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Abstract Despite clinical data stretching over millennia, the neurobiological basis of the effectiveness of acupuncture in treating diseases of the central nervous system has remained elusive. Here, using an established model of acupuncture treatment in Parkinson's disease (PD) model mice, we show that peripheral acupuncture stimulation activates hypothalamic melanin‐concentrating hormone (MCH) neurons via nerve conduction. We further identify two separate neural pathways originating from anatomically and electrophysiologically distinct MCH neuronal subpopulations, projecting to the substantia nigra and hippocampus, respectively. Through chemogenetic manipulation specifically targeting these MCH projections, their respective roles in mediating the acupuncture‐induced motor recovery and memory improvements following PD onset are demonstrated, as well as the underlying mechanisms mediating recovery from dopaminergic neurodegeneration, reactive gliosis, and impaired hippocampal synaptic plasticity. Collectively, these MCH neurons constitute not only a circuit‐based explanation for the therapeutic effectiveness of traditional acupuncture, but also a potential cellular target for treating both motor and non‐motor PD symptoms.

Abstract Direct lineage reprogramming into dopaminergic (DA) neurons holds great promise for the more effective production of DA neurons, offering potential therapeutic benefits for conditions such as Parkinson's disease. However, the reprogramming pathway for fully reprogrammed DA neurons remains largely unclear, resulting in immature and dead‐end states with low efficiency. In this study, using single‐cell RNA sequencing, the trajectory of reprogramming DA neurons at multiple time points, identifying a continuous pathway for their reprogramming is analyzed. It is identified that intermediate cell populations are crucial for resetting host cell fate during early DA neuronal reprogramming. Further, longitudinal dissection uncovered two distinct trajectories: one leading to successful reprogramming and the other to a dead end. Notably, Arid4b, a histone modifier, as a crucial regulator at this branch point, essential for the successful trajectory and acquisition of mature dopaminergic neuronal identity is identified. Consistently, overexpressing Arid4b in the DA neuronal reprogramming process increases the yield of iDA neurons and effectively reverses the disease phenotypes observed in the PD mouse brain. Thus, gaining insights into the cellular trajectory holds significant importance for devising regenerative medicine strategies, particularly in the context of addressing neurodegenerative disorders like Parkinson's disease.

Brain organoids have become a valuable tool for studying human brain development, disease modeling, and drug testing. However, generating brain organoids with mature neurons is time-intensive and often incomplete, limiting their utility in studying age-related neurodegenerative diseases such as Alzheimer’s disease (AD). Here, we report the generation of 3D brain organoids from human fibroblasts through direct reprogramming, with simplicity, efficiency, and reduced variability. We also demonstrate that induced brain organoids from APOE ε4 AD patient fibroblasts capture some disease-specific features and pathologies associated with APOE ε4 AD. Moreover, APOE ε4-induced brain organoids with mutant APP overexpression faithfully recapitulate the acceleration of AD-related pathologies, providing a more physiologically relevant and patient-specific model of familial AD. Importantly, transcriptome analysis reveals that gene sets specific to APOE ε4 patient-induced brain organoids are highly similar to those of APOE ε4 post-mortem AD brains. Overall, induced brain organoids from direct reprogramming offer a promising approach for more efficient and controlled studies of neurodegenerative disease modeling.

Abstract Brain organoids, which are three-dimensional cell culture models, have the ability to mimic certain structural and functional aspects of the human brain. However, creating these organoids can be a complicated and difficult process due to various technological hurdles. This study presents a method for effectively generating cerebral organoids from human induced pluripotent stem cells (hiPSCs) using electromagnetic gold nanoparticles (AuNPs). By exposing mature cerebral organoids to magnetized AuNPs, we were able to cultivate them in less than 3 weeks. The initial differentiation and neural induction of the neurosphere occurred within the first week, followed by maturation, including regional patterning and the formation of complex networks, during the subsequent 2 weeks under the influence of magnetized AuNPs. Furthermore, we observed a significant enhancement in neurogenic maturation in the brain organoids, as evidenced by increased histone acetylation in the presence of electromagnetic AuNPs. Consequently, electromagnetic AuNPs offer a promising in vitro system for efficiently generating more advanced human brain organoids that closely resemble the complexity of the human brain.

Researchers have just discovered an alternative to synthetic corrosion inhibitors, which are hazardous and terrible for the ecosystem, to prevent rusting in the environment. A metal corrodes when it is subjected to corrosive media (acid, base, or saline) and they deteriorate, leading to failure. The most straightforward and affordable corrosion protection and prevention technique in acidic environments has been proven to be corrosion inhibitors. On industrial surfaces, pieces of machinery, or vessels, these inhibitors slow the rate of corrosion, preventing the monetary losses brought on by metallic corrosion. Recently, attention has been directed to developing ecologically appropriate corrosion retardation methods because inorganic and organic inhibitors are harmful and expensive. Recent studies have focused on green mild steel (MS) corrosion inhibitors that mimic industrial processes in acidic conditions. This presentation briefly covers the many types of corrosion, the corrosion process and the most recent studies on using natural plant extracts as corrosion inhibitors. Since they are safe and cost-effective, green corrosion inhibitors are a new trend in preventing corrosion. These inhibitors are produced from various plant parts, and inhibition efficiency (IE) also depends on them. To ascertain the IE of the corrosion inhibitor, some experiments, including computational studies (quantum calculations and MD simulations), electrochemical measurements (electrochemical impedance (EIS) and potentio-dynamic polarization), surface morphology atomic force microscopy (AFM), scanning electron microscopy (SEM)/energy-dispersive X-ray analysis (EDX) and UV–visible spectroscopy are carried out. It has been demonstrated that the IE is maximum for green corrosion inhibitors compared to synthetic inhibitors. This paper provides an overview of the properties, mechanism of corrosion inhibitors, nature of green corrosion inhibitors and their IE obtained by performing tests. This review article discussion shows that reinforcement with plant extract performs well in aggressive environments, which is evident from electrochemical studies and surface analysis when compared to reinforcement with inhibitors.

Oligodendrocytes have been increasingly shown to be involved in Alzheimer’s disease (AD). Here, the authors perform single-cell RNA-sequencing on APP NL-G-F mice and describe a disease-associated oligodendrocyte (DAO) population. They find inhibition of Erk1/2 signaling in DAOs rescues impaired axonal myelination and cognitive decline in an AD mouse model.

Abstract Background The ε4 allele of apolipoprotein E (APOE ε4) is the strongest known genetic risk factor for late-onset Alzheimer’s disease (AD), associated with amyloid pathogenesis. However, it is not clear how APOE ε4 accelerates amyloid-beta (Aβ) deposition during the seeding stage of amyloid development in AD patient neurons. Methods AD patient induced neurons (iNs) with an APOE ε4 inducible system were prepared from skin fibroblasts of AD patients. Transcriptome analysis was performed using RNA isolated from the AD patient iNs expressing APOE ε4 at amyloid-seeding and amyloid-aggregation stages. Knockdown of IGFBP3 was applied in the iNs to investigate the role of IGFBP3 in the APOE ε4-mediated amyloidosis. Results We optimized amyloid seeding stage in the iNs of AD patients that transiently expressed APOE ε4. Remarkably, we demonstrated that Aβ pathology was aggravated by the induction of APOE ε4 gene expression at the amyloid early-seeding stage in the iNs of AD patients. Moreover, transcriptome analysis in the early-seeding stage revealed that IGFBP3 was functionally important in the molecular pathology of APOE ε4-associated AD. Conclusions Our findings suggest that the presence of APOE ε4 at the early Aβ-seeding stage in patient iNs is critical for aggravation of sporadic AD pathology. These results provide insights into the importance of APOE ε4 expression for the progression and pathogenesis of sporadic AD.

Abstract Background Aberrant DNA methylation patterns have been observed in neurodegenerative diseases, including Alzheimer's disease (AD), and dynamic changes in DNA methylation are closely associated with the onset and progression of these diseases. Particularly, hypomethylation of the amyloid precursor protein gene (APP) has been reported in patients with AD. Methods In this study, we used catalytically inactivated Cas9 (dCas9) fused with Dnmt3a for targeted DNA methylation of APP, and showed that the CRISPR/dCas9-Dnmt3a-mediated DNA methylation system could efficiently induce targeted DNA methylation of APP both in vivo and in vitro. Results We hypothesized that the targeted methylation of the APP promoter might rescue AD-related neuronal cell death by reducing APP mRNA expression. The cultured APP-KI mouse primary neurons exhibited an altered DNA-methylation pattern on the APP promoter after dCas9-Dnmt3a treatment. Likewise, the APP mRNA level was significantly reduced in the dCas9-Dnmt3a-treated wild-type and APP-KI mouse primary neurons. We also observed decreased amyloid-beta (Aβ) peptide level and Aβ42/40 ratio in the dCas9-Dnmt3a-treated APP-KI mouse neurons compared to the control APP-KI mouse neurons. In addition, neuronal cell death was significantly decreased in the dCas9-Dnmt3a-treated APP-KI mouse neurons. Furthermore, the in vivo methylation of APP in the brain via dCas9-Dnmt3a treatment altered Aβ plaques and attenuated cognitive and behavioral impairments in the APP-KI mouse model. Conclusions These results suggest that the targeted methylation of APP via dCas9-Dnmt3a treatment can be a potential therapeutic strategy for AD.

Abstract For decades, nanoparticles (NPs) have been widely implemented in various biomedical fields due to their unique optical, thermal, and tunable properties. Particularly, gold nanoparticles (AuNPs) have opened new frontiers in sensing, targeted drug delivery, imaging, and photodynamic therapy, showing promising results for the treatment of various intractable diseases that affect quality of life and longevity. Despite the tremendous achievements of AuNPs-based approaches in biomedical applications, few AuNP-based nanomedicines have been evaluated in clinical trials, which is likely due to a shortage of understanding of the biological and pathological effects of AuNPs. The biological fate of AuNPs is tightly related to a variety of physicochemical parameters including size, shape, chemical structure of ligands, charge, and protein corona, and therefore evaluating the effects of these parameters on specific biological interactions is a major ongoing challenge. Therefore, this review focuses on ongoing nanotoxicology studies that aim to characterize the effect of various AuNP characteristics on AuNP-induced toxicity. Specifically, we focus on understanding how each parameter alters the specific biological interactions of AuNPs via mechanistic analysis of nano-bio interactions. We also discuss different cellular functions affected by AuNP treatment (e.g., cell motility, ROS generation, interaction with DNA, and immune response) to understand their potential human health risks. The information discussed herein could contribute to the safe usage of nanomedicine by providing a basis for appropriate risk assessment and for the development of nano-QSAR models.

We developed a 0.1‐μm metamorphic high electron mobility transistor and fabricated a W‐band monolithic microwave integrated circuit chipset with our in‐house technology to verify the performance and usability of the developed technology. The DC characteristics were a drain current density of 747 mA/mm and a maximum transconductance of 1.354 S/mm; the RF characteristics were a cutoff frequency of 210 GHz and a maximum oscillation frequency of 252 GHz. A frequency multiplier was developed to increase the frequency of the input signal. The fabricated multiplier showed high output values (more than 0 dBm) in the 94 GHz–108 GHz band and achieved excellent spurious suppression. A low‐noise amplifier (LNA) with a four‐stage single‐ended architecture using a common‐source stage was also developed. This LNA achieved a gain of 20 dB in a band between 83 GHz and 110 GHz and a noise figure lower than 3.8 dB with a frequency of 94 GHz. A W‐band image‐rejection mixer (IRM) with an external off‐chip coupler was also designed. The IRM provided a conversion gain of 13 dB–17 dB for RF frequencies of 80 GHz–110 GHz and image‐rejection ratios of 17 dB–19 dB for RF frequencies of 93 GHz–100 GHz.

Regenerative medicine: Protein boosts stem cell generation process Heightened expression of a DNA repair protein improves efficiency when generating induced pluripotent stem cells (iPSCs) for use in regenerative medicine. DNA demethylation – the removal of methyl groups from one of the DNA bases, cytosine – is required for effective reprogramming of cells other than sperm and egg cells to create iPSCs. Ineffective demethylation has been a key challenge for scientists to overcome in generating iPSCs efficiently. Now, Jongpil Kim and co-workers at Dongguk University in Seoul, South Korea, have demonstrated that the DNA repair protein Rad50 plays a regulatory role in DNA demethylation during cell reprogramming. Rad50 interacts with a key enzyme involved in demethylation, boosting the efficiency of the process. The team found that overexpressing Rad50 increased DNA demethylation during reprogramming, enhancing the efficiency of iPSC generation. Blocking Rad50 had the opposite effect.

Concrete is a versatile construction material used along with a reinforcement. Concrete is made up of binder materials and aggregates. Cement is a primary binder material used to produce conventional concrete. Carbon dioxide emissions in the atmosphere are a symptom of the issue related to Portland cement manufacture. It is estimated that one ton of cement produced releases an equal amount CO2 into atmosphere. On other hand, many industrial wastes are dumped in open spaces, leading to land pollution. Researchers have developed a construction material known as geopolymer concrete that uses industrial waste materials as a binder material to address these two issues. Excellent mechanical and durability characteristics are displayed by geopolymer concrete. For the creation of geopolymer concrete, fly ash is employed as a binder material. The drawback of utilizing fly ash is the curing method. Due to increased setting time, concrete samples require either heat curing or oven-curing. Geopolymer paste preparation is based on the type of binder materials used. In this study, GGBS is partially added with fly ash to cure specimens in ambient temperature due to presence of a higher amount calcium in GGBS. The present study investigates the consistency of geopolymer pastes, their workability, and the compressive strength of cement mortars by varying the amount of binder content (360 kg/m3 & 400 kg/m3). The molarity of NaOH was varied from 8 to 12. The ratio between binder material and alkaline to binder ratio were 0.45 and 0.50, respectively. The specimens were cured in both ambient and oven temperatures to study their strength development caused by temperature. A total of 396 specimens were cast to study the behavior of geopolymer concrete made with fly ash and GGBS (FAG). The test results revealed that the substitution of 50% GGBS with fly ash exhibited better strength properties during curing. Additionally, by increasing the binder content to 400 kg/m3, the results of 80% GGBS and 20% fly ash revealed excellent consistency among all other mixes. The oven-cured specimens showed more strength compared to specimens cured in ambient temperature, but the ambient cured specimens (ACS) attained the required strength. It was also not practically possible to cure the structural members by oven-curing in the field. The mix with 80% of GGBS and 20% fly ash can be used for construction. The required strength can also be achieved by increasing the molarity ratio.

Recent evidence indicates that gut microbiota could interact with the central nervous system and affect brain function, including cognition and memory. In this study, we investigated whether Bifidobacterium bifidum BGN4 (B. bifidum BGN4) and Bifidobacterium longum BORI (B. longum BORI) alleviated the pathological features in a mouse model of Alzheimer’s disease (AD). Administration of B. bifidum BGN4 and B. longum BORI effectively suppressed amyloidosis and apoptotic processes and improved synaptic plasticity by ameliorating the neuroinflammatory response and BDNF expression. Moreover, behavioral tests indicated that B. bifidum BGN4 and B. longum BORI attenuated the cognitive and memory disability of AD mice. Taken together, the present study highlights the therapeutic potential of B. bifidum BGN4 and B. longum BORI for suppressing the pathological features of AD.

Fractures: reprogramming cells to reduce risk in the elderly Reprogramming cells that produce connective tissue to form bone instead could help prevent fractures in the elderly. Bones weaken with age, and fractures are a significant health risk in ageing populations. Most current bone regeneration treatments use stem cells, which can differentiate into any type of cell and have infinite capacity to divide; however, they are difficult to source and can lead to tumor formation. Jongpil Kim at Dongguk University in South Korea and coworkers have reviewed a new method that uses genetic signals to transform connective tissue-forming cells into bone-producing cells. The reprogrammed cells have been shown to generate new bone at the desired site, and because they have already lost their capacity for infinite division, tumor formation risk is greatly reduced. This method shows promise to expand treatment options for fractures and osteoporosis.

Summary: Recent advances in generating three-dimensional (3D) organoid systems from stem cells offer new possibilities for disease modeling and drug screening because organoids can recapitulate aspects of in vivo architecture and physiology. In this study, we generate isogenic 3D midbrain organoids with or without a Parkinson's disease-associated LRRK2 G2019S mutation to study the pathogenic mechanisms associated with LRRK2 mutation. We demonstrate that these organoids can recapitulate the 3D pathological hallmarks observed in patients with LRRK2-associated sporadic Parkinson's disease. Importantly, analysis of the protein-protein interaction network in mutant organoids revealed that TXNIP, a thiol-oxidoreductase, is functionally important in the development of LRRK2-associated Parkinson's disease in a 3D environment. These results provide proof of principle for the utility of 3D organoid-based modeling of sporadic Parkinson's disease in advancing therapeutic discovery. : H. Kim and colleagues generated 3D midbrain organoids containing a G2019S mutation in LRRK2 and used this system for sporadic Parkinson’s disease (PD) modeling in vitro. Their results demonstrate that these 3D midbrain organoids can recapitulate the pathological features of LRRK2-associated sporadic PD. These results demonstrate that the 3D midbrain organoids are invaluable for recapitulating PD phenotypes and understanding the molecular underpinnings of these phenotypes. Keywords: Parkinson's disease, iPSC, organoids, disease modeling, midbrain

Abstract Background Although the dopamine precursor L-3, 4-dihydroxyphenylalanine ( l -dopa) remains the gold standard pharmacological therapy for patients with Parkinson’s disease (PD), long-term treatment with this drug has been known to result in several adverse effects, including l -dopa-induced dyskinesia (LID). Recently, our group reported that KD5040, a modified herbal remedy, had neuroprotective effects in both in vitro and in vivo models of PD. Thus, the present study investigated whether KD5040 would have synergistic effects with l -dopa and antidyskinetic effects caused by l -dopa as well. Methods The effects of KD5040 and l -dopa on motor function, expression levels of substance P (SP) and enkephalin (ENK) in the basal ganglia, and glutamate content in the motor cortex were assessed using behavioral assays, immunohistochemistry, Western blot analyses, and liquid chromatography tandem mass spectrometry in a mouse model of PD induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In addition, the antidyskinetic effects of KD5040 on pathological movements triggered by l -dopa were investigated by testing abnormal involuntary movements (AIMs) and measuring the activations of FosB, cAMP-dependent phosphor protein of 32 kDa (DARPP-32), extracellular signal-regulated kinases (ERK), and cAMP response element-binding (CREB) protein in the striatum. Results KD5040 synergistically improved the motor function when low-dose l -dopa (LL) was co-administered. In addition, it significantly reversed MPTP-induced lowering of SP, improved ENK levels in the basal ganglia, and ameliorated abnormal reduction in glutamate content in the motor cortex. Furthermore, KD5040 significantly lowered AIMs and controlled abnormal levels of striatal FosB, pDARPP-32, pERK, and pCREB induced by high-dose l -dopa. Conclusions KD5040 lowered the effective dose of l -dopa and alleviated LID. These findings suggest that KD5040 may be used as an adjunct therapy to enhance the efficacy of l -dopa and alleviate its adverse effects in patients with PD.

The clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 system has emerged as a powerful technology, with the potential to generate transgenic animals. Particularly, efficient and precise genetic editing with CRISPR/Cas9 offers immense prospects in various biotechnological applications. Here, we report that the histone deacetylase inhibitor valproic acid (VPA) significantly increases the efficiency of CRISPR/Cas9-mediated gene editing in mouse embryonic stem cells and embryos. This effect may be caused through globally enhanced chromatin accessibility, as indicate by histone hyperacetylation. Taken together, our results suggest that VPA can be used to increase the efficacy of CRISPR/Cas9 in generating transgenic systems.