Yam Code
Sign up
Login
New paste
Home
Trending
Archive
English
English
Tiếng Việt
भारत
Sign up
Login
New Paste
Browse
Consanguineous unions increase the frequency at which identical genomic segments are inherited along separate paths of descent, decreasing coalescence times for pairs of alleles drawn from an individual who is the offspring of a consanguineous pair. For an autosomal locus, it has recently been shown that the mean time to the most recent common ancestor (TMRCA) for two alleles in the same individual and the mean TMRCA for two alleles in two separate individuals both decrease with increasing consanguinity in a population. Here, we extend this analysis to the X chromosome, considering X-chromosomal coalescence times under a coalescent model with diploid, male-female mating pairs. We examine four possible first-cousin mating schemes that are equivalent in their effects on autosomes, but that have differing effects on the X chromosome patrilateral-parallel, patrilateral-cross, matrilateral-parallel, and matrilateral-cross. In each mating model, we calculate mean TMRCA for X-chromosomal alleles sampled either within or between individuals. We describe a consanguinity effect on X-chromosomal TMRCA that differs from the autosomal pattern under matrilateral but not under patrilateral first-cousin mating. For matrilateral first cousins, the effect of consanguinity in reducing TMRCA is stronger on the X chromosome than on the autosomes, with an increased effect of parallel-cousin mating compared to cross-cousin mating. The theoretical computations support the utility of the model in understanding patterns of genomic sharing on the X chromosome.Poxviruses are enveloped viruses with a linear, double-stranded DNA genome. Viral DNA synthesis is achieved by a functional DNA polymerase holoenzyme composed of three essential proteins. For vaccinia virus (VACV) these are E9, the catalytic subunit, a family B DNA polymerase, and the heterodimeric processivity factor formed by D4 and A20. The A20 protein links D4 to the catalytic subunit. High-resolution structures have been obtained for the VACV D4 protein in complex with an N-terminal fragment of A20 as well as for E9. In addition, biochemical studies provided evidence that a poxvirus-specific insertion (insert 3) in E9 interacts with the C-terminal residues of A20. Here, we provide solution structures of two different VACV A20 C-terminal constructs containing residues 304-426, fused at their C-terminus to either a BAP (Biotin Acceptor Peptide)-tag or a short peptide containing the helix of E9 insert 3. Together with results from titration studies, these structures shed light on the molecular interface between the catalytic subunit and the processivity factor component A20. The interface comprises hydrophobic residues conserved within the Chordopoxvirinae subfamily. Finally, we constructed a HADDOCK model of the VACV A20304-426-E9 complex, which is in excellent accordance with previous experimental data.Cardiac troponin (cTn) is made up of three subunits, cTnC, cTnI, and cTnT. https://www.selleckchem.com/products/ins018-055-ism001-055.html The regulatory N-terminal domain of cTnC (cNTnC) controls cardiac muscle contraction in a calcium-dependent manner. We show that calcium-saturated cNTnC can adopt two different orientations, with the "active" orientation consistent with the 2020 cryo-EM structure of the activated cardiac thin filament by Yamada et al. Using solution NMR 15N R2 relaxation analysis, we demonstrate that the two domains of cTnC tumble independently (average R2 10 s-1), being connected by a flexible linker. However, upon addition of cTnI1-77, the complex tumbles as a rigid unit (R2 30 s-1). cTnI phosphomimetic mutants S22D/S23D, S41D/S43D and dilated cardiomyopathy- (DCM-)associated mutations cTnI K35Q, cTnC D75Y, and cTnC G159D destabilize the active orientation of cNTnC, with intermediate 15N R2 rates (R2 17-23 s-1). The active orientation of cNTnC is stabilized by the flexible tails of cTnI, cTnI1-37 and cTnI135-209. Surprisingly, when cTnC is incorporated into complexes lacking these tails (cTnC-cTnI38-134, cTnC-cTnT223-288, or cTnC-cTnI38-134-cTnT223-288), the cNTnC domain is still immobilized, revealing a new interaction between cNTnC and the IT-arm that stabilizes a "dormant" orientation. We propose that the calcium sensitivity of the cardiac troponin complex is regulated by an equilibrium between active and dormant orientations, which can be shifted through post-translational modifications or DCM-associated mutations.Recent progress in structure-prediction methods that rely on deep learning suggests that the atomic structure of almost any protein may soon be predictable directly from its amino acid sequence. This much-awaited revolution was driven by substantial improvements in the reliability of methods for inferring the spatial distances between amino acid pairs from an analysis of homologous sequences. Improved reliability has been accompanied, however, by a reduced ability to detect amino acid relationships that are not due to direct spatial contacts, such as those that arise from protein dynamics or allostery. Given the central importance of dynamics and allostery to protein activity, we argue that an important future advance would extend modeling beyond predicting a single static structure. Here, we briefly review some of the developments that have led to the remarkable recent achievement in structure prediction and speculate what methods and sources of information may be leveraged in the future to develop a modeling framework that addresses protein dynamics and allostery.A series of new 17-cyanopyridine derivatives of pregnenolone have been synthesized, and their anti-proliferative activities against different human cancer cell lines were tested. The extensive structure-activity relationship (SAR) data suggested that the introduction of 2-amino-4-aryl-3-cyanopyridine to the D ring of pregnenolone may increase the anti-cancer activity. Among the products, the most potent compound 4j exhibited good growth inhibition against all the tested cells especially for PC- 3 cells with an IC50 value of 2.0 μM. Further mechanistic studies showed that 4j inhibited the formation of cell colonies and migration, increased the level of reactive oxygen species (ROS) in PC-3 cells in a concentration-dependent manner, and induced necroptosis through the phosphorylation of receptor interacting protein 1/3 (P-RIP1/3) and phosphorylation of mixed lineage kinase domain-like protein (P-MLKL) pathway. The 17-pregnenolone cyanopyridine derivatives hold promising potential as anti-proliferative agents, and the most potent compound could be used as a starting point for the development of new steroidal heterocycles with improved anticancer potency and selectivity.
Paste Settings
Paste Title :
[Optional]
Paste Folder :
[Optional]
Select
Syntax Highlighting :
[Optional]
Select
Markup
CSS
JavaScript
Bash
C
C#
C++
Java
JSON
Lua
Plaintext
C-like
ABAP
ActionScript
Ada
Apache Configuration
APL
AppleScript
Arduino
ARFF
AsciiDoc
6502 Assembly
ASP.NET (C#)
AutoHotKey
AutoIt
Basic
Batch
Bison
Brainfuck
Bro
CoffeeScript
Clojure
Crystal
Content-Security-Policy
CSS Extras
D
Dart
Diff
Django/Jinja2
Docker
Eiffel
Elixir
Elm
ERB
Erlang
F#
Flow
Fortran
GEDCOM
Gherkin
Git
GLSL
GameMaker Language
Go
GraphQL
Groovy
Haml
Handlebars
Haskell
Haxe
HTTP
HTTP Public-Key-Pins
HTTP Strict-Transport-Security
IchigoJam
Icon
Inform 7
INI
IO
J
Jolie
Julia
Keyman
Kotlin
LaTeX
Less
Liquid
Lisp
LiveScript
LOLCODE
Makefile
Markdown
Markup templating
MATLAB
MEL
Mizar
Monkey
N4JS
NASM
nginx
Nim
Nix
NSIS
Objective-C
OCaml
OpenCL
Oz
PARI/GP
Parser
Pascal
Perl
PHP
PHP Extras
PL/SQL
PowerShell
Processing
Prolog
.properties
Protocol Buffers
Pug
Puppet
Pure
Python
Q (kdb+ database)
Qore
R
React JSX
React TSX
Ren'py
Reason
reST (reStructuredText)
Rip
Roboconf
Ruby
Rust
SAS
Sass (Sass)
Sass (Scss)
Scala
Scheme
Smalltalk
Smarty
SQL
Soy (Closure Template)
Stylus
Swift
TAP
Tcl
Textile
Template Toolkit 2
Twig
TypeScript
VB.Net
Velocity
Verilog
VHDL
vim
Visual Basic
WebAssembly
Wiki markup
Xeora
Xojo (REALbasic)
XQuery
YAML
HTML
Paste Expiration :
[Optional]
Never
Self Destroy
10 Minutes
1 Hour
1 Day
1 Week
2 Weeks
1 Month
6 Months
1 Year
Paste Status :
[Optional]
Public
Unlisted
Private (members only)
Password :
[Optional]
Description:
[Optional]
Tags:
[Optional]
Encrypt Paste
(
?
)
Create New Paste
You are currently not logged in, this means you can not edit or delete anything you paste.
Sign Up
or
Login
Site Languages
×
English
Tiếng Việt
भारत