β-Amyloid (Aβ) Oligomers Impair Brain-derived Neurotrophic Factor Retrograde Trafficking by Down-regulating Ubiquitin C-terminal Hydrolase,UCH-L1

We previously found that BDNF-dependent retrograde trafficking is impaired in AD transgenic mouse neurons. Utilizing a novel microfluidic culture chamber, we demonstrate that Aβ oligomers compromise BDNF-mediated retrograde transport by impairing endosomal vesicle velocities, resulting in impaired downstream signaling driven by BDNF/TrkB, including ERK5 activation, and CREB-dependent gene regulation. Our data suggest that a key mechanism mediating the deficit involves ubiquitin C-terminal hydrolase L1 (UCH-L1), a deubiquitinating enzyme that functions to regulate cellular ubiquitin. Aβ-induced deficits in BDNF trafficking and signaling are mimicked by LDN (an inhibitor of UCH-L1) and can be reversed by increasing cellular UCH-L1 levels, demonstrated here using a transducible TAT-UCH-L1 strategy. Finally, our data reveal that UCH-L1 mRNA levels are decreased in the hippocampi of AD brains. Taken together, our data implicate that UCH-L1 is important for regulating neurotrophin receptor sorting to signaling endosomes and supporting retrograde transport. Further, our results support the idea that in AD, Aβ may down-regulate UCH-L1 in the AD brain, which in turn impairs BDNF/TrkB-mediated retrograde signaling, compromising synaptic plasticity and neuronal survival.     

Determinants of expression variability

The amount of tissue-specific expression variability (EV) across individuals is an essential characteristic of a gene and believed to have evolved, in part, under functional constraints. However, the determinants and functional implications of EV are only beginning to be investigated. Our analyses based on multiple expression profiles in 41 primary human tissues show that a gene’s EV is significantly correlated with a number of features pertaining to the genomic, epigenomic, regulatory, polymorphic, functional, structural and network characteristics of the gene. We found that (i) EV of a gene is encoded, in part, by its genomic context and is further influenced by the epigenome; (ii) strong promoters induce less variable expression; (iii) less variable gene loci evolve under purifying selection against copy number polymorphisms; (iv) genes that encode inherently disordered or highly interacting proteins exhibit lower variability; and (v) genes with less variable expression are enriched for house-keeping functions, while genes with highly variable expression tend to function in development and extra-cellular response and are associated with human diseases. Thus, our analysis reveals a number of potential mediators as well as functional and evolutionary correlates of EV, and provides new insights into the inherent variability in eukaryotic gene expression.     

ASP-56, a new actin sequestering protein from pig platelets with homology to CAP, an adenylate cyclase-associated protein from yeast.

A new 56 kDa actin-binding protein (ASP-56) was isolated from pig platelet lysate. In falling ball viscosimetry it caused a reduction in viscosity that could be attributed to a decrease in the concentration of polymeric actin. Fluorescence measurements with NBD-labelled actin showed reduction of polymeric actin, too. These results could be explained by sequestering of actin in a non-polymerizable 1:1 ASP-56/actin complex. Sequencing of about 20 tryptic peptides of ASP-56 and comparison with known sequences revealed about 60% homology to the adenylate cyclase-associated protein (CAP) from yeast.     

Lysine-derived cross-links in the egg shell membrane

Egg shell membrane protein contains significant quantities of the lysine-derived aldehyde, allysine, and its aldol condensation product. NaB³H₄ reduction followed by alkaline hydrolysis of purified protein revealed that there were six residues/1000 of both allysine and the reduced aldol while only traces of desmosine and isodesmosine were detected. The amino acid composition of the membrane protein did not resemble that of mammalian elastin.     

Plague Meningitis—A Retrospective Analysis of Cases Reported in the United States, 1970-1979

Meningitis caused by Yersinia pestis developed in 6 (6%) of a total of 105 patients with plague reported to the Centers for Disease Control from 1970 to 1979. Five of the six cases occurred in children aged 10 to 15 years. All six patients received antibiotic therapy before meningitis developed, which appeared between the 9th and 14th days after the onset of acute illness in five of the six patients. There were no neurologic sequelae. The antigenic and biochemical profiles of the Y pestis strains isolated from cerebrospinal fluid in the meningitis cases did not differ from those of the Y pestis strains obtained from blood and bubo aspirates in the other 99 patients, and neither did in vitro studies suggest antibiotic resistance. While plague meningitis is an uncommon complication of acute plague infection, physicians in the western United States should be aware that it may develop as much as 14 days after antibiotic therapy for the acute plague infection has been initiated.     

Global Epidemiology

A total of 62,811 cases of the acquired immunodeficiency syndrome (AIDS) have been reported to the World Health Organization from throughout the world. Extensive epidemiologic studies have shown that human immunodeficiency virus (HIV) infections are transmitted by three routes: sexual, parenteral and perinatal. Three geographic patterns of transmission have been defined. In pattern I, transmission occurs predominantly among homosexual and bisexual men and urban intravenous drug abusers; transmission via blood products has been controlled; the male:female sex ratio is 10:1 or more; population HIV seroprevalence is low, and perinatal transmission is uncommon (for instance, United States, western Europe). In pattern II, transmission is predominantly heterosexual and perinatal; transmission via blood products exists but is being reduced; unsterile needles and other skin-piercing instruments cause some parenteral transmission (magnitude not known); the male:female sex ratio is 1:1, and population seroprevalence often exceeds 1% (central Africa, Haiti). In pattern III, AIDS cases are just being documented and are generally due to sexual exposure abroad or imported blood products (Middle East, Asia).     

The presence of chlorophyll b and the estimation of phaeopigments in marine phytoplankton

A reverse-phase h.p.l.c. technique was used to estimate theconcentration of chlorophyll b in phytoplankton cultures, fecalpellets of Calanus pacificus, and suspended paniculate matterfrom the Central North Pacific, Oregon coastal waters, and DabobBay (a temperate fjord in Puget Sound, WA, USA). The purposewas to assess the distribution of this pigment in the euphoticzone and its effect on the fluorometnc estimation of phaeopigments.Analyses of natural waters confirm high chlorophyll b concentrations(median mass ratio of b:a > 0.3) at the depth of the chlorophylla maximum in tropical waters while values for temperate planktonare relatively low (median mass ratio of chl b:a = 0.05) andpatchy. Zooplankton fecal pellets showed a significant enrichmentin chlorophyll b, suggesting grazing as a mechanism to explainhigh concentrations of this pigment at the bottom of the euphoticzone. It is estimated that the presence of chlorophyll b couldcause an average overestimation of phaeopigment concentrationby the fluorometnc technique of 38% between 0 and 200 m in theCentral North Pacific. This effect is more pronounced at thelayer of chlorophyll b maximum (120–140 m). ¹Present address: Marine Biology Research Division, A-002, ScrippsInstitution of Oceanography, La Jolla, CA 92093, USA