Long-term exposure to air pollution may pose risk to brain structure, cognitive functions -- ScienceDaily

Air pollution, even at moderate levels, has long been recognized as a
factor in raising the risk of stroke. A new study suggests that
long-term exposure can cause damage to brain structures and impair
cognitive function in middle-aged and older adults.

Molecular Signatures of Major Depression: Current Biology

Adversity particularly in early life, can cause illness. Clues to the responsible
mechanisms may lie with the discovery of molecular signatures of stress,
some of which include alterations to an individual’s somatic genome.
Here, using genome sequences from 11,670 women, we observed a highly
significant association between a stress-related disease, major
depression, and the amount of mitochondrial DNA (p = 9.00 × 10−42, odds ratio 1.33 [95% confidence interval [CI] = 1.29–1.37]) and telomere length (p = 2.84 × 10−14,
odds ratio 0.85 [95% CI = 0.81–0.89]). While both telomere length and mitochondrial DNA amount were associated with adverse life events, conditional
regression analyses showed the molecular changes were contingent on the
depressed state. We tested this hypothesis with experiments in mice,
demonstrating that stress causes both molecular changes, which are
partly reversible and can be elicited by the administration of
corticosterone. Together, these results demonstrate that changes in the
amount of mitochondrial DNA and telomere length are consequences of stress and
entering a depressed state. These findings identify increased amounts of
mtDNA as a molecular marker of MD and have important implications for
understanding how stress causes the disease.

Gut bacteria in children with autism spectrum disorders: challenges and promise of studying how a complex community influences a complex disease

Recent studies suggest a role for the microbiota in autism spectrum
disorders (ASD), potentially arising from their role in modulating the
immune system and gastrointestinal (GI) function or from gut–brain
interactions dependent or independent from the immune system. GI
problems such as chronic constipation and/or diarrhea are common in
children with ASD, and significantly worsen their behavior and their
quality of life. Here we first summarize previously published data
supporting that GI dysfunction is common in individuals with ASD and the
role of the microbiota in ASD. Second, by comparing with other
publically available microbiome datasets, we provide some evidence that
the shifted microbiota can be a result of westernization and that this
shift could also be framing an altered immune system. Third, we explore
the possibility that gut–brain interactions could also be a direct
result of microbially produced metabolites.

TREM-2 promotes macrophage survival and lung disease after respiratory viral infection

Viral infections and type 2 immune responses are thought to be critical for the development of chronic respiratory disease, but the link between these events needs to be better defined. Here, we study a mouse model in which infection with a mouse parainfluenza virus known as Sendai virus (SeV) leads to long-term activation of innate immune cells that drive IL-13–dependent lung disease. We find that chronic postviral disease (signified by formation of excess airway mucus and accumulation of M2-differentiating lung macrophages) requires macrophage expression of triggering receptor expressed on myeloid cells-2 (TREM2). Analysis of mechanism shows that viral replication increases lung macrophage levels of intracellular and cell surface TREM2, and this action prevents macrophage apoptosis that would otherwise occur during the acute illness (5–12 d after inoculation).
However, the largest increases in TREM2 levels are found as the soluble form (sTREM-2) long after clearance of infection (49 d after inoculation). At this time, IL-13 and the adapter protein DAP12 promote TREM2 cleavage to sTREM2 that is unexpectedly active in preventing macrophage apoptosis. The results thereby define an unprecedented mechanism for a feed-forward expansion of lung macrophages (with IL-13 production and consequent M2 differentiation) that further explains how acute infection leads to chronic inflammatory disease.

Bee studies stir up pesticide debate : Nature News & Comment

The case for restricting a controversial family of insecticides is growing. Two studies published on 22 April in Nature1, 2
address outstanding questions about the threat that the chemicals pose
to bees, and come as regulators around the world gear up for a fresh
debate on pesticide restrictions.

Many bee
populations are in steep decline, with multiple causes identified,
including parasites and the loss of food sources. Also blamed are
neonicotinoids, a widely used class of insecticides that are often
applied to seeds, and find their way into the pollen and nectar of
plants. The use on seeds of three — clothianidin, imidacloprid and
thiamethoxam — is temporarily banned in the European Union because of
concern that they might harm pollinators; the ban is up for review in
December. In the United States, there are no such restrictions, but the
US Environmental Protection Agency said on 2 April that it was
“unlikely” to approve new outdoor neonicotinoid-pesticide uses without
new bee data.

Drug-based modulation of endogenous stem cells promotes functional remyelination in vivo : Nature : Nature Publishing Group

 Multiple sclerosis involves an aberrant autoimmune response and
progressive failure of remyelination in the central nervous system.
Prevention of neural degeneration and subsequent disability requires
remyelination through the generation of new oligodendrocytes, but
current treatments exclusively target the immune system. Oligodendrocyte
progenitor cells are stem cells in the central nervous system and the
principal source of myelinating oligodendrocytes1.
These cells are abundant in demyelinated regions of patients with
multiple sclerosis, yet fail to differentiate, thereby representing a
cellular target for pharmacological intervention2.
To discover therapeutic compounds for enhancing myelination from
endogenous oligodendrocyte progenitor cells, we screened a library of
bioactive small molecules on mouse pluripotent epiblast
stem-cell-derived oligodendrocyte progenitor cells3, 4, 5.
Here we show seven drugs function at nanomolar doses selectively to
enhance the generation of mature oligodendrocytes from progenitor cells in vitro.
Two drugs, miconazole and clobetasol, are effective in promoting
precocious myelination in organotypic cerebellar slice cultures, and in vivo
in early postnatal mouse pups. Systemic delivery of each of the two
drugs significantly increases the number of new oligodendrocytes and
enhances remyelination in a lysolecithin-induced mouse model of focal
demyelination. Administering each of the two drugs at the peak of
disease in an experimental autoimmune encephalomyelitis mouse model of
chronic progressive multiple sclerosis results in striking reversal of
disease severity. Immune response assays show that miconazole functions
directly as a remyelinating drug with no effect on the immune system,
whereas clobetasol is a potent immunosuppressant as well as a
remyelinating agent. Mechanistic studies show that miconazole and
clobetasol function in oligodendrocyte progenitor cells through
mitogen-activated protein kinase and glucocorticoid receptor signalling,
respectively. Furthermore, both drugs enhance the generation of human
oligodendrocytes from human oligodendrocyte progenitor cells in vitro.
Collectively, our results provide a rationale for testing miconazole
and clobetasol, or structurally modified derivatives, to enhance
remyelination in patients.

Beyond the association. Toxoplasma gondii in schizophrenia, bipolar disorder, and addiction: systematic review and meta-analysis -

Objective

To perform a meta-analysis on studies reporting prevalence of Toxoplasma gondii (T. gondii)
infection in any psychiatric disorder compared with healthy controls.
Our secondary objective was to analyze factors possibly moderating
heterogeneity.

Method

A systematic search was performed to identify studies into T. gondii
infection for all major psychiatric disorders versus healthy controls.
Methodological quality, publication bias, and possible moderators were
assessed.

Results

A
total of 2866 citations were retrieved and 50 studies finally included.
Significant odds ratios (ORs) with IgG antibodies were found in
schizophrenia (OR 1.81, P < 0.00001), bipolar disorder (OR 1.52, P = 0.02), obsessive–compulsive disorder (OR 3.4, P < 0.001), and addiction (OR 1.91, P < 0.00001), but not for major depression (OR 1.21, P = 0.28). Exploration of the association between T. gondii
and schizophrenia yielded a significant effect of seropositivity before
onset and serointensity, but not IgM antibodies or gender. The
amplitude of the OR was influenced by region and general seroprevalence.
Moderators together accounted for 56% of the observed variance in study
effects. After controlling for publication bias, the adjusted OR (1.43)
in schizophrenia remained significant.

Conclusion

These findings suggest that T. gondii infection is associated with several psychiatric disorders and that in schizophrenia reactivation of latent T. gondii infection may occur.

Gut Microbes Influence Circadian Clock | The Scientist Magazine®

The mammalian gut microbiome is involved in controlling the circadian
rhythm of its host, according to a mouse study published today (April
16) in Cell Host & Microbe. In both mice and humans, timing of feeding and diet type can impact the bacterial populations of the gut. Now, Eugene Chang
of the University of Chicago Medical Center and his colleagues have
found that mouse gut microbiota produce metabolites in diurnal patterns,
and these can influence the expression of circadian clock genes in the
liver.
The results provide additional support for the idea that the gut microbiome is dynamic, said Satchidananda Panda
of the Salk Institute for Biological Studies who was not involved in
the work. “At night, we go to bed with a bunch of bugs in our stomachs
and wake up in the morning with a different set of bugs,” said Panda.
“The implications are pretty big because there are more bacterial cells
in our guts than the number of cells in our body and these species
produce different enzymes and factors that have a big impact on our
overall metabolism.”

Frontiers | A review on computational systems biology of pathogen–host interactions | Infectious Diseases

Pathogens manipulate the cellular mechanisms of host organisms via pathogen–host
interactions (PHIs) in order to take advantage of the capabilities of
host cells, leading to infections. The crucial role of these
interspecies molecular interactions in initiating and sustaining
infections necessitates a thorough understanding of the corresponding
mechanisms. Unlike the traditional approach of considering the host or
pathogen separately, a systems-level approach, considering the PHI
system as a whole is indispensable to elucidate the mechanisms of
infection. Following the technological advances in the post-genomic era,
PHI data have been produced in large-scale within the last decade.
Systems biology-based methods for the inference and analysis of PHI
regulatory, metabolic, and protein–protein networks to shed light on
infection mechanisms are gaining increasing demand thanks to the
availability of omics data. The knowledge derived from the PHIs may
largely contribute to the identification of new and more efficient
therapeutics to prevent or cure infections. There are recent efforts for
the detailed documentation of these experimentally verified PHI data
through Web-based databases. Despite these advances in data archiving,
there are still large amounts of PHI data in the biomedical literature
yet to be discovered, and novel text mining methods are in development
to unearth such hidden data. Here, we review a collection of recent
studies on computational systems biology of PHIs with a special focus on
the methods for the inference and analysis of PHI networks, covering
also the Web-based databases and text-mining efforts to unravel the data
hidden in the literature.

Paternal sperm DNA methylation associated with early signs of autism risk in an autism-enriched cohort

Background: Epigenetic mechanisms such as
altered DNA methylation have been suggested to play a role in autism,
beginning with the classical
association of Prader-Willi syndrome, an imprinting
disorder, with autistic features.
Objectives: Here we tested for the relationship of paternal sperm DNA methylation with autism risk in offspring, examining an enriched-risk
cohort of fathers of autistic children.
Methods: We examined
genome-wide DNA methylation (DNAm) in paternal semen biosamples obtained
from an autism spectrum disorder (ASD)
enriched-risk pregnancy cohort, the Early Autism
Risk Longitudinal Investigation (EARLI) cohort, to estimate associations
between sperm DNAm and prospective ASD development,
using a 12-month ASD symptoms assessment, the Autism Observation Scale
for Infants (AOSI). We analysed methylation data
from 44 sperm samples run on the CHARM 3.0 array, which contains over 4
million
probes (over 7 million CpG sites), including 30
samples also run on the Illumina Infinium HumanMethylation450 (450K)
BeadChip
platform (∼485 000 CpG sites). We also examined
associated regions in an independent sample of post-mortem human brain
ASD
and control samples for which Illumina 450K DNA
methylation data were available.
Results: Using region-based statistical approaches, we identified 193 differentially methylated regions (DMRs) in paternal sperm with
a family-wise empirical P-value
[family-wise error rate (FWER)] <0.05 associated with performance on
the Autism Observational Scale for Infants (AOSI)
at 12 months of age in offspring. The DMRs
clustered near genes involved in developmental processes, including many
genes
in the SNORD family, within the
Prader-Willi syndrome gene cluster. These results were consistent among
the 75 probes on the Illumina
450K array that cover AOSI-associated DMRs from
CHARM. Further, 18 of 75 (24%) 450K array probes showed consistent
differences
in the cerebellums of autistic individuals compared
with controls.
Conclusions: These data
suggest that epigenetic differences in paternal sperm may contribute to
autism risk in offspring, and provide
evidence that directionally consistent, potentially
related epigenetic mechanisms may be operating in the cerebellum of
individuals
with autism.

The effects of in utero bisphenol A exposure on reproductive capacity in several generations of mice

In utero bisphenol A (BPA) exposure affects reproductive function in the
first generation (F1) of mice; however, not many studies have examined
the reproductive effects of BPA exposure on subsequent generations. In
this study, pregnant mice (F0) were orally dosed with vehicle, BPA (0.5,
20, and 50 μg/kg/day) or diethylstilbestrol (DES; 0.05 μg/kg/day) daily
from gestation day 11 until birth. F1 females were used to generate the
F2 generation, and F2 females were used to generate the F3 generation.
Breeding studies at the ages of 3, 6, and 9 months were conducted to
evaluate reproductive capacity over time. Further, studies were
conducted to evaluate pubertal onset, litter size, and percentage of
dead pups; and to calculate pregnancy rate, and mating, fertility, and
gestational indices. The results indicate that BPA exposure (0.5 and
50 μg/kg/day) significantly delayed the age at vaginal opening in the F3
generation compared to vehicle control. Both DES (0.05 μg/kg/day) and
BPA (50 μg/kg/day) significantly delayed the age at first estrus in the
F3 generation compared to vehicle control. BPA exposure reduced
gestational index in the F1 and F2 generations compared to control.
Further, BPA exposure (0.5 μg/kg/day) compromised the fertility index in
the F3 generation compared to control. Finally, in utero BPA exposure
reduced the ability of female mice to maintain pregnancies as they aged.
Collectively, these data suggest that BPA exposure affects reproductive
function in female mice and that some effects may be transgenerational
in nature.

New potential cause for Alzheimer's: Arginine deprivation: Medical Express

A new Duke University study in mice suggests that in Alzheimer's disease, certain
that normally protect the brain begin to abnormally consume an
important nutrient: arginine. Blocking this process with a
small-molecule drug prevented the characteristic brain plaques and
memory loss in a mouse model of the disease.



Arginine deprivation and immune suppression in a mouse model of
Alzheimer's disease," Matthew J. Kan, Jennifer E. Lee, Joan G. Wilson,
Angela L. Everhart, Candice M. Brown, Andrew N. Hoofnagle, Marilyn
Jansen, Michael P. Vitek, Michael D. Gunn, Carol A. Colton. Journal of
Neuroscience, April 15, 2015. DOI: 10.1523/JNEUROSCI.4668-14.2015

PLOS ONE: EBNA2 Binds to Genomic Intervals Associated with Multiple Sclerosis and Overlaps with Vitamin D Receptor Occupancy

Epstein-Barr virus (EBV) is a non-heritable factor that associates with
multiple sclerosis (MS). However its causal relationship with the
disease is still unclear. The virus establishes a complex co-existence
with the host that includes regulatory influences on gene expression.
Hence, if EBV contributes to the pathogenesis of MS it may do so by
interacting with disease predisposing genes. To verify this hypothesis
we evaluated EBV nuclear antigen 2 (EBNA2, a protein that recent works
by our and other groups have implicated in disease development) binding
inside MS associated genomic intervals. We found that EBNA2 binding
occurs within MS susceptibility sites more than expected by chance
(factor of observed vs expected overlap [O/E] = 5.392-fold, p
< 2.0e-05). This remains significant after controlling for multiple
genomic confounders. We then asked whether this observation is
significant per se or should also be viewed in the context of other
disease relevant gene-environment interactions, such as those
attributable to vitamin D. We therefore verified the overlap between
EBNA2 genomic occupancy and vitamin D receptor (VDR) binding sites.
EBNA2 shows a striking overlap with VDR binding sites (O/E = 96.16-fold,
p < 2.0e-05), even after controlling for the chromatin accessibility
state of shared regions (p <0.001). Furthermore, MS susceptibility
regions are preferentially targeted by both EBNA2 and VDR than by EBNA2
alone (enrichment difference = 1.722-fold, p = 0.0267). Taken together,
these findings demonstrate that EBV participates in the gene-environment
interactions that predispose to MS.

Blood–brain barrier dysfunction developed during normal aging is associated with inflammation and loss of tight junctions but not with leukocyte recruitment

Background

Functional loss of blood–brain barrier (BBB) is suggested to be pivotal to pathogenesis
and pathology of vascular-based neurodegenerative disorders such as Alzheimer’s disease.
We recently reported in wild-type mice maintained on standard diets, progressive deterioration
of capillary function with aging concomitant with heightened neuroinflammation. However,
the mice used in this study were relatively young (12 months of age) and potential
mechanisms for loss of capillary integrity were not investigated per se. The current study therefore extended the previous finding to investigate the effect
of aging on BBB integrity in aged mice at 24 months and its potential underlying molecular
mechanisms.

Results

Immunomicroscopy analyses confirmed significantly increased capillary permeability
with heightened neuroinflammation in naturally aged 24-month old mice compared to
young control at 3 months of age. Aged mice showed significant attenuation in the
expression of BBB tight junction proteins, occludin-1 and to lesser extent ZO-1 compared
to young mice. In addition, TNF-α in cerebral endothelial cells of aged mice was significantly
elevated compared to controls and this was associated with heightened peripheral inflammation.
The expression of ICAM-1 and VCAM-1 remained unelevated, and no sign of leukocyte
recruitment was observed in aged mice.

Conclusion

The BBB breakdown that occurs during ordinary aging is associated with inflammation
and disruption of tight junction complex assembly but not through leukocyte trafficking.

Translational Psychiatry - LPA signaling initiates schizophrenia-like brain and behavioral changes in a mouse model of prenatal brain hemorrhage

Genetic, environmental and neurodevelopmental factors are thought to
underlie the onset of neuropsychiatric disorders such as schizophrenia.
How these risk factors collectively contribute to pathology is unclear.
Here, we present a mouse model of prenatal intracerebral hemorrhage—an
identified risk factor for schizophrenia—using a serum-exposure
paradigm. This model exhibits behavioral, neurochemical and
schizophrenia-related gene expression alterations in adult females.
Behavioral alterations in amphetamine-induced locomotion, prepulse
inhibition, thigmotaxis and social interaction—in addition to increases
in tyrosine hydroxylase-positive dopaminergic cells in the substantia
nigra and ventral tegmental area and decreases in parvalbumin-positive
cells in the prefrontal cortex—were induced upon prenatal serum
exposure. Lysophosphatidic acid (LPA), a lipid component of serum, was
identified as a key molecular initiator of schizophrenia-like sequelae
induced by serum. Prenatal exposure to LPA alone phenocopied many of the
schizophrenia-like alterations seen in the serum model, whereas
pretreatment with an antagonist against the LPA receptor subtype LPA1
prevented many of the behavioral and neurochemical alterations. In
addition, both prenatal serum and LPA exposure altered the expression of
many genes and pathways related to schizophrenia, including the
expression of Grin2b, Slc17a7 and Grid1. These findings demonstrate that
aberrant LPA receptor signaling associated with fetal brain hemorrhage
may contribute to the development of some neuropsychiatric disorders.

Artificial sweeteners are not the answer to childhood obesity. - PubMed - NCBI

While no single factor is responsible for the recent, dramatic increases
in overweight and obesity, a scientific consensus has emerged
suggesting that consumption of sugar-sweetened products, especially
beverages, is casually linked to increases in risk of chronic,
debilitating diseases including type 2 diabetes, cardiovascular disease,
hypertension and stroke. One approach that might be beneficial would be
to replace sugar-sweetened items with products manufactured with
artificial sweeteners that provide sweet tastes but with fewer calories.
Unfortunately, evidence now indicates that artificial sweeteners are
also associated with increased risk of the same chronic diseases linked
to sugar consumption. Several biologically plausible mechanisms may
explain these counterintuitive negative associations. For example,
artificial sweeteners can interfere with basic learning processes that
serve to anticipate the normal consequences of consuming sugars, leading
to overeating, diminished release of hormones such as GLP-1, and
impaired blood glucose regulation. In addition, artificial sweeteners
can alter gut microbiota in rodent models and humans, which can also
contribute to impaired glucose regulation. Use of artificial sweeteners
may also be particularly problematic in children since exposure to
hyper-sweetened foods and beverages at young ages may have effects on
sweet preferences that persist into adulthood. Taken as a whole, current
evidence suggests that a focus on reducing sweetener intake, whether
the sweeteners are caloric or non-caloric, remains a better strategy for
combating overweight and obesity than use of artificial sweeteners.

Mount Sinai scientists establish link between ALS and the body's response to viral infection | EurekAlert! Science News

A key protein previously implicated in Lou Gehrig's disease and other
neurological diseases plays an important role in the response to viral
infection, according to a study led by scientists from the Icahn School
of Medicine at Mount Sinai published today in Nature Immunology.


Neurological diseases have long been associated with inflammation,
part of the body's response to injury or infection that occurs when
immune cells home in to attack invaders like bacteria and viruses, and
to drive healing, but the link between them has not been understood.
This new study result suggests that genetic changes take away the
ability of a protein called senataxin to moderate the inflammatory
response to certain viral infections, possibly leading to persistent
inflammation that could aggravate disease progression.
Using cutting-edge genomic tools, the scientists found that
senataxin is deployed to quench the body's natural antiviral response at
a specific point; without such control, prolonged exposure to the
antiviral response can lead to inflammation. People with
senataxin-related forms of ALS and ataxia have a defective SETX gene
that leads to a dysfunctional form of the protein.

Arsenic metabolism linked to diabetes incidence

Chin-Chi Kuo, M.D., M.P.H., from the Johns Hopkins Bloomberg
School of Public Health in Baltimore, and colleagues examined the
prospective association between low-moderate arsenic exposure and
arsenic metabolism with diabetes incidence. The investigators recruited
1,694 diabetes-free participants aged 45 to 75 years in 1989 to 1991 and
followed them through 1998 to 1999. The proportions of urine inorganic arsenic
(iAs), monomethylarsonate (MMA), and dimethylarsinate (DMA) over their
sum (expressed as iAs percent, MMA percent, and DMA percent) were used
as arsenic metabolism biomarkers.

Obese-type Gut Microbiota Induce Neurobehavioral Changes in the Absence of Obesity - Biological Psychiatry

Background

The prevalence of mental illness, particularly depression and dementia, is increased by obesity.
Here, we test the hypothesis that obesity-associated changes in gut microbiota are intrinsically able to impair neurocognitive behavior in mice.

Methods

Conventionally housed, nonobese, adult male C57BL/6 mice maintained on a normal chow diet were
subjected to a microbiome depletion/transplantation paradigm using microbiota isolated from donors on either a high-fat diet (HFD) or control diet. Following re-colonization, mice were subjected to
comprehensive behavioral and biochemical analyses.

Results

The mice given HFD microbiota had significant and selective disruptions in
exploratory, cognitive, and stereotypical behavior compared with mice
with control diet microbiota in the absence of significant differences
in body weight. Sequencing-based phylogenetic analysis confirmed the
presence of distinct core microbiota between groups, with alterations in
α- and β-diversity, modulation in taxonomic distribution, and
statistically significant alterations to metabolically active taxa. HFD
microbiota also disrupted markers of intestinal barrier function,
increased circulating endotoxin, and increased lymphocyte expression of
ionized calcium-binding adapter molecule 1, toll-like receptor 2, and
toll-like receptor 4. Finally, evaluation of brain homogenates revealed
that HFD-shaped microbiota increased neuroinflammation and disrupted
cerebrovascular homeostasis.

Conclusions

Collectively, these data reinforce the link between gut dysbiosis and neurologic dysfunction and suggest that dietary and/or pharmacologic manipulation of gut microbiota could attenuate the neurologic complications of obesity.