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Kansas City University of Medicine and Biosciences
Biochemistry 1
M1: Biochemistry 2
M1: Biochemistry 2
Biochemistry 1
Kansas City University of Medicine and Biosciences
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Anna N.
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Medical Biochemistry - An Illustrated Review
Effects of glucagon, epinephrine, cortisol, and insulin on glucose metabolism
(pg. 98)
Fasting state:
Glucagon/Epi stimulates GNG and glycogenlysis
Depletion of glycogen stores, then CORTISOL induces transcription of GNG enzymes
Fed state
Insulin stimulates glycolysis and glycogengenesis
Insulin inhibits activity/transcription of GNG enzymes
Lipophilic vs. hydrophilic medications
(pg. 98)
oral medications with signaling molecules that have LONG half lives
injectable medications with signaling molecules that have SHORT half lives
i.e. epinephrine injections given for anaphylactic shock
Diversity in GPCR signaling
(pg. 101)
Binding of the same hormone on different types of GPCR activates different G-proteins to induce different physiological changes
Ex. Epinephrine signaling produce cAMP which causes smooth muscle relaxation and cardiac muscle contraction
B-Agonist and their effects
(pg. 101)
Albuterol is a B-agonist of ACh
Binds B2-adrenergic receptors to relax bronchial smooth muscles and stimulate heart muscle contractions
Used to treat asthma and COPD, causes tachycardia
Patients unresponsive to albuterol are given Epi
Nitric Oxide and Smooth muscle relaxation
(pg. 102)
NO: paracrine hormone synthesized and released from endothelium
Activates guanylate cyclase in smooth muscle to produce cGMP and activate PKG, resulting in smooth muscle relaxation and vasodilation
NTG decomposes NO in body to produce similar effects
NTG coupled with cGMP phosphodiesterases leads to extreme vasodilation = xtreme low BP
Active CDK-complexes (cyclin dependent kinases)
(pg. 370)
Cyclin binding to CDK causes only partial activation of CDK's kinase activity. BUT without cyclin, CDK is inactive
CAKs = CDK activating kinases phosphorylates CDK on specific residues to fully activate them
active CDK phosphorylates other molecule involved in the cell cycle
Antihistamines inhibit GPCR signaling
(pg. 102)
Histamine = hydrophilic ligand binds to 4 GPCRs (H1-H4)
Anti-histamines = lipophilic molecule that binds to H1 GPCR to inhibit ligand binding
Anti-histamine meds used to treat allergies and can act as anti-emetics
RAS and cancer
(pg. 104)
Defective RAS or its GEFs/GAPs
point mutations in RAS gene decrease intrinsic GTPase activity, keeps it active, Gly to Val
Neurofibromatosis: inactivating mutation in neurofibromin (NF-1) gene which usually encodes GAP (p120AP) for RAS
No NF-1 = prolonged RAS activity = uncontrollable promotion of nerve tissue growth = tumors
Recognition domains
(pg. 105)
Adaptor proteins have special domains that recognize and bind to motifs on the receptor-ligand complex that has autophosphorylated on its tyrosine residue
i.e.: GRB-2 and IRS-1 with SH2 or PTB domains
Small G-proteins
(pg. 105)
monomeric with single polypeptide chain
intrinsic GTPase activity
Control cell proliferation, intracellular vesicular traffic, survival and apoptosis, etc
Mutations can lead to cancer
Ex: RAS, RAB, RHO, ARF, RAN
Insulin resistance
(pg. 105)
loss of insulin stimulation on GLUT 4 uptake activity
Possibly, serine/thronine phosphorylation of IRSs appears to inactivate its activity vs. activation by tyrosine kinase
Multiple kinases involved in Ser/Thr kinase acitivity which is stimulated by free FA, hyperinsulinemia, and cytokines
adenylate cyclase
(pg. 100)
stimulates ATP ---> cAMP
activated by Gs-alpha protein
inhibited by Gi-alpha protein
inner-membrane protein
Protein Kinase A (PKA)
(pg. 100)
2 regulatory and 2 active subunits that are activated by cAMP,
cytosolic enzyme
PKA phosphorylates target enzyme to
- Activate/inactivate
- Alter localization
- Alter amount/abundance
- Induce conformational change
Phospholipase C (PLC)
(pg. 102)
membrane bound protein
activated by Gq-alpha protein
PLC cleaves PIP
Inositol 1,4,5-triphosphate (IP
(pg. 102)
Hydrophilic 2nd messenger from cleavage of PIP
via PLC
Binds and opens IP
-gated Ca
channel on ER
high [cytosolic Ca
] = PKC translocation to inner PM to be activated by DAG
Ca also binds to calmodulin for further activation of other enzymes, i.e Cam-Kinases, phosphatases
(pg. 102)
inner PM bound protein derived from PIP2 cleavage via PLC
Activates PKC that is recruited to the inner PM
Protein Kinase C (PKC)
(pg. 102)
recruited to inner PM via IP3 and activated by DAG
PKC phosphorylates Ser/Thr residues of target proteins to affect cellular metab. growth, and differentiation
(pg. 99)
many different kinds of receptor types that will activate different trimeric G-proteins
7-transmembrane domains
active GPCRs act as guanine nucleotide exchange factors (GEFs) to promote G-protein activation
Receptor Tyrosine Kinases (RTKs)
3 domains with only 1 transmembrane domain
Signaling molecules that bind = growth factors
Ligand binds to induce dimerization of receptor
Autophosphorylation of intracellular tyrosine residue
Adaptor/docking proteins with SH2 domains bind to active RAS-dependent/independent pathways
Desensitization of cellular signals
Hormone/signal level drops - decrease AC activity = low cAMP
Remove signaling molecule: phosphodiesterase will remove cAMP/cGMP
receptor sequestration: endosome - save for later
Receptor destruction: endosome + lysosome protesases
RAS-dependent insulin signaling
involves the monomeric G-protein RAS
insulin binds IRS-1 (RTK) and autophosphorylates
Active IRS-1 binds GRB2
GRB2 binds SOS which acts as GEF to activate transmembrane protein RAS-GTP
RAS-GTP binds RAF to activate its kinase activity
downstream kinase cascade of Mek to Erk leading to changes in gene expression or protein activity
Growth factors
primarily binds RTKS
many different kinds named based on which tissues there were first discovered in
BUT they are found in many different cell types
DNA content
(pg. 366)
DNA in each phase of the cell cycle varies in ploidy
By labeling cells with DNA-binding fluorescent dye and sorting them, cells in different phases of the cell cycle can be distinguished
Cell types
(pg. 366)
Permanent cells: remain in G0, ex. cardiac muscle cells, neurons, and RBCs
Stable cells: Cells in G0 that can return to G1 when stimulated by growth factors allowing for regeneration of damaged tissues, ex. hepatocytes and epithelial cells of kindey
Labile cells: constantly dividing, never enters G0, ex. bone marrow, GI epithelium, hair follicles
(pg. 366)
Somatic = 2N = 46 chromosomes
Germline = 1N = 23 unpaired chromosomes
Proteolysis of Cyclins
(pg. 368)
Polyubiquitination of cyclin via ubiquintin ligases will lead to degradation and thus, inactivation of CDKs
Some ubiquitin ligases can degrade CKIs, thus re-activating CDKs
Retinoblastoma and the RB protein
(pg. 371)
1/20,000 rate in childhood development
Familial form = tumors in both eyes, one RB gene is mutated/lost in every cell in the body and become predisposed to cancer
Non-hereditary form = tumor in one eye, cancerous cells contain different somatic mutations in 2 copies of the RB gene, not in every cell
p53 and cancer
(pg. 371)
p53 as TF for p21 CKI of GS phase = no cell cycle
Li-Fraumeni syndrome and ataxia telangiectasia = cancers due to defective p53 activation
Ex: metabolic activation of benzayrene in cigarette smoke and Aflatoxin produces a mutagen that cases mutations in p53 gene by changing G to T nucleotide
>50% of all human cancers exhibit p53 mutations
Replicative cell senescence
(pg. 371)
Aging cell cultures eventually stops dividing even with GF due to progressive shortening of the teleomeres of chromosomes with ech division
Somatic cells lack telomerase needed to maintain telomere length and protect by promoting end cap structures
Age induced DNA damage could lead to p53 medicate cell-cycle arrest at G1 check point
DNA damage activates protein kinases
phosphorylation of p53
MDM2 inhibitor releases active-phos. p53
p53 serves as TF for transcription of p21
p21 binds and inhibits cyclin/CDK complexes of G1/2 and S phase so RB remains hypophos. so E2F is inactive and halts cell cycle
Myc Activation
RAS signaling activates transcription of Myc gene to produce the Myc protein TF
Myc TF promotes the transcription cyclin D and subsequent activation of its CDK to begin G1 phase of cell cycle
Ative Cyclin D-CDK4/6 phos. RB to activate E2F to proceed with the cell cycle
Fibrosarcomas in chickens
(pg. 376)
Rous sarcoma retrovirus (RSV) could case fibrosarcomas in chicken
RSV incorporates host proto-oncogene c-src into its genome.
Mutations during replication turns transforms it into oncogene v-src
CDK-activating Kinases (CAKs)
phosphorylates T-loop at the "cave site" of cyclin-CDK complex to FULLY activate it
WEE1 Kinase
Phosphorylates "roof" site of fully activated cyclin-CDK complex to inactivate it
serves as TF for the transcription of Cyclin E/A that is necessary to go through G
and S phase
normally bound and inactivated by RB protein
hyperphosphorylation of RB releases active E2F
phosphatase that dephosphorylates "roof" site of inhibited cyclin-CDK complex
reverse the inhibition by WEE1 kinase
CDK inhibitor proteins (CKIs)
p27 binds to fully active cyclin-CDK complex to inactivte.
Retinoblastoma protein (RB)
tumor suppressor protein
hypophosphorylated RB binds and inactivate E2F
Hyperphosphorylated RB by G1 and G1/S CDKs causes it to release E2F
E2F act as transcription factors for cyclin E and A that are used in the S and M phase
S and M cyclin-CDK keeps RB phosphorylated
degradation of cyclins in M phase dephosphorylates RB
programmed cell death without any inflammatory or immune response
involves proteolytic cascade of procaspase activation to caspase
Initiator caspase: initiates apoptosis, caspase 8/9
Executioner caspase: destroy targets, caspase 3
Regulation of CDK activity
phosphorylation of CDK - WEE1
Binding of CKI - p27/p21
Proteolysis of cyclin - occurs during the transition of Metaphase --> anaphase
APC/C: anaphase-promoting cyclosome - a ubiquintin ligase that tags M-cyclins for degradation
anaphase promoting complex/cyclosome
Inactive APC/C is activated upon binding with CDC20
Active APC/C induces polyubiquintination of M-cyclins which then dissociates from CDK and is degraded
CDK now inactive/dephosphorylated
induces metaphase to anaphase
Extrinsic Pathway of Apoptosis
Stimuli: removal of survival factors (FAS) and proteins of tumor necrosis factor family (TNF-a)
FAS binds a homotrimer FAS death receptor
DISC formation which includes FADD, death effector domain, and procaspase 8
Activation of caspase 8 via autocatalysis/clevage into heterodimer
Downstream activation of executioner casepase 3
Intrinsic Pathway of Apoptosis
triggered by DNA damage, cell cycle defects, GF withdrawal
mitochondrial dependent pathway
Stressed mito. releases Cytochrome C via aggregated BAX
Cyto-C binds APAF1 and multiple assembles into apoptosome
Apoptosome recruits and activates caspase 9
Caspase 9 activates downstream activation of caspase 3
BCL binds BAX on out mito. membrane to prevent aggregation and release of Cyto C
Gain of function mutations in proto-oncogenes
Mutations changing protooncogenes in to malignant oncogenes
point mutations: formation of protein with abnormally high activity
gene amplifications: proto-oncogenes are actually normal but high [s] leads to hyperactivity resulting in growth stimulation
Chromosomal translocation: genetic rearrangement brings proto-oncogenes under a stronger promoter or fuses it with a hyperactive protein
Viral oncogenes
retrovirus infects host and integrates into genome
During viral replication, it accidentally incorporates host proto-oncogene into its on genome
Because virus have no mechanism of DNA repair, mutations can occur transforming proto-oncogenes into oncogenes
Viral oncogene can now infect other cells in host and cause tumors
Retinoblastoma protein (RB)
tumor suppressor that binds and inactivate E2F
Common oncogenes
Breast cancer: HER2 --> NEU receptors. Mutation of Val to Glu causes RTK activation even w/out ligand
Glioblastoma: EGF --> EGFRvIII, deletion of ligand binding domain, RTK always active
Chronic myelogenous leukemia: Chr 9/22 translocate results in der(22) Philadelphia Chr producing fused unregulated tyrosine kinase protein, BCR-ABL
Mutation in proto-oncogene / tumor suppressor gene, B-catenin (hyperproliferative epithelium)
Proliferation of mutated cell (early adenoma)
Activation of RAS to drive further cell cycle (intermediate adenoma)
Invasion into surrounding tissues (late adenoma)
Invasion in to blood vessels (carcinoma -metastasis b/c changes in intercellular adhesion
JAK-STAT receptors
More direct route for impacting transcription
Receptors bind cytokines, dimerizes, then binds 2 intracellular JAKs
JAKs phosphorylates each other and the receptor
Receptors binds and phosphorylates STATs
STATs dissociates from receptor, dimerizes, and translocate to the nucleus
Ser-Thr receptors and Smad
Smads can control cell proliferation
Type II receptor binds TGFb and phosphorylates Type II receptor on serine residue
Activated Type I receptor recruits and phosphorylates R-Smad
R-Smad complexes with Co-Smad and migrates to the nucleus
Congenital vs. genetic diseases
Congenital diseases can be genetic but not always. It can be due to improper developmental errors
Metacentric chromosome
equal p and q arm
submetacentric chromosome
p arm < q arm
acrocentric chromosome
p arm << q arm
centromere nearly at terminus
telocentric chromosome
no centromere, just one arm.
humans do not have telocentric chromosome, only mice
chromosome abbreviations
ex: Chr16p11.2
"chromosome 16
region 1
band 1
sub band 2
on the p arm"
"Rhythm and BlueS"
Metaphase I & II is the place where things can go wrong = nondisjunction
esp. @ prometaphase, , spindle fibers can fail to attach to the tetrad/chromatid for equal separation in anaphase = nondisjunction
Cohesion Complex
"sticky" proteins that wraps around and keeps sister chromatids attached
facilitates spindle attachment and recombination
Cohesion complex can get phosphorylated, "lose its stickiness" and disappears, allowing separation during anaphase
Cornelia de Lang syndrome: mutated cohesion complex, characteristic synophrys (unibrow)
chromosome changes in which humans have </> 46 chromosomes
Structural chromosome changes
Rearrangements: balanced/unbalanced
Prader-Willi Syndrome
related to chromosome 15 and genomic imprinting
the deletion of at hotspots of BOTH SNRPN gene on 2 chromosome 15s
Angelman Syndrome
related to chromosome 15 and genomic imprinting
results from deletion at hotspots of BOTH UBE3A gene on 2 chrom. 15
Genomic imprinting
parent specific methylation on chrom that was established during gamete formation
normal process that down regulates expression of a particular gene
Male: methylation of UBE3A
Female: methylation of SNRPN
nondisjunction at meiosis I
homologues fail to separate at anaphase 1.
results in 2 trisomy (23+1) gametes and 2 monosomy (23-1)
most monosomies do not live except for Turner's syndrome
nondisjunction at meiosis II
sister chromatids fail to separate at anaphase II
1 trisomy
1 monosomy
2 euploidy
Chromosome rescue
explains presence of uniparental disomy
in cases of trisomy via nondisjunction, cell will try to get rid of one of the chromosome
there is a 1/3 chance cell will get rid of a chromosome that will result in the 2 remaining being from the same parent
XX: during blastocyst stage, one X in each cell is inactivated randomly into a Barr body. Further development leads to randomized expression of genes on the single active paternal/maternal inherited X.
Women are mosaics of their paternal/maternal X genes. Ex. tortoise cat fur
Men only have X from mother = not mosaics
occurs in the lateral 1/3 of uterine tube
Phase 1: sperm penetration of corona radiata
Phase 2: sperm binding and penetration of zona pellucida via a
crosome reaction and subsequent cortical reaction
Phase 3: Sperm head/tail enter oocyte. 2nd meiotic division --> 2nd polar body
acrosome reaction
Sperm binds SED1/ZP3 protein receptor on zona pellucida
Initiation of acrosome hydrolytic degradation of the zona pellucida
ZP2 receptor on sperm binds to receptor on zona to keep it attached
Cortical reaction
Sperm fuses with oocyte PM
Oocyte cortical granules spill out into preivitelline space and initiates the cortical reaction that prevents polyspermy
change in composition of zona pellucida
SLOW process
Zona & cortical reactions
Fast component: Zona reaction
change in resting potential of oocyte PM to prevent polyspermy
Slow component: Cortical reaction
release of cortical granules containing enzymes that destorys ZP3 receptors and prevents polyspermy
genetically different cells in an individual who developed from a single fertilized egg
cells within one individual have different genetic make up
Somatic mosaicism - nondisjunction in early division leading to abnormal ploidy in various cells in a person
Can be normal: lyonzation creating Barr bodies
monozygotic twins
single fertilized egg splits into embryos sharing same placenta
inner cell mass splits into 2 during blastocyst stage
dizygotic twins
two separate eggs fertilized by 2 separate sperms
two separate blastocyst implants
different placenta
polar (half-identical) twins
polar body of first meiotic division is also fertilized by a different sperm
Thus, twins share genes from the one egg and from two sperms
Twins share all of maternal DNA but only half of paternal DNA
genetically different cells lines in an individual who developed from 2 different fertilized eggs
"fusion of fraternal twins"
Explains presence of intersex individuals having both female/male genitalia
Nuclear fusion of gametes
in mammals, fusion of egg/sperm genes takes 12hrs
once 2N: mitotic division and embyrogenesis begins
compacted 16 cell stage in embryogensis that will further divide and segregate into blastocyst
presence of blastocoele fluid cavity to act as cushion for division
inner cell mass
blastocyst proteases degrades zona pellucida to "hatch" out
Totipotent stem cells
present during morula stage (blastomere stage)
Cells can grow into an entire organism
Pluripotent stem cells
inner mass cells
cannot grow into a whole organism
forms the 3 derm cells and any of its subsequent organs/tissues
Unipotent stem cells
can only form tissues of that specific cell line
Conjoined Twins
incomplete monozygotic twins
Caused by secondary fusion of inner cell mass or development of 2 primitive streaks
Parasitic twins
smaller but often complete portion of the body of a second twin protrudes from the body of the normal twin
parasitic twin is not alive
fetus in fetu
inclusion twinning
fetus trapped inside its twin
not alive
craniofacial duplication (diprosopus)
NOT abnormal twinning
results from defective Shh (Sonic hedgehogh) protein that leads to duplication of facial features
an immunoglobin required for sperm/egg fusion and subsequent acrosome reaction
defective izumo leads to infertility
fetal contribution to the placenta
consists of
XE mesoderm (splanchnic)
(week 1)
Trophoblast differentiation
(week 2)
Embryoblast differentiation into epiblast and hypoblast (bilaminar disc)
formation of amniotic and yolk sac
Formation of XE mesoderm from epiblast
Formation of XE coelom (chorionic cavity) in the XE mesoderm that fills with fluid
(week 3)
appearance of primitive streak
formation of notochord
Extraembryonic mesoderm
(XE mesoderm)
derived from epiblast & yolk sac
Formation begins during week 2 and finished by week 3
layer underneath the cytotrophoblast
gives mechanical and trophic support by developing XE coelom
Initiates formation of placenta
occurs at week 3
appearance of primitive streak
cells differentiate at PS to form a middle MESOdermal layer and displace most of the hypoblast cells to form ENDOdermal layer
ECTOderm forms from the epiblast
Bilaminar to TRIlaminar embryonic disc
forms in mesoderm layer
long flexible rod of mesoderm around which the embryo develops
foundations of vertebral column
Will bring about formation of neural tube
sacrococcygeal teratoma (SCT)
remnants of primitive streak upon birth
derived from all 3 germ layers with blood supply
usually benign
Caudal Dysplasia/regression syndrome
caused by germ layer defects
defective fusion/underdevelopment of lower limbs
VATERL mnemonics: vertebral abnormal, anal atresia, traceho fistula, renal defects, and limb defects
Weeks of major morphological abnormalities
Week 3: CNS heart
Week 4/5: Eyes, limbs
Week 6: ears, teeth
Week 7: palate
family of lipid autacoid mediators derived form oxidative transformation of 20-carb PUFA
Prostaglandins, thromboxanes, and leukotrienes
Mediate autocrine and paracrine
NOT hormones, Short lived local signaling mol.
rapid metabolism via 15-OH PDGH or degradation limits accumulation in circulation
serves as cellular structural support and signaling/stimulus response coupling
There are specific enzymes that enrich unsaturated FA with specific double bonds
Arachidonic acid make 2' PG and Thromboxanes
omega 3 PUFA make 3' PG and thromboxanes
Arachidonic acid (C20:4)
5,8,11,14 cis-eicosatetranoic acid
present in beef
Dominant PUFA in most cellular membranes
substrate for cyclo-oxygenase
makes 2' PG and thromboxanes via arachidonic cascade
Cyclooxygenase (COX)
converts AA + O2 ---> PGH2 (endoperoxide)
requires Fe coenzyme
COX 1 is constitutive, always made and present but NOT present in RBCs.
COX 2 is inducible, made only when needed, ex. kidneys
PG isomerases
converts PGH2 ---> PGE2, PGF2-alpha, PGD2
15-OH PG dehydrogenase
inactivates PGD, PGE, and PGF2
PGs & Tx biosynthesis
made upon demand, not stored
limited in duration/scope by ...
(1) availability of O2 and AA
(2) auto-inactivation of COX
(3) rapid degradation of PGs
(4) spontaneous hydrolysis of Tx/PGI2
Autocrine signaling
Cell has enzymes to synthesize PGs/Tx
the same cell expresses receptors for PGs/Tx
The same cell responds when PG/Tx binds to its receptors
Paracrine signaling
Cell A lack enzymes to make PGs/Tx BUT has receptors for it
Cell B makes PG/Tx and secretes it to stimulate the neighboring cell A
PG & Tx receptors
7 transmembrane domains
Not every cell has every receptor
ability of receptor to bind their specific ligand is based on small highly specific differences in their molecular structure
EP2/EP4/IP eicosanoid receptors
EP= PGE2 and IP = PGI2 (prostacyclin)
couple with Gs-protein and induce signaling cascade involved in the activation of Adenylate Cyclase
increases cAMP to relax smooth muscles
Vasodilate smooth muscles
FP & TP receptors
FP = PGF2-alpha TP = TxA2
couple with Gq stimulatory protein to activate PLC
PLC makes DAG and IP3, thus increasing intracellular [Ca]
works to contract smooth muscles
vasoconstrict blood vessels
angina pectoris
imbalance of vasodilation & vasoconstriction of coronary artery
Ex. excess TxA2 and deficient PGI2
responds to physiological stimuli to regulate physiological functions
made almost in every cell except RBCs
functions in gut, reproduction, and development
Ex. gastric acid stimulates COX1 activity to make PGE2 that forms mucosal cytoprotection and gut motility, deficient PGE2 leads to ulcers
Ex: PGs dilate cervix and contracts uterus
inducible, found in some tissues at some times
responds to pathological stimuli, ie. inflammatory cytokines or growth factors (cancer)
BUT is normally expressed with prominent role in kidneys and brain because of high demand overwhelming activity of COX 1
COX 1 and COX 2 in renal physiology
renin as physiological stimulus
important detox function of the kidney requires higher demand for COX2 on top of COX 1 activity
facilitates renal blood flow, filtration of Na and H2O excretion
defective COX 2, deficient PGs, leads to Na/H2O retention and mild hypertension
COX 2 during inflammation
inflammation stimulates AA release
COX 1 & COX 2 together makes abundant PGE2
high [PGE2] causes bad pain, erythema, and edema
no nucleus, cannot induce expression of COX2
stimulated by collagen and thrombin
TxA synthase makes PGH2 --> TxA2 which constricts blood vessels and amplifies platelet aggregation
autocrine/paracrine signaling of TxA2 binding on platelet and smooth muscle receptors
nucleus present, can induce expression of COX2
makes PGI2 (prostaclyciln) which relaxes blood vessels and inhibits platelet aggregation
Vessel damage: collagen stimulates PGI2 formation around cut to work against TxA2 so that aggregation is localized
PGI2 binds IP receptors on platelets and smooth muscles
Partitioning of PGH2 for hemostasis
COX1 is widespread but varying isomerases in tissues makes different eicosanoid, thus exerting opposing physiological effects
Endothelial cells have PGI2 synthase to make PGI2 = vasodilate
Platelets have Tx synthase to make TxA2 = vasoconstrict
COX 2 induction in endothelial cells
COX 2 is inducible in endothelium
Good: protects against unwanted thrombosis
Bad: part of underlying disease progression of atherosclerosis and inflammation
defective COX2 (or COX1) means low PGI2, allowing for TxA2 to dominate = platelet aggregation around plaque = blocks vessel
Omega-3 FA rich diet
eicosapentaenoic acid (EPA, 5 dbs) found in fish eventually replaces some arachidonic acid in membrane and competitively binds with COX
COX1 --> PGH3 --> PGI3 and TxA3 instead
PGI3 still works as vasodilator and inhibits platelet aggregation, reduce inflammation
TxA3 is a WEAK vasoconstrictor and platelet aggregation
made by leukocytes and have conjugated trienes in their structure
Prostaglandins and the gut
gastric acid serves as physiological stimulus
COX 1 makes PGE2
PGE2 binds to EP receptors of cells in gut
Production of mucosal cytoprotection and stimulates gastric motility
Low PGE2 = ulcers, high PGE2 = cramps/diarrhea
Prostaglandins and reproduction
During birth, endocrine hormones and mechanical stretching of uterus serves as physiological stimulus
COX1 --> PGE2 and PGF2alpha
Binds EP and FP receptors in uterine cells
works to dilate cervix, contract the uterus, and facilitates parturition
Deficit = delayed birth, excess = premature labor
Prostaglandins and neonatal development
fetal lung maturation = stimulus
PGE2 binds EP4 receptor
PGE2:EP4 keeps ductus arteriosus in fetus open so maternal blood bypasses fetal lungs
At birth, neonatal lung matures and metabolizes PGE2 so nothing keeps the ductus open
non-steroidal anti-inflammatory drug
inhibits COX 1/2 activity
GI: low mucosal cytoprotecton = ulcers
neonate lung: premature closing of ductus arteriosis
Uterus: low PG = delayed contractions and cervix dilation
makes leukotrienes
binds EP2 and EP4 receptors coupled with Gs-protein
Activates Adenylate cyclase
increases [cAMP] to relax smooth muscles
Prostacyclin (PGI2)
binds IP receptors coupled with Gs-protein
Activates Adenylate cyclase
increases [cAMP] to relax smooth muscles
Thromboxane A2 (TxA
Binds TP receptors coupled with Gq-protein
activates phospholipase C
production of IP3, DAG, and high intracellular Ca
stimulates smooth muscle contraction
Binds FP receptors coupled with Gq-protein
activates phospholipase C
production of IP3, DAG, and high intracellular Ca
stimulates smooth muscle contraction
Autosomal dominant
affected offspring has one affected parent (AA) or (Aa) and usually one parent is normal
unaffected offspring do not transmit trait (aa)
Males/females can transmit to both males/females
Trait is expected in every generation inherited at ~50%
Autosomal recessive
2 copies of affected allele is needed for expression
Most affected have normal parents,
1:4 siblings affected
Males/females can be affected
Affected (aa) mates with (AA) tends to have normal (Aa) children
more likely affected with consanguinity
X-linked recessive
unaffected males do not transmit disease (XY)
female carriers transmit affected allele to 50% sons/daughters (X
X-linked dominant
very rare
No carriers, all expresses the disease
both males/females affected
females transmit to 50% offspring
Affected male will transmit to all daugthers
frequency with which the gene manifests in a population
"how many people show the phenotype"
describes range of phenotype, varying phenotypes
ex: varying color/#/size of cafe-au-lait spots
Population genetics
study of distribution of genes in a population
how genes behave in a population
Hardy-Weinberg Theorm
large population
random mating
no selection
no mutations
no migrations
Cell Signaling
stimulus induces signaling cell to produce signaling molecules
Binding to receptors to induce a cellular response
results in cytoskeletal, membrane, protein translation, and cell cycle changes
Cellular responses to external signal
Fast response - change in activity/function of enzymes
Slow response - affects gene expression, thus [protein]
Direct cell signaling (juxtacrine)
signaling cell produce signaling molecule that remains attached to membrane
Cell presents signal directly to receptors on another cell
Intracellular receptors
consists of:
transcription activating domain (N-terminus)
Ligand-binding domain (C-terminus)
DNA binding domain
activate receptor has regions 1 & 2 bound by co-activator proteins and region 3 binds to DNA to affect transcription
S-phase chemotherapies
Topoisomerase I inhibitors
Topoisomerase II inhibitors
Cytotoxic Antibiotics
Alkylating agents
G2-phase chemotherapies
Topoisomeriase I inhibitors
Cytotoxic Antibiotics
Alkylating agents
M-phase chemotherapies
Mitotic inhibitors
Topoisomerase I inhibitors
Alkylating agents
Alkylating agent chemotherapy
blocks DNA replication
affects all cell phases
Anti-metabolites chemotherapy
inhibit enzymes involved in DNA synthesis
Affects S-phase
Topoisomerase I inhibitors chemotherapy
Inhibit topoisomerase I, an enzyme that removes supercoils in DNA
Affects S, G2, and M phase
Topoisomerase II inhibitors chemotherapy
inhibits topoisomerase II, an enzyme that resolves tangles in DNA
Affects S phase
Cytotoxic Antibiotics chemotherapy
Intercalate between bases in DNA to inhibit DNA synthesis
Affects S and G2 phase
Mitotic inhibitors chemotherapy
Arrest cells in during metaphase of mitosis
affects M phase
Treats breast cancer
inhibits HER2 receptor thus inhibits mutated NEU receptor
treats Glioblastoma
inhibits EGF receptor
treats Chronic myelogenous leukemia
inhibits the fused BCR-ABL protein
proto-oncogene c-Src
ligand-independent tyrosine kinase protein that phosphorylates other enzymes in signaling cascade
similar to RAS
includes an SH2 and SH3 domain
activation promotes survival, proliferation, angiogenesis,
Transcription factors of embryonic development
General and specific TFs that act on promoters/enhancers to activate/repress gene transcription
Homebox - containing genes & homeodomain proteins
T-box gene family
Helix-loop-helix (basic)
Zing Finger proteins
Subdivision of TFs in embryonic development
interactions with DNA
5 Homeoproteins
structure has 3 a-helixes that are made of 60 highly conserved a.a
homeobox gene has 180 nucleotides that code for homeoporteins
Homeobox DNA sequence are involved in regulation of morphogensis, laying out general body plan
HOX genes (humans)
(Hox - vertebrates)
39 homologous homeobox genes in 4 clusters on 4 diff. chrom
in 13 paralogous groups
carniocaudal segmentation function, setting up structures along main body axis
genes expressed 3' to 5', anteriorly to posteriorly
regulation: high [retinoic acid] = poor vertebral formation
LOS: P/A transformation, GOF: A/P transformation
PAX gene
(homeobox w/ 9 members)
PAX proteins contain 128 a.a. paired domain
formation of tissues/organs, post-natal functions, nervous system development, differentiation of epithelial to mesenchyme
Aniridia - mutated PAX6 leads to complete/partial absence of the iris
PAX6 also involved in eye/CNS/pancreas development
LIM proteins
(homeodomain proteins)
Binds to DNA in nucleus or cytoplasm
Involved in formation of ~all body segments
-/- LIM proteins = headless mammalian embyros
DIX genes
(6 member homeobox)
phylogenetically conserved
important in patterning of limbs and morphogenesis of jaws/inner ear
MSX genes
(6 types homeobox)
Prenatally - inhibitors of cell differentiation
Postnatally - maintain proliferative capacity to tissues
involved in epithelial - mesenchymal interaction in the face along the cranial sutures and the limbs
T-box (Tbx) gene family
100 members, 18 in humans, found in all bilaterians and cnidaria
Important in mesoderm development and specifies forelimbs vs. hindlimb
Helix-loop-helix (basic) TF
proteins with 2 a-helixes and basic a.a loop that facilitates DNA binding
TF forms with 2 proteins dimerizes
Regulates myogensis
Forkhead (Fox) gene family
Helix-loop-helix subgroup with >100members
regulate cell growth, proliferation, differentiation, and longevity
"pioneering transcription activity" = can bind and act on CONDENSED chromatin. no unwinding
multiple small domains work together to regulate
FOXP2 in speech/language muscle development, defect is inheritable
Zinc Finger proteins
Coded by SOX and WTI genes
regulate myogenesis, bone/cartilage/tooth development
cystidine/histidine units bound by zinc that inserts into DNA helix
zinc deficiency = skeletal growth retardation, pathogenesis of osteoporosis
Sox genes
(a ZF-TF)
regulates skeletal, reproductive, respiratory, and facial development
binds to minor groove of DNA
belongs to HMG-box super family of homologous sequences
Campomelic dysplasia: defective Sox9
SoxA = SRY, sex determining region of Y chrom.
(a ZF-TF)
Wilms' tumor suppressor gene
regulate kidney and gonadal development
Denys-Drash syndrome - urogenital abnormalties
Fraiser syndrome - urogenital abnormalities
Signaling molecules
TGF-B super family
TGF-B: BMPs
Fibroblast GF (FGF)
Hedgehog family
Wnt family
TGF-B super family
"transforming growth factor"
regulates embryogenesis and postnatal life
formation, structures, and modifications varies
(bone morphogenic protein)
a TGF-B member, 15 other types involved in skeletal development, etc
inhibits neural formation during differentiation of dermal cells
Active BMP-4: ectoderm --> epidermis
inhibited BMP-4: ectoderm --> neural plate
inhibited by Noggin, Chordin, FGF produced by notochord
role in angiogenesis, wound healing, limb/brain development
Secreted FGFs are associated with ECM and need heparin sulfate to activate receptors
22 members with 100 isoforms
Sonic Hedgehog (SHH)
bound to cholesterol and secreted, involved in everything!
Binds PTCH receptor to inhibit transmembrane Smoothened (SMO) --> no transcription
regulates organogenesis, brain, facial/limb patterning (craniofacial duplication)
Controls adult stem cell division, involved in cancer development
Indian Hedgehog protein (IHH)
involved in chondrocyte differentiation, proliferation, and maturation during endochondral ossification
Desert hedgehog protein (DHH)
defects are associated with partial gonadal dysgenesis with polyneuropaty
Wnt family
18 members that have diff roles in diff vertebrates
mammals: gastrulation and organogenesis
interacts with ECM/ regulate cellular interactions during emyrogenesis
Wnt proteins bind Frizzled/LRP receptors
activate signal cascade --> b-catenin --> bind TCF in nucleus --> transcription of Wnt target genes
regulated by inhibition by other proteins
Other actions of signaling molecules
inhibits actions of other signaling molecules
normal development requires balance of counteracting inhibitors
SHH/FGF = positive regulators of growth
BMP = negative regulators of growth
Notch receptor
basic membrane receptor that is preserved unchanged through the animal kingdom
Retinoic Acid
Metabolite of Vit. A
normally, serves as an intracellular signaling molecule for Hox genes. guides development of the posterior portion of the embryo along the axis
PTCH (Patched receptor)
tumor supressor, transmembrane receptor for SHH
PTCH inhibits SMO
defective PTCH = uncontrolled SMO signaling cascade activity, increase gene transcription
PTCH mutations is the basis for basal cell carinoma
fibroblasts and collagen covering the bone but not the articular surfaces
Sharpey's fibers that penetrate the bone matrix
osteoprogenitor cells lines the inner layer
high vascular/nerve supply, inflammation = shin splints pain "overuse injury"
connective tissue lining the marry cavity of the bone
contains osteoprogenitor cells
lamellar bone
Haversian systems (osteons) circular arrangement of collagen fibers around the central Haversian canal
Lacunae: spaces for osteocytes to reside in the lamellae
Canaliculi: small canals that radiates from from lacuna and house osteocyte cytoplasmic processes
blood vessels found in Haversian Canal
bone matrix
Type 1 collagen, proteoglycans, karatan sulfate, chondritin sulfate
Ca-phosphate - hydroxyapatite
Interstitial lamellae
the result of bone remodeling
residuals of remodeled osteons
Osteoprogenitor cells
resting cells capable of becoming osteoblasts
resemble fibroblasts/other mesenchymal cells
Differentiation regulated by BMP and CFBA1
(core binding factor alpha 1)
Woven bone
temporary bone with unaligned collagen fibers
weaker than lamellar bone
can be found in developing bones
Active cells: basophilic & cuboidal
Inactive: squamous cells
found in newly secreted matrix
initial differentiation from osteoprogenitor cells via Sox9 then further by CFBA1, Run2x, and osteocalin
necessary TF for osteoblast differentiation
act as first tissue indicator for osteogenesis
-/- mice have skeletons made entirely of cartilage instead of bone
non-mineralized matrix deposited from osteoblasts consisting of:
Type I collagen
bone sialoprotein
resorption of bone
large and multi-nucleated cell located in Howship's lacunae (subosteoclastic comp.)
derived from monocyte-macrophage progenitor cells from the bone marrow
Mononuclear phagocyte system
Mechanism of Osteoclasts in the Howship's lacuna
part of the osteoclast nearest the mineralized bone of the compartment has a RUFFLED border
it has vesicles that supply acidic environment for breakdown of mineralized bone
activity is regulated by PTH and calcitonin
2 methods of osteogenesis
Intramembraneous osteogenesis
Mesenchymal differentiation to osteoblast
Deposit of osteoid matrix
Formation of primary bone
Formation of ossification centers that eventually connect to form traeculae
woven bone --> lamellar bone
Endochondral Osteogenesis
Hyaline chondrocytes hypertrophy at midshaft - 1'ossification center
production of Type X collagen to promote angiogenesis
blood vessels promotes calcification of ECM
Chondrocytes undergo apoptosis
2' ossification centers at the epiphysis
Zones of endochondral ossification
reserve zone - hyaline cartilage below the epiphyseal cartilage
proliferative zone of chondrocytes
hypertrophic zone - angiogenesis, chon. enlarge, matrix calcifies
vascular invasion zone - osteoprogenitor cell and blood vessel invades
Trabecular bone remodeling on bone surface
osteoclasts resorbs outer--> inner until it hits a cement line
Osteoblasts lays down bone to close the resorption space
Activation of bone remodeling
initiated by blood vessel damage in the Haversian canal
causes intense proliferation of osteoprogenitor cells form periosteum and endosteum
any clots or cellular debris resulting from the damage are removed by macrophage
Osteoblast bone repair s/p fracture
formation of cellular collar around fracture site
Woven bone is formed
Trabeculae of bone unite to form bony callus to temporarily unite bone fragements
Woven bone remodeled to lamellar bone
General features of bone
mineralized ECM - hydroxyapatite
made of cells, fibers, and ground substance
functions as: mechanical support, locomotion, protection, and Ca/P ion storage
Trabecular bone
spongy/cancellous bone
woven/lamellar bone with spaces for bone marrow
General Aspects of muscles
Function: movement and mechanical energy via energy from ATP
Embryonic mesenchymal myoblasts form multi-nucleated myotubes that develops into muscle cells/fibers
Muscle arrangement
Muscle (made of many fascicles), surrounded by epimysium
Fascicles (made of many muscle cells) surrounded by perimysium
Muscle cells surrounded by endomysium
Each muscle cell with sarcolemma PM
Diagnostic characteristics of skeletal muscles
striated and non-branching
peripheral nuclei
lots of cytoplasm
Muscle fiber (cell)
each muscle cell contains 300-3000 myofibrils
contains sarcoplasm, sarcoplasmic reticulum, mitochondria, peripheral nuclei
T-tubules and sarcoplasmic reticulum
T-tubules turn transverse from sarcolemma into the muscle fibers to facilitate depolarization wave. 2/
SR: stores Ca can be released/sequestered to regulate contraction
Triad = 2 terminal SR cisternae + 1 T-tubule
functional, contractile unit of skeletal muscle
repeats of sacromeres form myofibril
Thin filaments
F-actin made of double stranded chains of round monomers
Tropomyosin strands run along the grooves of actin chains
Troponin sits on top of actin chain and binds to tropomyosin
Thick filaments
Myosin filaments made of 2 heavy globular head chains and 2 light chains
Globular heads bind actin
Nebulin molecule
Extends from Z-line along one thing actin filament
acts as template for regulation of actin filament length
Titin molecule
Extends from Z-line to M-line along myosin
maintains central position of the thick filaments
During relaxation, titin contributes to the elasticity of muscles
Scaffolding proteins
Cytoskeleton network that support myofibrils and coordinate contraction
Desmin filaments: attached to sacrolemma--> Z-disc to form lattice
Plectin filaments link desmin together
aB crystallin HSP protects desmin from stress
a-actinin protein attaches actin at the Z-line
Satellite cells
located between sarcolemma and basal lamina
repair and regrow damaged muscle by producing myogenic precursor cells
capable or regeneration of more satellite cells
Innervation of muscle cells
innervated by alpha-motor neurons at the NMJ
A motor unit = a motor neuron and all the muscle cells it innervates
one motor neuron controlling only a small amount of myofibrils allows for fine movements/sensation
Type 1 muscle fibers
Red slow twitch fibers
Type II muscle fibers
White fast twitch fibers that fatigues easily
Type IIA = more intermediate type
Type IIB= high in myosin ATPase activity
Sensory innervations of muscle cells
Neuromuscular spindles: encapsulated sensors that help monitor position in space and state of contraction
General characteristics of cartilage
Avascular and non-innervated
Functions as s
hock absorber, bone growth/repair, joint movement, bears mechanical stress
Classified by function and location
dense connective tissue around hyaline/elastic cartilage
carries blood supply for the avascular cartilage
Fibrogenic cells: outer layer becoming fibroblasts to provide ground substance
Chondrogenic cells: inner layer, precursor of chondroblasts and osteoprogenitor cells
flat cells with large nucleus and pale vacuolated cytoplasm
replicates and secrete cartilaginous ECM
round cells with small dark nuclei
often found in groups of 2-8 cells known as Isogenous groups
Isogenous groups are diagnostic feature of chondrocytes
breaks down cartilage, resorption
function to remove calcified cartilage during endochondral ossification
Extracellular Matrix
Proteoglycans: Aggrecan, Keratan/Heparan/Chondroitin sulfates
Hylauronic acid
Glycoproteins: link proteins, fibronectin, and Chondronectin that binds C4/C6 sulfates, HA, and integrins: help maintain contact with fibrous and amorphous matrix
Hylauronic Acid supplements
FDA approved tx for joint disorders, cataract removal, retinal repair, corneal transplants
Applied to skin to heal wounds, skin ulcers, and moisturizers
used as lip filler in surgery
Territorial Matrix
High GAGs, low collagen
found immediately around each chonrocyte
Inter-territorial Matrix (IM)
High collagen II, low proteoglycans
Hyaline Cartilage
extensive cross-linking of long proteoglycans + collagen II
Normally surrounded/nourished by perichondrium but in
articular surfaces, it is nourished by synovium
Found in embryo skeleton, epiphyseal plates, articular joints
Hormone effects on cartilage
abnormal growth and calcifications stim. by hormones/vitamins
growth stim.: somatotropin, thyroxine, testosterone
Matrix formation/growth inhibited by cortisone, hydrocortisone, estradiol
Vitamin effects on Cartilage
Hypovitamin A: reduces width of epiphyseal plate, retards growth
Hypovitamin C: inhibits matrix synthesis, deformation of epiphyseal plates -- > SCURVY
Hypovitamin D: leads to deficient dietary calcium absorption. Chondrocytes proliferate but matrix does not calcify properly --> RICKETS
Elastic Cartilage
elastic fibers in matrix
has increased flexibility that allows retention of original shape after deformation
Auricle, ear tubes, ear lobes, epiglottis, laryngeal cartilages
NO perichondrium and
Cc arranged in rows
Matrix abundant in Collagen I and II
Ground substance has dermatan and chondroitin sulfate
Stronger but less flexible then elastic cartilage
attachment of ligaments to articular surfaces, menisci, intervertebral discs, symphysis pubis
may result from damage to hyaline cartilage
Appositional Growth of cartilage
Chondrogenic cells in inner layer of perichondrium produce collagen I
Then cells differentiate to chondroblasts and secrete collagen II and ground substance
Nutrients diffuse in and waste diffuse out to capillaries
Interstitial growth of cartilage
Takes place within the cartilage mass
Cc divide within their lacunae, creating isogenous groups
New Cc secretes more matrix to increase mass of cartilage
Overall growth due to secretion of matrix
limited by avascular nature
Cartilage repair
repaired primarily by perichondrium
Repair more common during growth
Adults has low production of Cc, and usually results in dense CT
Proximity of blood vessels stimulates bone repair instead of cartilage repair
Ex: Cranial Synostosis
Synovial Joints (articular cartilage)
Hyaline cartilage, no nerves or blood vessels which reduces friction between bones
NO perichondrium
nourished by synovial fluids/membrane capillaries
fibrous Articular capsule strengthened by accessory ligaments (intrinsic/extrinsic)
ligaments help limit joint movement
Synovial membrane
regenerative vascular CT membrane that lines the entire joint cavity except for the articular cartilag
B cells produce synovial fluid with HA & Lubricin to increase viscosity and decrease friction
A cells: phagocytic, lysosomes clear cavity of debris formed by friction of articular cartilage
Chorionic Villus sampling (CVS)
small sample of the placenta taken from the chorionic villi where it attaches to the uterine wall
a type of prenatal diagnostic test to detect chromosomal problems
done transcervical, transvaginal, and aminocentesis
Buccopharyngeal membrame
appears upon formation of the primitive streak
opposite end of the primitive streak
4 traits of chordates
Ectodermal spinal cord
postanal tail
Pharyngeal slit will become jaw and inner ear in vertebrates (via DIX TF induction)
a GRK: G-protein receptor kinase that inhibits GCPR signalling
Activated GCPR stimulates GRK to phosphorylate it multiple times on the 3rd intracellular loop
Arrestin then binds the phosphorylated GCPR to prevent interaction with G-proteins
Ras - dependent signaling
insulin-RTK binds and phos. IRS-1
GRB2 binds IRS-1
SOS binds GRB2 to activate RAS
Activation of MAP kinase pathway
Alteration in gene transcriptions
Ex: increased transcription of glucokinase
RAS- independent signaling
insulin-RTK binds and phos. IRS-1
PI3-k adaptor protein binds IRS-1
Activation of PKB
downstream phos./activation of proteins involved in enzyme activity
Ex: increased GLUT 4 movement to PM and activation of glycogen synthase
Improving on insulin via recombinant DNA technology
Normal insulin: Pro-28 and Lys 29 on C-term of B-chain and Asn-21 on A-chain
Lispro: Lys-28, Pro-29 thus is faster acting and readily absorbable
Novalog: Pro-28 changed to Asp-28, fast acting and readily absorbable
Lantac: Asn-21 changed to Gly-21 and two Arg added to C-term = longer acting analogue
Insulin structure
Preporinsulin: has signal peptide that localizes it to the ER
Proinsulin: A change is cleaved in the Golgi
Insulin: A chain and B chain bound together by disulfide bonds
Small portion of the the antigen that the Fab recognizes and binds
One antigen can have different epitopes on their surfaces
A specific kind of antibody can only bind its specific epitope
Generation of monoclonal antibody
Multiple Myeloma: in the presence of antigens, diseaed plasma cells that will divide uncontrollably to produce the 1 specific antibody against the antigen that induced its synthesis
Clinically, fusing of short lived normal anti-body producing cells with myeloma cells (hybridomas) will allow for monoclonal antibody production
Can grow in cell culture or inject in mice, producing ascites fluid filled with Ig
Generation of Polyclonal Antibodies to a specific antigen
Inject antigen into rabbit 2x for 3 weeks
Stimulates Ig production in rabbit
Blood is then drawn from immunized rabbits and centrifuged
The serum (antiserum) contains mixture of Igs
Each Ig recognizes a diff epitope on the antigen
Risk of nonspecific Ig because of other antigens present in mice already
Indirect immuno-cytochemistry
Very sensitive method b/c while the 1' antibody only binds once to 1 antigen, it is itself recognized by many 2' antibody molecules
Labels/marks on the 2' antibody then makes the entire complex readily detectable, thus indicating the presence of antigen
Fluorescent dyes or horseradish peroxidase commonly used as markers
Detection via markers
Horseradish peroxidase (HRP): catalyzes oxidation of an added substrate to produce a colored product or release of light
Alkaline phosphatase (AP): catalyzes hydrolysis of phos. groups from any added substrates, resulting in a colored product or release of light
ELISA - Chromogenic substrate detection
Substrates converted to insoluble colored products that precipitate to solid susrface
HRP substrate: diaminobenzidine (DAB) to BROWN precipitate
AP substrate: 5-bromo-4-chloro-3-indolyl phosphate + nitro blue tetrazolium (BCIP/NBT) produces Pi and formation of blue/purple precipitate
ELISA - Chemiluminescent substrate detection
Substrates causes chemical reaction that produces energy in the form of light
HRP substrate: Luminol oxidation produces excited state that decays to produce light
light captured by Xray
Yields greatest sensitivity
indirect ELISA for HIV testing
Viral load cannot quantitively be detected because it is present in T-cells, not blood. Instead, the AMOUNT OF IG made in response to the HIV infection can predict the viral load
HIV antigens added to well FIRST then patient blood sample (with Ig in it) is added and binds to antigen
2' enzyme-linked Ig is added to bind human Ig and catalyze enzyme reaction to detect
Sandwich ELISA for pregnancy tests
allows for detection and quantification of ANTIGEN
Known Ig is added to well FIRST
patient's sample (containing the antigen) is added to bind Ig
2' enzyme-linked Ig specific to the antigen is added and catalyze enzyme reaction to detect
Extent of reaction is directly proportional to amount of antigen present (light or dark signal?)
ELISA: Troponin level detection after AMI
utilizes sandwich ELISA at various times to detect amount of troponin
Light colored before MI means low troponin
Dark color after MI means high troponin
Why indirect vs. direct ELISA for HIV testing
1' Ig is from the patient's body and does not have an enzyme-linked
Need synthetic 2' enzyme linked Ig to bind and detect
Analysis of protein expression/alteration
large scale study of an entire set of proteins made in an organism
analyze protein function based on its post-translational modifications
Mass spectrometry
Protein is digested by non specific protease - Trypsin
2 rounds of liquid chromotography, anion-exchange, reverse phase column
Ionize the pieces so it can be detected
Detector "shoot" the pieces of protein up. The way the pieces fall and force a which it falls will be indicative of its size
Early detection of HIV via Western blotting
Before body even makes anti-HIV Ig, there is high [HIV p24] antigen that can be detected
Pt's blood with many proteins are separated on SDS page and transferred to nitrocellulose
1' Ig that is known to bind to HIV p24 is added
2' enzyme linked Ig added and reaction is visualized
The more detections, the more antigen is present
Founder stem cells
Each organ/tissue has fix # of founder cell populations that are programmed to have fixed fix # of divisions - size of an organ is predetermined
If adult organ needs to be renewed, founder stem cells can divide AS stem cells to produce 1 daughter stem cell that remains a stem cell and another that will undergo transient amplifying divisions: Asymmetric divison
Isolation of embryonic stem cells
Cells in suspension are tagged with fluroescent markers specific for undiff. stem cells
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text:
Gates Foundation expands digital divide initiative
The Bill & Melinda Gates Foundation has announced a new US$328 million ($415.5 million) plan to provide computer and Internet services through public libraries in developing nations.
The Bill & Melinda Gates Foundation has announced a new US$328 million ($415.5 million) plan to provide computer and Internet services through public libraries in developing nations.
The Free Software Foundation's (FSF) General Public Licence (GPL) is undergoing its biggest overhaul in 15 years and local members of the free software community are participating in the development process.
The U.S. Department of Commerce (DOC) has approved an agreement for VeriSign to continue to operate the .com domain for six more years, despite objections about pricing and security.
While it's taken Microsoft half a decade to bring out a new version of its client operating system, the real development work on Windows Vista only took around two years, according to the head of the company.
Whether as home users or office workers, humans remain the weakest link when it comes to IT security. Sophos expects hackers to exploit this fact and predicts social engineering to rise in 2007.
Ken Kutaragi will leave his position as president of Sony Computer Entertainment (SCEI), the Sony unit responsible for the PlayStation family of games consoles, and hand day-to-day control of the company to Kaz Hirai, previously head of SCEI's U.S. u...
Advanced Micro Devices (AMD) launched a motherboard with four cores on Thursday, targeting gaming enthusiasts in an effort to keep pace with the release of quad-core chips by rival Intel.
Financial traders at a London company wear shorts to work because heat from workstations under their desks is so bad. Hewlett-Packard (HP) has invented technology to take the workstations out from under the desks and replace them with blade-style com...
A press conference this week on Second Life, the virtual world where "land" and buildings are now so valuable someone is claiming to have made a million dollars, proved remarkably like a reporter's first life.
Intel has started to produce samples of a quad-core processor called Penryn that offers faster clock speeds and larger cache sizes, according to an executive.
The latest business news, reviews, features and whitepapers
Visit our shop for the best deals on hot products
Watch our video news and reviews from around the world
Comprehensive buying guides, features, and step-by-step articles
First impression on unpacking the Q702 test unit was the solid feel and clean, minimalist styling.
For work use, Microsoft Word and Excel programs pre-installed on the device are adequate for preparing short documents.
The Fujitsu LifeBook UH574 allowed for great mobility without being obnoxiously heavy or clunky. Its twelve hours of battery life did not disappoint.
The screen was particularly good. It is bright and visible from most angles, however heat is an issue, particularly around the Windows button on the front, and on the back where the battery housing is located.
My first impression after unboxing the Q702 is that it is a nice looking unit. Styling is somewhat minimalist but very effective. The tablet part, once detached, has a nice weight, and no buttons or switches are located in awkward or intrusive positions.

subset: commoncrawl


text:
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text:
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Chris Maresca's Techdirt Comments
Latest Comments (
On the post:
KlearGear Apparently Healthier Than Ever, Announces Plans To Start F**cking Customers Through Amazon Fulfillment
Chris Maresca
Sep 3rd, 2014 @ 1:11pm
Looks like Chenal Brands == KlearGear
According to whois - chenals.com is registered to Megan Tolcher, who is apparently KlearGear's 'Director of Merchandising' (according to this article
Interestingly, there is an address in Grandville, Michigan attached to the Whois record, which is for a mail forwarding service... And it's the same address KlearGear has been using.
On the post:
University of Oregon Slaps Student With Five Conduct Charges Over Four Words
Chris Maresca
Aug 28th, 2014 @ 9:09am
Re: Wow
Maybe I'm an idiot, but I don't understand how the first comment was sexually loaded....
Seems like a random phrase whose meaning is in the eye of the receiver.
On the post:
Why Do Police In Suburban St. Louis Have More Powerful Weapons Than Marines In Afghanistan?
Chris Maresca
Aug 21st, 2014 @ 9:32am
Re: Total BS
What they are not carrying is typical riot gear. Shields, helmets that cover the back of the neck, truncheons or other non-lethal 'weapons', fire-proof padded hard-plastic protective leg/arm/shoulder protection, etc. See this image
and this image
for what real riot police should look like (note the absence of guns).
It seems to me the are woefully unprepared for crowd control and are resorting to 'force project' and the threat of violence instead.
Basically, they look, are equipped and are acting as a military combat unit, which, of course, is making things worse.
On the post:
Why Do Police In Suburban St. Louis Have More Powerful Weapons Than Marines In Afghanistan?
Chris Maresca
Aug 21st, 2014 @ 9:24am
Re: Re: A good reason not to visit the USA
One other note - the police in both France & the Netherlands is significantly better trained to deal with both non-violent & violent protests, probably because these sorts of protests are far, far more common.
That said, they are also much, much more likely to use a lot of non-lethal violence on protestors (truncheons, whips, rubber bullets, horses, tear gas, water canons, etc) but are equally likely to just hid behind large plexi shields (Roman phalanx-style) while being pelted with stuff.
On the post:
Why Do Police In Suburban St. Louis Have More Powerful Weapons Than Marines In Afghanistan?
Chris Maresca
Aug 21st, 2014 @ 9:18am
Re: A good reason not to visit the USA
I don't know what country you live in, but I've lived in 7 different countries and it isn't any better anywhere else. In fact, it's significantly worse in many places, including some European countries where national police forces are actually part of military, e.g. the Gendarmerie in France and the MA in the Netherlands.
On the post:
Specially-Designated 'FOIA Denial Officers' Are Handling The Dept. Of Education's Rejected Requests
Chris Maresca
Aug 14th, 2014 @ 11:22am
Easy fix - FOIA Review Officer
On the post:
If You Want To Know How Supporting Techdirt Can Help Shift The Debate In Washington DC, Read This
Chris Maresca
Jul 29th, 2014 @ 3:33pm
Re: Re: Re: Re: Re:
One way to fix it is to have stronger institutions. One of the most corrosive aspects of the US body politic is the fact that the President appoints almost all of management in the entire government, many levels down from cabinet secretaries.
The result of this is that agencies have virtually zero institutional power and are governed basically by people who have 'bought' their way into management positions. And they have zero long term stake in anything since they'll be gone in 4 years and there is no career path.
Then again, in a democracy you get the government you choose, so maybe this is what the American people want.
On the post:
If You Want To Know How Supporting Techdirt Can Help Shift The Debate In Washington DC, Read This
Chris Maresca
Jul 29th, 2014 @ 12:30pm
Re: Re: Re: Re:
Well, I used to work for the government and the one thing I would say about this is that there are a lot of people in the government trying to 'do the right thing'.
They are overworked, underpaid, under-resourced and have a political system stacked against them. And they are also under-appreciated by the general public. Part of the issue is that 'doing the right thing' is different from person to person and entrenched interests are experts at exploiting this.
And because the US system pushes political patronage down to the lowest level of government, there isn't a strong institutional push-back against political shenanigans or constitutionally dubious actions. Never mind that a lot of institutional knowledge & power walks out the door every 4 to 8 years...
On the post:
SEC Goes After Those Offering Facebook Shares Pre-IPO
Chris Maresca
Mar 16th, 2012 @ 6:11pm
It's already happening. Quite a few companies go public on AIM in London and Prada recently went public in Hong Kong.
It's generally much easier to access capital markets overseas vs the US, the reason more people don't do it is because of the added complexity.
On the post:
SEC Goes After Those Offering Facebook Shares Pre-IPO
Chris Maresca
Mar 16th, 2012 @ 5:25pm
Not that much of an issue
1. SharesPost is in trouble because it didn't register as a broker and is brokering securities. Duh.
2. Other markets have no issues and there are at least 1/2 dozen others. Besides, a very, very well informed source tells me that few shares are actually sold in any secondary transactions as companies almost always exercise their right of first refusal.
3. The 500 shareholder limit is almost never an issue because it only applies to people in the US and most of the demand is from overseas. Also, most (all?) SEC rules related to private stock transactions only apply in the US, which is why quite a lot of secondary activities take place overseas.
Really this is about the SEC going after people doing stupid things - e.g. brokering stock transactions without a license and advertising private stock for sale, both of which are big no-nos & finance 101. These people deserve to have the book thrown at them.
Other than that, there is really no story here.
On the post:
Prominent Rightwing Blogger Promises To Work Hard To Defeat Any Rightwing SOPA Supporters In Congress
Dec 24th, 2011 @ 1:10am
Re: Re: Re:
Google Disney's extension of copyright on a certain mouse.
It should have been public domain by now. Learn your history.
Corporations have been stealing from the public for the last 40 years by repeatedly extending copyright. Now the shoe is on the other foot and the only defense is ad-hominy attacks.
On the post:
Author Puts Article Online, Insists That Due To Copyright, You Cannot Link To It
Chris Maresca
Nov 11th, 2011 @ 5:52pm
What's the point of the URL at the bottom?
So, if they don't want anyone to link to it, why are they putting a URL at the bottom?
Inquiring minds want to know....
On the post:
The Revolution Will Not Be Infringed Upon: Long Island Couple Files To Trademark 'Occupy Wall St.'
Chris Maresca
Oct 26th, 2011 @ 9:01am
Not related
These people are giving me a bad name....
On the post:
Find A Massive Security Hole At American Express? If You're Not A Cardholder, It Doesn't Care
Chris Maresca
Oct 11th, 2011 @ 6:05pm
whois americanexpress.com = firstname.lastname@example.com
security "researcher" == fail
On the post:
Meghan McCain Slapped Down; Will It Be A SLAPP Down?
Chris Maresca
Oct 10th, 2011 @ 1:35pm
Who on earth is Meghan Mcain?
Never heard of her, can't be anyone I should care about. She should be happy a parody is giving her some attention...
On the post:
Since When Did US Diplomats Become Microsoft Sales Staff?
Chris Maresca
Sep 7th, 2011 @ 3:29pm
Apple can easily get the exact same help if they ask. My guess is they don't care - their products sell without government help.
On the post:
Since When Did US Diplomats Become Microsoft Sales Staff?
Chris Maresca
Sep 7th, 2011 @ 3:26pm
Re: Re: Re: Re: Re: Re:
Well, they do both. They push US companies as a whole, but when a specific company (e.g. Dark Helment, Inc) comes to them for help on a specific topic (and it's within guidelines), then they will help a specific company with said topic. Also applies to narrow industry sectors.
It's pretty much equal access, although the quality of the help you might get is highly variable. It's also true that the more effort you put into preparing, the more likely a positive outcome (and effective help).
And they are not averse to putting together specialist teams to help companies on specific issues, esp. where it relates to government (where they, obviously, have the most access/influence) - see this FCS page -
- obviously, the bigger the company, the more incentive FCS and other agencies have to help.
I would also point out that the US gov't, via it's embassies, gathers a lot of economic data about markets and makes it available to everyone. It's a good starting point for figure out how to work with foreign markets...
On the post:
Since When Did US Diplomats Become Microsoft Sales Staff?
Chris Maresca
Sep 7th, 2011 @ 10:55am
Re: Re: Re: Re:
Hmmm, I think this topic may be outside of your knowledge sphere. There are 30+ people at the Dept. of Commerce who's only job is to help Boeing with exports.
Why? Because Boeing is the single largest exporter in the US.
And any US business that needs export assistance can contact the local embassy/consulate for help with introductions, business development and even sometimes marketing. The reverse is also true, if you want to buy US goods, embassies have specialist staff to help find the right company. It's very company to company specific work and it happens every day.
On the post:
Since When Did US Diplomats Become Microsoft Sales Staff?
Chris Maresca
Sep 7th, 2011 @ 10:50am
Re: Re:
It's absolutely part of their job description. In fact, it's a core part of their job. My father was a career diplomat, I worked at FAS in Vienna, Austria (see post below) and my wife is a consular official - we all have been heavily involved in helping companies get more business.
Pushing and facilitating exports is a core diplomatic function, probably more than it's ever been. I've work on the contract negotiations (as a gov't. official) between private sector companies, facilitating the conversation and providing a back channel.
This sort of deep involvement is probably the most valuable thing embassies do these days.
On the post:
Since When Did US Diplomats Become Microsoft Sales Staff?
Chris Maresca
Sep 7th, 2011 @ 10:42am
Don't be surprised, it's part of their job description...
... all embassies, from all countries, help sell the products from their country. It pretty much doesn't matter what it is, that's a core part of all missions. And their are specialist for most industry verticals doing this.
Back in the late '80s, I helped sell US foodstuffs to the Soviet Union. I was working for the Foreign Agricultural Service, a part of the USDA which is present in a lot of embassies. It was my job to help market and sell US agricultural products to Austria, Hungary and Czechoslovakia - and, as it happens, the Soviet Union.
It makes no sense for an embassy to push anything open source or free as that brings zero economic benefit to the country. They might do so as part of a wider policy initiative, but most policies are not so prescriptive.
It's important to remember that diplomats don't exist for altruistic reasons. Their job is to gather information and knowledge about a country/region and to use that knowledge to push the interests of their country at every level, but particularly economically.
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text:
- Northern New York Newspapers
- Watertown
- Ogdensburg
- Massena-Potsdam
- Lowville
- Carthage
- Malone
- NNY Business
- NNY Living
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POTSDAM - Since the first day of practice, members of the Heuvelton boys soccer team have been talking about making some history.
On Thursday night, at Potsdam Central School, the 11-3-2 Bulldogs capped an historic season with a victory of utmost significance as they downed Harrisville 1-0 to claim the schools first Section 10 Class D Championship. It also claimed the first league or sectional soccer championship since a Valley League Playoff title in 1980.
That one boys soccer banner in the gym is so old that it is falling apart, said senior Aaron Cobb who was honored after the game as the NAC West Division Offensive MVP.
We wanted to put a brand new one up there.
The second-seeded Bulldogs long-awaited banner was secured with a third victory of the season over fifth seeded NAC West rival Harrisville (11-4-0). It completed a Night for the Bulldogs following Chateaugays 3-0 victory over Parishville-Hopkinton in the Girls Class D Championship Game.
Heuveltons victory was decided when senior Jon Sloan converted the second of the Bulldogs best two scoring chances of the night, in a matter of seconds, with 27:55 remaining in the game. On the first opportunity, Harrisville keeper Zane Mono (10 saves) made a diving save to deflect a point blank shot by Cobb just wide of the net.
Senior Mike Guardino followed with a corner kick which deflected off a defender to Sloan who buried a shot from the top of the bubble.
The ball came right off the defenders chest and I had a great look. I felt that it was now or never and I got off a really good shot, said Sloan after the Bulldogs remained unbeaten (3-0-1) on games played on all-weather turf this season.
Soccer is my favorite sport and to win this title as a senior is just amazing. Coach (Dave Steele) did a good job scheduling games on turf fields for us. We feel very comfortable on turf and I think that meant a lot.
The Bulldogs will return to the Potsdam Central Turf field on Saturday meeting undefeated Section 7 Champion Chazy at 2 p.m. for a berth in the New York State Class D Final Four. The Chateaugay Girls host Elizabethtown at noon.
We had some chances which we didnt convert and they had two really good chances and got one. Defensively, we made one mistake in the second half and they converted which is a credit to them said Harrisville Coach Shane Countryman after leading Class D1 Champion Harrisville to its fourth trip to the Overall Class D finals in the last five years.
This is only my second year after taking over a great program from Rick Bearor. Our players work very hard and they play in the summer.
Led by co-captains Joe Butts, Nick Weir, Tim Fowler and Justin Hartle, the Pirates also worked extremely hard pressing forward in quest of a tying goal over the last 10 minutes. The Heuvelton backfield of Matt Guardino, Cody Holland, Jeff Arquitt and Lucas Brown were all called up for clutch stops and goaltender Chris Power made the best of his 13 saves to deflect a shot by Jared Dreythaler with a diving effort.
With 5:53 to play, Dedrick Johnson blocked a free kick by Tim Fowler just outside of the penalty area which proved to be the Pirates final significant threat.
Our defense played extremely well tonight. When Jack Tennant was injured, Will Tennant came in and won some really big balls for us, said Heuvelton Coach Dave Steele. This a great group of guys who really worked hard. They wanted to make some history this year and they went out and made a lot of history.
Thousands of readers like you have made Northern New York Newspapers the number one ranked website* for local news and sports coverage in the north country.
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Latest Updates
September 29, 2015
Cuban prisoner of conscience Ciro Alexis Casanova Pérez was released from prison in Villa Clara province on 10 June.
Press Release
September 25, 2015
In response to reports that Saudi national Shaker Aamer will be transferred to the UK after being held without charge or trial at Guantanamo Bay for more than 13 years, Amnesty International USA Ex...
August 31, 2015
Belarusian prisoner of conscience Yury Rubtsou was released from penal colony in the eastern city of Bobruisk on 22 August.
Press Release
August 27, 2015
The use of enforced disappearance by governments to silence its critics and instill fear into targeted groups continues unabated in every region of the world, said Amnesty International as the worl...


text:
"This quarter our patient care centers were challenged with an extended period of bad weather affecting many parts of the country. Our team rose to the occasion by controlling expenses, which allowed us to meet our EPS target and to deliver double-digit earnings growth for the quarter," commented Thomas F. Kirk, President and Chief Executive Officer of Hanger Orthopedic Group. Mr. Kirk added, "We are comfortable with the prospects for growth in our patient care business for the remainder of 2011. The assimilation of ACP into the Hanger family is progressing as planned. As a result, we remain optimistic about the balance of the year."
The Company has substantially completed the relocation of its corporate headquarters from Bethesda, Maryland to Austin, Texas. The cost of the move is reported as a separate component of income from operations. The Company anticipates incurring $1.0 to $2.0 million of additional costs in 2011 as the final employee moves are completed.
For 2011, Hanger is increasing guidance. The Company continues to expect full year revenues of between $945 million and $955 million and has increased the expected range of adjusted diluted EPS to $1.66 to $1.71, from $1.63 to $1.68, due to the expected impact of the
|SOURCE Hanger Orthopedic Group, Inc.
Copyright©2010 PR Newswire.
All rights reserved


text:
Diversification. It's such a critical practice when it comes to investing and managing money. Diversification is also key when it comes to driving and increasing traffic to your blog. You're not going to get all of your gains from a single source. Here are 3 ways to diversify and increase your blog traffic.
Archive | SEORSS feed for this section
3 Ways to Diversify and Increase Your Blog Traffic
7 Tips for Winning Favor with Google
SEO, otherwise known as Search Engine Optimization, is so intriguing isn't it? It's this idea that you can outsmart an algorithm and consistently outperform a moving target. The concept behind SEO is not much different than the concept behind trying to consistently beat the S&P. Most people (and professionals) can't do it. Your chances of […]
Search Engine Optimization: Your 5 Step Onsite Optimization Checklist
If you're new to Search Engine Optimization (SEO), it can seem like a dark art. It just looks and sounds so complicated. But I have some good news – it isn't. At least, it doesn't have to be. As a small business, you are not likely to have a huge marketing budget, and you can […]
Four Tips for Optimizing Your Online Presence
In order to have any opportunity to get found by your target markets online, you must optimize your online presence. Search engine optimization is a very broad concept in and of itself, and it's one that creates a lot of confusion. I'm going to give you 4 tips that work for optimizing your online presence. […]
Get Found By Your Niche Markets with Google's Social Search
Well, it's official. Google announced last week that they will be incorporating "social" into mainstream search results, placing more emphasis on the social connections that you have in addition to serving up relevant content pages. Translation: most likely, no two people will get the same results when they search, and they'll also find results from […]
Why Online Reputation and Influence Matter More than SEO
If your efforts are centered on ranking in search engine results, your wasting your time and money as a professional. Learn what matters more than SEO!
- Establishing Online Authority with Google+
- 7 Reasons Why Financial Advisors Should Use WordPress
- Where Are the Financial Advisor Thought Leaders?
- Will Financial Advisors Get to Be Socially Authentic?
- How to Build an Awesome Twitter Profile
- How to Use Storytelling as a Marketing Strategy
- Thought Leadership Content Marketing in Social Media Times
- 5 Steps to a Smarter LinkedIn Network
- WA 21: A Conversation with Jay Palter on All Things Digital Marketing (for Professionals)
- WA 20: How Ted Jenkin Attracts New Clients to His Gen XY Financial Firm
- WA19: A Conversation With Carl Richards, Founder of Behavior Gap
- WA 18: DIY Video Tips and Tools With Caleb Wojcik
- WA 17: BrightScope is Bringing Greater Transparency to Investors
- WA 16: 7 Tips to Power Up Your LinkedIn Profile for Influence
About Wired Advisor
Stephanie Sammons is the founder and CEO of Wired Advisor. We help entrepreneurial financial advisors and firms build a more powerful digital presence.


text:
Pain Relief Tablet/Capsule
Pain is a sensation that is transmitted from an area of tissue damage or stress along the sensory nerves to the brain. The brain interprets the information as the sensation of pain. Substances that decrease pain either interfere with the ability of nerves to conduct messages, or alter the brains capacity to receive sensations. Pain may be a symptom of an underlying pathological condition, such as inflammation. It may also be due to other causes, such as bruising, infection, burns, headaches, and sprains and strains.
Natures Sunshine Anti-Inflam Capsules 100
This formula contains herbs traditionally used in the temporary relief of arthritic pain.$42.25 $32.43
Voltaren Rapid 12.5mg Tablets 30
Specialised relief for muscle and back pain, to help get you moving again. THIS PRODUCT IS AVAILABLE TO NEW ZEALAND CUSTOMERS ONLY AS IT IS PRESCRIPTION ONLY IN SOME COUNTRIES.$14.45
Sudafed PE Nasal Decongestant Tablets 24
Helps to reduce the swelling and secretions in the nasal passages and sinuses caused by sinusitis.$13.07
Panadol Optizorb Tablets 100
Povides fast, temporary effective relief of pain and discomfort.$19.64
Panadol Optizorb Caplets 48
Panadol caplets gives fast effective easy to swallow temporary relief of pain.$11.72
Panadol Back & Neck Long Lasting Caplets 36
Provides effective relief from back and neck pain for up to 8 hours.$10.33
Pamol for Children Pain & Fever Relief Strawberry 100ml
Suitable for children 1 year and over. Colour free. Strawberry flavour.$12.28
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Clinically proven pain relief tablet to contain ibuprofen 200mg and paracetamol 500mg.$35.96
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text:
The time has come to throw in the towel with the Silver Volvo — the 1999 XC70. It was a sweet ride while it lasted, the most comfortable and best handling car I've ever owned, but it's time is at an end. I'm going to tear everything out of it to maximize the amount I get from it, and then scrap what's left over. As of today I've got everything, but I'm probably to hang on to the 3rd row seats, the wheels, the horns, the hitch, and the after-market stereo for now.
But available is:
Rear Hatch
Extra set of Brand New Hatch Struts
All glass
Driver Seat (one rip/burst)
Passenger Seat
Climate control unit
MAF (I think I have a working spare as well)
Tons of relays
5 coils
Fuel rail
5 Injectors
XeMODeX ETM (very low mileage)
Brake callipers
Roof rack w/ rails
Eventually I'll have the bevel gear and tranny and driveshaft.
Let me know if there's anything you want! If you're one of the first to come, you can help me break down the car in exchange for a better price on the parts. The car is located out of Kalama.
This post is part of the thread: Silver Volvo – an ongoing story on this site. View the thread timeline for more context on this post.


text:
GABA and the Basal Ganglia
Edited By
- J. Tepper
- E. Abercrombie
- J. Bolam
Over the past 25 years the amount of data pertaining to the GABAergic function in the basal ganglia has increased dramatically. GABA and the Basal Ganglia - From Molecules to Systems is a comprehensive review of the current state-of-the-art of knowledge about the neuroanatomy, neuropharmacology and neurophysiology of the basal ganglia, focusing on its GABAergic microcircuitry. It serves as a complete reference to the body of knowledge about the basal ganglia, its constituent neurons, and their interconnections. This volume is designed to serve as a convenient all-in-one review and reference for experienced basal ganglia researchers as well as an introduction to the functional organization of the basal ganglia and its GABAergic circuitry for students and researchers new to the field.View full description
Book information
- Published: April 2007
- Imprint: ELSEVIER


text:
Accesand acest site va dati acordul de a instala cookies pe calculatorul Dvs. Acestea sunt inofensive si nu vor putea niciodata sa va identifice personal.
The preloaded software for the Enhanced Performance keyboard may corrupt registry keys in the Microsoft Registry.
Any of the following systems running Microsoft Windows XP configured with Enhanced Performance keyboard with replacement (FRU) part number of 89P8800:
Corrupted folders in the registry do not contain any values; they are empty and can be deleted from the registry.
Attention: Using the Microsoft Registry Editor incorrectly can cause serious problems that may require you to reinstall your operating system. Use the Microsoft Registry Editor at your own risk.
For information on how to edit the registry, view the online Help topics, "Changing keys and values", "Add and delete information in the registry", and "Edit registry data" in the Microsoft Registry Editor.
Note: Backup the registry before editing.Editing the registry
Lenovo este dedicat mediului prin operațiuni de la design de produs până la soluții de reciclare.


text:
son of a b*** the backs heat up too?!
i just thought the 2 settings were for how much you wanted your !Removed! to be grilled - hence me defaulting to what i thought was the '1' setting - which turns out to be the base setting???
- GlynnZS likes this


text:
A Witch Meadow Road group home that came under fire this year after one of its residents escaped and tried to break into four surrounding residences has been vacated, Salem First Selectman Kevin Lyden said on Friday."I think this will definitely bring closure now that it's vacant," Lyden said. "We're not against group homes. It was just the unfortunate and sad incident that happened with this."
NORWICH — The Dime Bank branch on West Town Street in Norwich was robbed this afternoon, Norwich police confirmed to The Bulletin. The bank was robbed at about noon, police said. The suspect, a white male between 20 and 35 years old,...
HARTFORD — A Thompson man will serve two years in prison and then seven years of supervised release for trading child pornography on the Internet.
HOUSTON - One person was killed and another wounded during a shooting Friday at a Texas Southern University student-housing complex, and the Houston campus has been placed on lockdown, university and police officials said.
SALEM - A Witch Meadow Road group home that came under fire this year after one of its residents escaped and tried to break into four surrounding residences has been vacated, First Selectman Kevin Lyden said in an email on...
Police say a woman driving in circles in a Gastonia intersection rammed two police vehicles and struck two others before overturning her car down a hill. The incident occurred around 4:25 p.m. Thursday at the intersection of Ozark Avenue...
A man authorities say faked being a doctor and offered fixes for incurable STDs out of an east valley home also was a porn actor selling sex toys and escort and massage services, according to court papers. Rick Van Thiel, 52, now faces one...
FLAGSTAFF, Ariz. - An overnight confrontation between two groups of students escalated into gunfire Friday when a freshman at Northern Arizona University killed one person and wounded three others, authorities said Friday.
FLAGSTAFF, Ariz. - The latest on the shooting at Northern Arizona University (all times local): 7:30 a.m.
HARTFORD - A Hartford police officer has reported that his service weapon and other items were stolen from his personal vehicle.
HARTFORD — A Hartford man says he kicked and held a man at gunpoint after discovering a burglar at his father's home shoving Christmas decorations into a garbage bag. The Hartford Courant reports the man says the front door was open...
Norwich Directory
Business Name
Location, ST | website.com


text:
According to the article, the United States Mint has sold 85,000 American Eagle gold coins since May 1. When that last happened, the price of gold coins increased 21 percent in the next year. A group of investors polled by Bloomberg expected the price of gold to appreciate 17 percent by December 31 to a record $1,750 per ounce and continue the rally in 2012.
Continued weakness in the United States dollar and the fear around the ongoing debt ceiling crisis in Washington could support the price of gold coins this week.
Global Gold Group is offering gold coin buyers, or those looking to invest in gold coins, a free Investment Gold Guide simply by visiting its website. Check out http://www.aglobalcurrency.com today.


text:
Upcoming EventsRead more
Pro Bull Riding
Gates Open: 4:00 pm Bull Riding: 7:00 pm
Pre-show Activities: 4:00 – 7:00 pm
Mutton Bustin': Registration 5:00 pm – Event: 5:30 pm
Special Events
- September 5, 2015
All American Cowboy Gathering
This a a family fun day of cowboy music, food and western activities. The Cowboy culture comes to life.
- December 5, 2015
Christmas On The Ranch
A family Christmas celebration under the stars.
Experience the rustic country atmosphere
Surrounded by the sights and sounds of ranch life. We have opened our ranch for Private Events, Corporate Outings, Reunions, Weddings, Graduation Parties and Private Group Tours
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Buckin' Ohio is proud to be associated with SEBRA, a national pro bull riding association.
Latest NewsSee all news
Buckin' Ohio is a family owned and operated bucking bull ranch.
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Contact Us
Address: 8154 Garman Rd., Burbank, OH 44214
Email: [email protected]


text:
Gustavo Razzetti | February 26, 2013 | Comments
People don't engage with brands, people engage with a purpose. And the most successful case studies are precisely those that embrace this approach.
It was Social Media Week in Miami and I had the honor to be part of the LATISM panel "The Evolution of Hispanic Social Media" with Fernando Rodríguez and Cristina Rua from the Ford Motor team and Juan Rótulo, digital editor of PeopleenEspañol.com.
I was asked by many fellow tweeps to share some of the discussions. The panel was too intense (and extensive), making it hard to capture all the insights. I'd rather focus on sharing some of the content I presented. Hopefully, the other participants can do the same in the coming days.
The Cultural Connection
Social media is allowing people to (re)connect with their Latino tribe. Either by leveraging their social spirit or identity construction. Social media is fueling Latinos to connect to their Latino culture, even for those that - formerly - didn't feel the need to. Shared social causes and interests are making diverse and divergent Latino groups come together.
Mainstream interests and Latino passions. Latinos are cultural chameleons, and social media is the perfect playground for them to show their colors. Depending on the topic, their colors might be more Latino (the way they socialize) or American (at work). But in many cases they show a bicultural behavior where they combine both. Entertainment is a perfect example. Take the Xfinity Latino Facebook page. It provides a comprehensive take on entertainment, both mainstream and Latino. But it provides a take on Latino entertainment that you can't find on the general market page, making it for everyone who's passionate about Latino entertainment (not just Latinos).
People engage with Latino interests or with a "Latino perspective." The raison d'être for a specific Hispanic social media platform is to go deeper into Latino behaviors or interests that haven't been "covered" by the mainstream. Or to provide a space where mainstream issues can be discussed through the Latino lens.
The excellent work that Adrian Carrasquillo and his team are doing with NBC Latino is a perfect example of this. This "New voice of American Hispanics" provides a space to discuss parenting, politics, news, and entertainment, the Latino way.
The Secret of Social Success
Social media has become so big that sometimes we forget to approach it as part of the overall marketing strategy. Successful brands have a holistic approach rather than approaching social media as a standalone tactic.
We know that Latinos show a higher engagement with brand pages versus non-Hispanics. But that doesn't mean that they will follow any brand. People don't engage with brands, people engage with a purpose. And the most successful case studies are precisely those that embrace this approach.
Latinos are completely aware of milk's functional benefits. So the California Milk Board had the challenge to build a higher emotional connection between milk and consumers. Through a fictitious character, "The Master of the Glass Half-Full," CMPB engaged consumers, promoting a more positive approach to everyday life. By providing "daily glasses of positivity," the "Master" is always inspiring people to see the glass half-full.
Hispanics have a cultural tendency to believe in fate and blame: accidents cannot be controlled or avoided. They refer to it as "mala suerte" or bad luck. Considering Allstate's purpose - to provide everyday protection - what better approach than personifying bad luck? This hedonist and Machiavellian character allows people to interact with everyday "mala suerte" experiences (including theirs). Allstate helps Latinos be prepared in case "Bad Luck" shows up.
We know that Latinos love celebrities. And considering its 242,000 followers on Facebook and 680,000 on Twitter, it's clear that People en Español is doing it right. Special editions like the "50 Más Bellos" (50 most beautiful men) or the 25 most influential Latinas drive huge fan engagement. Even unsung heroes have the chance to be selected, like when the Grammy-awarded Olga Tañon suggested that a nun from Colombia be included in the list of the most "poderosas" Latinas.
The Future Is Definitely Social
I don't like being asked to provide predictions: the present is changing so fast already. I prefer monitoring what's happening today and testing new things as a way of anticipating new consumer behaviors. Trends don't appear all of a sudden; they start little by little and then turn into something big. Here are some of the changes that we should monitor for 2013.
As a final word, we need to remember that social is not about interacting with a tool or a device, but rather networking with real people. Enjoy this funny example of how a social-mobile experience can engage people in the "real" world.
Gustavo Razzetti is EVP, Managing Director of Lapiz, the Latino shop of Leo Burnett. He has 20+ years of experience in integrated marketing communications in U.S. and Latin American markets.
A change agent, with the expertise of transforming agencies into digital at the core shops, Razzetti has become one of the leading voices when it comes to understanding the new market dynamics of US Latinos.
Former Chief Strategy & Engagement Officer at Grupo Gallegos, president of GlobalHue NY and CEO of Euro RSCG Latino. Razzetti's career is marked by extensive experience working with top consumer brands such as Comcast, Walgreens, Verizon, Nestlé, Chivas Regal, General Motors, Coca-Cola, and BBVA, and 200 others. He also served as CEO of Euro RSCG both in Puerto Rico and in Argentina. Prior to that, Gustavo was CEO and founding partner of WhyNet - the no. 1 interactive agency in Argentina.
Strategist by conviction, digital pioneer by choice, leader by evolution; Razzetti has received recognitions that include Effie awards, Gran Prix AMBA, Euro RSCG's CBI Award, and Strategic Planning Director of the Year, McCann Erickson. Many of the campaigns he strategically led won Cannes, Clio, New York Festival, London, and FIAP awards, among others.
On a personal note, Gustavo loves scuba diving, bicycling, gourmet cooking, and fine wines.
October 21-22, 2015
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October 13, 2015
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November 12, 2015


text:
An Approach to Sustainable Water Management Using Natural Resource Accounts: the Use of Water, the Economic Value of Water, and Implications for Policy
Lange, G.M.
Refereed StatusNon-Refereed
MetadataShow full item record
A Natural Resource Accounting project is currently underway to document the status of the nation's resources and their current economic use. Accounts for water constitute a major component of the Natural Resource Accounts (NRA) since water is the limiting resource for economic development in Namibia, as it is for much of Southern Africa. The NRA include both stock and use accounts for water, as well as related environmental statistics. In order to design development strategies that are sustainable over the long run, it is essential to know the full value of this scarce resource. This is especially important for a resource like water which is used throughout the economy and must be managed to achieve sometimes conflicting economic, social, and political objectives. A comparison is made of user fees, costs of delivery, and the economic contribution of water in different sectors of the economy as a first step toward estimating the opportunity cost of water. As in many countries,.....
JournalResearch Discussion Paper
Document Languageen
CitationResearch Discussion Paper, 18, 45 p.
- Miscellaneous [667]


text:
The researchers hope to find a way to diagnose oral cancers in the earliest, more treatable stages, and to eventually halt cancer growth once diagnosed.
For years, researchers thought hBDs were "the good guys" in the mouth, said Weinberg, "but we are finding it isn't always so." The recent discovery by Case Western Reserve dental researcher and additional co-investigator Dr. Ge Jin has shown this not to be the case.
In tissue studies, Jin reported the disappearance of hBD-2, another innate peptide in the mouth's lining that protects against microbial challenges, and the proliferation of hBD-3 in cancerous tissues.
The finding led the dental researchers to hypothesize that an abundance of hBD-3 in saliva and tissue might be a way to diagnose oral cancers.
"Our team recently found that the HPV type most implicated in head and neck cancer promotes hBD-3 overexpression," Weinberg said.
Zender, a head and neck surgeon who treats benign and cancerous lesions of the mouth and throat, heard about Weinberg's interest in studying the hBD-3 connection to cancer. The collaboration was forged during a meeting between Weinberg and Cliff Megerian, the chair of the Department of Otolaryngology.
Their study includes several components:
|Contact: Susan Griffith
Case Western Reserve University


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Movie Info
Climate catastrophe? Normal solar activity? The end of civilization as we know it? Cool It is based upon the book of the same name and lectures by Bjorn Lomborg, the controversial author of The Skeptical Environmentalist. Acclaimed award-winning filmmaker Ondi Timoner travels the world with Lomborg exploring the real facts and true science of global warming and its impact. Lomborg is the founder of the economic think tank, Copenhagen Consensus, which brings together the world's leading economists to prioritize major global problems -- among them malaria, the lack of potable water and HIV/AIDS -- based upon a cost/benefit analysis of available solutions. Amidst the strong and polarized opinions within the global warming debate, Cool It follows Lomborg on his mission to bring the smartest solutions to our energy needs, carbon emissions and other major problems in the world. -- (C) Roadside Attractions … More
|PG (for thematic elements)
|Directed By:
|Ondi Timoner
|Written By:
|Terry Botwick, Sarah Gibson, Bjorn Lomborg, Ondi Timoner
|In Theaters:
|Nov 12, 2010 Limited
|On DVD:
|Mar 29, 2011
|Box Office: