Accelerating drug discovery for Alzheimer's disease: best practices for preclinical animal studies

Animal models have contributed significantly to our understanding of the underlying biological mechanisms of Alzheimer's disease (AD). As a result, over 300 interventions have been investigated and reported to mitigate pathological phenotypes or improve behavior in AD animal models or both. To date, however, very few of these findings have resulted in target validation in humans or successful translation to disease-modifying therapies. Challenges in translating preclinical studies to clinical trials include the inability of animal models to recapitulate the human disease, variations in breeding and colony maintenance, lack of standards in design, conduct and analysis of animal trials, and publication bias due to under-reporting of negative results in the scientific literature. The quality of animal model research on novel therapeutics can be improved by bringing the rigor of human clinical trials to animal studies. Research communities in several disease areas have developed recommendations for the conduct and reporting of preclinical studies in order to increase their validity, reproducibility, and predictive value. To address these issues in the AD community, the Alzheimer's Drug Discovery Foundation partnered with Charles River Discovery Services (Morrisville, NC, USA) and Cerebricon Ltd. (Kuopio, Finland) to convene an expert advisory panel of academic, industry, and government scientists to make recommendations on best practices for animal studies testing investigational AD therapies. The panel produced recommendations regarding the measurement, analysis, and reporting of relevant AD targets, th choice of animal model, quality control measures for breeding and colony maintenance, and preclinical animal study design. Major considerations to incorporate into preclinical study design include a priori hypotheses, pharmacokinetics-pharmacodynamics studies prior to proof-of-concept testing, biomarker measurements, sample size determination, and power analysis. The panel also recommended distinguishing between pilot 'exploratory' animal studies and more extensive 'therapeutic' studies to guide interpretation. Finally, the panel proposed infrastructure and resource development, such as the establishment of a public data repository in which both positive animal studies and negative ones could be reported. By promoting best practices, these recommendations can improve the methodological quality and predictive value of AD animal studies and make the translation to human clinical trials more efficient and reliable

Kynurenine 3-Monooxygenase Inhibition in Blood Ameliorates Neurodegeneration

SummaryMetabolites in the kynurenine pathway, generated by tryptophan degradation, are thought to play an important role in neurodegenerative disorders, including Alzheimer's and Huntington's diseases. In these disorders, glutamate receptor-mediated excitotoxicity and free radical formation have been correlated with decreased levels of the neuroprotective metabolite kynurenic acid. Here, we describe the synthesis and characterization of JM6, a small-molecule prodrug inhibitor of kynurenine 3-monooxygenase (KMO). Chronic oral administration of JM6 inhibits KMO in the blood, increasing kynurenic acid levels and reducing extracellular glutamate in the brain. In a transgenic mouse model of Alzheimer's disease, JM6 prevents spatial memory deficits, anxiety-related behavior, and synaptic loss. JM6 also extends life span, prevents synaptic loss, and decreases microglial activation in a mouse model of Huntington's disease. These findings support a critical link between tryptophan metabolism in the blood and neurodegeneration, and they provide a foundation for treatment of neurodegenerative diseases

COL25A1 triggers and promotes Alzheimer’s disease-like pathology in vivo

Collagen XXV alpha 1 (COL25A1) is a collagenous type II transmembrane protein purified from senile plaques of Alzheimer’s disease (AD) brains. COL25A1 alleles have been associated with increased risk for AD in a Swedish population. COL25A1 is specifically expressed in neurons and binds to aggregated Aβ in vitro. However, its contribution to the pathogenesis of AD and in vivo function are unknown. Here, we report that over-expression of COL25A1 in transgenic mice increases p35/p25 and β-site APP-cleaving enzyme 1 (BACE1) levels, facilitates intracellular aggregation and extracellular matrix deposits of Aβ, and causes synaptophysin loss and astrocyte activation. COL25A1 mice displayed reduced anxiety-like behavior in elevated plus maze and open field tests and significantly slower swimming speed in Morris water maze. In stable cell lines, motifs in noncollagenous domains of COL25A1 were important for the induction of BACE1 expression. These findings demonstrate that COL25A1 leads to AD-like pathology in vivo. Modulation of COL25A1 function may represent an alternative therapeutic intervention for AD

Wellbeing indicators affecting female entrepreneurship in OECD countries

[EN] The objective of this research is to know which wellbeing indicators, such as work-life balance, educational level, income or job security, are related to the rate of female entrepreneurship in 29 OECD countries. In addition, these countries have been classified according to the motivation of the entrepreneur either by necessity or by opportunity. The empiric study is focused on 29 OECD countries covering the different geographic areas (Western Europe, Central and Eastern Europe, Middle East, etc.) Due to the fact that the sample is relatively small, it is essential to use a selective approach when selecting the causal conditions. To this end, fsQCA is the most appropriate methodology for such a small data set. A total of 5 variables have been used: an independent variable (female TEA ratio), and four dependent variables (work life balance, educational level, sustainable household income and job security). Data measuring female TEA ratio have been obtained from Global Entrepreneur Monitor (GEM in Global report, 2015) data base, while data measuring wellbeing dimensions were taken from the Better Life Index (OECD in How¿s life? Measuring wellbeing, 2015. http://www.oecdbetterlifeindex.org). The results of this piece of research show that countries with high sustainable household income together with high level of education achieves high female entrepreneurship ratio with both, a good work-life balance (despite of a high unemployment probability), or a high labour-personal imbalance (in this latter, with a low probability of unemployment).This work has been funded by the R + D project for emerging research groups with reference (GVA) GV/2016/078.Ribes-Giner, G.; Moya Clemente, I.; Cervelló Royo, RE.; Perelló Marín, MR. (2019). Wellbeing indicators affecting female entrepreneurship in OECD countries. 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Res. 21(3), 472–488 (2015). https://doi.org/10.1108/IJEBR-12-2013-0210Bianchi, M., Parisi, V., Salvatore, R.: Female entrepreneurs: motivations and constraints. An Italian regional study. Int. J. Gend. Entrep. 8(3), 198–220 (2016). https://doi.org/10.1108/IJGE-08-2015-0029Bittencourt Marconatto, D.A., Barin-Cruz, L., Pozzebon, M., Poitras, J.E.: Developing sustainable business models within BOP contexts: mobilizing native capability to cope with government programs. J. Clean. Prod. 129, 735–748 (2016). https://doi.org/10.1016/j.jclepro.2016.03.038Boarini, R., Comola, M., Smith, C., Manchin, R., de Keulenaer, F.: What makes for a better life? The determinants of subjective well-being in OECD countries—evidence from the Gallup World Poll. OECD statistics working papers, 2012(3), 0_1 (2012). https://doi.org/10.1787/5k9b9ltjm937-enBoarini, R., D’Ercole, M.M.: Going beyond GDP: an OECD perspective. Fisc. 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Wellbeing 2(3), 222–235 (2012). https://doi.org/10.5502/ijw.v2i3.4Fiss, P.C.: Building better casual theories: a fuzzy set approach to typologies in organization research. Acad. Manag. J. 54(2), 393–420 (2011)Fleche, S., Smith, C., Sorsa, P.: Exploring determinants of subjective wellbeing in OECD countries (2011)Fleche, S., Smith, C., Sorsa, P.: Exploring determinants of subjective wellbeing in OECD countries evidence from the world value survey. Working papers, OECD Statistics (2012). https://doi.org/10.1787/5kg0k6zlcm5k-enFoley, A., Griffith, B.: Education, training and the promotion of high quality entrepreneurs in the Republic of Ireland. In: Scott, M.G., Rosa, P., Klandt, H. (eds.) Educating Entrepreneurs for Wealth Creation. Ashgate, Aldershot (1998)Garikipati, S.: Microcredit and women’s empowerment: through the lens of time-use data from rural India. Dev. Change 43(3), 719–750 (2012). https://doi.org/10.1111/j.1467-7660.2012.01780.xGEM (Global Entrepreneurship Monitor): Global report (2015)Harter, J.K., Schmidt, F.L., Keyes, C.L.M.: Wellbeing in the workplace and its relationship to business outcomes. A review of the Gallup studies. In: Keyes, C.L.M., Haidt, J. (eds.) Flourishing: The Positive Person and the Good Life, pp. 205–224. American Psychologi cal Association, Washington (2003)Henry, C., Foss, L., Ahl, H.: Gender and entrepreneurship research: a review of methodological approaches. Int. Small Bus. J. 34(3), 217–241 (2015). https://doi.org/10.1177/0266242614549779Hessels, J., Van Gelderen, M., Thurik, R.: Entrepreneurial aspirations, motivations, and their drivers”. Small Bus. Econ. 31(3), 323–339 (2008). https://doi.org/10.1007/s11187-008-9134-xIezzi, D.F., Deriu, F.: Women active citizenship and wellbeing: the Italian case. Qual. Quant. 48(2), 845–862 (2014)Jansson, T.: Housing choices and labor income risk. J. Urban Econ. 99, 107–119 (2017). https://doi.org/10.1016/j.jue.2016.12.006Johansen, V., Foss, L.: The effects of entrepreneurship education—does gender matter? Int. J. Entrep. Small Bus. 20(3), 255–271 (2013). https://doi.org/10.1504/IJESB.2013.056889Judge, W.Q., Hu, H.W., Gabrielsson, J., Talaulicar, T., Witt, M.A., Zattoni, A., Kibler, B.: Configurations of capacity for change in entrepreneurial threshold firms: imprinting and strategic choice perspectives. J. Manag. Stud. 52(4), 506–530 (2015). https://doi.org/10.1111/joms.12121Kautonen, T., Kibler, E., Minniti, M.: Late-career entrepreneurship, income and quality of life. J. Bus. Ventur. 32(3), 318–333 (2017). https://doi.org/10.1016/j.jbusvent.2017.02.005Kephart, P., Schumacher, L.: Has the “glass ceiling” cracked? An exploration of women entrepreneurship. J. Leadersh. Organ. Stud. 12(1), 2–15 (2005). https://doi.org/10.1177/107179190501200102Kirkwood, J.: Motivational factors in a push–pull theory of entrepreneurship. Gend. Manag. Int. J. 24(5), 346–364 (2009). https://doi.org/10.1108/17542410910968805Kobeissi, N.: Gender factors and female entrepreneurship: International evidence and policy implications. J. Int. Entrep. 8, 1–35 (2010). Retrieved from https://doi.org/10.1007/s10843-010-0045-yKuckertz, A., Berger, E.S.C., Allmendinger, M.P.: What drives entrepreneurship? A configurational analysis of the determinants of entrepreneurship in innovation-driven economies. Die Betriebswirtschaft/Bus. Adm. Rev. 75(4), 273–288 (2015). https://doi.org/10.1017/cbo9781107415324.004La Placa, V., McNaught, A., Knight, A.: Discourse on wellbeing in research and practice. Int. J. Wellbeing 3, 116–125 (2013). https://doi.org/10.5502/ijw.v3i1.7Langowitz, N., Minniti, M.: The entrepreneurial propensity of women. Entrep. 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Stockholm School of Economics, Stockholm (2015)Thiem, A., Dusa, A.: QCA: a package for qualitative comparative analysis. R package version 2.0. R J. 5, 87–97 (2013). Retrieved from https://cran.r-project.org/web/packages/QCA/index.htmlTorri, M.M.C., Martinez, A.: Women’s empowerment and micro-entrepreneurship in India: constructing a new development paradigm? Prog. Dev. Stud. 14(1), 31–48 (2014). https://doi.org/10.1177/1464993413504347Tur-Porcar, A., Mas-Tur, A., Belso, J.A.: Barriers to women entrepreneurship. Different methods, different results? Qual. Quant. 51(5), 2019–2034 (2017)Uy, M.A., Foo, M.Der, Song, Z.: Joint effects of prior start-up experience and coping strategies on entrepreneurs’ psychological wellbeing. J. Bus. Ventur. 28(5), 583–597 (2013). https://doi.org/10.1016/j.jbusvent.2012.04.003Uy, M.A., Sun, S., Foo, M.Der: Affect spin, entrepreneurs’ wellbeing, and venture goal progress: the moderating role of goal orientation. J. Bus. 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Management of thyroid nodules

SCOPUS: re.jinfo:eu-repo/semantics/publishe

COVID-19 and olfactory dysfunction : an ENT perspective to the current COVID-19 pandemic

The current COVID-19 or Sars-CoV-2 pandemic increased awareness of hyposmia or anosmia, as this can be an accompanying symptom. In mild cases, anosmia without rhinorrhea can be the only presenting symptom of this infection. Timely identification can lead to early detection of otherwise asymptomatic carriers. History taking and essential clinical assessment with appropriate protective measures can be performed in patients in whom COVID-19 is suspected. Patients with anosmia without nasal obstruction should be considered COVID-19 suspect and this should initiate testing or self-isolation. As for treatment of hyposmia or anosmia, the authors do not advise treatment with systemic corticosteroids in patients with COVID-19. Based on expert opinion, nasal corticosteroids can be considered, with a preference for spray formulation. Patients who were already using topical or inhalation corticosteroids for proven pre-existing disease (such as asthma and/or allergy) should be advised to continue their maintenance therapy. ENT (Ear Nose Throat) focus on hyposmia and anosmia should be continued, to gain additional knowledge of the disease mechanisms of COVID-19 and improve follow-up, not only on the pneumological aspects but also to evaluate the impact on quality of life of potentially long-term side effects caused by anosmia

COVID-19 and olfactory dysfunction - an ENT perspective to the current COVID-19 pandemic

status: publishe

GluN2A-Selective Pyridopyrimidinone Series of NMDAR Positive Allosteric Modulators with an Improved <i>in Vivo</i> Profile

The <i>N</i>-methyl-d-aspartate receptor (NMDAR) is an ionotropic glutamate receptor, gated by the endogenous coagonists glutamate and glycine, permeable to Ca²⁺ and Na⁺. NMDAR dysfunction is associated with numerous neurological and psychiatric disorders, including schizophrenia, depression, and Alzheimer’s disease. Recently, we have disclosed GNE-0723 (<b>1</b>), a GluN2A subunit-selective and brain-penetrant positive allosteric modulator (PAM) of NMDARs. This work highlights the discovery of a related pyridopyrimidinone core with distinct structure–activity relationships, despite the structural similarity to GNE-0723. GNE-5729 (<b>13</b>), a pyridopyrimidinone-based NMDAR PAM, was identified with both an improved pharmacokinetic profile and increased selectivity against AMPARs. We also include X-ray structure analysis and modeling to propose hypotheses for the activity and selectivity differences