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Every living
thing is connected via webs of genetic and epigenetic
relationships.
mRNAs function as cross-kingdom master regulators of the
fellowship of the biosphere.
Produced by
bacteria,
fungi, plants, and
animals, mRNAs are capable of surviving digestive and assimilative processes
intact, entering the tissues of organisms, affecting the expression of a wide
range of genes. |
"The viral network we have detailed is a snapshot
of the early stages of an epidemic, before the evolutionary paths of
COVID-19 become obscured by vast numbers of mutations. It's like catching
an incipient supernova in the act." - Peter Forster
"At the beginning
of an article on the human immunodeficiency virus, (HIV, the
putative causal
agent of AIDS that he and others isolated), Dr. Robert C. Gallo observes
without comment that epidemiologists had named the new disease "acquired immune
deficiency syndrome."
By attributing the power to name the disorder to
them, Dr. Gallo shows us how prominent a part epidemiology has played in
defining and ordering this "medical mystery."
I examine the role of
epidemiology in characterizing HIV infection.
Faced with
a new disease of unknown origin,
epidemiologists and their collaborators constructed, over time, hypothetical
models to explain the disorder in order to contain it.
Prior to the
isolation of a putative causal agent, HIV, epidemiologists played a central
role in defining the new syndrome, first developing a "life-style" model and,
later, a model based on hepatitis B.
Supplanted by
virologists and other "bench" scientists working in laboratories,
epidemiologists have continued to define important dimensions of the disorder
and raise disquieting questions.
Epidemiologists were concerned with
defining the natural history of HIV infection, the extent to which it spread
within population groups, factors affecting the spread rates of the virus.
Epidemiology, unlike virology, has a strong social dimension in that it
explicitly incorporates perceptions of a population's social relations,
behavioral patterns, and experiences into its explanations of disease." - Gerald M.
Oppenheimer
In
the Eye of the Storm: The Epidemiological Construction of
AIDS
mRNAs are short non-coding
RNA molecules involved in the posttranscriptional epigenetic regulation of gene
expression.
Recent data show that mRNAs can be found in body fluids,
and these mRNAs might enter cells giving rise to
a hormone like way of
action.
mRNAs released in body fluids might affect other
individuals, and there are some data of potential cross-species action of
mRNAs.
mRNAs traverse the
gastrointestinal tract.
mRNAs wander via the
food-chain.
Master regulatory mRNAs may influence gene
expression.
mRNA genes,
located in the non-protein coding "dark matter" of the genome, may facilitate
interindividual and cross-species epigenetic communication via information
transfer by coded gene products. |
HIV-infected cells persist only for a day or
two. HTLV is thought to replicate by promoting proliferation of infected
cells. "Assume about 10 years between HIV infection and diagnosis of AIDS."
- ASF
The simian foamy virus (SFV), a spumavirus, has been co-speciated
with Old World primates for about 30 million years, making them the oldest
known vertebrate RNA (ribonucleic acid) or retrovirus.
late 1950's SV40, a retrovirus, is identified in the injected
form of the polio vaccine.
This is
believed to be due to kidney cells from infected
monkeys being used to amplify the vaccine
virus during production.
Both the Sabin vaccine (oral, live virus)
and the Salk vaccine (injectable,
killed virus) are affected; the technique used to inactivate
the polio virus in the Salk vaccine, by means of
formaldehyde, does
not reliably dissolve SV40.
When two or
more vaccines are mixed together in the same formulation, the two vaccines can
interfere.
This most frequently occurs with 'live'
attenuated vaccines, where one of the
vaccine components is more robust than the others and suppresses the growth and
immune response of the other
components.
This phenomenon is first noted in the trivalent Sabin polio
vaccine, where the amount of serotype 2 virus in the vaccine has to be reduced
to stop it from interfering with the "take" of the serotype 1 and 3 in the
vaccine.
SIVagm is a lentivirus also a retrovirus.
The genome consists of two strands, a longer negative-sense strand and
a shorter and positive-sense strand of variable length.
In the virion
these strands are arranged such that the two ends of the long strand meet but
are not covalently bonded
together.
The virus binds to receptors allowing viral particles to enter
the cytoplasm.
This is then translocated to the nucleus, where the
partially double stranded DNA is 'repaired' by the
viral polymerase to
form a complete circular dsDNA genome (called covalently-closed-circular DNA or
cccDNA).
The genome then undergoes transcription
by the host cell RNA polymerase and the pregenomicRNA (pgRNA) is sent out of
the nucleus.
A polymerase is an enzyme that
synthesizes long chains of
polymers.
(DNA polymerase and RNA polymerase are used to assemble
DNA and RNA molecules, respectively, by copying a DNA template strand using
base-pairing interactions or RNA by half ladder replication.)
pgRNA
penetrates an assembled viral capsid containing the viral polymerase.
Inside this capsid the genome is converted from RNA to pdsDNA through
activity of the polymerase as an RNA-dependent-DNA-polymerase and subsequently
as an RNAse to eliminate the pgRNA transcript.
New virions either leave
the cell to infect others or are immediately dismantled so the new viral
genomes can enter the nucleus and magnify the infection.
The virions
that leave the cell egress through budding.
This is a deoxyribonucleic
acid virus.
1958 Denis Parsons Burkitt describes
a β lymphocyte cancer of the lymphatic system found in the germinal
center.
Michael Anthony Epstein, a British pathologist and academic,
proposes Burkitt's lymphoma is a cancer caused by a virus.
Epstein
changes his research focus to a viral origin of Burkitt's
lymphoma.
After more than two years of working with tumour cells from
Burkitt's patients Epstein claims to have isolated the the EpsteinBarr
virus.
Epstein-Barr virus, also known as human herpesvirus 4, is a
member of the herpes virus family. It is one of the most common human
virus.
EpsteinBarr infection is found in most patients with
Burkitt lymphoma.
Burkitt lymphoma strikes 30-40% of individuals with
HIV-induced AIDS.
Mononucleosis is thought to spread most commonly
through bodily fluids.
Adolescents were told if you kissed you would get
the Kissing disease.
Mono Virus
Discovery
Infectious Mononucleosis (Mono) | Epstein-Barr
Virus
Exaggerated Villainy of the Epstein-Barr Virus
Neurological Symptoms in Multiple Sclerosis
Morphologic Features of Epstein-Barr Virus Infection in the GI
Tract
Relationship between Epstein-Barr and Cell
Membrane
"Blastoid cell cultures derived from
leukocytes of patients in the acute
stage of infectious mononucleosis (IM) and harboring Epstein-Barr (EB) virus in
at least 1% of the cells were found to possess antigens in their membranes
which presently are indistinguishable from those detected in Burkitt's lymphoma
(BL) cells by the techniques employed." - Rockefeller University
Press
Peptides derived from cellular proteins are
continuously exposed at the cell surface.
late 1960s Observers "isolate" and
then inoculate with the MS-2 strain of hepatitis B virus.
Hepatitis
virus replicates through an RNA intermediate form by reverse transcription, and
in this respect they are similar to retrovirus.
Hepatitis B virus
belongs to the Hepadnavirus family.
Hepadnavirus have very small
genomes of partially double-stranded, partially single stranded circular DNA.
Was There an AIDS Contract?
What Really Caused The AIDS Epidemic?
early 1970s
African rhesus monkeys are used in the manufacture of the hepatitis B
vaccine.
Human hepatitis B virus cultured
in vivo in rhesus monkeys are
returned to humans whose infected blood serum is then pooled to develop four
different strains of experimental hepatitis B vaccine.
Experimental vaccine clinical trial in
New York City and central Africa.
Hepatitis B vaccine recipients worldwide,
including gay men in New York, and
Black Africans in Central
Africa, are exposed to simian virus including SV40, SIVagm, and perhaps
others.
A generally neglected evolutionary route of SIVagm to HIV-1
zoonosis sequentially involves:
a) human incubation for more than a
decade of polio vaccine contaminants and recombinants including SV40, SFR, and
possibly SIVagm;
b) the pooling of infected blood serum donated by
hundreds of gay American and Black African hepatitis B vaccine recipients who had
subsequently received injections with cultured
strains of hepatitis B virus;
c) the biohazardous laboratory
conditions and viral containment problems reported by the hepatitis B vaccine
investigators and their affiliates;
This series of events provides the
best explanation for an early to mid-1970s "punctuated origin event" most
precisely fitting etiological
determinations of the HIV-1/AIDS pandemic.
There
is evidence demonstrating that the
schizophrenia
associated retrovirus (SZRV) is an
autoimmune disorder causing
retrovirus in the Type-D family of retrovirus, e.g., SRV-1 (simian retrovirus
type 1), SRV-2 (simian retrovirus type 2), M7 (baboon endogenous retrovirus),
SMRV-H (squirrel monkey retrovirus), HTLV (human
T lymphocyte leukaemia virus) and distantly-related to
HIV (human immunodeficiency
virus).
1972 World Health Organization Bulletin No. 47
refers to creation of an immune virus and suggests that a useful way to study
the effects would be "to put it into a vaccination program and observe the
results".
Curiously the spread of
HIV infection in Central Africa
coincides precisely with an intense
smallpox vaccination campaign.
Information on Central African
countries infected with HIV
matches WHO figures indicating the number of people vaccinated in these
areas.
Government
Documents Locked Up for 30 Years Prove This Vaccine
Unsafe
HIV vaccine development
presents novel challenges on multiple levels.
The chief challenge is
HIV human retrovirus replicates by irreversibly inserting its genes into the
host genome.
HIV infection is established permanently in a matter of
days or even hours, and it cannot be cleared by primary or anamnestic
responses.
In addition to integrating into the host genome, HIV
replicates in CD4+ T cells that are key players in protective immunity.
These features suggest a different path to a HIV vaccine from
traditional design that led to successful vaccines against other infectious
agents.
Inability to yield an HIV vaccine became
abundantly clear in six large HIV vaccine trials, where efficacy was not
observed.
Strikingly, vaccination increased the risk of
infection in two of these studies that
selectively targeted T lymphocyte
immunity, providing a stark contrast between the development of
conventional and HIV vaccines. |
1983
French team at the Pasteur Institute in Paris led by Luc
Montagnier, publish a paper in Science describing a retrovirus, LAV (lymphadenopathy associated virus),
isolated from a patient at risk for AIDS.
LAV affects the way the
immune system
works.
May 6, 1983 "The disease was
first believed to be confined to a particular epidemiologically defined segment
of the population.
Earlier hypotheses suggested there was something
within the lifestyle of male homosexuals that predisposed them to this
syndrome.
Theories put forth suggesting drugs such as amyl nitrite,
antigenic overload, and medications taken for multiple infections affecting
male homosexuals." - Anthony S. Fauci, National Institutes of Health;
Acquired Immune Deficiency Syndrome: Ever-Broadening Clinical
Spectrum
May 4, 1984 Robert
Gallo, an observer at the
National Cancer Institute where he has worked for 30 years mainly as
head of the Laboratory of Tumor Cell Biology, and collaborators publish
a series of four papers in Science demonstrating that a retrovirus they
claim to have isolated is the cause of AIDS, HTLV-III, related to the
leukaemia virus of Gallo's
earlier work.
Method of continuous production of retrovirus
(HTLV-III)
1987
Immune system compromise brings AIDS
companion cancers include Kaposi sarcoma,
aggressive βlymphocyte
non-Hodgkin lymphoma and cervical cancer.
Other cancers linked to immune compromised by HIV/AIDS are head and
neck, anal, lung, testicle, skin, and liver cancers as well as Hodgkin
lymphoma.
Out of
court settlement between the National Institutes of Health (NIH)and
Pasteur Institute in Paris.
Results from
our analysis suggest that subjects with bipolar disorder and history of
cannabis use disorders demonstrate significantly better neurocognitive
performance, particularly on measures of attention,
processing speed, and working memory.
These findings are consistent
with a previous study that demonstrated that bipolar subjects with history of
cannabis use had superior verbal fluency performance as compared to bipolar
patients without a history of cannabis use (Ringen et al., 2010).
Similar results have also been found in
schizophrenia in
several studies (Rabin et al., 2011).
These data could be interpreted
to suggest that cannabis use may have a beneficial effect on cognitive
functioning in patients with severe psychiatric disorders. |
1988
Amalgamated HepB vaccine
introduced.
1991
Amalgamated HepB vaccine
mandated by Centers for Disease Control in 44 US states for initial use
in infants as young as two months.
New York Times, Mar 17th, "US
Vaccine Plan Uses Welfare Offices":
Feds are
considered denying nutritional benefits to families who refuse vaccinations.
The begins the process of mandating Hepatitis B vaccinations for all
infants in the United States. Many infants receive multiple doses from birth.
Following years of controversy surrounding the
out of court settlement between the
National Institutes of Health and the Pasteur Institute, Gallo
admits the virus he claimed to have discovered in 1984 is in reality a virus
sent to him from France the year before, putting an end to a six-year effort by
Gallo and his employer, the National Institutes of Health, to claim the
AIDS virus as an independent
discovery.
Hepatitis
B vaccination of male neonates and autism diagnosis
Court Admits Hepatitis B Vaccine Caused Fatal Autoimmune
Disorder
Connective Tissue Disease Following Hepatitis B
Vaccination
1993 "This paper shows how to
equate different aspects of imperfection in a prophylactic vaccine in terms of
impact upon levels of herd immunity, and hence upon the vaccine coverage
required for eradication.
Such
comparisons reveal
that an otherwise perfect vaccine that gives protection which wanes with a
half-life of 10 years is only as good as a vaccine that works in 30% of people
giving them complete, lifelong protection." - Imperfect vaccines and herd immunity to HIV
1994 20,000 American children and adolescents are
diagnosed with bipolar disorder.
1995 Gallo with his colleagues Paolo Lusso and
Fiorenza Cocchi publish
their discovery that chemokines, a class of naturally occurring compounds,
are potent and specific HIV inhibitors.
This discovery is heralded by
Science magazine as one of the top scientific breakthroughs of the year.
The role chemokines play in controlling the progression of HIV
infection influences thinking on how AIDS works against the human immune
system.
1996 "Despite unanimous
literature of double-blind studies indicating
antiDepressant
are no more effective than placebo in treating depression in children and
adolescents, such medications continue to be in wide use." - Rhoda L. Fisher
and Seymour Fisher, "antiDepressant for Children," The Journal of Nervous
and Mental Diseases (1996, v.184, no.2)
Gallo, Robert R. Redfield
and William A. Blattner, found the Institute of Human
Virology.
2003 800,000 children and adolescents are
diagnosed with bipolar
disorder - exponentially increasing 40 times levels 9 years
earlier.
2005 Dr. Frederick K.
Goodwin warns that children
with bipolar disorder who were left untreated could suffer brain damage.
Dr. Frederick K. Goodwin, a former director of the National Institute of Mental
Health, and host of the popular public radio program "The Infinite
Mind," produced by Lichtenstein Creative Media, earns at least $1.3
million from 2000 to 2007 giving marketing lectures for drugmakers.
"Boys, behaving aggressively
exhibiting irritable behavior become compliant when given mood stabilizers and
parents are relieved of the
stigma of poor parenting as bipolar disorder is thought to be an
inherited trait."
Modern treatments - mood stabilizers in
particular - have been proven both
safe and effective
in
bipolar children." -
Frederick K. Goodwin
"I call it the
juvenile bipolar juggernaut.
The diagnoses has been broadened considerably and I think that's a big
problem." - Joseph Woolston, Yale
"The risk of violence on these
drugs has been known for 50 years.
Giving these drugs to healthy
volunteers can cause them to become violent.
The data has been out
there in warnings in many countries for years.
There is no doctor who can say
they have been unaware of this issue.
If there are,
they are simply not
professional." - David Healy
2007
Gallo and his team are awarded a $15 million grant from the Gates Foundation for research into
a preventive vaccine for HIV/AIDS.
2010
Abstract:
"To develop safer and more effective vectors for
gene therapy of X-linked severe combined immunodeficiency (SCID-X1), we
have evaluated new self-inactivating lentiviral vectors based on the HIV virus.
The CL20i4-hγc-Revgen vector contains the entire human common
γ chain (γc) genomic sequence driven by the
γc promoter.
The CL20i4-EF1α
-hγcOPT vector uses a promoter fragment from the
eukaryotic elongation factor alpha
(EF1α ) gene to express a codon-optimized human γc cDNA.
Both vectors contain a 400-bp insulator fragment from the chicken
ß-globin locus within the self-inactivating long-terminal repeat.
Transduction of bone marrow cells using either of these vectors
restored T, B, and natural killer lymphocyte development and function in a
mouse SCID-X1 transplantation model.
Transduction of human
CD34+ bone marrow cells from SCID-X1 patients with either vector
restored T lymphocyte
development in an in vitro assay.
In
safety studies using a
Jurkat LMO2 activation assay, only the CL20i4-EF1α-hγcOPT
vector lacked the ability to transactivate LMO2 protein expression, whereas the
CL20i4-hγc-Revgen vector significantly activated LMO2 protein
expression.
In addition, the CL20i4-EF1α-hγcOPT
vector has not caused any tumors in
transfected mice.
We conclude that the
CL20i4-EF1a-hγcOPT vector may be
suitable for testing in a
clinical trial based on these preclinical demonstrations of
efficacy and safety.
A
self-inactivating lentiviral vector for SCID-X1 gene therapy
2011 Gallo and his team received $23.4 million from a
consortium of funding sources to support the next phase of research into the
Institute of Human Virology's (IHV) promising HIV/AIDS preventive
vaccine candidate.
The IHV vaccine program grants included $16.8 million
from the Gates
Foundation, $2.2 million from the U.S. Army's Military HIV Research
Program (MHRP), and other research funding from a variety of sources including
the National Institutes of Health.
2019
Abstract:
Gene correction in human long-term hematopoietic
stem cells (LT-HSCs)
could be an effective therapy for monogenic diseases of the blood and immune
system.
Here we describe an approach for X-linked sSevere cCombined
iImmunodeficiency (SCID-X1) using targeted integration of a cDNA into the
endogenous start codon to functionally correct disease-causing mutations
throughout the gene.
Using a CRISPR-Cas9/AAV6 based strategy, we
achieve up to 20% targeted integration frequencies in LT-HSCs.
As
measures of the lack of toxicity we observe no evidence of abnormal
hematopoiesis following transplantation and no evidence of off-target mutations
using a high-fidelity Cas9 as a ribonucleoprotein complex.
We achieve
high levels of targeting frequencies (median 45%) in CD34+ HSPCs
from six SCID-X1 patients and demonstrate rescue of lymphopoietic defect in a
patient derived HSPC population in vitro and in vivo.
In sum, our study
provides specificity,
toxicity and
efficacy data supportive of clinical development of genome editing to treat
SCID-Xl.
Gene correction for SCID-X1 in long-term hematopoietic stem
cells
Gastrointestinal (GI) tract disease/inflammation is a hallmark of
HIV/SIV infection.
Recreational and medical use of cannabis among human
immunodeficiency virus (HIV)-infected individuals has increased in recent
years.
In simian immunodeficiency virus (SIV)-infected macaques,
chronic administration of Δ9tetrahydrocannabinol
(Δ9THC) inhibited viral replication and intestinal inflammation
and slowed disease progression.
Persistent gastrointestinal
inflammation has been proposed to facilitate microbial translocation and
systemic immune activation and promote disease progression. Cannabinoids
including Δ9THC attenuated intestinal inflammation in mouse
colitis models and SIV-infected rhesus macaques.
To determine if the
anti-inflammatory effects of
Δ9THC involved differential mRNA (mRNA) modulation, we profiled
mRNA expression at 14, 30, and 60 days postinfection (days p.i.) in the
intestine of uninfected macaques receiving Δ9THC (n=3) and
SIV-infected macaques administered either vehicle (VEH/SIV; n=4) or THC
(THC/SIV; n=4).
Chronic Δ9THC administration to
uninfected macaques significantly and positively modulated intestinal mRNA
expression by increasing the total number of differentially expressed mRNAs
from 14 to 60 days p.i. At 60 days p.i., ~28% of mRNAs showed decreased
expression in the VEH/SIV group compared to none showing decrease in the
THC/SIV group.
Furthermore, compared to the VEH/SIV group, THC
selectively upregulated the expression of miR-10a, miR-24, miR-99b, miR-145,
miR-149, and miR-187, previously been shown to target proinflammatory
molecules.
NOX4, a potent reactive oxygen species generator, was
confirmed as a direct miR-99b target. A significant increase in NOX4+ crypt
epithelial cells was detected in VEH/SIV macaques compared to the THC/SIV
group.
We speculate that miR-99b-mediated NOX4 downregulation may
protect the intestinal epithelium from oxidative stress-induced damage.
These results support a role for differential mRNA induction in
THC-mediated suppression of intestinal inflammation.
Whether similar
mRNA modulation occurs in other tissues requires further
investigation.
Previously, we showed that chronic treatment of
SIV-infected macaques with Δ9tetrahydrocannabinol
(Δ9THC) increased survival and decreased viral replication and
infection-induced gastrointestinal inflammation.
Here, we show that
chronic THC administration to SIV-infected macaques induced an
anti-inflammatory mRNA expression
profile in the intestine at 60 days p.i.
These included several mRNAs
bioinformatically predicted to directly target CXCL12, a chemokine known to
regulate lymphocyte and macrophage trafficking into the intestine.
Specifically, mR-99b was significantly upregulated in THC-treated
SIV-infected macaques and confirmed to directly target NADPH oxidase 4 (NOX4),
a reactive oxygen species generator known to damage intestinal epithelial
cells.
Elevated mR-99b expression was associated with a significantly
decreased number of NOX4+ epithelial cells in the intestines of THC-treated
SIV-infected macaques.
Overall, our results show that selective
upregulation of anti-inflammatory
mRNA expression contributes to THC-mediated suppression of gastrointestinal
inflammation and maintenance of intestinal homeostasis. |
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