298 research outputs found
A novel route to product specificity in the Suv4-20 family of histone H4K20 methyltransferases
The delivery of site-specific post-translational modifications to histones generates an epigenetic regulatory network that directs fundamental DNA-mediated processes and governs key stages in development. Methylation of histone H4 lysine-20 has been implicated in DNA repair, transcriptional silencing, genomic stability and regulation of replication. We present the structure of the histone H4K20 methyltransferase Suv4-20h2 in complex with its histone H4 peptide substrate and S-adenosyl methionine cofactor. Analysis of the structure reveals that the Suv4-20h2 active site diverges from the canonical SET domain configuration and generates a high degree of both substrate and product specificity. Together with supporting biochemical data comparing Suv4-20h1 and Suv4-20h2, we demonstrate that the Suv4-20 family enzymes take a previously mono-methylated H4K20 substrate and generate an exclusively di-methylated product. We therefore predict that other enzymes are responsible for the tri-methylation of histone H4K20 that marks silenced heterochromatin
℮-conome: an automated tissue counting platform of cone photoreceptors for rodent models of retinitis pigmentosa
<p>Abstract</p> <p>Background</p> <p>Retinitis pigmentosa is characterized by the sequential loss of rod and cone photoreceptors. The preservation of cones would prevent blindness due to their essential role in human vision. Rod-derived Cone Viability Factor is a thioredoxin-like protein that is secreted by rods and is involved in cone survival. To validate the activity of Rod-derived Cone Viability Factors (RdCVFs) as therapeutic agents for treating retinitis Pigmentosa, we have developed e-conome, an automated cell counting platform for retinal flat mounts of rodent models of cone degeneration. This automated quantification method allows for faster data analysis thereby accelerating translational research.</p> <p>Methods</p> <p>An inverted fluorescent microscope, motorized and coupled to a CCD camera records images of cones labeled with fluorescent peanut agglutinin lectin on flat-mounted retinas. In an average of 300 fields per retina, nine Z-planes at magnification X40 are acquired after two-stage autofocus individually for each field. The projection of the stack of 9 images is subject to a threshold, filtered to exclude aberrant images based on preset variables. The cones are identified by treating the resulting image using 13 variables empirically determined. The cone density is calculated over the 300 fields.</p> <p>Results</p> <p>The method was validated by comparison to the conventional stereological counting. The decrease in cone density in <it>rd1 </it>mouse was found to be equivalent to the decrease determined by stereological counting. We also studied the spatiotemporal pattern of the degeneration of cones in the <it>rd1 </it>mouse and show that while the reduction in cone density starts in the central part of the retina, cone degeneration progresses at the same speed over the whole retinal surface. We finally show that for mice with an inactivation of the Nucleoredoxin-like genes <it>Nxnl1 </it>or <it>Nxnl2 </it>encoding RdCVFs, the loss of cones is more pronounced in the ventral retina.</p> <p>Conclusion</p> <p>The automated platform ℮-conome used here for retinal disease is a tool that can broadly accelerate translational research for neurodegenerative diseases.</p
Mutagenesis of the NaChBac sodium channel discloses a functional role for a conserved S6 asparagine
Asparagine is conserved in the S6 transmembrane segments of all voltage-gated sodium, calcium, and TRP channels identified to date. A broad spectrum of channelopathies including cardiac arrhythmias, epilepsy, muscle diseases, and pain disorders is associated with its mutation. To investigate its effects on sodium channel functional properties, we mutated the simple prokaryotic sodium channel NaChBac. Electrophysiological characterization of the N225D mutant reveals that this conservative substitution shifts the voltage-dependence of inactivation by 25 mV to more hyperpolarized potentials. The mutant also displays greater thermostability, as determined by synchrotron radiation circular dichroism spectroscopy studies of purified channels. Based on our analyses of high-resolution structures of NaChBac homologues, we suggest that the side-chain amine group of asparagine 225 forms one or more hydrogen bonds with different channel elements and that these interactions are important for normal channel function. The N225D mutation eliminates these hydrogen bonds and the structural consequences involve an enhanced channel inactivation
Measurement of Exclusive B Decays to Final States Containing a Charmed Baryon
Using data collected by the CLEO detector in the Upsilon(4S) region, we
report new measurements of the exclusive decays of B mesons into final states
of the type Lambda_c^+ p-bar n(pi), where n=0,1,2,3. We find signals in modes
with one, two and three pions and an upper limit for the two body decay
Lambda_c^+ pbar. We also make the first measurements of exclusive decays of B
mesons to Sigma_c p-bar n(pi), where n=0,1,2. We find signals in modes with one
and two pions and an upper limit for the two body decay Sigma_c p-bar.
Measurements of these modes shed light on the mechanisms involved in B decays
to baryons.Comment: 11 pages postscript, also available through
http://w4.lns.cornell.edu/public/CLNS, submitted to PR
Measurement of the Masses and Widths of the Sigma_c^++ and Sigma_c^0 Charmed Baryons
Using data recorded by the CLEO II and CLEO II.V detector configurations at
CESR, we report new measurements of the masses of the Sigma_c^{++} and
Sigma_c^0 charmed baryons, and the first measurements of their intrinsic
widths. We find M(Sigma_c^{++}) - M(Lambda_c^+) = 167.4 +- 0.1 +- 0.2 MeV,
Gamma(Sigma_c^{++}) = 2.3 +- 0.2 +- 0.3 MeV, and M(Sigma_c^0) - M(Lambda_c^+) =
167.2 +- 0.1 +- 0.2 MeV, Gamma(Sigma_c^0) = 2.5 +- 0.2 +- 0.3 MeV, where the
uncertainties are statistical and systematic, respectively.Comment: 9 pages postscript, also available through
http://w4.lns.cornell.edu/public/CLNS, submitted to PRD, Rapid
Communications. Reference [13] correcte
Evidence for the Decay
We present a search for the ``wrong-sign'' decay D0 -> K+ pi- pi+ pi- using 9
fb-1 of e+e- collisions on and just below the Upsilon(4S) resonance. This decay
can occur either through a doubly Cabibbo-suppressed process or through mixing
to a D0bar followed by a Cabibbo-favored process. Our result for the
time-integrated wrong-sign rate relative to the decay D0 -> K- pi+ pi- pi+ is
(0.0041 +0.0012-0.0011(stat.) +-0.0004(syst.))x(1.07 +-0.10)(phase space),
which has a statistical significance of 3.9 standard deviations.Comment: 9 pages postscript, also available through
http://w4.lns.cornell.edu/public/CLNS, submitted to PR
Hadronic Mass Moments in Inclusive Semileptonic B Meson Decays
We have measured the first and second moments of the hadronic mass-squared
distribution in B -> X_c l nu, for P(lepton) > 1.5 GeV/c. We find <M_X^2 -
M_D[Bar]^2> = 0.251 +- 0.066 GeV^2, )^2 > = 0.576 +- 0.170
GeV^4, where M_D[Bar] is the spin-averaged D meson mass.
From that first moment and the first moment of the photon energy spectrum in
b -> s gamma, we find the HQET parameter lambda_1 (MS[Bar], to order 1/M^3 and
beta_0 alpha_s^2) to be -0.24 +- 0.11 GeV^2. Using these first moments and the
B semileptonic width, and assuming parton-hadron duality, we obtain |V_cb| =
0.0404 +- 0.0013.Comment: 11 pages postscript, also available through
http://w4.lns.cornell.edu/public/CLNS, submitted to PR
Observation of Exclusive barB --> D(*) K*- Decays
We report the first observation of the exclusive decays \bar B\to
D^{(*)}K^{*-}, using 9.66 x 10^{6} B\bar{B} pairs collected at the \Upsilon(4S)
with the CLEO detector. We measure the following branching fractions: {\cal
B}(B^- -> D^0 K^{*-})=(6.1 +- 1.6 +-1.7)x10^{-4}, {\cal B}(\bar{B^0} ->
D^+K^{*-})=(3.7 +- 1.5 +- 1.0) x 10^{-4}, {\cal B}(\bar{B^0} ->
D^{*+}K^{*-})=(3.8 +- 1.3 +- 0.8) x 10^{-4} and {\cal B}(B^- --> D^{*0}
K^{*-})=(7.7 +- 2.2 +- 2.6) x 10^{-4}. The \bar B ->D^*K^{*-} branching ratios
are the averages of those corresponding to the 00 and 11 helicity states. The
errors shown are statistical and systematic, respectively.Comment: 9 pages postscript, also available through
http://w4.lns.cornell.edu/public/CLNS, Published in
Phys.Rev.Lett.88:101803,200
Observation of the Charmed Baryon at CLEO
The CLEO experiment at the CESR collider has used 13.7 fb of data to
search for the production of the (css-ground state) in
collisions at {\rm GeV}. The modes used to
study the are ,
, , , and
. We observe a signal of 40.49.0(stat) events
at a mass of 2694.62.6(stat)1.9(syst) {\rm MeV/}, for all modes
combined.Comment: 10 pages postscript, also available through
http://w4.lns.cornell.edu/public/CLN
Observation of and
We have studied two-body charmless hadronic decays of mesons into the
final states phi K and phi K^*. Using 9.7 million pairs collected
with the CLEO II detector, we observe the decays B- -> phi K- and B0 -> phi K*0
with the following branching fractions: BR(B- -> phi K-)=(5.5 +2.1-1.8 +- 0.6)
x 10^{-6} and BR(B0 -> phi K*0)=(11.5 +4.5-3.7 +1.8-1.7) x 10^{-6}. We also see
evidence for the decays B0 -> phi K0 and B- -> phi K*-. However, since the
statistical significance is not overwhelming for these modes we determine upper
limits of <12.3 x 10^{-6} and <22.5 x 10^{-6} (90% C.L.) respectively.Comment: 9 pages postscript, also available through
http://w4.lns.cornell.edu/public/CLN
- …