London Report: The Lords Committee Speaks Walter C. Patterson

Patterson, Walter C.

doi:10.1080/00139157.1975.9929646

Cited by 8 publications

(12 citation statements)

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“…Alzheimer’s disease (AD), the most common form of dementia (∼70%) in the elderly, is a chronic and neurodegenerative brain disorder characterized by memory loss and other cognitive impairments. In 2018, the number of people living with dementia in the world was estimated at 50 million and this number will likely more than triple to 152 million by 2050 . With only four drugs approved (Donepezil, Galantamine, Rivastigmine, and Memantine) to barely relieve the symptoms of AD, finding a cure, or at least a treatment that delays the progression of the disease, remains a real challenge for the community.…”

Section: Introduction: General Remarks About Alzheimer’s Disease Nowa...mentioning

confidence: 99%

Matrix Metalloproteinases as New Targets in Alzheimer’s Disease: Opportunities and Challenges

et al. 2020

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Although matrix metalloproteinases (MMPs) are implicated in the regulation of numerous physiological processes, evidences of their pathological roles have also been obtained in the last decades, making MMPs attractive therapeutic targets for several diseases. Recent discoveries of their involvement in central nervous system (CNS) disorders, and in particular in Alzheimer's disease (AD), have paved the way to consider MMP modulators as promising therapeutic strategies. Over the past few decades, diverse approaches have been undertaken in the design of 2 therapeutic agents targeting MMPs for various purposes, leading, more recently, to encouraging developments. In this article, we will present recent examples of inhibitors ranging from small molecules and peptidomimetics to biologics. We will also discuss the scientific knowledge that has led to the development of emerging tools and techniques to overcome the challenges of selective MMP inhibition.

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Section: Introduction: General Remarks About Alzheimer’s Disease Nowa...mentioning

confidence: 99%

Matrix Metalloproteinases as New Targets in Alzheimer’s Disease: Opportunities and Challenges

et al. 2020

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“…An estimated 50 million people globally are living with dementia, and that number is expected to triple by the year 2050. 1 Alzheimer’s disease (AD) is the most common cause of dementia, responsible for approximately 60% of cases, affects 10% of people over the age of 65, and is currently the sixth leading cause of death in the United States. 2 The available FDA-approved treatments for those suffering with AD are designed to slow the cognitive decline associated with the underlying neurodegeneration, not stop or slow the disease progress, and there have been no new treatments approved since 2003.…”

Section: Introductionmentioning

confidence: 99%

Machine Learning for Discovery of GSK3β Inhibitors

et al. 2020

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Alzheimer’s disease (AD) is the most common cause of dementia, affecting approximately 35 million people worldwide. The current treatment options for people with AD consist of drugs designed to slow the rate of decline in memory and cognition, but these treatments are not curative, and patients eventually suffer complete cognitive injury. With the substantial amounts of published data on targets for this disease, we proposed that machine learning software could be used to find novel small-molecule treatments that can supplement the AD drugs currently on the market. In order to do this, we used publicly available data in ChEMBL to build and validate Bayesian machine learning models for AD target proteins. The first AD target that we have addressed with this method is the serine–threonine kinase glycogen synthase kinase 3 beta (GSK3β), which is a proline-directed serine–threonine kinase that phosphorylates the microtubule-stabilizing protein tau. This phosphorylation prompts tau to dissociate from the microtubule and form insoluble oligomers called paired helical filaments, which are one of the components of the neurofibrillary tangles found in AD brains. Using our Bayesian machine learning model for GSK3β consisting of 2368 molecules, this model produced a five-fold cross validation ROC of 0.905. This model was also used for virtual screening of large libraries of FDA-approved drugs and clinical candidates. Subsequent testing of selected compounds revealed a selective small-molecule inhibitor, ruboxistaurin, with activity against GSK3β (avg IC 50 = 97.3 nM) and GSK3α (IC 50 = 695.9 nM). Several other structurally diverse inhibitors were also identified. We are now applying this machine learning approach to additional AD targets to identify approved drugs or clinical trial candidates that can be repurposed as AD therapeutics. This represents a viable approach to accelerate drug discovery and do so at a fraction of the cost of traditional high throughput screening.

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“…I have departed from this nomenclature in three cases, using intercalar for his opisthotic, vomer for pre vomer, and six hypurals plus a parhypural as opposed to seven hypurals. In addition, I have added, in parentheses, the more recent terminology for the bones of the lower jaw (Nelson, 1973), hyoid arch (Nelson, 1969) and occipital region (Patterson, 1975).…”

Section: Osteology Section Introductionmentioning

confidence: 99%

Systematics, osteology and the phylogenetic relationships of fishes of the Ostariophysan subfamily Anostominae (Characoidei, Anostominae)

Winterbottom¹

1980

117

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The systematics of the South American characoid subfamily Anostominae is reviewed on the basis of 36 morphometric and meristic characters, and the osteology is described. A new genus, Pseudanos, is described for a monophyletic lineage previously assigned to Anostomus. Two new species, Anostomus intermedius dind Pseudanos irinae, are described. The subfamily consists of five genera, three of which are monotypic. A hypothesis of the phylogenetic relationships of the members of the Anostominae is presented, based primarily on their osteology. The monotypic genera together form a monophyletic assemblage. Zoogeographic interpretations are not attempted, since vast areas (particularly in the central Amazon basin) are as yet either not or inadequately sampled. Considerable distributional extensions and discovery of new forms are to be expected in the future. Abstracto La sistematica de los Characoides Sud-Americanos (Caracoides), subfamilia Anostominae es revisada en base a 36 caracteres morfometricos y meristicos, describiendo tambien su osteologia. Un nuevo genero, Pseudanos es descrito en un lineage monofiletico, anteriormente asignado a Anostomus. Dos nuevas especies son descritas: Anostomus intermedius y Pseudanos irinae. La subfamilia consiste de cinco generos, tres de los cuales son monotipicos. Se presento una hipotesis de la relacion filetica de los Anostominae, basada principalmente en su osteologia. Los generos monotipicos forman en conjunto un grupo monofiletico. Interpretaciones zoogeograficas no son intentadas, ya que regiones muy vastas (especialmente en la Cuenca Central del Amazona) no han sido aun, o solo parcialmente estudiadas. Una distribucion extensional mucho mayor y el descubrimiento de nuevas formas se esperan en el futuro. Although this paper is not concerned with the relationships of the entire family Anostomidae, I propose a new concept for the subfamily Anostominae (here conceived as encompassing the genera Anostomus, Pseudanos, Gnathodolus, Sartor and Synaptolaemus) on the basis of its monophyly (see the diagnosis of the subfamily, p. 4, and discussion, p. 48). Other genera I recognize in the family Anostomidae (but here exclude from the Anostominae) are Abramites, Anostomoides, Laemolvta, Leporellus, Leporinus, Rhytiodus and Schizodon, following Myers (1950) and Gery (1961, 1972/73). This number will probably be increased when further specimens make it possible to describe formally an anostomid with more than 65 lateral line scales from the vicinity of Manaus figured and described (but not named) by Gery (1972/73), and another form from the Essequibo River which has an incomplete lateral line (and is represented by three small specimens in the collections of the National Museum of Canada). After this paper had been accepted for publication, I received a copy of Gery's (1977) "Characoids of the world". In this work, Gery recognizes the family Anostomidae, and includes all the genera accepted here. However, we differ significantly in subsequent subdivision. Gery (op. cit.) recognizes a subfa...

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London Report: The Lords Committee Speaks Walter C. Patterson

Cited by 8 publications

References 0 publications

Matrix Metalloproteinases as New Targets in Alzheimer’s Disease: Opportunities and Challenges

Matrix Metalloproteinases as New Targets in Alzheimer’s Disease: Opportunities and Challenges

Machine Learning for Discovery of GSK3β Inhibitors

Systematics, osteology and the phylogenetic relationships of fishes of the Ostariophysan subfamily Anostominae (Characoidei, Anostominae)

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