Optimization and Characterization of the F-LSR Manufacturing Process Using Quaternary Ammonium Silanolate as an Initiator for Synthesizing Fluorosilicone.

Due to the growing demand for versatile hybrid materials that can withstand harsh conditions (below -40 °C), fluorosilicone copolymers are becoming promising materials that can overcome the limited operating temperature of conventional rubber. In order to synthesize a fluorosilicone copolymer, a potent initiator capable of simultaneously initiating various siloxane monomers in anionic ring-opening polymerization (AROP) is required. In this study, tetramethyl ammonium silanolate (TMAS), a quaternary ammonium (QA) anion, was employed as an initiator for AROP, thereby fluoro-methyl-vinyl-silicone (FVMQ) and fluoro-hydrido-methyl-silicone (FHMQ) were successfully synthesized under optimized conditions. FT-IR, NMR, and GPC analyses confirmed that the chain length and functional group content of FVMQ and FHMQ are controlled by changing the ratio of the components. Moreover, fluorine-involved liquid silicone rubber (F-LSR) was prepared with FVMQ as the main chain and FHMQ as a crosslinker. The tensile strength, elongation, and hardness of each F-LSR sample were measured. Finally, it was confirmed through TGA, DSC, TR-test, and embrittlement testing that elastic retention at low temperatures improved even though the heat resistance slightly decreased as the trifluoropropyl group increased in F-LSR. We anticipate that the optimization of fluorosilicone synthesis initiated by QA and the comprehensive characterization of F-LSRs with different fluorine content and chain lengths will be pivotal to academia and industry.

Antihypertriglyceridemia activities of naturally fermented green tea, Heukcha, extract through modulation of lipid metabolism in rats fed a high-fructose diet.

Hypertriglyceridemia, a symptom of elevated triglyceride level in the blood, is a potent risk factor for cardiovascular and metabolic disorders. Among the numerous treatments to regulate circulating triglyceride levels, fibrates are widely used to treat hypertriglyceridemia, although they also have side effects such as hepatotoxicity and gallstone formation. In the present study, we aimed to investigate the blood triglyceride-lowering effects of a naturally fermented green tea extract (NFGT) and the underlying mechanisms on hypertriglyceridemia in vitro and in vivo models. NFGT suppressed the expression of lipogenic genes, while augmented expression of fatty acid oxidation-related genes in cultured cells, leading to the significant decrease of intracellular triglyceride content. NFGT treated group in fructose-induced hypertriglyceridemic rat model significantly decreased plasma and hepatic triglyceride, which was accompanied by an increase in excretion of fecal fat. Taken together, we propose that NFGT could be potentially a novel functional ingredient to prevent or treat hypertriglyceridemia.

Green Tea Encourages Growth of Akkermansia muciniphila.

Trillions of microorganisms reside in the hosts' gut. Since diverse activities of gut microbiota affect the hosts' health status, maintenance of gut microbiota is important for maintaining human health. Green tea (GT) has multiple beneficial effects on energy metabolism with antiobesity, antidiabetic, and hypolipidemic properties. As GT contains a large amount of bioactive ingredients (e.g., catechins), which can be metabolized by microorganisms, it would be feasible that consumption of GT may cause compositional changes in gut microbiota, and that the changes in gut microbiota would be associated with the beneficial effects of GT. In this study, we demonstrated that consumption of GT extract relieves high-fat diet-induced metabolic abnormalities. Interestingly, GT administration significantly encouraged the growth of Akkermansia muciniphila (Akkermansia), a beneficial microorganism to relieve obesity and related metabolic disorders. Finally, we found that epigallocatechin gallate is the component of GT that stimulates the growth of Akkermansia. According to these data, we propose that GT could be a prebiotic agent for Akkermansia to treat metabolic syndromes.

A TRPV1 antagonist, PAC-14028 does not increase the risk of tumorigenesis in chemically induced mouse skin carcinogenesis.

PAC-14028 (Asivatrep: C21H22F5N3O3S) cream is a novel, topical nonsteroidal, anti-inflammatory, and TRPV1 (transient receptor potential vanilloid subfamily, member 1) antagonist for the treatment of mild to moderate atopic dermatitis. Concerns about the risk of tumor development by TRPV1 blockade in the skin have been prompted, but these findings were proved to be indirect or are still controversial. This study was tested to determine whether TRPV1 selective antagonist, PAC-14028 cream is safe from the promotion of skin tumorigenesis in the two-stage carcinogenesis model. PAC-14028 cream, 0.25%, 0.5%, or 1.0% was applied once daily topically to mouse skin for up to 24 weeks in two-stage chemical carcinogenesis testing using 7, 12-dimethylbenz[a]anthracene (DMBA) and 12-O-tetradecanoylphorbol-13-acetate (TPA). Morbidity/death, clinical signs, tumor formation, activity of EGFR/Akt/mTOR signaling, and systemic exposure to PAC-14028 were investigated. Daily dermal administration of PAC-14028, was not skin carcinogenic. There was also no evidence on the activation of EGFR/Akt/mTOR signaling pathway by the topical treatment of PAC-14028. On Day 169, 1.0% (20 mg/kg/day) of PAC-14028 in female mice resulted in a Cmax and AUC0-τ of 12916.0 ng/mL and 78962.9 ng‧hr/mL, respectively. PAC-14028 cream was well tolerated and did not increase the risk of skin tumorigenesis in two-stage carcinogenesis study.

[Response Patterns of Nursing Unit Managers regarding Workplace Bullying: A Q Methodology Approach].

PURPOSE: The purpose of this study was to identify the response patterns of nursing unit managers regarding workplace bullying. METHODS: Q methodology was used to identify the response patterns. Thirty-six Q samples were selected from the Q population of 210 that included literature reviews and in-depth interviews with clinical nurses and nursing managers. Participants were 30 nursing unit managers who had experience managing workplace bullying and they classified the Q samples into a normal distribution frame measured on a nine-point scale. The data were analyzed using the PC-QUANL program. RESULTS: Five types of response patterns were identified: (1) sympathetic-understanding acceleration, (2) harmonious-team approach, (3) preventive-organizational management, (4) passive observation, and (5) leading-active intervention. The preventive-organizational management type was most frequently used by the nursing unit managers. CONCLUSION: The results of this study indicated that nursing unit managers attempted to prevent and solve workplace bullying in various ways. Therefore, it is necessary to develop and conduct leadership training and intervention programs that appropriately address the response patterns of nursing unit managers, such as those identified in this study.

Gallocatechin Gallate-Containing Fermented Green Tea Extract Ameliorates Obesity and Hypertriglyceridemia Through the Modulation of Lipid Metabolism in Adipocytes and Myocytes.

Green tea is reported to exert beneficial effects on metabolic disorders through the regulation of lipid metabolism. On the contrary, fermented food products have been introduced to improve human health by modulating immune response and energy metabolism. To maximize health benefit, we applied fermentation processing to green tea. Fermented green tea extract (FGT) inhibited adipogenesis and lipogenesis in cultured adipocytes, whereas it augmented mRNA expression of fatty acid oxidation-related genes in differentiated myocytes. In diet-induced obese mice, FGT blunted body weight and fat mass gain by 69.7% and 56.7%, respectively. FGT also improved circulating triglyceride concentrations by 32.6%. Similar to in vitro results, FGT suppressed lipogenesis and promoted lipid catabolism in peripheral tissues. In addition, FGT administration modulated the composition of certain gut microbiota which are associated with obesity and related metabolic disorders. Among the various components of FGT, gallocatechin gallate is suggested to mediate the effect of FGT on lipid metabolism. Taken together, we propose FGT as a novel functional food to benefit human health by controlling adiposity and lipid metabolism.

Green satsuma mandarin orange (Citrus unshiu) extract reduces adiposity and induces uncoupling protein expression in skeletal muscle of obese mice.

Increased fat mass, which is induced by the storage of excess nutrients, is considered a causal factor for various metabolic disorders, including insulin resistance, type 2 diabetes, hyperlipidemia, hyperglycemia, hypertension, atherosclerosis, and non-alcoholic fatty liver disease. Therefore, it is necessary to prevent hyperadiposity to sustain a healthy life. Recently, uncoupling proteins (UCPs) were suggested to be molecular targets for curing obesity and its complications. In this study, green satsuma mandarin orange (Citrus unshiu) extract (GME) increased UCP3 expression in cultured myocytes. In a diet-induced obese animal model, administration of GME reduced fat mass and average fat cell size. Similar to in vitro experiments, GME restored expression of UCP3 in skeletal muscle. Moreover, GME also induced UCP2 expression in skeletal muscle. In conclusion, GME is suggested to be a novel functional dietary supplement for adiposity control through induction of UCPs.

The role of liquid-liquid phase separation in aggregation of the TDP-43 low-complexity domain.

Pathological aggregation of the transactive response DNA-binding protein of 43 kDa (TDP-43) is associated with several neurodegenerative disorders, including ALS, frontotemporal dementia, chronic traumatic encephalopathy, and Alzheimer's disease. TDP-43 aggregation appears to be largely driven by its low-complexity domain (LCD), which also has a high propensity to undergo liquid-liquid phase separation (LLPS). However, the mechanism of TDP-43 LCD pathological aggregation and, most importantly, the relationship between the aggregation process and LLPS remains largely unknown. Here, we show that amyloid formation by the LCD is controlled by electrostatic repulsion. We also demonstrate that the liquid droplet environment strongly accelerates LCD fibrillation and that its aggregation under LLPS conditions involves several distinct events, culminating in rapid assembly of fibrillar aggregates that emanate from within mature liquid droplets. These combined results strongly suggest that LLPS may play a major role in pathological TDP-43 aggregation, contributing to pathogenesis in neurodegenerative diseases.

Orally administered collagen peptide protects against UVB-induced skin aging through the absorption of dipeptide forms, Gly-Pro and Pro-Hyp.

Collagen hydrolysate is a well-known nutritional supplement for the improvement of healthy skin. Here, collagen peptide NS (CPNS) from fish scale was prepared, and its physicochemical properties were investigated. Gly-Pro was revealed as a representative low molecular weight peptide of CPNS, by performing prep-HPLC and LC-MS/MS. CPNS treatment attenuated matrix metalloproteinase-1 production and increased the synthesis of type 1 procollagen in HDF cells. After orally administering CPNS to rats, the plasma concentrations of Gly-Pro and Pro-Hyp increased dramatically. To examine the protective effects of CPNS against ultraviolet B (UVB)-induced photoaging in vivo, the dorsal skins of hairless mice were exposed to UVB and supplemented with CPNS for 12 weeks. The CPNS consumption significantly attenuated UVB-induced wrinkle formation, transepidermal water loss, and epidermis thickness, and increased skin hydration. Collectively, these results suggest that bioactive peptides of CPNS, Gly-Pro and Pro-Hyp, exert beneficial effects on skin health.

Multipolydioxanone scaffold improves upper lip and forehead wrinkles: A 12-month outcome.

BACKGROUND: The safety and wrinkle-reducing effects of multipolydioxanone (PDO) scaffold have been confirmed in animal, and clinical tests for 3 months, but the 12-month outcomes, are unknown. OBJECTIVE: The safety and efficacy of multi-PDO scaffold were tested in animal models and in humans for 12 months. METHODS: In the animal study, a multi-PDO scaffold was implanted into the panniculus carnosus of rat dorsal skin (n = 18) and into the subcutaneous layer of minipig dorsal skin (n = 2) followed by histological staining and analysis. In a human study, a multi-PDO scaffold was implanted deep into the periosteal subcutaneous layer under the wrinkles on the upper lips and forehead, followed by evaluation of clinical changes using digital photography and PRIMOS. RESULTS: A multi-PDO scaffold was not observed after 6 months in rats and minipigs. However, the newly formed tissues within the hollow body of the scaffolds were maintained for up to 12 months. The enhanced effect on the upper lips and forehead wrinkles lasted up to 12 months without any side effects. CONCLUSION: A multi-PDO scaffold represents a new tool to improve upper lips and forehead wrinkles.

A novel, topical, nonsteroidal, TRPV1 antagonist, PAC-14028 cream improves skin barrier function and exerts anti-inflammatory action through modulating epidermal differentiation markers and suppressing Th2 cytokines in atopic dermatitis.

BACKGROUND: Although it is established that epidermal barrier disturbance and immune dysfunction resulting in IgE sensitization are critical factors in the development of cutaneous inflammation, the pathogenesis and targeted therapy of atopic dermatitis (AD)-specific pathways have still been unknown. OBJECTIVE: Taking into account the fact that Th2 cytokines in AD have both unique and overlapping functions including increased epidermal thickening, inflammation, and decreased expressing of the barrier proteins keratinocyte differentiation, we sought to clarify our hypothesis that TRPV1 antagonist plays a critical role in skin barrier function and can be a therapeutic target for AD. METHODS: AD-like dermatitis was induced in hairless mice by repeated oxazolone (Ox) challenges to hairless mice. The functional studies concerning skin barrier function, anti-inflammatory action, and molecular mechanism by TRPV1 antagonism were conducted by histopathological assays, ELISA, qPCR, western blotting, and skin blood flow measurement. RESULTS: Topically administered TRPV1 antagonist, PAC-14028 (Asivatrep: C21H22F5N3O3S), improved AD-like dermatitis and skin barrier functions, and restored the expression of epidermal differentiation markers. In addition, the PAC-14028 cream significantly inhibited cutaneous inflammation by decreasing the expression of serum IgE, and the epidermal expression of IL-4, and IL-13 in Ox-AD mice. These results may provide a novel insight into the molecular mechanism of PAC-14028 cream involved in anti-inflammatory effects and skin barrier functions by suppressing the multiple signaling pathways including IL-4/-13-mediated activation of JAK/STAT, TRPV1, and neuropeptides. CONCLUSION: PAC-14028 cream can be a potential therapeutic tool for the treatment of chronic inflammation and disrupted barrier function in patients with AD.

Physical properties of a novel small-particle hyaluronic acid filler: In vitro, in vivo, and clinical studies.

BACKGROUND: Infraorbital region is one of the most important regions that show the signs of aging. In recent years, hyaluronic acid (HA) fillers have been used to correct this region for esthetic treatments. Although HA fillers with various physical properties are used, limited research has been performed to compare their efficacy. OBJECTIVE: We aimed to compare three HA fillers to determine which is the most appropriate filler for the correction of the infraorbital region and evaluate the correction of such by performing a clinical test using CLEVIEL Fine. METHODS: We performed in vitro and in vivo tests using one new HA filler and two other commercial HA fillers. We compared the rheological properties, resistance to degradation, and in vivo duration test results of the three fillers. Nine patients participated in the clinical test using CLEVIEL Fine for 24 weeks. RESULTS: CLEVIEL Fine showed good rheological and physical characteristics for the infraorbital region. It had a low elasticity and cohesiveness, low incidence of postinjection swelling, high tanδ, narrow particle distribution, and small particle size. Further, it showed better resistance to the enzymes and radicals in the in vitro test than the other two HA fillers and a similar duration in the mouse test. In the clinical test, all patients showed good elasticity and hydration in the infraorbital region for 24 weeks. CONCLUSIONS: CLEVIEL Fine was proven to be safe and effective based on the in vitro, in vivo, and clinical study results.

Do TRPV1 antagonists increase the risk for skin tumourigenesis? A collaborative in vitro and in vivo assessment.

A recent hypothesis suggesting that the pharmacological target TRPV1 (transient receptor potential vanilloid subfamily, member 1) may function as a tumour suppressor, which potentially impacts the development of TRPV1 antagonist therapeutics for a range of conditions. However, little is known about the long-term physiologic effects of TRPV1 blockade in the skin. In vitro and in vivo studies suggested that the potent TRPV1 competitive antagonist AMG-9810 promoted proliferation in N/TERT1 cells (telomerase-immortalised primary human keratinocytes 1) and tumour development in mouse skin that was mediated through EGFR/Akt/mTOR signalling. We attempted to reproduce the reported in vitro and in vivo findings to further explore this hypothesis to understand the underlying mechanism and the risk associated with TRPV1 antagonism in the skin. In vitro proliferation studies using multiple methods and topical application with AMG-9810 and structurally similar TRPV1 antagonists such as SB-705498 and PAC-14028 were performed. Although we confirmed expression of TRPV1 in primary human epidermal keratinocytes (HEKn) and spontaneously immortalised human keratinocytes (HaCaT), we were unable to demonstrate cell proliferation in either cell type or any clear evidence of increased expression of proteins in the EGFR/Akt/mTOR signalling pathway with these molecules. We were also unable to demonstrate skin tumour promotion or underlying molecular mechanisms involved in the EGFR/Akt/mTOR signalling pathway in a single-dose and two-stage carcinogenesis mouse study treated with TRPV1 antagonists. In conclusion, our data suggest that inhibiting the pharmacological function of TRPV1 in skin by specific antagonists has not been considered to be indicative of skin tumour development.

Quercetin and fisetin enhanced the small intestine cellular uptake and plasma levels of epi-catechins in in vitro and in vivo models.

Quercetin and fisetin, known as catechol-containing flavonoids, could positively affect the absorption of catechins due to their strong affinity for catechol-O-methyl transferase (COMT), which can methylate and cause the excretion of catechins. The current study examined the effect of quercetin and fisetin on the absorption of epi-catechins (ECs) by using a Caco-2 cell line and an in vivo model. The intestinal transport of total catechins by Caco-2 cells was enhanced from 1.3- to 1.6-fold and 1.4- to 1.7-fold by adding quercetin and fisetin, respectively, compared to the control. It was even higher in the treatment with a mixture of quercetin and fisetin. While EC had the highest value of intestinal transport (169% of the control) in 10% quercetin treatment, EGC (235%), EGCG (244%), and ECG (242%) were significantly transported in the treatment with a 5% mixture of quercetin and fisetin (p < 0.05). In an in vivo pharmacokinetic study, the values of the area under the plasma concentration-time curve (AUC, ng h mL-1) were also higher in rats orally administered EGCG with 10% quercetin (365.5 ± 25.5) or 10% fisetin (825.3 ± 46.7) than in those administered EGCG only (111.3 ± 13.1). Methylated quercetin and methylated fisetin were determined to be m/z 317.24 and m/z 301.25 [M + H]+ with their own product ions, respectively. The results indicate that quercetin or fisetin is superior to ECs for methylation by COMT.

Influence of flavonol-rich excipient food (onion peel and Dendropanax morbifera) on the bioavailability of green tea epicatechins in vitro and in vivo.

The impacts of onion peel (OP) and Dendropanax morbifera (DM), as excipient foods rich in flavonols, on the digestive recovery, intestinal absorption, and pharmacokinetics of GT epicatechins were studied via an in vitro digestion model system with Caco-2 cells and an in vivo study. The digestive stability of total epicatechins recovered from GT upon the addition of 2% DM was up to 1.12 times higher than that observed with OP. The combined effects of OP and DM, which were observed with 2% OP + DM in a ratio of 1 : 4 (w : w), significantly increased (by a factor of 1.31) the digestive recovery of total epicatechins (p < 0.05). Remarkable cellular uptakes of EC (185.36%) and ECG (188.08%) were found with 4% OP + DM (4 : 1, w : w), and those of EGC (112.30%) and EGCG (136.27%) were obtained with 2% OP + DM (4 : 1, w : w) and 1% OP + DM (1 : 1, w : w), respectively. The peak plasma concentrations of total epicatechins from GT, GT + 5% OP, GT + 5% DM, and GT + 2% OP + 2% DM were 1044.78 ± 609.10, 2267.18 ± 3734.38, 1270.35 ± 547.59, and 714.53 ± 499.27 ng mL-1, respectively. The Cmax value of total epicatechins in rats orally administrated with GT with 5% OP was found to be approximately twice of that obtained with GT alone. The co-ingestion of GT with flavonol-rich excipient foods possibly enhances the absorption of epicatechins because flavonols act as not only enhancers of digestive stability but also modulators of the biotransformation of epicatechins. The results obtained from the current study suggest that the absorption of GT catechins can vary depending upon the kinds and doses of excipient foods co-ingested.

Fermented green tea extract exhibits hypolipidaemic effects through the inhibition of pancreatic lipase and promotion of energy expenditure.

Hyperlipidaemia is a major cause of atherosclerosis and related CVD and can be prevented with natural substances. Previously, we reported that a novel Bacillus-fermented green tea (FGT) exerts anti-obesity and hypolipidaemic effects. This study further investigated the hypotriglyceridaemic and anti-obesogenic effects of FGT and its underlying mechanisms. FGT effectively inhibited pancreatic lipase activity in vitro (IC50, 0·48 mg/ml) and ameliorated postprandial lipaemia in rats (26 % reduction with 500 mg/kg FGT). In hypertriglyceridaemic hamsters, FGT administration significantly reduced plasma TAG levels. In mice, FGT administration (500 mg/kg) for 2 weeks augmented energy expenditure by 22 % through the induction of plasma serotonin, a neurotransmitter that modulates energy expenditure and mRNA expressions of lipid metabolism genes in peripheral tissues. Analysis of the gut microbiota showed that FGT reduced the proportion of the phylum Firmicutes in hamsters, which could further contribute to its anti-obesity effects. Collectively, these data demonstrate that FGT decreases plasma TAG levels via multiple mechanisms including inhibition of pancreatic lipase, augmentation of energy expenditure, induction of serotonin secretion and alteration of gut microbiota. These results suggest that FGT may be a useful natural agent for preventing hypertriglyceridaemia and obesity.

Amyloid fibrils from the N-terminal prion protein fragment are infectious.

Recombinant C-terminally truncated prion protein PrP23-144 (which corresponds to the Y145Stop PrP variant associated with a Gerstmann-Sträussler-Scheinker-like prion disease) spontaneously forms amyloid fibrils with a parallel in-register ß-sheet architecture and ß-sheet core mapping to residues ∼112-139. Here we report that mice (both tga20 and wild type) inoculated with a murine (moPrP23-144) version of these fibrils develop clinical prion disease with a 100% attack rate. Remarkably, even though fibrils in the inoculum lack the entire C-terminal domain of PrP, brains of clinically sick mice accumulate longer proteinase K-resistant (PrPres) fragments of ∼17-32 kDa, similar to those observed in classical scrapie strains. Shorter, Gerstmann-Sträussler-Scheinker-like PrPres fragments are also present. The evidence that moPrP23-144 amyloid fibrils generated in the absence of any cofactors are bona fide prions provides a strong support for the protein-only hypothesis of prion diseases in its pure form, arguing against the notion that nonproteinaceous cofactors are obligatory structural components of all infectious prions. Furthermore, our finding that a relatively short ß-sheet core of PrP23-144 fibrils (residues ∼112-139) with a parallel in-register organization of ß-strands is capable of seeding the conversion of full-length prion protein to the infectious form has important implications for the ongoing debate regarding structural aspects of prion protein conversion and molecular architecture of mammalian prions.

Multi-polydioxanone (PDO) scaffold for forehead wrinkle correction: A pilot study.

BACKGROUND: Forehead wrinkles are the result of contracture of the frontalis muscle and the skin aging process. Currently, hyaluronic acid filler and botulinum toxin are the main materials used for correction of these wrinkles. In addition, polydioxanone (PDO) thread has also been applied for this treatment. OBJECTIVE: In order to evaluate the efficacy and safety of multi-PDO scaffold in animal and human skin, we tested PDO insertion in rat and mini-pig models and human volunteers with forehead wrinkles. METHODS: A stent-shaped multi-PDO scaffold was inserted under the panniculus carnosus of rat dorsal skin and the subcutaneous layer of mini-pig dorsal skin and forehead wrinkles in three human volunteers. RESULTS: Histological analysis at 12 weeks revealed evidence of de novo collagen synthesis, which was consistent with clinical results on photo evaluation. CONCLUSION: Stent-shaped multi-PDO scaffolds may be another effective and safe treatment modality for reduction of forehead wrinkles.

Soluble prion protein and its N-terminal fragment prevent impairment of synaptic plasticity by Aß oligomers: Implications for novel therapeutic strategy in Alzheimer's disease.

The pathogenic process in Alzheimer's disease (AD) appears to be closely linked to the neurotoxic action of amyloid-ß (Aß) oligomers. Recent studies have shown that these oligomers bind with high affinity to the membrane-anchored cellular prion protein (PrP(C)). It has also been proposed that this binding might mediate some of the toxic effects of the oligomers. Here, we show that the soluble (membrane anchor-free) recombinant human prion protein (rPrP) and its N-terminal fragment N1 block Aß oligomers-induced inhibition of long-term potentiation (LTP) in hippocampal slices, an important surrogate marker of cognitive deficit associated with AD. rPrP and N1 are also strikingly potent inhibitors of Aß cytotoxicity in primary hippocampal neurons. Furthermore, experiments using hippocampal slices and neurons from wild-type and PrP(C) null mice (as well as rat neurons in which PrP(C) expression was greatly reduced by gene silencing) indicate that, in contrast to the impairment of synaptic plasticity by Aß oligomers, the cytotoxic effects of these oligomers, and the inhibition of these effects by rPrP and N1, are independent of the presence of endogenous PrP(C). This suggests fundamentally different mechanisms by which soluble rPrP and its fragments inhibit these two toxic responses to Aß. Overall, these findings provide strong support to recent suggestions that PrP-based compounds may offer new avenues for pharmacological intervention in AD.