The Two Component Stressors

The Two Component Stressors
Introduction
Bacteria are prone to various stressors so they need to sense and respond to these fluctuating
conditions in order to survive. Two–component plays an important role in the bacterial kingdom to
sense and adapt themselves to these varieties of stressors, for example oxidative stress, protein
misfolding, nutrient starvation and many more. It is first described by Ninfa and Magasanik (1986)
in the study of nitrogen starvation in Escherichia coli. Two–component system consists of a sensor
histidine kinase and its cognate response regulator (Koretke,K.K. 2000). Sensor histidine kinase is
bifunctional which means it can function as both kinase and phosphatase. It autophosphorylates
itself upon sensing a signal, whereby the phosphoryl group from ATP molecule is transferred to a
specific histine residue on the histidine kinase. It then acts as phosphodonor substrate for its cognate
response regulator. The cognate response regulators is acting as phosphatase to the histidine kinase
as it catalyses the transfer of the phosphoryl group from histidine kinase to its conserved aspartic
acid residue. Once phosphorylated, response regulator undergoes conformational change which
activates the output domain leading to either stimulation or repression of the targeted genes. As
mentioned earlier on, histidine kinase protein also acts as phosphatase for its cognate response
regulator if it is not stimulated to autophosphorylate.
This system has vast variations and the common
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Essay
I unmistakably recall my amazement as I watched my high school chemistry teacher balance an
oxidation–reduction reaction on the board; in that moment, I became passionate about the molecular
world. On the surface, the challenging coursework caught my curiosity, yet deep within was an
internal connection to chemistry I had not experienced prior. This fascination with the molecular
world was continually refined throughout my undergraduate coursework; however, no topic inspired
me more than the molecular mechanisms underlying learning and memory in the brain. Shortly
after, my first undergraduate research experience solidified my intuition to pursue a career
investigating molecular mechanisms underlying conditions of impaired learning and ... Show more
content on Helpwriting.net ...
Yet of the countless learning experiences encountered at IUPUI, none of these have better prepared
me for the IBMG program than my research experience with Dr. Anthony Baucum.
In Dr. Baucum's laboratory, I investigated a novel protein interaction between two scaffolding
proteins, SAPAP3 and spinophilin. Spinophilin localizes to dendritic spines in striatal medium spiny
neurons and plays an important role in regulating long–term depression (LTD), the molecular
mechanism responsible for weakening the strength of a synapse. Interestingly, Dr. Baucum
identified SAPAP3 as a novel interactor of Spinophilin through a proteomics screen. After
conducting an extensive literature review, I noticed both of these proteins held a physiological
relationship with metabotropic glutamate receptor 5 (mGluR5), a putative regulator of striatal LTD.
Due to this connection, I investigated the role mGluR5 plays in regulating the interaction between
these two proteins of interest using numerous molecular biology and biochemical techniques, such
as PCR, mutagenesis, immunoprecipitation, western blot, and others. We determined that mGluR5,
as well as its second messenger protein kinase C, increase the strength of this interaction. Through
many experiments, we now hypothesize this novel interaction to regulate LTD in the striatum. After
working on this project for two and a half years, a manuscript is now in

Body Weight, Height, Percent Body Fat And Squat Strength Test
There were no differences among groups for age, body weight, height, percent body fat and Squat
strength test (Table 4). Moreover, the 9–day analysis revealed no differences in energy, protein, fat
and carbohydrate intake between groups throughout the study as shown in table 1.
Muscle Soreness
Regarding muscle soreness, the pre–exercise values were not different among groups. Muscle
soreness significantly increased above baseline in all groups at all time points (p < 0.05; Fig 2). Peak
soreness occurred in all groups at 24 hrs after exercise. Also, the three groups had no effect on
soreness scores.
Serum Marker
Means CK levels are presented in Fig3. CK level reached its peak activity 48 hours after exercise
with significant differences ... Show more content on Helpwriting.net ...
Possible explanations for differences between our findings and other published data could be
attributed to age, exercise protocol and intensity of exercise. Serum creatine kinase (CK) and lactate
dehydrogenase (LDH) are an indication of the degree of metabolic adaptation to physical training of
skeletal muscles. These enzymes are involved in muscle metabolism, and their serum concentration
is normally very low. They increase considerably after intensive exercise. Changes in serum activity
of muscle enzymes have been reported in normal subjects and athletes after strenuous exercise. The
amount of enzyme efflux from muscle tissue to serum can be influenced by physical exercise. These
results showed that the use of BCAA didn 't reduce serum CK activity 24 and 48 hrs after heavy
resistance exercise. Serum CK activity was elevated in all groups after exercise and was highest in
the placebo group. It was obvious in BCAA group that the Ck and LDH levels were non–
significantly lower than the control one indicating that the muscle soreness is lower (higher muscle
fitness). The positive action of BCAA in lowering the muscle soreness could be referred to
– It 's compensatory and protective impacts on muscle tissue where valine,

The Relationship Between Grks And Arrestins
2.3.2 GRKs and –arrestins
GPCR desensitization is a deactivation of GPCR–elicited signaling following prolonged or repeated
agonist exposure. A major mechanism underlying desensitization is agonist–stimulated
phosphorylation and endocytosis of the receptor. The second messenger–dependent protein kinases
were originally regarded as the principal mediators of GPCR phosphorylation and desensitization.
However, following the discovery of G protein–coupled receptor kinases (GRKs, originally called
–adrenoceptor kinases), the GRKs have been shown to play a central role in the agonist–induced
desensitization of many GPCRs (Kelly 2008). The GRK family of serine/threonine kinases
comprises seven members. Based on sequence homology, vertebrate ... Show more content on
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For example, –arrestins can mediate sustained ERK phosphorylation or protective mGluR
signaling, which are G protein–independent processes (Emery 2010, Wang 2016). At the end of
GPCR cycles, a regulator of G protein signaling (RGS) acts as GTPase activating proteins (GAPs),
leading to GTP hydrolysis and reversing the receptor to an initial resting state (Sato 2015).
Different GRK subtypes combined with the action of –arrestins can contribute the endocytosis of
Group I mGluRs in an agonist–dependent manner; however, the results are inconsistent (reviewed in
Refs: Iacovelli 2013, Kim 2008). Both GRK2 and GRK4 induce the agonist–induced internalization
of mGluR1a, which appears to require GRK2–mediated phosphorylation of the S869–V893 region
of mGluR1a when expressed in HEK cells (Iacovelli 2003, Sallese 2000, Mundell 2003). These
agonist–induced internalization processes are –arrestin 1/2 and dynamin–dependent (Mundell
2001, 2002, 2003). –arrestin 1 appears to be important in mGluR1 endocytosis; however, the
agonist–stimulated internalization of mGluR1a is observed only when –arrestin 1 is co–expressed
with either GRK2 or GRK5 in HEK cells. GRK2, GRK5, –arrestin 1, or –arrestin2 individually
has no significant effect on the internalization of mGluR1a (Dale 2001). –arrestin 1, but not –
arrestin 2, selectively interacts with mGluR1a and is redistributed to the same

Identification and Characterizaation of Three GS Isoforms...
3. Results
3.1. Identification and characterization of three GS isoforms
Three different GS sequences (GS01, GS02 and GS03) have been identified through the sequencing
and blastx searching. All the sequences contain a complete coding sequence (CDS) region and 5′
and 3′–UTRs. In this study we have attempted the characterization of the multiple GS cDNAs
present. The characteristics details of the full–length cDNAs of GS01 (Accession No. JQ740737),
GS02 (Accession No. JQ740738) and GS03 (Accession No. JX457351) are given in Table 2.
Analysis with the UTRscan tool revealed the presence of one Musashi Binding Element (MBE) in
both GS01 and GS02 transcripts. But there was no MBE present in GS03 UTR. Conserved Domain
Database search (CD–search) ... Show more content on Helpwriting.net ...
NetPhos 2.0 analysis projected 9/11/11 serine, 2/3/2 threonine and 5/7/7 tyrosine phosphorylation
sites for GS01/GS02/GS03 proteins respectively. The homology modelling of the enzyme shows 12
identical subunits, arranged in two layers of 6. The secondary structure of GS consisted of 7 alpha
helix and 15 beta strands. The binding residues, predicted by the RaptorX binding web server, and
the corresponding ligands for the three different GS proteins are given in Table 3.
3.3. Phylogenetic analysis
The alignment of the multiple GS amino acid sequences with fishes, amphibians and mammalian
proteins is presented in Fig. . The homologous active site residues for GS in C. batrachus were
determined using the Salmonella typhimurium GS X–ray crystallography structure (Gill and
Eisenberg, 2001). The pairwise alignment shows presence of 15 of the 16 residues identified in
Salmonella. The residues are completely conserved among fishes, amphibians and mammals (Fig.).
With respect to the Salmonella, only three of 15 residues present in catfish are substituted (positions
194, 196 and 246). The phylogenetic tree clearly revealed
3.4. Differential expression of GS mRNA transcripts in NH4Cl–treated fish
There were significant increases of expression of different GS mRNA (GS01, GS02 and GS03)
transcripts in different tissues (liver, kidney, brain and muscle) following the 50 mM NH4Cl
treatment. In the brain, where

The Role Of Posttranslational Mofication In Archaea
The role of posttranslational modification (PTM) in the diverse environments of archaea diversifies
with the individual archaea. There are over 300,000 PTMs across about 5500 species of organisms.
One such PTM is reversible phosphorylation. This activity involves the activity of protein kinases
and phosphatases. Protein kinases move the γ–phosphate group to another transcription factor or
protein and protein phosphatases remove a phosphate group. Reversible phosphorylation is
ubiquitous in the three domains of life and was first demonstrated around 1950 by Krebbs and
Fischer in rabbit muscle tissue. It was later demonstrated by Wang and Koshland (1978) in
Salmonela typhimerium and finally in archaea, Haloarchaea salinarium by Spudich and ... Show
more content on Helpwriting.net ...
(He, Liu and Zou 2016)
Two component systems are not well studied in Euryarcheota, but extremophilic methanogens and
halophiles have been sequenced and researchers have found these types of systems are found in
Halobacterium salinarium, Halofarax volcanii, Methanosaeta harundinacea and Methanosarcina
barkeri.
Esser and colleagues also found that Tyrosine , Serine and Threonine phosphorylation are
commonalities in eukaryotes and archaea. A group of protein kinases called Hanks type kinases are
classified according to function. The kinases that phosphorylate Serine and Threonine are the most
common these are referred to in the article as STK's. STK's require autophosphorylation like other
TCS but rely on a manganese ion and substrates such as Casein and bovine serum albumen for cell
growth. Esser and colleagues cite a study by Wang et al 2010 using Sulfolobus tokodaii strain 7.
This study by Wang and colleagues shows the importance of the Manganese ion and four other
amino acids when either of them are mutated.
The function of eSTK's involve activation of the gene flaB. Once activated a complex of two protein
kinases and a phosphatase (ArnABC) along with ArnD, function in regulating motility. In a study by
Reimann et al 2012 ArnC was deleted and this resulted in sparse amounts of cell motility. However
deletion of ArnD proved to increase motility to a hyper motile state. This deletion study shows how
important phosphatases

MAPK And The Regulation Of The Isolation Of Eukaryotic Cells
Introduction Isolation of DNA along with transcriptional material in the nucleus, by the nuclear
envelope, from the cytoplasm and the translational material held there gives the opportunity for
exact regulation (Lange et al, 2006). The nuclear envelope provides the ability for regulation of gene
expression and signal transduction. With this regulation cells can, if exposed to an extracellular
signal, perceive and create an intracellular response to withstand or react to such a signal, for
example, by signalling cascades with the use of mitogen–activated protein kinases (MAPKs)
(Brown and Sacks, 2009). A protein kinase can phosphorylate a protein at serine, threonine or
tyrosine residues which can affect its position within the cell ... Show more content on
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The many isoforms of JNK could have varying catalytic activity on their substrates such as the
means to phosphorylate a transcription factor (c–Jun) in JNK1 and JNK2 (Liu et al, 2004). JNK
phosphorylate either serine or threonine residues when there is a proline after it (Hibi et al, 1993).
JNK can also be phosphorylated by autophosphorylation most notable in the JNK2 isoforms where
it still allows initiation of substrates with the strongest occurrence in JNK22 (Tsuiki et al, 2003).
There are three kinases involved in the MAPK phosphorelay system which act in series: MAPK
kinase kinase (MKKK), MAP kinase (MKK) and MAPK (JNK), which respond to external stimuli,
shown in Figure 1 (Johnson et al, 2005). There are a wide range of stimuli that can activate
regulation of JNK including ultraviolet irradiation, growth factors (tumour necrosis factor–),
cytokines and even protein synthesis inhibitors (anisomycin) activates MKKK and using
phosphorylation to activate the next kinase in the process, MKK, which in turn phosphorylates
MAPK (Dérijard et al, 1994; Kallunki et al, 1994; Lange–Carter et al, 1993). There are 13 different
MKKK including MEKK1–4, MLK2/3 and DLK that can act in the JNK pathway which provides
the ability to responds these different external signals (Brown and Sacks, 2009; Dérijard et al, 1994;
Johnson and Lapadat, 2002; Kallunki et al, 1994). In the sequence of MEKK there are specific
motifs

A Report On Gleevec ( Imatinib Mesylate )
Gleevec (imatinib mesylate)
Antineoplastic
MW = 589.7 g/mol pKa = 5.5
Chemical Formula = C29H31N7O ● CH4SO3
IUPAC name: N–(4–methyl–3–{[4–(pyridine–3–yl) pyrimidin–2–yl]amino}phenyl)–4–((4–
methylpiperazin–1–yl) methyl]benzamide
Description
Imatinib mesylate is a protein tyrosine kinase (RTK) inhibitor that exhibits high specificity and
potency for ABL, c–kit, and PDGF receptors, which often harbor activating mutations and are
typically mutually exclusive of each other and within specific cancer types.2 The compound has
been approved as a targeted chemotherapy for Philadelphia chromosome positive chronic and acute
myeloid leukemia (Ph+ CML and AML), Ph+ acute lymphoblastic leukemia (ALL), platelet–derived
growth factor receptor (PDGFR) aberrancy–related myelodysplastic or myeloproliferative
pathologies, kit+ expressing advanced gastrointestinal stromal tumors (GIST), and for FIP1L1–
PDGFRα gene fusion expressing hypereosinophilic syndrome (HES) or chronic eosinophilic
leukemia (CEL).1 Imatinib is available in 100 mg and 400 mg tablets for case–dependent single
agent or adjunct therapy1. Therapeutic doses range from 100 mg to 800 mg/day, depending on
diagnosis, age, and hepatic function.1 The drug exhibits pH–dependent solubility in aqueous
solutions (soluble at pH ≤ 5.5), varying solubility in polar protic solvents, and is immiscible in polar
aprotic liquids.1
Mechanism of Action
Imatinib is a competitive antagonist that exhibits specific activity for ABL, c–kit, and PDGFR

CMMB 403
CMMB 403 Paper
Topic – Gene FGFR3
Using these three articles (or more), you should tell the story of the discovery and developmental
function (including the relevant signaling pathway) –
One of your additional papers should concern the discovery of the function of the gene in humans
(i.e. the human mutant phenotype)
Introduction
Achondroplasia is when cartilage during development is not developed into bone, which results in
dwarfism. This condition also characterized by short limbs is initiated by a gain of function mutation
in the FGFR3 gene. This mutation is a point mutation. When this mutation occurs, the receptor of
the FGF does not need the FGF signal to be activated. This causes the chondrocytes to stop dividing
and start differentiating into cartilage prematurely and the bones fail to grow to their proper length,
thus resulting in the short limbs that result from this mutation. (textbook) The FGFR3 gene encodes
for the Fibroblast growth factor receptor 3 protein. Textbook ... Show more content on
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Initially called protein 17B, FGFR3 was discovered based on the similarities Paper 1 discovered
FGFR3 through the use of homologous genes of other FGFRs. Regions such as the kinase domain
and the C terminus were used to test the extent of homology between Protein 17B and the FGFRs.
Paper 1 used a human cDNA library which was hybridized in low stringency. Then under high
stringency, a partial FGFR3 clone was used as a probe. The DNA was cloned using
dideoxynucleotide chain termination method. A mutation in the FGFR3 gene causes a premature
activation of the STAT pathway which also leads to the premature production of phoshorylated Stat1
protein. The phophorylated Stat1 protein encodes genes for cell cycle inhibition, these leads to a
decreased number of chondrocytes and hence shorter skeletal

The diacylglycerol (DAG) mediated regulation of protein...
The diacylglycerol (DAG) mediated regulation of protein kinase C (PKC) family of serine/threonine
kinases plays a critical role in several intracellular signaling pathways and the pathology of several
diseases including cancer, neurological, cardiovascular, and others. In consequence, PKC isozymes
are being actively pursued as the subject of intense research and drug development. Depending on
their enzymatic properties and activation mechanism, the mammalian PKC isoenzymes have been
categorized into classical (calcium–, DAG–, and phospholipid–dependent), novel (calcium–
independent, but DAG– and phospholipid–dependent), and atypical (calcium– and DAG–
independent) subgroups. The DAGs selectively interact with the C1 domain of PKC isoenzymes. ...
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Therefore, C1 domains have become an attractive objective in designing selective PKC ligands.
There are two functionally nonequivalent C1 domains (C1a and C1b) positioned in tandem within
the regulatory domain of classical and novel PKC isozymes. The PKCα–C1a and PKCθ–C1b
subdmains shows higher DAG binding affinity than the C1b and C1a subdomain respectively. For
PKCδ–C1b/a subdomains, conflicting results have been reported regarding their DAG binding
affinity. Accumulating evidences suggest that anionic phospholipids like PS, phosphatidic acid (PA)
and phosphatidylglycerol (PG) enhance the DAG dependent membrane binding affinity and PKC
activity; although the anionic phospholipid dependence varies considerably among the PKC
isozymes. Among the classical PKCs, PKCα and PKCβII prefer PS to PG, whereas PKCγ shows
comparable affinity for PS and PG. Among the novel PKCs, PKCδ and PKCθ show a certain degree
of PS selectivity, whereas PKCε shows preference for PA. In case of isolated C1b subdomains,
similar selectivities have been observed for PKCδ, PKCθ and PKCε. Whereas the PKCβII–C1b
subdomain shows little preference between PS and PG. However, the reported experimental
measurements used either only DAG or a combination of separate DAG and anionic lipid molecules
in solution or under liposomal environment to determine the DAG dependent membrane binding
capabilities of the

Oxidative Stress Key Research Data and Analysis
Key Research Data and Analysis Study 1: Ipc1 controls the Pkc1 activation by modulation of DAG
Regulation of DAG and phytoceramide by Ipc1. When Wild type and GAL7::IPC1 strains were
exposed to galactose and glucose, DAG (activator of PKC1) levels in the GAL7::IPC1 strain
increased when IPC1 was induced by galactose, and decreased when IPC1 was repressed by
glucose. Furthermore, phytoceramide levels were increased when IPC1 was down regulated by
glucose in the GAL7::IPC1 strain. In both wild type strains, no change was seen when IPC1 was up
or down regulated, as expected (Fig. 2). PKC1 activity in relation to DAG and Phytoceramide
exposure. Since IPC1 regulates DAG and phytoceramide levels, the authors wanted to explore if
DAG or phytoceramide can control PKC1 activity. DAG or phytoceramide were delivered in Triton
x–100 lipid micelles and histone phosphorylation by recombinant PKC1 was measured in absence
or presence of lipids. Without lipids, Pkc1 activity was 31.5 pmol/min/mg. When DAG subspecies
were added, Pkc1 activity increased up to two fold (Fig. 3A). In order to make sure kinase activity
measured was specific to Pkc1, APP1 activity was measured when exposed to DAG subspecies and
as expected, did not cause phosphorylation of histone, which was expected (Fig. 3B). When
phytoceramide lipids were added, Pkc1 activity decreased by about 50% compared to no
phytoceramide, which was expected because phtyoceramide is an inhibitor of Pkc1 (Fig. 3C). Study
2:

Stc Case Study
1) The Philadelphia chromosome is chromosome 22, which has undergone a reciprocal translocation
with chromosome 9, such that the long arm of chromosome 22 has been replaced with the long arm
of chromosome 9. This chromosome is relevant to cancer because the long arm of chromosome 9
contains human c–abl oncogene, which becomes fused to the breakpoint cluster region (bcr) in the
Philadelphia chromosome, following translocation. Presence of this bcr–abl gene fusion produces a
poorly regulated tyrosine kinase, which results in a much higher level of cell proliferation. The
action of this tyrosine kinase results in chronic myelogenous leukemia (CML) symptoms, such as
overproduction of white blood cells.
2) Opposed to structural data alone, NMR ... Show more content on Helpwriting.net ...
This will result in the substrate concentration remaining relatively constant, while only the
concentration of the enzyme changes over time. These conditions result in the kinetic order to be the
same with respect to enzyme concentration and with time; thus, mimicking first–order kinetics.
3b) A non–linear response is observed here because the binding of enzyme to substrate does not
follow simple pseudo–first–order kinetics, but instead there is a two–step process involving rate–
limiting changes in protein conformation. These findings support the previously proposed model of
substrate binding, in that there is a fast step of enzyme binding to substrate, followed by a slow
conformational change in the enzyme once bound to substrate. The plateau in the observed rates
indicates the maximal rate at which enzyme can bind to substrate, with Abl binding with a maximal
rate of 20 s–1 and Src binding with a maximal rate of 2 s–1.
4) For Abl, the indicated residues are within the C lobe of the enzyme, and are not in direct contact
with Gleevec when it is bound. For Src, the indicated residues are within the N lobe of the enzyme,
and within the Gleevec binding site, such that they may be making direct contact with Gleevec.
Since these residues are within the Gleevec binding region, they demonstrate the complex, two–step,
fast and slow exchange that is occurring with Src; whereas, the residues indicated in Abl are not

Cell And Breast Cancers And Colorectal Cancer
An antimetabolite, 5FU is a pyrimidine analog that irreversibly inhibits TS. Thymidine is a
nucleoside and a major component of the DNA and is hence required by cells for proliferation.
Deoxyuridine monophostate (dUMP) upon methylation by TS generates thymidine monophostate
(dTMP). 5FU interrupts the activity of TS and creates a shortage in the levels of dTMP. Thus the
rapidly proliferating cells undergo death due to lack of thymidine nucleoside. The drug has
successful applications in colorectal and breast cancers and is used in various combination therapies
with methotrexate (Maddur et al., 2009). The concentration used for the experiments is 10 µM
Oxaliplatin is an antineoplastic platinum drug. Platinum drugs target DNA synthesis by ... Show
215 cells have high proliferating rates as compared to 253 cells. To generate metformin resistant
cells, 215 and 253 were cultured 4–8 weeks in the presence of 3mM of metformin. Cells were
considered resistant after 3 serial passages in vitro.
For the generation and enrichment of cancer stem cells, PDAC cells at 106 cells/ml concentration
were grown in a serum free Dulbecco's Modified Eagle's Medium (DMEM–F12) complemented
with B–27 and FGF. The cells were seeded in ultra–low attachment flasks. This aids in the
development and the expansion of the PDAC spheres (cancer stem cells). Metformin was added (at
1:1000 dilution) in case of culturing metformin resistant spheres. All the cells were contained in a
T–75 flask and incubated at 37°C.
The regular cancer cells were seeded at 106 cells/ml concentration in RPMI containing 10% (v/v)
FBS. The cells were cultured in regular attachment T–75 flasks. Metformin at 1:1000 dilutions was
added in case of culturing metformin resistant PDAC cells.
After incubating for 7 days, spheres increase in size and range from 40–120 µm. For serial
passaging, spheres were harvested using 40 µm cell strainers (filters), trypsinised to dissociate into
single cells and then grown again for 4 days in the same conditions.
Growth media was aspirated and the flask was washed with PBS. The cells were trypsinised and
kept in an incubator at 37°C until the cells

Article Critique On Carbohydrate And Protein During Training
Article Critiques
Assignment Six
Hall, A. H., Leveritt, M. D., Ahuja, K. D., & Shing, C. M. (2013). Coingestion of carbohydrate and
protein during training reduces training stress and enhances subsequent exercise performance.
Applied Physiology, Nutrition & Metabolism, 38(6), 597–604.
Despite extensive research on the benefits of carbohydrate (CHO) ingestion improving endurance
performance, there are still a lot of questions in the literature about whether or not the simultaneous
ingestion of CHO and protein is advantageous compared to other methods in enhancing
performance (Hall et al., 2013). According to Hall and colleagues (2013), there have been an
number of studies that have shown potentially performance enhancing benefits of co–ingestion of
protein and CHO such as enhanced glycogen synthesis post–exercise, decreased muscle soreness,
muscle damage, positive net protein balance, and even modest performance benefits (Hall et al.,
2013).
Purpose. Hall and colleagues (2013) looked to determine the potential impact of protein and CHO
co–ingestion has compared to 'isoenergetic CHO beverage during exercise'. Specifically, Hall and
colleagues (2013) wanted to explore the impact that consumption of such a beverage would have on
cycling performance after a four hour rest period. Also, the impact that consumption would have on
blood plasma markers of muscle damage and muscle soreness, as well as insulin and glucose levels
(Hall et al., 2013).
Methods. A modest sample

A Case Report Of Suspected Malignant Hyperthermia Where...
Title: A Case Report of Suspected Malignant Hyperthermia where Patient Survived the Episode.
Abstract; Malignant hyperthermia is rare inherited disorder in our part of world, there are only few
cases reported in literature in India who were suspected of having this condition. Overall incidence
of malignant hyperthermia during general anesthesia is estimated to range from 1: 5,000 to 1:
50,000–100,000 and mortality rate is estimated to be less than 5% in presence of standard care. In
India there is no centre where invitro halothane caffeine contraction test (IVHCT) is performed to
confirm diagnosis in suspected cases. Secondly dantrolene drug of choice for this condition is not
freely available in market in India and is stored only in some hospitals in few major cities. Among
the cases reported of suspected of malignant hyperthermia in India almost 50% have survived the
condition despite non availability of dantrolene emphasising role of early detection and aggressive
management in these cases.
Key words .Malignant hyperthermia,dantrolene,halothane ,caffeine,contraction.
Introduction
Malignant hyperthermia is a relatively rare disease in India with very few case reports present in the
literature in this regard. Malignant hyperthermia was brought into attention for anaesthetic world by
deaths attributable to general anaesthetics in a family living in Melbourne, Australia [1]. Incidence
of malignant hyperthermia during general anesthesia is estimated to

Cavk Synthesis
7. Regulation of CaCCs: The biophysical properties of CaCCs can be determined through varying
alternative splicing patterns on different exons of ANO gene. Though the dissimilar patterns
observed are believed not to change the overall topology of the channel 18,51, it is suggested that
alternative splicing can produce various channels with different biophysical properties, regulatory
mechanisms, and subcellular localizations 18,51,54. The EAVK sequence, as part of the first
intracellular loop in CaCCs, is regulated by alternative splicing 51 and believed to have a pivotal
role in biophysical and gating properties of the channel 43. Besides alternative splicing as a
posttranscriptional modification that modulates the activity ... Show more content on
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High throughput screening of CaCCs can help us identify the specific activators and inhibitors of
these channels and with the help of fully–controlled electrophysiological experiments combined
with biochemical and biophysical studies, we can unravel therapeutic targets of CaCCs for the
treatment of cystic fibrosis and other diseases related to chloride dysregulation. Though the
discovery of ANO1 and ANO2 as CaCCs has revolutionized our understanding of the great role that
anion's homeostasis could play in different physiological and pathological conditions, there still are
some important questions needed to be answered. In comparison to ANO1, ANO2 activation
kinetics are faster 49, ANO2 has less sensitivity to Ca2+ concentrations 27 and provides smaller
single unit conductance 90, issues that should be considered more seriously upon realizing why the
existence of different ANO isoforms (ANO1 and ANO2) with diverse characteristics is necessary in
the cells. It is still unknown if these discrete characteristics can be assigned to specific modules. In
addition to other members of the Anoctamin family, other transmembrane proteins with ambiguous
function should be studied to see if they have the same characteristics of CaCCs or other related
channels and transporters responsible for the flow of Cl− and other anions across the biological
membranes. As well, the regulatory roles that cations can play in regard

The Affects of Duchenne Muscular Distrophy
The affects of Duchenne muscular dystrophy as well as various solutions performed to provide
accurate diagnoses and treatment of Duchenne muscular dystrophy.
1. Introduction
Duchenne muscular dystrophy (DMD) is defined as a chronic form of dystrophy that is caused by a
mutated gene. This essay critically discusses Duchenne muscular dystrophy as a whole, including all
the symptoms, causes as well as treatment.
2. Overview of Duchenne muscular dystrophy
Duchenne muscular dystrophy was discovered by a French neurologist, Guillaume Duchenne.
According to Emery (1994 : 23) Guillaume Duchenne invented an instrument, Duchenne's trocar, to
remove small portions of tissue in the body (biopsy).
Duchenne muscular dystrophy is a gender–linked inherited disorder. To illustrate, males only have
one X chromosome, therefore they do not have a second X chromosome to make up for the
damaged gene. Females can only become carriers of the disease, as females have a second X
chromosomes to make up for the damaged gene.
http://www.nlm.nih.gov/medlineplus/ency/imagepages/19097.htm
According to Green (2014) the (DMD) gene for dystrophin, which is a protein that is present in
muscles, is the second largest gene. A deficiency of dystrophin results in the damage of muscle
fibres, resulting in a loss of muscle functioning. This disorder affects mainly the legs and pelvic
region of the body. However it could also affect the heart, the respiratory system, as well as rarely
the brain. Duchenne

Axonal Death And Alzheimer 's Disease
Introduction Axonal death is a main element in many neurodegenerative diseases. It has been
observed in many neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease.
Axon degeneration does not necessarily have to involve the typical apoptotic pathway regardless of
the morphological similarities to cells undergoing apoptosis. Yang et al. focused on axonal death in
traumatic injury because it has been shown to be independent of the necroptotic pathway. This was
discovered since treatment with necroptosis inhibitors did not protect axons. To reiterate, axonal
death in traumatic injury has commonalities with other diseases such as Alzheimer's disease and
Parkinson's disease. If there is a greater understanding for the ... Show more content on
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Axonal degeneration does have a significant impact on many neurodegenerative diseases. Their
research found that this particular pathway, Sarm1–MAPK pathway, may be a common pathway for
different types of axonal degeneration, not just from traumatic injury. If the main pathway or
underlying mechanism that drives these diseases is uncovered and understood, then this can lead to
creating different methods to protect synapses and axons in these diseases. Other research can focus
on trying to inhibit the Sarm1–MAPK pathway, or at least inhibit distinct components within it.
Their research is pertinent to finding a cure or possible treatments for many of these diseases. This
will have multiple implications on society, medicine, and the quality of life for many people
suffering with the many debilitating symptoms associated with these diseases.
Experimental System In order to examine axons undergoing degeneration after traumatic injury,
they observed axons of retinal ganglion cells (RGCs) in mouse optic nerves. These RGCs were
labeled with TdTomato fluorescent protein in order to visualize the axon degeneration following the
optic nerve crush–the traumatic injury. Then using the transgenic mouse line, Yang et al. examined
the cytosolic version of Nmnat1. In addition, they used wild–type mice that were transduced with
TdTomato and a specific shRNA targeting Sarm1

A Research Study On Protein Arginine And C Met Are...
Specific aims: EGFR and c–Met are receptor tyrosine kinases (RTKs), and tyrosine kinase inhibitors
(TKIs) against these receptors have been initially effective when prescribed to patients in
combination with traditional chemotherapy or radiation. However, the overall efficacy of TKIs is
limited due to the development of resistance as seen through clinical trials in NSCLC. Epithelial
Mesenchymal Transition (EMT) is a process by which epithelial cells undergo phenotypic and
morphological changes to acquire mesenchymal characteristics including increased motility and
invasiveness. Currently, the role of EMT in TKI drug resistance is poorly understood. EMT results
in loss of tight junction proteins such as E–cadherin and upregulation of transcriptional repressors of
these proteins such as ZEB1. Recently, protein arginine methyl transferase 1 (PRMT1) has been
shown to be an important regulator of EMT, cancer cell migration and metastasis. However, the role
of PRMT1 in TKI resistance is not known. In this study, we propose to evaluate the role of EMT
proteins in TKI resistance using H2170 and H358 cell lines (wild type EGFR) that were made
resistant to an EGFR inhibitor, erlotinib and a c–Met inhibitor, SU11274 and a combination of both.
H3255 cell line (with L858R EGFR mutation), and H1975 cell line with L858R and T790M EGFR
mutations which we have made resistant to erlotinib will also be used. Our recent in vitro studies
indicate that TKI resistance may be due to the activation

Of EGFR And Transducer Signals At The Rtks?
The TKs are classified as receptor and non receptor TKs. The receptor TKs, transducer signals from
extracellular to the cytoplasm but the non RTKs are intracellular, it transmits intracellular signals
(Pawson, 2002). For example the known RTKs of EGFR and platelet derived growth factor
receptors (PDGFR) are monomers placed in the cell membrane. When the ligands were binding to
their extracellular domain resulting RTKs are activated. The ligands of epidermal growth factor
(EGF), platelet derived growth factor (PDGF) etc., are extracellular signal molecules that induce
receptor dimerization except insulin receptor (IR). Ligand binding domain of the RTKs may contain
disulphide bond that connects the extracellular and intracellular regions of ... Show more content on
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Another way the cytoplasmic MAPK can be activated by some other cytoplasmic proteins, for
example the stress–activated MAPK, p38, is phosphorylated by the cascade, which start in the inside
cell membrane–bound TNF–receptor–associated factor 6 (TRAF6) and ended in phosphorylated p38
in the nucleus. This induces effects such as cell motility, inflammation, chromatin remodeling,
osmoregulation and apoptosis (Johnson and Lapadat, 2002; Guicciardi and Gores, 2003).
Kinases mediated tumorogenesis in lung malignancies:
Normally in healthy cells, the protein kinases (PK) may act as proto–oncogenes or tumour
suppressor. However, alteration in PKs may lead to development of cancer by several mechanisms,
including the activation of cell multiply pathways, genomic instability, diminish of apoptotic
pathways, the endorsement of angiogenesis and cell motility. Receptor and non receptor TKs are
mostly deregulated in several types of cancer. EGFR is a transmembrane receptor kinase that is
overexpressed or aberrantly activated in NSLC.
Davies et al. in 2005 screened 26 primary lung neoplasm and seven lung cancer cell lines for
somatic mutation through the coding sequences of 518 protein kinases (f1.3 Mb of DNA per
sample). From this they found 188 somatic mutations, of these 127 were missense mutation, 13
nonsense, six frameshift, one in–frame insertion, six splice site, and 35 synonymous

Phosphorylation Is The Formation Of A High Energy Bond...
Phosphorylation is the formation of a high–energy bond between a phosphate group and a target
molecule in the presence of an enzyme. In a cellular environment, it is estimated that 1/10th to half
of the total proteins are phosphorylated to perform a specific function in the cell. The concept of
protein phosphorylation was first introduced by Edmond Fischer and Edwin Krebs in the year 1955,
where they elucidated the necessity of ATP and a kinase (Known then as "converting enzyme").
Interestingly, a reaction which involved protein phosphatases (PP) was reported a decade earlier, but
it was not characterized as PP reaction because of the inability to detect inorganic phosphate as a
product.1
Since the above mentioned early discoveries, it has been well established in eukaryotic cells that
reversible phosphorylation of proteins, executed by kinases and PP, regulate major signal
transduction cascades. The highly specific signaling and reversible nature of phosphorylation seems
to suggest that there would be similar number of protein kinases and PP, but sequencing of human
genome has revealed that about 3% of the genome codes for kinases and PP, out of which
serine/threonine phosphatases (PSP) are 2–5 times fewer than serine/threonine kinases (PSK). This
irregularity in between PSK and PSP can be explained by the combinatorial formation of PSP
holoenzyme formed in between common catalytic and varying regulatory subunits.1
This short review focuses on one of the major PSP, known

Conservative Helix Loop Helix : A Protein Kinase
Conservative helix–loop–helix ubiquitous kinase (CHUK) is a protein kinase has many cellular
targets and also plays a role in NF–kappa B transcription. NF–kappa B is a key mediator in
immunity. The CHUK SNP rs11591741 was also associated with response to etanercept (Murdaca
2014). The Fc receptor is a receptor for the Fc portion of immunoglobulins. This receptor is found
on the surface of mainly immune cells. They have a protective function and bind to antibodies
attached to infected cells or invading pathogens. They can stimulate phagocytotic or cytotoxic cells.
Fc receptor polymorphisms FcIIIA–V158F and FcIIA–H131R are significantly associated
with lower body surface area (BSA) of psoriasiform plaques in the intermediate point of treatment
with TNF–alpha inhibitors (P=0.02, P=0.03) (Julia, M). Late cornified envelope (LCE) encodes for
stratum corneum related proteins. Patients with the LCE DD genotype had a high frequency of not
reaching PASI 75 with TNF–alpha inhibitors (P=0.028) (Batalla). IL–12 and IL–23 antagonists IL–
23 is a proinflammatory cytokine that drives the local Th17 effector response, which leads to the
expression of various IL–23 dependent genes, including IL–17A. Th17 cells have been linked to the
pathogenesis of psoriasis. Polymorphisms in genes related to IL–12 have been linked to efficacy
with anti–TNF–alpha treatment. Patients with the IL–23 receptor SNP rs11209026 GG genotype
who were treated with TNF–alpha inhibitors achieved PASI90 at 6 months

Neuroblastoma Biology Essay
A major player in neuroblastoma biology is MYC, it is normally contained within our cells and is a
large protein that functions as a transcription factor. MYC is known to be a proto–oncogene which
normally activates gene expression, it can also repress it depending on what gene it sits on.
Myc belongs to a family of related human genes which are known through (Hart et al 2010) to have
evolved from primordial myc–like genes found in Drosophila and Hydra, these include; c–MYC,
MYC–N and MYC–L. The expression of c–Myc is seen in all tissues whereas MYCN is expressed
in the nervous system and MYC–L is found initially in the lungs. Myc proteins are basic helix–
loop–helix (HLH) leucine zipper transcription factors by which MYCN and c–Myc share ... Show
Inhibition of this pathway was seen to decrease the neuroblastoma tumour mass as well as the
oncogene MYCN protein expression, and in neuroblastoma cells lines the use of AKT specific
inhibitors induced apoptotic cell death. Another pathway relevant to MYCN is the glycogen
synthase kinase 3 (GSK3) pathway which is known to be involved in a large number of signalling
pathways [e.g., Wnt, PI3K/Akt, mitogen–activated protein kinase (MAPK), and p53], many of
which are associated with the neural crest. Wnt signalling is known to be crucial in the induction,
delamination and differentiation of the neural crest and GSK3 is seen to be a negative mediator of
this pathway. Mammalian GSK3 is generated from two genes GSK3α and GSK3β, GSK3β
phosphorylates and stabilizes the MYCN protein, this in turn can enable the dephosphorylation of a
different site that can lead to MYCN degradation.
The cell cycle and cell differentiation are processes where they appear to be regulated by sensitive
molecular mechanisms such as cyclins. Cell division mechanisms involve protein kinases and their
activators which are necessary for the cell cycle to proceed. The protein kinases are modulated by
signals that involve changes in the expression patterns of these kinases, post–translational
modifications and

Kennedy 's Disease : An Incurable Neuromuscular Disorder
Kennedy's Disease is an Incurable Neuromuscular Disorder.
What is Kennedy's Disease? Kennedy's disease is an inherited neurodegenerative disorder that
affects both the spinal and bulbar neurons. KD is a lower motor neuron disorder because it interrupts
the transmission of nerve cell signals in the brain and spinal cord. This interruption affects the spinal
and bulbar neurons causing the major symptoms muscle atrophy, weakness, contraction
fasciulations, and bulbar weakness. KD is the first of the neurodegenerative disease for which the
molecular basis was discovered to be the expansion of a trinucleotide CAG repeat in the causative
gene (Banno, 2012, p.313). The disease is inherited from an impaired x gene. Since KD is a
recessive X– linked gene it primarily affects males. Females are rarely affected because they have
two X chromosomes and are usually just carriers of the defective gene. The carriers of the gene are
usually asymptotic but occasionally can develop mid symptoms. (Cell and Tissue Research, 2012, p.
13)
KD is a very rare disorder, the prevalence thought to be 2 per 100,000 people according to the Cell
and Tissue Research article. It is thought that KD is often misdiagnosis as amyotrophic lateral
sclerosis (ALS). The first case ever recorded of KD came from a patient who was previously
diagnosis with ALS and wanted a seconded opinion. The onset for KD is usually midlife, the range
being from 30–60 years of age. The onset is often preceded by non–specific

Essay On Silico Analysis Of FLT3 Gene
In silico analysis of single nucleotide polymorphism (SNP) in human FLT3 gene
ABSTRACT
FLT3 is a member of extracellular receptors on hematopoietic precursors and belongs to the class 3
tyrosine kinase receptor. The FLT3 receptor is receptor gene encodes a 993–amino acid protein. Its
location on the chromosome is 13q12. FLT3 receptor ligand , FL–like tyrosine kinase poisoning 3
receptor interaction works to maintain, spread and differentiate from the normal hematopoietic stem.
The damaging mutations for FLT3 gene have not been predicted in silico. The current work was
done to determine the harmful single nucleotide polymorphisms in FLT3 gene of Homo sapiens by
Several bioinformatics tools to identify functional SNPs, predict damaging ... Show more content on
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In addition, FMS–like tyrosine kinase–3 receptor expressed in most acute lymphoblastic leukemia
cells and acute myeloid leukemia(Drexler, Meyer et al. 1999). FMS–like tyrosine kinase–3 receptor
mutations are identified in about 30% of the adult with acute myeloid leukemia, and leukocytosis
and poor prognosis(Rasko, Metcalf et al. 1995, Kiyoi and Naoe 2002, D Kottaridis, Gale et al. 2003,
Levis and Small 2003, Stirewalt and Radich 2003, Naoe and Kiyoi 2004, Kiyoi, Yanada et al. 2005).
In normal bone marrow, expression appears to be restricted to early progenitors, includingCD34_
cells with high levels of expression of CD117 (c–KIT)(Rasko, Metcalf et al. 1995, Drexler 1996,
Kiyoi, Yanada et al. 2005). FMS–like tyrosine kinase–3 receptor is also expressed at high levels in a
spectrum of hematologic malignancies including 70% to 100% of myelogenous leukemia of all
French–American British subtypes–precursor cell acute lymphoblastic leukemia , a fraction of T–
cell acute lymphoblastic leukemia, and chronic myelogenous leukemia in lymphoid blast
crisis(Mackarehtschian, Hardin et al. 1995, Kiyoi, Yanada et al. 2005).
Targeted disruption of FMS–like tyrosine kinase–3 receptor in healthy adult mice with normal
mature hematopoietic populations(Savvides, Boone et al. 2000). However, there are deficiencies in
primitive B–lymphoid progenitors, and bone marrow transplantation experiments that show reduced
ability of stem cells lacking FMS–like tyrosine kinase–3

The Endoplasmic Reticulum
1. Introduction
The endoplasmic reticulum (ER) is the central intracellular organelle providing stringent quality
control systems to protein synthesis. Upon accumulation of misfolded/ unfolded proteins in the ER,
eukaryotic cells have developed an evolutionarily conserved adaptive mechanism, unfolded protein
response (UPR), to clear these proteins and restore ER homeostasis. The ability to respond to
perturbations in ER function is critical for cell survival but chronic or amplified ER stress can lead
to apoptosis to protect the organism by removing the stressed cells. Growing evidence suggests that
ER stress–mediated apoptosis may contribute to pathophysiological processes involved in a number
of diseases such as neurodegenerative disease, diabetes, atherosclerosis and renal disease [1]. This
term paper intends to address (i) ER stress–mediated signaling, (ii) molecular mechanisms linking
ER stress to apoptosis and (iii) a potential role of ER stress in autoimmunity in the context of type I
diabetes.
2. The Endoplasmic Reticulum
The endoplasmic reticulum (ER) is an essential organelle that is a major place for the biogenesis of
cellular components including proteins, lipids, and carbohydrates and internal calcium storage. ER
is primarily responsible for protein translocation, protein folding and protein post modification.
Proper folding of protein in the ER is accomplished with the aid of ER resident proteins or enzymes
such as chaperones. Binding of chaperones to

Anilinoquinazoline Mechans Of Egfr
Specifically the genetic alteration of epidermal growth factor receptor (EGFR) and anaplastic
lymphoma kinase (ALK) genes encodes targetable tyrosine kinases, involved in growth factor
receptor signaling and these genes has changed the way these cancers are diagnosed and treated. As
gefitinib and erlotinib are competitive inhibitors of the EGFR tyrosine kinase, in the last decade
several clinical trials of advanced–stage lung cancer.
Covalent inhibitors are a class of kinase inhibitors, which forming covalent bond to the active site of
kinase, most commonly by reacting with a nucleophilic cysteine residue (Cohen et al., 2005; Kwak
et al., 2005). The most clinically using advanced irreversible kinase inhibitors of the (EGFR) are
HKI–272 ... Show more content on Helpwriting.net ...
Polier et al. 2013 identified a new mode of action for ATP–competitive kinase inhibitors, is a
significant class of anticancer agents, these inhibitors are used in the clinic (Polier et al., 2013). This
discovery of new inhibitory mechanism of action exposes the interactions among the chaperone
protein heat shock protein 90 (HSP90), its co–chaperone CDC37 (a scaffold protein) and the protein
kinases that they regulate. However, the inhibition of Hsp90 in vivo cause in degradation of kinase
clients, with a curative effect in dependent cancers. Result of this study shows that the Cdc37
binding to protein kinases is itself disturbed by ATP–competitive kinase inhibitors (vemurafenib and
lapatinib). Polier et al used the commonly mutated BRAF kinase model to perform their
investigations.
Malignant pleural mesothelioma (MPM) is a disease with few therapeutic options. Protein kinase C
beta (PKCß) is involved in important cellular functions. It was highly expressed in the majority of
MPM cells. Enzastaurin (LY317615.HCl) is a novel inhibitor of PKC, which has preclinical activity
against MPM, and exhibited synergism with cisplatin. PKCß inhibition in MPM might be able to
reduce the invasiveness of MPM by affecting cytoskeletal function (Faoroa et al., 2008).
At least 40 kinases are known to be

Cushing's Disease
Introduction Cushing's syndrome(CS) results from prolonged exposure to excess free
glucocorticoids. Around 10–15 per million people are affected by CS every year(1). Most patients
with CS have an Adrenocorticotrophic(ACTH)– secreting pituitary adenoma, which is otherwise
known as Cushing's disease. Other causes of CS include adrenal tumours, ectopic ACTH–secreting
tumours and exogenous steroid use. Except for exogenous steroid use, the other mentioned causes of
CS can all be caused by genetic mutations. Currently, very little is known about the prevalence of
genetic mutations in CS. This essay will discuss the key genetic mutations that cause CS and
explore the advantages of identifying the mutations with regards to clinical management of CS. ...
Menin acts as an adaptor protein regulating multiple pathways involved in differentiation, DNA
repair, proliferation and epigenetic modification. It is also expressed in all adult tissues which
strongly indicates a key role in cell cycle regulation. This is emphasised by the fact that MEN1
knockout mice(12) die in utero with neural, hepatic and cardiac abnormalities. However, there is
still a mystery to why the absence of a functioning ubiquitous protein only causes proliferation in
endocrine tissue. This is partially answered by the mechanism of menin. In p27kip and p18ink4c
double knockout mice(13), the mice develop parathyroid and pituitary adenomas. In other words, a
very similar picture to MEN1. This is highly suggestive of menin working upstream of other cell
cycle regulators, such as p27kip and p18ink4c. It also indicates that in endocrine cells there are no
mechanisms to compensate for deficiency in functional menin, whilst in other tissue types can
compensate. This explains why menin deficiency seems to result in endocrine

Leucine-Rich Repeat Kinase 2 : An Analysis Of Parkinson's...
Leucine–Rich Repeat Kinase 2 is associated with several diseases, such as cancer, inflammatory
bowel disease and multibacillary leprosy, but has its clearest link with Parkinson's disease (Cogo,
Greggio & Lewis, 2017). Up to now, several PD–associated autosomal dominant mutations in
LRRK2 have been discovered, including G2019S, R1441C/G/H, Y1699C, I2020T and N1437H,
indicated in figure 2. Of these mutations, which all entail amino acid
Figure 3. Illustration of the protein secondary and tertiary structure of the kinase domain of the
LRRK2 protein of a brown rat, consisting of both α–helices and β–sheets, coloured coded from red
at the N–terminus to blue at the C–terminus. Shown in 'sticks' format is the highly selective, potent
... Show more content on Helpwriting.net ...
This suggests that both enzymatic structures are of critical value for maintaining normal
physiological LRRK2 function. Mutation R1441C/G/H has been shown to up–regulate kinase
activity as well, suggesting that mutations that occur in the ROC domain also increase kinase
activity (Li, Tan & Yu, 2014). MacLeod et al. (2006) have revealed by pathologically examining
patients with LRRK2 mutations that degeneration of dopamine neurons in the SN occurs. They
showed mammalian LRRK2 plays an essential role in regulating neurite maintenance and neuronal
survival, since mutant forms of LRRK2 led to reduced neurone process length and complexity and
ultimately apoptosis. Overexpression of both G2019S and I2020T resulted in a dramatic neurite
length reduction, as can clearly be seen in figure 4 (MacLeod et al., 2006). As a follow–up,
Parisiadou et al. showed in 2009 that this neuronal development was regulated by LRRK2 through
modulation of ERM (ezrin, radixin and moesin) protein activity and actin polymerisation
(Parisiadou et al., 2009). They showed that over–expression of LRRK2 due to the G2019S mutation
inhibited neurone outgrowth, increased phosphorylation of ERM proteins and increased the content
of F–actin, which is actin that is present in linear polymer microfilaments, in filopodia. ERM
proteins are, therefore, thought to be a physiological substrate of the kinase activity of LRRK2. It is
this increased presence of ERM proteins that plays a role in the developmental

Activation of Protein Kinases by Means of Stochastic...
Short overview The current technology is based on protein kinase activation by means of stochastic
resonance mediated through pulsed electrical fields of very low signal strength. The mode of action
reveals how even small pulsed electrical fields can have a major influence on cellular function and
physiological consequences. It is well known that biological sensory systems transform analog
quantities such us pressure, temperature, electric fields (E–fields) etc. into trains of information. All
the features of systems exhibiting stochastic resonance were found to be present in cell signaling
systems which are intrinsically noisy, nonlinear threshold systems. We observed the effects of
pulsed electrical fields of intensity near that of ... Show more content on Helpwriting.net ...
We visualize the mechanism as that of a working Brownian ratchet where transitions into a different
activated state can be favored. We observed that changing frequencies of E–fields causes enhanced
activation from 2 to 100 Hz and that higher frequencies cause reduced activation. Thus the system
fulfills the requirements of a stochastic resonance system with a '∩' shaped curve. Introduction:
Stochastic resonance (SR) occurs in a system with a threshold or barrier such as in a protein when a
correct input of information transfer (changes in specific electrical fields effecting charged particles
and signal–to–noise ratio) is maximized in the presence of a specific non–zero level of stochastic
input noise (such as randomly fluctuating electrical fields) thereby lowering the response threshold.
The system will then resonate at a particular noise level. Thus, stochastic resonance is a term which
describes that one time scale is established by the period of the external stimulus and the other by
the position to position switching rate induced by the stochastic process or noise. By this effect a
synchronization of a nonlinear system to a weak periodic signal can be enhanced by the presence of
random fluctuations. A weak periodic signal is one which cannot by itself produce switchin g
between positions in protein subunits. In such systems the essence of the signal enhancing effect of
SR can be understood in following way: In the absence of stimuli there are few and random

Duchenne Muscular Dystrophy Essay
Duchenne's muscular dystrophy, also known as psuedohypertrophic muscular dystrophy, is a typical
sex–linked disorder in which the muscles degenerate throughout a person's life. It literally means
"faulty nutrition of the muscles." Muscular Dystrophy has no cures, and this particular type of
muscular dystrophy affects only males. One in 3,500 baby boys are born with this disorder and
survival is rare beyond the early 30s, death is usually caused by a respiratory disease. (ygyh.org)
Duchenne's muscular dystrophy is named after the French neurologist, Guillaume B. A. Duchenne,
who lived from 1806 to 1875. In 1861 he became the first person to describe the disorder. In 1951
Elizabeth Shull Russell, an American geneticist, ... Show more content on Helpwriting.net ...
(www.ncdi.nlm.nih.gov) Usually, children with muscular dystrophy develop normally during the
first few years of their life. In time some common symptoms appear, including: stumbling,
waddling, difficulty climbing stairs, and toe walking (walking on the toes, not letting the heels hit
the floor). It is also very common for a child with MD to develop large calf muscles. This is a
condition called calf pseudo hypertrophy, in which the muscle tissue is destroyed and replaced by
fat. (www.kidshealth.org) Duchenne?s muscular dystrophy usually affects the patient by age five,
and they?re usually in a wheelchair by the age of twelve. Over time the muscles weaken in the
shoulders, back, arms, and legs. Eventually the respiratory muscles are affected, and a ventilator is
required to assist with breathing. Kids with this form of MD usually have a life span of around
twenty years. Most kids with Duchenne?s muscular dystrophy are of average intelligence, although
one–third of MD cases also experience learning disabilities, and a few cases have mental
retardation. (www.kidshealth.org) Physical therapy can be used to help a child maintain muscle tone,
thereby extending their lifespan. For those that do have Duchenne?s muscular dystrophy activity is
highly encouraged. Inactivity can worsen the muscle disease. Leg braces can also allow a child with
MD to walk independently for a longer period of time.

Inclusion Body Myositis ,or IBM, is one of many muscle...
Inclusion Body Myositis ,or IBM, is one of many muscle diseases known as inflammatory
myopathies, which causes slowly progressing muscular atrophy and weakness(NINDS IBM
,2014,para 1). Let it be known that in this paper, I shall define IBM, give it's symptoms and signs, as
well as whether or not it is related to birth defects, trauma or age related pathology. A prognosis and
diagnosis , for said disease, will be given ; as well as , whether or not it is treatable. I will also
mention the research being conducted on IBM. Inclusion Body Myositis? Inclusion Body Myositis,
or IBM, is a rare inflammatory muscle disease which affects the proximal(near the trunk of the
body) and distal(far from the trunk of the body) muscles. It is most evident ... Show more content on
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Some people complain of a loss of balance, this is probably because the muscles become unable to
compensate for an off–balance posture. Serious injury from tripping and falling down is a common
risk with Inclusion Body Myositis. In addition severe muscle pain is another commonly noted
symptom. The diagnosis for IBM, although difficult, simply because the symptoms may be caused
by other illnesses, is based on clinical signs and subsequent testing. Many tests can help diagnose
the disease , including a blood test that screens for creatine kinase or CK levels. The result of muscle
cell damage is the blood enzyme CK. High CK levels would then show strange muscle damage. An
electromyography, which is a technique for recording the electrical activity of muscles, can be used
to recognize characteristic abnormalities. The best way to diagnose Inclusion Body Myositis ,
however, is a muscle biopsy, where a small sample of muscle is removed for laboratory analysis
(IBM illnessopedia,n.d.,para 3) . Muscle resonance imaging scans may also reveal changes in the
muscles. (Travers, P. ,2010, June 17)
Prognosis, Treatment and Research The prognosis or outlook for patients suffering from IBM is not
good. So far IBM is generally resistant to most therapies. Its rate of progression also seems to be
unaffected by available treatments(NINDS IBM ,2014,para 3). According to "Seminars in
Neurology " IBM

What Is Muscular Dystrophy?
Muscular Dystrophy When people hear about diseases most of them don't understand what exactly
causes the disease in the first place, or even how widespread it could be. So they go about their days
ignoring the disease all together. Such as the case for Muscular Dystrophy (MD). According to the
Center for Disease Control (CDC) Muscular Dystrophy in its more predominant forms affects 1 in
every 5,000 males. The two most common forms of Muscular Dystrophy, Duchenne and Becker
(DBMD), affects 1 in every 7,250 males aged 5 – 24 years (CDC, 2017). Muscular Dystrophy has
been shown to affect males more so than females. It has also been shown that DBMD among Non–
Hispanic blacks were lower than Hispanics and Non–Hispanic whites. (CDC). In 2009 ... Show
The only thing available to patients are treatments to try and slow down the process of muscle
degradation. There are only two current types of treatments available for patients, drugs and
physical therapy. The two most common types of drugs given are corticosteroids and heart
medications. Corticosteroids can help increase muscle strength and slow progression, although their
long–term use can weaken bones and increase weight gain. Now if the muscular dystrophy impacts
the heart, beta blockers and angiotensin–converting enzyme (ACE) inhibitors may be useful. Now
there are four different types of physical therapy that may help out, the first one is just general
exercise because it helps keep the limbs limber and in motion for longer than if you weren't to
exercise. Now if your muscles weaken to the point where it becomes hard to breath, then a breathing
assistant will be given to help ease the flow of air that you produce. When MD has reached its
advanced stages, then braces and mobility aids are given to keep you moving and to stretch your
muscles and tendons as to slow down the process of weakening muscles. (MNT) The two most
effective ways of treating MD were the corticosteroids and also general exercise. Since the
corticosteroids in the long run cause you to gain weight, the general exercise helps keep that in
check along with keeping you active. Unfortunately with these treatments it does not stop MD from

Rapamycin Analysis
Introduction:
Cell behavior is regulated by numerous environmental signals with associated alterations in the
expression of various genes involved in cellular physiology. As result, protein synthesis is
consequently downregulated, therefore having a negative impact on growth and proliferation. An
understanding of the mechanisms by which cells receive and integrate extracellular signals,
triggering a cascade of intracellular signals that influence cell growth and metabolism, is essential to
developing a well–targeted therapeutic. One of these mechanisms is the mechanistic target of
rapamycin, also known as the mammalian target of rapamycin, (mTOR) which links growth factors,
nutrients and energy availability to cell survival, growth, proliferation, ... Show more content on
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The N–terminus of mTOR contains two tandem repeated HEAT motifs (protein interaction domains
found in Huntington, Elongation factor 3, PR35/A and TOR), followed by a FAT (domain shared by
FRAP, Ataxia telangiectasia muted, and TRRAP, all of which are PIKK family members) domain, a
FRM (FKBP12–rapamycin–binding site, found in all eukaryotic TOR orthologs) domain, a PtdIns
3– kinase related catalytic domain, an auto–inhibitory (repressor domain or RD domain), and a
FATC (FAT C terminus) domain that is located at the C–terminus of the protein. The FRB domain
forms a deep hydrophobic cleft that serves as the high–affinity binding site for the inhibitory
complex FKBP12–rapamycin (Adapted from

Second Messenger Research Paper
Second messengers and their actions
Second messengers are intracellular molecules that transmit received signs at receptors on the cell
surface to the target molecules. They also, expand strength of signals.
Second messenger are classified into three major classes:
1) Cyclic nucleotides.
2) Inositol triphosphate IP3 and diacylglycerol DAG.
3) Calcium ions Ca3+.
Common mechanism of second messenger system:
There are several different secondary messenger systems, but they all are quite similar in overall
mechanism, although the substances involved and overall effects can vary.
This conformation change can affect the activity of the receptor and result in the production of
active second messages.
The G–protein is bound to the inner membrane of the ... Show more content on Helpwriting.net ...
Action of cGMP:
It is action is mediated by Protein Kinase G (PKG) , a cGMP–dependent protein kinase, that
phosphorylates target proteins in the cell.
 Inositol trisphosphate (IP3) and diacylglycerol (DAG):
Synthesis of IP3 and DAG:
Peptides and protein hormones like: (vasopressin, thyroid–stimulating hormone (TSH), and
angiotensin) and neurotransmitters like GABA bind to G protein–coupled receptors (GPCRs).
That binding activates the intracellular enzyme phospholipase C (PLC).
The intracellular enzyme phospholipase C (PLC) hydrolyzes phospholipids specifically
phosphatidylinositol–4,5–bisphosphate (PIP2) which is found in the inner layer of the plasma
membrane. this Hydrolysis of PIP2 yields two products:
– Inositol trisphosphate (IP3) .
– diacylglycerol (DAG). 1. Inositol trisphosphate (IP3):
IP3 action:
IP3 is soluble molecule that at first diffuses through the cytosol, then it binds binds to receptors on
the endoplasmic reticulum which as a result cause the release of calcium ions (Ca2+) into the
cytosol.
The final result is elevating in the intracellular calcium which itself triggers the

Insulin Research Paper
Insulin is a major metabolism regulating hormone. It is secreted by beta cells of the pancreas. Its
function is to counter the concerted actions of a number of hyperglycemiagenerating hormones and
to maintain low blood glucose levels. Insulin also stimulates lipogenesis, diminishes lipolysis, and
increases amino acid transport into cells. Insulin is a member of a family of structurally and
functionally similar molecules that includes the insulinlike growth factors, IGF1 and IGF2, and
relaxin. Insulin modulates transcription and stimulates protein translocation, cell growth, DNA
synthesis, and cell replication, effects that it holds in common with the insulinlike growth factors
and relaxin.
Insulin secretion from beta cells is principally regulated ... Show more content on Helpwriting.net ...
Each IRS molecule has four sequences that are approximately TyrXXMet.
TyrXXMet
is a recurring sequence that is responsible for the IRS molecules' affinity of the receptor tyrosine
kinase. IRS molecules activate when the tyrosine kinase phosphorylates these Tyrosines. An
example is SH2 is a domain present in many signaltransduction proteins. SH2 domains are host to
specific phosphotyrosine sequences, such as those in activated IRS proteins. This is a specific
process, so each SH2 domain has a binding preference to an approximate sequence including
phosphotyrosine. A large group of lipid kinases have SH2 domains that are attracted to IRS proteins.
These lipid kinases react at the 3position of inositol in phosphatidylinositol 4,5bisphosphate
(PIP 2 ) and add a phosphoryl group. By attracting the lipid kinases to IRS proteins, the reaction
moves the kinases to PIP 2 located on the membrane where it can phosphorylate them to
phosphatidylinositol
3,4,5trisphosphate
(PIP 3 )
This causes a cascade which activates the protein kinase PDK1, which phosphorylates the protein
kinase Akt, thus activating it as well. Akt is a free moving kinase inside the

Essay about Dietary Supplements Used by Athletes: Creatine
Creatine (Cr) is a popular dietary supplement used by athletes to increase sports performance,
muscle mass, and strength. Creatine was first discovered in "1835, when a French scientist reported
finding this constituent of meat" (Demant & Rhodes, 1999). This organic compound is
manufactured endogenously by the liver and kidneys "from the amino acids glycine, arginine and
methionine" for energy stipulation during muscular contraction. (Arazi, Rahmaninia, Hoseini, &
Asadi, 2011). Creatine is either converted into free form Cr or phosphorylated form as known as
creatine phosphate (CP). The endogenous production and exogenous consumption of Cr yields
about 1 gram a day for the average person (Cooper, Naclerio, Allfrove , & Jimenez, 2012). In ...
The biological value in whey protein enhances the body's ability to absorb essential amino acids
after resistance training decreasing the athlete's recovery time. When athletes combine whey protein
and creatine monohydrate they expect "a greater increase in lean tissue mass and muscular strength
than supplementations with whey protein alone" (Burke, Chilibeck, Davison, Candow, Farthing, &
Smith–Palmer 2001, p 350). Exogenous Cr supplementation increases the body's Cr levels until
saturation occurs. This saturation of Cr increases the PCK shuttle continuum allowing training
intensity, volume, and duration of the exercise the athlete is performing to continue at a maximum
rate. Any excess Cr in the blood is cleared through sweat, urination or renal filtration. Measurements
in strength and peak torques of athletes supplementing with whey protein and creatine monohydrate
(WC), whey protein (W), and a placebo (P) were taken. According to Burke et al, (2001) "repeated
measure analysis of variance was used to assess changes in body composition, strength, and peak
torque for the three groups (WC vs. W vs. P) across time" (p. 354). A twelve week strength training
program was constructed and consisted of a "4–day split routine involving whole body musculature"
(Burke et al, 2001. p 352). Subjects used detailed training logs to compare progress over the 12
week experiment. The end result from this experiment shows that subjects who "supplemented with
both creatine and whey

Different Types Of Stresses From The Internal And External...
Throughout the lifetime of a living organism, it is exposed to many different types of stresses from
the internal and external environment. In order to maintain homeostasis, cells must be poised to
activate appropriate cellular stress responses to overcome the initial stress stimulus. Mitogen–
activated protein kinase (MAPK) pathways are crucial among the major pathways that regulate
stress responses. There are six conserved and ubiquitous MAPK signalling pathways in mammalian
systems that coordinate and integrate responses to various stimuli. The architecture of each pathway
is conserved, with the 'core signalling module' consisting of a phosphorylation cascade which is
mediated by three classes of protein kinases: the MAPK kinase kinase (MAP3K), the MAPK kinase
(MAP2K) and the MAPK. Within this pathway, the MAP3K is activated or inactivated by various
stimuli resulting in the successive phosphorylation and activation of MAP2K, which in turn
phosphorylates and activates MAPK. Activated MAPK's then regulate the appropriate cellular
responses by activating or inactivating cellular targets, such as other protein kinases or transcription
factors. Due to the position of MAP3K's at the apex of the 'core signalling module', it is important to
understand their regulatory mechanisms as the MAPK pathway is dependent on their activation.
Apoptosis signal–regulating kinase 1 (ASK1) is a MAP3K family member. This MAP3K is
activated in response to a host of cellular stress stimuli,

Myosin And Myosin Function And Its Effect On A Huge Number...
Abstract:
The actin–myosin interaction is most commonly known for its role in sliding filament theory, where
myosin II bundles interact with actin filaments to shorten muscle sarcomeres and ultimately contract
the muscle. However the myosin superfamily is huge, numbering 17 different proteins to date, and
encompassing many different roles. The interaction of myosin and actin in non–muscle cells is thus
a huge topic, but in understanding the structure, function and regulation of this part of the
cytoskeleton, it is possible to find new drug targets and design new treatments to a huge number of
diseases. One such target is the Rho–associated protein kinases (ROCKs), which are responsible for
the regulation of the actin myosin cytoskeleton. This report aims to briefly cover the basic role of
the actin–myosin cytoskeleton in non–muscle cells, how it is regulated by the ROCK family of
serine/threonine kinases, and how ROCK inhibitors have could have huge therapeutic potential.
Introduction:
The cell cytoskeleton in an immensely complex system of protein filaments and motors, which is
responsible for maintaining the rigidity and architecture of the eukaryotic cell, while transporting
vesicles and organelles throughout the cell and assisting in cell movement. There are 3 types of
protein filaments in the cytoskeleton – actin filaments, intermediate filaments, and microtubules –
and 3 associated motor proteins – myosin, dynein, and kinesin. Of particular interest, and the focus
of

The Two Component Stressors

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