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Introduction: Acute lung injury (ALI) is an inflammatory disorder of pulmonary or extrapulmonary origin. We have previously demonstrated that netrin-1 dampens murine ALI, and in an attempt to advance this finding into future clinical practice we evaluated whether netrin-1 would reduce alveolar inflammation during porcine ALI. Methods: This was a controlled in vivo experimental study in pigs. We induced ALI through lipoploysaccharide (LPS) infusion (50 micro g/kg) for 2 hours. Following this, we exposed animals to either vehicle, intravenous netrin-1 (netrin-1 i.v.) or inhaled netrin-1 (netrin-1 inh.). Serum samples and bronchoalveolar lavage (BAL) were obtained to determine levels of tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta, interleukin-6 and interleukin-8 at baseline and 6 hours following treatment. Myeloperoxidase activity (MPO) and protein levels were determined in the BAL, and tissue samples were obtained for histological evaluation. Finally, animals were scanned with spiral CT. Results: Following LPS infusion, animals developed acute pulmonary injury. Serum levels of TNF-alpha and IL-6 were significantly reduced in the netrin-1 i.v. group. BAL demonstrated significantly reduced cytokine levels 6 hours post-netrin-1 treatment (TNF-alpha: vehicle 633 ± 172 pg/ml, netrin-1 i.v. 84 ± 5 pg/ml, netrin-1 inh. 168 ± 74 pg/ml; both P < 0.05). MPO activity and protein content were significantly reduced in BAL samples from netrin-1-treated animals. Histological sections confirmed reduced inflammatory changes in the netrin-1-treated animals. Computed tomography corroborated reduced pulmonary damage in both netrin-1-treated groups. Conclusions: We conclude that treatment with the endogenous anti-inflammatory protein netrin-1 reduces pulmonary inflammation during the initial stages of ALI and should be pursued as a future therapeutic option.
The goal of this project is to develop a framework for a cell that takes in consideration its internal structure, using an agent-based approach. In this framework, a cell was simulated as many sub-particles interacting to each other. This sub-particles can, in principle, represent any internal structure from the cell (organelles, etc). In the model discussed here, two types of sub-particles were used: membrane sub-particles and cytosolic elements. A kinetic and dynamic Delaunay triangulation was used in order to define the neighborhood relations between the sub-particles. However, it was soon noted that the relations defined by the Delaunay triangulation were not suitable to define the interactions between membrane sub-particles. The cell membrane is a lipid bilayer, and does not present any long range interactions between their sub-particles. This means that the membrane particles should not be able to interact in a long range. Instead, their interactions should be confined to the two-dimensional surface supposedly formed by the membrane. A method to select, from the original three-dimensional triangulations, connections restricted to the two-dimensional surface formed by the cell membrane was then developed. The algorithm uses as starting point the three-dimensional Delaunay triangulation involving both internal and membrane sub-particles. From this triangulation, only the subset of connections between membrane sub-particles was considered. Since the cell is full of internal particles, the collection of the membrane particles' connections will resemble the surface to be obtained, even though it will still have many connections that do not belong to the restricted triangulation on the surface. This "thick surface" was called a quasi-surface. The following step was to refine the quasi-surface, cutting out some of the connections so that the ones left made a proper surface triangulation with the membrane points. For that, the quasi-surface was separated in clusters. Clusters are defined as areas on the quasi-surface that are not yet properly triangulated on a two-dimensional surface. Each of the clusters was then re-triangulated independently, using re-triangulation methods also developed during this work. The interactions between cytosolic elements was given by a Lennard-Jones potential, as well as the interactions between cytosolic elements and membrane particles. Between only membrane particles, the interactions were given by an elastic interaction. For each particle, the equation of motion was written. The algorithm chosen to solve the equations of motion was the Verlet algorithm. Since the cytosol can be approximated as a gel, it is reasonable to suppose that the sub-cellular particles are moving in an overdamped environment. Therefore, an overdamped approximation was used for all interactions. Additionally, an adaptive algorithm was used in order to define the size of the time step used in each interaction. After the method to re-triangulate the membrane points was implemented, the time needed to re-triangulate a single cluster was studied, followed by an analysis on how the time needed to re-triangulate each point in a cluster varied with the cluster size. The frequency of appearance for each cluster size was also compared, as this information is necessary to guarantee that the total time needed by to re-triangulate a cell is convergent. At last, the total time spent re-triangulating a surface was plotted, as well as a scaling for the total re-triangulation time with the variation. Even though there is still a lot to be done, the work presented here is an important step on the way to the main goal of this project: to create an agent-based framework that not only allows the simulation of any sub-cellular structure of interest but also provides meaningful interaction relations to particles belonging to the cell membrane.
During a 4-week run in October–November 2006, a pilot experiment was performed at the CERN Proton Synchrotron in preparation for the Cosmics Leaving OUtdoor Droplets (CLOUD) experiment, whose aim is to study the possible influence of cosmic rays on clouds. The purpose of the pilot experiment was firstly to carry out exploratory measurements of the effect of ionising particle radiation on aerosol formation from trace H2SO4 vapour and secondly to provide technical input for the CLOUD design. A total of 44 nucleation bursts were produced and recorded, with formation rates of particles above the 3 nm detection threshold of between 0.1 and 100 cm -3 s -1, and growth rates between 2 and 37 nm h -1. The corresponding H2O concentrations were typically around 106 cm -3 or less. The experimentally-measured formation rates and htwosofour concentrations are comparable to those found in the atmosphere, supporting the idea that sulphuric acid is involved in the nucleation of atmospheric aerosols. However, sulphuric acid alone is not able to explain the observed rapid growth rates, which suggests the presence of additional trace vapours in the aerosol chamber, whose identity is unknown. By analysing the charged fraction, a few of the aerosol bursts appear to have a contribution from ion-induced nucleation and ion-ion recombination to form neutral clusters. Some indications were also found for the accelerator beam timing and intensity to influence the aerosol particle formation rate at the highest experimental SO2 concentrations of 6 ppb, although none was found at lower concentrations. Overall, the exploratory measurements provide suggestive evidence for ion-induced nucleation or ion-ion recombination as sources of aerosol particles. However in order to quantify the conditions under which ion processes become significant, improvements are needed in controlling the experimental variables and in the reproducibility of the experiments. Finally, concerning technical aspects, the most important lessons for the CLOUD design include the stringent requirement of internal cleanliness of the aerosol chamber, as well as maintenance of extremely stable temperatures (variations below 0.1 °C)
Aging of biological systems ultimately leads to death of the individual. In humans, organ failure as the result of functional impairments after stroke, cardio-vascular disease, tumor development, neurodegeneration and other diseases are certainly crucial in bringing life to an end. But what happens in individuals with no obvious disease or disorders?
Plasticity resembling spike-timing dependent synaptic plasticity: the evidence in human cortex
(2010)
Spike-timing dependent plasticity (STDP) has been studied extensively in a variety of animal models during the past decade but whether it can be studied at the systems level of the human cortex has been a matter of debate. Only recently newly developed non-invasive brain stimulation techniques such as transcranial magnetic stimulation (TMS) have made it possible to induce and assess timing dependent plasticity in conscious human subjects. This review will present a critical synopsis of these experiments, which suggest that several of the principal characteristics and molecular mechanisms of TMS-induced plasticity correspond to those of STDP as studied at a cellular level. TMS combined with a second phasic stimulation modality can induce bidirectional long-lasting changes in the excitability of the stimulated cortex, whose polarity depends on the order of the associated stimulus-evoked events within a critical time window of tens of milliseconds. Pharmacological evidence suggests an NMDA receptor mediated form of synaptic plasticity. Studies in human motor cortex demonstrated that motor learning significantly modulates TMS-induced timing dependent plasticity, and, conversely, may be modulated bidirectionally by prior TMS-induced plasticity, providing circumstantial evidence that long-term potentiation-like mechanisms may be involved in motor learning. In summary, convergent evidence is being accumulated for the contention that it is now possible to induce STDP-like changes in the intact human central nervous system by means of TMS to study and interfere with synaptic plasticity in neural circuits in the context of behavior such as learning and memory. Keywords: spike-timing dependent plasticity, long-term potentiation, long-term depression, paired associative stimulation, transcranial magnetic stimulation, human, cortex, translational neuroscience
Potentiation of glycine-gated NR1/NR3A NMDA receptors relieves Ca2+-dependent outward rectification
(2010)
Glycine has diverse functions within the mammalian central nervous system. It inhibits postsynaptic neurons via strychnine-sensitive glycine receptors (GlyRs) and enhances neuronal excitation through co-activation of N-methyl-D-aspartate (NMDA) receptors. Classical Ca2+-permeable NMDA receptors are composed of glycine-binding NR1 and glutamate-binding NR2 subunits, and hence require both glutamate and glycine for efficient activation. In contrast, recombinant receptors composed of NR1 and the glycine binding NR3A and/or NR3B subunits lack glutamate binding sites and can be activated by glycine alone. Therefore these receptors are also named “excitatory glycine receptors”. Co-application of antagonists of the NR1 glycine-binding site or of the divalent cation Zn2+ markedly enhances the glycine responses of these receptors. To gain further insight into the properties of these glycine-gated NMDA receptors, we investigated their current-voltage (I–V) dependence. Whole-cell current-voltage relations of glycine currents recorded from NR1/NR3B and NR1/NR3A/NR3B expressing oocytes were found to be linear under our recording conditions. In contrast, NR1/NR3A receptors displayed a strong outwardly rectifying I–V relation. Interestingly, the voltage-dependent inward current block was abolished in the presence of NR1 antagonists, Zn2+ or a combination of both. Further analysis revealed that Ca2+ (1.8 mM) present in our recording solutions was responsible for the voltage-dependent inhibition of ion flux through NR1/NR3A receptors. Since physiological concentrations of the divalent cation Mg2+ did not affect the I–V dependence, our data suggest that relief of the voltage-dependent Ca2+ block of NR1/NR3A receptors by Zn2+ may be important for the regulation of excitatory glycinergic transmission, according to the Mg2+-block of conventional NR1/NR2 NMDA receptors. Keywords: NMDA receptor, excitatory glycine receptor, voltage block, NR3 subunit, supralinear potentiation, Zn2+, NR1 antagonist, ligand-binding domain
Although models based on independent component analysis (ICA) have been successful in explaining various properties of sensory coding in the cortex, it remains unclear how networks of spiking neurons using realistic plasticity rules can realize such computation. Here, we propose a biologically plausible mechanism for ICA-like learning with spiking neurons. Our model combines spike-timing dependent plasticity and synaptic scaling with an intrinsic plasticity rule that regulates neuronal excitability to maximize information transmission. We show that a stochastically spiking neuron learns one independent component for inputs encoded either as rates or using spike-spike correlations. Furthermore, different independent components can be recovered, when the activity of different neurons is decorrelated by adaptive lateral inhibition.
We examined whether positive transfer of cognitive training, which so far has been observed for individual tests only, also generalizes to cognitive abilities, thereby carrying greater promise for improving everyday intellectual competence in adulthood and old age. In the COGITO Study, 101 younger and 103 older adults practiced six tests of perceptual speed (PS), three tests of working memory (WM), and three tests of episodic memory (EM) for over 100 daily 1-h sessions. Transfer assessment included multiple tests of PS, WM, EM, and reasoning. In both age groups, reliable positive transfer was found not only for individual tests but also for cognitive abilities, represented as latent factors. Furthermore, the pattern of correlations between latent change factors of practiced and latent change factors of transfer tasks indicates systematic relations at the level of broad abilities, making the interpretation of effects as resulting from unspecific increases in motivation or self-concept less likely. Keywords: cognitive training, cognitive abilities, transfer, latent factors, working memory
Disruptive behaviour disorders are reflected by a great variety of symptoms ranging from impulsive-hot tempered quarrels to purposeful and goal directed acts of cruelty. A growing body of data indicates that there are neurobiological factors that increase the risk for developing disruptive behaviour disorders. In this review, we give a broad overview of recent studies investigating physiological, neural, genetic factors, and specific neurotransmitter systems. We also discuss the impact of psychosocial risk and consider the effects of gene-environment interactions. Due to the heterogeneity of disruptive behaviour disorders, it is concluded that specific subtypes of disruptive behaviour should be considered both in terms their biological basis and in regard to specific treatment needs.
Tubular carbonate concretions of up to 1 m in length and perpendicular to bedding, occur abundantly in the Upper Pliensbachian (upper Amaltheus margaritatus Zone, Gibbosus Subzone) in outcrops (Fontaneilles section) in the vicinity of Rivière-sûr-Tarn, southern France. Stable isotope analyses of these concretions show negative delta 13C values that decrease from the rim to the center from - 18.8‰ to - 25.7‰ (V-PDB), but normal marine delta 18 O values (- 1.8‰). Carbon isotope analyses of Late Pliensbachian bulk carbonate (matrix) samples from the Fontaneilles section show clearly decreasing C-isotope values across the A. margaritatus Zone, from +1‰ to - 3‰ (V-PDB). Isotope analyses of coeval belemnite rostra do not document such a negative C-isotope trend with values remaining stable around +2‰ (V-PDB). Computer tomographic (CT) scanning of the tubular concretions show multiple canals that are lined or filled entirely with pyrite. Previously, the formation of these concretions with one, two, or more central tubes, has been ascribed to the activity of an enigmatic organism, possibly with annelid or arthropod affinities, known asTisoa siphonalis. Our results suggest tisoan structures are abiogenic. Based on our geochemical analyses and sedimentological observations we suggest that these concretions formed as a combination of the anaerobic oxidation of methane (AOM) and sulfate reduction within the sediment. Fluids rich in methane and/or hydrocarbons likely altered local bulk rock carbon isotope records, but did not affect the global carbon cycle. Interestingly, Tisoa siphonalis has been described from many locations in the Grands Causses Basin in southern France, and from northern France and Luxemburg, always occurring at the same stratigraphic level. Upper Pliensbachian authigenic carbonates thus possibly cover an area of many thousand square kilometers. Greatly reduced sedimentation rates are needed to explain the stabilization of the sulfate-methane transition zone in the sedimentary column in order for the tubular concretions to form. Late Pliensbachian cooling, reducing run-off, and/or the influx of colder water and more vigorous circulation could be responsible for a halt in sedimentation. At the same time (thermogenic) methane may have destabilized during a major phase of Late Pliensbachian sea level fall. As such Tisoa siphonalis is more than a geological curiosity, and its further study could prove pivotal in understanding Early Jurassic paleoenvironmental change.
Background: Abnormalities of 11q23 involving the MLL gene are found in approximately 10% of human leukemias. To date, nearly 100 different chromosome bands have been described in rearrangements involving 11q23 and 64 fusion genes have been cloned and characterized at the molecular level. In this work we present the identification of a novel MLL fusion partner in a pediatric patient with de novo biphenotypic acute leukemia. Methods: Cytogenetics, fluorescence in situ hybridization (FISH), molecular studies (RT-PCR and LDI-PCR), and bioinformatic sequence analysis were used to characterize the CT45A2 gene as novel MLL fusion partner in pediatric acute leukemia. Results: Fluorescence in situ hybridization of the patient G-banded metaphases demonstrated a cryptic insertion of 11q23 in Xq26.3 involving the MLL gene. Breakpoint fusion analysis revealed that a DNA fragment of 653 kb from 11q23, containing MLL exons 1-9 in addition to 16 other 11q23 genes, was inserted into the upstream region of the CT45A2 gene located at Xq26.3. In addition, a deletion at Xq26.3 encompassing the 3' region of the DDX26B gene (exons 9-16) and the entire CT45A1 gene was identified. RNA analysis revealed the presence of a novel MLL-CT45A2 fusion transcript in which the first 9 exons of the MLL gene were fused in-frame to exon 2 of the CT45A2 gene, resulting in a spliced MLL fusion transcript with an intact open reading frame. The resulting chimeric transcript predicts a fusion protein where the N-terminus of MLL is fused to the entire open reading frame of CT45A2. Finally, we demonstrate that all breakpoint regions are rich in long repetitive motifs, namely LINE/L1 and SINE/Alu sequences, but all breakpoints were exclusively identified outside these repetitive DNA sequences. Conclusion: We have identified CT45A2 as a novel spliced MLL fusion partner in a pediatric patient with de novo biphenotypic acute leukemia, as a result of a cryptic insertion of 11q23 in Xq26.3. Since CT45A2 is the first Cancer/Testis antigen family gene found fused with MLL in acute leukemia, future studies addressing its biologic relevance for leukemogenesis are warranted.
Background: The enhancer of zeste homolog 2 (EZH2) gene exerts oncogene-like activities and its (over)expression has been linked to several human malignancies. Here, we studied a possible association between EZH2 expression and prognosis in patients with renal cell carcinoma (RCC). Methods: EZH2 protein expression in RCC specimens was analyzed by immunohistochemistry using a tissue microarray (TMA) containing RCC tumor tissue and corresponding normal tissue samples of 520 patients. For immunohistochemical assessment of EZH2 expression, nuclear staining quantity was evaluated using a semiquantitative score. The effect of EZH2 expression on cancer specific survival (CSS) was assessed by univariate and multivariate Cox regression analyses. Results: During follow-up, 147 patients (28%) had died of their disease, median follow-up of patients still alive was 6.0 years (range 0 - 16.1 years). EZH2 nuclear staining was present in tumor cores of 411 (79%) patients. A multivariate Cox regression analysis revealed that high nuclear EZH2 expression was an independent predictor of poor CSS (>25-50% vs. 0%: HR 2.72, p = 0.025) in patients suffering from non-metastatic RCC. Apart from high nuclear EZH2 expression, tumor stage and Fuhrman's grading emerged as significant prognostic markers. In metastatic disease, nuclear EZH2 expression and histopathological subtype were independent predictive parameters of poor CSS (EZH2: 1-5%: HR 2.63, p = 0.043, >5-25%: HR 3.35, p = 0.013, >25%-50%: HR 4.92, p = 0.003, all compared to 0%: HR 0.36, p = 0.025, respectively). Conclusions: This study defines EZH2 as a powerful independent unfavourable prognostic marker of CSS in patients with metastatic and non-metastatic RCC.
The editorial board of Aging reviews research papers published in 2009,which they believe have or will have a significant impact on aging research.Among many others, the topics include genes that accelerate aging or incontrast promote longevity in model organisms, DNA damage responsesand telomeres, molecular mechanisms of life span extension by calorierestriction and pharmacologic interventions into aging. The emergingmessage in 2009 is that aging is not random but determined by agenetically-regulated longevity network and can be decelerated bothgenetically and pharmacologically.
Filamentous fungi are of great importance in ecology, agriculture, medicine, and biotechnology. Thus, it is not surprising that genomes for more than 100 filamentous fungi have been sequenced, most of them by Sanger sequencing. While next-generation sequencing techniques have revolutionized genome resequencing, e.g. for strain comparisons, genetic mapping, or transcriptome and ChIP analyses, de novo assembly of eukaryotic genomes still presents significant hurdles, because of their large size and stretches of repetitive sequences. Filamentous fungi contain few repetitive regions in their 30–90 Mb genomes and thus are suitable candidates to test de novo genome assembly from short sequence reads. Here, we present a high-quality draft sequence of the Sordaria macrospora genome that was obtained by a combination of Illumina/Solexa and Roche/454 sequencing. Paired-end Solexa sequencing of genomic DNA to 85-fold coverage and an additional 10-fold coverage by single-end 454 sequencing resulted in ~4 Gb of DNA sequence. Reads were assembled to a 40 Mb draft version (N50 of 117 kb) with the Velvet assembler. Comparative analysis with Neurospora genomes increased the N50 to 498 kb. The S. macrospora genome contains even fewer repeat regions than its closest sequenced relative, Neurospora crassa. Comparison with genomes of other fungi showed that S. macrospora, a model organism for morphogenesis and meiosis, harbors duplications of several genes involved in self/nonself-recognition. Furthermore, S. macrospora contains more polyketide biosynthesis genes than N. crassa. Phylogenetic analyses suggest that some of these genes may have been acquired by horizontal gene transfer from a distantly related ascomycete group. Our study shows that, for typical filamentous fungi, de novo assembly of genomes from short sequence reads alone is feasible, that a mixture of Solexa and 454 sequencing substantially improves the assembly, and that the resulting data can be used for comparative studies to address basic questions of fungal biology.
If insufficiently treated, Lyme borreliosis can evolve into an inflammatory disorder affecting skin, joints, and the CNS. Early innate immunity may determine host responses targeting infection. Thus, we sought to characterize the immediate cytokine storm associated with exposure of PBMC to moderate levels of live Borrelia burgdorferi. Since Th17 cytokines are connected to host defense against extracellular bacteria, we focused on interleukin (IL)-17 and IL-22. Here, we report that, despite induction of inflammatory cytokines including IL-23, IL-17 remained barely detectable in response to B. burgdorferi. In contrast, T cell-dependent expression of IL-22 became evident within 10 h of exposure to the spirochetes. This dichotomy was unrelated to interferon-gamma but to a large part dependent on caspase-1 and IL-1 bioactivity derived from monocytes. In fact, IL-1beta as a single stimulus induced IL-22 but not IL-17. Neutrophils display antibacterial activity against B. burgdorferi, particularly when opsonized by antibodies. Since neutrophilic inflammation, indicative of IL-17 bioactivity, is scarcely observed in Erythema migrans, a manifestation of skin inflammation after infection, protective and antibacterial properties of IL-22 may close this gap and serve essential functions in the initial phase of spirochete infection.
Background: Familial hemophagocytosis (FHL) is a rare disease associated with defects in proteins involved in CD8+ T-cell cytotoxicity. Hyperactivation of immune cells results in a perilous, Th1-driven cytokine storm. We set out to explore the regulation of cytokines in an FHL patient who was clinically stable on low-dose immunosuppressive therapy after bone marrow transplantation over a six-month period. During this period, chimerism analyses showed that the fraction of host cells was between 1 and 10%. Both parents of the patient as well as healthy volunteers were studied for comparison. Methods/Principal Findings: Using ELISA, quantitative real-time PCR, and clinical laboratory methods, we investigated constitutive and inducible cytokines, polymorphisms, and clinical parameters in whole blood and whole blood cultures. Although routine laboratory tests were within the normal range, the chemokines IP-10 and IL-8 as well as the cytokine IL-27p28 were increased up to 10-fold under constitutive and stimulated conditions compared to healthy controls. Moreover, high levels of IFNgamma and TNFalpha were produced upon stimulation. Unexpectedly, IFNgamma induction of IL-18 binding protein (IL-18BP) was markedly reduced (1.6-fold vs 5-fold in controls). The patient's mother featured intermediately increased cytokine levels, whereas levels in the father were similar to those in the controls. Conclusions/Significance: Since IL-18 plays a major role in perpetuating hemophagocytosis, the failure of IFNgamma to induce IL-18BP may constitute a fundamental pathogenetic mechanism. Furthermore, increased production of IL-8 and IL-27 appears to be associated with this disease. Such dysregulation of cytokines was also found in the heterozygous parents, providing a novel insight into genotype-phenotype correlation of FHL which may encourage future research of this rare disease.
We solved the crystal structure of a novel type of c-ring isolated from Bacillus pseudofirmus OF4 at 2.5 Å, revealing a cylinder with a tridecameric stoichiometry, a central pore, and an overall shape that is distinct from those reported thus far. Within the groove of two neighboring c-subunits, the conserved glutamate of the outer helix shares the proton with a bound water molecule which itself is coordinated by three other amino acids of outer helices. Although none of the inner helices contributes to ion binding and the glutamate has no other hydrogen bonding partner than the water oxygen, the site remains in a stable, ion-locked conformation that represents the functional state present at the c-ring/membrane interface during rotation. This structure reveals a new, third type of ion coordination in ATP synthases. It appears in the ion binding site of an alkaliphile in which it represents a finely tuned adaptation of the proton affinity during the reaction cycle. Formal Correction: This article has been formally corrected to address the following errors. 1. The images for Figures S2 and S3 were incorrectly switched. The image that appears as Figure S2 should be Figure S3, and the image that appears as Figure S3 should be Figure S2. The figure legends appear in the correct order. Please view the correct... (read formal correction) 2. The images for Figures S2 and S3 were incorrectly switched. The image that appears as Figure S2 should be Figure S3, and the image that appears as Figure S3 should be Figure S2. The figure legends appear in the correct order. Please view the correct... (read formal correction)
Background: Falciparum Malaria, an infectious disease caused by the apicomplexan parasite Plasmodium falciparum, is among the leading causes of death and morbidity attributable to infectious diseases worldwide. In Gabon, Central Africa, one out of four inpatients have severe malarial anemia (SMA), a life-threatening complication if left untreated. Emerging drug resistant parasites might aggravate the situation. This case control study investigates biomarkers of enhanced hemolysis in hospitalized children with either SMA or mild malaria (MM). Methods and Findings: Ninety-one children were included, thereof 39 SMA patients. Strict inclusion criteria were chosen to exclude other causes of anemia. At diagnosis, erythrophagocytosis (a direct marker for extravascular hemolysis, EVH) was enhanced in SMA compared to MM patients (5.0 arbitrary units (AU) (interquartile range (IR): 2.2–9.6) vs. 2.1 AU (IR: 1.3–3.9), p<0.01). Furthermore, indirect markers for EVH, (i.e. serum neopterin levels, spleen size enlargement and monocyte pigment) were significantly increased in SMA patients. Markers for erythrocyte ageing, such as CD35 (complement receptor 1), CD55 (decay acceleration factor) and phosphatidylserine exposure (annexin-V-binding) were investigated by flow cytometry. In SMA patients, levels of CD35 and CD55 on the red blood cell surface were decreased and erythrocyte removal markers were increased when compared to MM or reconvalescent patients. Additionally, intravascular hemolysis (IVH) was quantified using several indirect markers (LDH, alpha-HBDH, haptoglobin and hemopexin), which all showed elevated IVH in SMA. The presence of both IVH and EVH predicted the need for blood transfusion during antimalarial treatment (odds ratio 61.5, 95% confidence interval (CI): 8.9–427). Interestingly, this subpopulation is characterized by a significantly lowered reticulocyte production index (RPI, p<0.05). Conclusions: Our results show the multifactorial pathophysiology of SMA, whereby EVH and IVH play a particularly important role. We propose a model where removal of infected and non-infected erythrocytes of all ages (including reticulocytes) by EVH and IVH is a main mechanism of SMA. Further studies are underway to investigate the mechanism and extent of reticulocyte removal to identify possible interventions to reduce the risk of SMA development.
Proteins can be acetylated at the alpha-amino group of the N-terminal amino acid (methionine or the penultimate amino acid after methionine removal) or at the epsilon-amino group of internal lysines. In eukaryotes the majority of proteins are N-terminally acetylated, while this is extremely rare in bacteria. A variety of studies about N-terminal acetylation in archaea have been reported recently, and it was revealed that a considerable fraction of proteins is N-terminally acetylated in haloarchaea and Sulfolobus, while this does not seem to apply for methanogenic archaea. Many eukaryotic proteins are modified by differential internal acetylation, which is important for a variety of processes. Until very recently, only two bacterial proteins were known to be acetylation targets, but now 125 acetylation sites are known for E. coli. Knowledge about internal acetylation in archaea is extremely limited; only two target proteins are known, only one of which--Alba--was used to study differential acetylation. However, indications accumulate that the degree of internal acetylation of archaeal proteins might be underestimated, and differential acetylation has been shown to be essential for the viability of haloarchaea. Focused proteomic approaches are needed to get an overview of the extent of internal protein acetylation in archaea.