PLCB1 may represent a potential therapeutic target for protecting neuronal cells against excitotoxicity in AD progression.

Modulating Energetic Characteristics of Multicomponent 1D Coordination Polymers: Interplay of Metal-Ligand Coordination Modes.

The energetic properties of multicomponent explosive materials can be altered for high detonation capabilities and minimized safety risk by changing their building components. We synthesized energetic coordination polymers (ECPs) using a 5,5'-bis(tetrazole)-1,1'-diolate linker and a N,N-dimethylacetamide (DMA) solvent, together with Cu and Mn metal cations. The new compounds, ECP-1 and ECP-2, contain two different types of 1D chain structures, straight and helical. We have conducted comprehensive studies on these ECP structures, energetic properties, and sensitivity and found excellent insensitivity owing to the long chain-to-chain distances created by the DMA solvent molecules. The results indicate that the metals as well as solvents used are crucial components influencing both the structure and energetic properties.

Objective comparison of methods to decode anomalous diffusion.

Deviations from Brownian motion leading to anomalous diffusion are found in transport dynamics from quantum physics to life sciences. The characterization of anomalous diffusion from the measurement of an individual trajectory is a challenging task, which traditionally relies on calculating the trajectory mean squared displacement. However, this approach breaks down for cases of practical interest, e.g., short or noisy trajectories, heterogeneous behaviour, or non-ergodic processes. Recently, several new approaches have been proposed, mostly building on the ongoing machine-learning revolution. To perform an objective comparison of methods, we gathered the community and organized an open competition, the Anomalous Diffusion challenge (AnDi). Participating teams applied their algorithms to a commonly-defined dataset including diverse conditions. Although no single method performed best across all scenarios, machine-learning-based approaches achieved superior performance for all tasks. The discussion of the challenge results provides practical advice for users and a benchmark for developers.

Role of Zr6 Metal Nodes in Zr-Based Metal-Organic Frameworks for Catalytic Detoxification of Pesticides.

Pesticides are chemicals widely used for agricultural industry, despite their negative impact on health and environment. Although various methods have been developed for pesticide degradation to remedy such adverse effects, conventional materials often take hours to days for complete decomposition and are difficult to recycle. Here, we demonstrate the rapid degradation of organophosphate pesticides with a Zr-based metal-organic framework (MOF), showing complete degradation within 15 min. MOFs with different active site structures (Zr node connectivity and geometry) were compared, and a porphyrin-based MOF with six-connected Zr nodes showed remarkable degradation efficiency with half-lives of a few minutes. Such a high efficiency was further confirmed in a simple flow system for several cycles. This study reveals that MOFs can be highly potent heterogeneous catalysts for organophosphate pesticide degradation, suggesting that coordination geometry of the Zr node significantly influences the catalytic activity.

ALS2 regulates endosomal trafficking, postsynaptic development, and neuronal survival.

Mutations in the human ALS2 gene cause recessive juvenile-onset amyotrophic lateral sclerosis and related motor neuron diseases. Although the ALS2 protein has been identified as a guanine-nucleotide exchange factor for the small GTPase Rab5, its physiological roles remain largely unknown. Here, we demonstrate that the Drosophila homologue of ALS2 (dALS2) promotes postsynaptic development by activating the Frizzled nuclear import (FNI) pathway. dALS2 loss causes structural defects in the postsynaptic subsynaptic reticulum (SSR), recapitulating the phenotypes observed in FNI pathway mutants. Consistently, these developmental phenotypes are rescued by postsynaptic expression of the signaling-competent C-terminal fragment of Drosophila Frizzled-2 (dFz2). We further demonstrate that dALS2 directs early to late endosome trafficking and that the dFz2 C terminus is cleaved in late endosomes. Finally, dALS2 loss causes age-dependent progressive defects resembling ALS, including locomotor impairment and brain neurodegeneration, independently of the FNI pathway. These findings establish novel regulatory roles for dALS2 in endosomal trafficking, synaptic development, and neuronal survival.

Electrically Elicited Force Response Characteristics of Forearm Extensor Muscles for Electrical Muscle Stimulation-Based Haptic Rendering.

A haptic interface based on electrical muscle stimulation (EMS) has huge potential in terms of usability and applicability compared with conventional haptic interfaces. This study analyzed the force response characteristics of forearm extensor muscles for EMS-based haptic rendering. We introduced a simplified mathematical model of the force response, which has been developed in the field of rehabilitation, and experimentally validated its feasibility for haptic applications. Two important features of the force response, namely the peak force and response time, with respect to the frequency and amplitude of the electrical stimulation were identified by investigating the experimental force response of the forearm extensor muscles. An exponential function was proposed to estimate the peak force with respect to the frequency and amplitude, and it was verified by comparing with the measured peak force. The response time characteristics were also examined with respect to the frequency and amplitude. A frequency-dependent tendency, i.e., an increase in response time with increasing frequency, was observed, whereas there was no correlation with the amplitude. The analysis of the force response characteristics with the application of the proposed force response model may help enhance the fidelity of EMS-based haptic rendering.

miR-16-5p is upregulated by amyloid ß deposition in Alzheimer's disease models and induces neuronal cell apoptosis through direct targeting and suppression of BCL-2.

Alzheimer's disease (AD) is the most common form of dementia with irreversible neurodegeneration. Accumulation of amyloid beta (Aß) in the brain is considered to be a major cause of neuronal cell death in AD, but the neurotoxic mechanism of Aß is not yet fully understood. Here, we focused on the role of microRNAs (miRNAs) in Aß-induced neuronal cell death. In microarray and RT-qPCR analysis of plasma miRNAs obtained from 5 familiar AD mutations (5xFAD) and wild-type (WT) mice of various ages, miR-16-5p showed a significant age-related change that was accompanied by neuronal cell death in the brain tissue of 5xFAD mice. In addition, increased miR-16-5p was prominent near Aß plaque-deposition sites in 5xFAD mouse brains. Aß treatment induced miR-16-5p upregulation and apoptosis in primary cultured mouse cortical neurons and the SH-SY5Y human neuroblastoma cell line. In silico analysis and reporter gene assays indicated that miR-16-5p directly targets the mRNA encoding the anti-apoptotic factor, B cell lymphoma-2 (BCL-2), in the neuronal cell line. Overexpression of miR-16-5p in SH-SY5Y cells downregulated BCL-2 expression and induced apoptosis. These results collectively suggest that the miR-16-5p/BCL-2 axis plays an important role for neuronal cell apoptosis in AD.

Mechanical Effects of Cochlear Implants on Residual Hearing Loss: A Finite Element Analysis.

The effects of cochlear implants on residual hearing loss is investigated through a finite element model of human auditory periphery consisting of the cochlea and middle ear. The simulation results show that a round window stiffness is the dominant factor in residual hearing loss. The increased round window stiffness to five times caused over 4 dB residual hearing loss at low frequencies below 500 Hz. Without considering round window ossification, inserting a cochlear implant can show at most 4 dB difference of residual hearing loss in magnitude from the no-implant case although the cochlear implant's geometry and position has been varied. If the stiffness of the round window is the same, the simulation results suggest to use a thin-straight-cochlear implant inserted into the lateral side in order to preserve residual hearing at frequencies below 700 Hz. In addition, when the distance between the basilar membrane and a cochlear implant is closer, the residual hearing loss becomes severe at high frequencies above 1 kHz. The results would be helpful for choice of a cochlear implant depending on a patient's condition.