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Article ; Online: Molecular mechanisms linking type 2 diabetes mellitus and late-onset Alzheimer's disease: A systematic review and qualitative meta-analysis.

Lemche, Erwin / Killick, Richard / Mitchell, Jackie / Caton, Paul W / Choudhary, Pratik / Howard, Jane K

2024 Volume 196, Page(s) 106485

Abstract: Research evidence indicating common metabolic mechanisms through which type 2 diabetes mellitus (T2DM) increases risk of late-onset Alzheimer's dementia (LOAD) has accumulated over recent decades. The aim of this systematic review is to provide a ... ...

Abstract	Research evidence indicating common metabolic mechanisms through which type 2 diabetes mellitus (T2DM) increases risk of late-onset Alzheimer's dementia (LOAD) has accumulated over recent decades. The aim of this systematic review is to provide a comprehensive review of common mechanisms, which have hitherto been discussed in separate perspectives, and to assemble and evaluate candidate loci and epigenetic modifications contributing to polygenic risk linkages between T2DM and LOAD. For the systematic review on pathophysiological mechanisms, both human and animal studies up to December 2023 are included. For the qualitative meta-analysis of genomic bases, human association studies were examined; for epigenetic mechanisms, data from human studies and animal models were accepted. Papers describing pathophysiological studies were identified in databases, and further literature gathered from cited work. For genomic and epigenomic studies, literature mining was conducted by formalised search codes using Boolean operators in search engines, and augmented by GeneRif citations in Entrez Gene, and other sources (WikiGenes, etc.). For the systematic review of pathophysiological mechanisms, 923 publications were evaluated, and 138 gene loci extracted for testing candidate risk linkages. 3 57 publications were evaluated for genomic association and descriptions of epigenomic modifications. Overall accumulated results highlight insulin signalling, inflammation and inflammasome pathways, proteolysis, gluconeogenesis and glycolysis, glycosylation, lipoprotein metabolism and oxidation, cell cycle regulation or survival, autophagic-lysosomal pathways, and energy. Documented findings suggest interplay between brain insulin resistance, neuroinflammation, insult compensatory mechanisms, and peripheral metabolic dysregulation in T2DM and LOAD linkage. The results allow for more streamlined longitudinal studies of T2DM-LOAD risk linkages.
Language	English
Publishing date	2024-04-21
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	1211786-9
ISSN	1095-953X ; 0969-9961
ISSN (online)	1095-953X
ISSN	0969-9961
DOI	10.1016/j.nbd.2024.106485
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Article: Effect of the ROCK inhibitor fasudil on the brain proteomic profile in the tau transgenic mouse model of Alzheimer's disease.

Collu, Roberto / Yin, Zheng / Giunti, Elisa / Daley, Sarah / Chen, Mei / Morin, Peter / Killick, Richard / Wong, Stephen T C / Xia, Weiming

Frontiers in aging neuroscience

2024 Volume 16, Page(s) 1323563

Abstract: Introduction: The goal of this study is to explore the pharmacological potential of the amyloid-reducing vasodilator fasudil, a selective Ras homolog (Rho)-associated kinases (ROCK) inhibitor, in the P301S tau transgenic mouse model (Line PS19) of ... ...

Abstract	Introduction: The goal of this study is to explore the pharmacological potential of the amyloid-reducing vasodilator fasudil, a selective Ras homolog (Rho)-associated kinases (ROCK) inhibitor, in the P301S tau transgenic mouse model (Line PS19) of neurodegenerative tauopathy and Alzheimer's disease (AD). Methods: We used LC-MS/MS, ELISA and bioinformatic approaches to investigate the effect of treatment with fasudil on the brain proteomic profile in PS19 tau transgenic mice. We also explored the efficacy of fasudil in reducing tau phosphorylation, and the potential beneficial and/or toxic effects of its administration in mice. Results: Proteomic profiling of mice brains exposed to fasudil revealed the activation of the mitochondrial tricarboxylic acid (TCA) cycle and blood-brain barrier (BBB) gap junction metabolic pathways. We also observed a significant negative correlation between the brain levels of phosphorylated tau (pTau) at residue 396 and both fasudil and its metabolite hydroxyfasudil. Conclusions: Our results provide evidence on the activation of proteins and pathways related to mitochondria and BBB functions by fasudil treatment and support its further development and therapeutic potential for AD.
Language	English
Publishing date	2024-02-19
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2558898-9
ISSN	1663-4365
ISSN	1663-4365
DOI	10.3389/fnagi.2024.1323563
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Article ; Online: Neurodegenerative Disease Associated Pathways in the Brains of Triple Transgenic Alzheimer's Model Mice Are Reversed Following Two Weeks of Peripheral Administration of Fasudil.

Killick, Richard / Elliott, Christina / Ribe, Elena / Broadstock, Martin / Ballard, Clive / Aarsland, Dag / Williams, Gareth

International journal of molecular sciences

2023 Volume 24, Issue 13

Abstract: The pan Rho-associated coiled-coil-containing protein kinase (ROCK) inhibitor fasudil acts as a vasodilator and has been used as a medication for post-cerebral stroke for the past 29 years in Japan and China. More recently, based on the involvement of ... ...

Abstract	The pan Rho-associated coiled-coil-containing protein kinase (ROCK) inhibitor fasudil acts as a vasodilator and has been used as a medication for post-cerebral stroke for the past 29 years in Japan and China. More recently, based on the involvement of ROCK inhibition in synaptic function, neuronal survival, and processes associated with neuroinflammation, it has been suggested that the drug may be repurposed for neurodegenerative diseases. Indeed, fasudil has demonstrated preclinical efficacy in many neurodegenerative disease models. To facilitate an understanding of the wider biological processes at play due to ROCK inhibition in the context of neurodegeneration, we performed a global gene expression analysis on the brains of Alzheimer's disease model mice treated with fasudil via peripheral IP injection. We then performed a comparative analysis of the fasudil-driven transcriptional profile with profiles generated from a meta-analysis of multiple neurodegenerative diseases. Our results show that fasudil tends to drive gene expression in a reverse sense to that seen in brains with post-mortem neurodegenerative disease. The results are most striking in terms of pathway enrichment analysis, where pathways perturbed in Alzheimer's and Parkinson's diseases are overwhelmingly driven in the opposite direction by fasudil treatment. Thus, our results bolster the repurposing potential of fasudil by demonstrating an anti-neurodegenerative phenotype in a disease context and highlight the potential of in vivo transcriptional profiling of drug activity.
MeSH term(s)	Animals ; Mice ; 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/pharmacology ; Alzheimer Disease/drug therapy ; Alzheimer Disease/genetics ; Brain/metabolism ; Mice, Transgenic ; Neurodegenerative Diseases/drug therapy ; Protein Kinase Inhibitors/pharmacology ; rho-Associated Kinases/metabolism
Chemical Substances	1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine (84477-87-2) ; fasudil (Q0CH43PGXS) ; Protein Kinase Inhibitors ; rho-Associated Kinases (EC 2.7.11.1)
Language	English
Publishing date	2023-07-07
Publishing country	Switzerland
Document type	Meta-Analysis ; Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms241311219
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Article ; Online: Reconstructing the geological provenance and long-distance movement of rectangular, fishtail, and croisette copper ingots in Iron Age Zambia and Zimbabwe.

Stephens, Jay / Killick, David / Chirikure, Shadreck

PloS one

2023 Volume 18, Issue 3, Page(s) e0282660

Abstract: The southern third of Africa is unusually rich in copper ore deposits. These were exploited ...

Abstract	The southern third of Africa is unusually rich in copper ore deposits. These were exploited by precolonial populations to manufacture wound-wire bangles, other forms of jewelry, and large copper ingots that were used as stores of copper or as forms of prestige. Rectangular, fishtail, and croisette ingots dating between the 5th and 20th centuries CE have been found in many locations in the Democratic Republic of the Congo (DRC), Zambia, and Zimbabwe, with isolated finds in Malawi and Mozambique. Molds for casting these ingots have been found mostly in the Central African Copperbelt, but also around the Magondi Belt copper deposits in northern Zimbabwe. For years, scholars have debated whether these ingots were exclusively made in the Copperbelt or if the molds found in Zimbabwe indicate that local copies were produced from Magondi Belt copper ore (Garlake 1970; Bisson 1976). Before the recent application of lead isotopic and chemical methods to provenance copper in central and southern Africa, there was no way to discern between these hypotheses. Rademakers et al. (2019) and Stephens et al. (2020) showed that copper artifacts from southern DRC (mostly from Upemba) and from northwestern Botswana (Tsodilo Hills) match the lead isotope ratios of ores from the Copperbelt. Building upon these previous studies, we present here the first results from a copper provenance project across the southern third of Africa, from the Copperbelt to northern South Africa. We apply lead isotopic analysis (LIA) and chemical analyses to establish the provenance of 29 croisette ingots recovered in Zimbabwe, 2 fishtail and 1 rectangular ingot recovered from sites in Zambia, and an "X" shaped ingot smelted in an experiment in Zambia in the 1970's. Our chemistry and lead isotopic results indicate that 16 of these objects were smelted with copper from the Copperbelt, 16 objects source more specifically to the Kipushi deposit within this geological district, and only one HXR ingot sources to the Magondi Belt in Zimbabwe. Taken together, we clearly illustrate that croisette ingots were traveling significant distances to reach their eventual sites of deposition, and that there was also local production of these objects in Zimbabwe.
MeSH term(s)	Zambia ; Zimbabwe ; Copper ; Africa, Southern ; Botswana
Chemical Substances	Copper (789U1901C5)
Language	English
Publishing date	2023-03-22
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0282660
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Book ; Online: RoboLLM

Long, Zijun / Killick, George / McCreadie, Richard / Camarasa, Gerardo Aragon

Robotic Vision Tasks Grounded on Multimodal Large Language Models

2023

Abstract: Robotic vision applications often necessitate a wide range of visual perception tasks, such as object detection, segmentation, and identification. While there have been substantial advances in these individual tasks, integrating specialized models into a ...

Abstract	Robotic vision applications often necessitate a wide range of visual perception tasks, such as object detection, segmentation, and identification. While there have been substantial advances in these individual tasks, integrating specialized models into a unified vision pipeline presents significant engineering challenges and costs. Recently, Multimodal Large Language Models (MLLMs) have emerged as novel backbones for various downstream tasks. We argue that leveraging the pre-training capabilities of MLLMs enables the creation of a simplified framework, thus mitigating the need for task-specific encoders. Specifically, the large-scale pretrained knowledge in MLLMs allows for easier fine-tuning to downstream robotic vision tasks and yields superior performance. We introduce the RoboLLM framework, equipped with a BEiT-3 backbone, to address all visual perception tasks in the ARMBench challenge-a large-scale robotic manipulation dataset about real-world warehouse scenarios. RoboLLM not only outperforms existing baselines but also substantially reduces the engineering burden associated with model selection and tuning. The source code is publicly available at https://github.com/longkukuhi/armbench.
Keywords	Computer Science - Robotics ; Computer Science - Computer Vision and Pattern Recognition
Subject code	004
Publishing date	2023-10-16
Publishing country	us
Document type	Book ; Online
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Article ; Online: Transcription-based drug repurposing for COVID-19.

Killick, Richard / Ballard, Clive / Doherty, Patrick / Williams, Gareth

Virus research

2020 Volume 290, Page(s) 198176

Abstract: We have utilised the transcriptional response of lung epithelial cells following infection by the original Severe Acute Respiratory Syndrome coronavirus (SARS) to identify repurposable drugs for COVID-19. Drugs best able to recapitulate the infection ... ...

Abstract	We have utilised the transcriptional response of lung epithelial cells following infection by the original Severe Acute Respiratory Syndrome coronavirus (SARS) to identify repurposable drugs for COVID-19. Drugs best able to recapitulate the infection profile are highly enriched for antiviral activity. Nine of these have been tested against SARS-2 and found to potently antagonise SARS-2 infection/replication, with a number now being considered for clinical trials. It is hoped that this approach may serve to broaden the spectrum of approved drugs that should be further assessed as potential anti-COVID-19 agents and may help elucidate how this seemingly disparate collection of drugs are able to inhibit SARS-2 infection/replication.
MeSH term(s)	Antiviral Agents/chemistry ; Antiviral Agents/pharmacology ; Antiviral Agents/therapeutic use ; COVID-19/virology ; Drug Repositioning ; Epithelial Cells/drug effects ; Epithelial Cells/pathology ; Epithelial Cells/virology ; Gene Expression Profiling ; Humans ; Lung/drug effects ; Lung/pathology ; Lung/virology ; Severe acute respiratory syndrome-related coronavirus/drug effects ; Severe acute respiratory syndrome-related coronavirus/physiology ; SARS-CoV-2/drug effects ; SARS-CoV-2/physiology ; Transcriptome/drug effects ; COVID-19 Drug Treatment
Chemical Substances	Antiviral Agents
Keywords	covid19
Language	English
Publishing date	2020-09-25
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	605780-9
ISSN	1872-7492 ; 0168-1702
ISSN (online)	1872-7492
ISSN	0168-1702
DOI	10.1016/j.virusres.2020.198176
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Article ; Online: NRF2: An emerging role in neural stem cell regulation and neurogenesis.

Boorman, Emily / Killick, Richard / Aarsland, Dag / Zunszain, Patricia / Mann, Giovanni E

Free radical biology & medicine

2022 Volume 193, Issue Pt 1, Page(s) 437–446

Abstract: The birth of new neurons from neural stem cells (NSC)s during developmental and adult neurogenesis arises from a myriad of highly complex signalling cascades. Emerging as one of these is the nuclear factor erythroid 2-related factor (NRF2)-signaling ... ...

Abstract	The birth of new neurons from neural stem cells (NSC)s during developmental and adult neurogenesis arises from a myriad of highly complex signalling cascades. Emerging as one of these is the nuclear factor erythroid 2-related factor (NRF2)-signaling pathway. Regulation by NRF2 is reported to span the neurogenic process from early neural lineage specification and NSC regulation to neuronal fate commitment and differentiation. Here, we review these reports selecting only those where NRF2 signaling was directly manipulated to provide a clearer case for a direct role of NRF2 in embryonic and adult neurogenesis. With few studies providing mechanistic insight into this relationship, we lastly discuss key pathways linking NRF2 and stem cell regulation outside the neural lineage to shed light on mechanisms that may also be relevant to NSCs and neurogenesis.
MeSH term(s)	NF-E2-Related Factor 2/genetics ; NF-E2-Related Factor 2/metabolism ; Neural Stem Cells ; Neurogenesis ; Neurons/metabolism ; Cell Differentiation
Chemical Substances	NF-E2-Related Factor 2
Language	English
Publishing date	2022-10-19
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	807032-5
ISSN	1873-4596 ; 0891-5849
ISSN (online)	1873-4596
ISSN	0891-5849
DOI	10.1016/j.freeradbiomed.2022.10.301
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Article: Transcription-based drug repurposing for COVID-19

Killick, Richard / Ballard, Clive / Doherty, Patrick / Williams, Gareth

Virus research. 2020 Dec., v. 290

2020

Abstract	We have utilised the transcriptional response of lung epithelial cells following infection by the original Severe Acute Respiratory Syndrome coronavirus (SARS) to identify repurposable drugs for COVID-19. Drugs best able to recapitulate the infection profile are highly enriched for antiviral activity. Nine of these have been tested against SARS-2 and found to potently antagonise SARS-2 infection/replication, with a number now being considered for clinical trials. It is hoped that this approach may serve to broaden the spectrum of approved drugs that should be further assessed as potential anti−COVID-19 agents and may help elucidate how this seemingly disparate collection of drugs are able to inhibit SARS-2 infection/replication.
Keywords	COVID-19 infection ; Severe acute respiratory syndrome coronavirus ; antiviral properties ; drugs ; epithelium ; lungs ; research ; transcription (genetics) ; viruses
Language	English
Dates of publication	2020-12
Publishing place	Elsevier B.V.
Document type	Article
Note	NAL-AP-2-clean
ZDB-ID	605780-9
ISSN	1872-7492 ; 0168-1702
ISSN (online)	1872-7492
ISSN	0168-1702
DOI	10.1016/j.virusres.2020.198176
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Neurodegenerative Disease Associated Pathways in the Brains of Triple Transgenic Alzheimer’s Model Mice Are Reversed Following Two Weeks of Peripheral Administration of Fasudil

Richard Killick / Christina Elliott / Elena Ribe / Martin Broadstock / Clive Ballard / Dag Aarsland / Gareth Williams

International Journal of Molecular Sciences, Vol 24, Iss 11219, p

2023 Volume 11219

Abstract	The pan Rho-associated coiled-coil-containing protein kinase (ROCK) inhibitor fasudil acts as a vasodilator and has been used as a medication for post-cerebral stroke for the past 29 years in Japan and China. More recently, based on the involvement of ROCK inhibition in synaptic function, neuronal survival, and processes associated with neuroinflammation, it has been suggested that the drug may be repurposed for neurodegenerative diseases. Indeed, fasudil has demonstrated preclinical efficacy in many neurodegenerative disease models. To facilitate an understanding of the wider biological processes at play due to ROCK inhibition in the context of neurodegeneration, we performed a global gene expression analysis on the brains of Alzheimer’s disease model mice treated with fasudil via peripheral IP injection. We then performed a comparative analysis of the fasudil-driven transcriptional profile with profiles generated from a meta-analysis of multiple neurodegenerative diseases. Our results show that fasudil tends to drive gene expression in a reverse sense to that seen in brains with post-mortem neurodegenerative disease. The results are most striking in terms of pathway enrichment analysis, where pathways perturbed in Alzheimer’s and Parkinson’s diseases are overwhelmingly driven in the opposite direction by fasudil treatment. Thus, our results bolster the repurposing potential of fasudil by demonstrating an anti-neurodegenerative phenotype in a disease context and highlight the potential of in vivo transcriptional profiling of drug activity.
Keywords	Alzheimer’s disease ; Parkinson’s disease ; transcriptional profiling ; fasudil ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	570
Language	English
Publishing date	2023-07-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
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Article ; Online: Iron chelation therapy in low risk myelodysplastic syndrome.

Killick, Sally B

British journal of haematology

2017 Volume 177, Issue 3, Page(s) 375–387

Abstract: ... the majority of patients will require transfusion support at some point. Blood transfusions are rich in iron ...

Abstract	Anaemia is the commonest cytopenia seen in patients with myelodysplastic syndrome (MDS), and the majority of patients will require transfusion support at some point. Blood transfusions are rich in iron, which leads to the accumulation of body iron over time. It is accepted that this ultimately causes end organ damage and may impact on both morbidity and mortality. In addition, recent data has increased our interest in the subject with regard to the potential impact on stem cell transplant outcome and an anti-leukaemic effect of iron chelation therapy. There is still debate over which patients should receive iron chelation therapy, but the emergence of new diagnostic and prognostic markers in MDS may help decision making in the clinic setting.
MeSH term(s)	Chelation Therapy/methods ; Evidence-Based Medicine/methods ; Humans ; Iron Chelating Agents/therapeutic use ; Iron Overload/drug therapy ; Iron Overload/etiology ; Myelodysplastic Syndromes/therapy ; Prognosis ; Transfusion Reaction
Chemical Substances	Iron Chelating Agents
Language	English
Publishing date	2017-05
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	80077-6
ISSN	1365-2141 ; 0007-1048
ISSN (online)	1365-2141
ISSN	0007-1048
DOI	10.1111/bjh.14602
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