Pseudo-acetylation of multiple sites on human Tau proteins alters Tau phosphorylation and microtubule binding, and ameliorates amyloid beta toxicity

Tau is a microtubule-associated protein that is highly soluble and natively unfolded. Its dysfunction is involved in the pathogenesis of several neurodegenerative disorders including Alzheimer's disease (AD), where it aggregates within neurons. Deciphering the physiological and pathogenic roles of human Tau (hTau) is crucial to further understand the mechanisms leading to its dysfunction in vivo. We have used a knock-out/knock-in strategy in Drosophila to generate a strain with hTau inserted into the endogenous fly tau locus and expressed under the control of the endogenous fly tau promoter, thus avoiding potential toxicity due to genetic over-expression. hTau knock-in (KI) proteins were expressed at normal, endogenous levels, bound to fly microtubules and were post-translationally modified, hence displaying physiological properties. We used this new model to investigate the effects of acetylation on hTau toxicity in vivo. The simultaneous pseudo-acetylation of hTau at lysines 163, 280, 281 and 369 drastically decreased hTau phosphorylation and significantly reduced its binding to microtubules in vivo. These molecular alterations were associated with ameliorated amyloid beta toxicity. Our results indicate acetylation of hTau on multiple sites regulates its biology and ameliorates amyloid beta toxicity in vivo

Evidence for the Rare Decay B -> K*ll and Measurement of the B -> Kll Branching Fraction

We present evidence for the flavor-changing neutral current decay $B\to K^*\ell^+\ell^-$ and a measurement of the branching fraction for the related process $B\to K\ell^+\ell^-$, where $\ell^+\ell^-$ is either an $e^+e^-$ or $\mu^+\mu^-$ pair. These decays are highly suppressed in the Standard Model, and they are sensitive to contributions from new particles in the intermediate state. The data sample comprises $123\times 10^6$ $\Upsilon(4S)\to B\bar{B}$ decays collected with the Babar detector at the PEP-II $e^+e^-$ storage ring. Averaging over $K^{(*)}$ isospin and lepton flavor, we obtain the branching fractions ${\mathcal B}(B\to K\ell^+\ell^-)=(0.65^{+0.14}_{-0.13}\pm 0.04)\times 10^{-6}$ and ${\mathcal B}(B\to K^*\ell^+\ell^-)=(0.88^{+0.33}_{-0.29}\pm 0.10)\times 10^{-6}$, where the uncertainties are statistical and systematic, respectively. The significance of the $B\to K\ell^+\ell^-$ signal is over $8\sigma$, while for $B\to K^*\ell^+\ell^-$ it is $3.3\sigma$.Comment: 7 pages, 2 postscript figues, submitted to Phys. Rev. Let

Measurement of Branching Fraction and Dalitz Distribution for B0->D(*)+/- K0 pi-/+ Decays

We present measurements of the branching fractions for the three-body decays B0 -> D(*)-/+ K0 pi^+/-$and their resonant submodes$B0 -> D(*)-/+ K*+/- using a sample of approximately 88 million BBbar pairs collected by the BABAR detector at the PEP-II asymmetric energy storage ring. We measure: B(B0->D-/+ K0 pi+/-)=(4.9 +/- 0.7(stat) +/- 0.5 (syst)) 10^{-4} B(B0->D*-/+ K0 pi+/-)=(3.0 +/- 0.7(stat) +/- 0.3 (syst)) 10^{-4} B(B0->D-/+ K*+/-)=(4.6 +/- 0.6(stat) +/- 0.5 (syst)) 10^{-4} B(B0->D*-/+ K*+/-)=(3.2 +/- 0.6(stat) +/- 0.3 (syst)) 10^{-4} From these measurements we determine the fractions of resonant events to be : f(B0-> D-/+ K*+/-) = 0.63 +/- 0.08(stat) +/- 0.04(syst) f(B0-> D*-/+ K*+/-) = 0.72 +/- 0.14(stat) +/- 0.05(syst)Comment: 7 pages, 3 figures submitted to Phys. Rev. Let

Impaired hypoglycaemia awareness in type 1 diabetes:lessons from the lab

Hypoglycaemia remains the most common metabolic adverse effect of insulin and sulfonylurea therapy in diabetes. Repeated exposure to hypoglycaemia leads to a change in the symptom complex that characterises hypoglycaemia, culminating in a clinical phenomenon referred to as impaired awareness of hypoglycaemia (IAH). IAH effects approximately 20–25% of people with type 1 diabetes and increases the risk of severe hypoglycaemia. This review focuses on the mechanisms that are responsible for the much higher frequency of hypoglycaemia in people with diabetes compared with those without, and subsequently how repeated exposure to hypoglycaemia leads to the development of IAH. The mechanisms that result in IAH development are incompletely understood and likely to reflect changes in multiple aspects of the counterregulatory response to hypoglycaemia, from adaptations within glucose and non-glucose-sensing cells to changes in the integrative networks that govern glucose homeostasis. Finally, we propose that the general process that incorporates many of these changes and results in IAH following recurrent hypoglycaemia is a form of adaptive memory called ‘habituation’

Characterization of the Interaction between the Cohesin Subunits Rad21 and SA1/2

The cohesin complex is responsible for the fidelity of chromosomal segregation during mitosis. It consists of four core subunits, namely Rad21/Mcd1/Scc1, Smc1, Smc3, and one of the yeast Scc3 orthologs SA1 or SA2. Sister chromatid cohesion is generated during DNA replication and maintained until the onset of anaphase. Among the many proposed models of the cohesin complex, the ﾒcoreﾒ cohesin subunits Smc1, Smc3, and Rad21 are almost universally displayed as tripartite ring. However, other than its supportive role in the cohesin ring, little is known about the fourth core subunit SA1/SA2. To gain deeper insight into the function of SA1/SA2 in the cohesin complex, we have mapped the interactive regions of SA2 and Rad21 in vitro and ex vivo. Whereas SA2 interacts with Rad21 through a broad region (301ﾖ750 aa), Rad21 binds to SA proteins through two SA-binding motifs on Rad21, namely N-terminal (NT) and middle part (MP) SA-binding motif, located At 60-81 aa of the N-terminus and 383ﾖ392 aa of the MP of Rad21, respectively. The MP SA-binding motif is a 10 amino acid, a-helical motif. Deletion of these 10 amino acids or mutation of three conserved amino acids (L385, F389, and T390) in this ahelical motif significantly hinders Rad21 from physically interacting with SA1/2. Besides the MP SA-binding motif, the NT SAbinding motif is also important for SA1/2 interaction. Although mutations on both SA-binding motifs disrupt Rad21-SA1/2 interaction, they had no apparent effect on the Smc1-Smc3-Rad21 interaction. However, the Rad21-Rad21 dimerization was reduced by the mutations, indicating potential involvement of the two SA-binding motifs in the formation of the two-ring handcuff for chromosomal cohesion. Furthermore, mutant Rad21 proteins failed to significantly rescue precocious chromosome separation caused by depletion of endogenous Rad21 in mitotic cells, further indicating the physiological significance of the two SA-binding motifs of Rad21

Measurement of the Branching Fraction for B- --> D0 K*-

We present a measurement of the branching fraction for the decay B- --> D0 K*- using a sample of approximately 86 million BBbar pairs collected by the BaBar detector from e+e- collisions near the Y(4S) resonance. The D0 is detected through its decays to K- pi+, K- pi+ pi0 and K- pi+ pi- pi+, and the K*- through its decay to K0S pi-. We measure the branching fraction to be B.F.(B- --> D0 K*-)= (6.3 +/- 0.7(stat.) +/- 0.5(syst.)) x 10^{-4}.Comment: 7 pages, 1 postscript figure, submitted to Phys. Rev. D (Rapid Communications

Do lambs perceive regular human stroking as pleasant? Behavior and heart rate variability analyses

Stroking by humans is beneficial to the human-animal relationship and improves welfare in many species that express intraspecific allogrooming, but very few studies have looked at species like sheep that do not express such contact except around parturition. This study investigated the way lambs perceive regular human tactile contact using behavioral and physiological responses. Twenty-four lambs were reared and bucket-fed in groups of four. All were stroked daily by their familiar caregiver. At 8 weeks of age, the lambs were individually tested in their home pen but in a 1×1m open-barred pen after a 15h period of habituation to physical separation from peers while remaining in visual and auditory contact. Half of the lambs received stroking by their caregiver for 8min and half were exposed to their caregiver’s immobile presence. Heart rate and heart rate variability were recorded and analyzed by 2-min slots over the same interval based on three measures: mean heart rate value (HR), root mean square of successive differences (RMSSD) and standard deviation of all intervals measured between consecutive sinus beats (SDNN). Behavioral responses (ear postures of the lamb and time spent in contact with the familiar caregiver, on the knees of the familiar caregiver, and moving) were recorded throughout the test. Lamb HR decreased continuously while in the presence of their caregiver. Lambs being stroked showed slower HR and higher RMSSD which reflected positive emotional states compared to lambs left unstroked. All behavioral variables were highly correlated with the main component axis of the PCA analyses: the more the animals stayed in contact with their caregiver, the less they moved and the more their ears were hanging. This first component clearly differentiates lambs being stroked or not. Behavioral and physiological observations support the hypothesis that gentle physical contact with the caregiver is perceived positively by lambs

Reduced engagement with social stimuli in 6-month-old infants with later Autism Spectrum Disorder: a longitudinal prospective study of infants at high familial risk

Background: Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder that affects more than 1% of the population, and close to 20% of prospectively studied infants with an older sibling with ASD. Although significant progress has been made in characterizing the emergence of behavioral symptoms of ASD, far less is known about the underlying disruptions to early learning. Recent models suggest that core aspects of the causal path to ASD may only be apparent in early infancy. Here, we investigated social attention in 6- and 12-month-old infants who did and did not meet criteria for ASD at 24 months using both cognitive and electrophysiological methods. We hypothesized that a reduction in attention engagement to faces would be associated with later ASD. Methods: In a prospective longitudinal design, we used measures of both visual attention (habituation) and brain function (event-related potentials to faces and objects) at 6 and 12 months, and investigated the relationship to ASD outcome at 24 months. Results: High-risk infants who met criteria for ASD at 24 months showed shorter epochs of visual attention, faster but less prolonged neural activation to faces, and delayed sensitization responses (increases in looking) to faces at 6 months; these differences were less apparent at 12 months. These findings are consistent with disrupted engagement of sustained attention to social stimuli. Conclusions: These findings suggest that there may be fundamental early disruptions to attention engagement that may have cascading consequences for later social functioning

Measurement of the B+ --> p pbar K+ Branching Fraction and Study of the Decay Dynamics

With a sample of 232x10^6 Upsilon(4S) --> BBbar events collected with the BaBar detector, we study the decay B+ --> p pbar K+ excluding charmonium decays to ppbar. We measure a branching fraction Br(B+ --> p pbar K+)=(6.7+/-0.5+/-0.4)x10^{-6}. An enhancement at low ppbar mass is observed and the Dalitz plot asymmetry suggests dominance of the penguin amplitude in this B decay. We search for a pentaquark candidate Theta*++ decaying into pK+ in the mass range 1.43 to 2.00 GeV/c2 and set limits on Br(B+ --> Theta*++pbar)xBr(Theta*++ --> pK+) at the 10^{-7} level.Comment: 8 pages, 7 postscript figures, submitted to Phys. Rev. D (Rapid Communications

An imaging system for standardized quantitative analysis of C. elegans behavior

BACKGROUND: The nematode Caenorhabditis elegans is widely used for the genetic analysis of neuronal cell biology, development, and behavior. Because traditional methods for evaluating behavioral phenotypes are qualitative and imprecise, there is a need for tools that allow quantitation and standardization of C. elegans behavioral assays. RESULTS: Here we describe a tracking and imaging system for the automated analysis of C. elegans morphology and behavior. Using this system, it is possible to record the behavior of individual nematodes over long time periods and quantify 144 specific phenotypic parameters. CONCLUSIONS: These tools for phenotypic analysis will provide reliable, comprehensive scoring of a wide range of behavioral abnormalities, and will make it possible to standardize assays such that behavioral data from different labs can readily be compared. In addition, this system will facilitate high-throughput collection of phenotypic data that can ultimately be used to generate a comprehensive database of C. elegans phenotypic information. AVAILABILITY: The hardware configuration and software for the system are available from [email protected]