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JOURNAL ARTICLE
Lea Jessica Albrecht, Anna Höwner, Klaus Griewank, Smiths S Lueong, Nils von Neuhoff, Peter A Horn, Antje Sucker, Annette Paschen, Elisabeth Livingstone, Selma Ugurel, Lisa Zimmer, Susanne Horn, Jens T Siveke, Dirk Schadendorf, Renáta Váraljai, Alexander Roesch
BACKGROUND: Plasma-derived tumour-specific cell-free nucleic acids are increasingly utilized as a minimally invasive, real-time biomarker approach in many solid tumours. Circulating tumour DNA of melanoma-specific mutations is currently the best studied liquid biopsy biomarker for melanoma. However, the combination of hotspot genetic alterations covers only around 80% of all melanoma patients. Therefore, alternative approaches are needed to enable the follow-up of all genotypes, including wild-type...
November 2022: Clinical and Translational Medicine
#22
RANDOMIZED CONTROLLED TRIAL
Ana Ramos-Levi, Ana Barabash, Johanna Valerio, Nuria García de la Torre, Leire Mendizabal, Mirella Zulueta, Maria Paz de Miguel, Angel Diaz, Alejandra Duran, Cristina Familiar, Inés Jimenez, Laura Del Valle, Veronica Melero, Inmaculada Moraga, Miguel A Herraiz, María José Torrejon, Maddi Arregi, Laureano Simón, Miguel A Rubio, Alfonso L Calle-Pascual
Hypothesis: Gestational diabetes mellitus (GDM) entails a complex underlying pathogenesis, with a specific genetic background and the effect of environmental factors. This study examines the link between a set of single nucleotide polymorphisms (SNPs) associated with diabetes and the development of GDM in pregnant women with different ethnicities, and evaluates its potential modulation with a clinical intervention based on a Mediterranean diet. Methods: 2418 women from our hospital-based cohort of pregnant women screened for GDM from January 2015 to November 2017 (the San Carlos Cohort, randomized controlled trial for the prevention of GDM ISRCTN84389045 and real-world study ISRCTN13389832) were assessed for evaluation...
2022: Frontiers in Endocrinology
#23
JOURNAL ARTICLE
Vladimir Volloch, Sophia Rits-Volloch
We posit that Alzheimer's disease (AD) is driven by amyloid-β (Aβ) generated in the amyloid-β protein precursor (AβPP) independent pathway activated by AβPP-derived Aβ accumulated intraneuronally in a life-long process. This interpretation constitutes the Amyloid Cascade Hypothesis 2.0 (ACH2.0). It defines a tandem intraneuronal -Aβ ( i Aβ)-anchored cascade occurrence: intraneuronally-accumulated, AβPP-derived i Aβ triggers relatively benign cascade that activates the AβPP-independent i Aβ-generating pathway, which, in turn, initiates the second, devastating cascade that includes tau pathology and leads to neuronal loss...
2022: JAD Reports
#24
JOURNAL ARTICLE
Lingfeng Tang, Di Zhang, Pu Han, Xinrui Kang, Anqi Zheng, Zepeng Xu, Xin Zhao, Vivien Ya-Fan Wang, Jianxun Qi, Qihui Wang, Kefang Liu, George F Gao
Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused a global pandemic. Intermediate horseshoe bats ( Rhinolophus affinis ) are hosts of RaTG13, the second most phylogenetically related viruses to SARS-CoV-2. We report the binding between intermediate horseshoe bat ACE2 (bACE2-Ra) and SARS-CoV-2 receptor-binding domain (RBD), supporting the pseudotyped SARS-CoV-2 viral infection. A 3.3 Å resolution crystal structure of the bACE2-Ra/SARS-CoV-2 RBD complex was determined...
2022: International Journal of Biological Sciences
#25
JOURNAL ARTICLE
Sophie-Marie Aicher, Felix Streicher, Maxime Chazal, Delphine Planas, Dongsheng Luo, Julian Buchrieser, Monika Nemcova, Veronika Seidlova, Jan Zukal, Jordi Serra-Cobo, Dominique Pontier, Bertrand Pain, Gert Zimmer, Olivier Schwartz, Philippe Roingeard, Jiri Pikula, Laurent Dacheux, Nolwenn Jouvenet
Bats are natural reservoirs of numerous coronaviruses, including the potential ancestor of SARS-CoV-2. Knowledge concerning the interaction between coronaviruses and bat cells is sparse. We investigated the ability of primary cells from Rhinolophus and Myotis species, as well as of established and novel cell lines from Myotis myotis , Eptesicus serotinus , Tadarida brasiliensis , and Nyctalus noctula, to support SARS-CoV-2 replication. None of these cells were permissive to infection, not even the ones expressing detectable levels of angiotensin-converting enzyme 2 (ACE2), which serves as the viral receptor in many mammalian species...
July 5, 2022: Journal of Virology
#26
JOURNAL ARTICLE
Paige Mumford, Justin Tosh, Silvia Anderle, Eleni Gkanatsiou Wikberg, Gloria Lau, Sue Noy, Karen Cleverley, Takashi Saito, Takaomi C Saido, Eugene Yu, Gunnar Brinkmalm, Erik Portelius, Kaj Blennow, Henrik Zetterberg, Victor Tybulewicz, Elizabeth M C Fisher, Frances K Wiseman
Individuals who have Down syndrome (DS) frequently develop early onset Alzheimer's disease (AD), a neurodegenerative condition caused by the buildup of aggregated amyloid-β (Aβ) and tau proteins in the brain. Aβ is produced by amyloid precursor protein ( APP ), a gene located on chromosome 21. People who have DS have three copies of chromosome 21 and thus also an additional copy of APP ; this genetic change drives the early development of AD in these individuals. Here we use a combination of next-generation mouse models of DS (Tc1, Dp3Tyb, Dp(10)2Yey and Dp(17)3Yey) and a knockin mouse model of Aβ accumulation ( AppNL-F ) to determine how chromosome 21 genes, other than APP , modulate APP/Aβ in the brain when in three copies...
August 17, 2022: Journal of Neuroscience
#27
JOURNAL ARTICLE
Baljit Kaur, Vivesh, Palwinder Singh
Alzheimer's disease (AD) is a common neurodegenerative disorder which is almost incurable with the existing therapeutic interventions. Due to the high-risk factors associated with this disease, there is a global pursuit of new anti-AD agents. Herein, we explore the biochemical pathways which are responsible for the initiation/propagation of the disease. It is observed that out of the two isoforms of β-secretase, β-site amyloid precursor protein cleaving enzyme 1 (BACE1) and β-site amyloid precursor protein cleaving enzyme 2 (BACE2) present in the brain, BACE1 plays the predominant role in the commencement of AD...
July 1, 2022: Mini Reviews in Medicinal Chemistry
#28
JOURNAL ARTICLE
Chen Lyu, Manyan Huang, Nianjun Liu, Zhongxue Chen, Philip J Lupo, Benjamin Tycko, John S Witte, Charlotte A Hobbs, Ming Li
MOTIVATION: CpG sites within the same genomic region often share similar methylation patterns and tend to be co-regulated by multiple genetic variants that may interact with one another. RESULTS: We propose a multi-trait methylation random field (multi-MRF) method to evaluate the joint association between a set of CpG sites and a set of genetic variants. The proposed method has several advantages. First, it is a multi-trait method that allows flexible correlation structures between neighboring CpG sites (e...
July 4, 2022: Bioinformatics
#29
JOURNAL ARTICLE
M C Fabbri, A Crovetti, L Tinacci, F Bertelloni, A Armani, M Mazzei, F Fratini, R Bozzi, F Cecchi
Wild boar (Sus scrofa L.) is one of the large mammals most spread worldwide, highly adaptable, and its population rapidly increased in many areas in Europe, including Italy, where Tuscany is considered particularly suitable for wild boar. Wild boars are potential hosts for different etiological agents, such as Brucella spp., Leptospira spp. and Pseudorabies virus and they can contribute to maintain and/or to disseminate some bacterial or viral pathogens to humans and domestic animals, above all-in free-range farms...
May 17, 2022: Scientific Reports
#30
JOURNAL ARTICLE
Jiamou Ren, Shuli Zhang, Xiaoling Wang, Yuxin Deng, Yi Zhao, Yan Xiao, Jian Liu, Liangzhao Chu, Xiaolan Qi
Myocyte enhancer factor 2C (MEF2C) is highly expressed in the nervous system, and regulates neuro-development, synaptic plasticity, and inflammation. However, its mechanism in Alzheimer's disease (AD) is underestimated. In this study, the role and mechanism of MEF2C were investigated in the brain tissue specimens from patients with AD, APPswe/PSEN1dE9 double transgenic (APP/PS1_DT) mice, and SH-SY5Y cells treated with β-amyloid peptide (Aβ). The results indicated that the expression of MEF2C is significantly reduced, and the expression of MEF2C/Aβ in different parts of brain is negatively correlated in patients with AD...
January 25, 2022: Acta Biochimica et Biophysica Sinica
#31
JOURNAL ARTICLE
Juan Luo, Hailin Zou, Yibo Guo, Ke Huang, Elly Sau-Wai Ngan, Peng Li
β-site APP-cleaving enzyme 2 (BACE2) is a homolog of BACE1, which is considered as the most promising therapeutic target for Alzheimer's disease (AD). However, the expression and functional role of BACE2 in central nervous system (CNS) remain obscured. Previously, we identified several BACE2 rare variants in Hirschsprung disease (HSCR) patients and proved that BACE2-mediated APP cleavage might represent a novel HSCR pathogenesis mechanism in enteric nervous system. Here, we validated that these HSCR-associated BACE2 variants were loss-of-function mutations...
February 2, 2022: Cell Death Discovery
#32
JOURNAL ARTICLE
Calwing Liao, Charles-Etienne Castonguay, Karl Heilbron, Veikko Vuokila, Miranda Medeiros, Gabrielle Houle, Fulya Akçimen, Jay P Ross, Helene Catoire, Monica Diez-Fairen, Jooeun Kang, Stefanie H Mueller, Simon L Girard, Franziska Hopfner, Delia Lorenz, Lorraine N Clark, Alexandra I Soto-Beasley, Stephan Klebe, Mark Hallett, Zbigniew K Wszolek, Manuela Pendziwiat, Oswaldo Lorenzo-Betancor, Klaus Seppi, Daniela Berg, Carles Vilariño-Güell, Ronald B Postuma, Geneviève Bernard, Nicolas Dupré, Joseph Jankovic, Claudia M Testa, Owen A Ross, Thomas Arzberger, Sylvain Chouinard, Elan D Louis, Paola Mandich, Carmine Vitale, Paolo Barone, Elena García-Martín, Hortensia Alonso-Navarro, José A G Agúndez, Félix Javier Jiménez-Jiménez, Pau Pastor, Alex Rajput, Günther Deuschl, Gregor Kuhlenbaümer, Inge A Meijer, Patrick A Dion, Guy A Rouleau
Importance: Essential tremor (ET) is one of the most common movement disorders, affecting 5% of the general population older than 65 years. Common variants are thought to contribute toward susceptibility to ET, but no variants have been robustly identified. Objective: To identify common genetic factors associated with risk of ET. Design, Setting, and Participants: Case-control genome-wide association study. Inverse-variance meta-analysis was used to combine cohorts...
February 1, 2022: JAMA Neurology
#33
JOURNAL ARTICLE
BACE1: a key regulator in Alzheimer's disease progression and current development of its inhibitors.
Smith Patel, Ankush Vardhaman Bansoad, Rakesh Singh, Gopal L Khatik
BACKGROUND: Alzheimer's disease (AD) is a chronic neurodegenerative disease where no specific disease-modifying treatment is currently available. β-secretase (BACE1) is considered the potential and rationale target because it is involved in the rate-limiting step, which produces toxic Aβ42 peptides leading to deposits in the form of amyloid plaques extracellularly leading to AD. OBJECTIVE: The role and implications of BACE1 and its inhibitors in the management of AD are discussed...
November 30, 2021: Current Neuropharmacology
#34
JOURNAL ARTICLE
Carolina Francelin, Sayak K Mitter, Qingwen Qian, Sandeep Kumar Barodia, Colin Ip, Xiaoping Qi, Hongmei Gu, Judith Quigley, Matthew S Goldberg, Maria B Grant, Michael E Boulton
BACE1 is a key enzyme facilitating the generation of neurotoxic β-amyloid (Aβ) peptide. However, given that BACE1 has multiple substrates we explored the importance of BACE1 in the maintenance of retinal pigment epithelial (RPE) cell homeostasis under oxidative stress. Inhibition of BACE1 reduced mitochondrial membrane potential, increased mitochondrial fragmentation, and increased cleaved caspase-3 expression in cells under oxidative stress. BACE1 inhibition also resulted in significantly lower levels of mitochondrial fusion proteins OPA1 and MFN1 suggesting a higher rate of mitochondrial fission while increasing the levels of mitophagic proteins Parkin and PINK1 and autophagosome numbers...
September 28, 2021: Antioxidants (Basel, Switzerland)
#35
JOURNAL ARTICLE
Rainer Machauer, Rainer Lueoend, Konstanze Hurth, Siem J Veenstra, Heinrich Rueeger, Markus Voegtle, Marina Tintelnot-Blomley, Jean-Michel Rondeau, Laura H Jacobson, Grit Laue, Karen Beltz, Ulf Neumann
After identification of lead compound 6 , 5-amino-1,4-oxazine BACE1 inhibitors were optimized in order to improve potency, brain penetration, and metabolic stability. Insertion of a methyl and a trifluoromethyl group at the 6-position of the 5-amino-1,4-oxazine led to 8 ( NB-360 ), an inhibitor with a p K a of 7.1, a very low P-glycoprotein efflux ratio, and excellent pharmacological profile, enabling high central nervous system penetration and exposure. Fur color changes observed with NB-360 in efficacy studies in preclinical animal models triggered further optimization of the series...
October 14, 2021: Journal of Medicinal Chemistry
#36
JOURNAL ARTICLE
Linda M Polfus, Burcu F Darst, Heather Highland, Xin Sheng, Maggie C Y Ng, Jennifer E Below, Lauren Petty, Stephanie Bien, Xueling Sim, Wei Wang, Pierre Fontanillas, Yesha Patel, Michael Preuss, Claudia Schurmann, Zhaohui Du, Yingchang Lu, Suhn K Rhie, Joseph M Mercader, Teresa Tusie-Luna, Clicerio González-Villalpando, Lorena Orozco, Cassandra N Spracklen, Brian E Cade, Richard A Jensen, Meng Sun, Yoonjung Yoonie Joo, Ping An, Lisa R Yanek, Lawrence F Bielak, Salman Tajuddin, Aude Nicolas, Guanjie Chen, Laura Raffield, Xiuqing Guo, Wei-Min Chen, Girish N Nadkarni, Mariaelisa Graff, Ran Tao, James S Pankow, Martha Daviglus, Qibin Qi, Eric A Boerwinkle, Simin Liu, Lawrence S Phillips, Ulrike Peters, Chris Carlson, Lynne R Wikens, Loic Le Marchand, Kari E North, Steven Buyske, Charles Kooperberg, Ruth J F Loos, Daniel O Stram, Christopher A Haiman
Genomic discovery and characterization of risk loci for type 2 diabetes (T2D) have been conducted primarily in individuals of European ancestry. We conducted a multiethnic genome-wide association study of T2D among 53,102 cases and 193,679 control subjects from African, Hispanic, Asian, Native Hawaiian, and European population groups in the Population Architecture Genomics and Epidemiology (PAGE) and Diabetes Genetics Replication and Meta-analysis (DIAGRAM) Consortia. In individuals of African ancestry, we discovered a risk variant in the TGFB1 gene (rs11466334, risk allele frequency (RAF) = 6...
April 8, 2021: HGG advances
#37
JOURNAL ARTICLE
Gregory J Tawa, John Braisted, David Gerhold, Gurmit Grewal, Christina Mazcko, Matthew Breen, Gurusingham Sittampalam, Amy K LeBlanc
Understanding relationships between spontaneous cancer in companion (pet) canines and humans can facilitate biomarker and drug development in both species. Towards this end we developed an experimental-bioinformatic protocol that analyzes canine transcriptomics data in the context of existing human data to evaluate comparative relevance of canine to human cancer. We used this protocol to characterize five canine cancers: melanoma, osteosarcoma, pulmonary carcinoma, B- and T-cell lymphoma, in 60 dogs. We applied an unsupervised, iterative clustering method that yielded five co-expression modules and found that each cancer exhibited a unique module expression profile...
September 27, 2021: PLoS Computational Biology
#38
JOURNAL ARTICLE
Tatsuhiko Ueno, Eriko Matsuoka, Naoya Asada, Shiho Yamamoto, Naoki Kanegawa, Mana Ito, Hisanori Ito, Diederik Moechars, Frederik J R Rombouts, Harrie J M Gijsen, Ken-Ichi Kusakabe
β-Site amyloid precursor protein-cleaving enzyme 1 (BACE1) is considered to be a promising target for treating Alzheimer's disease. However, all clinical BACE1 inhibitors have failed due to lack of efficacy, and some have even led to cognitive worsening. Recent evidence points to the importance of avoiding BACE2 inhibition along with careful dose titration. In this study, we focused on the fact that the 10s loop lining the S3 pocket in BACE1 can form both "open (up)" and "closed (down)" conformations, whereas in BACE2, it prefers to adopt a "closed" form; thus, more space is available in BACE1...
October 14, 2021: Journal of Medicinal Chemistry
#39
JOURNAL ARTICLE
Frederik J R Rombouts, Ken-Ichi Kusakabe, Richard Alexander, Nigel Austin, Herman Borghys, Michel De Cleyn, Deborah Dhuyvetter, Harrie J M Gijsen, Brian Hrupka, Tom Jacobs, Soufyan Jerhaoui, Lieve Lammens, Laurent Leclercq, Koichi Tsubone, Tatsuhiko Ueno, Kenji Morimoto, Shunsuke Einaru, Hirokazu Sumiyoshi, An Van den Bergh, Ann Vos, Michel Surkyn, Ard Teisman, Diederik Moechars
The discovery of a novel 2-aminotetrahydropyridine class of BACE1 inhibitors is described. Their pKa and lipophilicity were modulated by a pending sulfonyl group, while good permeability and brain penetration were achieved via intramolecular hydrogen bonding. BACE1 selectivity over BACE2 was achieved in the S3 pocket by a novel bicyclic ring system. An optimization addressing reactive metabolite formation, cardiovascular safety, and CNS toxicity is described, leading to the clinical candidate JNJ-67569762 ( 12 ), which gave robust dose-dependent BACE1-mediated amyloid β lowering without showing BACE2-dependent hair depigmentation in preclinical models...
September 23, 2021: Journal of Medicinal Chemistry
#40
JOURNAL ARTICLE
Umesh Chandra Dash, Sandeep Kumar Swain, Satish Kanhar, Purusottam Banjare, Partha Pratim Roy, Jagneshwar Dandapat, Atish Kumar Sahoo
ETHNOPHARMACOLOGICAL RELEVANCE: Geophila repens (L.) I.M. Johnst (Rubiaceae) is a small perennial creeper native to India, China, and other countries in Southeast Asia. The hot decoction of leaves is used orally for memory enhancing by the local folk of Andhra Pradesh, India. The ethnomedicinal claim of G. repens as memory enhancer was initially studied by the authors. Results demonstrated the important antioxidant and anticholinesterase activities of isolated molecule Pentylcurcumene and bioactive hydroalcohol extract of leaves of G...
September 14, 2021: Journal of Ethnopharmacology
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