92 research outputs found
Mass, Energy, and Cost Balances in Water Distribution Systems with PATs: The Trondheim Network Case Study
No full textIn water distribution systems, the substitution of regulating valves by pumps as turbines (PATs) is sustainable if the energy recovery balances the installation and maintenance costs, with a comparable and efficient reduction of the volume lost by leakage. Hence, the installation feasibility and regulation of a PAT require analysis of the introduced effects on the components of the energy, mass, and cost balances. In this paper these effects are explored by means of a case study, i.e., the water distribution system of Trondheim, Norway. Different hydraulic regulations of a PAT are analyzed to maximize the recovered energy, considering the daily variation of the system functioning conditions and the substitution of valves of different kinds, meaning a constant opening degree, a fixed value of pressure at a node of the system, and a control in time of the setting. A feasible solution for the Trondheim network is shown, consisting of the implementation of two twin PATs in parallel with a discontinuous functioning of one of them
Dysregulation of receptor induced apoptosis during human leishmaniasis : a possible mechanism of skin ulceration
No full textLeishmaniasis is endemic in 88 countries and 12 million people per year have been estimated to be at risk of infection. The causative agent, the protozoan Leishmania, is spread by sand-flies and infects macrophages in the mammalian host. Leishmaniasis in humans form a spectrum of clinical presentations. In cutaneous leishmaniasis (CL) caused by L. major, the infection is localised in the skin and manifests as one or several ulcers that typically spontaneously heal within one year after infection, often leaving marked scarring. In visceral leishmaniasis (VL) caused by L. donovani, infected macrophages are found in liver, spleen, bone marrow and lymph-nodes and the infection leads to hepatosplenomegaly, wasting, fever and if not treated, to death. Systemic T-cell deficiency occurs early during VL and leads to uncontrolled parasite replication. In general, solid immunity upon healing occurs after resolved VL and CL.In this thesis, the hypothesis that alterations of death receptor-mediated apoptosis have an impact on the pathogenesis of human leishmaniasis has been explored. During VL, dysregulation of the Fas/FasL pathway was investigated, both at one site of infection, the spleen, and on circulating lymphocytes from the peripheral blood. In the case of CL the hypothesis was that increased death receptor-mediated apoptosis in the microenvironment surrounding infected macrophages may induce bystandard apoptosis of keratinocytes, leading to skin ulceration.Dysiregulation of the Fas/FasL pathway occured during human VL and CL. Levels of soluble Fas (sFas) and soluble Fas ligand (sFasL) were elevated in plasma of patients with active VL and individuals co-infected with VL-HIV-1 compared to healthy controls, and the levels of sFas and sFasL were normalized 6 months after successful treatment. During active VL, the expression of membrane bound Fas, and to a lower extent Fast., was up-regulated on spleen cells, where parasites multiply. In contrast, expression of Fas and Fast- were not altered on peripheral blood mononuclear cells (PBMC) during VL. Furthermore, in vitro infection of macrophages with L. donovani results in up-regulation of Fas expression on the surface of infected cells and increases the levels of sFasL in supernatants from infected cultures. During active CL caused by L. major, a disease mainly localised to the skin, the Fas and Fast- levels were not altered in serum or on PBMCs analysed ex vivo. However, when CL PBMCs were restimulated with L. major, Fas was up-regulated on effector T-cells and high levels of sFasL were detected in the supernatants as compared to control PBMCs.Keratinocyte apoptosis is altered during CL. Dysregulation of the Fas/FasL pathway in the microenvironment surrounding L. major infected macrophages under the skin was visualised in biopsies collected from CL patients. A substantial number of apoptotic keratinocytes were observed in the epidermis of morphologically active and healing CL skin samples. Fas expression was increased on the epidermis in active CL, whereas FasL expressing macrophages and T-cells were found in the subepidermal infiltrate during active disease. Supernatants from re-stimulated CL-PBMC cultures containing high levels of sFasL induced apoptosis in human keratinocyte cell line (HaCaT), and apoptosis could be inhibited in 213 supernatants by blocking Fas. A commercial apoptosis-specific microarray was used to assess alterations in keratinocyte RNAexpression during exposure to supernatants from L. major infected PBMCs. Fas and TRAIL mRNA and protein expression were significantly up-regulated compared to untreated keratinocytes. Supernatant induced apoptosis of keratinocytes was partly inhibited through blocking Fas or FasL, and more efficiently through inhibition of TRAIL by neutralising antibodies or soluble TRAIL-R. Furthermore, TRAIL expressing keratinocytes were detected in skin biopsies from CL cases.Blocking the Fas/FasL pathway in vivo may reduce ulceration during murine CL. In order to obtain the proof of the concept that Fas/FasL signalling is involved in keratinocyte-apoptosis leading to ulceration in the skin during CL, the Fas/FasL pathway was blocked in a murine model of CL by intraperitoneal treatment with Fast- neutralising antibodies (MFL-4). Skin inflammation, skin ulceration and ulcer size were followed weekly and compared to infected, untreated mice. Our results suggests that blocking Fas/FasL signalling during murine CL lead to less apoptotic keratinocytes and diminished ulceration. During treatment, the number of IFNgammaproducing CD8+CD3+ cells was increased at the site of infection when Fast- was neutralised which is suggestive of efficient parasite eradication. However, there was no reduction of parasite load at the site of infection or in draining lymph nodes and parasite replication was high upon discontinuation of anti-FasL treatment.Conclusion: The Fas/FasL pathway was shown to be dysregulated both in human VL and CL. A possible mechanism of ulcer formation during CL was proposed by apoptotic death of keratinocytes through enhanced Fast- and TRAIL signalling. This data was further strengthened in a treatment experiment in a murine model of CL, where blocking the Fas/FasL system reduced ulcer formation during L. major infection.List of scientific papersI. Eidsmo L, Wolday D, Berhe N, Sabri F, Satti I, El Hassan AM, Sundar S, Chiodi F, Akuffo H (2002). Alteration of Fas and Fas ligand expression during human visceral leishmaniasis. Clin Exp Immunol. 130(2): 307-13. https://doi.org/10.1046/j.1365-2249.2002.01976.x II. Eidsmo L, Nylen S, Khamesipour A, Hedblad MA, Chiodi F, Akuffo H (2005). The contribution of the Fas/FasL apoptotic pathway in ulcer formation during Leishmania major-induced cutaneous Leishmaniasis. Am J Pathol. 166(4): 1099-108. https://doi.org/10.1016/S0002-9440(10)62330-9 III. Eidsmo L, Fluur C, Eriksson Ygberg S, DeMilito A, Rethi B, Akuffo H, Chiodi F (2006). FasL and TRAIL induced epidermal apoptosis and skin ulceration upon exposure to Leishmania major infection. [Submitted]IV. Eidsmo L, Nylen Spoormaker S, Lieke T, Peters N, Yagita H, Sacks D, Akuffo H, Chiodi F (2006). The effect of neutralisation of FasL on skin ulceration in murine models of cutaneous leishmaniasis. [Manuscript]</p
Dysregulation of receptor induced apoptosis during human leishmaniasis : a possible mechanism of skin ulceration [Elektronisk resurs]
No full textLeishmaniasis is endemic in 88 countries and 12 million people per year have been estimated to be at risk of infection. The causative agent, the protozoan Leishmania, is spread by sand-flies and infects macrophages in the mammalian host. Leishmaniasis in humans form a spectrum of clinical presentations. In cutaneous leishmaniasis (CL) caused by L. major, the infection is localised in the skin and manifests as one or several ulcers that typically spontaneously heal within one year after infection, often leaving marked scarring. In visceral leishmaniasis (VL) caused by L. donovani, infected macrophages are found in liver, spleen, bone marrow and lymph-nodes and the infection leads to hepatosplenomegaly, wasting, fever and if not treated, to death. Systemic T-cell deficiency occurs early during VL and leads to uncontrolled parasite replication. In general, solid immunity upon healing occurs after resolved VL and CL. In this thesis, the hypothesis that alterations of death receptor-mediated apoptosis have an impact on the pathogenesis of human leishmaniasis has been explored. During VL, dysregulation of the Fas/FasL pathway was investigated, both at one site of infection, the spleen, and on circulating lymphocytes from the peripheral blood. In the case of CL the hypothesis was that increased death receptor-mediated apoptosis in the microenvironment surrounding infected macrophages may induce bystandard apoptosis of keratinocytes, leading to skin ulceration. Dysiregulation of the Fas/FasL pathway occured during human VL and CL. Levels of soluble Fas (sFas) and soluble Fas ligand (sFasL) were elevated in plasma of patients with active VL and individuals co-infected with VL-HIV-1 compared to healthy controls, and the levels of sFas and sFasL were normalized 6 months after successful treatment. During active VL, the expression of membrane bound Fas, and to a lower extent Fast., was up-regulated on spleen cells, where parasites multiply. In contrast, expression of Fas and Fast- were not altered on peripheral blood mononuclear cells (PBMC) during VL. Furthermore, in vitro infection of macrophages with L. donovani results in up-regulation of Fas expression on the surface of infected cells and increases the levels of sFasL in supernatants from infected cultures. During active CL caused by L. major, a disease mainly localised to the skin, the Fas and Fast- levels were not altered in serum or on PBMCs analysed ex vivo. However, when CL PBMCs were restimulated with L. major, Fas was up-regulated on effector T-cells and high levels of sFasL were detected in the supernatants as compared to control PBMCs. Keratinocyte apoptosis is altered during CL. Dysregulation of the Fas/FasL pathway in the microenvironment surrounding L. major infected macrophages under the skin was visualised in biopsies collected from CL patients. A substantial number of apoptotic keratinocytes were observed in the epidermis of morphologically active and healing CL skin samples. Fas expression was increased on the epidermis in active CL, whereas FasL expressing macrophages and T-cells were found in the subepidermal infiltrate during active disease. Supernatants from re-stimulated CL-PBMC cultures containing high levels of sFasL induced apoptosis in human keratinocyte cell line (HaCaT), and apoptosis could be inhibited in 213 supernatants by blocking Fas. A commercial apoptosis-specific microarray was used to assess alterations in keratinocyte RNAexpression during exposure to supernatants from L. major infected PBMCs. Fas and TRAIL mRNA and protein expression were significantly up-regulated compared to untreated keratinocytes. Supernatant induced apoptosis of keratinocytes was partly inhibited through blocking Fas or FasL, and more efficiently through inhibition of TRAIL by neutralising antibodies or soluble TRAIL-R. Furthermore, TRAIL expressing keratinocytes were detected in skin biopsies from CL cases. Blocking the Fas/FasL pathway in vivo may reduce ulceration during murine CL. In order to obtain the proof of the concept that Fas/FasL signalling is involved in keratinocyte-apoptosis leading to ulceration in the skin during CL, the Fas/FasL pathway was blocked in a murine model of CL by intraperitoneal treatment with Fast- neutralising antibodies (MFL-4). Skin inflammation, skin ulceration and ulcer size were followed weekly and compared to infected, untreated mice. Our results suggests that blocking Fas/FasL signalling during murine CL lead to less apoptotic keratinocytes and diminished ulceration. During treatment, the number of IFNgammaproducing CD8+CD3+ cells was increased at the site of infection when Fast- was neutralised which is suggestive of efficient parasite eradication. However, there was no reduction of parasite load at the site of infection or in draining lymph nodes and parasite replication was high upon discontinuation of anti-FasL treatment. Conclusion: The Fas/FasL pathway was shown to be dysregulated both in human VL and CL. A possible mechanism of ulcer formation during CL was proposed by apoptotic death of keratinocytes through enhanced Fast- and TRAIL signalling. This data was further strengthened in a treatment experiment in a murine model of CL, where blocking the Fas/FasL system reduced ulcer formation during L. major infection
[Future of university clinics: conditions for young researching physicians must be improved]
No full textSTEROID 21-HYDROXYLASE IN THE KIDNEY - DEMONSTRATION OF LEVELS OF MESSENGER-RNA WHICH CORRELATE WITH THE LEVEL OF ACTIVITY
No full textComposition and maintenance of skin resident T-cells in health and disease
No full textTissue-resident memory T cells (TRM) reside in healthy skin at sites of previous infections. Upon re-infection, TRM cells rapidly respond by initiating tissue inflammation and exert effector functions to eliminate pathogens. TRM cells are potent effector cells and as such, they are key players in focal inflammatory skin diseases. This doctoral thesis investigates effects of aging, tissue microenvironment, and inflammatory skin diseases on the composition of human TRM cells by analyzing patient material with technologies including single cell sequencing with T cell receptor sequencing and mechanistic experiments. The aim was to elucidate the composition and mechanisms for long-term maintenance of the TRM cell population in the skin.PAPER I showed that the number of TRM cells, in particular epidermal cytotoxic CD103+CD49a+ TRM cells increased with age in human skin and maintained functionality and diversity in the skin of the elderly.PAPER II investigated the T cell composition in never-lesional skin of psoriasis patients (NLP) compared to healthy skin. NLP showed higher frequencies of IL-17 and IFN-g producing CCR6+ T cells and CD103+CD49a- TRM cells compared to healthy skin. CCL20, the ligand for CCR6, was upregulated in the epidermis of NLP at baseline, indicating tissue wide pro-inflammatory changes in the microenvironment poised towards disease development.PAPER III analyzed T cell composition in joint and skin in patients living with psoriasis arthritis. Only discreet T cell clonal overlap was detected between these two anatomically distinct and the few shared clones showed different phenotypes in different sites, indicating tissue microenvironment specific adaption of T cells.PAPER IV To address the origin or TRM cells in adult human skin, clonal overlap between circulating T cell populations and skin TRM cell populations was assessed. Central memory T cells (TCM) were superior in giving rise to CD103+CD49a+TRM-like cells. RUNX3 and RUNX2 regulated CD49a expression and TRM cell differentiation. The study suggests that TCM could serve as a circulating precursor for cytotoxic CD103+CD49a+ TRM cells.PAPER V explored the possibility of local TRM precursor cells in humans to replenish the pool of skin TRM cells. A small population of CD69+CD62L+ CD103-CD49a- TRM cells enriched in genes related to multipotency and lower differentiated was found in skin and showed clonal overlap with CD103+CD49a+TRM cells. CD69+CD62L+ TRM cells excelled in proliferation and developed into CD103+CD49a+ TRM-like cells that acquired functional similarities to bona fide TRM cells following stimulation. This indicates that CD69+CD62L+ TRM can act as a local precursor to replenish the pool of skin TRM cells.In conclusion, TRM compositions are altered during healthy ageing (PAPER I) and in different psoriasis- affected microenvironments (PAPER II and III). Human skin TRM cells can be maintained through two mechanisms local and systemic. Circulatory counterparts potentially can provide immunity to distant body sites (PAPER IV and V).List of scientific papersI. Skin T cells maintain their diversity and functionality in the elderly. Hanako Koguchi-Yoshioka , Elena Hoffer, Stanley Cheuk, Yutaka Matsumura, Sa Vo, Petra Kjellman, Lucian Grema, Yosuke Ishitsuka, Yoshiyuki Nakamura, Naoko Okiyama, Yasuhiro Fujisawa, Manabu Fujimoto M, Liv Eidsmo, Rachael A Clark, Rei Watanabe. Communications biology. 2021, Vol 4, Page 1-8. https://doi.org/10.1038/s42003-020-01551-7 II. A skewed pool of resident T cells triggers psoriasis-associated tissue responses in never-lesional skin from patients with psoriasis. Irene Gallais Serezal, Elena Hoffer, Borislav Ignatov, Beatrice Zitti, Marucs Ehrström, Liv Eidsmo. The Journal of Allergy and Clinical Immunology. 2019, Vol 143, Pages 1444- 1454. https://doi.org/10.1016/j.jaci.2018.08.048 III. Clonal overlap of pathogenic IL-17-Producing T cell clones in psoriasis lesions and joints of psoriatic arthritis patients. Wenning Zheng*, Elena Hoffer*, Daniel Sortebech, Martin Skeppsholm, Josefin Lysell** and Liv Eidsmo**. *Co-first author. **Co-senior authors. [Manuscript]IV. Human skin-resident CD8+ T cells require RUNX2 and RUNX3 for induction of cytotoxicity and expression of the integrin CD49a. Beatrice Zitti,* Elena Hoffer*, Wenning Zheng, Ram Vinay Pandey, Heinrich Schlums, Giovanna Perinetti Casoni, Irene Fusi, Lien Nguyen, Jaanika Kärner, Efthymia Kokkinou, Anna Carrasco, Jessica Gahm, Marcus Ehrström, Staffan Happaniemi, Åsa V Keita, Carlotte RH Hedin, Jenny Mjösberg, Liv Eidsmo**, Yenan T Bryceson**. Immunity. 2023, Vol 56, Page 1285-1302. *Co-first author. **Co-senior authors. https://doi.org/10.1016/j.immuni.2023.05.003 V. Epidermal CD69+CD62L+ TRM, a subset with renewal capacity gives rise to CD103+CD49a+ TRM- like cells. Elena Hoffer*, Wenning Zheng*, Beatrice Zitti, Danie Sortebech, Rasmus Agerholm-Nielsen, Chenming Zhang, Trine Schønfeldt, Tilen Trselic, Sofia Papavasileiou, Jaanika Kärner, Marcus Ehrström, Jessica Gahm, Jenny Mjösberg, Josefin Lysell, Niels Odum, YenanT Bryceson, Patrick Brunner, Carmen Gerlach, Liv Eidsmo. *Co-first author. [Manuscript]</p
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