Unexpected relationships between four large deletions in the human β-globin gene cluster.

Two independent gamma delta beta-thalassemias are each associated with large deletions. We show, by comparing DNA sequences, that the deletions are due to non-homologous DNA exchanges. The 5' breakpoints are located approximately the same distance apart and in the same order along the DNA as their 3' breakpoints. Two independent cases of hereditary persistence of fetal hemoglobin, also involving large deletions, show the same unexpected relationship between their 5' and 3' breakpoints. This relationship is most simply explained if, within each pair, the deletions are of approximately the same length. The results suggest that the four deletions were generated by a common mechanism. Perhaps their 5' and 3' breakpoints are physically close in the nucleus, although far apart on the linear DNA

A tetraethylene glycol coat gives gold nanoparticles long in vivo half-lives with minimal increase in size

In this study, we describe the experiments determining whether coating gold nanoparticles with tetraethylene glycol (TEG) provides pharmacologically relevant advantages, such as increased serum half-life and resistance to protein adsorption. Monodisperse TEG-coated, NaBH4-reduced gold nanoparticles with a hydrodynamic size comparable to albumin were synthesized by reducing gold chloride with NaBH4 under alkaline conditions in the presence of TEG-SH. The particles were characterized by gel electrophoresis, column chromatography, and transmission electron microscopy. The nanoparticles were subsequently injected intravenously into mice, and their half-lives and final destinations were determined via photometric analysis, light microscopy (LM), and transmission electron microscopy. The TEG particles had a long half-life (~400 minutes) that was not influenced by splenectomy. After 500 minutes of injection, TEG particles were found in kidney proximal tubule cell vesicles and in spleen red and white pulp. The particles induced apoptosis in the spleen red pulp but not in white pulp or the kidney. Some of the TEG particles appeared to have undergone ligand exchange reactions that increased their charge. The TEG particles were shown to be resistant to nonspecific protein adsorption, as judged by gel electrophoresis and column chromatography. These results demonstrate that naturally monodisperse, small-sized gold nanoparticles coated with TEG have long in vivo plasma half-lives, are minimally toxic, and are resistant to protein adsorption. This suggests that a TEG coating should be considered as an alternative to a polyethylene glycol coating, which is polydisperse and of much larger size

Studies of hepatic synthesis in vivo of plasma proteins, including orosomucoid, transferrin, α-antitrypsin, C8, and factor B

Serum protein types were determined in eight recipients and donors in cases of hepatic homotransplantation. A change from recipient type to donor type was observed for factor B, C8, orosomucoid, haptoglobin, transferrin, α1-antitrypsin, C3 and C6, but not for Gm and Inv immunoglobulin markers. The results indicate that all the proteins studied (except immunoglobulins) are produced primarily by the liver in vivo. © 1980

An overview of adakite, tonalite-trondhjemite-granodiorite (TTG), and sanukitoid; relationships and some implications for crustal evolution.

Abstract Examination of an extensive adakite geochemical database identifies two distinct compositional groups. One consists of high-SiO 2 adakites (HSA) which is considered to represent subducted basaltic slab-melts that have reacted with peridotite during ascent through mantle wedge. The second group consists of low-SiO 2 adakites (LSA) which we interpret to have formed by melting of a peridotitic mantle wedge whose composition has been modified by reaction with felsic slab-melts. The chemical composition of less differentiated (primitive) Archaean tonalite-trondhjemite-granodiorite (TTG) magmas evolved from 4.0 to 2.5 Ga. Mg# (molecular Mg/(Mg+Fe 2+ ), Ni, and Cr contents increased over this period of time and we interpret these changes in terms of changes in the degree to which the TTG magmas interacted with mantle peridotite. Over the same period, concentrations of (CaO+Na 2 O) and Sr also increased, as the amount of plagioclase, residual from basalt melting, decreased in response to increased pressures at the site of slab-melting. In the Early Archaean, it appears that these interactions were very rare or absent thus leading to the conclusion that subduction was typically flat and lacked the development of a mantle wedge. In contrast, the relatively lower heat production by~2.5 Ga meant that slab-melting occurred at greater depth, where plagioclase was no longer stable, and where the development of a thick mantle wedge ensured interaction between the slab-melts and mantle peridotite. Close compositional similarities between HSA and Late Archaean TTG (Tb~3.0 Ga) strongly suggest a petrogenetic analogy. However, an analogy between the older Archaean TTG and HSA is not complete because evidence for mantle wedge interaction is missing in most Early Archaean TTGs. Late Archaean sanukitoids and the compositionally similar Closepet-type granites have compositions significantly different from TTG of all ages. However, they show some affinity with LSA which could be considered as their possible analogue. These magmas are all thought to result from melting of a mantle peridotite whose composition has been modified by reaction with slab-melts. We propose that all these magmas are directly linked to slab-melting. Archaean TTG and HSA represent slab-melts that have interacted with peridotite to varying extent, whereas sanukitoids, Closepet-type granites, and LSA correspond to melts of peridotite previously metasomatised by slab-melt. The changes observed from Early Archaean TTG to Late Archaean TTG and to sanukitoids reflect change in both the nature and efficiency of interaction between slab-melt and mantle wedge peridotite. Comparisons between all of these rocks suggest that ancient styles of subduction that have operated since at least~3.3 Ga persist in a limited way today. The secular changes in the degree and style of these interactions is a direct consequence of the cooling of Earth that modified the thermal and dynamic parameters at the subducted slab-mantle wedge interface.

Standing in a Garden of Forking Paths

According to the Path Principle, it is permissible to expand your set of beliefs iff (and because) the evidence you possess provides adequate support for such beliefs. If there is no path from here to there, you cannot add a belief to your belief set. If some thinker with the same type of evidential support has a path that they can take, so do you. The paths exist because of the evidence you possess and the support it provides. Evidential support grounds propositional justification. The principle is mistaken. There are permissible steps you may take that others may not even if you have the very same evidence. There are permissible steps that you cannot take that others can even if your beliefs receive the same type of evidential support. Because we have to assume almost nothing about the nature of evidential support to establish these results, we should reject evidentialism

Permeation of macromolecules into the renal glomerular basement membrane and capture by the tubules

Human kidneys contain ∼2 x 106 glomeruli that produce ∼180 L per day of primary filtrate. Downstream tubules reabsorb most of the water, salt, and desirable low-molecular weight substances, leaving 1 to 2 L per day of urine containing undesirable waste products. Currently, most investigators think that the primary filtrate is low in protein because fluid exiting the glomerulus passes through slits spanned by a diaphragm that acts as a low-porosity molecular sieve. Our experiments challenge this view; they show that size-dependent permeation into the glomerular basement membrane and into a gel-like coat that covers the slits, together with saturable tubular reabsorption, determines which macromolecules reach the urine. The slit diaphragm is essential for capillary structure but may not directly determine glomerular size selectivity

A Burgessian critique of nominalistic tendencies in contemporary mathematics and its historiography

We analyze the developments in mathematical rigor from the viewpoint of a Burgessian critique of nominalistic reconstructions. We apply such a critique to the reconstruction of infinitesimal analysis accomplished through the efforts of Cantor, Dedekind, and Weierstrass; to the reconstruction of Cauchy's foundational work associated with the work of Boyer and Grabiner; and to Bishop's constructivist reconstruction of classical analysis. We examine the effects of a nominalist disposition on historiography, teaching, and research.Comment: 57 pages; 3 figures. Corrected misprint

Greenstone burial–exhumation cycles at the late Archean transition to plate tectonics

Converging lines of evidence suggest that, during the late Archean, Earth completed its transition from a stagnant-lid to a plate tectonics regime,although how and when this transition occurred is debated. The geological record indicates that some form of subduction, a key component of plate tectonics—has operated since the Mesoarchean, even though the tectonic style and timescales of burial and exhumation cycles within ancient convergent margins are poorly constrained.Here, we present a Neoarchean pressure–temperature–time (P–T–t) path from supracrustal rocks of the transpressional Yilgarn orogen (Western Australia), which documents how sea-floor-altered rocks underwent deep burial then exhumation during shortening that was unrelated to the episode of burial. Archean subduction, even if generally short-lived, was capable of producing eclogites along converging lithosphere boundaries, although exhumation processes in those environments were likely less efficient than today, such that return of high-pressure rocks to the surface was rare