Developing effective drugs for Alzheimer's disease (AD), the most common cause of dementia, has been difficult because of complicated pathogenesis. Here, we report an efficient, network-based ...drug-screening platform developed by integrating mathematical modeling and the pathological features of AD with human iPSC-derived cerebral organoids (iCOs), including CRISPR-Cas9-edited isogenic lines. We use 1300 organoids from 11 participants to build a high-content screening (HCS) system and test blood-brain barrier-permeable FDA-approved drugs. Our study provides a strategy for precision medicine through the convergence of mathematical modeling and a miniature pathological brain model using iCOs.
Alzheimer's disease (AD) is an age‐related neurodegenerative disease. The most common pathological hallmarks are amyloid plaques and neurofibrillary tangles in the brain. In the brains of patients ...with AD, pathological tau is abnormally accumulated causing neuronal loss, synaptic dysfunction, and cognitive decline. We found a histone deacetylase 6 (HDAC6) inhibitor, CKD‐504, changed the tau interactome dramatically to degrade pathological tau not only in AD animal model (ADLPAPT) brains containing both amyloid plaques and neurofibrillary tangles but also in AD patient‐derived brain organoids. Acetylated tau recruited chaperone proteins such as Hsp40, Hsp70, and Hsp110, and this complex bound to novel tau E3 ligases including UBE2O and RNF14. This complex degraded pathological tau through proteasomal pathway. We also identified the responsible acetylation sites on tau. These dramatic tau‐interactome changes may result in tau degradation, leading to the recovery of synaptic pathology and cognitive decline in the ADLPAPT mice.
In AD, as overall level of acetylation is down‐regulated, interactions of tau with indicated chaperones and E3 ligases may be insufficient to degrade pathologic tau and hardly degraded by UPS and become aggregated. CKD‐504, an HDAC6 inhibitor, elevates interactions of tau with chaperones and E3 ligases through increasing acetylation of each protein, resulting in ubiquitination and degradation of tau by UPS. Finally, degradation of tau rescues cognitive impairment in AD model mice.
Virtual reality (VR) is a promising solution for individuals with Parkinson's disease (PD) who experience symptoms that affect their daily activities and independence. Through VR-based ...rehabilitation, patients can improve their motor skills in a safe and stress-free environment, making it an attractive alternative to traditional in-person rehabilitation during the COVID-19 pandemic. This study aimed to provide the most recent and convincing evidence on the rehabilitative effects of VR technology compared with conventional treatments.
Two investigators systematically searched Embase, MEDLINE, CINAHL, PEDro, and the Cochrane Library from their inception until May 31, 2022, to identify randomized controlled trials (RCTs) comparing the effectiveness of VR training with that of conventional treatment for patients with PD. Studies were selected based on the patient, intervention, comparator, and outcome criteria and assessed for the risk of bias using the Cochrane tool. Meta-analysis was conducted by pooling mean differences with 95% confidence intervals.
A total of 14 RCTs, involving 524 participants, were included in the meta-analysis. The results indicated that VR-based rehabilitation significantly improved balance function, as measured using the Berg balance scale (BBS) and activities-specific balance confidence. However, no statistically significant differences in gait ability, activities of daily living, motor function, and quality of life were observed between the experimental and control groups. Subgroup analysis revealed that combination therapy affected heterogeneity in the BBS analysis. Meta-regression analysis demonstrated a significant positive relationship, indicating that more recent studies have shown greater improvements in balance function.
This study's findings suggest that VR-based rehabilitation is a promising intervention for improving balance function in patients for PD compared with conventional treatment, and recent research supports its efficacy. However, future research should focus on conducting long-term follow-up studies and developing standardized protocols to comprehensively establish this intervention's potential benefits.
Piezo channels are mechanosensitive ion channels. Piezo1 is primarily expressed in nonsensory tissues, whereas Piezo2 is predominantly found in sensory tissues, including dorsal root ganglion (DRG) ...neurons. However, a recent study demonstrated the intracellular calcium response to Yoda1, a selective Piezo1 agonist, in trigeminal ganglion (TG) neurons. Herein, we investigate the expression of
mRNA and protein in mouse and human DRG neurons and the activation of Piezo1 via calcium influx by Yoda1. Yoda1 induces inward currents mainly in small- (< 25 μm) and medium-sized (25-35 μm) mouse DRG neurons. The Yoda1-induced Ca
response is inhibited by cationic channel blocker, ruthenium red and cationic mechanosensitive channel blocker, GsMTx4. To confirm the specific inhibition of Piezo1, we performed an adeno-associated virus serotype 2/5 (AAV2/5)-mediated delivery of short hairpin RNA (shRNA) into mouse DRG neurons. AAV2/5 transfection downregulates
mRNA expression and reduces Ca
response by Yoda1. Piezo1 also shows physiological functions with transient receptor potential vanilloid 1 (TRPV1) in the same DRG neurons and is regulated by the activation of TRPV1 in mouse DRG sensory neurons. Overall, we found that Piezo1 has physiological functions in DRG neurons and that TRPV1 activation inhibits an inward current induced by Yoda1.
Owing to the hasty growth of communication technologies in the Underwater Internet of Things (UIoT), many researchers and industries focus on enhancing the existing technologies of UIoT systems for ...developing numerous applications such as oceanography, diver networks monitoring, deep-sea exploration and early warning systems. In a constrained UIoT environment, communication media such as acoustic, infrared (IR), visible light, radiofrequency (RF) and magnet induction (MI) are generally used to transmit information via digitally linked underwater devices. However, each medium has its technical limitations: for example, the acoustic medium has challenges such as narrow-channel bandwidth, low data rate, high cost, etc., and optical medium has challenges such as high absorption, scattering, long-distance data transmission, etc. Moreover, the malicious node can steal the underwater data by employing blackhole attacks, routing attacks, Sybil attacks, etc. Furthermore, due to heavyweight, the existing privacy and security mechanism of the terrestrial internet of things (IoT) cannot be applied directly to UIoT environment. Hence, this paper aims to provide a systematic review of recent trends, applications, communication technologies, challenges, security threats and privacy issues of UIoT system. Additionally, this paper highlights the methods of preventing the technical challenges and security attacks of the UIoT environment. Finally, this systematic review contributes much to the profit of researchers to analyze and improve the performance of services in UIoT applications.
Targeted protein degradation allows targeting undruggable proteins for therapeutic applications as well as eliminating proteins of interest for research purposes. While several degraders that harness ...the proteasome or the lysosome have been developed, a technology that simultaneously degrades targets and accelerates cellular autophagic flux is still missing. In this study, we develop a general chemical tool and platform technology termed AUTOphagy-TArgeting Chimera (AUTOTAC), which employs bifunctional molecules composed of target-binding ligands linked to autophagy-targeting ligands. AUTOTACs bind the ZZ domain of the otherwise dormant autophagy receptor p62/Sequestosome-1/SQSTM1, which is activated into oligomeric bodies in complex with targets for their sequestration and degradation. We use AUTOTACs to degrade various oncoproteins and degradation-resistant aggregates in neurodegeneration at nanomolar DC
values in vitro and in vivo. AUTOTAC provides a platform for selective proteolysis in basic research and drug development.
Zeolitic imidazolate frameworks (ZIFs) are a subclass of metal–organic frameworks (MOFs). These robust, porous materials have garnered significant interest because of their outstanding properties as ...catalysts for the oxygen evolution reaction (OER) and oxygen reduction reaction (ORR). Herein, the synthesis of Co‐ and Ni‐containing ZIF‐67 embedded in carbon nanotubes (CNTs) to be used as a cathode material for rechargeable zinc–air batteries is described. Carbon‐nanotube‐encapsulated metallic Co and Ni form via calcination of the MOF at 700 °C for 4 h and are characterized by X‐ray diffraction and transmission electron microscopy (TEM). Co and Ni graphitization within the CNTs is analyzed by Raman spectroscopy, and morphologies are assessed by scanning electron microscopy (SEM) and TEM. Excellent electrochemical performance of the prepared catalysts during charging and discharging reveals that the catalyst is stable for well over 500 h. Moreover, superior OER performance is observed when CNT@Co or CNT@Ni is used as a bifunctional catalyst in the zinc–air battery.
Co or Ni encapsulated in the carbon nanotubes CNT@(Co or Ni) was obtained via calcination of Co‐ and Ni‐ZIF‐67. The porous CNT@(Co or Ni) exhibits superior electrochemical performance when used as a cathode material for oxygen reduction reaction (ORR) and oxygen evolution reaction (OER).
Osteoporosis has a complex etiology and is considered a multifactorial polygenic disease, in which genetic determinants are modulated by hormonal, lifestyle, environmental, and nutritional factors. ...Therefore, investigating these multiple factors, and the interactions between them, might lead to a better understanding of osteoporosis pathogenesis, and possible therapeutic interventions. The objective of this study was to identify the relationship between three blood metals (Pb, Cd, and Al), in smoking and nonsmoking patients' sera, and prevalence of osteoporosis. In particular, we focused on gene-environment interactions of metal exposure, including a dataset obtained through genome-wide association study (GWAS). Subsequently, we conducted a pathway-based analysis, using a GWAS dataset, to elucidate how metal exposure influences susceptibility to osteoporosis. In this study, we evaluated blood metal exposures for estimating the prevalence of osteoporosis in 443 participants (aged 53.24 ± 8.29), from the Republic of Korea. Those analyses revealed a negative association between lead blood levels and bone mineral density in current smokers (p trend <0.01). By further using GWAS-based pathway analysis, we found nuclear receptor (FDR<0.05) and VEGF pathways (FDR<0.05) to be significantly upregulated by blood lead burden, with regard to the prevalence of osteoporosis, in current smokers. These findings suggest that the intracellular pathways of angiogenesis and nuclear hormonal signaling can modulate interactions between lead exposure and genetic variation, with regard to susceptibility to diminished bone mineral density. Our findings may provide new leads for understanding the mechanisms underlying the development of osteoporosis, including possible interventions.
β‐Catenin is a central player in Wnt signaling, and activation of Wnt signaling is associated with cancer development. E‐cadherin in complex with β‐catenin mediates cell–cell adhesion, which ...suppresses β‐catenin‐dependent Wnt signaling. Recently, a tumor‐suppressive role for E‐cadherin has been reconsidered, as re‐expression of E‐cadherin was reported to enhance the metastatic potential of malignant tumors. To explore the role of E‐cadherin, we established an E‐cadherin‐expressing cell line, EC96, from AGS cells that featured undetectable E‐cadherin expression and a high level of Wnt signaling. In EC96 cells, E‐cadherin re‐expression enhanced cell proliferation, although Wnt signaling activity was reduced. Subsequent analysis revealed that nuclear factor‐κB (NF‐κB) activation and consequent c‐myc expression might be involved in E‐cadherin expression‐mediated cell proliferation. To facilitate rapid proliferation, EC96 cells enhance glucose uptake and produce ATP using both mitochondria oxidative phosphorylation and glycolysis, whereas AGS cells use these mechanisms less efficiently. These events appeared to be mediated by NF‐κB activation. Therefore, E‐cadherin re‐expression and subsequent induction of NF‐κB signaling likely enhance energy production and cell proliferation.
E‐cadherin re‐expression enhanced cell proliferation, although Wnt signaling activity was reduced. To facilitate rapid proliferation, EC96 cells enhance glucose uptake and produce ATP using both mitochondria OXPHOS and glycolysis, whereas AGS cells utilize these mechanisms less efficiently. E‐cadherin re‐expression and subsequent induction of NF‐kappaB signaling likely enhance energy production and cell proliferation.
Lean-burn combustion technology is generally conceived to improve the thermal efficiency of spark ignition (SI) engines. Such an improved efficiency mitigates CO2 emission, and thus, the lean-burn ...technology helps transition toward a carbon-neutral society. However, it is required to limit the NOx emission at the same time by extending a lean limit as much as possible to lower the flame temperature. Recently, stretched sparks caused by a high-intensity tumble flow have been found to significantly extend a lean-burn limit and shorten an overall combustion duration. Here, we presented an experimental study to better understand the underlying mechanism of the stretched spark for the ignition of lean mixtures. We conceived a spark-to-piston concept and configured a pin-to-disk electrode inside a small combustion chamber introducing an adjustable interelectrode gap. As the interelectrode gap increased, a lean limit for a complete burning regime was extended, and the combustion duration was shortened. A negative applied voltage to the pin-electrode facilitated the extension of the lean limit and a faster combustion for a larger gap compared to a positive one. The effect of a tumble flow mimicked by a high-speed jet on the lean limit and the combustion duration were also investigated. A stretched spark, due to its gliding root on the disk-electrode, extended the lean limit, and the high-speed jet shortened the combustion duration. The restrike phenomenon could not be observed in the present configuration, indicating a minimized cyclic variation due to misfire.
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