Pathogenesis And Endocytosis

Pathogenesis And Endocytosis
The proposed mechanism is that the mutated α–synuclein binds directly to the ER–Golgi SNARE
complex inhibiting its assembly (Gitler et al., 2008). Altering vesicle trafficking at any point inside
the cell can lead to an accumulation of proteins, which can have severe consequences for
dopaminergic neurons. The endocytic pathway is also important in the pathogenesis of Prkinson's
disease. Mutations in the cyclin G associated kinase (GAK) are important for endocytosis. Single
nucleotide polymorphisms (SNPs) have actually been identified that can be associated with risk
factors for sporadic Parkinson's disease (Nalls et al., 2014). A relationship between one GAK SNPs
and increased levels of the protein α–synuclein has been demonstrated on a ... Show more content
on Helpwriting.net ...
It is possible that α–synuclein causes the ER stress by interrupting the vesicular protein trafficking
and causing the ER to be overworked. It is also found that mutations in the parkin gene end up
forming aggregations of its own substrates in the ER, which leads to stress and death of dopamine
neurons (Imai et al., 2001). Other than the stress on the ER created by clusters of incorrectly folded
α–synuclein proteins, mitochondria that are functioning improperly can also induce stress on the ER.
Parkin is an E3 ubiquitin ligase responsible for regulating many cellular processes by tagging
proteins with ubiquitin for their destruction (Dawson and Dawson 2010). A loss of function
mutation in the parkin gene is seen to play a major role in altering the function of mitochondria
leading to stress on the ER (Bouman et al., 2011). Mutations in PINK1 (PTEN induced putative
kinase 1) affect pakin translocation and cause mitochondria to accumulate which increases the
vulnerability of dopamine neurons (Song et al., 2013). Along with this, muations in both the parkin
gene and PINK1 cause ER stress by increasing contacts between ER and dysfunctional
mitochondrial, which can lead to neurodegeneration (Celardo et al., 2016). In rare forms of heredity
Parkinson's disease, mutations in
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How Does Diabetes Mellitus Affect The Individual 's...
Metabolism is a sequence of biochemical reactions that take place in every single cell and organ to
maintain the organism growth, reproduction, damage repair, and adaptation to the surrounding
environment. These reactions involve catabolism and anabolism using the major sources of energy:
proteins, lipids, and carbohydrates. Furthermore, any disruption in the regulation of the metabolic
processes affects the individual's morbidity and mortality [1]. Accordingly, in this chapter, we are
going to discuss diabetes mellitus, which is one of the main metabolic disorders.
1.1.1 Pancreatic regulation of Blood Glucose
The regulation of the cornerstone of the whole body energy, glucose, in blood stream by the
pancreas, specifically the islets of Langerhans, is very critical through the secretion of insulin and
glucagon. Insulin, which is secreted from beta cells of the islets of Langerhans in response to high
blood glucose levels, has an anabolic effect via its stimulation of glucose uptake in peripheral,
skeletal muscle, as well as central, brain, tissues to be stored in the form of glycogen and fat [2]. On
the other hand, low glucose levels enhance pancreatic alpha cells secretion of Glucagon that plays
the catabolic role through stimulation of stored glycogen breakdown and formation of glucose from
non–carbohydrate sources via glycogenolysis and hepatic gluconeogenesis, respectively [2]. This
mechanism is well controlled through the opposite secretion of these hormones in response

Role Of Phosphorylation Of Second Messenger Dependent On...
1. What is the role of the phosphorylation of GPCRs in the process known as "receptor
desensitization?" First describe the process, or what is meant, by the term "receptor desensitization."
What does it mean when we say that the receptor is "uncoupled" versus "down–regulation" of the
receptor? Define and contrast the roles of the "second messenger–dependent" protein kinases versus
the "G protein–coupled receptor" kinases in the process of receptor desensitization. What do the
terms "homologous" versus "heterologous" desensitization refer to? (Ferguson, Pharmacological
Reviews 53:1–24, 2001; Gainetdinov et al., Annual Review of Neuroscience 27:107–144, 2004;
Vasudevan et al., Cell Cycle 10:3684–3691, 2011).
Receptor desensitization: ... Show more content on Helpwriting.net ...
This process called the "uncoupled". "Down regulation" means the receptor mRNA and protein
synthesis decrease and the preexisting receptor degradation. The "uncouple" and "down regulation"
are both involved in the receptor desensitization, but in different steps. These steps are following
described. First, the receptor uncouple from heterotrimeric G proteins; Second, cell surface
receptors internalize into intracellular membranous compartments; Third, receptor mRNA and
protein synthesis decrease result in the down regulation of the total cellular complement of
receptors, as well as both the lysosomal and plasma membrane degradation of pre–existing
receptors. There are two generally kinases which are G protein coupled receptor kinase GRKs and
second messenger–dependent protein kinases(e.g., PKA and PKC). The G protein coupled receptor
kinase only act on the phosphorylate agonist activate receptor. For example, GRK family members
work on activated receptors, and then promote the binding of cytosolic arrestins, which sterically
uncouple the receptor from heterotrimeric G protein. In contrast, second messenger–dependent
proteins kinases act on both phosphorylate agonist–activated GPCRs and other phosphorylates
receptors that have not been exposed to agonist. Thus, agonist–independent phosphorylation can
only happen with the second messenger–dependent protein kinases, but GRKs cannot do it. When
we recognize the

Essay on Biology Case Study
Advanced Cell Biology II Step 1: How will you identify the "vital" cellular protein that the virus
targets for degradation? (Hint: think proteomics). (3 pts.) First, since we know the viral RNA
sequence and its targeting protein, we can investigate it in bioinformatics database, and can acquire
some clues or hints about the target proteins. From the bioinformatics database, we might be able to
find its structure, similarity with other proteins, functions, and binding domains. In other words, we
can get some partial or complete amino sequences of the targeting proteins or information about
likeness. Second, in order to further confirm the information about characteristics and function of
the targeting protein that we have ... Show more content on Helpwriting.net ...
Since we have already known the amino sequence of the protein in previous step, we can narrow
down the targeting ubiquitin ligase based on existing research data such as papers, NCBI data. There
are many types of ubiquitin ligases in cells. However, we can make some candidate groups of
targeting E3 based on the bioinformatics database. We will use antibodies which specifically bind to
each type of ubiquitin ligase and impede its function. For example, the antibodies may covalently
bind to the targeting ubiquitin ligase, and therefore, impede its function. Then, we will measure the
amount of targeting protein. If we find that the amount of targeting protein is not changed in a cell,
we can identify the target ubiquitin ligase. This is because only when the function of the target
ubiquitin ligase is impeded, the degradation of the targeting protein will not be occurred. Step 3:
What protein will be your drug target? What property of that protein will you target? Design an
assay/approach to identify an antidote for "degron". (4 pts.) Since "degron" targets a vital cellular
protein for ubiquitin–dependent degradation, if we block its process of degradation, we can
effectively turn off its effect. As mentioned earlier, ubiquitin ligase brings specificity. Since we have
already known which ubiquitin ligase is

Turnover Mechanisms
Turnover mechanisms such as ubiquitination must be carefully regulated, as it is very significant in
metabolic regulation, and removing errors which arise during the transcription and translating
process, as well as protein activation and degradation which is necessary for some signalling
pathways. Proteins that are targeted for degradation use energy from ATP hydrolysis to form an
isopeptide bond between the targeted protein and ubiquitin. In addition, the activated carboxyl
terminal glycine of ubiquitin is covalently bonded to the ε–amino groups in multiple Lys located in
the protein.
Ubiquitin is composed of 3 enzyme units, which facilitate the breakdown of proteins into amino
acids, these are E1: ubiquitin activating enzyme, E2: ubiquitin–conjugating enzyme and E3:
ubiquitin–protein ligase. Once targeted proteins are marked by ubiquitin for degradation, a
proteasome will digest the protein and break it down into its constituent amino acids, while the
ubiquitin is cleaved off and recycled for future use. ... Show more content on Helpwriting.net ...
Proteins that are targeted for degradation use energy from ATP hydrolysis to form an isopeptide
bond between the targeted protein and ubiquitin. In addition, the activated carboxyl terminal glycine
of ubiquitin is covalently bonded to the ε–amino groups in multiple Lys located in the

Skeletal Muscle Myogenesis
Skeletal muscles are highly complex and heterogeneous tissues, serving a multitude of functions in
different organisms. The process of generating muscle myogenesis can be divided into several
distinct phases [40]. Ubiquitin–mediated protein degradation is one of the main mechanisms for
controlling proteolysis, which is crucial for muscle development and maintenance. Recently notch
signaling has appeared as a key player in skeletal muscle development and regeneration. Simply
stated, Notch signaling inhibits differentiation. Accordingly, fine–tuning the pathway is essential for
proper muscle homeostasis.Less is known regarding the functions of ASB proteins in muscle
development, although various ASB proteins are found to be expressed in the skeletal ... Show more
content on Helpwriting.net ...
Studies identified desmin as a new ASB2β target for proteasomal degradation in cardiomyocytes
suggesting accumulation of desmin could contribute to UPS impairment in HCM mice and patients.
Desmin is a muscle–specific, type III intermediate filament that integrates the sarcolemma, Z disk,
and nuclear membrane in sarcomeres and regulates sarcomere architecture[43]. Recently ASB2 was
found to be assisting in the ubiquitination of Notch targets such as E2A and Janus kinase 2 by
forming a non–canonical E3 ligase complex[44]. Jak2 is likely bound with ASB2, but bound with
E2A via F–BOX containing protein, Skp2, also known to associate with Skp1 and Cul1. Moreover,
ASB2 was activated by Notch signaling showing its involvement as regulator of Notch signaling. In
multicellular organisms, Notch signaling pathway is a highly conserved signaling pathway. In spite
of the fact that ASB2 is involved in degrading key proteins involved in cell proliferation and
differentiation, more studies are required to understand the variations occurring in the ASB2–
mediated ubiquitylation

Ubiquitin Lab Report
 INTRODUCTION: Ubiquitin is a small protein that is found in almost all cellular tissues in
humans and other eukaryotic organisms, which helps to regulate the processes of other proteins in
the body. Through a process known as ubiquitination or ubiquitylation, an ubiquitin molecule can
bind to a substrate protein, changing the way it functions. This can lead to a number of different
outcome. It is most widely recognised for its role in apoptosis of proteins, earning it the title of the
molecular "kiss of death" for proteins, although it also plays a major part in several other cellular
processes related to the regulation of proteins. Ubiquitin is a highly conserved 8.5 kDa protein that
is abundant in all types of cells and exists as a free molecule or ... Show more content on
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Ubiquitination requires three types of enzyme: ubiquitin–activating enzymes, ubiquitin–conjugating
enzymes, and ubiquitin ligases, known as E1s, E2s, and E3s, respectively. The process consists of
three main steps: o Activation: Ubiquitin is activated in a two–step reaction by an E1 ubiquitin–
activating enzyme, which is dependent on ATP. The initial step involves production of a ubiquitin–
adenylate intermediate. The E1 binds both ATP and ubiquitin and catalyses the acyl–adenylation of
the C–terminus of the ubiquitin molecule. The second step transfers ubiquitin to an active site
cysteine residue, with release of AMP. This step results in a thioester linkage between the C–
terminal carboxyl group of ubiquitin and the E1 cysteine sulfhydryl group. o Conjugation: E2
ubiquitin–conjugating enzymes catalyze the transfer of ubiquitin from E1 to the active site cysteine
of the E2 via a esterification reaction. In order to perform this reaction, the E2 binds to both
activated ubiquitin and the E1 enzyme. Humans possess 35 different E2 enzymes, whereas other
eukaryotic organisms have between 16 and

Pulsing Target Gene Induction
Some signal transduction systems produce multiple pulses of target gene expression in succession
when exposed to a constant level of stimulus (Levine et al., 2013) (Fig. 1.1B). Although pulsing is
similar to transcriptional bursting in that target gene expression levels increase and decrease
repetitively, pulsing is regulated by genetic circuits that activate and deactivate pathway output
regulators with a defined frequency and amplitude instead of relying on stochastic gene expression
(Levine et al., 2013; Raj and van Oudenaarden, 2008). Pulsing can be beneficial during signal
transduction by allowing cells to respond in ways that would be difficult to achieve with a simpler
response (Levine et al., 2013).
The response of p53 to double strand breaks in mammalian cells is a ... Show more content on
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In response to γ–irradiation mediated DNA damage, ATM kinase activates the tumor suppressor
protein, p53, via phosphorylation. Once activated, p53 initiates two negative feedback loops. The
first negative feedback loop is caused by p53 activating the expression of the E3 ubiquitin ligase
Mdm2, allowing Mdm2 to target p53 for degradation. The second negative feedback loop is the
result of p53 activating the expression of the phosphatase Wip1, which dephosphorylates p53 and
therefore reduces its stability. Wip1 also targets ATM kinase, which requires phosphorylation in
order to be in the active state. Therefore, the increased activity of Wip1 silences ATM kinase, which
prevents the activation of p53. If DNA damage persists in the cell, ATM kinase activates p53 once
more after Wip1 expression levels have subsided. Pulsing of p53 activity results in cell–cycle arrest
and DNA repair, and continues until DNA damage has been completely repaired.

Human Papillomavirus ( Hpv ) Family
Human papillomavirus (HPV) family is a subset of viruses characterized by their double–stranded
circular DNA in which the capsid is icosahedral. About 150 HPV types have been isolated and
entirely sequenced. According to the homologous nucleotide sequence of the major capsid protein
(L1), the HPV types are categorized into different genera namely: Alpha genus, beta genus, gamma,
mu, and nu in addition to HPV types with a skin tropism that appears to be linked with the growth of
benign cutaneous lesions. There are approximately 30 HPV types included in the alpha genus which
characterized by their ability to infect the mucosa of the genital and oral tract as well as several
benign cutaneous HPV types that are associated with the development of common skin warts. The
(alpha) HPV types are divided according to their oncogenic potential into two groups: low–risk(LR)
HPVs (e.g. types 6 and 11) and high–risk (HR) HPVs. The former group is mainly associated with
benign genital warts and the latter group contains viruses considered to be the etiological agents of
cervical as well as head and neck cancers. Dozen of different HR HPV types: 16, 18,31, 33, 35, 39,
45, 51, 52, 56, 58, and 59 were categorized by the International Agency for Research on Cancer
(IARC) as carcinogenic to humans.
The genomic organization of all HPV family members is typical, with 8 or 9 open reading frames
(ORFs) found on the same DNA strand. The HPV genome can be divided into three different
regions: (1) a

The Formation Of Cellulose Fibrils Essay
Other genes like chvA, chvB, pscA and att regulate the formation of cellulose fibrils which are
required for the first step of weak and reversible attachment. Cellulose fibrils help the bacteria to
attach to the wounded parts of the plant and also anchoring to each other forming a microcolony.
VirD4 protein and 11 VirB proteins make up type IV secretion system for the transfer of T–DNA
and several other Vir proteins like VirE2, VirF etc to the host cell. VirD4 also promotes interaction
of the processed T–DNA/VirD2 complex. As discussed earlier the T–DNA/VirD2 complex in turn
transforms into the T–strand that is then transferred into the plant cell. Most VirB proteins help
either in forming the membrane channel or serve as ATPase to provide energy. T–pilus is then
formed by VirB2 ,VirB5, VirB7, VirB2 as they are the major pilin protein.
So the first major step in the transfer of T strand is the formation of a long flexious appendage
known as the T–pilus (Bulgakov, 2000) . The detection of presence of acetosyringone and other
substances activates the expression of 11 genes in VirB operon which are responsible for the
formation of the T–pilus. Other products of VirB genes like VirB6, VirB7 etc are used to transfer
other subunits across the plasma memebrane.
Now the T–DNA is delivered as a single stranded DNA molecule coupled with the VirD2 protein in
the plant cell. The T–DNA is then integrated into the plant chromosome and are expressed by plants
transcriptional machinery.

Characterization Of Cin1
Given the conserved nature of intracellular trafficking, Cin1 appears to be unique to Cn, as a Cin1
homolog was not found in Sc nor Ca. Likewise, a Pan1 homologs was not found in Cn. However, by
reciprocal BLASTp search, several proteins with significant homologies to proteins participating in
Sc and Ca Pan1 pathways were identified {Wang, 2011 #5646}. Among them, an EH protein
homologous to Sc Ede1 was selected for further analysis as Sc Ede1 is one of the key partners of
Pan1. Characterization of the Cn Ede1 homolog and examination of its interaction with Cin1 will
reveal whether Cin1 mediates the only endocytic pathway or there are additional endocytic
pathways in Cn. In addition, to analyze if Cin1 and Ede1 affect protein trafficking ... Show more
Cn Ede1 is predicted to encode a 1593 AA protein with three N–terminal EH domains and one C–
terminal ubiquitin–associated (UBA) domain. An ede1 mutant has been generated in preparation for
this proposal, and the initial examination indicated that the ede1 mutant has a defect in early
endocytosis while maintaining normal morphology (Fig. 4B), suggesting functional similarity to Sc
Ede1. A WT gene complemented strain (ede1 EDE1) will be generated and further phenotypic
characterization for growth, mating, endocytic transport, and virulence characteristics will be
performed. An ede1 cin1 double knockout mutant will also be generated through a second knockout
approach. The double mutant strain will be compared to single gene knockout strains if obtained. To
examine Cin1 and Ede1 interaction, a yeast two–hybrid (Y2H) screen will be performed first,
followed by validation with co–immunoprecipitation (IP). Here, only the fusion constructs specific
to Ede1 homolog are needed, as the pGADT7–CIN1 fusion construct was constructed and used
previously in our lab {Shen, 2010 #5449; Shen, 2011 #5640; Shen, 2012 #5719}. These tests will
help to determine if Cn evolves a unique Cin1–Ede1 endocytic pathway or more than one endocytic
pathways are present.
1b. Comparative examination of Cin1 and Ede1 in membrane trafficking by LOPIT.
Endomembrane trafficking includes the transport of integral membrane resident proteins and
peripherally associated proteins that are

Functions of Ubiquitin Specific Proteases Essay
Eukaryotic cells rely on the ubiquitination of proteins for the proper control of their internal
processes. Adding multiple ubiquitin groups aids in the breakdown of proteins, whereas adding only
one ubiquitin serves regulatory roles other than degradation. The enzymatic activity of two protease
classes frees ubiquitin groups from associated proteins: Ubiquitin specific proteases (USP) and
Ubiquitin C–terminal hydrolases (UCH). USPs are strongly involved in eukaryotic cellular functions
and are found in copious amounts. Certain protein ligases attach ubiquitin to proteins, which
degrades them and interferes with normal cellular functions. The discovery of a specific de–
ubiquitinating enzyme (HAUSP/USP7) found in humans was due to its ... Show more content on
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The labels associated with the resulting proteins from previous steps were rinsed and removed.
USP7 was purified and utilized in sedimentation trials in varying concentrations. Absorbance
analysis was carried out after the samples were centrifuged. EBNA1 was purified, ubiquitinated, and
combined with USP7, which was purified in previous steps. SDS–PAGE was used to disrupt the
protein interaction and separate them. The separated fragments were then used in a western blot, and
analyzed after probing. The affinity of USP7 for EBNA1 and p53 was tested using a stepwise
combination of titration, incubation, and fluorescence analysis. Lastly, amino acid residues of
EBNA1and USP7 were studied by gel filtration and size–exclusion chromatography. USP7 was
found as hexahistidine fusion after being inserted (through a vector) in insect cells. The de–
ubiquitinating capacity of USP7 for conjugated ubiquitin groups was observed on EBNA1, and was
shown to an efficient process. The capacity of USP7 to de–ubiquitinate specific proteins in various
environments (acidity, presence of inhibitors, and salt concentration) was studied. As seen in figure
2, USP7 sensitivity to salt concentration and acidity showed a steep slope followed by a plateau at
lower salt concentrations and higher pH levels, while lower pH and higher salt concentrations
rendered a steeper, less plateau–like graph. USP7 was found to be a monomer with multiple
domains, each involved

Regulation and Functions of the p53 Protein
p53 gene, also known as tumor protein 53 (TP53), encodes for a tumor suppressor protein which
regulates the cell cycle and apoptosis. The p53 protein has been described as the guardian of the
genome (1) because of its role in preventing genetic mutation. It belongs to a protein family which
includes p53, p63 and p73 and these are structurally and functionally related to each other. However,
p53 seems to have evolved as a tumor suppressor in higher organisms, while p63 and p73 play a role
in normal developmental biology (2).
Structure of p53
P53 functions primarily as a transcription factor, and is biologically active as a homo–tetramer
comprising of 4 X 393 amino acid residues. Each monomer comprises of several functional
domains:
1. An acidic N–terminus transcription–activating domain 1 and 2 (TAD1/2) – This region interacts
with various transcription factors
2. Proline–rich region (PRR) – This plays a role in p53 stability
3. Central DNA binding domain (DBD) – required for binding to specific sites on the DNA.
4. Tetramerization domain (OD) – required for the assembly of the functional tetramer.
5. Carboxyl terminus domain (CTD) – which is bound to DNA binding domain and is involved in
negative modulation of DNA binding domain.
The central DNA binding domain is the most highly conserved region of p53, when compared to its
other family members, p63 and p73. Loss of tumor suppressor function of p53, as seen in most
cancers, results from missense mutations in the DNA

Why The Hpv E6 Oncoprotein With The Help Of Bioinformatics...
Purpose of the project: The purpose of the project is to understand the HPV E6 oncoprotein with the
help of bioinformatics tools like Rasmol, Blast, ClustalW, Prosite and Palign.
Introduction: Human Papillomavirus commonly called as HPV has been known to cause genital
infections in males and females. It is a DNA virus from the papillomavirus family and one of the
most common virus that are known to cause tumors. There are about more than 120 different viruses
but only about 40 of them are transmitted sexually. HPVs usually infect the mucosal membranes and
different sites in the body like skin, mouth, throat and genitals.
HPVs are divided into two different categories low–risk and high–risk depending how they behave
overtime. 'High–risk' mucosal HPVs are the causative agents of cervical cancers, with HPV16 and
HPV18 being the most common oncogenic types associated with 50% and 20% of the carcinomas
respectively (Bosch et al., 1995). There are two viral protein that causes the degradation of the
tumor suppressor genes; E6 and E7. These two protein work together to cause the tumor by
destroying the host machinery. E6 oncoprotein has the capacity to block apoptosis, changes the
function of several proteins and thereby modifying the signals of the cells. One of the major
function of the E6 protein is to target the p53 (a tumor suppressor protein), it inactivates and recruit
the E3 ubiquitin ligase E6AP (Huibregtse et al., 1991; Scheffner et al., 1993) by binding to a
conserved

Ubiquitin Lab Report
Cell homeostasis is a complex yet strictly regulated by many regulators. Different from big role–
player such as enzymes in many signaling pathways, the universal consensus of small regulator
ubiquitin contributes a great length to the of the complex post translational regulating protein
system. Consisting of 76–residue protein, ubiquitin not only highly expresses in cell for various
signal transduction pathways, it also is one of the most resilience and packed protein that is highly
conserved among the eukaryotes[1]. Ubiquitin is firstly produced intracellularly as precursor fusion
protein chain consisting polyubiquitin or ubiquitin fused to amino–terminus of Ribosomal protein
40S and 60S units; the generation of free ubiquitin from these precursor ... Show more content on
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The de–ubiquitinase (DUB) will cleave this precursor into free monomer ubiquitin molecules and
can be activated and attached to the target protein through ATP dependent process called
ubiquitination with the help of activating enzyme E1, conjugating enzyme E2, and ligase E3.
Through forming (iso)–peptide, thioester, or ester bond between carboxyl groups of C–terminal
glycine 76 on ubiquitin and the ε–amino group of the lysine, cysteine, serine/threonine on the
substrate, respectively, the poly–ubiquitin chain is formed [3]. Based on the different internal Lysine
(Lys6, Lys11, Lys27, Lys29, Lys33, Lys48, and Lys63) and on the proximal ubiquitin, the (iso)–
peptide bond can be form with another ubiquitin, distal mono–ubiquitin [4, 5]. Consequently, seven
conventional poly–ubiquitin chains resulting in different 3–dimentional shapes explaining its
different characteristics inherited upon binding to the target protein [5, 6]. With ranging more than
500 putative E3 ligases exist in human, the E3 ligase will tag the poly–ubiquitin chain to the target
protein with high specificity

The Bottleneck Effects: The Bottleneck Effect
Genetif Drift3,4 A certain characteristic could vanish within a population. A generation could miss a
few genes into their descendants, and only certain genes is kept. This phenomena is called genetic
drift. Genetic drift is the fluctuation/ alteration of gene frequency. Like in the population of
wildflower, if the allele Cw is decreasing than CR allelle , there may be two possibilities. One, an
animal may stepped on the plant containing Cw allele and reducing its chance to pass it to the next
generation, or in fertilization it simply have few offspring, that by chance contain more CR allele
than Cw. there are 2 known concepts of genetic drift the bottleneck effect and the founder effect.
The Bottleneck Effect The bottleneck effect is the ... Show more content on Helpwriting.net ...
But these slight changes will accumulate overtime to produce a new strains of viral genetic
information that could not be recognized by the host antibodies. That is why we could develop flu
symptoms every time we catch a flu. Because their antigenic properties changes all the time, that is
why different flu vaccines is needed and flu vaccines is developed and changed each year. If a virus
can originally infect one species and then infect another, antigenic shift usually play a part in that
process. Antigenic shift occurs if there is a major changes in the genetic sequence of a virus in a
short amount of time, not accumulation of mutation overtime like in antigenic drift. Antigenic shift
cause the change in the hemagglutinin and/or the hemagglutinin and neuraminidase The example is
in the virus H1N1, that originally infect birds. The mechanism of antigenic shift happen in 3 ways:
Theory 1 1. if the animal (chicken/ duck) are infected by Influenza A virus from birds and also from
human viral strain 2. the genes from both virus can combined and produced a new strains of virus
Theory 2 The bird strain of influenza A can directly passes the influenza virus to humans without
changing the genetic

Pan1 And Genetic Domain Structures
In contrast to Sc, Ca, and Mo that share the Pan1–Las17/Bee1 endocytic pathway, Cn appears to
adopt a distinct Cin1–Wsp1 endocytic pathway for transport, growth, and virulence [22]. Both Cin1
and Wsp1 display domain structures similar, but not identical, to human ITSN1 and WASp than to
Sc/Ca Pan1 and Las17/Bee1 [23, 24]. These findings suggest a unique intracellular transport process
occurring in Cn and raise several important questions. As endocytic proteins function by interacting
with other partner proteins, what are the other binding partners of Cin1 in the pathway? Does Cin1–
mediated endocytic pathway contribute to specific virulence characteristics? We are uniquely
positioned to address these critical questions.
In terms of domain ... Show more content on Helpwriting.net ...
The intriguing finding that Cin1–S confers a CNS survival advantage provides a novel avenue to
probe the CNS propensity of Cn. Finally, given the importance of exRNA in intercellular cellular
communication, it is tempting to speculate that Cin1 regulates uptake and export of exRNA to play a
role in host–pathogen interactions and pathogenesis. Because of our recent advances, we believe we
may possess an unprecedented system to probe the mechanism of pathogenesis in Cn.
C. Approach Cn is a haploid budding yeast with a well–defined life cycle. It also has proven to be a
tractable research model in which classical and molecular approaches, as well as both in vitro and in
vivo models, are available for studying host–pathogen interactions and pathogenesis. In addition,
genomic and proteomic approaches including microarray, whole transcriptome shotgun sequencing
(RNA–Seq), and proteomics have all been employed to study pathogenesis of Cn [35–37]. This
well–established model organism and available research resources will be invaluable for us to
pursue our research goals.
In Cn, Cin1 is required for the endocytic transport of the lipophilic styryl dye FM4–64, normal
morphology, proper localization of a Lac1–DsRed fusion protein, mating, and the production of
capsule, urease, and phospholipases [22]. Cin1 also regulates the actin cytoskeleton upstream of the
WASp homolog Wsp1 and Cdc42 [23, 24]. This pleiotropic function is

Muscle Atrophy Research Paper
Cellular and Molecular Mechanisms of Muscle Atrophy
The Ubiquitin–Proteasome System The ubiquitin–proteasome system is needed to rid muscles of
sarcomeric proteins when there are muscle changes. "A decrease in muscle mass is associated with:
(1) An increased conjugation of ubiquitin to muscle proteins; (2) an increased proteasomal ATP–
dependent activity; (3) increased protein breakdown that can be efficiently blocked by proteasome
inhibitors; and (4) upregulation of transcripts encoding ubiquitin, some ubiquitin–conjugating
enzymes (E2), a few ubiquitin– protein ligases (E3) and several proteasome subunits" (Lecker et al.,
2006, p. 25). Muscle atrophy is best defined as an active process that is controlled by a specific set
of signaling pathways ... Show more content on Helpwriting.net ...
A., Bedard, N., Baracos, V., Attaix, D. and Wing, S. S.
(2005). USP19 is a ubiquitin–specific protease regulated in rat skeletal muscle during catabolic
states. Am. J. Physiol. Endocrinology and Metabolism. 288, E693–E700.
Judge, A. R., Koncarevic, A., Hunter, R. B., Liou, H. C., Jackman, R. W. and
Kandarian, S. C. (2007). Role for IkappaBalpha, but not c–Rel, in skeletal muscle atrophy.
American Journal of Physiology: Cell Physiology. 292, C372–C382.
Lecker, S. H., Goldberg, A. L. and Mitch, W. E. (2006). Protein degradation by the ubiquitin–
proteasome pathway in normal and disease states. Journal of the American Society of Nephrology.
17,1807–1819.
Mittal, A., Bhatnagar, S., Kumar, A., Lach–Trifilieff, E., Wauters, S., Li, H.,
Makonchuk, D. Y., Glass, D. J. and Kumar, A. (2010). The TWEAK–Fn14 system is a critical
regulator of denervation–induced skeletal muscle atrophy in mice. The Journal of Cell Biology. 188,
833–849.
Mizushima, N., Levine, B., Cuervo, A. M. and Klionsky, D. J. (2008). Autophagy fights disease
through cellular self–digestion. Nature. 451, 1069–1075.
Narendra, D. P. and Youle, R. J. (2011). Targeting mitochondrial dysfunction: role for
PINK1 and Parkin in mitochondrial quality control. Antioxidants and Redox Signaling. 14,

Dna Ligase Essay
In humans, three major types of DNA ligases are reported: DNA ligase I (hligI), DNA ligase III
(hligIII) and DNA ligase IV (hligIV). hligI plays an important role in DNA replication by joining
Okazaki fragments on the lagging strand of DNA. Apart from this it also plays important roles in
DNA damage repair pathways, single strand breaks are repaired by nucleotide excision repair (NER)
and base excision repair (BER) pathways. Results of preclinical studies support that Human DNA
ligases are an attractive target for the development of new anticancer agents for selective inhibition
against rapidly proliferating cancer cells. In this mini–review, we will provide a brief discourse of
the recently reported human DNA ligase inhibitors as ... Show more content on Helpwriting.net ...
Pyridoxal phosphate (PLP, 1) binds to AMP–binding site of AdD which may lead to inhibition of
human DNA ligase I (hligI). Nucleoside analogs such as 9–β–D–arabinofuranosyl–2–fluoroadenine
(F–ara–ATP, 2), and distamycin A (3) and its phenyl mustard derivative (FCE24517, 4),[3,4] that
have been reported to inhibit the adenylation step of ligation at high micromolar concentrations (Fig.
4).
Fig. 4: Structures of hligI Inhibitors: Binds AMP–binding site of AdD The DNA binding domain
(DBD) of human ligase interacts with the minor groove of DNA, Adenylation domain (AdD),
oligonucleotide/oligosaccharide binding–fold (OB–fold) of hLigI and it stimulates the DNA end–
joining activity of the catalytic core.[2, 5] Thus, inhibition of DNA ligation can be accomplished by
targeting the DBD with specific inhibitors. Some ligase inhibitors that target the DBD, inhibit the
transfer of AMP from Ligase to the 5'–phosphate of nicked DNA. L67 ((E)–2–(3,5–dibromo–4–
methylphenylamino)–N'–(2–hydroxy–5–nitrob enzylidene) aceto hydrazide) (5) inhibits the second
step of ligation by hLigI and hLigIII in a competitive manner (IC50–10 ± 3 μM for hLigI and
hLigIII) and L189 ((E)–6–amino–5–(benzylideneamino)–2–mercaptop yrimidin–4–ol) (6) inhibits
the second step of ligation by hLigI, hLigIII, and hLigIV in a competitive manner (IC50 values of 5
± 2, 9 ± 2, and 5 ± 2 μM against

Cystic Fibrosis Analysis
To understand the effects that Cystic Fibrosis has, it is important to discuss CFTR synthesis and
trafficking. Mutations in the CFTR results in protein misfolding, causing a defect in cellular
processing and trafficking that targets the protein for degradation and reduces the quantity of CFTR
at the cell surface [56]. In order for the CFTR to function correctly, then it must be synthesized,
folded, and transported to the apical membrane of the cell without problem. The CFTR passes
through quality control systems to get rid of misfolded proteins that would not function properly or
that could become damaged [16]. It is apparent that only 33% of CFTR folds correctly and is
allowed to leave the endoplasmic reticulum [8]. The nucleus is the site ... Show more content on
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One system detects defects in the cytosolic parts of the CFTR while the other detects defects within
the endoplasmic reticulum membrane. It is apparent that ubiquitylating proteins work with specific
factors in order to detect misfolding. For example, Hsp70 detects mutations in the cytosolic regions
of the CFTR. It is suspected that Hsp70 keeps the CFTR soluble until the E3 ligase CHIP binds with
it. The complex that forms between these two redirects the CFTR to the degradation pathway.
Derlin–1 is involved with detecting defects in the endoplasmic reticulum membrane and is involved
in the retro–translocation of CFTR from the endoplasmic reticulum so that it can be send to the
proteasome for degradation [20]. If the CFTR protein is folded correctly within the endoplasmic
reticulum, then it is sent to the Golgi apparatus. The coat protein complex II (COPII), which is
found within the ER membrane, helps to maintain the correct CFTR structure and location,
conformation, and protein–protein interactions as this occurs. Final processing for the CFTR is
carried out within the Golgi, as the CFTR replaces a mannose–enriched side chain with a mature
complex oligosaccharide side chain. After this is completed, the CFTR is moved to the apical
membrane where it has a half–life of 12 to 24 hours. If a CFTR is functioning poorly within the
membrane, then it can be recognized by Hsc70 and then

Gardner 's Respiratory Virus ( Grv )
Gardner's Respiratory Virus (GRV) is an enveloped, single–stranded RNA (ssRNA) virus that has
been shown to cause both upper and lower respiratory tract infections. This virus is an intracellular
virus capable of replicating free within the cytoplasm of host cells. Spread through small, airborne
viral droplets, GRV invades the physical barrier that is the mucosal surface lining the lungs and
respiratory tract. The cells that line this surface are mostly epithelial cells, and GRV enters these
cells by being transported across their membranes through receptor mediated endocytosis. Once
inside the host cell, GRV replicates and begins its cytopathic effects on the host cells; the infected
epithelial cells undergo structural changes that lead to irritation, inflammation, and eventual lysis
that can weaken these mucosal surfaces, making the host more susceptible to further pathogenic
attack. As with similar viruses, once the first line of defense is breached and GRV is transported into
the host cells, the immune response, involving both the innate and adaptive branches of the immune
system is initiated and attempts to remove the virus as well as prevent future infection. GRV
however, is highly evolved and possesses various evasion mechanisms that prevent the immune
system from accomplishing its job; luckily, a drug does exist to help eliminate the virus.
Expected Immune Response The innate immune response is meant to prevent further invasion and
replication of the pathogen

Causes Of Neurogenesis Of Autism
Neurogenesis of Autism
Molecular switching on/off due to genetic mutation is one of the causes of developing Autism. In a
new study, neurogenesis mechanism which increases the risk of development the autistic spectrum
disorder has been explored.
UBE3A gene encoded an enzyme in human named Ubiquitin–protein ligase E3A. Changes in this
gene may cause different neurodevelopmental disorders including Autism and Angelman syndrome.
Autism is a genetically heterogeneous disorder associated with synaptic deficits, social impairment,
and stereotyped behaviors. For a number of years, researchers in genetic science have been
exploring so many gene mutations in patients with autism and their families but how these
mutations affect protein function or contribute to disease was unknown. It is therefore welcome
news that recent study explored the molecular mechanism that seems to underlie autism disorders. ...
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Based on the new version (2013) of Diagnostic and Statistical Manual of Mental Disorders (DSM–
5), Autism Spectrum Disorder (ASD) is a complex developmental disorder that can cause problems
with thinking, feeling, language and the ability to relate to others. The effects this neurological
disorder, which is due to the malfunctioning of the brain are different in each person . The concept
of autistic spectrum disorder is broad, and not restricted to the classic clinical picture. ASD
Characteristics in DSM–5 changed from triad (social, communication, behavioral) into a dyad by
combining the social and communication domains and it showed the importance of these

Liddle's Syndrome
4.2.0 Mutations: As was previously outlined, the cause of Liddle's syndrome is from ENaC over
presenting in the ASDN due to a mutation to the channel is the cause of Liddle's syndrome. It has
been shown that mutations on the gamma and beta subunits are responsible for the gain of function
in the ENaC. No mutation has been observed yet for the alpha subunit. Mutations occur at the level
of the gene for the beta and gamma subunit and cause either missense, nonsense or frameshift
mutations in the mRNA of the PY motif for ENaC(ref). This results in either a truncated protein or
elimination of some amino acids from the PY motif, which interfere with the binding ability of
Nedd4 ligase and inhibit Nedd4 ligase binding, respectively. Overall, this either decreases or
eliminates the possibility of Nedd4–2 ligases' ability to tag and degrade the ENaC. With the inability
to control ENaC surface expression at the kidney, its reabsorption of sodium will be markedly
increased due to ... Show more content on Helpwriting.net ...
As has been discussed, an inheritable mutation in genes coding for the beta and gamma subunits of
the ENaC, causing deletion or truncation of the PY motif leads to a disruption in ENaC
ubiquitination. Ubiquitination itself is the process of tagging a protein with a series of glycosyl
subunits, signalling its degradation at the proteasome, destroying the channel. With this inhibition in
ubiquitination, ENaC is expected to and is seen to have a much larger surface expression and
channel open probability, leading to an overall increase in sodium reabsorption which causes the
characteristic symptoms of Liddle's syndrome. Through understanding the two major regulatory
mechanisms at the levels of protein trafficking of the ion channel and protein–protein interactions
with the channel itself, better methods of control and a better understanding of Liddle's syndrome
can be

Acute Myeloid Leukemia
Acute myeloid leukemia (AML) is a type of cancer that is defined by permeation of the bone
marrow, blood, and other tissues by proliferative, clonal, abnormally differentiated, and occasionally
poorly differentiated treated cells of the hematopoietic system(1). The dynamic interaction between
leukemia cells and the bone marrow microenvironment is one of the characteristics of leukemia. The
important components of the bone marrow environment include tumor cells, extracellular matrix,
non–tomur cells (fibroblasts, stromal cells, immune cells) and hypoxia(2). It is well– known in solid
tumors that the excessive proliferation of tumor cells causes a severe hypoxia, which can lead to
tumor progression. In the hematologic malignancies, there is the ... Show more content on
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Angiogenesis refers to the formation of new blood vessels from the previous arteries(11). Studies
have shown that tumor development and invasion in solid tumors are associated with angiogenesis,
and recent evidence suggests that angiogenesis may be in the development of acute myeloid
leukemia(12). In acute myeloid leukemia, angiogenesis directly contributes to the tumor progression
by the provision of necessary factors for blast proliferation as well as through angiogenic
factors(13)..significant angiogenic factors include VEGF–A, BFGF, PDGF, FGF, in which among
them VEGF–A is the most important. Furthermore the angiogenesis, VEGF–A has other functions in
the progress of leukemia cells, which performs these functions by autocrine and paracrine loops.
When VEGF–A binds to its receptors on leukemia cells it stimulates proliferation in these cells and
also increases survival by reducing apoptotic proteins (autocrine).

Ubiquitination: An Unneeded Protein Analysis
You are a frustrated student who has a big biochemistry test tomorrow, but no time to look over
material because he have to work at Kroger tonight until closing because you used up all your sick
days. Your annoying boss tells you there is a shipment of new milk and meat products coming in and
the old, expired products must be removed. He gives you bright green stickers to stick onto the
expired products that need to be removed from the shelves. As you are doing this, you start to think
about your test and try to apply biochemistry to real–life situations, but to no avail. You get more
frustrated and contemplate quitting your job right there. Suddenly, you think about the word 'quit'
and realize you have to know about ubiquitin for tomorrow's test. You remember one of ubiquitin's
many roles is to tag an unneeded protein for its destruction. Then you start realizing that labeling
stickers on expired products so they can be removed in a supermarket is like ubiquitin labeling old,
outdated proteins in our cells so they can be removed for the proteins still needed ... Show more
The protein usually targets old, dysfunctional proteins from the cell cycle, which makes sense for
controlled cell division. The ubiquitination mechanism was originally obscure, but made more clear
in the mid–1980's by Aaron Ciechhanover, Avram Hershko, and Irwin Rose, which helped them win
the Nobel Prize for Chemistry in 2004 (Nobel Prize website). Initially, the process was looked at as
proteolytic system utilizing ATP. Many ATP–dependent proteolysis factor 1 (APF–1) molecules
linked with a substrates that were later found to be deteriorated with free APF–1 in the cellular
extract (Ciechhanover, 2012). APF–1 was called ubiquitin and it uses its C–terminal glycine to
conjugate to the substrate's

Angelman Syndrome
There are many diseases and syndromes that occur in the developmental stage of human
development. One of the many syndromes is Angelman syndrome. When this syndrome was first
discovered by Harry Angelman, it was known as "happy puppet syndrome". This syndrome is not
typically diagnosed at birth, but can also be diagnosed from the ages of one to six. This syndrome is
a neuro–genetic disorder that occurs in one in 15,000 people. Because of its rareness, this syndrome
is often misdiagnosed as autism or cerebral palsy. Make thesis– Angelman syndrome is caused by a
defect in the UBE3A gene, has various symptoms, that can be misdiagnosed, and patients will live
with lifelong treatment. The are various causes of Angelman syndrome, but the main cause ... Show
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Angelman syndrome can be diagnosed within the first year of the life if the abnormalities are
noticed and investigated, but the disorder is more often diagnosed between 1 and 4 years of age as
the child's abnormalities become more clinically apparent (Bevinetto). In order to confirm the
diagnosis, a blood test must be done to look at the child's genetics (Angelman). Then, a combination
of genetic test can reveal the chromosome defects. There are three different defect tests may reveal:
parental DNA pattern, missing chromosome, or gene mutation. Parental DNA pattern test screens for
three of the four genetic defaults that cause this syndrome. To find out if the chromosome is missing
either a fluorescence in situ hybridization (FISH) test or a comparative genomic hybridization test
(CGH) can show if portions of chromosomes are missing. It is rare if Angelman syndrome occurs
with only a gene mutation. This happens when the UBE3A gene is present and active, but mutated.
A UBE3A gene sequencing test is used to look for maternal mutation (Mayo). After the diagnosis is
complete, treatments are discussed with the patient and their

Dna Synthesis Case Study
To achieve accuracy of DNA replication after the unwinding of DNA, the DNA must be
synthesized. DNA synthesis, in the case, the two strands are disconnected and then turned into
single–stranded DNA. This is called replication fork. The replication fork acts as a model for DNA
synthesis. However, the site of impaired or mutated DNA can cause a lower rate pf success for DNA
synthesis. Impaired DNA can also lead to unprocessed and unligated okazaki fragments. Okazaki
frgaments are small DNA fragments that are linked to the lagging strand of DNA. The research
article suggest that okazaki fragemts should be tracked for the benefit of cancer patients. For
instamce, the lack of DNA ligase 1 is caused by the delay of okazaki frgaments. DNA ligase 1 ...
An ubiquitin can change the way a cell functions or even where the call is located. The researchers
then use a cdc9 with a wild–type of DNA ligase 1 to determine whether PCNA ubiquitination
happens because of the nicked DNA or because of the lack of PCNA–DNA ligase interaction. While
reviewing this, they noticed that the cdc9 mutants come to a halt during the later phases of the cell
cycle and they collect unligated okazaki fragments. THis proves that PCNA ubiquitination occurs
because of the nicked DNA. The nicks are left behind for repairin the last phase of the cell cycle,
G2. Although they discovered this, they alos discovered that breaks in the DNA were present in the
cdc9 mutants. They caused the replication forks to be held up. These breaks need to be repair via
HR. To repair the breaks they suggest RAD52 to be used. Unfortunately, RAD52 was unsuccessful
and did not interact with the mutant. They then test if RAD59 can be used to repair the breaks. THey
recognize that RAD59 played an important role in supporting the kinase needed for checkpoint
activation of the cell cycle, known s Mec1. However, RAD59instead deactivated Mec1 by
restraining a protein coding gene called

The Von Hippel-Lindau (VHL) Gene
The Von Hippel–Lindau (VHL) gene was first discovered as a tumor suppressor gene in 1993 by
Latif, et al. (1). The gene was identified in an attempt to determine the driver of tumorigenesis in
Von Hippel–Lindau Disease. VHL disease is an autosomal dominant hereditary cancer syndrome
that is characterized by tumor and cyst formation throughout the body, with those infected especially
predisposed to hemangioblastomas of the central nervous system, eyes, pancreas, and kidney. Latif,
et al. were able to match the gene region to chromosome 3p.25–26 by positional cloning and created
a map of the region using pulsed–field gel electrophoresis in order to isolate the prospective genes.
The DNA of 221 VHL patients was then probed using specified plasmids to determine that there
were 28 rearrangements present, with three large non–overlapping deletions detected in the
hypothesized VHL gene segment. This sequence was conserved across different species, with
implications of its necessity for normal cellular function, pointing to its role as a tumor suppressor.
Since part of the sequence of the protein product (pVHL) also matched (48%) to that of a surface
membrane protein sequence in Trypanosoma brucei, pVHL is thought to have some role in signal
transduction or cell adhesion as well.
The VHL gene itself is made of three exon segments located on chromosome 3p25. Patients with
VHL syndrome are heterozygotes of the VHL gene, with one allele that is a mutated or inactivated
copy of the

Alzheimer 's Disease : The Most Widespread Age Related...
Alzheimer's disease (AD) and Parkinson's disease (PD) are the most widespread age–related
neurodegenerative diseases. Both diseases impact a considerable number of people, where AD
occurs in around 10 percent of the population greater than the age of 65 while PD occurs in roughly
1 percent of the population above the age of 65. AD is considered to be the most widespread cause
of dementia, characterised by the progressive memory and cognitive deficits which impair ones day
to day activities. The pathological hallmark of AD comprises of extracellular accumulation of senile
plaques consisting of mainly amyloid–beta (Aβ) peptides, along with neurofibrillary tangles which
are composed of the phosphorylated tau protein, located in the hippocampus and cortex. Conversely,
PD is considered to be the most widespread movement disorder that is characterised by symptoms
such as rigidity slow movements, resting tremor and other instabilities. The extreme loss of
dopaminergic neurones in the substantia nigra is what defines PD, as the loss of this nerve cell can
be linked to Lewy bodies containing aggregates of a soluble protein called α–synuclein. The
aggregation of prion proteins and their transmissibility from one cell to another has been shown to
be evident (Cushman et al.; Goedert et al. 2010), therefore strongly suggesting that these events may
play a role in pathogenesis for many diseases, including both AD and PD. While none of these
diseases is infectious in an identical way as

Research Paper On Angelman Syndrome
Angelman Syndrome is a hard disease affecting the nervous system. It is a lot of work to go through
to have this syndrome. This disease is another story. Kids with this syndrome have side–to–side
curvature of the spine. This disorder causes development disabilities and nerve–related symptoms.
This syndrome is most often caused by problems with a gene located on chromosome 15 called the
ubiquitin protein ligase E3A (UBE3A) gene. Typically, kids are happy, excitable demeanor, with
frequent smiling, laughter, and hand flapping movements, difficulty sleeping, and problems with
movement and balance. Kids with this disease have distinctive facial features. This disease is
noticeable by the age of 6 to 12 months. Parental DNA pattern test is a test

Sequence And Sequence Of Proteins
Sequence Information of Proteins
Just as members in the same family often resemble each other, similarly structured molecules are
often grouped in the same category. There are several methods of comparing amino acid sequencing
and determining how closely they are related. A simple example is the sequence–comparison
method. Sequence databases are searched for a specific amino acid sequence of unknown
characteristics. A set of molecules that are similar in structure can give insight into the properties of
the unknown sequence of amino acids.
To determine the similarity between 2 amino acid sequences, one can apply sequence alignment.
This method aligns the 2 sequences and slides them past each other one amino acid at a time and
calculates what position has the greatest amount of matched residues. However, there is a drawback
to this method in that it does not show all of the possible alignments. To counteract this, one can
induce a gap in one of the sequences to increase the total possibilities of matches. The gap will
compensate for the insertions of deletions of sequences in a gene that is absent in the second
sequence.
However, simply comparing the identities of amino acids cannot account for everything. To increase
the accuracy in the comparing two sequences there are 2 kinds of substitutions that can be made to
further progress the determination of amino acids. The first is a conservative substitution which
substitutes one amino acid with another amino acid that is

Angelman Syndrome Research Paper
Angelman Syndrome is a rare disease that affects one in every 20,000 children. The disease used to
be known as "happy puppet syndrome" because children that have it have happy moods and their
gestures look like a puppets. However, the only name that is used for the disease today is Angelman
Syndrome or AS. This disease is caused by a mutation in chromosome fifteen. It is disease that
should be taken very seriously.
Angelman Syndrome is neurons in the brain that lack the expression of a non–functional UBE3A.
UBE3A is Ubiquitin–protein ligase and E3A is an enzyme that is encoded in humans by the UBE3A
gene. This enzyme includes targeting protein that declines inside cells. Angelman Syndrome is
affected by problems with a gene in chromosome fifteen which is called Ubiquitin–protein ligase
E3A (UBE3A). Symptoms are usually noticed during six to twelve months of age in a child. A lack
of crawling or babbling, having a frequent smile, laughter, and a happy, excitable personality are
early symptoms of the disease. As a person gets older they have minimal or no speech and have an
inability to walk, move or balance well, which is also called ataxia. They display jerking
movements, tongue thrusting, bursts of laughter and have epilepsy. ... Show more content on
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The tests that are done check for developmental delays, small head size and flatness on the back of
the head. If the disease is found in someone there is no cure for it. Researchers are focusing on how
to treat the specific gene. There isn't a lot that you can do for the disease, but you can do some
treatments that can help with symptoms. Some people have to take anti–seizure medication. Others
go to communication, behavior and physical therapy to help with walking or balance issues.
Seizures are recurrent in people that have Angelman Syndrome and those reoccurring seizures can
make their symptoms

A Research Study On Cultured And Handled At 20. C Using...
Nematodes were cultured and handled at 20 °C using standard methods (Brenner, 1974). C. elegans
strains used in this study are as follows: N2 Bristol and MR156: rrIs01[Pelt–2::GFP; unc–119(+)] X,
which were used as wild type. CB3514: lin–23(e1883)/dpy–10(e128) II, YHS47: lin–
23(e1883)/dpy–10(e128) II; rrIs01[Pelt–2::GFP + unc–119(+)] X, DH2: zyg–11(b2) II. DS97: mat–
2(ax76) II, EU593: mel–26(or184) I, EU640: cul–2(or209) III, UP63: mat–3(ku233) III, NJ582:
cul–1(e1756)/unc–69(e587) III, VC141: zif–1(gk117) III, VC370: rfp–1(ok572)/eT1 III; +/eT1 V,
VC562: rbx–1(ok782) V/nT1[qls51] (IV;V), VC684: rbpl–1(ok907) I/hT2[bli–4(e937)let–?
(q782)gls48] (I;III), VC954: rnf–113(ok1401) III/hT2[bli–4(e937) let–?(q782)qls48] (I;III),
VC1241: skr–1(ok1696) I, VC1439: skr–2(ok1938) I/hT2[bli–4(e937) let–?(q782)qls48] (I;III),
YHS171: rfp–1(ok572) III/hT2[bli–4(e937)let–?(q782)gls48] (I;III); rrIs01[Pelt–2::GFP + unc–
119(+)] X, YHS161: rbx–1(ok782) V/nT1[qls51] (IV;V); rrIs01[Pelt–2::GFP + unc–119(+)] X, and
YHS163: skr–1(ok1696) I; rrIs01[Pelt–2::GFP + unc–119(+)] X.
Quantification of intestinal nuclei and microscopy
To examine the number of intestinal nuclei marked by GFP using an elt–2::GFP transgene, worms
were transferred to 0.2 mM tetramisole in M9 buffer on a poly–L–lysine–coated slide glass, covered
with a coverslip and observed using a fluorescence microscope (Zeiss Axioskop 2, Carl Zeiss,
Germany). Otherwise, DNA of some strains, whose intestine is not marked with intestinal

Angelman Syndrome Research Paper
An English physician discovered Angelman syndrome in 1965, Dr. Harry Angelman, who described
this disorder by three patient, which showed similar characteristics such as: stiff, jerky gait, absent
speech, and excessive laughter and seizures. Angelman syndrome is a severe intellectual disability
resulting in ataxia (movement and balance difficulties), epilepsy, behavioral uniqueness, mental
retardation, and severe speech impairment. The occurrence of this genetic disorder is approximately
1/20,000 births. The disorder is categorized as a neurodevelopment disorder as it affects primarily
the nervous system. Patients have been described as having an angel–like demeanor as they are
frequently smiling and/or laughing; the patients have a very happy and excitable personality.
Exterior qualities recognized are the following: having light skin, reduced retinal pigment, low hair
bulb tyrosinase activity, and incomplete melanization of melaonsomes. Typically newborns will not
show abnormalities in the phenotype. Starting around the age of six months parents will start to see
developmental delays in their child. The clinical features as mentioned above do not ... Show more
First, the most common, which affects 75% of the population, is resulting from de novo maternal
deletions involving chromosome 15q.11.2–913. Second, approximately 25% of the population
results in mutations in gene encoding the ubiquitin protein ligase E3A gene. Third, there are 2–3%
whom results in AS through imprinting defects. Lastly, 2% of the population results from
uniparental disomy of 15q11.2–913, where the child receives two copies of a chromosome from
parent and no copies from the other parent. The image below (Figure 1) shows the different genetic
mechanisms that cause Angelman syndrome. We have a side–by–side visual of the chromosome and
what the defect(s) look like, and where it takes place on the maternal

Klhl3 Gene Essay
The KLHL3 gene (Kelch like family member 3) creates a protein that works in conjunction with
proteasomes to degrade unwanted proteins via an ubiquitin–proteasome system. KLHL3 is mainly
expressed in the cerebellum and the distal collecting tubule in the kidneys (3). is Though expressed
in the KLHL3 protein has a N–terminal BTB domain, a C–terminal that has Ketch–like repeats, and
a BACK domain, forming a conformation that is a bladed beta propeller structure (1). The protein
produced by this gene is part of a complex (E3 ubiquitin ligase), which functions to indicate
damaged and additional proteins by labelling these with ubiquitin, which is the tag later recognized
by proteasomes for breakdown (4). This labelling is possible with the ... Show more content on
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Mutations for KLHL3 that cause disease all involve missense mutations, resulting in a different
amino acid, again noting the inability to interact with substrates (7). One mutation, for example,
resulted in a cytosine to thymine nucleotide change at codon 410, changing from a serine to a
leucine amino acid. This change in polarity, moving from a polar to nonpolar amino acid, disrupts
regular formation of the E3 complex, not allowing for ubiquitin attachment. These missense
mutations often inhibit the ability of the KLHL3 protein to form the E3 ubiquitin ligase complex,
and so this prevents the normal function of identifying extraneous and damaged proteins, resulting
in an excess of WNK4, due to no protein degradation as a result of the inability to tag these excess
proteins. This inability to form the complex in some mutations is a result of the cluster of serine
residues that were affected by the mutation, building up on the propeller domains, disrupting
interactions with substrate and/or altering protein structure, though it is more common to see one or
the other (6). This leads to high blood pressure, due to no control over WNK4 concentrations in the
blood. It was commented on that the majority of mutations affected the ability of the KLHL3 to
associate with the rest of the complex, therefore unable to

According to Inderjeet Dokal there are currently 13 known...
According to Inderjeet Dokal there are currently 13 known variations of genes that cause FA and
they are as follows: "FANCA, FANCB, FANCC, FANCD1, FANCD2, FANCE, FANCF, FANCG,
FANCI, FANCJ, FANCL, FANCM, and FANCN" (Dokal, 2008). Dokal and many other doctors
agree that FA is a very penetrant genetic disorder. That is, all of these subtypes of the FA gene can
cause many of the different types of cancer and bone marrow deficiencies that are associated with
FA. For example, in the list given by Dokal, the subtype FANCA is known to express as a gene that
controls certain aspects of protein coding. This one genetic subtype causes breakdowns in the
various checkpoints throughout the cell cycle. As you can imagine, this one gene can destroy ...
The expressivity and penetrance of FA are largely based on the number and type of subtypes present.
It was found that a large amount of the subtypes of FA actually interact with each other in one form
or another to cause reactions and abnormalities in many of the pathways that are critical to the
replication and regulation of DNA in each of the cells pathways. Interestingly enough, if just one of
the subtypes is not present, then the expression of the interference is not as extreme as it could be if
all of the subtypes needed for a category were present.
With that said, it's important to understand what happens during a normal cycle of DNA replication.
This will provide a greater understanding of the effects of FA on the DNA replication process. By
understanding the processes and events of replication you can see how those subtypes of FA like
FANCL can be so detrimental to the affected individuals' cells. The process of replication in regards
to DNA is a complicated set of processes in which thousands of base pairs are accurately copied and
translated to produce new strands of DNA. It's important to note that DNA replication is a semi–
conservative process, this means that every time a new DNA molecule is formed, an old strand is
incorporated along with the new strand. Each cycle recycles at least one of the old strands. The
process of DNA replication begins at specific sites called the origin of replication. This

The Importance Of Neural Stem Cells
My combined interest in discovery and earning a Ph.D. eventually led to my first research
experience through the NeuroSURP program at Rutgers University. There, I became a part of the
laboratory of Dr. Emanuel DiCicco–Bloom and worked on a project titled," Neural Stem Cells from
Autism Spectrum Disorder (ASD) Patient Exhibit Abnormal Neurite Outgrowth." Autism Spectrum
Disorder (ASD) is a highly heritable neurodevelopmental disorder of impaired communication skills
and repetitive restrictive behavior. Studies have concluded that genes implicated in ASD diagnoses
converge to regulate signaling pathways for neurodevelopmental processes like migration,
proliferation, and differentiation. Basic fibroblast growth factor (FGF–2) has been proven ... Show
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With continued experimentation to validate or expand upon these hypotheses, we may be able to
explain postulate how this dysfunction leads to ASD phenotypes, and how those developmental
disorders may be prevented.
I continued my passion for research in the neuroscience laboratory of Dr. Raimi Quiton in the
Psychology Department of the Univeristy of Maryland, Baltimore County UMBC . Through this lab
I had the opportunity to investigate the effect of biopsychosocial factors on human pain modulation.
Implications of this study stretch to health care and treatment for individuals within diverse groups.
With the right application, it can also help to decrease the stereotypes imposed upon certain patient
groups when given pain treatment. These outcomes, though far away at this point, have allowed me
to be a part of an experience that speaks to my ambition of effecting social change through research.
Despite this experience being a world away from the cell culture of the previous summer, I became
HIPAA certified, ethics trained, and became trained for human pain testing. In addition to
conducting thermal and pressurized pain experiments, I also managed projects within the lab,
collected and analyzed data, planned experiments, and trained new research assistants. During
extended periods when my mentor and principle investigator were away on

Gfe3 Synthesis
In a recent study, researchers report a novel and easy way to hijack the brain's natural processes.
This technique, which involves the fusion protein GFE3, interferes with the inhibitory synapses
between neurons resulting in an overall rise in the brain's electrical activity.
The team, led by Don B. Arnold, professor of biological sciences at the University of Southern
California, used GFE3 which is a fusion of two proteins: E3 ligase, which degrades proteins; and
FingR, which recognizes and binds to proteins in inhibitory synapses.
Arnold explains: "Rather than a cell deciding when a protein needs to be degraded, we sort of hijack
the process."
Synapses can either be excitatory or inhibitory, depending on whether the postsynaptic neuron is ...
For this, they used the zebrafish as an animal model.
They created genetically modified zebrafish by injecting the zygotes with the GFE3 construct that
was further modified to be expressed only in the spine.
Consistent with their earlier results, imaging techniques show the absence of the inhibitory proteins
in the spines of the zebrafish. Interestingly, they also found that zebrafish injected with GFE3 had
sharply reduced motor coordination described by poor tail flicking motions.
Perhaps most remarkably, however, is that the team was able to show that the effects of GFE3 were
reversible; something that other similar techniques do not have. The team did this by further
modifying GFE3 to be expressed only when the chemical dox is present.
When they removed dox, the team observed that GFE3 disappeared and the inhibitory proteins
returned.
This study represents one of the first few studies that have focused on a protein–centric approach to
controlling neurons and synapses. According to Arnold, further studies could contribute to therapies
and drugs predicated on the ability to finely tune the brain. This is especially useful in diseases
caused by altered brain chemistry like schizophrenia and

Traf4 Case Study
Introduction In the article, "TRAF6 Restricts p53 Mitochondrial Translocation, Apoptosis, and
Tumor Suppression," the experimental study looks specifically at the TRAF6 E3 ligase and its
different effects on the mitochondrial tumor protein 53 (p53). The p53 gene plays a role in
regulation of the cell cycle and cell fate determination. A mutation in the p53 gene is repeatedly seen
in characterized human cancer cells. TRAF6 is shown to inhibit p53 activity by K63–linked
ubiquitination at K24 of p53 in the cytosol. This ubiquitination inhibits the interaction between p53
and MCL–1/BAK; therefore, this restricts p53 from the mitochondria and prevents apoptosis.
Furthermore, this study shows that genotoxic stress affects MCL–1/BAK and p53 ... Show more
Previous studies have suggested that K63 ubiquitination is associated with anti–apoptotic protein
trafficking pathways. Figure 1 addresses whether K63 ubiquitination is accomplished by the TRAF6
E3 ligase. An immunoblot of p53 was used for U2SO cells in a Ni–NTA assay to determine if K63–
linked ubiquitination of p53 was associated with TRAF6. U2SO cells were used because of their
high proliferation rates. Flag–TRAF6 and p53 were included in the western blot as controls for this
assay. Ubiquitin was tagged with histidine and TRAF6 was tagged with the Flag antibody to assess
protein to protein interactions. This assay shows ubiquitination of p53 in the presence of His–Ub
and Flag–TRAF6 indicating that K63 linked ubiquitination of p53 depends on TRAF6. To determine
if specifically, K63–linked ubiquitination occurs through TRAF6 the authors assessed whether
TRAF6 promotes K48–linked ubiquitination of p53 and proteasomal degradation. An immunoblot
for HA in a Ni–NTA pull–down assay was generated to assess if ubiquitination and proteasomal
degradation occurs at K48 and K63 by TRAF6. HA–p53 and Flag–TRAF6 in U2SO cells were used
to show protein–protein interaction. A

Pathogenesis And Endocytosis

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