Malaria and obesity: obese mice are resistant to cerebral malaria

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Genome Wide Analysis of Inbred Mouse Lines Identifies a Locus Containing Ppar-γ as Contributing to Enhanced Malaria Survival

The genetic background of a patient determines in part if a person develops a mild form of malaria and recovers, or develops a severe form and dies. We have used a mouse model to detect genes involved in the resistance or susceptibility to Plasmodium berghei malaria infection. To this end we first characterized 32 different mouse strains infected with P. berghei and identified survival as the best trait to discriminate between the strains. We found a locus on chromosome 6 by linking the survival phenotypes of the mouse strains to their genetic variations using genome wide analyses such as haplotype associated mapping and the efficient mixed-model for association. This new locus involved in malaria resistance contains only two genes and confirms the importance of Ppar-γ in malaria infection

Light paintings

Opinnäytetyössäni käsittelen omaa taiteellista tuotantoani. Aluksi kerron kuinka olen päätynyt tekemään sitä mitä teen ja esittelen kuvasarjani. Tämän jälkeen käyn läpi käsitteitä, jotka liittyvät työhöni. Oma työskentelyni on kehittynyt kohti valon kuvaamista. Kuvaan valoa tietyn ajan kuluessa tai aikaa tietyssä valossa. Miten päin asiaa haluaakaan ajatella. Tutkin valon luonteita vuorokauden- ja vuodenaikojen muutoksina. Kuinka erilainen valo on eri aikoina? Miten se muuttaa kohdettaan? Ja kuinka se suhteutuu ympäristön väreihin? Tekstissäni perehdyn valoon Claude Monetin kautta. Kävelyllä on ollut tärkeä merkitys teosteni synnylle. Se toimii inspiraation lähteenä ja oli merkittävässä roolissa ensimmäisissä sarjoissani. Käsittelen kävelyn teemaa Richard Longin työskentelyn avulla. Aika, vuodenajat, toisto ja sattuma, sekä valokuvauksen ja maalauksen suhde ovat aiheina seuraavissa luvuissa. Käyn näitä asioita läpi taiteilijoiden avulla, joiden teoksiin ja työskentelyyn olen tutustunut kirjoittaessani tätä lopputyötä. Yhteistä kaikille valitsemilleni taiteilijoille tai teoksille on pitkien ajanjaksojen käyttäminen. Muita yhdistäviä tekijöitä ovat työskentelymetodit, tekniikka tai visuaalinen lopputulos

Brain angiotensin-converting enzymes: role of angiotensin-converting enzyme 2 in processing angiotensin II in mice

Angiotensin (Ang)-converting enzyme 2 (ACE2) metabolizes Ang II to the vasodilatory peptide Ang(1-7), while neprilysin (NEP) generates Ang(1-7) from Ang I. Experiments used novel Surface Enhanced Laser Desorption Ionization-Time of Flight (SELDI-TOF) mass spectroscopic (MS) assays to study Ang processing. Mass spectroscopy was used to measure proteolytic conversion of Ang peptide substrates to their specific peptide products. We compared ACE/ACE2 activity in plasma, brain and kidney from C57BL/6 and NEP(-/-) mice. Plasma or tissue extracts were incubated with Ang I or Ang II (1296 or 1045, m/z, respectively), and generated peptides were monitored with MS. Angiotensin-converting enzyme 2 activity was detected in kidney and brain, but not in plasma. Brain ACE2 activity was highest in hypothalamus. Angiotensin-converting enzyme 2 activity was inhibited by the specific ACE2 inhibitor, DX600 (10 mu M, 99% inhibition), but not by the ACE inhibitor, captopril (10 mu M). Both MS and colorimetric assays showed high ACE activity in plasma and kidney with low levels in brain. To extend these findings, ACE measurements were made in ACE overexpressing mice. Angiotensin-converting enzyme four-copy mice showed higher ACE activity in kidney and plasma with low levels in hypothalamus. In hypothalamus from NEP(-/-) mice, generation of Ang(1-7) from Ang I was decreased, suggesting a role for NEP in Ang metabolism. With Ang II as substrate, there was no difference between NEP(-/-) and wild-type control mice, indicating that other enzymes may contribute to generation of Ang(1-7). The data suggest a predominant role of hypothalamic ACE2 in the processing of Ang II, in contrast to ACE, which is most active in plasma.93566567

New mass spectrometric assay for angiotensin-converting enzyme 2 activity

A novel assay was developed for evaluation of mouse angiotensin- converting enzyme ( ACE) 2 and recombinant human ACE2 ( rACE2) activity. Using surface- enhanced laser desorption/ ionization time of flight mass spectrometry ( MS) with ProteinChip Array technology, ACE1 and ACE2 activity could be measured using natural peptide substrates. Plasma from C57BL/ 6 mice, kidney from wild- type and ACE2 knockout mice, and rACE2 were used for assay validation. Plasma or tissue extracts were incubated with angiotensin I ( Ang I; 1296 m/ z) or angiotensin II ( Ang II; 1045 m/ z). Reaction mixtures were spotted onto the ProteinChips WCX2 and peptides detected using surface- enhanced laser desorption/ ionization time of flight MS. MS peaks for the substrates, Ang I and Ang II, and the generated peptides, Ang ( 1- 7) and Ang ( 1- 9), were monitored. The ACE2 inhibitor MLN 4760 ( 0.01 to 100 mu mol/ L) significantly inhibited rACE2 activity ( IC50 = 3 nmol/ L). Ang II was preferably cleaved by rACE2 ( km = 5 mu mol/ L), whereas Ang I was not a good substrate for rACE2. There was no detectable ACE2 activity in plasma. Assay specificity was validated in a model of ACE2 gene deletion. In kidney extract from ACE2- deficient mice, there was no generation of Ang ( 1- 7) from Ang II. However, Ang ( 1- 7) was produced when Ang I was used as a substrate. In conclusion, we developed a specific and sensitive assay for ACE2 activity, which used the natural endogenous peptide substrate Ang II. This approach allows for the rapid screening for ACE2, which has applications in drug testing, high- throughput enzymatic assays, and identification of novel substrates/ inhibitors of the renin- angiotensin system.4751010101

Diabetic db/db mice exhibit central nervous system and peripheral molecular alterations as seen in neurological disorders

The db/db mouse is a widely used preclinical model in diabetes research. Recent studies have shown that these mice also display aspects of psychosis and depression-like behaviors as seen in some psychiatric disorders. Here, we have performed multiplex immunoassay and liquid chromatography mass spectrometry profiling of the plasma and brain samples from db/db and control mice to identify altered pathways, which could be related to these behavioral abnormalities. This is the first study to carry out profiling of the brain proteome in this model. Plasma from the db/db mice had increased levels of leptin and insulin, decreased levels of peptide YY, glucagon and prolactin and alterations in inflammation-related proteins, compared with control mice. Frontal cortex tissue from the db/db mice showed changes in proteins involved in energy metabolism, cellular structure and neural functioning, and the hippocampus had changes in proteins involved in the same pathways, with additional effects on cellular signalling proteins. The overlap of these findings with effects seen in type 2 diabetes, schizophrenia, major depressive disorder and Alzheimer's disease might contribute to a common endophenotype seen in metabolic and neurological disorders

Reversal of type 2 diabetes in mice by products of malaria parasites. II. Role of inositol phosphoglycans (IPGs).

We have previously shown that infection with Plasmodium yoelii malaria or injection of extracts from malaria-parasitized red cells induces hypoglycemia in normal mice and normalizes the hyperglycemia in mice made moderately diabetic with streptozotocin. Inositol phosphoglycans (IPGs) are released outside cells by hydrolysis of membrane-bound glycosylphosphatidylinositols (GPIs), and act as second messengers mediating insulin action. The C57BL/Ks-db/db and C57BL/6J-ob/ob mice offer good models for studies on human obesity and Type 2 diabetes. In the present study, we show that a single iv injection of IPG-A or IPG-P extracted from P. yoelii significantly (P < 0.02) lowers the blood glucose in STZ-diabetic, db/db, and in ob/ob mice for at least 4--6 h. Using rat white adipocytes, IPG-P increased lipogenesis by 20--30% in the presence and absence of maximal concentrations of insulin (10(-8) M) (P < 0.01) and stimulated pyruvate dehydrogenase (PDH) phosphatase in a dose-related manner. Both IPG-A and IPG-P inhibited c-AMP-dependent protein kinase (PKA) in a dose-related manner. Compositional analysis of IPGs after 24 h hydrolysis revealed the presence of myo-inositol, phosphorus, galactosamine, glucosamine, and glucose in both IPG-A and IPG-P. However, hydrolysis of IPGs for 4 h highlighted differences between IPG-A and IPG-P. There are some functional similarities between P. yoelii IPGs and those previously described for mammalian liver. However, this is the first report of the hypoglycemic effect of IPGs in murine models of Type 2 diabetes. We suggest that IPGs isolated from P. yoelii, when fully characterized, may provide structural information for the synthesis of new drugs for the management of diabetes mellitus

Relationship between renal and cardiovascular changes in a murine model of glucose intolerance

Nutrition is an important variable which may affect the risk for renal disease. We previously showed that a high fructose diet in mice produced hypertension and sympathetic activation [8]. The purpose of this study was to determine if a fructose diet altered renal function. A high fructose diet for 12 weeks impaired glucose tolerance, but caused no change in body weight, blood glucose or plasma insulin. Impairment in renal function was documented by the almost two fold increase in urinary protein excretion (Control: 6.6 +/- 0.6 vs. Fructose: 15.0 +/- 0.7 mmol protein/mmol creatinine; p < 0.05) which was also accompanied by increases in urinary volume. The diet produced little change in renal histology, kidney weight or kidney weight/body weight ratio. Urinary excretion of angiotensin II/creatinine (Control: 78.9 +/- 16.6 vs. Fructose: 80.5 +/- 14.2 pg/mmol) and renal angiotensin converting enzyme activity (Control: 9.2 +/- 1.6 vs. Fructose: 7.6 +/- 1.0 ACE units) were not different between groups. There was a positive correlation between mean arterial pressure (r = 0.7, p = 0.01), blood pressure variability (BPV) (r = 0.7, p = 0.02), low frequency BPV component (r = 0.677, p = 0.03) and urinary protein excretion. Results show that consumption of a high fructose diet in mice had deleterious effects on renal function, which were correlated with cardiovascular changes. (c) 2007 Published by Elsevier B.V.139416991