The rockefeller university

The expression of the six types of human Hb subunits over time is currently considered to be regulated mainly by transcription factors that bind to upstream control regions of the gene (the extrinsic component of regulation). Here, we describe how subunit pairing and further assembly to tetramers in the liganded state is influenced by the affinity of subunits for one another (the intrinsic component of regulation). The adult Hb dimers have the strongest subunit interfaces and the embryonic Hbs the weakest, with fetal Hbs being of intermediate strength, corresponding to the temporal order of their expression. These variable subunit binding strengths and the attenuating effects of acetylation contribute to the differences with which these Hb types form functional O2-binding tetramers consistent with gene switching.

There is growing evidence that functional brain images in alert task-engaged subjects contain task-related but stimulus-independent signals in addition to stimulus-evoked responses. It is important to separate these different components when analyzing the neuroimaging signal. Using intrinsic-signal optical imaging combined with electrophysiology we had earlier reported a particular 'trial-related signal' in the primary visual cortex (V1) of alert monkeys performing periodic fixation tasks. This signal periodically modulated V1 tissue blood volume, in time with anticipated trial onsets. Unlike visually evoked blood volume changes, however, this signal was present even in total darkness. Further, it could not be predicted by concurrently recorded spiking or local field potentials. Here we use our earlier recording techniques to analyze the spatial distribution of this trial-related signal over our imaged area (10 mm square, subdivided into a 16 x 16 grid, i.e. at 625 mu m resolution). We show that the signal is spatially coherent and essentially homogeneous over the imaged region and fails to be predicted by concurrent electrode recordings even at the resolution of a single grid square at the electrode tip. As a corollary we show that the signal is critically linked to the animals' engagement in a task. Not only does the trial-related signal entrain accurately and precisely to any task timing at which the animal was willing to perform: the signal also loses the entrained trial-locked pattern dramatically, within a single trial, when the animal stops performing correctly. Thus the signal is very unlikely to be an ongoing task-independent vascular oscillation. These findings will help categorize the likely distinct varieties of non-stimulus-related signals evoked during behavioral tasks, and lead to a further understanding of the elements comprising the net neuroimaging response. (C) 2011 Elsevier Inc. All rights reserved.

Estradiol affects hippocampal-dependent spatial memory and underlying structural and electrical synaptic plasticity in female mice and rats. Using estrogen receptor (ER) alpha and beta knockout mice and wild-type littermates, we investigated the role of ERs in estradiol effects on multiple pathways important for hippocampal plasticity and learning. Six hours of estradiol administration increased immunoreactivity for phosphorylated Akt throughout the hippocampal formation, whereas 48 h of estradiol increased immunoreactivity for phosphorylated TrkB receptor. Estradiol effects on phosphorylated Akt and TrkB immunoreactivities were abolished in ER alpha and ER beta knockout mice. Estradiol also had distinct effects on immunoreactivity for post-synaptic density 95 (PSD-95) and brain derived-neurotrophic factor (BDNF) mRNA in ER alpha and beta knockout mice. Thus, estradiol acts through both ERs alpha and beta in several subregions of the hippocampal formation. The different effects of estradiol at 6 and 48 h indicate that several mechanisms of estrogen receptor signaling contribute to this female hormone's influence on hippocampal synaptic plasticity. By further delineating these mechanisms, we will better understand and predict the effects of endogenous and exogenous ovarian steroids on mood, cognition, and other hippocampal-dependent behaviors. (C) 2011 IBRO. Published by Elsevier Ltd. All rights reserved.

Cedric Blanpain from the Interdisciplinary Research Institute, Universite libre de Bruxelles earned the 2012 ISSCR-University of Pittsburgh Outstanding Young Investigator Award for his exceptional achievements as an early-career stem cell researcher.

We search for high-mass resonances decaying into Z boson pairs using data corresponding to 6 fb(-1) collected by the CDF experiment in p (p) over bar collisions at root s = 1.96 TeV. The search is performed in three distinct final states: ZZ -> l(+)l(-)l(+)l(-), ZZ -> l(+)l(-)vv, and ZZ -> l(+)l(-)jj. For a Randall-Sundrum graviton G*, the 95% CL upper limits on the production cross section times branching ratio to ZZ, sigma(p (p) over bar -> G* -> ZZ), vary between 0.26 pb and 0.045 pb in the mass range 300 < M-G* < 1000 GeV/c(2).

We report on a measurement of CP-violating asymmetries (A(CP)) in the Cabibbo-suppressed D-0 -> pi(+) pi(-) and D-0 -> K+ K- decays reconstructed in a data sample corresponding to 5.9 fb(-1) of integrated luminosity collected by the upgraded Collider Detector at Fermilab. We use the strong decay D*(+) -> D-0 pi(+) to identify the flavor of the charmed meson at production and exploit CP-conserving strong c (c) over bar pair production in p (p) over bar collisions. High-statistics samples of Cabibbo-favored D-0 -> K- pi(+) decays with and without a D*(+/-) tag are used to correct for instrumental effects and significantly reduce systematic uncertainties. We measure A(CP)(D-0 -> pi(+) pi(-)) = (+0.22 +/- 0.24(stat) +/- 0.11(syst))% and A(CP)(D-0 -> K+K-) = (-0.24 +/- 0.22(stat) +/- 0.09(syst))%, in agreement with CP conservation. These are the most precise determinations from a single experiment to date. Under the assumption of negligible direct CP violation in D-0 -> pi(+) pi(-) and D-0 -> K+ K- decays, the results provide an upper limit to the CP-violating asymmetry in D-0 mixing,vertical bar A(CP)(ind)(D-0)vertical bar < 0.13% at the 90% confidence level.

Down syndrome cell adhesion molecule (DSCAM) has mainly been characterized for its function as an adhesion molecule in axon growth and in self-recognition between dendrites of the same neuron. Recently, it has been shown that DSCAM can bind to Netrin-1 and that downregulation of DSCAM expression by siRNAs in chick and rodent spinal cords leads to impaired growth and turning response of commissural axons to Netrin-1. To investigate the effect of complete genetic ablation of DSCAM on Netrin-1-induced axon guidance, we analyzed spinal commissural neurons in DSCAM-null mice and found that they extend axons that reach and cross the floor plate and express apparently normal levels of the Netrin receptors DCC (deleted in colorectal carcinoma) and Neogenin. In vitro, commissural neurons in dorsal spinal cord explants of DSCAM-null embryos show normal outgrowth in response to Netrin-1. We therefore conclude that DSCAM is not required for Netrin-induced commissural axon outgrowth and guidance in mice.

Passive transfer of broadly neutralizing human antibodies against HIV-1 protects macaques against infection. However, HIV-1 uses several strategies to escape antibody neutralization, including mutation of the gp160 viral surface spike, a glycan shield to block antibody access to the spike, and expression of a limited number of viral surface spikes, which interferes with bivalent antibody binding. The latter is thought to decrease antibody apparent affinity or avidity, thereby interfering with neutralizing activity. To test the idea that increasing apparent affinity might enhance neutralizing activity, we engineered bispecific anti-HIV-1 antibodies (BiAbs) that can bind bivalently by virtue of one scFv arm that binds to gp120 and a second arm to the gp41 subunit of gp160. The individual arms of the BiAbs preserved the binding specificities of the original anti-HIV IgG antibodies and together bound simultaneously to gp120 and gp41. Heterotypic bivalent binding enhanced neutralization compared with the parental antibodies. We conclude that antibody recognition and viral neutralization of HIV can be improved by heteroligation.

While a high-fat diet when compared to low-fat diet is known to produce overeating and health complications, less is known about the effects produced by fat-rich diets differing in their specific composition of fat. This study examined the effects of a high-fat diet containing relatively high levels of saturated compared to unsaturated fatty acids (HiSat) to a high-fat diet with higher levels of unsaturated fatty acids (USat). A HiSat compared to USat meal caused rats to consume more calories in a subsequent chow test meal. The HiSat meal also increased circulating levels of triglycerides (TG) and expression of the orexigenic peptides, galanin (GAL) in the hypothalamic paraventricular nucleus (PVN) and orexin (OX) in the perifornical lateral hypothalamus (PFLH). A similar increase in TG levels and PVN GAL and PFLH OX was also seen in rats given chronic access to the HiSat compared to USat diet, while neuropeptide Y (NPY) and agouti-related protein (AgRP) in the arcuate nucleus showed decreased expression. The importance of TG in producing these changes was supported by the finding that the TG-lowering medication gemfibrozil as compared to vehicle, when peripherally administered before consumption of a HiSat meal, significantly decreased the expression of OX, while increasing the expression of NPY and AgRP. These findings substantiate the importance of the fat composition in a diet, indicating that those rich in saturated compared to unsaturated fatty acids may promote overeating by increasing circulating lipids and specific hypothalamic peptides, GAL and OX, known to preferentially stimulate the consumption of a fat-rich diet. Published by Elsevier B.V.

Alzheimer's disease (AD) is characterized by amyloid-beta (Abeta) plaques, tau tangles, brain atrophy, and vascular pathology. Vascular defects include cerebrovascular dysfunction, decreased cerebral blood flow, and blood brain barrier (BBB) disruption, among others. Here, we review the evidence that links Abeta with the vascular pathology present in AD, with a specific focus on the hemostatic system and the clotting protein fibrinogen. Fibrinogen is normally found circulating in blood, but in AD it deposits with Abeta in the brain parenchyma and cerebral blood vessels. We found that Abeta and fibrin(ogen) interact, and their binding leads to increased fibrinogen aggregation, Abeta fibrillization, and the formation of degradation-resistant fibrin clots. Decreasing fibrinogen levels not only lessens cerebral amyloid angiopathy and BBB permeability, but it also reduces microglial activation and improves cognitive performance in AD mouse models. Moreover, a prothrombotic state in AD is evidenced by increased clot formation, decreased fibrinolysis, and elevated levels of coagulation factors and activated platelets. Abnormal deposition and persistence of fibrin(ogen) in AD may result from Abeta-fibrin(ogen) binding and altered hemostasis and could thus contribute to Abeta deposition, decreased cerebral blood flow, exacerbated neuroinflammation, and eventual neurodegeneration. Blocking the interaction between fibrin(ogen) and Abeta may be a promising therapeutic target for AD.