Характер роста щенков собак разных типов

Character of growth of puppies (large and fine breeds) from 2 to 6 months years old is revealed. During this period, the small and medium breeds of puppies are more developed then the large breeds. Thus tends to gain live weight, height of the shoulder, chest, metacarpus and bone index.Выявлен характер роста щенков собак крупных, средних и мелких пород с 2-х до 6-месячного возраста. Более интенсивно в этот возрастной период формируются щенки мелких и средних пород, чем крупных, при превосходстве относительных приростов живой массы, высоты в холке, обхвата груди, пясти и индексов обхвата груди и костистости

The grown's character of puppies different breeds

Character of growth of puppies (large and fine breeds) from 2 to 6 months years old is revealed. During this period, the small and medium breeds of puppies are more developed then the large breeds. Thus tends to gain live weight, height of the shoulder, chest, metacarpus and bone index

A High-Throughput Cell-Based Screen Identified a 2-[(E)-2-Phenylvinyl]-8-Quinolinol Core Structure That Activates p53

p53 function is frequently inhibited in cancer either through mutations or by increased degradation via MDM2 and/or E6AP E3-ubiquitin ligases. Most agents that restore p53 expression act by binding MDM2 or E6AP to prevent p53 degradation. However, fewer compounds directly bind to and activate p53. Here, we identified compounds that shared a core structure that bound p53, caused nuclear localization of p53 and caused cell death. To identify these compounds, we developed a novel cell-based screen to redirect p53 degradation to the Skip-Cullin-F-box (SCF) ubiquitin ligase complex in cells expressing high levels of p53. In a multiplexed assay, we coupled p53 targeted degradation with Rb1 targeted degradation in order to identify compounds that prevented p53 degradation while not inhibiting degradation through the SCF complex or other proteolytic machinery. High-throughput screening identified several leads that shared a common 2-[(E)-2-phenylvinyl]-8-quinolinol core structure that stabilized p53. Surface plasmon resonance analysis indicated that these compounds bound p53 with a KD of 200 ± 52 nM. Furthermore, these compounds increased p53 nuclear localization and transcription of the p53 target genes PUMA, BAX, p21 and FAS in cancer cells. Although p53-null cells had a 2.5±0.5-fold greater viability compared to p53 wild type cells after treatment with core compounds, loss of p53 did not completely rescue cell viability suggesting that compounds may target both p53-dependent and p53-independent pathways to inhibit cell proliferation. Thus, we present a novel, cell-based high-throughput screen to identify a 2-[(E)-2-phenylvinyl]-8-quinolinol core structure that bound to p53 and increased p53 activity in cancer cells. These compounds may serve as anti-neoplastic agents in part by targeting p53 as well as other potential pathways

The common 2-[(E)-2-phenylvinyl]-8-quinolinol core structure did not cause DNA damage or inhibit proteasome activity.

<p>(A) Compounds did not cause double stranded DNA damage as measured by γH2AX phosphorylation. C33a cells were treated with 30 μM of compounds or cisplatin for 4 hrs, fixed and stained for phosphorylated γH2AX. (B) Quantitation of phosphorylated γH2AX positive nuclei. Results are from 10 fields per 2 replicates of the indicated condition. Impact of compounds on proteasome activity as measured by chymotrypsin-like activity (C) or trypsin-like activity (D). For (C) and (D), C33a cells were incubated for 2 hrs with the indicated compounds at 10 μM or 30 μM and assessed for chymotrypsin and trypsin activity using Proteasome-Glo assay. Paired T test were used to determine significance.</p

High-throughput screen for compounds that stabilized the p53 reporter assay.

<p>(A) TE6 abrogated p53-Luc luciferase activity. C33a cells were infected with Ad-p53-Luc alone or with Ad-Red, Ad-TE6 or Ad-TE7. (B) TE7 abrogated Rb-Ren luciferase activity. C33a cells were infected with Ad-Rb-Ren alone or with Ad-Red, Ad-TE6 or Ad-TE7. (C) TE6 promoted proteasome degradation of the p53-Luc reporter. C33a cells infected with Ad-p53-Luc and the cognate Ad-TE6 or non-cognate Ad-TE7 and treated with different concentrations of the proteasome inhibitor bortezomib or the p53 inhibitor RITA. (D) High throughput screening using the TE6-p53-Luc reporter detected compounds that restored p53 activity. A plot of 465 compounds selected from 158,000 compounds that induced p53-Luc or Rb-Ren activity at least 2-fold above background. p53-Luc activity was normalized to the corresponding Rb-Ren activity and vice versa to account for potential proteasome inhibitors or compounds with cytotoxic activity. The dark grey area indicates compounds that restored p53-Luc activity; the light grey area indicates compounds that restored Rb-Ren activity. Paired t-tests were used to determine significance.</p

Pentameric assembly of potassium channel tetramerization domain-containing protein 5.

We report the X-ray crystal structure of human potassium channel tetramerization domain-containing protein 5 (KCTD5), the first member of the family to be so characterized. Four findings were unexpected. First, the structure reveals assemblies of five subunits while tetramers were anticipated; pentameric stoichiometry is observed also in solution by scanning transmission electron microscopy mass analysis and analytical ultracentrifugation. Second, the same BTB (bric-a-brac, tramtrack, broad complex) domain surface mediates the assembly of five KCTD5 and four voltage-gated K(+) (Kv) channel subunits; four amino acid differences appear crucial. Third, KCTD5 complexes have well-defined N- and C-terminal modules separated by a flexible linker that swivels by approximately 30 degrees; the C-module shows a new fold and is required to bind Golgi reassembly stacking protein 55 with approximately 1 microM affinity, as judged by surface plasmon resonance and ultracentrifugation. Fourth, despite the homology reflected in its name, KCTD5 does not impact the operation of Kv4.2, Kv3.4, Kv2.1, or Kv1.2 channels

The common 2-[(E)-2-phenylvinyl]-8-quinolinol core structure bound p53 and disrupted p53 degradation.

<p>(A) Of the 269 potential compounds that increased p53-Luc activity by ≥2-fold above background, 6 structures shared common core 2-[(E)-2-phenylvinyl]-8-quinolinol structure. (B) Structure activity relationship studies identified additional compounds containing a core 2-[(E)-2-phenylvinyl]-8-quinolinol structure that disrupted p53 degradation. Upper panel: Activity of compounds in C33a cells expressing TE6 and p53-Luc. Lower panel: Activity of compounds in HeLa cells expressing p53-Luc. (C) 2-[(E)-2-phenylvinyl]-8-quinolinol compounds rescued p53 degradation. The top 11 compounds in (B) were assayed for restoration of p53-Luc activity in C33a cells expressing TE6, in HeLa cells or in C33a cells expressing dsRed. * indicates P < .001. (D) Compounds containing the core structure restored p53 activity <i>in vitro</i>. Recombinant E6 was incubated with the indicated compounds as well as with cell lysates containing p53-Luc protein. (E) Surface plasmon resonance demonstrated that compound 4 bound to p53 with a K_D of 200 + 52 nM. p53 recombinant proteins were amino terminally linked to a Biacore chip. Compound 4 was run at concentrations from 1–25 μM over the Biacore chip and association and disassociation times recorded. (F) Compound 4 docks with the DNA binding domain pocket of p53. Molecular modeling was performed with MolDock.</p