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Book: BACE

John, Varghese

lead target for orchestrated therapy of Alzheimer's disease

2010

Author's details	ed. by Varghese John
Keywords	Alzheimer Disease / drug therapy ; Amyloid Precursor Protein Secretases / pharmacology ; Amyloid Precursor Protein Secretases / therapeutic use
Language	English
Size	XVI, 250, [16] S. : Ill., graph. Darst.
Publisher	Wiley-Blackwell
Publishing place	Hoboken, NJ
Publishing country	United States
Document type	Book
Note	Includes bibliographical references and index
HBZ-ID	HT016314758
ISBN	978-0-470-29342-3 ; 0-470-29342-X
Database	Catalogue ZB MED Medicine, Health

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Article: Designing Physical Human-Robot Interaction Interfaces: A Scalable Method for Simulation Based Design.

John Varghese, Rohit / Mukherjee, Gaurav / Deshpande, Ashish

Frontiers in neurorobotics

2022 Volume 15, Page(s) 727534

Abstract: Designing the physical coupling between the human body and the wearable robot is a challenging endeavor. The typical approach of tightening the wearable robot against the body, and softening the interface materials does not work well. It makes the task ... ...

Abstract	Designing the physical coupling between the human body and the wearable robot is a challenging endeavor. The typical approach of tightening the wearable robot against the body, and softening the interface materials does not work well. It makes the task of simultaneously improving comfort, and anchoring the robot to the body at the physical human robot interaction interface (PHRII), difficult. Characterizing this behavior experimentally with sensors at the interface is challenging due to the soft-soft interactions between the PHRII materials and the human tissue. Therefore, modeling the interaction between the wearable robot and the hand is a necessary step to improve design. In this paper, we introduce a methodology to systematically improve the design of the PHRII by combining experimentally measured characteristics of the biological tissue with a novel dynamic modeling tool. Using a novel and scalable simulation framework, HuRoSim, we quantified the interaction between the human hand and an exoskeleton. In the first of our experiments, we use HuRoSim to predict complex interactions between the hand and the coupled exoskeleton. In our second experiment, we then demonstrate how HuRoSim can be coupled with experimental measurements of the stiffness of the dorsal surface of the hand to optimize the design of the PHRII. This approach of data-driven modeling of the interaction between the body and a wearable robot, such as a hand exoskeleton, can be generalized to other forms of wearable devices as well, demonstrating a scalable and systematic method for improving the design of the PHRII for future devices coupled to the body.
Language	English
Publishing date	2022-02-18
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2453002-5
ISSN	1662-5218
ISSN	1662-5218
DOI	10.3389/fnbot.2021.727534
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Article ; Online: Sustainability and inclusiveness in a competitive market

John Varghese Thekkekara

Christian Journal for Global Health, Vol 7, Iss 2, Pp 7-

A study of faith-based hospitals in India

2020 Volume 18

Abstract: Introduction: The Christian Healthcare Network is the largest faith-based healthcare network in India, functioning, most often, in the hard-to-reach and underdeveloped areas. It is facing serious challenges such as being forced to comply with the recent ... ...

Abstract	Introduction: The Christian Healthcare Network is the largest faith-based healthcare network in India, functioning, most often, in the hard-to-reach and underdeveloped areas. It is facing serious challenges such as being forced to comply with the recent changes in government regulations, policies, and globalized market situations. Such changes in the social and financial environment are driving hospitals to adopt newer strategies to remain sustainable. Some of the mission hospitals are compromising their mission goals for which they were founded. If financial viability becomes the goal, social responsibility to the community and the true meaning of mission gets distorted. Their mission must remain the primary belief system, which legitimizes the structural arrangements and ideology of business. Mission and business must go hand-in-hand. Methods: An embedded case study method was used to purposively study 16 selected cases of Christian faith-based hospitals (FBHs) pan India with the objective to understand the nature of services employed, the role played by FBHs in India in different contexts, their challenges in the changing business environment, and how successful they were in remaining both sustainable and inclusive at the same time. Results: The study found that despite the variation in the services and infrastructure of mission hospitals across India, these facilities have had an on-going commitment and a long-standing operation with regard to population health. In their different settings, they are either the only service provider or the referral centre for the public facilities and the trusted choice of the middle- and lower-middle class population. The least sustainable and inclusive among them seem to have deviated from their founding objectives due to market changes, but more than a quarter of them were successful in remaining inclusive and sustainable. In pursuit of competitive advantages, some of them remained sustainable by dropping their inclusiveness, while a few ended up in existential crisis ...
Keywords	faith-based hospitals ; indian mission hospitals ; sustainability ; inclusive healthcare ; not-for-profit hospitals ; Public aspects of medicine ; RA1-1270 ; Practical religion. The Christian life ; BV4485-5099
Subject code	380
Language	English
Publishing date	2020-01-01T00:00:00Z
Publisher	Health for All Nations
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Book: BACE

John, Varghese

lead target for orchestrated therapy of Alzheimer's disease

2010

Author's details	edited by Varghese John
MeSH term(s)	Alzheimer Disease/drug therapy ; Amyloid Precursor Protein Secretases/therapeutic use ; Amyloid Precursor Protein Secretases/pharmacology
Language	English
Size	xvi, 250 p. :, ill.
Publisher	Wiley
Publishing place	Hoboken, N.J
Document type	Book
ISBN	9780470293423 ; 047029342X
Database	Catalogue of the US National Library of Medicine (NLM)

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Article ; Online: Simultaneous isolation of intact brain cells and cell-specific extracellular vesicles from cryopreserved Alzheimer's disease cortex.

Melnik, Mikhail / Miyoshi, Emily / Ma, Ricky / Corrada, Maria / Kawas, Claudia / Bohannan, Ryan / Caraway, Chad / Miller, Carol A / Hinman, Jason D / John, Varghese / Bilousova, Tina / Gylys, Karen H

Journal of neuroscience methods

2024 Volume 406, Page(s) 110137

Abstract: Background: The neuronal and gliaI populations within the brain are tightly interwoven, making isolation and study of large populations of a single cell type from brain tissue a major technical challenge. Concurrently, cell-type specific extracellular ... ...

Abstract	Background: The neuronal and gliaI populations within the brain are tightly interwoven, making isolation and study of large populations of a single cell type from brain tissue a major technical challenge. Concurrently, cell-type specific extracellular vesicles (EVs) hold enormous diagnostic and therapeutic potential in neurodegenerative disorders including Alzheimer's disease (AD). New method: Postmortem AD cortical samples were thawed and gently dissociated. Following filtration, myelin and red blood cell removal, cell pellets were immunolabeled with fluorescent antibodies and analyzed by flow cytometry. The cell pellet supernatant was applied to a triple sucrose cushion for brain EV isolation. Results: Neuronal, astrocyte and microglial cell populations were identified. Cell integrity was demonstrated using calcein AM, which is retained by cells with esterase activity and an intact membrane. For some experiments cell pellets were fixed, permeabilized, and immunolabeled for cell-specific markers. Characterization of brain small EV fractions showed the expected size, depletion of EV negative markers, and enrichment in positive and cell-type specific markers. Comparison with existing methods and conclusions: We optimized and integrated established protocols, aiming to maximize information obtained from each human autopsy brain sample. The uniqueness of our method lies in its capability to isolate cells and EVs from a single cryopreserved brain sample. Our results not only demonstrate the feasibility of isolating specific brain cell subpopulations for RNA-seq but also validate these subpopulations at the protein level. The accelerated study of EVs from human samples is crucial for a better understanding of their contribution to neuron/glial crosstalk and disease progression.
MeSH term(s)	Humans ; Alzheimer Disease/metabolism ; Alzheimer Disease/pathology ; Extracellular Vesicles/metabolism ; Cryopreservation/methods ; Cerebral Cortex/cytology ; Cerebral Cortex/metabolism ; Neurons/metabolism ; Aged ; Male ; Female ; Astrocytes/metabolism ; Aged, 80 and over ; Cell Separation/methods ; Flow Cytometry/methods ; Microglia/metabolism
Language	English
Publishing date	2024-04-14
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	282721-9
ISSN	1872-678X ; 0165-0270
ISSN (online)	1872-678X
ISSN	0165-0270
DOI	10.1016/j.jneumeth.2024.110137
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Article ; Online: Behavioral Deficits and Brain α-Synuclein and Phosphorylated Serine-129 α-Synuclein in Male and Female Mice Overexpressing Human α-Synuclein.

Gabrielyan, Lilit / Liang, Honghui / Minalyan, Artem / Hatami, Asa / John, Varghese / Wang, Lixin

Journal of Alzheimer's disease : JAD

2021 Volume 79, Issue 2, Page(s) 875–893

Abstract: Background: Alpha-synuclein (α-syn) is involved in pathology of Parkinson's disease, and 90% of α-syn in Lewy bodies is phosphorylated at serine 129 (pS129 α-syn).: Objective: To assess behavior impairments and brain levels of α-syn and pS129 α-syn ... ...

Abstract	Background: Alpha-synuclein (α-syn) is involved in pathology of Parkinson's disease, and 90% of α-syn in Lewy bodies is phosphorylated at serine 129 (pS129 α-syn). Objective: To assess behavior impairments and brain levels of α-syn and pS129 α-syn in mice overexpressing human α-syn under Thy1 promoter (Thy1-α-syn) and wild type (wt) littermates. Methods: Motor and non-motor behaviors were monitored, brain human α-syn levels measured by ELISA, and α-syn and pS129 α-syn mapped by immunohistochemistry. Results: Male and female wt littermates did not show differences in the behavioral tests. Male Thy1-α-syn mice displayed more severe impairments than female counterparts in cotton nesting, pole tests, adhesive removal, finding buried food, and marble burying. Concentrations of human α-syn in the olfactory regions, cortex, nigrostriatal system, and dorsal medulla were significantly increased in Thy1-α-syn mice, higher in males than females. Immunoreactivity of α-syn was not simply increased in Thy1-α-syn mice but had altered localization in somas and fibers in a few brain areas. Abundant pS129 α-syn existed in many brain areas of Thy1-α-syn mice, while there was none or only a small amount in a few brain regions of wt mice. The substantia nigra, olfactory regions, amygdala, lateral parabrachial nucleus, and dorsal vagal complex displayed different distribution patterns between wt and transgenic mice, but not between sexes. Conclusion: The severer abnormal behaviors in male than female Thy1-α-syn mice may be related to higher brain levels of human α-syn, in the absence of sex differences in the altered brain immunoreactivity patterns of α-syn and pS129 α-syn.
MeSH term(s)	Animals ; Behavior, Animal ; Brain/metabolism ; Brain/pathology ; Brain Chemistry ; Enzyme-Linked Immunosorbent Assay ; Female ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Phosphorylation ; Serine/metabolism ; Sex Factors ; alpha-Synuclein/analysis ; alpha-Synuclein/metabolism
Chemical Substances	SNCA protein, human ; alpha-Synuclein ; Serine (452VLY9402)
Language	English
Publishing date	2021-01-06
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1440127-7
ISSN	1875-8908 ; 1387-2877
ISSN (online)	1875-8908
ISSN	1387-2877
DOI	10.3233/JAD-200983
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Article: Epidemiology of hospital-based COVID- 19 cluster in a tertiary care cancer hospital, Chennai, India 2020.

Barani, Suganya / Jahan, Nuzrath / Karuppiah, Mathan / Chaudhuri, Sirshendu / Raju, Mohankumar / Ponnaiah, Manickam / Rajaraman, Swaminathan / Vaidhyalingam, Venktesh / Ganeshkumar, Parasuraman / Kumar Cp, Girish / Muthappan, Sendhilkumar / Murugesan, Jegadeesan / Srinivasan, Mahalakshmi / Krishnan, Usha / John Varghese, Alby

Clinical epidemiology and global health

2021 Volume 12, Page(s) 100889

Abstract: Objectives: To identify risk factors associated with Coronavirus disease 2019 (COVID-19) in a Tertiary care cancer hospital-based cluster and recommend control measures.: Methods: We conducted tracing and confirmation among hospital and community ... ...

Abstract	Objectives: To identify risk factors associated with Coronavirus disease 2019 (COVID-19) in a Tertiary care cancer hospital-based cluster and recommend control measures. Methods: We conducted tracing and confirmation among hospital and community contacts. We telephonically interviewed and abstracted information from hospital records and registers. We described the cluster by time, place and person. We conducted unmatched case-control study to compare risk factors and computed Odds Ratio (OR) and 95% confidence interval. Results: We confirmed COVID-19 in 21 of 1478 tested (1.4%). Secondary attack (%) of COVID-19 among 824 contacts was higher among in-patients of block A (18), household contacts (3.4), housekeeping staff (3.3) and nurses (1.7). The cluster started on April 22 with two successive peaks five days apart and lasted until May 8. Being male, patients aged >33 years [OR = 30·7; 95% CI = 3·6 to 264], having hypertension [OR = 4·3; 95% CI = 1·1 to 16·7] or diabetes [OR = 3·8; 95% CI = 1·0 to 14·1] were associated with COVID-19. Mask compliance was poor (20%) among hospital workers. Discussion: We recommended screening of all patients for diabetes and hypertension and isolation/testing of anyone with influenza-like illness for preventing COVID-19 clusters in hospital settings.
Language	English
Publishing date	2021-11-04
Publishing country	India
Document type	Journal Article
ISSN	2452-0918
ISSN	2452-0918
DOI	10.1016/j.cegh.2021.100889
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Article: Human beta-secretase (BACE) and BACE inhibitors: progress report.

John, Varghese

Current topics in medicinal chemistry

2006 Volume 6, Issue 6, Page(s) 569–578

Abstract: A key step in the processing of the integral membrane protein APP, or Amyloid Precursor Protein is through the proteolytic cleavage by the enzyme beta-Secretase (BACE). The proteolysis of APP by BACE, followed by subsequent C-terminal cleavage(s) by ... ...

Abstract	A key step in the processing of the integral membrane protein APP, or Amyloid Precursor Protein is through the proteolytic cleavage by the enzyme beta-Secretase (BACE). The proteolysis of APP by BACE, followed by subsequent C-terminal cleavage(s) by gamma-secretase, results in the formation of the amyloid beta (Abeta) peptide. The principal component of the neuritic plaque found in the brains of Alzheimer's Disease (AD) patients is Abeta which is a neurotoxic and highly aggregatory peptide segment of APP. The amyloid hypothesis holds that the neuronal dysfunction and clinical manifestation of AD is a consequence of the long term deposition and accumulation of 40-42 amino-acid long Abeta peptides, and that this process leads to the onset and progression of AD. Due to the apparent causal relationship between Abeta and AD, the so-called "secretases" that produce Abeta have been targeted for development of inhibitors that might serve as therapeutic agents for treatment of this dreaded, and ever more prevalent disease. Herein will be discussed our current understanding of BACE, its role in the formation of neuritic plaques and the known inhibitors of the enzyme.
MeSH term(s)	Alzheimer Disease/drug therapy ; Alzheimer Disease/metabolism ; Amino Acid Sequence ; Amyloid Precursor Protein Secretases ; Amyloid beta-Peptides/metabolism ; Amyloid beta-Protein Precursor/chemistry ; Amyloid beta-Protein Precursor/metabolism ; Animals ; Aspartic Acid Endopeptidases ; Binding Sites/drug effects ; Endopeptidases/chemistry ; Endopeptidases/metabolism ; Humans ; Molecular Sequence Data ; Molecular Structure ; Plaque, Amyloid/chemistry ; Plaque, Amyloid/metabolism ; Protease Inhibitors/chemistry ; Protease Inhibitors/pharmacology ; Protease Nexins ; Receptors, Cell Surface/chemistry ; Receptors, Cell Surface/metabolism
Chemical Substances	APP protein, human ; Amyloid beta-Peptides ; Amyloid beta-Protein Precursor ; Protease Inhibitors ; Protease Nexins ; Receptors, Cell Surface ; Amyloid Precursor Protein Secretases (EC 3.4.-) ; Endopeptidases (EC 3.4.-) ; Aspartic Acid Endopeptidases (EC 3.4.23.-) ; BACE1 protein, human (EC 3.4.23.46)
Language	English
Publishing date	2006-05-19
Publishing country	United Arab Emirates
Document type	Journal Article ; Review
ZDB-ID	2064823-6
ISSN	1873-4294 ; 1568-0266
ISSN (online)	1873-4294
ISSN	1568-0266
DOI	10.2174/156802606776743084
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Article: A therapeutic small molecule lead enhances γ-oscillations and improves cognition/memory in Alzheimer's disease model mice.

Wei, Xiaofei / Campagna, Jesus J / Jagodzinska, Barbara / Wi, Dongwook / Cohn, Whitaker / Lee, Jessica / Zhu, Chunni / Huang, Christine S / Molnár, László / Houser, Carolyn R / John, Varghese / Mody, Istvan

bioRxiv : the preprint server for biology

2023

Abstract: Brain rhythms provide the timing and concurrence of brain activity required for linking together neuronal ensembles engaged in specific tasks. In particular, the γ-oscillations (30-120 Hz) orchestrate neuronal circuits underlying cognitive processes and ... ...

Abstract	Brain rhythms provide the timing and concurrence of brain activity required for linking together neuronal ensembles engaged in specific tasks. In particular, the γ-oscillations (30-120 Hz) orchestrate neuronal circuits underlying cognitive processes and working memory. These oscillations are reduced in numerous neurological and psychiatric disorders, including early cognitive decline in Alzheimer's disease (AD). Here we report on a potent brain permeable small molecule, DDL-920 that increases γ-oscillations and improves cognition/memory in a mouse model of AD, thus showing promise as a new class of therapeutics for AD. As a first in CNS pharmacotherapy, our lead candidate acts as a potent, efficacious, and selective negative allosteric modulator (NAM) of the γ-aminobutyric acid type A receptors (GABA
Language	English
Publishing date	2023-12-06
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.12.04.569994
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Article ; Online: Pharmacological Inhibition of p-21 Activated Kinase (PAK) Restores Impaired Neurite Outgrowth and Remodeling in a Cellular Model of Down Syndrome.

Barraza-Núñez, Natalia / Pérez-Núñez, Ramón / Gaete-Ramírez, Belén / Barrios-Garrido, Alejandra / Arriagada, Christian / Poksay, Karen / John, Varghese / Barnier, Jean-Vianney / Cárdenas, Ana María / Caviedes, Pablo

Neurotoxicity research

2023 Volume 41, Issue 3, Page(s) 256–269

Abstract: Down syndrome (DS) is characterized by the trisomy of chromosome 21 and by cognitive deficits that have been related to neuronal morphological alterations in humans, as well as in animal models. The gene encoding for amyloid precursor protein (APP) is ... ...

Abstract	Down syndrome (DS) is characterized by the trisomy of chromosome 21 and by cognitive deficits that have been related to neuronal morphological alterations in humans, as well as in animal models. The gene encoding for amyloid precursor protein (APP) is present in autosome 21, and its overexpression in DS has been linked to neuronal dysfunction, cognitive deficit, and Alzheimer's disease-like dementia. In particular, the neuronal ability to extend processes and branching is affected. Current evidence suggests that APP could also regulate neurite growth through its role in the actin cytoskeleton, in part by influencing p21-activated kinase (PAK) activity. The latter effect is carried out by an increased abundance of the caspase cleavage-released carboxy-terminal C31 fragment. In this work, using a neuronal cell line named CTb, which derived from the cerebral cortex of a trisomy 16 mouse, an animal model of human DS, we observed an overexpression of APP, elevated caspase activity, augmented cleavage of the C-terminal fragment of APP, and increased PAK1 phosphorylation. Morphometric analyses showed that inhibition of PAK1 activity with FRAX486 increased the average length of the neurites, the number of crossings per Sholl ring, the formation of new processes, and stimulated the loss of processes. Considering our results, we propose that PAK hyperphosphorylation impairs neurite outgrowth and remodeling in the cellular model of DS, and therefore we suggest that PAK1 may be a potential pharmacological target.
MeSH term(s)	Mice ; Humans ; Animals ; Down Syndrome/drug therapy ; Down Syndrome/genetics ; Trisomy ; Neurons/metabolism ; Neurites/metabolism ; Amyloid beta-Protein Precursor/genetics ; Amyloid beta-Protein Precursor/metabolism ; Neuronal Outgrowth ; Caspases/metabolism
Chemical Substances	Amyloid beta-Protein Precursor ; Caspases (EC 3.4.22.-)
Language	English
Publishing date	2023-03-03
Publishing country	United States
Document type	Journal Article
ZDB-ID	2036826-4
ISSN	1476-3524 ; 1029-8428
ISSN (online)	1476-3524
ISSN	1029-8428
DOI	10.1007/s12640-023-00638-3
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