ORCID Profile
0000-0002-4174-2786
Current Organisations
The University of Edinburgh
,
NHS Lothian
,
Trent University
,
Malmö University
,
Osaka University
,
International Centre for Diarrhoeal Disease Research, Bangladesh
,
Mahidol University Phayathai Campus
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Publisher: American Association for the Advancement of Science (AAAS)
Date: 07-12-2022
DOI: 10.1126/SCITRANSLMED.ABJ4375
Abstract: Liver transplantation is the only curative option for patients with end-stage liver disease. Despite improvements in surgical techniques, nonanastomotic strictures (characterized by the progressive loss of biliary tract architecture) continue to occur after liver transplantation, negatively affecting liver function and frequently leading to graft loss and retransplantation. To study the biological effects of organ preservation before liver transplantation, we generated murine models that recapitulate liver procurement and static cold storage. In these models, we explored the response of cholangiocytes and hepatocytes to cold storage, focusing on responses that affect liver regeneration, including DNA damage, apoptosis, and cellular senescence. We show that biliary senescence was induced during organ retrieval and exacerbated during static cold storage, resulting in impaired biliary regeneration. We identified decoy receptor 2 (DCR2)–dependent responses in cholangiocytes and hepatocytes, which differentially affected the outcome of those populations during cold storage. Moreover, CRISPR-mediated DCR2 knockdown in vitro increased cholangiocyte proliferation and decreased cellular senescence but had the opposite effect in hepatocytes. Using the p21 KO model to inhibit senescence onset, we showed that biliary tract architecture was better preserved during cold storage. Similar results were achieved by administering senolytic ABT737 to mice before procurement. Last, we perfused senolytics into discarded human donor livers and showed that biliary architecture and regenerative capacities were better preserved. Our results indicate that cholangiocytes are susceptible to senescence and identify the use of senolytics and the combination of senotherapies and machine-perfusion preservation to prevent this phenotype and reduce the incidence of biliary injury after transplantation.
Publisher: Elsevier BV
Date: 08-2020
Publisher: Elsevier BV
Date: 04-2021
DOI: 10.1016/J.JHEP.2020.11.018
Abstract: Cholangiocarcinoma (CCA) is a cancer of the hepatic bile ducts that is rarely resectable and is associated with poor prognosis. Tumour necrosis factor-like weak inducer of apoptosis (TWEAK) is known to signal via its receptor fibroblast growth factor-inducible 14 (Fn14) and induce cholangiocyte and myofibroblast proliferation in liver injury. We aimed to characterise its role in CCA. The expression of the TWEAK ligand and Fn14 receptor was assessed immunohistochemically and by bulk RNA and single cell transcriptomics of human liver tissue. Spatiotemporal dynamics of pathway regulation were comprehensively analysed in rat and mouse models of thioacetamide (TAA)-mediated CCA. Flow cytometry, qPCR and proteomic analyses of CCA cell lines and conditioned medium experiments with primary macrophages were performed to evaluate the downstream functions of TWEAK/Fn14. In vivo pathway manipulation was assessed via TWEAK overexpression in NICD/AKT-induced CCA or genetic Fn14 knockout during TAA-mediated carcinogenesis. Our data reveal TWEAK and Fn14 overexpression in multiple human CCA cohorts, and Fn14 upregulation in early TAA-induced carcinogenesis. TWEAK regulated the secretion of factors from CC-SW-1 and SNU-1079 CCA cells, inducing polarisation of proinflammatory CD206 These novel data provide evidence for the action of TWEAK/Fn14 on macrophage recruitment and phenotype, and cancer-associated fibroblast proliferation in CCA. Targeting TWEAK/Fn14 and its downstream signals may provide a means to inhibit CCA niche development and tumour growth. Cholangiocarcinoma is an aggressive, chemotherapy-resistant liver cancer. Interactions between tumour cells and cells that form a supportive environment for the tumour to grow are a source of this aggressiveness and resistance to chemotherapy. Herein, we describe interactions between tumour cells and their supportive environment via a chemical messenger, TWEAK and its receptor Fn14. TWEAK/Fn14 alters the recruitment and type of immune cells in tumours, increases the growth of cancer-associated fibroblasts in the tumour environment, and is a potential target to reduce tumour formation.
Publisher: Proceedings of the National Academy of Sciences
Date: 10-10-2016
Abstract: Clinical outcomes in cholangiocarcinoma (CC) are poor few patients are candidates for curative resection, and palliative chemotherapy produces only modest effects on survival. With an increasing incidence, new targets are urgently needed. Notch has been identified as having potential to induce CC when transgenically overexpressed, and this study aimed to characterize how endogenous Notch might drive tumorigenesis. We identify the atypical receptor Notch3 as differentially overactivated in CCs in humans, rats, and mice, with genetic deletion significantly reducing CC growth. Notch3 sustains tumor cell survival through PI3k/Akt activation via a noncanonical mechanism independent of Recombinant Signal Binding Protein for Immunoglobulin Kappa J Region (RBPJ), presenting an opportunity to target the pathway without disrupting classical Notch and bypassing toxicities associated with γ-secretase inhibitors.
Publisher: American Meteorological Society
Date: 08-08-2017
Abstract: Breaking planetary waves (BPWs) affect stratospheric dynamics by reshaping the waveguides, causing internal wave reflection, and preconditioning sudden stratospheric warmings. This study examines observed changes in BPWs during the northern winter resulting from enhanced solar forcing and the consequent effect on the seasonal development of the polar vortex. During the period 1979–2014, solar-induced changes in BPWs were first observed in the uppermost stratosphere. High solar forcing was marked by sharpening of the potential vorticity (PV) gradient at 30°–45°N, enhanced wave absorption at high latitudes, and a reduced PV gradient between these regions. These anomalies instigated an equatorward shift of the upper-stratospheric waveguide and enhanced downward wave reflection at high latitudes. The equatorward refraction of reflected waves from the polar upper stratosphere then led to enhanced wave absorption at 35°–45°N and 7–20 hPa, indicative of a widening of the midstratospheric surf zone. The stratospheric waveguide was thus constricted at about 45°–60°N and 5–10 hPa in early boreal winter reduced upward wave propagation through this region resulted in a stronger upper-stratospheric westerly jet. From January, the regions with enhanced BPWs acted as “barriers” for subsequent upward and equatorward wave propagation. As the waves were trapped within the stratosphere, anomalies of zonal wavenumbers 2 and 3 were reflected poleward from the stratospheric surf zone. Resonant excitation of some of these reflected waves resulted in rapid growth of wave disturbances and a more disturbed polar vortex in late winter. These results provide a process-oriented explanation for the observed solar cycle signal. They also highlight the importance of nonlinearity in the processes that drive the stratospheric response to external forcing.
Publisher: Verein zur Forderung des Open Access Publizierens in den Quantenwissenschaften
Date: 22-03-2022
DOI: 10.22331/Q-2022-03-22-671
Abstract: How can a multipartite single-photon path-entangled state be certified efficiently by means of local measurements? We address this question by constructing an entanglement witness based on local photon detections preceded by displacement operations to reveal genuine multipartite entanglement. Our witness is defined as a sum of three observables that can be measured locally and assessed with two measurement settings for any number of parties N . For any bipartition, the maximum mean value of the witness observable over biseparable states is bounded by the maximum eigenvalue of an N & #x00D7 N matrix, which can be computed efficiently. We demonstrate the applicability of our scheme by experimentally testing the witness for heralded 4- and 8-partite single-photon path-entangled states. Our implementation shows the scalability of our witness and opens the door for distributing photonic multipartite entanglement in quantum networks at high rates.
Publisher: Informa UK Limited
Date: 16-09-2009
Publisher: Springer Science and Business Media LLC
Date: 22-08-2007
DOI: 10.1007/S10461-007-9300-1
Abstract: This paper evaluates the effectiveness of respondent driven s ling (RDS) to s le males who have sex with males (MSM) in Dhaka, Bangladesh. A major objective for conducting this survey was to determine whether RDS can be a viable s ling method for future routine serologic and behavioral surveillance of MSM as well as other socially networked, hard to reach populations in Bangladesh. We assessed the feasibility of RDS (survey duration MSM social network properties number and types of initial recruits) to recruit a erse group of MSM, the efficacy of an innovative technique (systematic coupon reduction) to manage the implementation and completion of the RDS recruitment process and reasons why MSM participated or did not participate. The findings provide useful information for improving RDS field techniques and demonstrate that RDS is an effective s ling method for recruiting erse groups of MSM to participate in HIV related serologic and behavioral surveys in Dhaka.
Publisher: Springer Science and Business Media LLC
Date: 09-03-2018
DOI: 10.1038/S41467-018-03299-5
Abstract: Cellular senescence is a mechanism that provides an irreversible barrier to cell cycle progression to prevent undesired proliferation. However, under pathological circumstances, senescence can adversely affect organ function, viability and regeneration. We have developed a mouse model of biliary senescence, based on the conditional deletion of Mdm2 in bile ducts under the control of the Krt19 promoter, that exhibits features of biliary disease. Here we report that senescent cholangiocytes induce profound alterations in the cellular and signalling microenvironment, with recruitment of myofibroblasts and macrophages causing collagen deposition, TGFβ production and induction of senescence in surrounding cholangiocytes and hepatocytes. Finally, we study how inhibition of TGFβ-signalling disrupts the transmission of senescence and restores liver function. We identify cellular senescence as a detrimental mechanism in the development of biliary injury. Our results identify TGFβ as a potential therapeutic target to limit senescence-dependent aggravation in human cholangiopathies.
Publisher: IOP Publishing
Date: 20-07-2023
Abstract: Heralded single-photon sources (HSPS) intrinsically suffer from multiphoton emission, leading to a trade-off between the source’s single-photon quality and the heralding rate. A solution to this problem is to use photon-number-resolving (PNR) detectors to filter out the heralding events where more than one photon pair is created. Here, we demonstrate an improvement of a HSPS by heralding photons using a high-efficiency parallel superconducting nanowire single-photon detector (P-SNSPD) with PNR power. Specifically, we show a reduction in the g ( 2 ) ( 0 ) of the heralded single photon by ( 26.9 ± 0.1 ) % for a fixed pump power, or alternatively, an increase in the heralding rate by a factor of 1.368 ± 0.002 for a fixed g ( 2 ) ( 0 ) . We also demonstrate that such a PNR device can reveal thermal photon-number statistics of unheralded photons, which is enabled by our ability to construct its full input–output response function. These results are possible thanks to our P-SNSPD architecture that ensures non-latching operation with no electrical crosstalk, which are essential conditions necessary to obtain the correct photon-number statistics and also faster recovery times, therefore enabling fast heralding rates. These results show that our efficient PNR P-SNSPD architecture can significantly improve the performance of HSPSs and can precisely characterize them, making these detectors a useful tool for a wide range of optical quantum information protocols.
Publisher: Cold Spring Harbor Laboratory
Date: 27-03-2022
DOI: 10.1101/2022.03.25.485695
Abstract: Current approaches to stage chronic liver diseases have limited utility to directly predict liver cancer risk. Here, we employed single nucleus RNA sequencing (snRNA-seq) to characterize the cellular microenvironment of healthy and chronically injured pre-malignant livers using two distinct mouse models. Analysis of 40,748 hepatic nuclei unraveled a previously uncharacterized disease-associated hepatocyte transcriptional state (daHep). These cells were absent in healthy livers, but were increasingly prevalent as chronic liver disease progressed towards hepatocarcinogenesis. Gene expression deconvolution of 1,439 human liver transcriptomes from publicly available datasets revealed that daHep frequencies highly correlate with current histopathological liver disease staging systems. Importantly, we show that high daHep levels precede carcinogenesis in mice and humans and predict a higher risk of hepatocellular carcinoma (HCC) development. This novel transcriptional signature with diagnostic and, more importantly, prognostic significance has the potential to change the way chronic liver disease patients are staged, surveilled and risk-stratified.
Publisher: American Society for Microbiology
Date: 07-2016
DOI: 10.1128/AAC.00223-16
Publisher: American Physical Society (APS)
Date: 10-09-2020
Publisher: Elsevier BV
Date: 05-2023
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: Bangladesh
Location: No location found
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Timothy Kendall.