Browsing by Subject "DEPLETION"

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  • EBMT Pediat Dis Working Party; Balduzzi, Adriana; Boenig, Halvard; Jaerisch, Andrea; Vettenranta, Kim (2021)
    Up to 40% of donor-recipient pairs in SCT have some degree of ABO incompatibility, which may cause severe complications. The aim of this study was to describe available options and survey current practices by means of a questionnaire circulated within the EBMT Pediatric Diseases Working Party investigators. Major ABO incompatibility (donor's RBCs have antigens missing on the recipient's cell surface, towards which the recipient has circulating isohemagglutinins) requires most frequently an intervention in case of bone marrow grafts, as immediate or delayed hemolysis, delayed erythropoiesis and pure red cell aplasia may occur. RBC depletion from the graft (82%), recipient plasma-exchange (14%) were the most common practices, according to the survey. Graft manipulation is rarely needed in mobilized peripheral blood grafts. In case of minor incompatible grafts (donor has isohemagglutinins directed against recipient RBC antigens), isohemagglutinin depletion from the graft by plasma reduction/centrifugation may be considered, but acute tolerability of minor incompatible grafts is rarely an issue. According to the survey, minor ABO incompatibility was either managed by means of plasma removal from the graft, especially when isohemagglutinin titer was above a certain threshold, or led to no intervention at all (41%). Advantages and disadvantages of each method are discussed.
  • Licht, Tamar; Kreisel, Tirzah; Biala, Yoav; Mohan, Sandesh; Yaari, Yoel; Anisimov, Andrey; Alitalo, Kari; Keshet, Eli (2020)
    Multiple insults to the brain lead to neuronal cell death, thus raising the question to what extent can lost neurons be replenished by adult neurogenesis. Here we focused on the hippocampus and especially the dentate gyrus (DG), a vulnerable brain region and one of the two sites where adult neuronal stem cells (NSCs) reside. While adult hippocampal neurogenesis was extensively studied with regard to its contribution to cognitive enhancement, we focused on their underestimated capability to repair a massively injured, nonfunctional DG. To address this issue, we inflicted substantial DG-specific damage in mice of either sex either by diphtheria toxin-based ablation of >50% of mature DG granule cells (GCs) or by prolonged brain-specific VEGF overexpression culminating in extensive, highly selective loss of DG GCs (thereby also reinforcing the notion of selective DG vulnerability). The neurogenic system promoted effective regeneration by increasing NSCs proliferation/survival rates, restoring a nearly original DG mass, promoting proper rewiring of regenerated neurons to their afferent and efferent partners, and regaining of lost spatial memory. Notably, concomitantly with the natural age-related decline in the levels of neurogenesis, the regenerative capacity of the hippocampus also subsided with age. The study thus revealed an unappreciated regenerative potential of the young DG and suggests hippocampal NSCs as a critical reservoir enabling recovery from catastrophic DG damage.
  • Li, Shiqian; Prasanna, Xavier; Salo, Veijo T.; Vattulainen, Ilpo; Ikonen, Elina (2019)
    Auxin-inducible degron technology allows rapid and controlled protein depletion. However, basal degradation without auxin and inefficient auxin-inducible depletion have limited its utility. We have identified a potent auxin-inducible degron system composed of auxin receptor F-box protein AtAFB2 and short degron minilAA7. The system showed minimal basal degradation and enabled rapid auxin-inducible depletion of endogenous human transmembrane, cytoplasmic and nuclear proteins in 1 h with robust functional phenotypes.
  • Jokela, Manu; Tasca, Giorgio; Vihola, Anna; Mercuri, Eugenio; Jonson, Per-Harald; Lehtinen, Sara; Välipakka, Salla; Pane, Marika; Donati, Maria; Johari, Mridul; Savarese, Marco; Huovinen, Sanna; Isohanni, Pirjo; Palmio, Johanna; Hartikainen, Päivi; Udd, Bjarne (2019)
    Objective To identify the genetic defect causing a distal calf myopathy with cores. Methods Families with a genetically undetermined calf-predominant myopathy underwent detailed clinical evaluation, including EMG/nerve conduction studies, muscle biopsy, laboratory investigations, and muscle MRI. Next-generation sequencing and targeted Sanger sequencing were used to identify the causative genetic defect in each family. Results A novel deletion-insertion mutation in ryanodine receptor 1 (RYR1) was found in the proband of the index family and segregated with the disease in 6 affected relatives. Subsequently, we found 2 more families with a similar calf-predominant myopathy segregating with unique RYR1-mutated alleles. All patients showed a very slowly progressive myopathy without episodes of malignant hyperthermia or rhabdomyolysis. Muscle biopsy showed cores or core-like changes in all families. Conclusions Our findings expand the spectrum of RYR1-related disorders to include a calf-predominant myopathy with core pathology and autosomal dominant inheritance. Two families had unique and previously unreported RYR1 mutations, while affected persons in the third family carried 2 previously known mutations in the same dominant allele.
  • Chacon-Tanarro, A.; Pineda, J. E.; Caselli, P.; Bizzocchi, L.; Gutermuth, R. A.; Mason, B. S.; Gomez-Ruiz, A.; Harju, J.; Devlin, M.; Dicker, S. R.; Mroczkowski, T.; Romero, C. E.; Sievers, J.; Stanchfield, S.; Offner, S.; Sanchez-Argueelles, D. (2019)
    Context. The study of dust emission at millimeter wavelengths is important to shed light on the dust properties and physical structure of pre-stellar cores, the initial conditions in the process of star and planet formation. Aims. Using two new continuum facilities, AzTEC at the Large Millimeter Telescope Alfonso Serrano and MUSTANG-2 at the Green Bank Observatory, we aim to detect changes in the optical properties of dust grains as a function of radius for the well-known pre-stellar core L1544. Methods. We determined the emission profiles at 1.1 and 3.3 mm and examine whether they can be reproduced in terms of the current best physical models for L1544. We also made use of various tools to determine the radial distributions of the density, temperature, and dust opacity in a self-consistent manner. Results. We find that our observations cannot be reproduced without invoking opacity variations. New temperature and density profiles, as well as opacity variations across the core, have been derived with the new data. The opacity changes are consistent with the expected variations between uncoagulated bare grains, toward the outer regions of the core, and grains with thick ice mantles, toward the core center. A simple analytical grain growth model predicts the presence of grains of similar to 3-4 mu m within the central 2000 au for the new density profile.
  • Chatzidionysiou, Katerina; Lie, Elisabeth; Nasonov, Evgeny; Lukina, Galina; Hetland, Merete Lund; Tarp, Ulrik; Ancuta, Ioan; Pavelka, Karel; Nordstrom, Dan C.; Gabay, Cem; Canhao, Helene; Tomsic, Matija; van Riel, Piet L. C. M.; Gomez-Reino, Juan; Kvien, Tore K.; van Vollenhoven, Ronald F.; Rheumatic Dis Portuguese Register (2016)
    Background: The approved dose of rituximab (RTX) in rheumatoid arthritis is 1000 mg x 2, but some data have suggested similar clinical efficacy with 500 mg x 2. The purpose of this study was to compare the effectiveness of the regular and low doses given as first treatment course. Methods: Twelve European registries participating in the CERERRA collaboration (The European Collaborative Registries for the Evaluation of Rituximab in Rheumatoid Arthritis) submitted anonymized datasets with demographic, efficacy and treatment data for patients who had started RTX. Treatment effectiveness was assessed by DAS28 reductions and EULAR responses after 6 months. Results: Data on RTX dose were available for 2,873 patients, of whom 2,625 (91.4 %) and 248 (8.6 %) received 1000 mg x 2 and 500 mg x 2, respectively. Patients treated with 500 mg x 2 were significantly older, had longer disease duration, higher number of prior DMARDs, but lower number of prior biologics and lower baseline DAS28 than those treated with 1000 mg x 2. Fewer patients in the low-dose group received concomitant DMARDs but more frequently received concomitant corticosteroids. Both doses led to significant clinical improvements at 6 months. DAS28 reductions at 6 months were comparable in the 2 dose regimens [mean DeltaDAS28 +/- SD -2.0 +/- 1.3 (high dose) vs. -1.7 +/- 1.4 (low dose), p = 0.23 adjusted for baseline differences]. Similar percentages of patients achieved EULAR good response in the two dose groups, 18.4 % vs. 17.3 %, respectively (p = 0.36). Conclusions: In this large observational cohort initial treatment with RTX at 500 mg x 2 and 1000 mg x 2 led to comparable clinical outcomes at 6 months.
  • Khan, Sofia; Ince-Dunn, Gulayse; Suomalainen, Anu; Elo, Laura L. (2020)
    High-throughput technologies for genomics, transcriptomics, proteomics, and metabolomics, and integrative analysis of these data, enable new, systems-level insights into disease pathogenesis. Mitochondrial diseases are an excellent target for hypothesis-generating omics approaches, as the disease group is mechanistically exceptionally complex. Although the genetic background in mitochondrial diseases is in either the nuclear or the mitochondrial genome, the typical downstream effect is dysfunction of the mitochondrial respiratory chain. However, the clinical manifestations show unprecedented variability, including either systemic or tissue-specific effects across multiple organ systems, with mild to severe symptoms, and occurring at any age. So far, the omics approaches have provided mechanistic understanding of tissue-specificity and potential treatment options for mitochondrial diseases, such as metabolome remodeling. However, no curative treatments exist, suggesting that novel approaches are needed. In this Review, we discuss omics approaches and discoveries with the potential to elucidate mechanisms of and therapies for mitochondrial diseases.
  • Ignatenko, Olesia; Chilov, Dmitri; Paetau, Ilse; de Miguel, Elena; Jackson, Christopher B.; Capin, Gabrielle; Paetau, Anders; Terzioglu, Mugen; Euro, Liliya; Suomalainen, Anu (2018)
    Mitochondrial dysfunction manifests as different neurological diseases, but the mechanisms underlying the clinical variability remain poorly understood. To clarify whether different brain cells have differential sensitivity to mitochondrial dysfunction, we induced mitochondrial DNA (mtDNA) depletion in either neurons or astrocytes of mice, by inactivating Twinkle (TwKO), the replicative mtDNA helicase. Here we show that astrocytes, the most abundant cerebral cell type, are chronically activated upon mtDNA loss, leading to early-onset spongiotic degeneration of brain parenchyma, microgliosis and secondary neurodegeneration. Neuronal mtDNA loss does not, however, cause symptoms until 8 months of age. Findings in astrocyte-TwKO mimic neuropathology of Alpers syndrome, infantile-onset mitochondrial spongiotic encephalopathy caused by mtDNA maintenance defects. Our evidence indicates that (1) astrocytes are dependent on mtDNA integrity; (2) mitochondrial metabolism contributes to their activation; (3) chronic astrocyte activation has devastating consequences, underlying spongiotic encephalopathy; and that (4) astrocytes are a potential target for interventions.
  • Redaelli, E.; Bizzocchi, L.; Caselli, P.; Harju, J.; Chacon-Tanarro, A.; Leonardo, E.; Dore, L. (2018)
    Context. The N-15 fractionation has been observed to show large variations among astrophysical sources, depending both on the type of target and on the molecular tracer used. These variations cannot be reproduced by the current chemical models. Aims. Until now, the N-14/N-15 ratio in N2H+ has been accurately measured in only one prestellar source, L1544, where strong levels of fractionation, with depletion in N-15, are found (N-14/N-15 approximate to 1000). In this paper, we extend the sample to three more bona fide prestellar cores, in order to understand if the antifractionation in N2H+ is a common feature of this kind of source. Methods. We observed N2H+, (NNH+)-N-15, and (NNH+)-N-15 in L183, L429, and L694-2 with the IRAM 30m telescope. We modelled the emission with a non-local radiative transfer code in order to obtain accurate estimates of the molecular column densities, including the one for the optically thick N2H+. We used the most recent collisional rate coefficients available, and with these we also re-analysed the L1544 spectra previously published. Results. The obtained isotopic ratios are in the range 580-770 and significantly differ with the value, predicted by the most recent chemical models, of approximate to 440, close to the protosolar value. Our prestellar core sample shows a high level of depletion of N-15 in diazenylium, as previously found in L1544. A revision of the N chemical networks is needed in order to explain these results.
  • ESCV Network Next-Generation Seque; Xavier Lopez-Labrador, F.; Brown, Julianne R.; Fischer, Nicole; Auvinen, Eeva; de Vries, Jutte J. C. (2021)
    Metagenomic high-throughput sequencing (mHTS) is a hypothesis-free, universal pathogen detection technique for determination of the DNA/RNA sequences in a variety of sample types and infectious syndromes. mHTS is still in its early stages of translating into clinical application. To support the development, implementation and standardization of mHTS procedures for virus diagnostics, the European Society for Clinical Virology (ESCV) Network on Next-Generation Sequencing (ENNGS) has been established. The aim of ENNGS is to bring together professionals involved in mHTS for viral diagnostics to share methodologies and experiences, and to develop application recommendations. This manuscript aims to provide practical recommendations for the wet lab procedures necessary for implementation of mHTS for virus diagnostics and to give recommendations for development and validation of laboratory methods, including mHTS quality assurance, control and quality assessment protocols.
  • Sipilae, O.; Harju, J.; Caselli, P. (2017)
    Aims. We study whether or not rotational excitation can make a large difference to chemical models of the abundances of the H-3(+) isotopologs, including spin states, in physical conditions corresponding to starless cores and protostellar envelopes. Methods. We developed a new rate coefficient set for the chemistry of the H-3(+) isotopologs, allowing for rotational excitation, using previously published state-to-state rate coefficients. These new so-called species-to-species rate coefficients are compared with previously-used ground-state-to-species rate coefficients by calculating chemical evolution in variable physical conditions using a pseudo-time-dependent chemical code. Results. We find that the new species-to-species model produces different results to the ground state-to-species model at high density and toward increasing temperatures (T > 10 K). The most prominent difference is that the species-to-species model predicts a lower H-3(+) deuteration degree at high density owing to an increase of the rate coefficients of endothermic reactions that tend to decrease deuteration. For example at 20 K, the ground-state-to-species model overestimates the abundance of H2D+ by a factor of about two, while the abundance of D-3(+) can differ by up to an order of magnitude between the models. The spin-state abundance ratios of the various H-3(+) isotopologs are also a ffected, and the new model better reproduces recent observations of the abundances of ortho and para H2D+ and D2H+. The main caveat is that the applicability regime of the new rate coefficients depends on the critical densities of the various rotational transitions which vary with the abundances of the species and the temperature in dense clouds. Conclusions. The difference in the abundances of the H-3(+) isotopologs predicted by the species-to-species and ground state-to-species models is negligible at 10K corresponding to physical conditions in starless cores, but inclusion of the excited states is very important in studies of deuteration at higher temperatures, for example in protostellar envelopes. The species-to-species rate coefficients provide a more realistic approach to the chemistry of the H-3(+) isotopologs than the ground-state-to-species rate coefficients do, and so the former should be adopted in chemical models describing the chemistry of the H-3(+)+H-2 reacting system.
  • Caselli, Paola; Pineda, Jaime E.; Sipilae, Olli; Zhao, Bo; Redaelli, Elena; Spezzano, Silvia; Maureira, Maria Jose; Alves, Felipe; Bizzocchi, Luca; Bourke, Tyler L.; Chacon-Tanarro, Ana; Friesen, Rachel; Galli, Daniele; Harju, Jorma; Jimenez-Serra, Izaskun; Keto, Eric; Li, Zhi-Yun; Padovani, Marco; Schmiedeke, Anika; Tafalla, Mario; Vastel, Charlotte (2022)
    Prestellar cores represent the initial conditions in the process of star and planet formation. Their low temperatures (
  • Huang, Wengfeng; Zhang, Zheng; Li, Zhijun; Leppäranta, Matti; Arvola, Lauri; Song, Shuang; Huotari, Jussi; Lin, Zhanju (2021)
    Interaction of under-ice physical, chemical, and biological processes with lake ice/snow cover is examined to better understand how changing winter climate may affect lake ecosystems. We derived under-ice dissolved oxygen (DO) dynamics from high-frequency observations and modified a widely used lake metabolism model by including the effect of freezing and thawing on DO concentration. Estimates were produced for the production and respiration in a shallow lake on the Mongolian Plateau in three winters. Diel, synoptic, and seasonal variations in DO concentration were detected as responses to solar radiation, episodic snowfall events, and occasional convective mixing. Based on the observations and a radiative transfer model, incident solar radiation was partitioned into reflectance, absorbance, and transmittance by the snow and ice cover. For bare ice, the contributions of these three parts were 35%, 39%, and 26%, respectively, while under a new 4.5 cm thick snow cover, the corresponding values were 79%, 17%, and 3%. This points out the critical role of snow and ice on under-ice light conditions, which is the primary forcing for the temperature and the rate of photosynthesis under ice. The results showed three principal factors, which influenced under-ice DO and metabolism: (1) thickness and optical properties of ice and snow, which affected the light transfer and depth of the euphotic zone, (2) mediated radiation and ice-water heat transfer which controlled water temperature, and (3) DO exclusion during freezing and dilution by melt water. This study highlights the ecosystem characteristics in shallow ice-covered lakes in arid temperate regions and promotes our understanding of the response of the cold aquatic environment to climate change.
  • Song, Shuang; Li, Changyou; Shi, Xiaohong; Zhao, Shegnan; Tian, Weidong; Li, Zhijun; Bai, Yila; Cao, Xiaowei; Wang, Qingkai; Huotari, Jussi; Tulonen, Tiina; Uusheimo, Sari; Leppäranta, Matti; Loehr, John; Arvola, Lauri (2019)
    Winter is a long period of the annual cycle of many lakes in the northern hemisphere. Low irradiance, ice, and snow cover cause poor light penetration into the water column of these lakes. Therefore, in northern lakes, respiration often exceeds primary production leading to low dissolved oxygen concentrations. This study aimed to quantify under-ice metabolic processes during winter in an arid zone lake with little snow cover. This study was carried out in a mid-latitude lake in Inner Mongolia, northern China. The study lake receives relatively high incoming solar radiation on the ice in mid-winter, and radiation can penetrate down to the bottom sediment as the lake is shallow and the ice lacks snow cover. Primary production and respiration were estimated during two winters using high-frequency sensor measurements of dissolved oxygen. To quantify under-ice metabolic processes, sensors were deployed to different depths. During both winters, sensors collected data every 10 min over several weeks. The amount of solar radiation controlled photosynthesis under ice; temperature and photosynthesis together appeared to control respiration. The balance between gross primary production and ecosystem respiration was especially sensitive to changes in snow cover, and the balance between P and R decreased. Our data suggest that photosynthesis by plankton, submerged plants, and epiphytic algae may continue over winter in shallow lakes in mid-latitudes when there is no snow cover on the ice, as may occur in arid climates. The continuation of photosynthesis under ice buffers against dissolved oxygen depletion and prevents consequent harmful ecosystem effects.
  • Baronio, Diego; Chen, Yu-Chia; Decker, Amanda R.; Enckell, Louise; Fernandez-Lopez, Blanca; Semenova, Svetlana; Puttonen, Henri A. J.; Cornell, Robert A.; Panula, Pertti (2022)
    Aim We aimed at identifying potential roles of vesicular monoamine transporter 2, also known as Solute Carrier protein 18 A2 (SLC18A2) (hereafter, Vmat2), in brain monoamine regulation, their turnover, behaviour and brain development using a novel zebrafish model. Methods A zebrafish strain lacking functional Vmat2 was generated with the CRISPR/Cas9 system. Larval behaviour and heart rate were monitored. Monoamines and their metabolites were analysed with high-pressure liquid chromatography. Amine synthesising and degrading enzymes, and genes essential for brain development, were analysed with quantitative PCR, in situ hybridisation and immunocytochemistry. Results The 5-bp deletion in exon 3 caused an early frameshift and was lethal within 2 weeks post-fertilisation. Homozygous mutants (hereafter, mutants) displayed normal low locomotor activity during night-time but aberrant response to illumination changes. In mutants dopamine, noradrenaline, 5-hydroxytryptamine and histamine levels were reduced, whereas levels of dopamine and 5-hydroxytryptamine metabolites were increased, implying elevated monoamine turnover. Consistently, there were fewer histamine, 5-hydroxytryptamine and dopamine immunoreactive cells. Cellular dopamine immunostaining, in wild-type larvae more prominent in tyrosine hydroxylase 1 (Th1)-expressing than in Th2-expressing neurons, was absent in mutants. Despite reduced dopamine levels, mutants presented upregulated dopamine-synthesising enzymes. Further, in mutants the number of histidine decarboxylase-expressing neurons was increased, notch1a and pax2a were downregulated in brain proliferative zones. Conclusion Lack of Vmat2 increases monoamine turnover and upregulates genes encoding amine-synthesising enzymes, including histidine decarboxylase. Notch1a and pax2a, genes implicated in stem cell development, are downregulated in mutants. The zebrafish vmat2 mutant strain may be a useful model to study how monoamine transport affects brain development and function, and for use in drug screening.