An acid-sensing ion channel that detects ischemic pain

Ischemic pain occurs when there is insufficient blood flow for the metabolic needs of an organ. The pain of a heart attack is the prototypical example. Multiple compounds released from ischemic muscle likely contribute to this pain by acting on sensory neurons that innervate muscle. One such compound is lactic acid. Here, we show that ASIC3 (acid-sensing ion channel #3) has the appropriate expression pattern and physical properties to be the detector of this lactic acid. In rats, it is expressed only in sensory neurons and then only on a minority (~40%) of these. Nevertheless, it is expressed at extremely high levels on virtually all dorsal root ganglion sensory neurons that innervate the heart. It is extraordinarily sensitive to protons (Hill slope 4, half-activating pH 6.7), allowing it to readily respond to the small changes in extracellular pH (from 7.4 to 7.0) that occur during muscle ischemia. Moreover, both extracellular lactate and extracellular ATP increase the sensitivity of ASIC3 to protons. This final property makes ASIC3 a "coincidence detector" of three molecules that appear during ischemia, thereby allowing it to better detect acidosis caused by ischemia than other forms of systemic acidosis such as hypercapnia.

Effects of diet and exercise training on neurovascular control during mental stress in obese women

Since neurovascular control is altered in obese subjects, we hypothesized that weight loss by diet (D) or diet plus exercise training (D + ET) would improve neurovascular control during mental stress in obese women. In a study with a dietary reduction of 600 kcal/day with or without exercise training for 4 months, 53 obese women were subdivided in D (N = 22, 33 ± 1 years, BMI 34 ± 1 kg/m²), D + ET (N = 22, 33 ± 1 years, BMI 33 ± 1 kg/m²), and nonadherent (NA, N = 9, 35 ± 2 years, BMI 33 ± 1 kg/m²) groups. Muscle sympathetic nerve activity (MSNA) was measured by microneurography and forearm blood flow by venous occlusion plethysmography. Mental stress was elicited by a 3-min Stroop color word test. Weight loss was similar between D and D + ET groups (87 ± 2 vs 79 ± 2 and 85 ± 2 vs 76 ± 2 kg, respectively, P < 0.05) with a significant reduction in MSNA during mental stress (58 ± 2 vs 50 ± 2, P = 0.0001, and 59 ± 3 vs 50 ± 2 bursts/100 beats, P = 0.0001, respectively), although the magnitude of the response was unchanged. Forearm vascular conductance during mental stress was significantly increased only in D + ET (2.74 ± 0.22 vs 3.52 ± 0.19 units, P = 0.02). Weight loss reduces MSNA during mental stress in obese women. The increase in forearm vascular conductance after weight loss provides convincing evidence for D + ET interventions as a nonpharmacologic therapy of human obesity.

Systemic and regional hemodynamic effects of enalaprilat infusion in experimental normotensive sepsis

Angiotensin-converting enzyme inhibitors have been shown to improve splanchnic perfusion in distinct shock states. We hypothesized that enalaprilat potentiates the benefits of early fluid resuscitation in severe experimental sepsis, particularly in the splanchnic region. Anesthetized and mechanically ventilated mongrel dogs received an intravenous infusion of live Escherichia coli over a period of 30 min. Thereafter, two interventions were performed: fluid infusion (normal saline, 32 mL/kg over 30 min) and enalaprilat infusion (0.02 mg kg-1 min-1 for 60 min) in randomized groups. The following groups were studied: controls (fluid infusion, N = 4), E1 (enalaprilat infusion followed by fluid infusion, N = 5) and E2 (fluid infusion followed by enalaprilat infusion, N = 5). All animals were observed for a 120 min after bacterial infusion. Mean arterial pressure, cardiac output (CO), portal vein blood flow (PVBF), systemic and regional oxygen-derived variables, and lactate levels were measured. Rapid and progressive reductions in CO and PVBF were induced by the infusion of live bacteria, while minor changes were observed in mean arterial pressure. Systemic and regional territories showed a significant increase in oxygen extraction and lactate levels. Widening venous-arterial and portal-arterial pCO2 gradients were also detected. Fluid replacement promoted transient benefits in CO and PVBF. Enalaprilat after fluid resuscitation did not affect systemic or regional hemodynamic variables. We conclude that in this model of normotensive sepsis inhibition of angiotensin-converting enzyme did not interfere with the course of systemic or regional hemodynamic and oxygen-derived variables.

Cytoadhesion of Plasmodium falciparum-infected erythrocytes and the infected placenta: a two-way pathway

Malaria is undoubtedly the world's most devastating parasitic disease, affecting 300 to 500 million people every year. Some cases of Plasmodium falciparum infection progress to the deadly forms of the disease responsible for 1 to 3 million deaths annually. P. falciparum-infected erythrocytes adhere to host receptors in the deep microvasculature of several organs. The cytoadhesion of infected erythrocytes to placental syncytiotrophoblast receptors leads to pregnancy-associated malaria (PAM). This specific maternal-fetal syndrome causes maternal anemia, low birth weight and the death of 62,000 to 363,000 infants per year in sub-Saharan Africa, and thus has a poor outcome for both mother and fetus. However, PAM and non-PAM parasites have been shown to differ antigenically and genetically. After multiple pregnancies, women from different geographical areas develop adhesion-blocking antibodies that protect against placental parasitemia and clinical symptoms of PAM. The recent description of a new parasite ligand encoded by the var2CSA gene as the only gene up-regulated in PAM parasites renders the development of an anti-PAM vaccine more feasible. The search for a vaccine to prevent P. falciparum sequestration in the placenta by eliciting adhesion-blocking antibodies and a cellular immune response, and the development of new methods for evaluating such antibodies should be key priorities in mother-child health programs in areas of endemic malaria. This review summarizes the main molecular, immunological and physiopathological aspects of PAM, including findings related to new targets in the P. falciparum var gene family. Finally, we focus on a new methodology for mimicking cytoadhesion under blood flow conditions in human placental tissue.

Parasympathetic dysfunction is associated with insulin resistance in fructose-fed female rats

The objective of the present study was to identify metabolic, cardiovascular and autonomic changes induced by fructose overload administered in the drinking water of rats for 8 weeks. Female Wistar rats (200-220 g) were divided into 2 groups: control (N = 8) and fructose-fed rats (N = 5; 100 mg/L fructose in drinking water for 8 weeks). The autonomic control of heart rate was evaluated by pharmacological blockade using atropine (3 mg/kg) and propranolol (4 mg/kg). The animals were submitted to an intravenous insulin tolerance test (ITT) and to blood glucose measurement. The fructose overload induced a significant increase in body weight (~10%) and in fasting glycemia (~28%). The rate constant of glucose disappearance (KITT) during ITT was lower in fructose-fed rats (3.25 ± 0.7%/min) compared with controls (4.95 ± 0.3%/min, P < 0.05) indicating insulin resistance. The fructose-fed group presented increased arterial pressure compared to controls (122 ± 3 vs 108 ± 1 mmHg, P < 0.05) and a reduction in vagal tonus (31 ± 9 vs 55 ± 5 bpm in controls, P < 0.05). No changes in sympathetic tonus were observed. A positive correlation, tested by the Pearson correlation, was demonstrable between cardiac vagal tonus and KITT (r = 0.8, P = 0.02). These data provided new information regarding the role of parasympathetic dysfunction associated with insulin resistance in the development of early metabolic and cardiovascular alterations induced by a high fructose diet.

Endogenous angiotensin II modulates nNOS expression in renovascular hypertension

Nitric oxide (NO) influences renal blood flow mainly as a result of neuronal nitric oxide synthase (nNOS). Nevertheless, it is unclear how nNOS expression is modulated by endogenous angiotensin II, an inhibitor of NO function. We tested the hypothesis that the angiotensin II AT1 receptor and oxidative stress mediated by NADPH oxidase contribute to the modulation of renal nNOS expression in two-kidney, one-clip (2K1C) hypertensive rats. Experiments were performed on male Wistar rats (150 to 170 g body weight) divided into 2K1C (N = 19) and sham-operated (N = 19) groups. nNOS expression in kidneys of 2K1C hypertensive rats (N = 9) was compared by Western blotting to that of 2K1C rats treated with low doses of the AT1 antagonist losartan (10 mg·kg-1·day-1; N = 5) or the superoxide scavenger tempol (0.2 mmol·kg-1·day-1; N = 5), which still remain hypertensive. After 28 days, nNOS expression was significantly increased by 1.7-fold in the clipped kidneys of 2K1C rats and by 3-fold in the non-clipped kidneys of 2K1C rats compared with sham rats, but was normalized by losartan. With tempol treatment, nNOS expression increased 2-fold in the clipped kidneys and 1.4-fold in the non-clipped kidneys compared with sham rats. The changes in nNOS expression were not followed by changes in the enzyme activity, as measured indirectly by the cGMP method. In conclusion, AT1 receptors and oxidative stress seem to be primary stimuli for increased nNOS expression, but this up-regulation does not result in higher enzyme activity.

Effects of sirolimus alone or in combination with cyclosporine A on renal ischemia/reperfusion injury

Calcineurin inhibitors exacerbate ischemic injury in transplanted kidneys, but it is not known if sirolimus protects or exacerbates the transplanted kidney from ischemic injury. We determined the effects of sirolimus alone or in combination with cyclosporin A (CsA) on oxygenated and hypoxic/reoxygenated rat proximal tubules in the following in vitro groups containing 6-9 rats per group: sirolimus (10, 50, 100, 250, 500, and 1000 ηg/mL); CsA (100 µg/mL); sirolimus (50 and 250 ηg/mL) + CsA (100 µg/mL); control; vehicle (20% ethanol). For in vivo studies, 3-week-old Wistar rats (150-250 g) were submitted to left nephrectomy and 30-min renal artery clamping. Renal function and histological evaluation were performed 24 h and 7 days after ischemia (I) in five groups: sham, I, I + SRL (3 mg·kg-1·day-1, po), I + CsA (3 mg·kg-1·day-1, sc), I + SRL + CsA. Sirolimus did not injure oxygenated or hypoxic/reoxygenated proximal tubules and did not potentiate the tubular toxic effects of CsA. Neither drug affected the glomerular filtration rate (GFR) at 24 h. GFR was reduced in CsA-treated rats on day 7 (0.5 ± 0.1 mL/min) but not in rats receiving sirolimus + CsA (0.8 ± 0.1 mL/min) despite the reduction in renal blood flow (3.9 ± 0.5 mL/min). Acute tubular necrosis regeneration was similar for all groups. Sirolimus alone was not toxic and did not enhance hypoxia/reoxygenation injury or CsA toxicity to proximal tubules. Despite its hemodynamic effects, sirolimus protected post-ischemic kidneys against CsA toxicity.

The modified 2VO ischemia protocol causes cognitive impairment similar to that induced by the standard method, but with a better survival rate

Permanent bilateral occlusion of the common carotid arteries (2VO) in the rat has been established as a valid experimental model to investigate the effects of chronic cerebral hypoperfusion on cognitive function and neurodegenerative processes. Our aim was to compare the cognitive and morphological outcomes following the standard 2VO procedure, in which there is concomitant artery ligation, with those of a modified protocol, with a 1-week interval between artery occlusions to avoid an abrupt reduction of cerebral blood flow, as assessed by animal performance in the water maze and damage extension to the hippocampus and striatum. Male Wistar rats (N = 47) aged 3 months were subjected to chronic hypoperfusion by permanent bilateral ligation of the common carotid arteries using either the standard or the modified protocol, with the right carotid being the first to be occluded. Three months after the surgical procedure, rat performance in the water maze was assessed to investigate long-term effects on spatial learning and memory and their brains were processed in order to estimate hippocampal volume and striatal area. Both groups of hypoperfused rats showed deficits in reference (F(8,172) = 7.0951, P < 0.00001) and working spatial memory [2nd (F(2,44) = 7.6884, P < 0.001), 3rd (F(2,44) = 21.481, P < 0.00001) and 4th trials (F(2,44) = 28.620, P < 0.0001)]; however, no evidence of tissue atrophy was found in the brain structures studied. Despite similar behavioral and morphological outcomes, the rats submitted to the modified protocol showed a significant increase in survival rate, during the 3 months of the experiment (P < 0.02).

Exogenous normal lymph alleviates microcirculation disturbances and abnormal hemorheological properties in rats with disseminated intravascular coagulation

Disturbances of the microcirculation and abnormal hemorheological properties are important factors that play an important role in disseminated intravascular coagulation (DIC) and result in organ dysfunction or failure. In the present study, we established an animal model of DIC using intravenous Dextran 500 in rats, and used exogenous normal lymph corresponding to 1/15 of whole blood volume for injection through the left jugular vein. We found that normal lymph could improve the blood pressure and survival time of rats with DIC. The results regarding the mesenteric microcirculation showed that the abnormality of the diameter of mesenteric microvessels and micro-blood flow speed in the DIC+lymph group was significantly less than in the DIC+saline group. Whole blood viscosity, relative viscosity, plasma viscosity, hematocrit (Hct), erythrocyte sedimentation rate (ESR), and electrophoresis time of erythrocytes were significantly increased in the DIC+saline group compared to the control group. The electrophoretic length and migration of erythrocytes from the DIC+saline and DIC+lymph groups were significantly slower than the control group. Blood relative viscosity, Hct, ESR, and electrophoretic time of erythrocytes were significantly increased in the DIC+lymph group compared to the control group. Whole blood viscosity, relative viscosity and reduced viscosity were significantly lower in the DIC+lymph group than in the DIC+saline group, and erythrocyte deformability index was also significantly higher than in the DIC+saline and control groups. These results suggest that exogenous normal lymph could markedly improve the acute microcirculation disturbance and the abnormal hemorheological properties in rats with DIC induced by Dextran 500.

High levels of LDL-C combined with low levels of HDL-C further increase platelet activation in hypercholesterolemic patients

High levels of low-density lipoprotein cholesterol (LDL-C) enhance platelet activation, whereas high levels of high-density lipoprotein cholesterol (HDL-C) exert a cardioprotective effect. However, the effects on platelet activation of high levels of LDL-C combined with low levels of HDL-C (HLC) have not yet been reported. We aimed to evaluate the platelet activation marker of HLC patients and investigate the antiplatelet effect of atorvastatin on this population. Forty-eight patients with high levels of LDL-C were enrolled. Among these, 23 had HLC and the other 25 had high levels of LDL-C combined with normal levels of HDL-C (HNC). A total of 35 normocholesterolemic (NOMC) volunteers were included as controls. Whole blood flow cytometry and platelet aggregation measurements were performed on all participants to detect the following platelet activation markers: CD62p (P-selectin), PAC-1 (GPIIb/IIIa), and maximal platelet aggregation (MPAG). A daily dose of 20 mg atorvastatin was administered to patients with high levels of LDL-C, and the above assessments were obtained at baseline and after 1 and 2 months of treatment. The expression of platelets CD62p and PAC-1 was increased in HNC patients compared to NOMC volunteers (P<0.01 and P<0.05). Furthermore, the surface expression of platelets CD62p and PAC-1 was greater among HLC patients than among HNC patients (P<0.01 and P<0.05). Although the expression of CD62p and PAC-1 decreased significantly after atorvastatin treatment, it remained higher in the HLC group than in the HNC group (P<0.05 and P=0.116). The reduction of HDL-C further increased platelet activation in patients with high levels of LDL-C. Platelet activation remained higher among HLC patients regardless of atorvastatin treatment.

Spectrally Tuned Lanthanide Photoluminescence for Point-of-Care Testing

Point-of-care (POC) –diagnostics is a field with rapidly growing market share. As these applications become more widely used, there is an increasing pressure to improve their performance to match the one of a central laboratory tests. Lanthanide luminescence has been widely utilized in diagnostics because of the numerous advantages gained by the utilization of time-resolved or anti-Stokes detection. So far the use of lanthanide labels in POC has been scarce due to limitations set by the instrumentation required for their detection and the shortcomings, e.g. low brightness, of these labels. Along with the advances in the research of lanthanide luminescence, and in the field of semiconductors, these materials are becoming a feasible alternative for the signal generation also in the future POC assays. The aim of this thesis was to explore ways of utilizing time-resolved detection or anti-Stokes detection in POC applications. The long-lived fluorescence for the time-resolved measurement can be produced with lanthanide chelates. The ultraviolet (UV) excitation required by these chelates is cumbersome to produce with POC compatible fluorescence readers. In this thesis the use of a novel light-harvesting ligand was studied. This molecule can be used to excite Eu(III)-ions at wavelengths extending up to visible part of the spectrum. An enhancement solution based on this ligand showed a good performance in a proof-of-concept -bioaffinity assay and produced a bright signal upon 365 nm excitation thanks to the high molar absorptivity of the chelate. These features are crucial when developing miniaturized readers for the time-resolved detection of fluorescence. Upconverting phosphors (UCPs) were studied as an internal light source in glucose-sensing dry chemistry test strips and ways of utilizing their various emission wavelengths and near-infrared excitation were explored. The use of nanosized NaYF :Yb3+,Tm3+-particles enabled the replacement of an external UV-light source with a NIR-laser and gave an additional degree of freedom in the optical setup of the detector instrument. The new method enabled a blood glucose measurement with results comparable to a current standard method of measuring reflectance. Microsized visible emitting UCPs were used in a similar manner, but with a broad absorbing indicator compound filtering the excitation and emission wavelengths of the UCP. This approach resulted in a novel way of benefitting from the non-linear relationship between the excitation power and emission intensity of the UCPs, and enabled the amplification of the signal response from the indicator dye.

Toisen jäte on toisen raaka-aine – Kierrätys ja uudelleenvalmistus taloudellisesti ja ekologisesti kestävänä liiketoimintamahdollisuutena

Toisen jäte on toisen raaka-aine – Kierrätys ja uudelleenvalmistus taloudellisesti ja ekologisesti kestävänä liiketoimintamahdollisuutena Väitöskirjatutkimus tarkastelee kierrätystä ja uudelleenvalmistusta sekä siihen perustuvaa kierrätysliiketoimintaa taloudellisesti ja ekologisesti kestävänä liiketoimintamahdollisuutena. Tässä kestävyys tarkoittaa jätekysymysten ratkaisemista tavalla, joka mahdollistaa kestävän kehityksen periaatteiden mukaisen yhteiskunnan kehittymisen. Jätteisiin liittyvät taloudelliset ja ekolo- giset kysymykset ovat merkittävä yhteiskunnallinen haaste. Tämä luo tarpeen tutkimukselle, jonka lähtökohtana on jätekysymysten moniulotteinen tarkas- telu ja yksittäisen yrityksen toiminnan suhteuttaminen osaksi laajempaa kokonaisuutta. Tässä tutkimuksessa jätteen hyödyntämistä materiaalina lähestytään sekä empiirisesti yrityksen näkökulmasta että teoreettisesti systeemiajattelun tarjoamasta laajemmasta perspektiivistä. Tutkimuksen tavoitteena on ymmär- tää kierrätystä ja uudelleenvalmistusta liiketoimintamahdollisuutena, niiden merkitystä yrityksessä, alueella ja kierrätystaloudessa sekä näiden vuorovai- kutteista suhdetta taloudelliseen ja ekologiseen kestävyyteen nähden. Tutki- muskysymys on tärkeä, koska siihen vastaamalla syvennetään ymmärrystä yrityksissä tapahtuvan kierrätyksen ja uudelleenvalmistuksen merkityksestä kestävämmän yhteiskunnan rakentumisessa. Tutkimuksen teoriaperusta pohjautuu teollisen ekologian kirjallisuuteen ja ekoteollisen kehityksen tutkimukseen. Kierrätysliiketoiminnan kestävyyden tarkastelu rakentuu tutkimuksessa teollisen ekologian ja ekoteollisen kehityk- sen lähtökohtana olevaan win-win-ajatteluun, jonka mukaan hyvä ympäristö- suorituskyky ja hyvä taloudellinen suorituskyky voivat vahvistaa toisiaan. Kierrätysliiketoiminnan teoreettisessa tarkastelussa keskeisiä elementtejä ovat kierrätystalouden malli, teollisen ekologian alueelliset systeemit, ekoteolliset verkostot ja yrityksen rooli teollista ekologiaa soveltavana toimijana. Tutki- muksen keskeisenä kontribuutiona on yritysnäkökulman integroiminen aiem- paa vahvemmin osaksi teollisen ekologian diskursseja. Kierrätysliiketoiminnan taloudelliseen ja ekologiseen kannattavuuteen ja sen myötä kestävyyteen liittyviä kysymyksiä on lähestytty tekemällä yritys- haastatteluja ja hyödyntämällä valmista haastatteluaineistoa. Tutkimusta varten haastattelin 10 kierrätysliiketoimintaa harjoittavaa yritystä vuosina 2007 ja 2008. Tämän lisäksi tutkimuksessa on hyödynnetty Turun ammatti- korkeakoulun ja Turku Science Parkin toteuttamassa RESU-hankkeessa (Kierrätysliiketoiminta ja resurssitehokkuus Varsinais-Suomen vahvuudeksi – RESU) vuosina 2013 ja 2014 kerättyä aineistoa. Hankkeessa haastateltiin yhteensä 25 jätemateriaalia hyödyntävää ja/tai tuottavaa yritystä. Aineistojen analysointimenetelmänä on sisällönanalyysi. Analyysin tulok- sena muodostettiin yhteensä viisi pääteemaa ja 12 alateemaa. Teemat kuvaavat kierrätysliiketoimintaa aiempaa moniulotteisemmin ja näin syventävät ymmär- rystä ilmiön merkityksestä kestävämmän yhteiskunnan rakentumisessa. Teolli- sen ekologian alaan kuuluvat kvalitatiiviset tutkimukset ovat melko harvinai- sia, joten tämän väitöstutkimuksen ilmeisenä vahvuutena on laadullisen tutkimusmenetelmän hyödyntäminen. Tutkimuksen tuloksena voidaan todeta, että kierrätystalouden kehittymistä edistävä kierrätysliiketoiminta on monimuotoista ja sisältää erilaisia liiketoi- mintamahdollisuuksia sekä arvoketjuja. Paikallistuntemus ja keskeinen sijainti jätemateriaalien tuottajien suhteen on tärkeä kriteeri kierrätysliiketoiminnassa, mutta jätemateriaaleja myös kuljetetaan pitkiä matkoja. Paikallisia tai alueelli- sia jätevirtoja hyödyntävä kierrätysliiketoiminta voi tukea alueellista kestä- vyyttä, mutta toisinaan myös keskitetty hyödyntäminen voi olla kestävä vaih- toehto. Yhteistyöverkostot ovat tärkeitä jätemateriaalin laadun ja saatavuuden näkökulmasta. Tutkimus osoittaa, että kierrätysliiketoimintaa harjoittavat yritykset ovat samalla sekä kierrätystalouden käytännön toimeenpanijoita että uuden toimintakulttuurin luojia. Tutkimuksen tulosten perusteella voidaan esittää johtopäätös, että kierrä- tysliiketoiminta on taloudellisesti ja ekologisesti kannattava liiketoimintamah- dollisuus. Win-win-ratkaisut eivät kuitenkaan takaa kierrätysliiketoiminnan kestävyyttä. Kierrätysliiketoiminnan kestävyyden arvioiminen edellyttää laajaa perspektiiviä ja toiminnan vaikutusten suhteuttamista mittakaavaan, ajalliseen ulottuvuuteen, interventioon ja sosiaalisiin kysymyksiin. Teolliseen ekologiaan perustuva kierrätysliiketoiminta luo mahdollisuuksia edistää kestävyyttä, joten tällä perusteella kierrätystä ja uudelleenvalmistusta voidaan pitää kestävänä liiketoimintamahdollisuutena. Avainsanat: kierrätysliiketoiminta, kierrätys, uudelleenvalmistus, systeemiajattelu, teollinen ekologia, ekoteollinen kehitys, kierrätystalous, win-win-ajattelu, kestävyys One company's waste is another's raw material –Recycling and remanufacturing as an economically and environmentally sustainable business opportunity The thesis investigates whether product recycling and remanufacturing can serve as a business opportunity that is economically and ecologically sustaina- ble. In this effort, my idea is to contribute to solving the waste issue in a manner that makes it possible to strive toward sustainable societal develop- ment. The economic and ecological questions associated with waste flows are a significant challenge. The complexity of the issue requires a multidimen- sional approach in which the operation of an individual company is viewed in the context of the larger societal system. In this thesis waste utilization as a resource with value is considered both from an empirical perspective on the firm as well as from a more general viewpoint offered by systems analysis. The objective of the thesis is to under- stand recycling and remanufacturing as a business opportunity. The thesis considers the meaning of recycling and remanufacturing for a single company, for the region the company is located and for the recycling economy. The objective of this study is important for it enhances the understanding of the product recycling and remanufacturing processes that take place within busi- ness organizations and how these processes affect societal sustainable development. The theoretical basis arises from industrial ecology and from the literature on eco-industrial development. The business-economic win-win situation and this vision serve as the basic position from which recycling business is inves- tigated in the thesis. In the theoretical discussion, key elements are recycling economy model, regional and local industrial ecosystems, eco-industrial networks and the role of a company as an actor that applies industrial ecology in practice. The main contribution of this study lies in integrating the company perspective more strongly into the industrial ecology discourses. The recycling business has been studied by conducting interviews in companies and by secondary analysis of an existing interview material. During 2007 and 2008 I made 10 interviews in companies that are active in recycling business. In addition, I used interview material gathered for the project “Recycling business and resource efficiency as the strength of Southwest Finland” (RESU) by Turku University of Applied Sciences and Turku Science Park during the period 2013–2014. This data covers altogether 25 businesses that either utilize and/or produce waste materials. The data has been analyzed using the content analysis method. This process led to the development of 5 main themes and 12 sub-themes. These themes describe the recycling business multi-dimensionally and thus understanding of the phenomenon and its role in building a sustainable society are substantially deepened in this research. In the field of industrial ecology qualitative studies are relatively rare and therefore the qualitative research approach is an evident strength of the thesis. The results show that the recycling business activity supporting recycling economy has diverse dimensions including various business opportunities and diverse value chains. The results show that for waste producers it is important to know the local situational factors and to have a central geographical location. Waste materials are, however, transported over long distances as well. The study indicates that local waste flow utilization can support regional sustainability, while occasionally a more centralized utilization can be sustain- able. Collaboration networks are important to secure the quality and availabil- ity of utilizable waste materials. The thesis demonstrates that the companies practicing recycling business serve simultaneously as actors that implement recycling economy and enhance a new operation culture within the business community. The overall conclusion of the thesis argues that recycling business is a business opportunity that can support both an economically and environmen- tally viable business operation. However, win-win solutions do not secure the sustainability of recycling business. The sustainability evaluation of recycling business requires a holistic systems perspective. The actions undertaken need to be considered with changing spatial and temporal system boundaries, societal intervention and placed in the context of relevant societal issues. Industrial ecology -based recycling business creates opportunities for sustain- ability and thus recycling and remanufacturing present an opportunity for sustainable business. Keywords: Recycling business; Recycling; Remanufacturing, Systems thinking; Industrial ecology; Eco-industrial development; Recycling Economy; Win-Win thinking; Sustainability

Modulation of TGF-β signaling by Hypoxia

A tumor is a fast-growing malignant tissue. This creates areas inside the tumor that are distant from local blood vessels to be able to get enough oxygen. This hypoxic condition activates a transcription factor called hypoxia inducible factor (HIF). HIF responses help a cell to adapt to decreased oxygen by activating glycolytic and angiogenesis pathways and by regulating apoptotic responses. Hypoxia drives the upregulation of a growth factor called transforming growth factor beta (TGF-beta). Similar to a hypoxia response, TGF is an important regulator of cell fate. TGF-β and HIF pathways regulate partially overlapping target genes. This regulation can also be cooperative. The TGF-beta signal is initiated by activation of plasma membrane receptors that then activate effector proteins called small mothers against decapentaplegic (Smad) homologs. In healthy tissue, TGF-β keeps cell proliferation and growth under control. During cancer progression, TGF-beta has shown a dual role, whereby it inhibits initial tumor formation but, conversely, in an existent tumor, TGF-beta drives malignant progression. Along with HIF and TGF-beta also protein dephosphorylation is an important regulatory mechanism of cell fate. Protein dephosphorylation is catalyzed by protein phosphatases such as Protein phosphatase 2A (PP2A). PP2A is a ubiquitous phosphatase that can exist in various active forms. PP2A can specifically regulate TGF-beta signaling either by enhancing or inhibiting the receptor activity. This work demonstrates that during hypoxia, PP2A is able to fine-tune TGF-beta signal by specifically targeting Smad3 effector in a Smad7-dependent manner. Inactivation of Smad3 in hypoxia leads to malignant conversion of TGF-beta signaling.

Cardiac Imaging in the Diagnosis of Coronary Artery Disease: The Value of Quantitative Imaging of Myocardial Perfusion and Deformation

Atherosclerosis is a chronic and progressive disease of the vasculature. Increasing coronary atherosclerosis can lead to obstructive coronary artery disease (CAD) or myocardial infarction. Computed tomography angiography (CTA) allows noninvasive assessment of coronary anatomy and quantitation of atherosclerotic burden. Myocardial blood flow (MBF) can be accurately measured in absolute terms (mL/g/min) by positron emission tomography (PET) with [15O] H O as a radiotracer. We studied the coronary microvascular dysfunction as a risk factor for future coronary calcification in healthy young men by measuring the coronary flow reserve (CFR) which is the ratio between resting and hyperemic MBF. Impaired vasodilator function was not linked with accelerated atherosclerosis 11 years later. Currently, there is a global interest in quantitative PET perfusion imaging. We established optimal thresholds of [15O] H O PET perfusion for diagnosis of CAD (hyperemic MBF of 2.3 mL/g/min and CFR of 2.5) in the first multicenter study of this type (Turku, Amsterdam and Uppsala). In myocardial bridging a segment of the coronary artery travels inside the myocardium and can be seen as intramural course (CTA) or systolic compression (invasive coronary angiography). Myocardial bridging is frequently linked with proximal atherosclerotic plaques. We used quantitative [15O] H O PET perfusion to evaluate the hemodynamic effects of myocardial bridging. Myocardial bridging was not associated with decreased absolute MBF or increased atherosclerotic burden. Speckle tracking allows quantitative echocardiographic imaging of myocardial deformation. Speckle tracking during dobutamine stress echocardiography was feasible and comparable to subjective wall motion analysis in the diagnosis of CAD. In addition, it correctly risk stratified patients with multivessel disease and extensive ischemia.

Post-hatch heat warms adult beaks: irreversible physiological plasticity in Japanese quail

Across taxa, the early rearing environment contributes to adult morphological and physiological variation. For example, in birds, environmental temperature plays a key role in shaping bill size and clinal trends across latitudinal/thermal gradients. Such patterns support the role of the bill as a thermal window and in thermal balance. It remains unknown whether bill size and thermal function are reversibly plastic. We raised Japanese quail in warm (308C) or cold (158C) environments and then at a common intermediate temperature. We predicted that birds raised in cold temperatures would develop smaller bills than warm-reared individuals, and that regulation of blood flow to the bill in response to changing temperatures would parallel the bill’s role in thermal balance. Cold-reared birds developed shorter bills, although bill size exhibited ‘catch-up’ growth once adults were placed at a common temperature. Despite having lived in a common thermal environment as adults, individuals that were initially reared in the warmth had higher bill surface temperatures than coldreared individuals, particularly under cold conditions. This suggests that blood vessel density and/or the control over blood flow in the bill retained a memory of early thermal ontogeny. We conclude that post-hatch temperature reversibly affects adult bill morphology but irreversibly influences the thermal physiological role of bills and may play an underappreciated role in avian energetics