Microarray analysis reveals global modulation of endogenous retroelement transcription by microbes.

BACKGROUND:

A substantial proportion of both the mouse and human genomes comprise of endogenous retroelements (REs), which include endogenous retroviruses. Over evolutionary time, REs
accumulate inactivating mutations or deletions and thus lose the ability
to replicate. Additionally, REs can be transcriptionally repressed by
dedicated mechanisms of the host. Nevertheless, many of them still
possess and express intact open reading frames, and their
transcriptional activity has been associated with many physiological and
pathological processes of the host. However, this association remains
tenuous due to incomplete understanding of the mechanism by which RE
transcription is regulated. Here, we use a bioinformatics tool to
examine RE transcriptional activity, measured by microarrays, in murine
and human immune cells responding to microbial stimulation.

RESULTS:

Immune cell activation by microbial signals in vitro caused extensive changes
in the transcription not only of the host genes involved in the immune
response, but also of numerous REs. Modulated REs were frequently found
near or embedded within similarly-modulated host genes. Focusing on
probes reporting single-integration, intergenic REs, revealed extensive
transcriptional responsiveness of these elements to microbial signals.
Microbial stimulation modulated RE expression in a cell-intrinsic
manner. In line with these results, the transcriptional activity of
numerous REs followed characteristics in different tissues according to
exposure to environmental microbes and was further heavily altered
during viral infection or imbalances with intestinal microbiota, both in
mice and humans.

CONCLUSIONS:

Together, these results highlight the utility of improved methodologies in assessing RE
transcription profiles in both archived and new microarray data sets.
More importantly, application of this methodology suggests that immune
activation, as a result of infection with pathogens or dysbiosis with
commensal microbes, causes global modulation of RE transcription. RE
responsiveness to external stimuli should, therefore, be considered in
any association between RE transcription and disease.

Endocannabinoid CB1 antagonists inhibit hepatitis C virus production, providing a novel class of antiviral host targeting agents.

Direct acting antivirals have significantly improved treatment outcomes
in chronic hepatitis C (CHC), but side effects, drug resistance and cost
mean that better treatments are still needed. Lipid metabolism is
closely linked with hepatitis C virus (HCV) replication and
endocannabinoids are major regulators of lipid homeostasis. The
cannabinoid 1 (CB1) receptor mediates these effects in the liver. We
have previously shown up-regulation of CB1 receptors in the livers of
patients with CHC, and in a HCV cell culture model. Here we investigated
whether CB1 blockade inhibits HCV replication. The antiviral effect of a
CB1 antagonist, AM251 was examined in the JFH1 cell culture and
subgenomic replicon models. The effects on the expression of genes
involved in lipid metabolism were also measured. CB1 shRNA was used to
confirm that the effects were specific for the cannabinoid receptor.
Treatment with AM251 strongly inhibited HCV RNA (~70%), viral protein
(~80%), the production of new virus particles (~70%), and virus
infectivity (~90%). As expected, AM251 reduced the expression of
pro-lipogenic genes (SREBP-1c, FASN, SCD1 and ACC1) and stimulated genes
promoting lipid oxidation (CPT1 and PPARα). This effect was mediated by
AMPK. Stable CB1 knockdown of cells infected with HCV showed reduced
levels of HCV RNA, compared with controls. Reduced CB1 signalling
inhibits HCV replication using either pharmacological inhibitors or CB1
shRNA. This may be due, at least in part, to reduced lipogenesis,
mediated by AMPK activation. We suggest that CB1 antagonists may
represent an entirely new class of drugs with activity against HCV.

Active Invasion of Porphyromonas gingivalis and Infection-Induced Complement Activation in ApoE-/- Mice Brains.

Periodontal disease is a polymicrobial inflammatory disease that leads to chronic
systemic inflammation and direct infiltration of bacteria/bacterial components,
which may contribute to the development of Alzheimer's disease. ApoE-/- mice were
orally infected (n = 12) with Porphyromonas gingivalis, Treponema denticola,
Tannerella forsythia, and Fusobacterium nucleatum as mono- and polymicrobial
infections. ApoE-/- mice were sacrificed following 12 and 24 weeks of chronic
infection. Bacterial genomic DNA was isolated from all brain tissues except for
the F. nucleatum mono-infected group. Polymerase chain reaction was performed
using universal 16 s rDNA primers and species-specific primer sets for each
organism to determine whether the infecting pathogens accessed the brain.
Sequencing amplification products confirmed the invasion of bacteria into the
brain during infection. The innate immune responses were detected using
antibodies against complement activation products of C3 convertase stage and the 
membrane attack complex. Molecular methods demonstrated that 6 out of 12 ApoE-/- 
mice brains contained P. gingivalis genomic DNA at 12 weeks (p = 0.006), and 9
out of 12 at 24 weeks of infection (p = 0.0001). Microglia in both infected and
control groups demonstrated strong intracellular labeling with C3 and C9, due to 
on-going biosynthesis. The pyramidal neurons of the hippocampus in 4 out of 12
infected mice brains demonstrated characteristic opsonization with C3 activation 
fragments (p = 0.032). These results show that the oral pathogen P. gingivalis
was able to access the ApoE-/- mice brain and thereby contributed to complement
activation with bystander neuronal injury.

Pesticide linked to three generations of disease: Methoxychlor causes epigenetic changes -- ScienceDaily

Washington State University researchers say ancestral exposures to the pesticide methoxychlor may lead to adult onset kidney disease, ovarian disease and obesity in future generations.
When Skinner and his colleagues exposed gestating rats to methoxychlor at a range typical of high environmental exposures, they saw increases in the incidence of kidney disease, ovary disease and obesity in offspring spanning three generations. The incidence of multiple diseases increased in the third generation or "great-grandchildren."
The researchers say the pesticide may be affecting how genes are turned on and off in the progeny of an exposed animal, even though its DNA and gene sequences remain unchanged.

Immunosenescence is associated with human cytomegalovirus and shortened telomeres in type I bipolar disorder.

OBJECTIVE:

Bipolar disorder (BD) has been associated with
persistent low-grade inflammation and premature cell senescence, as
shown by reduced telomere length (TL). The human cytomegalovirus (CMV)
has increasingly been implicated in accelerated immunosenescence in
aging studies. Here, we compared CMV serology and its relationships with
cell senescence markers, including TL and lymphocyte subsets, in
patients with type I BD and healthy controls.

METHODS:

Twenty-two
euthymic female patients with BD type I and 17 age-matched healthy
controls were selected for the study. A sample of blood was collected
and mononuclear cells and DNA were isolated and TL measured. CMV
immunoglobulin M (IgM) and IgG titers were measured using
chemiluminescent assays. Lymphocyte subsets [T, natural killer (NK) and
NKT] were phenotyped by flow cytometry.

RESULTS:

Individuals
with BD had shorter TLs but higher CMV IgG levels than controls (both p
< 0.01). CMV IgG level was inversely correlated with TL. None of the
subjects showed IgM reactivity for CMV, excluding acute viral
infection. CMV IgG level was associated with expansion of senescent
CD8+CD28- T cells and NK cells, which are involved in viral control.

CONCLUSIONS:

These
data support the hypothesis of accelerated aging in BD, as shown by
shortened telomeres, higher seropositivity for CMV, and expansion of
senescent T cells.

JAMA Network | JAMA | Research on Psychiatric Disorders Targets Inflammation

JAMA Network | JAMA | Research on Psychiatric Disorders Targets Inflammation

Childhood Epstein-Barr Virus infection and subsequent risk of psychotic experiences in adolescence

BACKGROUND:

Several studies suggest a link between early-life infection and adult schizophrenia. Cross-sectional studies have reported: (1) increased prevalence of Epstein-Barr Virus (EBV), a
member of the Herpesviridae family in schizophrenia; (2) a possible role
of Herpes simplex virus in cognitive dysfunction in schizophrenia and
healthy controls. We report a longitudinal serological study of
early-life EBV infection, childhood IQ, and subsequent risk of psychotic
experiences (PE) in adolescence.

METHODS:

Serum antibodies to EBV (anti-VCA IgG) were measured in 530 participants from
the ALSPAC cohort at age 4years. Assessments for IQ at age 9 and PE at
age 13 were attended by 401 and 366 of these individuals, respectively.
Logistic regression calculated odds ratio (OR) for PE in EBV-exposed,
compared with unexposed group. Mean IQ scores were compared between
these groups; effect of IQ on the EBV-PE association was examined.
Potential confounders included age, gender, ethnicity, social class,
household crowding, and concurrent depression and anxiety.

RESULTS:

About 25% of the sample was exposed to EBV at age 4. EBV exposure was
associated with subsequent risk of definite PE in adolescence; OR 5.37
(95% CI 1.71-16.87), which remained significant after confounding
adjustment. EBV-exposed individuals compared with unexposed performed
worse on all IQ measures; mean difference in full-scale IQ 4.15 (95% CI
0.44-7.87); however, this was explained by socio-demographic
differences. The EBV-PE association was not explained by IQ.

CONCLUSIONS:

Early-life exposure to EBV is associated with PE in adolescence, consistent with a
role of infection/immune dysfunction in the aetiology of psychosis.

Study examines therapeutic bacteria’s ability to prevent obesity | Research News @ Vanderbilt | Vanderbilt University

A probiotic that prevents obesity could be on the horizon.


Bacteria that produce a therapeutic compound in the gut inhibit
weight gain, insulin resistance and other adverse effects of a high-fat
diet in mice, Vanderbilt University investigators have discovered.

Reactivated herpes simplex infection increases the risk of Alzheimer's disease.

BACKGROUND:Previous studies have suggested a link between
herpes simplex virus (HSV) type 1 and the development of Alzheimer's
disease (AD).

METHODS:The present analysis included 3432 persons (53.9% women, mean age at inclusion 62.7 ± 14.4 years) with a mean follow-up time of 11.3 years. The number of incident AD cases was
245. Serum samples were analyzed for anti-HSV antibodies (immunoglobulin
(Ig)G and IgM) by enzyme-linked immunosorbent assays.

RESULTS
:The presence of anti-HSV IgG antibodies was not associated with an
increased risk for AD, controlled for age and sex (hazard ratio, HR,
0.993, P = .979). However, the presence of anti-HSV IgM at baseline was
associated with an increased risk of developing AD (HR 1.959, P = .012).

CONCLUSION:Positivity for anti-HSV IgM, a sign of reactivated infection, was found to almost
double the risk for AD, whereas the presence of anti-HSV IgG antibodies
did not affect the risk.

RNA-directed gene editing specifically eradicates latent and prevents new HIV-1 infection

For more than three decades since the discovery of HIV-1, AIDS remains a major public health problem affecting greater than 35.3 million people worldwide. Current antiretroviral therapy has failed to eradicate HIV-1, partly due to the persistence of viral reservoirs. RNA-guided HIV-1 genome cleavage by the Cas9 technology has shown promising efficacy in disrupting the HIV-1 genome in latently infected cells, suppressing viral gene expression and replication, and immunizing uninfected cells against HIV-1 infection. These properties may provide a viable path toward a permanent cure for AIDS, and provide a means to vaccinate against other pathogenic viruses. Given the ease and rapidity of Cas9/guide RNA development, personalized therapies for individual patients with HIV-1 variants can be developed instantly.

A new cellular garbage control pathway with relevance for human neurodegenerative diseases: Max Planck Institute of Biochemistry |

Several human neurodegenerative diseases, including Alzheimer’s,
Parkinson’s and Huntington’s disease but also ageing, are linked to an
accumulation of abnormal and aggregated proteins in cells. Cellular
“garbage” of this type can be removed from cells by sweeping them to a
cellular recycling station known as the lysosome. Scientists at the Max
Planck Institute of Biochemistry in Martinsried, Germany, now discovered
a new family of helper proteins that recognize labeled cellular protein
waste and guide them efficiently to the lysosome for destruction and
subsequent recycling into their reusable compounds. The results of this
study, now published in the journal Cell, are crucial for our
understanding how cells remove cellular waste and will open new avenues
for studies aimed to fight neurodegenerative diseases.

Toxoplasma gondii can stop cancer in its tracks as a vaccine

A healthy immune system responds vigorously to T. gondii in a manner that parallels how the immune system attacks a tumor.
In response to T. gondii, the body produces natural killer cells and cytotoxic T cells. These cell types wage war against cancer cells.
Cancer can shut down the body's defensive mechanisms, but introducing
T. gondii into a tumor environment can jump start the immune system.

Engineering T. gondii as a Cancer Vaccine

Since it isn't safe to inject a cancer patient with live replicating
strains of T. gondii, Bzik and Fox created "cps," an immunotherapeutic
vaccine. Based on the parasite's biochemical pathways, they delete a
Toxoplasma gene needed to make a building block of its genome and create
a mutant parasite that can be grown in the laboratory but is unable to
reproduce in animals or people. Cps is both nonreplicating and safe.
Even when the host is immune deficient, cps still retains that unique
biology that stimulates the ideal vaccine responses.
Published laboratory studies from the Geisel School of Medicine at
Dartmouth labs have tested the cps vaccine in extremely aggressive
lethal mouse models of melanoma or ovarian cancer and found
unprecedented high rates of cancer survival.
"Cps stimulates amazingly effective immunotherapy against cancers,
superior to anything seen before," said Bzik. "The ability of cps to
communicate in different and unique ways with the cancer and special
cells of the immune system breaks the control that cancer has leveraged
over the immune system."



Arthritis drug (TNF antagonist) shown to slow Alzheimer's down

A small randomised control study at the University of Southampton
tested the drug Etanercept on patients with mild to moderate
Alzheimer's.
Forty-one participants were either given the drug or a placebo every
week for six months. They were then assessed for memory function,
efficiency of day-to-day activities and behaviour.
Results showed that patients who were given Etanercept did not get
any worse during the six month follow up compared to those on the
placebo, who did decline.
Etanercept works by blocking the effects of a protein in the blood
called TNFα which is released by blood cells as part on the body's
inflammatory response. Professor Holmes' group has already shown that
people with Alzheimer's that have high levels of active TNFα in their
blood do worse than those who have very low levels. Etanercept acts to
markedly reduce the active levels of TNFα. 

One Injection of FGF1 Stops Diabetes in Its Tracks

In mice with diet-induced  diabetes—the equivalent of type 2 diabetes in humans—a single injection
of the protein FGF1 is enough to restore blood sugar levels to a healthy range for more than two days. The discovery by Salk scientists,  published in the journal Nature, could lead to a new generation of safer, more effective diabetes drugs.
The team found that sustained treatment with the protein doesn't
merely keep blood sugar under control, but also reverses insulin
insensitivity, the underlying physiological cause of diabetes. Equally
exciting, the newly developed treatment doesn't result in side effects
common to most current diabetes treatments.

Prenatal exposure to dichlorodiphenyltrichloroethane and obesity at 9 years of age in the CHAMACOS study cohort.

In-utero exposure to endocrine-disrupting compounds, including
dichlorodiphenyltrichloroethane (DDT) and its metabolite
dichlorodiphenylethylene (DDE), has been hypothesized to increase the
risk of obesity later in life. We examined the associations of maternal
serum concentrations of DDT and DDE during pregnancy with body mass
index, obesity, waist circumference, and percentage of body fat in
9-year-old children (n = 261) in the Center for the Health Assessment of
Mothers and Children of Salinas (CHAMACOS) Study, a longitudinal birth
cohort study in the Salinas Valley, California (2000-2010). We found
associations between prenatal exposure to DDT and DDE and several
measures of obesity at 9 years of age in boys but not in girls. For
example, among boys, 10-fold increases in prenatal DDT and DDE
concentrations were associated with increased odds of becoming
overweight or obese (for o,p'-DDT, adjusted odds ratio (OR) = 2.5, 95%
confidence interval (CI): 1.0, 6.3; for p,p'-DDT, adjusted OR = 2.1, 95%
CI: 1.0, 4.5; and for p,p'-DDE, adjusted OR = 1.97, 95% CI: 0.94,
4.13). The odds ratios for girls were nonsignificant. Results were
similar for body mass index z score, waist circumference z score, and
odds of increased waist circumference but were less consistent for
percentage of body fat. The difference by sex persisted after
considering pubertal status. These results provide support for the
chemical obesogen hypothesis.

Food-derived opioid peptides (from gliadin and casein) inhibit cysteine uptake with redox and epigenetic consequences.

Dietary interventions like gluten-free and casein-free diets have been
reported to improve intestinal, autoimmune and neurological symptoms in
patients with a variety of conditions; however, the underlying mechanism
of benefit for such diets remains unclear. Epigenetic programming,
including CpG methylation and histone modifications, occurring during
early postnatal development can influence the risk of disease in later
life, and such programming may be modulated by nutritional factors such
as milk and wheat, especially during the transition from a solely
milk-based diet to one that includes other forms of nutrition. The
hydrolytic digestion of casein (a major milk protein) and gliadin (a
wheat-derived protein) releases peptides with opioid activity, and in
the present study, we demonstrate that these food-derived proline-rich
opioid peptides modulate cysteine uptake in cultured human neuronal and
gastrointestinal (GI) epithelial cells via activation of opioid
receptors. Decreases in cysteine uptake were associated with changes in
the intracellular antioxidant glutathione and the methyl donor
S-adenosylmethionine. Bovine and human casein-derived opioid peptides
increased genome-wide DNA methylation in the transcription start site
region with a potency order similar to their inhibition of cysteine
uptake. Altered expression of genes involved in redox and methylation
homeostasis was also observed. These results illustrate the potential of
milk- and wheat-derived peptides to exert antioxidant and epigenetic
changes that may be particularly important during the postnatal
transition from placental to GI nutrition. Differences between peptides
derived from human and bovine milk may contribute to developmental
differences between breastfed and formula-fed infants. Restricted
antioxidant capacity, caused by wheat- and milk-derived opioid peptides,
may predispose susceptible individuals to inflammation and systemic
oxidation, partly explaining the benefits of gluten-free or casein-free
diets.

Cerebrospinal fluid and serum cytokine profiling to detect immune control of infectious and inflammatory neurological and psychiatric diseases.

The present study aimed at profiling inflammatory cytokines for
neurological and psychiatric diseases. A total of 86 patients with
meningitis, multiple sclerosis, tension-type headache, idiopathic facial
nerve palsy (IFNP), affective and schizophrenic disorders were tested
for both, serum and cerebrospinal fluid (CSF) using a multiplexed
cytokine ELISA for IFN-γ, TNF-α, IL-1β, IL-2, IL-4, IL-5, IL-8/CXCL8,
IL-10, IL12p70, IL-13 and IL-17. Cases with viral and bacterial
meningitis had unequivocally higher cytokine concentrations in the CSF
when compared with serum. Bacterial meningitis was unique by extremely
elevated IL-17, TNF-α and IL-1β, indicating a plethora of inflammatory
pathways, selectively activated in the CSF. In relapsing multiple
sclerosis, IFN-γ and IL-10 were elevated in both, serum and CSF, but
IL-12p70, IL-5, IL-13, and TNF-α were more prominent in serum than in
CSF. Qualitatively similar biomarker patterns were detected in patients
with idiopathic facial nerve palsy and tension-type cephalgia. Affective
and schizophrenic disorders clearly present with an inflammatory
phenotype in the CSF and also serum, the cytokines determined were in
general higher in schizophrenia. Except IFN-γ, schizophrenic patients
had higher IL-12p70 and a trend of higher IL-10 and IL-13 in serum
suggesting a more prominent TH2-type counter regulatory immune response
than in affective disorders. These differences were also mirrored in the
CSF. Elevated IL-8 appears to be the most sensitive marker for
inflammation in the CSF of all diseases studied, whereas TNF-α was
restricted to peripheral blood. With the exception of IL-8, all but
viral and bacterial meningitis, studied, displayed higher means of
elevated lymphokine concentrations in the serum than in the CSF. This
observation supports the concept of immunological crosstalk between
periphery and intrathecal immunity in neurological and psychiatric
diseases.

Acute glaucoma discovered to be an inflammatory disease -- ScienceDaily

Acute glaucoma in mice is largely an inflammatory disease and that high
pressure in the eye causes vision loss by setting in motion an
inflammatory response similar to that evoked by bacterial infections,
researchers have determined. The study has immediate clinical relevance
in treating the tens of millions of people worldwide from what is known
as acute closed-angle glaucoma.

Defects in fatty acid transport proteins linked to schizophrenia and autism | RIKEN

Using diverse methodologies, neuroscientists from the RIKEN Brain
Science Institute report that defects in Fatty Acid Binding Proteins
(FABPs) may help to explain the pathology in some cases of schizophrenia
and autism spectrum disorders. After identifying mutations in FABPs
from patients, the group led by Senior Team Leader Takeo Yoshikawa
determined that the genetic disruption of Fabps in mice mimics disease
behaviors seen in patients. This work suggests that disruption of FABPs
could be a common link underlying some forms of these two prevalent
mental disorders.

Here's the paper:-


Functional characterization of FABP3, 5 and 7 gene variants identified in schizophrenia and autism spectrum disorder and mouse behavioral studies

Novartis plans to test Alzheimer's drugs in patients without symptoms - FierceBiotech

Learning the lessons of failed trials in mild, moderate and severe Alzheimer's disease, Novartis is planning to study two new treatments on patients who are yet to show any symptoms, hoping to succeed where many others have slipped and delay the onset of the memory-destroying ailment.
In collaboration with the Banner Alzheimer's Institute, Novartis plans to study whether its two treatments--an immunotherapy and a BACE inhibitor--can prevent the buildup of amyloid proteins, considered by many to be a cause of Alzheimer's development. The first treatment, an injectable called CAD106, is designed spur the immune system's natural development of amyloid-blocking antibodies and is in Phase II on its own. The second drug, yet to enter clinical trials, is an oral inhibitor of an enzyme tied to amyloid production.
The plan is to recruit more than 1,300 cognitively healthy adults who have two copies of the APoE4 gene, which increases their risk of developing the disease. Participants will get either CAD106, the BACE inhibitor or placebo, and Novartis hopes to get started next year, pending regulatory approval.