Classical Fields Near Thermal Equilibrium

We discuss the classical limit for the long-distance (``soft'') modes of a quantum field when the hard modes of the field are in thermal equilibrium. We address the question of the correct semiclassical dynamics when a momentum cut-off is introduced. Higher order contributions leads to a stochastic interpretation for the effective action in analogy to Quantum Brownian Motion, resulting in dissipation and decoherence for the evolution of the soft modes. Particular emphasis is put on the understanding of dissipation. Our discussion focuses mostly on scalar fields, but we make some remarks on the extension to gauge theories.Comment: REVTeX, 6 figure

The metalloprotease ADAMTS4 generates N-truncated Aβ4–x species and marks oligodendrocytes as a source of amyloidogenic peptides in Alzheimer’s disease

Brain accumulation and aggregation of amyloid-β (Aβ) peptides is a critical step in the pathogenesis of Alzheimer’s disease (AD). Full-length Aβ peptides (mainly Aβ1–40 and Aβ1–42) are produced through sequential proteolytic cleavage of the amyloid precursor protein (APP) by β- and γ-secretases. However, studies of autopsy brain samples from AD patients have demonstrated that a large fraction of insoluble Aβ peptides are truncated at the N-terminus, with Aβ4–x peptides being particularly abundant. Aβ4–x peptides are highly aggregation prone, but their origin and any proteases involved in their generation are unknown. We have identified a recognition site for the secreted metalloprotease ADAMTS4 (a disintegrin and metalloproteinase with thrombospondin motifs 4) in the Aβ peptide sequence, which facilitates Aβ4–x peptide generation. Inducible overexpression of ADAMTS4 in HEK293 cells resulted in the secretion of Aβ4–40 but unchanged levels of Aβ1–x peptides. In the 5xFAD mouse model of amyloidosis, Aβ4–x peptides were present not only in amyloid plaque cores and vessel walls, but also in white matter structures co-localized with axonal APP. In the ADAMTS4−/− knockout background, Aβ4–40 levels were reduced confirming a pivotal role of ADAMTS4 in vivo. Surprisingly, in the adult murine brain, ADAMTS4 was exclusively expressed in oligodendrocytes. Cultured oligodendrocytes secreted a variety of Aβ species, but Aβ4–40 peptides were absent in cultures derived from ADAMTS4−/− mice indicating that the enzyme was essential for Aβ4–x production in this cell type. These findings establish an enzymatic mechanism for the generation of Aβ4–x peptides. They further identify oligodendrocytes as a source of these highly amyloidogenic Aβ peptides

Genomewide meta-analysis identifies loci associated with IGF-I and IGFBP-3 levels with impact on age-related traits

The growth hormone/insulin‐like growth factor (IGF) axis can be manipulated in animal models to promote longevity, and IGF‐related proteins including IGF‐I and IGF‐binding protein‐3 (IGFBP‐3) have also been implicated in risk of human diseases including cardiovascular diseases, diabetes, and cancer. Through genomewide association study of up to 30 884 adults of European ancestry from 21 studies, we confirmed and extended the list of previously identified loci associated with circulating IGF‐I and IGFBP‐3 concentrations (IGF1, IGFBP3, GCKR, TNS3, GHSR, FOXO3, ASXL2, NUBP2/IGFALS, SORCS2, and CELSR2). Significant sex interactions, which were characterized by different genotype–phenotype associations between men and women, were found only for associations of IGFBP‐3 concentrations with SNPs at the loci IGFBP3 and SORCS2. Analyses of SNPs, gene expression, and protein levels suggested that interplay between IGFBP3 and genes within the NUBP2 locus (IGFALS and HAGH) may affect circulating IGF‐I and IGFBP‐3 concentrations. The IGF‐I‐decreasing allele of SNP rs934073, which is an eQTL of ASXL2, was associated with lower adiposity and higher likelihood of survival beyond 90 years. The known longevity‐associated variant rs2153960 (FOXO3) was observed to be a genomewide significant SNP for IGF‐I concentrations. Bioinformatics analysis suggested enrichment of putative regulatory elements among these IGF‐I‐ and IGFBP‐3‐associated loci, particularly of rs646776 at CELSR2. In conclusion, this study identified several loci associated with circulating IGF‐I and IGFBP‐3 concentrations and provides clues to the potential role of the IGF axis in mediating effects of known (FOXO3) and novel (ASXL2) longevity‐associated loci

Hundreds of variants clustered in genomic loci and biological pathways affect human height

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.

Genomewide meta-analysis identifies loci associated with IGF-I and IGFBP-3 levels with impact on age-related traits

The growth hormone/insulin-like growth factor (IGF) axis can be manipulated in animal models to promote longevity, and IGF-related proteins including IGF-I and IGF-binding protein-3 (IGFBP-3) have also been implicated in risk of human diseases including cardiovascular diseases, diabetes, and cancer. Throug

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

The metalloprotease ADAMTS4 generates N-truncated A4-x species and marks oligodendrocytes as a source of amyloidogenic peptides in Alzheimer's disease

Brain accumulation and aggregation of amyloid- (A) peptides is a critical step in the pathogenesis of Alzheimer's disease (AD). Full-length A peptides (mainly A1-40 and A1-42) are produced through sequential proteolytic cleavage of the amyloid precursor protein (APP) by - and -secretases. However, studies of autopsy brain samples from AD patients have demonstrated that a large fraction of insoluble A peptides are truncated at the N-terminus, with A4-x peptides being particularly abundant. A4-x peptides are highly aggregation prone, but their origin and any proteases involved in their generation are unknown. We have identified a recognition site for the secreted metalloprotease ADAMTS4 (a disintegrin and metalloproteinase with thrombospondin motifs 4) in the A peptide sequence, which facilitates A4-x peptide generation. Inducible overexpression of ADAMTS4 in HEK293 cells resulted in the secretion of A4-40 but unchanged levels of A1-x peptides. In the 5xFAD mouse model of amyloidosis, A4-x peptides were present not only in amyloid plaque cores and vessel walls, but also in white matter structures co-localized with axonal APP. In the ADAMTS4(-/-) knockout background, A4-40 levels were reduced confirming a pivotal role of ADAMTS4 in vivo. Surprisingly, in the adult murine brain, ADAMTS4 was exclusively expressed in oligodendrocytes. Cultured oligodendrocytes secreted a variety of A species, but A4-40 peptides were absent in cultures derived from ADAMTS4(-/-) mice indicating that the enzyme was essential for A4-x production in this cell type. These findings establish an enzymatic mechanism for the generation of A4-x peptides. They further identify oligodendrocytes as a source of these highly amyloidogenic A peptides

Acute parathyroid hormone differentially regulates renal brush border membrane phosphate cotransporters

Renal phosphate reabsorption across the brush border membrane (BBM) in the proximal tubule is mediated by at least three transporters, NaPi-IIa (SLC34A1), NaPi-IIc (SLC34A3), and Pit-2 (SLC20A2). Parathyroid hormone (PTH) is a potent phosphaturic factor exerting an acute and chronic reduction in proximal tubule phosphate reabsorption. PTH acutely induces NaPi-IIa internalization from the BBM and lysosomal degradation, but its effects on NaPi-IIc and Pit-2 are unknown. In rats adapted to low phosphate diet, acute (30 and 60 min) application of PTH decreased BBM phosphate transport rates both in the absence and the presence of phosphonoformic acid, an inhibitor of SLC34 but not SLC20 transporters. Immunohistochemistry showed NaPi-IIa expression in the S1 to the S3 segment of superficial and juxtamedullary nephrons; NaPi-IIc was only detectable in S1 segments and Pit-2 in S1 and weakly in S2 segments of superficial and juxtamedullary nephrons. PTH reduced NaPi-IIa staining in the BBM with increased intracellular and lysosomal appearance. NaPi-IIa internalization was most prominent in S1 segments of superficial nephrons. We did not detect changes in NaPi-IIc and Pit-2 staining over this time period. Blockade of lysosomal protein degradation with leupeptin revealed NaPi-IIa accumulation in lysosomes, but no lysosomal staining for NaPi-IIc or Pit-2 could be detected. Immunoblotting of BBM confirmed the reduction in NaPi-IIa abundance and the absence of any effect on NaPi-IIc expression. Pit-2 protein abundance was also significantly reduced by PTH. Thus, function and expression of BBM phosphate cotransporters are differentially regulated allowing for fine-tuning of renal phosphate reabsorption

Quantitative Analyses of Cryptochrome-mBMAL1 Interactions: MECHANISTIC INSIGHTS INTO THE TRANSCRIPTIONAL REGULATION OF THE MAMMALIAN CIRCADIAN CLOCK*

The mammalian cryptochromes mCRY1 and mCRY2 act as transcriptional repressors within the 24-h transcription-translational feedback loop of the circadian clock. The C-terminal tail and a preceding predicted coiled coil (CC) of the mCRYs as well as the C-terminal region of the transcription factor mBMAL1 are involved in transcriptional feedback repression. Here we show by fluorescence polarization and isothermal titration calorimetry that purified mCRY1/2CCtail proteins form stable heterodimeric complexes with two C-terminal mBMAL1 fragments. The longer mBMAL1 fragment (BMAL490) includes Lys-537, which is rhythmically acetylated by mCLOCK in vivo. mCRY1 (but not mCRY2) has a lower affinity to BMAL490 than to the shorter mBMAL1 fragment (BMAL577) and a K537Q mutant version of BMAL490. Using peptide scan analysis we identify two mBMAL1 binding epitopes within the coiled coil and tail regions of mCRY1/2 and document the importance of positively charged mCRY1 residues for mBMAL1 binding. A synthetic mCRY coiled coil peptide binds equally well to the short and to the long (wild-type and K537Q mutant) mBMAL1 fragments. In contrast, a peptide including the mCRY1 tail epitope shows a lower affinity to BMAL490 compared with BMAL577 and BMAL490(K537Q). We propose that Lys-537mBMAL1 acetylation enhances mCRY1 binding by affecting electrostatic interactions predominantly with the mCRY1 tail. Our data reveal different molecular interactions of the mCRY1/2 tails with mBMAL1, which may contribute to the non-redundant clock functions of mCRY1 and mCRY2. Moreover, our study suggests the design of peptidic inhibitors targeting the interaction of the mCRY1 tail with mBMAL1