127 research outputs found
Mitochondrial Oxygen Monitoring During Surgical Repair of Congenital Diaphragmatic Hernia or Esophageal Atresia: A Feasibility Study
Current monitoring techniques in neonates lack sensitivity for hypoxia at cellular level.
The recent introduction of the non-invasive Cellular Oxygen METabolism (COMET)
monitor enables measuring in vivo mitochondrial oxygen tension (mitoPO2), based
on oxygen-dependent quenching of delayed fluorescence of 5-aminolevulinic acid
(ALA)-enhanced protoporphyri
Characterization of iodothyronine sulfatase activities in human and rat liver and placenta
In conditions associated with high serum iodothyronine sulfate
concentrations, e.g. during fetal development, desulfation of these
conjugates may be important in the regulation of thyroid hormone
homeostasis. However, little is known about which sulfatases are involved
in this process. Therefore, we investigated the hydrolysis of
iodothyronine sulfates by homogenates of V79 cells expressing the human
arylsulfatases A (ARSA), B (ARSB), or C (ARSC; steroid sulfatase), as well
as tissue fractions of human and rat liver and placenta. We found that
only the microsomal fraction from liver and placenta hydrolyzed
iodothyronine sulfates. Among the recombinant enzymes only the endoplasmic
reticulum-associated ARSC showed activity toward iodothyronine sulfates;
the soluble lysosomal ARSA and ARSB were inactive. Recombinant ARSC as
well as human placenta microsomes hydrolyzed iodothyronine sulfates with a
substrate preference for 3,3'-diiodothyronine sulfate (3,3'-T(2)S)
approximately T(3) sulfate (T(3)S) >> rT(3)S approximately T(4)S, whereas
human and rat liver microsomes showed a preference for 3,3'-T(2)S > T(3)S
>> rT(3)S approximately T(4)S. ARSC and the tissue microsomal sulfatases
were all characterized by high apparent K(m) values (>50 microM) for
3,3'-T(2)S and T(3)S. Iodothyronine sulfatase activity determined using
3,3'-T(2)S as a substrate was much higher in human liver microsomes than
in human placenta microsomes, although ARSC is expressed at higher levels
in human placenta than in human liver. The ratio of estrone sulfate to
T(2)S hydrolysis in human liver microsomes (0.2) differed largely from
that in ARSC homogenate (80) and human placenta microsomes (150). These
results suggest that ARSC accounts for the relatively low iodothyronine
sulfatase activity of human placenta, and that additional arylsulfatase(s)
contributes to the high iodothyronine sulfatase activity in human liver.
Further research is needed to identify these iodothyronine sulfatases, and
to study the physiological importance of the reversible sulfation of
iodothyronines in thyroid hormone metabolism
Characterization of human iodothyronine sulfotransferases
Sulfation is an important pathway of thyroid hormone metabolism that
facilitates the degradation of the hormone by the type I iodothyronine
deiodinase, but little is known about which human sulfotransferase
isoenzymes are involved. We have investigated the sulfation of the
prohormone T4, the active hormone T3, and the metabolites rT3 and
3,3'-diiodothyronine (3,3'-T2) by human liver and kidney cytosol as well
as by recombinant human SULT1A1 and SULT1A3, previously known as
phenol-preferring and monoamine-preferring phenol sulfotransferase,
respectively. In all cases, the substrate preference was 3,3'-T2 >> rT3 >
T3 > T4. The apparent Km values of 3,3'-T2 and T3 [at 50 micromol/L
3'-phosphoadenosine-5'-phosphosulfate (PAPS)] were 1.02 and 54.9
micromol/L for liver cytosol, 0.64 and 27.8 micromol/L for kidney cytosol,
0.14 and 29.1 micromol/L for SULT1A1, and 33 and 112 micromol/L for
SULT1A3, respectively. The apparent Km of PAPS (at 0.1 micromol/L 3,3'-T2)
was 6.0 micromol/L for liver cytosol, 9.0 micromol/L for kidney cytosol,
0.65 micromol/L for SULT1A1, and 2.7 micromol/L for SULT1A3. The sulfation
of 3,3'-T2 was inhibited by the other iodothyronines in a
concentration-dependent manner. The inhibition profiles of the 3,3'-T2
sulfotransferase activities of liver and kidney cytosol obtained by
addition of 10 micromol/L of the various analogs were better correlated
with the inhibition profile of SULT1A1 than with that of SULT1A3. These
results indicate similar substrate specificities for iodothyronine
sulfation by native human liver and kidney sulfotransferases and
recombinant SULT1A1 and SULT1A3. Of the latter, SULT1A1 clearly shows the
highest affinity for both iodothyronines and PAPS, but it remains to be
established whether it is the prominent isoenzyme for sulfation of thyroid
hormone in human liver and kidney
Mutational spectrum of the TSC1 gene in a cohort of 225 tuberous sclerosis complex patients: no evidence for genotype-phenotype correlation
Tuberous sclerosis complex is an inherited tumour suppressor syndrome,
caused by a mutation in either the TSC1 o
Thin-Film Metamaterials called Sculptured Thin Films
Morphology and performance are conjointed attributes of metamaterials, of
which sculptured thin films (STFs) are examples. STFs are assemblies of
nanowires that can be fabricated from many different materials, typically via
physical vapor deposition onto rotating substrates. The curvilinear--nanowire
morphology of STFs is determined by the substrate motions during fabrication.
The optical properties, especially, can be tailored by varying the morphology
of STFs. In many cases prototype devices have been fabricated for various
optical, thermal, chemical, and biological applications.Comment: to be published in Proc. ICTP School on Metamaterials (Augsut 2009,
Sibiu, Romania
Prenatal Correction of X-Linked Hypohidrotic Ectodermal Dysplasia.
Genetic deficiency of ectodysplasin A (EDA) causes X-linked hypohidrotic ectodermal dysplasia (XLHED), in which the development of sweat glands is irreversibly impaired, an condition that can lead to life-threatening hyperthermia. We observed normal development of mouse fetuses with Eda mutations after they had been exposed in utero to a recombinant protein that includes the receptor-binding domain of EDA. We administered this protein intraamniotically to two affected human twins at gestational weeks 26 and 31 and to a single affected human fetus at gestational week 26; the infants, born in week 33 (twins) and week 39 (singleton), were able to sweat normally, and XLHED-related illness had not developed by 14 to 22 months of age. (Funded by Edimer Pharmaceuticals and others.)
Rust never sleeps: the continuing story of the Iron Bolt
Since 1981, Gordon Research Conferences have been held on the topic of Oxygen Radicals on a biennial basis, to highlight and discuss the latest cutting edge research in this area. Since the first meeting, one special feature of this conference has been the awarding of the so-called Iron Bolt, an award that started in jest but has gained increasing reputation over the years. Since no written documentation exists for this Iron Bolt award, this perspective serves to overview the history of this unusual award, and highlights various experiences of previous winners of this “prestigious” award and other interesting anecdotes
Novel genetic loci associated with hippocampal volume
The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (rg =-0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness
ENIGMA and global neuroscience: A decade of large-scale studies of the brain in health and disease across more than 40 countries
This review summarizes the last decade of work by the ENIGMA (Enhancing NeuroImaging Genetics through Meta Analysis) Consortium, a global alliance of over 1400 scientists across 43 countries, studying the human brain in health and disease. Building on large-scale genetic studies that discovered the first robustly replicated genetic loci associated with brain metrics, ENIGMA has diversified into over 50 working groups (WGs), pooling worldwide data and expertise to answer fundamental questions in neuroscience, psychiatry, neurology, and genetics. Most ENIGMA WGs focus on specific psychiatric and neurological conditions, other WGs study normal variation due to sex and gender differences, or development and aging; still other WGs develop methodological pipelines and tools to facilitate harmonized analyses of "big data" (i.e., genetic and epigenetic data, multimodal MRI, and electroencephalography data). These international efforts have yielded the largest neuroimaging studies to date in schizophrenia, bipolar disorder, major depressive disorder, post-traumatic stress disorder, substance use disorders, obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, autism spectrum disorders, epilepsy, and 22q11.2 deletion syndrome. More recent ENIGMA WGs have formed to study anxiety disorders, suicidal thoughts and behavior, sleep and insomnia, eating disorders, irritability, brain injury, antisocial personality and conduct disorder, and dissociative identity disorder. Here, we summarize the first decade of ENIGMA's activities and ongoing projects, and describe the successes and challenges encountered along the way. We highlight the advantages of collaborative large-scale coordinated data analyses for testing reproducibility and robustness of findings, offering the opportunity to identify brain systems involved in clinical syndromes across diverse samples and associated genetic, environmental, demographic, cognitive, and psychosocial factors
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