Browsing by Subject "HYPOXIA"

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  • Wegelius, Asko; Pankakoski, Maiju; Tomppo, Liisa; Lehto, Ulriika; Lonnqvist, Jouko; Suvisaari, Jaana; Paunio, Tiina; Hennah, William (2015)
    Pre- and perinatal environmental factors have been shown to increase schizophrenia risk particularly when combined with genetic liability. The investigation of specific gene environment interactions in the etiology of psychiatric disorders has gained momentum. We used multivariate GEE regression modeling to investigate the interaction between genes of the DISCI pathway and birth weight, in relation to schizophrenia susceptibility in a Finnish schizophrenia family cohort. The study sample consisted of 457 subjects with both genotype and birth weight information. Gender and place of birth were adjusted for in the models. We found a significant interaction between birth weight and two NDE1 markers in relation to increased schizophrenia risk: a four SNP haplotype spanning NDE1 (b = 1.26, SE= 0.5, p = 0.012) and one of its constituent SNPs rs4781678 (b = 1.33, SE = 0.51, p = 0.010). Specifically, high birth weight (> 4000 g) was associated with increased schizophrenia risk among subjects homozygous for the previously identified risk alleles. The study was based on a family study sample with high genetic loading for schizophrenia and thus our findings cannot directly be generalized as representing the general population. Our results suggest that the functions mediated by NDE1 during the early stages of neurodevelopment are susceptible to the additional disruptive effects of pre- and perinatal environmental factors associated with high birth weight, augmenting schizophrenia susceptibility. (C) 2015 The Authors. Published by Elsevier Ireland Ltd.
  • Ning, Wenxin; Nielsen, Anne Birgitte; Norbäck Ivarsson, Lena; Jilbert, Thomas Stephen; Åkesson, Christine; Slomp, Caroline P.; Andren, Elinor; Broström, Anne; Filipsson, Helena L. (2018)
    Coastal environments have experienced large ecological changes as a result of human activities over the last 100-200 years. To understand the severity and potential consequences of such changes, paleoenvironmental records provide important contextual information. The Baltic Sea coastal zone is naturally a vulnerable system and subject to significant human-induced impacts. To put the recent environmental degradation in the Baltic coastal zone into a long-term perspective, and to assess the natural and anthropogenic drivers of environmental change, we present sedimentary records covering the last 1000 years obtained from a coastal inlet (Gasfjarden) and a nearby lake (Lake Storsjon) in Sweden. We investigate the links between a pollen-based land cover reconstruction from Lake Storsjon and paleoenvironmental variables from Gasfjarden itself, including diatom assemblages, organic carbon (C) and nitrogen (N) contents, stable C and N isotopic ratios, and biogenic silica contents. The Lake Storsjon record shows that regional land use was characterized by small-scale agricultural activity between 900 and 1400 CE, which slightly intensified between 1400 and 1800 CE. Substantial expansion of cropland was observed between 1800 and 1950 CE, before afforestation between 1950 and 2010 CE. From the Gasfjarden record, prior to 1800 CE, relatively minor changes in the diatom and geochemical proxies were found. The onset of cultural eutrophication in Gasfjarden can be traced to the 1800s and intensified land use is identified as the main driver. Anthropogenic activities in the 20th century have caused unprecedented ecosystem changes in the coastal inlet, as reflected in the diatom composition and geochemical proxies. (c) 2018 Elsevier Ltd. All rights reserved.
  • Rahikkala, Elisa; Myllykoski, Matti; Hinttala, Reetta; Vieira, Paivi; Nayebzadeh, Naemeh; Weiss, Simone; Plomp, Astrid S.; Bittner, Reginald E.; Kurki, Mitja I.; Kuismin, Outi; Lewis, Andrea M.; Väisänen, Marja-Leena; Kokkonen, Hannaleena; Westermann, Jonne; Bernert, Gunther; Tuominen, Hannu; Palotie, Aarno; Aaltonen, Lauri; Yang, Yaping; Potocki, Lorraine; Moilanen, Jukka; van Koningsbruggen, Silvana; Wang, Xia; Schmidt, Wolfgang M.; Koivunen, Peppi; Uusimaa, Johanna (2019)
    Purpose: A new syndrome with hypotonia, intellectual disability, and eye abnormalities (HIDEA) was previously described in a large consanguineous family. Linkage analysis identified the recessive disease locus, and genome sequencing yielded three candidate genes with potentially pathogenic biallelic variants: transketolase (TKT), transmembrane prolyl 4-hydroxylase (P4HTM), and ubiquitin specific peptidase 4 (USP4). However, the causative gene remained elusive. Methods: International collaboration and exome sequencing were used to identify new patients with HIDEA and biallelic, potentially pathogenic, P4HTM variants. Segregation analysis was performed using Sanger sequencing. P4H-TM wild-type and variant constructs without the transmembrane region were overexpressed in insect cells and analyzed using sodium dodecyl sulfate-polyacrylamide gel electrophoresis and western blot. Results: Five different homozygous or compound heterozygous pathogenic P4HTM gene variants were identified in six new and six previously published patients presenting with HIDEA. Hypoventilation, obstructive and central sleep apnea, and dysautonomia were identified as novel features associated with the phenotype. Characterization of three of the P4H-TM variants demonstrated yielding insoluble protein products and, thus, loss-of-function. Conclusions: Biallelic loss-of-function P4HTM variants were shown to cause HIDEA syndrome. Our findings enable diagnosis of the condition, and highlight the importance of assessing the need for noninvasive ventilatory support in patients.
  • Kallio, Pauliina; Jokinen, Elina; Högström, Jenny; Das, Suvendu; Heino, Sarika; Lähde, Marianne; Brodkin, Jefim; Korhonen, Emilia A.; Alitalo, Kari (2020)
    Abnormal vasculature in tumors leads to poor tissue perfusion and cytostatic drug delivery. Although drugs inducing vascular normalization, for example, angiopoietin-2 (Ang2)-blocking antibodies, have shown promising results in preclinical tumor models, clinical studies have so far shown only little efficacy. Because Ang2 is known to play a protective role in stressed endothelial cells, we tested here whether Ang2 blocking could enhance radiation-induced tumor vascular damage. Tumor-bearing mice were treated with anti-Ang2 antibodies every 3 or 4 days starting 3 days before 3 x 2 Gy or 4 x 0.5 Gy whole-body or tumor-focused radiation. Combination treatment with anti-Ang2 and radiation improved tumor growth inhibition and extended the survival of mice with melanoma or colorectal tumors. Single-cell RNA-sequencing revealed that Ang2 blocking rescued radiation-induced decreases inT cells and cells of the monocyte/macrophage lineage. In addition, anti-Ang2 enhanced radiation-induced apoptosis in cultured endothelial cells. In vivo, combination treatment decreased tumor vasculature and increased tumor necrosis in comparison with tumors treated with monotherapies. These results suggest that a combination of Ang2-blocking antibodies with radiation increases tumor growth inhibition and extends the survival of tumor-bearing mice. Significance: These findings offer a preclinical rationale for further testing of the use of radiation in combination with Ang2-blocking antibodies to improve the overall outcome of cancer treatment.
  • Davies, Emma; Dong, Meng; Gutekunst, Matthias; Narhi, Katja; van Zoggel, Hanneke J. A. A.; Blom, Sami; Nagaraj, Ashwini; Metsalu, Tauno; Oswald, Eva; Erkens-Schulze, Sigrun; San Martin, Juan A. Delgado; Turkki, Riku; Wedge, Stephen R.; af Hallstrom, Taija M.; Schueler, Julia; van Weerden, Wytske M.; Verschuren, Emmy W.; Barry, Simon T.; van der Kuip, Heiko; Hickman, John A. (2015)
    Precision-cut slices of in vivo tumours permit interrogation in vitro of heterogeneous cells from solid tumours together with their native microenvironment. They offer a low throughput but high content in vitro experimental platform. Using mouse models as surrogates for three common human solid tumours, we describe a standardised workflow for systematic comparison of tumour slice cultivation methods and a tissue microarray-based method to archive them. Cultivated slices were compared to their in vivo source tissue using immunohistochemical and transcriptional biomarkers, particularly of cellular stress. Mechanical slicing induced minimal stress. Cultivation of tumour slices required organotypic support materials and atmospheric oxygen for maintenance of integrity and was associated with significant temporal and loco-regional changes in protein expression, for example HIF-1 alpha. We recommend adherence to the robust workflow described, with recognition of temporal-spatial changes in protein expression before interrogation of tumour slices by pharmacological or other means.
  • Vered, Marilena; Lehtonen, Meri; Hotakainen, Lari; Pirila, Emma; Teppo, Susanna; Nyberg, Pia; Sormunen, Raija; Zlotogorski-Hurvitz, Ayelet; Salo, Tuula; Dayan, Dan (2015)
  • Lalowski, Maciej M.; Björk, Susann; Finckenberg, Piet; Soliymani, Rabah; Tarkia, Miikka; Calza, Giulio; Blokhina, Daria; Tulokas, Sari; Kankainen, Matti; Lakkisto, Päivi; Baumann, Marc; Kankuri, Esko; Mervaala, Eero (2018)
    The heart of a newborn mouse has an exceptional capacity to regenerate from myocardial injury that is lost within the first week of its life. In order to elucidate the molecular mechanisms taking place in the mouse heart during this critical period we applied an untargeted combinatory multiomics approach using large-scale mass spectrometry-based quantitative proteomics, metabolomics and mRNA sequencing on hearts from 1-day-old and 7-day-old mice. As a result, we quantified 1.937 proteins (366 differentially expressed), 612 metabolites (263 differentially regulated) and revealed 2.586 differentially expressed gene loci (2.175 annotated genes). The analyses pinpointed the fructose-induced glycolysis-pathway to be markedly active in 1-day-old neonatal mice. Integrated analysis of the data convincingly demonstrated cardiac metabolic reprogramming from glycolysis to oxidative phosphorylation in 7-days old mice, with increases of key enzymes and metabolites in fatty acid transport (acylcarnitines) and beta-oxidation. An upsurge in the formation of reactive oxygen species and an increase in oxidative stress markers, e.g., lipid peroxidation, altered sphingolipid and plasmalogen metabolism were also evident in 7-days mice. In vitro maintenance of physiological fetal hypoxic conditions retained the proliferative capacity of cardiomyocytes isolated from newborn mice hearts. In summary, we provide here a holistic, multiomics view toward early postnatal changes associated with loss of a tissue regenerative capacity in the neonatal mouse heart. These results may provide insight into mechanisms of human cardiac diseases associated with tissue regenerative incapacity at the molecular level, and offer a prospect to discovery of novel therapeutic targets.
  • Maximov, Alexey; Bonsdorff, Erik; Eremina, Tatjana; Kauppi, Laura; Norkko, Alf; Norkko, Joanna (2015)
    Marenzelleria spp. are among the most successful non-native benthic species in the Baltic Sea. These burrowing polychaetes dig deeper than most native Baltic species, performing previously lacking ecosystem functions. We examine evidence from experiments, field sampling and modelling that the introduction of Marenzelleria spp. affects nutrient cycling and biogeochemical processes at the sediment water interface. Over longer time scales, bioirrigation by Marenzelleria spp. has the potential to increase phosphorus retention in bottom deposits because of deeper oxygen penetration into sediments and formation of a deeper oxidized layer. In contrast, nitrogen fluxes from the sediment increase. As a consequence of a decline of the phosphate concentration and/or rising nitrogen/phosphorus ratio, some Northern Baltic ecosystems may experience improvement of the environment because of mitigation of eutrophication and harmful cyanobacteria blooms. Although it is difficult to unambiguously estimate the ecosystem-level consequences of invasion, in many cases it could be considered as positive due to increased structural and functional diversity. The long-term interactions with the native fauna still remain unknown, however, and in this paper we highlight the major knowledge gaps. (C) 2015 Institute of Oceanology of the Polish Academy of Sciences., Production and hosting by Elsevier Sp. z o.o.
  • Bhide, Amarnath; Räsänen, Juha; Huhta, Heikki; Junno, Juulia; Erkinaro, Tiina; Ohtonen, Pasi; Haapsamo, Mervi; Acharya, Ganesh (2017)
    We hypothesized that in near-term sheep fetuses, hypoxemia changes myocardial function as reflected in altered ventricular deformation on speckle-tracking echocardiography. Fetuses in 21 pregnant sheep were instrumented. After 4 d of recovery, fetal cardiac function was assessed by echocardiography at baseline, after 30 and 120 min of induced fetal hypoxemia and after its reversal. Left (LV) and right (RV) ventricular cardiac output and myocardial strain were measured. Baseline mean (standard deviation [ SD]) LV and RV global longitudinal strains were -18.7% (3.8) and -14.3% (5.3). Baseline RV global longitudinal and circumferential deformations were less compared with those of the left ventricle (p = 0.016 and p <0.005). LV, but not RV, global longitudinal strain was decreased (p = 0.003) compared with baseline with hypoxemia. Circumferential and radial strains did not exhibit significant changes. In the near-term sheep fetus, LV global longitudinal and circumferential strains are more negative than RV strains. Acute hypoxemia leads to LV rather than RV dysfunction as reflected by decreased deformation. (C) 2017 World Federation for Ultrasound in Medicine & Biology.
  • EPO-TBI Investigators Anzics Clin; Skrifvars, Markus B. (2019)
    Background Acute kidney injury (AKI) in traumatic brain injury (TBI) is poorly understood and it is unknown if it can be attenuated using erythropoietin (EPO). Methods Pre-planned analysis of patients included in the EPO-TBI ( NCT00987454) trial who were randomized to weekly EPO (40 000 units) or placebo (0.9% sodium chloride) subcutaneously up to three doses or until intensive care unit (ICU) discharge. Creatinine levels and urinary output (up to 7 days) were categorized according to the Kidney Disease Improving Global Outcome (KDIGO) classification. Severity of TBI was categorized with the International Mission for Prognosis and Analysis of Clinical Trials in TBI. Results Of 3348 screened patients, 606 were randomized and 603 were analyzed. Of these, 82 (14%) patients developed AKI according to KDIGO (60 [10%] with KDIGO 1, 11 [2%] patients with KDIGO 2, and 11 [2%] patients with KDIGO 3). Male gender (hazard ratio [HR] 4.0 95% confidence interval [CI] 1.4-11.2, P = 0.008) and severity of TBI (HR 1.3 95% CI 1.1-1.4, P <0.001 for each 10% increase in risk of poor 6 month outcome) predicted time to AKI. KDIGO stage 1 (HR 8.8 95% CI 4.5-17, P <0.001), KDIGO stage 2 (HR 13.2 95% CI 3.9-45.2, P <0.001) and KDIGO stage 3 (HR 11.7 95% CI 3.5-39.7, P <0.005) predicted time to mortality. EPO did not influence time to AKI (HR 1.08 95% CI 0.7-1.67, P = 0.73) or creatinine levels during ICU stay (P = 0.09). Conclusions Acute kidney injury is more common in male patients and those with severe compared to moderate TBI and appears associated with worse outcome. EPO does not prevent AKI after TBI.
  • Carstensen, Jacob; Conley, Daniel J.; Almroth-Rosell, Elin; Asmala, Eero; Bonsdorff, Erik; Fleming-Lehtinen, Vivi; Gustafsson, Bo G.; Gustafsson, Camilla; Heiskanen, Anna-Stiina; Janas, Urzsula; Norkko, Alf; Slomp, Caroline; Villnäs, Anna; Voss, Maren; Zilius, Mindaugas (2020)
    The coastal zone of the Baltic Sea is diverse with strong regional differences in the physico-chemical setting. This diversity is also reflected in the importance of different biogeochemical processes altering nutrient and organic matter fluxes on the passage from land to sea. This review investigates the most important processes for removal of nutrients and organic matter, and the factors that regulate the efficiency of the coastal filter. Nitrogen removal through denitrification is high in lagoons receiving large inputs of nitrate and organic matter. Phosphorus burial is high in archipelagos with substantial sedimentation, but the stability of different burial forms varies across the Baltic Sea. Organic matter processes are tightly linked to the nitrogen and phosphorus cycles. Moreover, these processes are strongly modulated depending on composition of vegetation and fauna. Managing coastal ecosystems to improve the effectiveness of the coastal filter can reduce eutrophication in the open Baltic Sea.
  • Jansson, Anna; Klais-Peets, Riina; Griniene, Evelina; Rubene, Gunta; Semenova, Anna; Lewandowska, Aleksandra; Engstrom-Öst, Jonna (2020)
    Functional traits are becoming more common in the analysis of marine zooplankton community dynamics associated with environmental change. We used zooplankton groups with common functional properties to assess long-term trends in the zooplankton caused by certain environmental conditions in a highly eutrophicated gulf. Time series of zooplankton traits have been collected since the 1960s in the Gulf of Riga, Baltic Sea, and were analyzed using a combination of multivariate methods (principal coordinate analysis) and generalized additive models. One of the most significant changes was the considerable increase in the amount of the zooplankton functional groups (FGR) in coastal springtime communities, and dominance shifts from more complex to simpler organism groups-cladocerans and rotifers. The results also show that functional trait organism complexity (body size) decreased considerably due to cladoceran and rotifer increase following elevated water temperature. Salinity and oxygen had negligible effects on the zooplankton community.
  • Laitakari, Anna; Tapio, Joona; Mäkelä, Kari A.; Herzig, Karl-Heinz; Dengler, Franziska; Gylling, Helena; Walkinshaw, Gail; Myllyharju, Johanna; Dimova, Elitsa Y.; Serpi, Raisa; Koivunen, Peppi (2020)
    Non-alcoholic fatty liver disease (NAFLD) parallels the global obesity epidemic with unmet therapeutic needs. We investigated whether inhibition of hypoxia-inducible factor prolyl 4-hydroxylase-2 (HIF-P4H-2), a key cellular oxygen sensor whose inhibition stabilizes HIF, would protect from NAFLD by subjecting HIF-P4H-2-deficient (Hif-p4h-2(gt/gt)) mice to a high-fat, high-fructose (HFHF) or high-fat, methionine-choline-deficient (HF-MCD) diet. On both diets, the Hif-p4h-2(gt/gt) mice gained less weight and had less white adipose tissue (WAT) and its inflammation, lower serum cholesterol levels, and lighter livers with less steatosis and lower serum ALT levels than the wild type (WT). The intake of fructose in majority of the Hif-p4h-2(gt/gt) tissues, including the liver, was 15-35% less than in the WT. We found upregulation of the key fructose transporter and metabolizing enzyme mRNAs, Slc2a2, Khka, and Khkc, and higher ketohexokinase activity in the Hif-p4h-2(gt/gt) small intestine relative to the WT, suggesting enhanced metabolism of fructose in the former. On the HF-MCD diet, the Hif-p4h-2(gt/gt) mice showed more browning of the WAT and increased thermogenesis. A pharmacological pan-HIF-P4H inhibitor protected WT mice on both diets against obesity, metabolic dysfunction, and liver damage. These data suggest that HIF-P4H-2 inhibition could be studied as a novel, comprehensive treatment strategy for NAFLD. Key messages center dot HIF-P4H-2 inhibition enhances intestinal fructose metabolism protecting the liver. center dot HIF-P4H-2 inhibition downregulates hepatic lipogenesis. center dot Induced browning of WAT and increased thermogenesis can also mediate protection. center dot HIF-P4H-2 inhibition offers a novel, comprehensive treatment strategy for NAFLD.
  • Salminen, Sarianna; Tammelin, Mira; Jilbert, Tom; Fukumoto, Yu; Saarni, Saija (2021)
    The influence of lake restoration efforts on lake bottom-water conditions and varve preservation is not well known. We studied varved sediments deposited during the last 80 years along a water-depth transect in the Enonsaari Deep, a deep-water area of the southernmost Enonselka Basin, Lake Vesijarvi, southern Finland. For the last few decades, the Enonselka Basin has been subject to ongoing restoration efforts. Varve, elemental, and diatom analyses were undertaken to explore how these actions and other human activities affected varve preservation in the Enonsaari Deep. In contrast to most varved Finnish lakes, whose water columns have a natural tendency to stratify, and possess varve records that span thousands of years, varve formation and preservation in Lake Vesijarvi was triggered by relatively recent anthropogenic stressors. The multi-core varve analysis revealed that sediment in the Enonsaari Deep was initially non-varved, but became fully varved in the late 1930s, a time of increasing anthropogenic influence on the lake. The largest spatial extent of varves occurred in the 1970s, which was followed by a period of less distinguishable varves, which coincided with diversion of sewage from the lake. Varve preservation weakened during subsequent decades and was terminated completely by lake aeration in the 2010s. Despite improvements in water quality, hypolimnetic oxygen depletion and varve preservation persisted beyond the reduction in sewage loading, initial aeration, and biomanipulation. These restoration efforts, however, along with other human actions such as harbor construction and dredging, did influence varve characteristics. Varves were also influenced by diatom responses to anthropogenic forcing, because diatoms form a substantial part of the varve structure. Of all the restoration efforts, a second episode of aeration seems to have had the single most dramatic impact on profundal conditions in the basin, resulting in replacement of a sediment accumulation zone by a transport or erosional zone in the Enonsaari Deep. We conclude that human activities in a lake and its catchment can alter lake hypolimnetic conditions, leading to shifts in lake bottom dynamics and changes in varve preservation.
  • Hermans, Martijn; Lenstra, Wytze K.; van Helmond, Niels A. G. M.; Behrends, Thilo; Egger, Matthias; Seguret, Marie J. M.; Gustafsson, Erik; Gustafsson, Bo G.; Slomp, Caroline P. (2019)
    The Baltic Sea is characterized by the largest area of hypoxic (oxygen (O-2) <2 mg L-1) bottom waters in the world's ocean induced by human activities. Natural ventilation of these O-2-depleted waters largely depends on episodic Major Baltic Inflows from the adjacent North Sea. In 2014 and 2015, two such inflows led to a strong rise in O-2 and decline in phosphate (HPO42-) in waters below 125 m depth in the Eastern Gotland Basin. This provided the opportunity to assess the impact of such re-oxygenation events on the cycles of manganese (Mn), iron (Fe) and phosphorus (P) in the sediment for the first time. We demonstrate that the re-oxygenation induced the activity of sulphur (S)-oxidising bacteria, known as Beggiatoaceae in the surface sediment where a thin oxic and suboxic layer developed. At the two deepest sites, strong enrichments of total Mn and to a lesser extent Fe oxides and P were observed in this surface layer. A combination of sequential sediment extractions and synchrotron-based X-ray spectroscopy revealed evidence for the abundant presence of P-bearing rhodochrosite and Mn(II) phosphates. In contrast to what is typically assumed, the formation of Fe oxides in the surface sediment was limited. We attribute this lack of Fe oxide formation to the high flux of reductants, such as sulphide, from deeper sediments which allows Fe (II) in the form of FeS to be preserved and restricts the penetration of O-2 into the sediment. We estimate that enhanced P sequestration in surface sediments accounts for only similar to 5% of water column HPO42- removal in the Eastern Gotland Basin linked to the recent inflows. The remaining HPO42- was transported to adjacent areas in the Baltic Sea. Our results highlight that the benthic O-2 demand arising from the accumulation of organic-rich sediments over several decades, the legacy of hypoxia, has major implications for the biogeochemical response of euxinic basins to re-oxygenation. In particular, P sequestration in the sediment in association with Fe oxides is limited. This implies that artificial ventilation projects that aim at removing water column HPO42- and thereby improving water quality in the Baltic Sea will likely not have the desired effect. (C) 2018 Elsevier Ltd. All rights reserved.
  • Jilbert, Tom; Jokinen, Sami; Saarinen, Timo; Mattus-Kumpunen, Ulpu; Simojoki, Asko; Saarni, Saija; Salminen, Sarianna; Niemist, Juha; Horppila, Jukka (2020)
    Using biogeochemical analyses of sediments and porewaters, we investigate the legacy of a brief, intense period of eutrophication on sedimentary phosphorus (P) cycling in a boreal lake (Enonselka basin, Lake Vesijarvi, Finland). Point-source sewage inputs in the twentieth century caused deoxygenation of the lake and accelerated the focusing of iron (Fe) and manganese (Mn) oxides into deeper areas. Early diagenesis under Fe-Mn-rich conditions now favors rapid burial of P in these areas, likely as a combination of both oxide-bound P phases and authigenic manganous vivianite. A new P budget for Enonselka basin shows that P burial causes an annual drawdown of 1.2% (+/- 0.2%) of the surface sediment P inventory, supporting a long-term trend towards recovery since the construction of a wastewater treatment plant in the mid-1970s. However, remineralization of organic matter and associated dissolution of Fe-Mn oxides continues to regenerate P from a deep reactive layer (20-60 cm depth) deposited at the height of past eutrophication, leading to an upwards diffusive flux of dissolved phosphate towards the surface sediments. The magnitude of this flux is similar to that of external P loading to the lake. The combined incoming fluxes of P are likely to retard the complete recovery from eutrophication by decades, despite ongoing restoration actions.
  • Byts, Nadiya; Sharma, Subodh; Malm, Tarja; Kaakinen, Mika; Korhonen, Paula; Jaakkonen, Laura; Keuters, Meike; Huuskonen, Mikko; Pietilä, Ilkka; Koistinaho, Jari; Koivunen, Peppi; Myllyharju, Johanna (2022)
    Hypoxia-inducible factor prolyl 4-hydroxylases (HIF-P4Hs) regulate the hypoxic induction of > 300 genes required for survival and adaptation under oxygen deprivation. Inhibition of HIF-P4H-2 has been shown to be protective in focal cerebral ischemia rodent models, while that of HIF-P4H-1 has no effects and inactivation of HIF-P4H-3 has adverse effects. A trans membrane prolyl 4-hydroxylase (P4H-TM) is highly expressed in the brain and contributes to the regulation of HIF, but the outcome of its inhibition on stroke is yet unknown. To study this, we subjected WT and P4htm(-/- )mice to permanent middle cerebral artery occlusion (pMCAO). Lack of P4H-TM had no effect on lesion size following pMCAO, but increased inflam-matory microgliosis and neutrophil infiltration was observed in the P4htm-/- cortex. Furthermore, both the permeability of blood brain barrier and ultrastructure of cerebral tight junctions were compromised in P4htm(-/-) mice. At the molecular level, P4H-TM deficiency led to increased expression of proinflammatory genes and robust activation of protein kinases in the cortex, while expression of tight junction proteins and the neuroprotective growth factors erythropoietin and vascular endothelial growth factor was reduced. Our data provide the first evidence that P4H-TM inactivation has no protective effect on infarct size and increases inflammatory microgliosis and neutrophil infiltration in the cortex at early stage after pMCAO. When considering HIF-P4H inhibitors as potential therapeutics in stroke, the current data support that isoenzyme-selective inhibitors that do not target P4H-TM or HIF-P4H-3 would be preferred.
  • Sinkko, Hanna; Hepolehto, Iina; Lyra, Christina; Rinta-Kanto, Johanna M.; Villnäs, Anna; Norkko, Joanna; Norkko, Alf; Timonen, Sari (2019)
    Coastal hypoxia is a major environmental problem worldwide. Hypoxia-induced changes in sediment bacterial communities harm marine ecosystems and alter biogeochemical cycles. Nevertheless, the resistance of sediment bacterial communities to hypoxic stress is unknown. We investigated changes in bacterial communities during hypoxic-anoxic disturbance by artificially inducing oxygen deficiency to the seafloor for 0, 3, 7, and 48 days, with subsequent molecular biological analyses. We further investigated relationships between bacterial communities, benthic macrofauna and nutrient effluxes across the sediment-water-interface during hypoxic-anoxic stress, considering differentially abundant operational taxonomic units (OTUs). The composition of the moderately abundant OTUs changed significantly after seven days of oxygen deficiency, while the abundant and rare OTUs first changed after 48 days. High bacterial diversity maintained the resistance of the communities during oxygen deficiency until it dropped after 48 days, likely due to anoxia-induced loss of macrofaunal diversity and bioturbation. Nutrient fluxes, especially ammonium, correlated positively with the moderate and rare OTUs, including potential sulfate reducers. Correlations may reflect bacteria-mediated nutrient effluxes that accelerate eutrophication. The study suggests that even slightly higher bottom-water oxygen concentrations, which could sustain macrofaunal bioturbation, enable bacterial communities to resist large compositional changes and decrease the harmful consequences of hypoxia in marine ecosystems.
  • Myllykangas, Jukka-Pekka; Rissanen, Antti J.; Hietanen, Susanna; Jilbert, Tom (2020)
    Methane is produced microbially in vast quantities in sediments throughout the world's oceans. However, anaerobic oxidation of methane (AOM) provides a near-quantitative sink for the produced methane and is primarily responsible for preventing methane emissions from the oceans to the atmosphere. AOM is a complex microbial process that involves several different microbial groups and metabolic pathways. The role of different electron acceptors in AOM has been studied for decades, yet large uncertainties remain, especially in terms of understanding the processes in natural settings. This study reports whole-core incubation methane oxidation rates along an estuarine gradient ranging from near fresh water to brackish conditions, and investigates the potential role of different electron acceptors in AOM. Microbial community structure involved in different methane processes is also studied in the same estuarine system using high throughput sequencing tools. Methane oxidation in the sediments was active in three distinct depth layers throughout the studied transect, with total oxidation rates increasing seawards. We find extensive evidence of non-sulphate AOM throughout the transect. The highest absolute AOM rates were observed below the sulphate-methane transition zone (SMTZ), strongly implicating the role of alternative electron acceptors (most likely iron and manganese oxides). However, oxidation rates were ultimately limited by methane availability. ANME-2a/b were the most abundant microbial phyla associated with AOM throughout the study sites, followed by ANME-2d in much lower abundances. Similarly to oxidation rates, highest abundances of microbial groups commonly associated with AOM were found well below the SMTZ, further reinforcing the importance of non-sulphate AOM in this system.
  • van Uitert, Miranda; Moerland, Perry D.; Enquobahrie, Daniel A.; Laivuori, Hannele; van der Post, Joris A. M.; Ris-Stalpers, Carrie; Afink, Gijs B. (2015)
    Studies using the placental transcriptome to identify key molecules relevant for preeclampsia are hampered by a relatively small sample size. In addition, they use a variety of bioinformatics and statistical methods, making comparison of findings challenging. To generate a more robust preeclampsia gene expression signature, we performed a meta-analysis on the original data of 11 placenta RNA microarray experiments, representing 139 normotensive and 116 preeclamptic pregnancies. Microarray data were pre-processed and analyzed using standardized bioinformatics and statistical procedures and the effect sizes were combined using an inverse-variance random-effects model. Interactions between genes in the resulting gene expression signature were identified by pathway analysis (Ingenuity Pathway Analysis, Gene Set Enrichment Analysis, Graphite) and protein-protein associations (STRING). This approach has resulted in a comprehensive list of differentially expressed genes that led to a 388-gene meta-signature of preeclamptic placenta. Pathway analysis highlights the involvement of the previously identified hypoxia/HIF1A pathway in the establishment of the preeclamptic gene expression profile, while analysis of protein interaction networks indicates CREBBP/EP300 as a novel element central to the preeclamptic placental transcriptome. In addition, there is an apparent high incidence of preeclampsia in women carrying a child with a mutation in CREBBP/EP300 (Rubinstein-Taybi Syndrome). The 388-gene preeclampsia meta-signature offers a vital starting point for further studies into the relevance of these genes (in particular CREBBP/EP300) and their concomitant pathways as biomarkers or functional molecules in preeclampsia. This will result in a better understanding of the molecular basis of this disease and opens up the opportunity to develop rational therapies targeting the placental dysfunction causal to preeclampsia.