For at least two reasons, the current transgenic animal models of Alzheimer's disease (AD) appear to be patently inadequate. They may be useful in many respects, the AD models; however, they are not. ...First, they are incapable of developing the full spectrum of the AD pathology. Second, they respond spectacularly well to drugs that are completely ineffective in the treatment of symptomatic AD. These observations indicate that both the transgenic animal models and the drugs faithfully reflect the theory that guided the design and development of both, the amyloid cascade hypothesis (ACH), and that both are inadequate because their underlying theory is. This conclusion necessitated the formulation of a new, all-encompassing theory of conventional AD-the ACH2.0. The two principal attributes of the ACH2.0 are the following. One, in conventional AD, the agent that causes the disease and drives its pathology is the intraneuronal amyloid-β (
Aβ) produced in two distinctly different pathways. Two, following the commencement of AD, the bulk of Aβ is generated independently of Aβ protein precursor (AβPP) and is retained inside the neuron as
Aβ. Within the framework of the ACH2.0, AβPP-derived
Aβ accumulates physiologically in a lifelong process. It cannot reach levels required to support the progression of AD; it does, however, cause the disease. Indeed, conventional AD occurs if and when the levels of AβPP-derived
Aβ cross the critical threshold, elicit the neuronal integrated stress response (ISR), and trigger the activation of the AβPP-independent
Aβ generation pathway; the disease commences only when this pathway is operational. The
Aβ produced in this pathway reaches levels sufficient to drive the AD pathology; it also propagates its own production and thus sustains the activity of the pathway and perpetuates its operation. The present study analyzes the reason underlying the evident inadequacy of the current transgenic animal models of AD. It concludes that they model, in fact, not Alzheimer's disease but rather the effects of the neuronal ISR sustained by AβPP-derived
Aβ, that this is due to the lack of the operational AβPP-independent
Aβ production pathway, and that this mechanism must be incorporated into any successful AD model faithfully emulating the disease. The study dissects the plausible molecular mechanisms of the AβPP-independent
Aβ production and the pathways leading to their activation, and introduces the concept of conventional versus unconventional Alzheimer's disease. It also proposes the path forward, posits the principles of design of productive transgenic animal models of the disease, and describes the molecular details of their construction.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
PT. Pusri utilizes Musi River water as a source of process water. Colloidal particles suspended in Musi River water cancause blockage and build-up of scale on pipes and process equipment. Therefore, ...a good coagulation process is needed to reduce the content of colloidal solids suspended in water by using a coagulant. Coagulants that are often used for water treatment include ACH, AS, and PAC. The objectives of the study are to assess the Effectiveness and to optimize the usage of the coagulant ACH, AS, and PAC on decreasing the turbidity of Musi River water sample as a raw water in utility unit of PT. Pusri. The coagulation process was carried out by varying the concentration of each coagulant and adding 0.1 ppm of coagulant aid for all samples. Fast and slow stirring was carried out each at a speed of 150 rpm 30 rpm for 10 minutes. From the experiments conducted, it was found that the most efective coagulants to be used were ACH and PAC with the addition of a smaller coagulant dose of 12 ppm to achieve the standard water quality used at PT. Pusri. Meanwhile, the use of AS has higher eficiency when compared to ACH and PAC because it is more cost efective.
The World Health Organization (WHO) announced that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may spread through aerosols, so-called airborne transmission, especially in a poorly ...ventilated indoor environment. Ventilation protects the occupants against airborne transmission. Various studies have been performed on the importance of sufficient ventilation for diluting the concentration of virus and lowering any subsequent dose inhaled by the occupants. However, the ventilation situation can be problematic in public buildings and other shared spaces, such as shops, offices, schools, and restaurants. If ventilation is provided by opening windows, the outdoor airflow rate depends strongly on the specific local conditions (opening sizes, relative positions, climatic and weather conditions).
This study uses field measurements to analyze the natural ventilation performance in a school building according to the window opening rates, positions, and weather conditions. The ventilation rates were calculated by the tracer gas decay method, and the infection risk was assessed using the Wells-Riley equation. Under cross-ventilation conditions, the average ventilation rates were measured at 6.51 h−1 for 15% window opening, and 11.20 h−1 for 30% window opening. For single-sided ventilation, the ventilation rates were reduced to about 30% of the values from the cross-ventilation cases. The infection probability is less than 1% in all cases when a mask is worn and more than 15% of the windows are open with cross-ventilation. With single-sided ventilation, if the exposure time is less than 1 h, the infection probability can be kept less than 1% with a mask. However, the infection probability exceeds 1% in all cases where exposure time is greater than 2 h, regardless of whether or not a mask is worn. Also, when the air conditioner was operated with a window opening ratio of 15%, power consumption increased by 10.2%.
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•Appropriate window opening rates to prevent viral air infection were analyzed.•Under cross-ventilation, the ventilation rates were 6.51 h−1 for 15% opening ratio.•For single-sided ventilation, the ventilation rates were reduced by about 30%.•Infection probability was less than 1% by 15% window opening and wearing a mask.•Power consumption for air-conditioning increased by 10.2% under 15% opening ratio.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Acetylcholine (ACh) plays an important role in memory function and has been implicated in aging‐related dementia, in which the impairment of hippocampus‐dependent learning strongly manifests. ...Cholinergic neurons densely innervate the hippocampus, mediating the formation of episodic as well as semantic memory. Here, we will review recent findings on acetylcholine's modulation of memory function, with a particular focus on hippocampus‐dependent learning, and the circuits involved. In addition, we will discuss the complexity of ACh actions in memory function to better understand the physiological role of ACh in memory.
This is an article for the special issue XVth International Symposium on Cholinergic Mechanisms.
The neuromodulator acetylcholine (ACh) plays a critical role in memory function, especially in the hippocampus‐dependent learning. The cholinergic system is severely affected in Alzheimer's disease, implicating its role in memory. In this review, the current knowledge on the cholinergic system and its modulation of hippocampal circuits have been reviewed. Furthermore, we describe factors that contribute to the complexity of ACh actions in memory function.
This is an article for the special issue XVth International Symposium on Cholinergic Mechanisms.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Since information is still limited whether atrial IK,ACh may become a potential therapeutic target to terminate persistent atrial fibrillation (AF), we assessed it by using the persistent AF canine ...model with representative IK,ACh inhibitor AVE0118 and class I drugs. AVE0118 (6 mg/kg, n = 7), disopyramide (3 mg/kg, n = 7) and cibenzoline (3 mg/kg, n = 6) terminated the AF in 3/7, 1/7 and 2/6 animals, respectively, whereas aprindine (3 mg/kg, n = 6) did not suppress it. These findings suggest that IK,ACh inhibition in addition to open-state INa suppression with slow dissociation kinetics can synergistically exert potent antiarrhythmic action against persistent AF.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
In 1929, Dale and Dudley described the first reported natural occurrence of acetylcholine (ACh) in an animal’s body. They identified this ACh in the spleens of horses and oxen, which we now know ...suggests possible involvement of ACh in the regulation of lymphocyte activity and immune function. However, the source and function of splenic ACh were left unexplored for several decades. Recent studies on the source of ACh in the blood revealed ACh synthesis catalyzed by choline acetyltransferase (ChAT) in CD4+ T cells. T and B cells, macrophages and dendritic cells (DCs) all express all five muscarinic ACh receptor subtypes (mAChRs) and several subtypes of nicotinic AChRs (nAChRs), including α7 nAChRs. Stimulation of these mAChRs and nAChRs by their respective agonists causes functional and biochemical changes in the cells. Using AChR knockout mice, we found that M1/M5 mAChR signaling up-regulates IgG1 and pro-inflammatory cytokine production, while α7 nAChR signaling has the opposite effect. These findings suggest that ACh synthesized by T cells acts in an autocrine/paracrine fashion at AChRs on various immune cells to modulate immune function. In addition, an endogenous allosteric and/or orthosteric α7 nAChR ligand, SLURP-1, facilitates functional development of T cells and increases ACh synthesis via up-regulation of ChAT mRNA expression. SLURP-1 is expressed in CD205+ DCs residing in the tonsil in close proximity to T cells, macrophages and B cells. Collectively, these findings suggest that ACh released from T cells along with SLURP-1 regulates cytokine production by activating α7 nAChRs on various immune cells, thereby facilitating T cell development and/or differentiation, leading to immune modulation.
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•ACh discovery in non-neuronal spleen hinted at the role of ACh in immune regulation.•Antigen presentation increases ChAT-catalyzed ACh synthesis in CD4+ T cells.•Lymphocytes, macrophages and DCs express both mAChRs and nAChRs, including α7 nAChR.•CD205+ DCs in the tonsil marginal zone express the α7 nAChR agonist SLURP-1.•SLURP-1 increases ACh synthesis in T cells by up-regulating ChAT gene expression.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Generalized pustular psoriasis (GPP) is a severe multi-systemic inflammatory disease characterized by neutrophilic pustulosis and triggered by pro-inflammatory IL-36 cytokines in skin. While 19%–41% ...of affected individuals harbor bi-allelic mutations in IL36RN, the genetic cause is not known in most cases. To identify and characterize new pathways involved in the pathogenesis of GPP, we performed whole-exome sequencing in 31 individuals with GPP and demonstrated effects of mutations in MPO encoding the neutrophilic enzyme myeloperoxidase (MPO). We discovered eight MPO mutations resulting in MPO -deficiency in neutrophils and monocytes. MPO mutations, primarily those resulting in complete MPO deficiency, cumulatively associated with GPP (p = 1.85E−08; OR = 6.47). The number of mutant MPO alleles significantly differed between 82 affected individuals and >4,900 control subjects (p = 1.04E−09); this effect was stronger when including IL36RN mutations (1.48E−13) and correlated with a younger age of onset (p = 0.0018). The activity of four proteases, previously implicated as activating enzymes of IL-36 precursors, correlated with MPO deficiency. Phorbol-myristate-acetate-induced formation of neutrophil extracellular traps (NETs) was reduced in affected cells (p = 0.015), and phagocytosis assays in MPO-deficient mice and human cells revealed altered neutrophil function and impaired clearance of neutrophils by monocytes (efferocytosis) allowing prolonged neutrophil persistence in inflammatory skin. MPO mutations contribute significantly to GPP’s pathogenesis. We implicate MPO as an inflammatory modulator in humans that regulates protease activity and NET formation and modifies efferocytosis. Our findings indicate possible implications for the application of MPO inhibitors in cardiovascular diseases. MPO and affected pathways represent attractive targets for inducing resolution of inflammation in neutrophil-mediated skin diseases.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The use of tobacco products is associated with an increased incidence of periodontal disease, poor response to periodontal therapy, and a high risk for developing head and neck cancer. Nicotine and ...tobacco-derived nitrosamines have been shown to exhibit their pathobiologic effects due in part to activation of the nicotinic acetylcholine (ACh) receptors (nAChRs), mainly α7 nAChR, expressed by oral keratinocytes (KCs). This study was designed to gain mechanistic insight into α7-mediated morbidity of tobacco products in the oral cavity. We investigated the signaling pathways downstream of α7 nAChR in monolayers of oral KCs exposed for 24 h to aged and diluted sidestream cigarette smoke (ADSS) or an equivalent concentration of pure nicotine. By both real-time polymerase chain reaction (PCR) and In-cell Western, the KCs stimulated with ADSS or nicotine showed multifold increases of STAT-3. These effects could be completely blocked or significantly (P<0.05) diminished if the cells were pretreated with the α7 antagonist α-bungarotoxin (αBTX) or transfected with anti-α7 small interfering RNA (siRNA-α7). The use of pathway inhibitors revealed that signaling through the Ras/Raf-1/MEK1/ERK steps mediated α7-dependent up-regulation of STAT-3. Targeted mutation of the α7 gene prevented ERK1/2 activation by nicotine. Using the gel mobility shift assay, we demonstrated that an increased protein binding activity of STAT-3 caused by ADSS or pure nicotine was mediated by janus-activated kinase (JAK)-2. Activation of JAK-2/STAT-3 pathway could be prevented by αBTX or siRNA-α7. Thus, nuclear transactivation of STAT-3 in KCs exposed to tobacco products is mediated via intracellular signaling downstream from α7, which proceeds via two complementary pathways. The Ras/Raf-1/MEK1/ERK cascade culminates in up-regulated expression of the gene encoding STAT-3, whereas recruitment and activation of tyrosine kinase JAK-2 phosphorylates it. Elucidation of this novel mechanism of nicotine-dependent nuclear transactivation of STAT-3 identifies oral α7 nAChR as a promising molecular target to prevent, reverse, or retard tobacco-related periodontal disease and progression of head and neck cancer by receptor inhibitors.--Arredondo, J., Chernyavsky, A. I., Jolkovsky, D. L., Pinkerton, K. E., Grando, S. A. Receptor-mediated tobacco toxicity: cooperation of the Ras/Raf-1/MEK1/ERK and JAK-2/STAT-3 pathways downstream of α7 nicotinic receptor in oral keratinocytes.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Acetylcholine (Ach) is the main neurotransmitter in the neuronal cholinergic system and also works as a signaling molecule in non-neuronal cells and tissues. The diversity of signaling pathways ...mediated by Ach provides a basis for understanding the biology of the cholinergic epithelial cells and immune cells in the gill of the species studied.
NECs in the gill were not found surprisingly, but specialized cells showing the morphological, histochemical and ultrastructural characteristics of eosinophils were located in the gill filaments and respiratory lamellae.
Much remains unknown about the interaction between the nerves and eosinophils that modulate both the release of acetylcholine and its nicotinic and muscarinic receptors including the role of acetylcholine in the mechanisms of O2 chemosensing. In this study we report for the first time the expression of Ach in the pavement cells of the gill lamellae in fish, the mast cells associated with eosinophils and nerve interaction for both immune cell types, in the gill of the extant butterfly fish Pantodon buchholzi. Multiple roles have been hypothesized for Ach and alpha nAChR in the gills. Among these there are the possible involvement of the pavement cells of the gill lamellae as O2 chemosensitive cells, the interaction of Ach positive mast cells with eosinophils and interaction of eosinophils with nerve terminals. This could be related to the use of the vesicular acetylcholine transporter (VAChT) and the alpha 2 subunit of the acetylcholine nicotinic receptor (alpha 2 nAChR). These data demonstrate the presence of Ach multiple sites of neuronal and non-neuronal release and reception within the gill and its ancestral signaling that arose during the evolutionary history of this conservative fish species.
•Immunocytochemical markers of acetylcholine and nAChR in the gill of butterfly fish.•Eosinophils and mast cells and their nerve interaction.•Absence of NECs is compensated by the cholinergic epithelial cells.•Ach signaling during evolutionary history.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Choline acetyltransferase (ChAT)-positive neurons in neural stem cell (NSC) niches can evoke adult neurogenesis (AN) and restore impaired brain function after injury, such as acute ischemic stroke ...(AIS). However, the relevant mechanism by which ChAT+ neurons develop in NSC niches is poorly understood. Our RNA-seq analysis revealed that dimethylarginine dimethylaminohydrolase 1 (DDAH1), a hydrolase for asymmetric NG,NG-dimethylarginine (ADMA), regulated genes responsible for the synthesis and transportation of acetylcholine (ACh) (Chat, Slc5a7 and Slc18a3) after stroke insult. The dual-luciferase reporter assay further suggested that DDAH1 controlled the activity of ChAT, possibly through hypoxia-inducible factor 1α (HIF-1α). KC7F2, an inhibitor of HIF-1α, abolished DDAH1-induced ChAT expression and suppressed neurogenesis. As expected, DDAH1 was clinically elevated in the blood of AIS patients and was positively correlated with AIS severity. By comparing the results among Ddah1 general knockout (KO) mice, transgenic (TG) mice and wild-type (WT) mice, we discovered that DDAH1 upregulated the proliferation and neural differentiation of NSCs in the subgranular zone (SGZ) under ischemic insult. As a result, DDAH1 may promote cognitive and motor function recovery against stroke impairment, while these neuroprotective effects are dramatically suppressed by NSC conditional knockout of Ddah1 in mice.
In the hippocampus, DDAH1 regulates the genes for the synthesis of ACh (Chat, Slc5a7 and Slc18a3) possibly through transcription factor HIF-1α which promotes neurogenesis and neural repair post-stroke. Display omitted
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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