Hippocampal expression of murine IL-4 results in exacerbation of amyloid deposition.

Pro-inflammatory stimuli, including cytokines like Interleukin-1beta, Interleukin-6 and Interferon-gamma, in the brain have been proposed to exacerbate existing Alzheimer's disease (AD) neuropathology by increasing amyloidogenic processing of APP and promoting further Abeta accumulation in AD. On the other hand, anti-inflammatory cytokines have been suggested to be neuroprotective by reducing neuroinflammation and clearing Abeta. To test this hypothesis, we used adeno-associated virus serotype 1 (AAV2/1) to express an anti-inflammatory cytokine, murine Interleukin-4 (mIL-4), in the hippocampus of APP transgenic TgCRND8 mice with pre-existing plaques.

RESULTS:

mIL-4 expression resulted in establishment of an "M2-like" phenotype in the brain and was accompanied by exacerbated Abeta deposition in TgCRND8 mice brains. No change in holo APP or APP C terminal fragment or phosphorylated tau levels were detected in mIL-4 expressing CRND8 cohorts. Biochemical analysis shows increases in both SDS soluble and insoluble Abeta. mIL-4 treatment attenuates soluble Abeta40 uptake by microglia but does not affect aggregated Abeta42 internalization by microglia or soluble Abeta40 internalization by astrocytes.

CONCLUSIONS:

Short term focal mIL-4 expression in the hippocampus leads to exacerbation of amyloid deposition in vivo, possibly mediated by acute suppression of glial clearance mechanisms. Given that recent preclinical data from independent groups indicate engagement of the innate immune system early on during disease pathogenesis may be beneficial, our present study strongly argues for a cautious re-examination of unwarranted side-effects of anti-inflammatory therapies for neurodegenerative diseases, including AD.

Staphylococcus aureus α-toxin modulates skin host response to viral infection.

Patients with atopic dermatitis (AD) with a history of eczema herpeticum have increased staphylococcal colonization and infections. However, whether Staphylococcus aureus alters the outcome of skin viral infection has not been determined.OBJECTIVE:We investigated whether S aureus toxins modulated host response to herpes simplex virus (HSV) 1 and vaccinia virus (VV) infections in normal human keratinocytes (NHKs) and in murine infection models.METHODS:NHKs were treated with S aureus toxins before incubation of viruses. BALB/c mice were inoculated with S aureus 2 days before VV scarification. Viral loads of HSV-1 and VV were evaluated by using real-time PCR, a viral plaque-forming assay, and immunofluorescence staining. Small interfering RNA duplexes were used to knockdown the gene expression of the cellular receptor of α-toxin, a disintegrin and metalloprotease 10 (ADAM10). ADAM10 protein and α-toxin heptamers were detected by using Western blot assays.RESULTS:We demonstrate that sublytic staphylococcal α-toxin increases viral loads of HSV-1 and VV in NHKs. Furthermore, we demonstrate in vivo that the VV load is significantly greater (P < .05) in murine skin inoculated with an α-toxin-producing S aureus strain compared with murine skin inoculated with the isogenic α-toxin-deleted strain. The viral enhancing effect of α-toxin is mediated by ADAM10 and is associated with its pore-forming property. Moreover, we demonstrate that α-toxin promotes viral entry in NHKs.CONCLUSION:
The current study introduces the novel concept that staphylococcal α-toxin promotes viral skin infection and provides a mechanism by which S aureus infection might predispose the host toward disseminated viral infections.
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Maternal immune activation causes age- and region-specific changes in brain cytokines in offspring throughout development.

Maternal infection is a risk factor for autism spectrum disorder (ASD) and schizophrenia (SZ). Indeed, modeling this risk factor in mice through maternal immune activation (MIA) causes ASD- and SZ-like neuropathologies and behaviors in the offspring. Although MIA upregulates pro-inflammatory cytokines in the fetal brain, whether MIA leads to long-lasting changes in brain cytokines during postnatal development remains unknown. Here, we tested this possibility by measuring protein levels of 23 cytokines in the blood and three brain regions from offspring of poly(I:C)- and saline-injected mice at five postnatal ages using multiplex arrays. Most cytokines examined are present in sera and brains throughout development. MIA induces changes in the levels of many cytokines in the brains and sera of offspring in a region- and age-specific manner. These MIA-induced changes follow a few, unexpected and distinct patterns. In frontal and cingulate cortices, several, mostly pro-inflammatory, cytokines are elevated at birth, followed by decreases during periods of synaptogenesis and plasticity, and increases again in the adult. Cytokines are also altered in postnatal hippocampus, but in a pattern distinct from the other regions. The MIA-induced changes in brain cytokines do not correlate with changes in serum cytokines from the same animals. Finally, these MIA-induced cytokine changes are not accompanied by breaches in the blood-brain barrier, immune cell infiltration or increases in microglial density. Together, these data indicate that MIA leads to long-lasting, region-specific changes in brain cytokines in offspring-similar to those reported for ASD and SZ-that may alter CNS development and behavior.

MicrobeWorld - Cancer drug shocks HIV out of hiding

Awakening the virus from its hiding place may allow its attack and elimination ...........

Maternal immune activation alters behavior in adult offspring, with subtle changes in the cortical transcriptome and epigenome.

Maternal immune activation during prenatal development, including treatment with the viral RNA mimic, polyriboinosinic-polyribocytidilic acid (poly IC), serves as a widely used animal model to induce behavioral deficits reminiscent of schizophrenia and related disease. Here, we report that massive cytokine activation after a single dose of poly IC in the prenatal period is associated with lasting working memory deficits in adult offspring. To explore whether dysregulated gene expression in cerebral cortex, contributes to cognitive dysfunction, we profiled the cortical transcriptome, and in addition, mapped the genome-wide distribution of trimethylated histone H3-lysine 4 (H3K4me3), an epigenetic mark sharply regulated at the 5' end of transcriptional units. However, deep sequencing-based H3K4me3 mapping and mRNA profiling by microarray did not reveal significant alterations in mature cerebral cortex after poly IC exposure at embryonic days E17.5 or E12.5. At a small set of genes (including suppressor of cytokine signaling Socs3), H3K4me3 was sensitive to activation of cytokine signaling in primary cultures from fetal forebrain but adult cortex of saline- and poly IC-exposed mice did not show significant differences. A limited set of transcription start sites (TSS), including Disrupted-in-Schizophrenia 1 (Disc1), a schizophrenia risk gene often implicated in gene-environment interaction models, showed altered H3K4me3 after prenatal poly IC but none of these differences survived after correcting for multiple comparisons. We conclude that prenatal poly IC is associated with cognitive deficits later in life, but without robust alterations in epigenetic regulation of gene expression in the cerebral cortex.

Alzheimer's BACE Inhibitor E2609 Receives Positive Phase I Clinical Results

Eisai in Europe today releases the first clinical data for E2609, a BACE (beta-site amyloid precursor protein-cleaving enzyme) inhibitor, presented during oral sessions at the Alzheimer's Association International Conference (AAIC) 2012 in Vancouver, Canada. This novel compound was discovered through a collaborative partnership between the company's European Knowledge Centre in Hatfield, UK and laboratories in Japan, and is being developed as a treatment for Alzheimer's disease.
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Discovery of new white blood cell reveals target for better vaccine design

Researchers in Newcastle and Singapore have identified a new type of white blood cell which activates a killing immune response to an external source -- providing a new potential target for vaccines for conditions such as cancer or Hepatitis B.
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Fluoxetine (a.k.a. Prozac) is effective as an anti-viral, study suggests

Human enteroviruses are members of a genus containing more than 100 distinct RNA viruses responsible for various life threatening infections, such as poliomyelitis and encephalitis. While immunization has all but eliminated the poliovirus, the archetype for the genus, no antiviral drugs currently exist for the treatment of enterovirus infections, which are often severe and potentially fatal. In view of its favorable pharmacokinetics and safety profile of fluoxetine -- which is in a class of compounds typically used in the treatment of depression, anxiety disorders and some personality disorders -- the research team found that it warrants additional study as a potential antiviral agent for enterovirus infections.
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In-utero exposure to magnetic fields associated with increased risk of obesity in childhood

In-utero exposure to relatively high magnetic field levels was associated with a 69 percent increased risk of being obese or overweight during childhood compared to lower in-utero magnetic field levels, according to a Kaiser Permanente study that appears in the current online version of Nature's Scientific Reports.


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Dissecting the mechanisms behind chronic inflammation

Upon infection or injury, immune cells are attracted to the site through the blood stream, a process known as inflammation. Although this is considered normal, prolonged activation of this process leads to the pathological state of chronic inflammation. It is becoming increasingly evident that chronic inflammation is the leading cause of many diseases including autoimmune disorders.

Acetyl-L-carnitine-mediated neuroprotection during hypoxia is attributed to ERK1/2-Nrf2-regulated mitochondrial biosynthesis.

Neuronal damage in hypoxia and several neurodegenerative disorders is invariably associated with oxidative damage and mitochondrial dysfunction. Administration of acetyl-L-carnitine (ALCAR) on the other hand attenuates neuronal damage, prevents apoptosis, and improves energy status in hypoxic stress through less understood mechanisms. Becasue mitochondrial biogenesis could be a possible mechanism for ALCAR-induced improvement in bioenergetics in neurons, the present study aimed at exploring signaling pathways of ALCAR-induced neuroprotection in hypoxia and possible occurrence of mitochondrial biogenesis. To create global hypoxia, adult Sprague-Dawley rats were exposed to a simulated altitude of 7,620 m at standard temperature and humidity conditions. We here demonstrate that administration of ALCAR to hypoxic rats for a period of 2 weeks effectively protected hippocampal neurons from mitochondrial dysfunction, excitotoxicity, and neurodegeneration. ALCAR administration resulted in peroxisome proliferator-activated receptor γ coactivator-1α and nuclear respiratory factor-1-induced mitochondrial biogenesis, the expression of which was regulated by an extracellular-related kinase-nuclear factor erythroid 2-related factor 2 (ERK-Nrf2)-mediated mechanism. Most notably, calcium buffering into nonfunctional mitochondria ameliorated excitotoxicity and improved bioenergetic status of the hippocampal neurons. Together, the data reveal the immense therapeutic potential of ALCAR for the treatment of ischemia, stroke, and other neurodegenerative disorders associated with hypoxic stress and excitotoxicity.
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Genome-wide genetic variations are highly correlated with proximal DNA methylation patterns.

5-methyl-cytosines at CpG sites frequently mutate into thymines, accounting for a large proportion of spontaneous point mutations. The repair system would leave substantial numbers of errors in neighboring regions if the synthesis of erased gaps around deaminated 5-methyl-cytosines is error-prone. Indeed, we identified an unexpected genome-wide role of the CpG methylation state as a major determinant of proximal natural genetic variation. Specifically, 507 Mbp (∼18%)of the human genome was within 10 bp of a CpG site; in these regions, the single nucleotide polymorphism (SNP) rate significantly increased by ∼50% (P < 10(-566) by a two-proportion z-test) if the neighboring CpG sites are methylated. To reconfirm this finding in another vertebrate, we compared six single-base resolution methylomes in two inbred medaka (Oryzias latipes) strains with sufficient genetic divergence (3.4%). We found that the SNP rate also increased by ∼50% (P < 10(-2170)), and the substitution rates in all dinucleotides increased simultaneously (P < 10(-441)) around methylated CpG sites. In the hypomethylated regions, the "CGCG" motif was significantly enriched (P < 10(-680)) and evolutionarily conserved (P = ∼ 0.203%), and slow CpG deamination rather than fast CpG gain was seen, indicating a possible role of CGCG as a candidate cis-element for the hypomethylation state. In regions that were hypermethylated in germline-like tissues but were hypomethylated in somatic liver cells, the SNP rate was significantly smaller than that in hypomethylated regions in both tissues, suggesting a positive selective pressure during DNA methylationreprogramming. This is the first report of findings showing that the CpGmethylation state is significantly correlated with the characteristics of evolutionary change in neighboring DNA.
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Effects of maternal immune activation on gene expression patterns in the fetal brain.

We are exploring the mechanisms underlying how maternal infection increases the risk for schizophrenia and autism in the offspring. Several mouse models of maternal immune activation (MIA) were used to examine the immediate effects of MIA induced by influenza virus, poly(I:C) and interleukin IL-6 on the fetal brain transcriptome. Our results indicate that all three MIA treatments lead to strong and common gene expression changes in the embryonic brain. Most notably, there is an acute and transient upregulation of the α, β and γ crystallin gene family. Furthermore, levels of crystallin gene expression are correlated with the severity of MIA as assessed by placental weight. The overall gene expression changes suggest that the response to MIA is a neuroprotective attempt by the developing brain to counteract environmental stress, but at a cost of disrupting typical neuronal differentiation and axonal growth. We propose that this cascade of events might parallel the mechanisms by which environmental insults contribute to the risk of neurodevelopmental disorders such as schizophrenia and autism.

NIH team describes protective role of skin microbiota

Although immune cells in the skin protect against harmful organisms, until now, it has not been known if the millions of naturally occurring commensal bacteria in the skin—collectively known as the skin microbiota—also have a beneficial role. Using mouse models, the NIH team observed that commensals contribute to protective immunity by interacting with the immune cells in the skin. Their findings appear online on July 26th in Science.

Bone marrow transplant eliminates signs of HIV infection

Two men with longstanding HIV infections no longer have detectable HIV in their blood cells following bone marrow transplants. The virus was easily detected in blood lymphocytes of both men prior to their transplants but became undetectable by eight months post-transplant. The men, who were treated at Brigham and Women's Hospital (BWH), have remained on anti-retroviral therapy. Their cases will be presented on July 26, 2012 at the International AIDS Conference by Timothy Henrich, MD and Daniel Kuritzkes, MD, physician-researchers in the Division of Infectious Diseases at BWH.

PLoS Pathogens: Toll-Like Receptors Promote Mutually Beneficial Commensal-Host Interactions

Toll-like receptors (TLRs) are evolutionarily conserved trans-membrane receptors that detect micro-organisms through the recognition of conserved molecular motifs. With each TLR able to recognize a discrete set of microbial ligands, TLRs represent an important mechanism by which the host detects a variety of microorganisms. Triggering of TLRs by pathogens is classically understood to result in an inflammatory immune response that supports the subsequent clearance of the offending microbe. However, animals are stably colonized by a consortium of symbiotic microbes (the microbiota) that possess many of the same structural motifs as pathogens, which raises the question of how the host is able to peacefully coexist with this community of organisms without suffering from chronic inflammatory disease. Paradoxical to its pro-inflammatory role during infection, recent studies have suggested that commensal bacterial recognition by TLRs is important for limiting inflammation within the intestine. While TLR expression on cells of the innate immune system (macrophages and dendritic cells) is largely thought to account for TLR function, cells of the adaptive immune system (T and B cells) and non-hematopoietic (epithelial) cells also express TLRs. Recent evidence has uncovered that the functional consequence of TLR engagement depends largely on the responding cell type and does not always result in inflammation. Here we will highlight how TLR engagement on epithelia, B and T cells promotes mutually beneficial interactions between hosts and their resident microbes.
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Adenylate Cyclases of Trypanosoma brucei Inhibit the Innate Immune Response of the Host

The parasite Trypanosoma brucei possesses a large family of transmembrane receptor–like adenylate cyclases. Activation of these enzymes requires the dimerization of the catalytic domain and typically occurs under stress. Using a dominant-negative strategy, we found that reducing adenylate cyclase activity by about 50% allowed trypanosome growth but reduced the parasite’s ability to control the early innate immune defense of the host. Specifically, activation of trypanosome adenylate cyclase resulting from parasite phagocytosis by liver myeloid cells inhibited the synthesis of the trypanosome-controlling cytokine tumor necrosis factor–α through activation of protein kinase A in these cells. Thus, adenylate cyclase activity of lyzed trypanosomes favors early host colonization by live parasites. The role of adenylate cyclases at the host-parasite interface could explain the expansion and polymorphism of this gene family.
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Alternative Medicines |ProbioticsThe Scientist

It’s a very exciting time to be a microbiologist,” says Maria Marco of the University of California, Davis, who studies how lactic acid bacteria, which include strains used in milk fermentation, interact with our intestines to improve health. She points to a confluence of genetic data from the Human Microbiome Project and experimental data, which together are beginning to illuminate the role of microbes in health.

Chronic vascular risk factors (cholesterol, homocysteine, ethanol) impair spatial memory, decline cholinergic neurons and induce blood-brain barrier leakage in rats in vivo.

Epidemiological studies show that vascular risk factors (e.g. atherosclerosis, diabetes, homocysteine, hypertension or cholesterol) may play a role in the development of Alzheimer's disease. Animal models may help to discover the role of vascular risk factors on cognition. In the present project we treated male Sprague Dawley rats with a diet containing homocysteine (hyperhomocysteinemia) or cholesterol (hypercholesterolemia) for 5months or exposed the rats to ethanol (20% in drinking water) or a combination of cholesterol+ethanol (mix) for 12months. Our experiments show that all 3 treatments (homocysteine, cholesterol, ethanol) declined spatial memory in the 8-arm radial maze, reduced the number of cholinergic neurons and induced blood-brain barrier leakage in the cortex. Rats treated with cholesterol also displayed markedly enhanced inflammation in the cortex. Levels of amyloid precursor protein, beta-amyloid((1-42)), as well as tau and phospho-tau 181 were significantly enhanced in the cortex of cholesterol-fed rats. A combination of ethanol and cholesterol did not further potentiate the effects on spatial memory, cholinergic neurons and blood-brain barrier leakage.The data suggest that chronic mild vascular risk factors over months induce small
lesions of the brain capillaries in the cortex, which may contribute to the development of vascular dementia or also Alzheimer's disease.
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Antidepressant ZOLOFT packs potential to fight fungal meningitis

The findings are the result of a two-year investigation by Xiaorong Lin, assistant professor of biology, and Matthew S. Sachs, professor of biology, involving sertraline hydrocholoride (ZOLOFT) and its effects on Cryptococcus neoformans, the major causative agent of fungal meningitis -- specifically, cryptococcal meningitis, which claims more than half a million lives worldwide each year, according to a 2009 Center for Disease Control (CDC) report.

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Ecstasy harms memory with one year of recreational use

New research published online July 25 by the scientific journal Addiction, gives some of the first information available on the actual risk of using ecstasy. It shows that even in recreational amounts over a relatively short time period, ecstasy users risk specific memory impairments. Further, as the nature of the impairments may not be immediately obvious to the user, it is possible people wouldn't get the signs that they are being damaged by drug use until it is too late.
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Mediterranean diet improves health

Podcast from LaTrobe University

Shortened telomere length tied to dementia, mortality risk

Shortened telomere length (TL) is associated with risks for dementia and mortality in a population of older adults, according to a study published online July 23 in the Archives of Neurology.

Starr collaboration illuminates mysterious pathway to immortality in cancer cells

(Medical Xpress) -- Cancer cells are immortal because they circumvent failsafe mechanisms that stop out-of-control cell proliferation. One of these mechanisms – the progressive shortening of chromosomes – is prevented by replenishment of telomeres, the protective elements at the ends of chromosomes. Most cancer cells do this with an enzyme called telomerase, but approximately 10 to 15 percent of human cancers use a different pathway called ALT (alternative lengthening of telomeres). Whether or not a tumor has ALT makes a difference. For example, people with glioblastoma live twice as long if the tumor uses ALT.

Read more at: http://medicalxpress.com/news/2012-07-starr-collaboration-illuminates-mysterious-pathway.html#jCp

Using Summary Data from the Danish National Registers to Estimate Heritabilities for Schizophrenia, Bipolar Disorder, and Major Depressive Disorder.

Estimates of heritability of psychiatric disorders quantify the genetic contribution to their etiology. Estimation of these parameters requires affected status on probands and their family members. Traditionally, heritabilities have been estimated from families ascertained from specific hospital registers, but accumulating sufficient numbers of families can be difficult. Larger sample sizes are achievable from national registries, but calculation of heritability from individual level data from these data sets is accompanied by other problems. Here, we use published summary data from a national population-based cohort of >2.6 million persons in Denmark to estimate heritabilities of schizophrenia, bipolar disorder, and major depressive disorder (MDD). The summary data comprised cumulative incidences up to 52 years of age for schizophrenia and bipolar disorder and up to 51 years for MDD in offspring where either one or both parents were diagnosed with one of these disorders. Estimates of the heritabilities of the liability to developing schizophrenia, bipolar disorder, and MDD are 0.67 (95% confidence interval (CI) 0.64-0.71), 0.62 (95% CI 0.58-0.65), and 0.32 (95% CI 0.30-0.34) respectively. The estimates may be inflated by common environmental effects, but despite this, they are somewhat lower for schizophrenia and bipolar disorder than those estimated from contemporary twin samples. The lower estimates may reflect the diverse environments (including diagnostic interpretation) that contribute to national data, compared to twin/family studies. Our estimates are similar to those estimated previously from national data of Sweden, and they may be more representative of the international samples brought together for large-scale genome-wide association studies. We investigated the estimation of genetic correlations from these data. We used simulation to conclude that estimates may not be interpretable and so report them only in the Section "Appendix."

RSNA press release: Sodium Buildup in Brain Linked to Disability in Multiple Sclerosis

A buildup of sodium in the brain detected by magnetic resonance imaging (MRI) may be a biomarker for the degeneration of nerve cells that occurs in patients with multiple sclerosis (MS), according to a new study published online in the journal Radiology. The study found that patients with early-stage MS showed sodium accumulation in specific brain regions, while patients with more advanced disease showed sodium accumulation throughout the whole brain. Sodium buildup in motor areas of the brain correlated directly to the degree of disability seen in the advanced-stage patients.
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Liver Cancer Could Be Due To Absence Of microrna MIR122

In this study,mice lacking the miR-122 gene developed fatty deposits in their livers, got hepatitis, and grew tumors that resembled hepatocellular carcinoma. These disease signs were accompanied by over-active cancer signalling pathways, and that the livers were full of inflammatory cells that produce tumor-generating molecules called cytokines, including two well-known to cancer researchers, IL-6 and TNF. MIR122 also regulates replication of the hepatitis C virus.

Rodents seem depressed from dim light at night, but it can be reversed

Chronic exposure to dim light at night can lead to depressive symptoms in rodents -- but these negative effects can be reversed simply by returning to a standard light-dark cycle, a new study suggests.

Pesticide exposure and child neurodevelopment: summary and implications.PubMed - NCBI

Widely used around the world, pesticides play an important role in protecting health, crops, and property. However, pesticides may also have detrimental effects on human health, with young children among the particularly vulnerable. Recent research suggests that even low levels of pesticide exposure can affect young children's neurological and behavioral development. Evidence shows a link between pesticides and neonatal reflexes, psychomotor and mental development, and attention-deficit hyperactivity disorder. Implications include a need for improved risk assessment and health histories by clinicians, greater education at all levels, more common use of integrated pest management, and continued policy and regulatory strategies to mitigate the effects of and the need for pesticides.
Related articles

New drug could treat Alzheimer's, multiple sclerosis and brain injury

A new class of drug developed at Northwestern University Feinberg School of Medicine shows early promise of being a one-size-fits-all therapy for Alzheimer's disease, Parkinson's disease, multiple sclerosis and traumatic brain injury by reducing inflammation in the brain.

MW151 and MW189 work by preventing the damaging overproduction of proinflammatory cytokines.

Read more at: http://medicalxpress.com/news/2012-07-drug-alzheimer-multiple-sclerosis-brain.html#jCp

Evidence of parallels between mercury intoxication and the brain pathology in autism.

The purpose of this review is to examine the parallels between the effects mercury intoxication on the brain and the brain pathology found in autism spectrum disorder (ASD). This review finds evidence of many parallels between the two, including: (1) microtubule degeneration, specifically large, long-range axon degeneration with subsequent abortive axonal sprouting (short, thin axons); (2) dentritic overgrowth; (3) neuroinflammation; (4) microglial/astrocytic activation; (5) brain immune response activation; (6) elevated glial fibrillary acidic protein; (7) oxidative stress and lipid peroxidation; (8) decreased reduced glutathione levels and elevated oxidized glutathione; (9) mitochondrial dysfunction; (10) disruption in calcium homeostasis and signaling; (11) inhibition of glutamic acid decarboxylase (GAD) activity; (12) disruption of GABAergic and glutamatergic homeostasis; (13) inhibition of IGF-1 and methionine synthase activity; (14) impairment in methylation; (15) vascular endothelial cell dysfunction and pathological changes of the blood vessels; (16) decreased cerebral/cerebellar blood flow; (17) increased amyloid precursor protein; (18) loss of granule and Purkinje neurons in the cerebellum; (19) increased pro-inflammatory cytokine levels in the brain (TNF-alppha, IFN-gamma, IL-1beta, IL-8); and (20) aberrant nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB). This review also discusses the ability of mercury to potentiate and work synergistically with other toxins and pathogens in a way that may contribute to the brain pathology in ASD. The evidence suggests that mercury may be either causal or contributory in the brain pathology in ASD, possibly working synergistically with other toxic compounds or pathogens to produce the brain pathology observed in those diagnosed with an ASD.

Futurity.org – Serious mental illness drives up cancer risk

People with serious mental illness such as schizophrenia and bipolar disorder are more than twice as likely to develop cancer than the general population -

Disease, lifestyle or drug treatment related ???

Neuregulin 1-ErbB4-PI3K signaling in schizophrenia and phosphoinositide 3-kinase-p110δ inhibition as a potential therapeutic strategy

Neuregulin 1 (NRG1) and ErbB4, critical neurodevelopmental genes, are implicated in schizophrenia, but the mediating mechanisms are unknown. Here we identify a genetically regulated, pharmacologically targetable, risk pathway associated with schizophrenia and with ErbB4 genetic variation involving increased expression of a PI3K-linked ErbB4 receptor (CYT-1) and the phosphoinositide 3-kinase subunit, p110δ (PIK3CD). In human lymphoblasts, NRG1-mediated phosphatidyl-inositol,3,4,5 triphosphate [PI(3,4,5)P3] signaling is predicted by schizophrenia-associated ErbB4 genotype and PIK3CD levels and is impaired in patients with schizophrenia. In human brain, the same ErbB4 genotype again predicts increased PIK3CD expression. Pharmacological inhibition of p110δ using the small molecule inhibitor, IC87114, blocks the effects of amphetamine in a mouse pharmacological model of psychosis and reverses schizophrenia-related phenotypes in a rat neonatal ventral hippocampal lesion model. Consistent with these antipsychotic-like properties, IC87114 increases AKT phosphorylation in brains of treated mice, implicating a mechanism of action. Finally, in two family-based genetic studies, PIK3CD shows evidence of association with schizophrenia. Our data provide insight into a mechanism of ErbB4 association with schizophrenia; reveal a previously unidentified biological and disease link between NRG1-ErbB4, p110δ, and AKT; and suggest that p110δ is a previously undescribed therapeutic target for the treatment of psychiatric disorders.

Maternal antibodies to infectious agents and risk for non-affective psychoses in the offspring-a matched case-control study.

An increasing number of studies suggest that certain maternal infections are associated with non-affective psychoses in the offspring. Here we investigated if maternal exposure to Toxoplasma gondii, cytomegalovirus (CMV), herpes simplex virus type 1 (HSV-1) or type 2 (HSV-2) prior to delivery was associated with future diagnosis of schizophrenia or other non-affective psychoses in the offspring.METHODS:This case-control study included 198 individuals born in Sweden 1975-85, diagnosed with schizophrenia (ICD-10, F20) and other non-affective psychoses (ICD-10, F21-29) as in- or outpatients, and 524 matched controls. Specific immunoglobulin G (IgG) levels in archived neonatal dried blood samples from these individuals were determined by immunoassays. Reference levels were determined by prevalences among pregnant women in Sweden 1975-85. Odds ratios (OR) for schizophrenia and other non-affective psychoses were calculated, considering maternal and gestational factors as covariates.RESULTS:Levels of IgG directed at T. gondii corresponding to maternal exposure was associated with subsequent schizophrenia (OR=2.1, 95% CI 1.0-4.5) as were levels of IgG directed at CMV (OR=2.2, 95% CI 1.0-5.1) but not at HSV-1 or -2. There were even stronger associations with higher levels of T. gondii or CMV antibodies. There were no associations between any of the infectious agents and other non-affective psychoses.CONCLUSIONS:This study supports findings of maternal exposure to T. gondii and schizophrenia risk in offspring, and extends the risk to also include maternal exposure to CMV. Future studies should confirm the association with CMV exposure and identify mechanisms underlying these associations.

CMV infection attenuates the disease course in a murine model of multiple sclerosis.

Recent evidence in multiple sclerosis (MS) suggests that active cytomegalovirus  infection may result in more benign clinical disease. The goal of this pilot study was to determine whether underlying murine CMV (MCMV) infection affects the course of the Theiler's murine encephalitis virus (TMEV) induced murine model of MS. A group of eight TMEV-infected mice were co-infected with MCMV at 2 weeks prior to TMEV infection while a second group of TMEV-infected mice received MCMV two weeks post TMEV. We also used 2 control groups, where at the above time points MCMV was replaced with PBS. Outcome measures included (1) monthly monitoring of disability via rotarod for 8 months; (2) in vivo MRI for brain atrophy studies and (3) FACS analysis of brain infiltrating lymphocytes at 8 months post TMEV infection. Co-infection with MCMV influenced the disease course in mice infected prior to TMEV infection. In this group, rotarod detectable motor performance was significantly improved starting 3 months post-infection and beyond (p≤0.024). In addition, their brain atrophy was close to 30% reduced at 8 months, but this was only present as a trend due to low power (p = 0.19). A significant reduction in the proportion of brain infiltrating CD3+ cells was detected in this group (p = 0.026), while the proportion of CD45+ Mac1+ cells significantly increased (p = 0.003). There was also a strong trend for a reduced proportion of CD4+ cells (p = 0.17) while CD8 and B220+ cell proportion did not change. These findings support an immunomodulatory effect of MCMV infection in this MS model. Future studies in this co-infection model will provide insight into mechanisms which modulate the development of demyelination and may be utilized for the development of novel therapeutic strategies.

Dynamic oscillation of translation and stress granule formation mark the cellular response to virus infection.

Virus infection-induced global protein synthesis suppression is linked to assembly of stress granules (SGs), cytosolic aggregates of stalled translation preinitiation complexes. To study long-term stress responses, we developed an imaging approach for extended observation and analysis of SG dynamics during persistent hepatitis C virus (HCV) infection. In combination with type 1 interferon, HCV infection induces highly dynamic assembly/disassembly of cytoplasmic SGs, concomitant with phases of active and stalled translation, delayed cell division, and prolonged cell survival. Double-stranded RNA (dsRNA), independent of viral replication, is sufficient to trigger these oscillations. Translation initiation factor eIF2α phosphorylation by protein kinase R mediates SG formation and translation arrest. This is antagonized by the upregulation of GADD34, the regulatory subunit of protein phosphatase 1 dephosphorylating eIF2α. Stress response oscillation is a general mechanism to prevent long-lasting translation repression and a conserved host cell reaction to multiple RNA viruses, which HCV may exploit to establish persistence.
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Two out of three very obese kids already have heart disease risk factors: High blood pressure, cholesterol, blood glucose evident even in under-12s

The prevalence of impaired fasting glucose in these children is worrying, considering the increasing prevalence worldwide of type 2 diabetes in children and adolescents," write the authors.
"Likewise, the high prevalence of hypertension and abnormal lipids may lead to cardiovascular disease in young adulthood," they add.
And they conclude: "Internationally accepted criteria for defining severe obesity and guidelines for early detection and treatment of severe obesity and [underlying ill health] are urgently needed."

Powerful class of antioxidants may be potent Parkinson's treatment

A class of antioxidants called synthetic triterpenoids blocked development of Parkinson's in an animal model that develops the disease in a handful of days, said Dr. Bobby Thomas, neuroscientist at the Medical College of Georgia at Georgia Health Sciences University and corresponding author of the study in the journal Antioxidants & Redox Signaling. Thomas and his colleagues were able to block the death of dopamine-producing brain cells that occurs in Parkinson's by using the drugs to bolster Nrf2, a natural antioxidant and inflammation fighter.

Read more at: http://medicalxpress.com/news/2012-07-powerful-class-antioxidants-potent-parkinson.html#jCp
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Alzheimer's drug fails in 1 study, 2nd continues

Pfizer Inc. said Monday that a closely watched experimental Alzheimer's drug failed to slow the disease in one late-stage study, but the drug maker said it will continue to study the drug's effect on a different group of patients.
Pfizer, which is testing bapineuzumab ( an antibody to beta-amyloid) with partner Johnson & Johnson, said the injected drug didn't slow mental or functional decline in patients with mild or moderate Alzheimer's disease. The study included patients who carry a gene called ApoE4, which gives people a higher risk of developing the memory-robbing disorder.


Tel Aviv University research links childhood obesity to cancer risk

Sea anemones venom key to Multiple Sclerosis treatment

(Medical Xpress) -- Sea anemones use venomous stinging tentacles to stun their prey, but one component of that venom is being used by researchers to treat the debilitating effects of Multiple Sclerosis (MS).

A new class of drug treatment is about to commence clinical trials, as the result of a decade-long investigation by Professor Ray Norton, from the Monash Institute of Pharmaceutical Sciences and his collaborators, who in the mid 1990s found a component of venom called ShK in the Caribbean sea anemone. The researchers found ShK blocks the Kv1.3 potassium channel located in white blood cells, known as T-cells, which are known to produce nerve damage in MS, one of the most common and debilitating diseases of the nervous system.

White Dental Fillings May Impair Kids' Behavior - Science News

A resin in the most commonly used white composite dental fillings may be linked to subtle neuropsychological deficits in children.Effects were seen only for fillings that used bis-GMA, a resin derived from bisphenol A

Study Shows Where Identical Twins Part Ways - Science News

Identical twins aren’t perfect carbon copies of each other even at birth.Twins emerge from the womb carrying different chemical marks on their DNA that influence the activity of individual genes, a new study shows. Known as epigenetic markers (e.g. gene methylation), these alterations don’t change the underlying genetic information. But by regulating the activity of certain genes, they can profoundly influence how the DNA blueprint is used to create and operate a living organism.
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GENEVESTIGATOR - shaping biological discovery

Genevestigator is a high performance search engine for gene expression. Our focus is on the deep integration of high quality, well annotated data with high-performance computing. This allows users to run unique types of queries across thousands of datasets simultaneously.
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Gene methylation sensitises PC12 cells to the toxic effects of Paraquat

Parkinson's disease (PD) is one of the common neurodegenerative diseases that result in the progressive damage of dopaminergic neurons. Environmental exposure, including paraquat, is considered risky for PD. Epigenetics refer to the study of heritable changes in gene expression that occur without a change in DNA sequence. Epigenetic abnormalities (e.g. DNA methylation) have also been found to be causative factors in aging disease, such as PD. How these risk factors cooperate to induce progressive neurodegeneration in PD remains largely unknown. In this study, the PC12 cells was pretreated with methyltransferase inhibitor 5'-aza-2-deoxycytidi(5'-aza-dC) for 24h, then exposed to paraquat for 12h. The biochemical mechanisms were investigated. The results showed that cell activity remarkably decreased and apoptotic cells increased after paraquat plus 5'-aza-dC treatment. Moreover, compared with paraquat treatment alone, after being exposed to paraquat plus 5'-aza-dC, the level of reactive oxygen species (ROS) increased significantly. The expression of bcl-2 decreased, expressions of bax increased, the rate of bcl-2/bax decreased, and thus expressions of cytochrome C increased. Our findings suggest that 5'-aza-dC modulating DNA methylation could sensitize paraquat toxic effects on PC12 cell by oxidative stress increment and mitochondrial deficit. Demonstration of the interaction of DNA methylation and paraquat provides additional new insights into the pathogenic mechanisms of PD.

Short-term intestinal parasite infection triggers specific cytokines that can prevent the development of type 1 diabetes

Short-term infection with intestinal worms (H. polygyrus)may provide long-term protection against type I diabetes (TID), suggests a study conducted by William Gause, PhD, and colleagues at the University of Medicine and Dentistry of New Jersey-New Jersey Medical School. The research has been published in the journal Mucosal Immunology.

Potent new compound virtually eliminates HIV in cell culture

A new study by scientists on the Florida campus of The Scripps Research Institute shows, in cell culture, a natural compound ( Cortistatin A) can virtually eliminate human immunodeficiency virus (HIV) in infected cells. The compound defines a novel class of HIV anti-viral drugs endowed with the capacity to repress viral replication in acutely and chronically infected cells.
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Entire genetic sequence of individual human sperm determined

Meiotic recombination and de novo mutation are the two main contributions toward gamete genome diversity, and many questions remain about how an individual human’s genome is edited by these two processes. Here, we describe a high-throughput method for single-cell whole-genome analysis that was used to measure the genomic diversity in one individual’s gamete genomes. A microfluidic system was used for highly parallel sample processing and to minimize nonspecific amplification. High-density genotyping results from 91 single cells were used to create a personal recombination map, which was consistent with population-wide data at low resolution but revealed significant differences from pedigree data at higher resolution. We used the data to test for meiotic drive and found evidence for gene conversion. High-throughput sequencing on 31 single cells was used to measure the frequency of large-scale genome instability, and deeper sequencing of eight single cells revealed de novo mutation rates with distinct characteristics.
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Viruses' copying mechanism demystified, opening the door to new vaccine strategies

Certain kinds of viruses such as those that cause the common cold, SARS, hepatitis, and encephalitis, copy themselves using a unique mechanism, according to a team of Penn State scientists that includes David Boehr, an assistant professor of chemistry and a co-leader of the research team. The discovery sheds light on a previously identified, but never-before-understood region of an enzyme associated with the process of replicating genetic material. The research is an important step toward the improvement of existing vaccines, as well as toward the design of vaccines against viruses that have eluded vaccination strategies in the past.

In utero exposure to diesel exhaust a possible risk factor for obesity

Pregnant mice exposed to high levels of air pollution gave birth to offspring with a significantly higher rate of obesity and insulin resistance in adulthood than those that were not exposed to air pollution. This effect seemed especially prevalent in male mice, which were heavier regardless of diet. These findings, published online in the FASEB Journal, suggests a link between diesel exhaust exposure in utero and bulging waistlines in adulthood.

High-throughput analysis of epistasis in genome-wide association studies with BiForce

Gene–gene interactions (epistasis) are thought to be important in shaping complex traits, but they have been under-explored in genome-wide association studies (GWAS) due to the computational challenge of enumerating billions of single nucleotide polymorphism (SNP) combinations. Fast screening tools are needed to make epistasis analysis routinely available in GWAS.
Results: We present BiForce to support high-throughput analysis of epistasis in GWAS for either quantitative or binary disease (case–control) traits. BiForce achieves great computational efficiency by using memory efficient data structures, Boolean bitwise operations and multithreaded parallelization. It performs a full pair-wise genome scan to detect interactions involving SNPs with or without significant marginal effects using appropriate Bonferroni-corrected significance thresholds. We show that BiForce is more powerful and significantly faster than published tools for both binary and quantitative traits in a series of performance tests on simulated and real datasets. We demonstrate BiForce in analysing eight metabolic traits in a GWAS cohort (323 697 SNPs, >4500 individuals) and two disease traits in another (>340 000 SNPs, >1750 cases and 1500 controls) on a 32-node computing cluster. BiForce completed analyses of the eight metabolic traits within 1 day, identified nine epistatic pairs of SNPs in five metabolic traits and 18 SNP pairs in two disease traits. BiForce can make the analysis of epistasis a routine exercise in GWAS and thus improve our understanding of the role of epistasis in the genetic regulation of complex traits.
Availability and implementation: The software is free and can be downloaded from http://bioinfo.utu.fi/BiForce/.

A blood-based screening tool for Alzheimer's disease that spans serum and plasma: findings from TARC and ADNI.

There is no rapid and cost effective tool that can be implemented as a front-line screening tool for Alzheimer's disease (AD) at the population level.OBJECTIVE:To generate and cross-validate a blood-based screener for AD that yields acceptable accuracy across both serum and plasma.DESIGN, SETTING, PARTICIPANTS:Analysis of serum biomarker proteins were conducted on 197 Alzheimer's disease (AD) participants and 199 control participants from the Texas Alzheimer's Research Consortium (TARC) with further analysis conducted on plasma proteins from 112 AD and 52 control participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI). The full algorithm was derived from a biomarker risk score, clinical lab (glucose, triglycerides, total cholesterol, homocysteine), and demographic (age, gender, education, APOE*E4 status) data.RESULTS:11 proteins met our criteria and were utilized for the biomarker risk score. The random forest (RF) biomarker risk score from the TARC serum samples (training set) yielded adequate accuracy in the ADNI plasma sample (training set) (AUC = 0.70, sensitivity (SN) = 0.54 and specificity (SP) = 0.78), which was below that obtained from ADNI cerebral spinal fluid (CSF) analyses (t-tau/Aβ ratio AUC = 0.92). However, the full algorithm yielded excellent accuracy (AUC = 0.88, SN = 0.75, and SP = 0.91). The likelihood ratio of having AD based on a positive test finding (LR+) = 7.03 (SE = 1.17; 95% CI = 4.49-14.47), the likelihood ratio of not having AD based on the algorithm (LR-) = 3.55 (SE = 1.15; 2.22-5.71), and the odds ratio of AD were calculated in the ADNI cohort (OR) = 28.70 (1.55; 95% CI = 11.86-69.47).

CONCLUSIONS:

It is possible to create a blood-based screening algorithm that works across both serum and plasma that provides a comparable screening accuracy to that obtained from CSF analyses.

How hosts recognize bacteria

Our innate immune system is clever. Certain structures, which are characteristic of many microorganisms are recognized via TLR which trigger the necessary inflammatory response. However, the situation can become dangerous: since this receptor system is so sensitive, the immune response to serious infections may be over-exaggerated and miss the mark. Blood poisoning and frequently septic shock is the result.

Are cardiac risk factors linked to less blood flow to the brain?

Metabolic syndrome, a term used to describe a combination of risk factors that often lead to heart disease and type 2 diabetes, seems to be linked to lower blood flow to the brain, according to research by the University of Wisconsin School of Medicine and Public Health.
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Link found between environmental toxins and stroke

(Medical Xpress) -- Individuals with elevated levels of PCBs and DDT in their blood run a greater risk of having a stroke. This is shown in a study from Uppsala University that is being published today in the scientific journal Environmental International.

Study of psychosis risk and brain to track effects of Omega-3 pills

Immune drug (B cell killer) helps patients with serious kidney disorder

Rituximab, commonly used to treat immune disorders such as lymphoma and arthritis also benefits patients with an immune disorder of the kidneys that can lead to kidney failure, according to a study appearing in an upcoming issue of new study in the Journal of the American Society of Nephrology (JASN). The findings could help people who are living with the condition, called idiopathic membranous nephropathy (IMN), avoid taking the potentially toxic medications that are currently prescribed to treat it.
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Beneficial bacteria may help ward off infection

(Medical Xpress) -- While many bacteria exist as aggressive pathogens, causing diseases ranging from tuberculosis and cholera, to plague, diphtheria and toxic shock syndrome, others play a less malevolent role and some are critical for human health.

Severe flu increases risk of Parkinson's: research

Severe influenza doubles the odds that a person will develop Parkinson's disease later in life, according to University of British Columbia researchers.

Read more at: http://medicalxpress.com/news/2012-07-severe-flu-parkinson.html#jCp

A comprehensive network and pathway analysis of candidate genes in major depressive disorder.

See also KEGG pathway analysis of major depression genes
Numerous genetic and genomic datasets related to complex diseases have been made available during the last decade. It is now a great challenge to assess such heterogeneous datasets to prioritize disease genes and perform follow up functional analysis and validation. Among complex disease studies, psychiatric disorders such as major depressive disorder (MDD) are especially in need of robust integrative analysis because these diseases are more complex than others, with weak genetic factors at various levels, including genetic markers, transcription (gene expression), epigenetics (methylation), protein, pathways and networks.

RESULTS:

In this study, we proposed a comprehensive analysis framework at the systems level and demonstrated it in MDD using a set of candidate genes that have recently been prioritized based on multiple lines of evidence including association, linkage, gene expression (both human and animal studies), regulatory pathway, and literature search. In the network analysis, we explored the topological characteristics of these genes in the context of the human interactome and compared them with two other complex diseases. The network topological features indicated that MDD is similar to schizophrenia compared to cancer. In the functional analysis, we performed the gene set enrichment analysis for both Gene Ontology categories and canonical pathways. Moreover, we proposed a unique pathway crosstalk approach to examine the dynamic interactions among biological pathways. Our pathway enrichment and crosstalk analyses revealed two unique pathway interaction modules that were significantly enriched with MDD genes. These two modules are neuro-transmission and immune system related, supporting the neuropathology hypothesis of MDD. Finally, we constructed a MDD-specific subnetwork, which recruited novel candidate genes with association signals from a major MDD GWAS dataset.

CONCLUSIONS:

This study is the first systematic network and pathway analysis of candidate genes in MDD, providing abundant important information about gene interaction and regulation in a major psychiatric disease. The results suggest potential functional components underlying the molecular mechanisms of MDD and, thus, facilitate generation of novel hypotheses in this disease. The systems biology based strategy in this study can be applied to many other complex diseases.

Polypill Could Cut Heart Attacks And Strokes Dramatically: Medical News Today

A randomized trial finds that giving over-50s a four-in-one "Polypill" ((amlodipine , losartan  for lowering blood pressure and simvastatin, for reducing cholesterol. ) to cut their risk of heart attack and stroke, led to large drops in blood cholesterol and blood pressure, the main causes of these two diseases. The trial's lead investigator says the expected impact of the Polypill would be to cut heart attacks and strokes, both leading causes of death worldwide, by two-thirds.

Genes, epigenetic regulation and environmental factors: which is the most relevant in developing autoimmune diseases?

Autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis and inflammatory bowel disease, have complex pathogeneses and likely multifactorial etiologies. The current paradigm for understanding their development is that the disease is triggered in genetically-susceptible individuals by exposure to environmental factors. Some of these environmental factors have been specifically identified, while others are hypothesized and not yet proven, and it is likely that most have yet to be identified. One interesting hypothesis is that environmental effects on immune responses could be mediated by changes in epigenetic regulation. Major mechanisms of epigenetic gene regulation include DNA methylation and histone modification. In these cases, gene expression is modified without involving changes in DNA sequence. Epigenetics is a new and interesting research field in autoimmune diseases. We review the roles of genetic factors, epigenetic regulation and the most studied environmental risk factors such as cigarette smoke, crystalline silica, Epstein-Barr virus, and reproductive hormones in the pathogenesis of autoimmune disease.

Futurity.org – Immune suppressants relieve severe asthma

A type of severe asthma (asthmatic granulomatosis) improves when treated with drugs that suppress the immune system.

Regional Astrocyte Allocation Regulates CNS Synaptogenesis and Repair

Astrocytes, the most abundant cell population in the central nervous system (CNS), are essential for normal neurological function. We show that astrocytes are allocated to spatial domains in mouse spinal cord and brain in accordance with their embryonic sites of origin in the ventricular zone. These domains remain stable throughout life without evidence of secondary tangential migration, even after acute CNS injury. Domain-specific depletion of astrocytes in ventral spinal cord resulted in abnormal motor neuron synaptogenesis, which was not rescued by immigration of astrocytes from adjoining regions. Our findings demonstrate that region-restricted astrocyte allocation is a general CNS phenomenon and reveal intrinsic limitations of the astroglial response to injury.
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Blood-Based Biomarkers for Alzheimer's Disease Identified

In the first study, researchers identified a panel of plasma biomarker candidates, including cortisol and pancreatic polypeptide (PP), which distinguishes individuals with AD from cognitively healthy control patients.
A second study confirmed CSF studies reporting increased levels, not only of PP, but also of N-terminal protein beta-type brain natriuretic peptide (NT-proBNP), in patients with AD and mild cognitive impairment (MCI).
Both studies appeared in the Archives of Neurology.

Intravenous immunoglobulin G Offers Long-term Stabilization of Alzheimer's Symptoms

Immunotherapy with intravenous immunoglobulin (IVIG/Gammagard, Baxter) appears to stabilize symptoms of Alzheimer's disease (AD) over the long term, new research shows.
Presented here at the Alzheimer's Association International Conference (AAIC) 2012, a small, open-label extension phase 2 trial showed that at 36 months, IVIG slowed the rate of expected cognitive decline in all participants. But the most striking finding was that it stopped decline in a subset of patients who received what proved to be the optimal dose of the immunotherapy for the entire study period.For this subset of 4 patients, measures of cognition, memory, daily functioning, and mood were unchanged from baseline after 3 years of treatment.
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Higher levels fat (ceramides) in blood may increase risk of Alzheimer’s - Chicago Sun-Times

A study of 99 elderly women from Baltimore, which was published online Wednesday in the journal Neurology, found that those who had a middle or high level of the fat known as serum ceramides were eight- to tenfold more likely to develop Alzheimer’s within nine years.
Serum ceramides play a role in cell suicide, which has been linked to brain degeneration and Alzheimer’s.disease
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Peripheral inflammation leads to central CNS inflammation : PNAS

During peripheral immune activation caused by an infection or an inflammatory condition, the innate immune response signals to the brain and causes an up-regulation of central nervous system (CNS) cytokine production. Central actions of proinflammatory cytokines, in particular IL-1β, are pivotal for the induction of fever and fatigue. In the present study, the influence of peripheral chronic joint inflammatory disease in rheumatoid arthritis (RA) on CNS inflammation was investigated. Intrathecal interleukin (IL)-1β concentrations were markedly elevated in RA patients compared with controls or with patients with multiple sclerosis. Conversely, the anti-inflammatory IL-1 receptor antagonist and IL-4 were decreased in RA cerebrospinal fluid (CSF). Tumor necrosis factor and IL-6 levels in the CSF did not differ between patients and controls. Concerning IL-1β, CSF concentrations in RA patients were higher than in serum, indicating local production in the CNS, and there was a positive correlation between CSF IL-1β and fatigue assessments. Next, spinal inflammation in experimental arthritis was investigated. A marked increase of IL-1β, IL-18, and tumor necrosis factor, but not IL-6 mRNA production, in the spinal cord was observed, coinciding with increased arthritis scores in the KBxN serum transfer model. These data provide evidence that peripheral inflammation such as arthritis is associated with an immunological activation in the CNS in both humans and mice, suggesting a possible therapeutic target for centrally affecting conditions as fatigue in chronic inflammatory diseases, for which to date there are no specific treatments.

MicrobeWorld - Symbiotic Bacteria Halt Malaria Life Cycle in Mosquitoes

Allowing mosquitos to feed on engineered strains of the symbiotic bacteria that naturally live in their midguts may provide the answer to preventing the malarial parasite Plasmodium from completing the relevant stages of its life cycle in the airborne host and being transmitted to humans, researchers claim. A team at the Johns Hopkins Bloomberg School of Public Health’s Malaria Research Institute has generated engineered strains of a common symbiotic bacterium Pantoea agglomerans that resides in the midgut of the anopheles mosquito. The bacterium is modified to secrete proteins that directly block development and survival of the Plasmodial ookinetes and oocysts developing in the midgut, which would normally give rise to the sporozoites that are transmitted into humans through the mosquito’s saliva.

Researchers find evidence of link between immune irregularities and autism

Scientists at the California Institute of Technology (Caltech) pioneered the study of the link between irregularities in the immune system and neurodevelopmental disorders such as autism a decade ago. Since then, studies of postmortem brains and of individuals with autism, as well as epidemiological studies, have supported the correlation between alterations in the immune system and autism spectrum disorder.

Read more at: http://medicalxpress.com/news/2012-07-evidence-link-immune-irregularities-autism.html#jCp

Researchers link two biological risk factors for schizophrenia

Previous studies found that one of the roles of astrocytes is to secrete the neurotransmitter D-serine, which helps promote the transmission of glutamate in the brain, believed to be a key to cognitive function. Schizophrenics have decreased glutamate transmission. It appears, Pletnikov says, that people with DISC1 mutations associated with the psychiatric illness are faster to metabolize D-serine, which leads to a decrease in the apparently crucial transmitter.

Sodium buildup in brain linked to disability in multiple sclerosis

A buildup of sodium in the brain detected by magnetic resonance imaging (MRI) may be a biomarker for the degeneration of nerve cells that occurs in patients with multiple sclerosis (MS), according to a new study published online in the journal Radiology.

Poisoning from industrial compounds can cause similar effects to ALS

Researchers from the Bellvitge Biomedical Research Institute (IDIBELL) at the University of Barcelona (UB) have coordinated a research into how the IDPN nitrile causes neurological syndromes similar to those of the amyotrophic lateral sclerosis (ALS), a severe neuromuscular degenerative disease. The study, led by Jordi Llorens, has been recently published in Neuropathology and Applied Neurobiology journal.

MNT: Trans Fat Ban Has Led To Healthier Fast Food Meals In NYC

The ban that New York City authorities introduced in 2006 to restrict use of trans fats in fast-food restaurants has led to residents eating healthier fast food meals that are substantially and significantly lower in trans fats. Also, those meals have not increased their saturated fat content to compensate.
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Neuropsychopharmacology - Predicting White Matter Integrity from Multiple Common Genetic Variants

Several common genetic variants have recently been discovered that appear to influence white matter microstructure, as measured by diffusion tensor imaging (DTI). Each genetic variant explains only a small proportion of the variance in brain microstructure, so we set out to explore their combined effect on the white matter integrity of the corpus callosum. We measured six common candidate single-nucleotide polymorphisms (SNPs) in the COMT, NTRK1, BDNF, ErbB4, CLU, and HFE genes, and investigated their individual and aggregate effects on white matter structure in 395 healthy adult twins and siblings (age: 20–30 years). All subjects were scanned with 4-tesla 94-direction high angular resolution diffusion imaging. When combined using mixed-effects linear regression, a joint model based on five of the candidate SNPs (COMT, NTRK1, ErbB4, CLU, and HFE) explained ~6% of the variance in the average fractional anisotropy (FA) of the corpus callosum. This predictive model had detectable effects on FA at 82% of the corpus callosum voxels, including the genu, body, and splenium. Predicting the brain's fiber microstructure from genotypes may ultimately help in early risk assessment, and eventually, in personalized treatment for neuropsychiatric disorders in which brain integrity and connectivity are affected.

Systems analysis of eleven rodent disease models reveals an inflammatome signature and key drivers

Common inflammatome gene signatures as well as disease-specific signatures were identified by analyzing 12 expression profiling data sets derived from 9 different tissues isolated from 11 rodent inflammatory disease models. The inflammatome signature significantly overlaps with known drug targets and co-expressed gene modules linked to metabolic disorders and cancer. A large proportion of genes in this signature are tightly connected in tissue-specific Bayesian networks (BNs) built from multiple independent mouse and human cohorts. Both the inflammatome signature and the corresponding consensus BNs are highly enriched for immune response-related genes supported as causal for adiposity, adipokine, diabetes, aortic lesion, bone, muscle, and cholesterol traits, suggesting the causal nature of the inflammatome for a variety of diseases. Integration of this inflammatome signature with the BNs uncovered 151 key drivers that appeared to be more biologically important than the non-drivers in terms of their impact on disease phenotypes. The identification of this inflammatome signature, its network architecture, and key drivers not only highlights the shared etiology but also pinpoints potential targets for intervention of various common diseases.
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Futurity.org – Sea moss compound flushes out latent HIV

STANFORD (US) — A new collection of compounds—derived from a tiny marine organism—activate hidden reservoirs of HIV that currently make AIDS nearly impossible to eradicate.

Transposable element recruitments in the mammalian placenta: impacts and mechanisms

Transposable elements (TEs) are mobile DNA elements found at high frequency in mammalian genomes. Although these elements are generally perceived as genomic parasites, they have the potential to influence host genome function in many beneficial ways. This article discusses the role TEs have played in the evolution of the placenta and pregnancy in viviparous mammals. Using examples from our own research and the literature, we argue that frequent recruitment of TEs, in particular of retroelements, has facilitated the extreme diversification of tissues at the maternal–fetal interface. We also discuss the mechanisms by which TEs have been recruited for functions during pregnancy. We argue that retroelements are pre-adapted to becoming cis-regulatory elements for host genomes because they need to utilize host regulatory signals for their own life cycle. However, although TEs contain some of the signals necessary for host functions upon insertion, they often require modification before acquiring a biological role in a host tissue. We discuss the process by which one TE was transformed into a promoter for prolactin expression in the endometrium, describing a model for TE domestication called ‘epistatic capture’.
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Scientists discover dendritic cells key to activating human immune responses

Scientists at A*STAR’s Singapore Immunology Network (SIgN), in collaboration with Newcastle University, UK, the Singapore Institute of Clinical Sciences and clinicians from multiple hospitals in Singapore, have identified a new subset of dendritic cells (DCs) in human peripheral tissue which have a critical role in activating our immune response against harmful pathogens. This research will have significant impact on the design of vaccines and other targeted immunotherapies. The scientists also showed for the first time that DC subsets are conserved between species, facilitating the translation of mouse functional DC studies to the human setting. These research findings were published in the July issue of the prestigious journal Immunity.

Early Epigenetic Influence |Differences in identical twinsThe Scientist

Random chance, plus small differences in uterine environments, give rise to divergent epigenetic patterns in identical twins.

Scientists identify critical cell in fighting E. coli infection

Despite ongoing public health efforts, E. coli outbreaks continue to infiltrate the food supply, annually causing significant sickness and death throughout the world. But the research community is gaining ground. In a major finding, published today in the scientific journal Nature, researchers from the La Jolla Institute for Allergy & Immunology have discovered a molecule's previously unknown role in fighting off E. coli and other bacterial infections, a discovery that could lead to new ways to protect people from these dangerous microorganisms.

Read more at: http://medicalxpress.com/news/2012-07-scientists-critical-cell-coli-infection.html#jCp
Despite ongoing public health efforts, E. coli outbreaks continue to infiltrate the food supply, annually causing significant sickness and death throughout the world. But the research community is gaining ground. In a major finding, published today in the scientific journal Nature, researchers from the La Jolla Institute for Allergy & Immunology have discovered a molecule's previously unknown role in fighting off E. coli and other bacterial infections, a discovery that could lead to new ways to protect people from these dangerous microorganisms.

Read more at: http://medicalxpress.com/news/2012-07-scientists-critical-cell-coli-infection.html#jCprrr
Despite ongoing public health efforts, E. coli outbreaks continue to infiltrate the food supply, annually causing significant sickness and death throughout the world. But the research community is gaining ground. In a major finding, published today in the scientific journal Nature, researchers from the La Jolla Institute for Allergy & Immunology have discovered a molecule's previously unknown role in fighting off E. coli and other bacterial infections, a discovery that could lead to new ways to protect people from these dangerous microorganisms.

Read more at: http://medicalxpress.com/news/2012-07-scientists-critical-cell-coli-infection.html#jCp
Despite ongoing public health efforts, E. coli outbreaks continue to infiltrate the food supply, annually causing significant sickness and death throughout the world. But the research community is gaining ground. In a major finding, published today in the scientific journal Nature, researchers from the La Jolla Institute for Allergy & Immunology have discovered a molecule's previously unknown role in fighting off E. coli and other bacterial infections, a discovery that could lead to new ways to protect people from these dangerous microorganisms.

Read more at: http://medicalxpress.com/news/2012-07-scientists-critical-cell-coli-infection.html#jCp
Despite ongoing public health efforts, E. coli outbreaks continue to infiltrate the food supply, annually causing significant sickness and death throughout the world. But the research community is gaining ground. In a major finding, published today in the scientific journal Nature, researchers from the La Jolla Institute for Allergy & Immunology have discovered a molecule's previously unknown role in fighting off E. coli and other bacterial infections, a discovery that could lead to new ways to protect people from these dangerous microorganisms.

Read more at: http://medicalxpress.com/news/2012-07-scientists-critical-cell-coli-infection.html#jCp
Despite ongoing public health efforts, E. coli outbreaks continue to infiltrate the food supply, annually causing significant sickness and death throughout the world. But the research community is gaining ground. In a major finding, published today in the scientific journal Nature, researchers from the La Jolla Institute for Allergy & Immunology have discovered a molecule's previously unknown role in fighting off E. coli and other bacterial infections, a discovery that could lead to new ways to protect people from these dangerous microorganisms.

Read more at: http://medicalxpress.com/news/2012-07-scientists-critical-cell-coli-infection.html#jCp
Despite ongoing public health efforts, E. coli outbreaks continue to infiltrate the food supply, annually causing significant sickness and death throughout the world. But the research community is gaining ground. In a major finding, published today in the scientific journal Nature, researchers from the La Jolla Institute for Allergy & Immunology have discovered a molecule's previously unknown role in fighting off E. coli and other bacterial infections, a discovery that could lead to new ways to protect people from these dangerous microorganisms.

Read more at: http://medicalxpress.com/news/2012-07-scientists-critical-cell-coli-infection.html#jCp
Despite ongoing public health efforts, E. coli outbreaks continue to infiltrate the food supply, annually causing significant sickness and death throughout the world. But the research community is gaining ground. In a major finding, published today in the scientific journal Nature, researchers from the La Jolla Institute for Allergy & Immunology have discovered a molecule's previously unknown role in fighting off E. coli and other bacterial infections, a discovery that could lead to new ways to protect people from these dangerous microorganisms.

Read more at: http://medicalxpress.com/news/2012-07-scientists-critical-cell-coli-infection.html#jCp
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Viral culprits may explain a host of tumors with as-yet unknown triggers- Science News

As of now, the official figure for the percentage of human cancers caused by viruses is around 20 percent — but most experts concede that number is largely an educated guess, accounting for known viruses behaving in predictable ways. “Thirty years ago, that number would have been 5 percent,” says Robert Garry, a virologist at Tulane University School of Medicine in New Orleans. “It’s a moving target. How high is it going to go? We don’t know.”

Some Personal Care Products May Raise Diabetes Risk: MNT

Women may be at higher risk of developing diabetes because of phthalates that exist in such personal care products as soaps, hair sprays, moisturizers, nail polish, and even perfume. Researchers from Brigham and Women's Hospital published a report in Environmental Health Perspectives explaining that the higher concentrations of phthalate metabolites in the urine of females compared to males might mean that women have a higher risk of developing diabetes.
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Babies In The Womb Affected By Pesticides In The Home: MNT

Air samples from homes of Hispanic mothers-to-be along the Texas-Mexico border contained multiple pesticides in a majority of the houses, according to a study conducted by the School of Medicine at The University of Texas Health Science Center San Antonio.
All the women were in the third trimester of pregnancy, when the fetal brain undergoes a growth spurt. Several studies have reported that pesticide exposure may adversely affect mental and motor development during infancy and childhood. The new report is in the summer issue of the Texas Public Health Journal sent to members this week.

Intrathecal, polyspecific antiviral immune response in oligoclonal band negative multiple sclerosis.

Oligoclonal bands (OCB) are detected in the cerebrospinal fluid (CSF) in more than 95% of patients with multiple sclerosis (MS) in the Western hemisphere. Here we evaluated the intrathecal, polyspecific antiviral immune response as a potential diagnostic CSF marker for OCB-negative MS patients.METHODOLOGY/PRINCIPAL FINDINGS:We tested 46 OCB-negative German patients with paraclinically well defined, definite MS. Sixteen OCB-negative patients with a clear diagnosis of other autoimmune CNS disorders and 37 neurological patients without evidence for autoimmune CNS inflammation served as control groups. Antibodies against measles, rubella, varicella zoster and herpes simplex virus in paired serum and CSF samples were determined by ELISA, and virus-specific immunoglobulin G antibody indices were calculated. An intrathecal antibody synthesis against at least one neurotropic virus was detected in 8 of 26 (31%) patients with relapsing-remitting MS, 8 of 12 (67%) with secondary progressive MS and 5 of 8 (63%) with primary progressive MS, in 3 of 16 (19%) CNS autoimmune and 3 of 37 (8%) non-autoimmune control patients. Antibody synthesis against two or more viruses was found in 11 of 46 (24%) MS patients but in neither of the two control groups. On average, MS patients with a positive antiviral immune response were older and had a longer disease duration than those without.CONCLUSION:Determination of the intrathecal, polyspecific antiviral immune response may allow to establish a CSF-supported diagnosis of MS in OCB-negative patients when two or more of the four virus antibody indices are elevated.

Futurity.org – How malaria outsmarts immune system memory

YALE (US) — The parasite that causes malaria creates its own version of a human immune hormon (Macrophage migration inhibitory factor) a trick that keeps the body from remembering the infection and developing immunity.

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Futurity.org – Alzheimer’s shows up decades before symptoms

WASHINGTON U.-ST. LOUIS (US) — The earliest changes due to Alzheimer’s disease can be detected 25 years before the estimated age of onset, an international team reports.

When Vaccines Turn Vicious | The Scientist

The very vaccines used to prevent a respiratory disease in chickens caused several recent outbreaks of the same disease at farms across Australia, according to a report published today (July 12) in Science. Different weakened versions of a live herpes virus used in the vaccines exchanged portions of their genomes, resulting in virulent, disease-causing strains. This suggests that such in-the-field genetic recombination is more common than previously thought, and has implications for both animal and human health.

Novel immune target identified in multiple sclerosis

(HealthDay) -- About half of a subgroup of patients with multiple sclerosis have autoantibodies to a potassium channel in the brain, according to a study published in the July 12 issue of the New England Journal of Medicine.

Oligodendroglia cells protect neurons against neurodegeneration

(Medical Xpress) -- Johns Hopkins researchers say they have discovered that the central nervous system's oligodendroglia cells, long believed to simply insulate nerves as they "fire" signals, are unexpectedly also vital to the survival of neurons. Damage to these insulators appears to contribute to brain injury in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease for the Yankee baseball great who died from the disease.

In vitro Anti-Toxoplasma gondii Activity of Root Extract/Fractions of Eurycoma longifolia Jack.

Toxoplasma gondii infection causes toxoplasmosis, an infectious disease with worldwide prevalence. The limited efficiency of drugs against this infection, their side effects and the potential appearance of resistant strains make the search of novel drugs an essential need. We examined Eurycoma longifolia root extract and fractions as potential sources of new compounds with high activity and low toxicity. The main goal of this study was to investigate the anti-T. gondii activity of crude extract (TACME) and four fractions (TAF 273, TAF 355, TAF 191 and TAF 401) from E. longifolia, with clindamycin as the positive control. METHODS: In vitro toxoplasmacidal evaluation was performed using Vero cells as host for T. gondii. Light microscopy technique was used to study in situ antiparasitic activity. RESULTS:Significant anti-T. gondii activity was observed with clindamycin (EC50 = 0.016 mug/ml), follow by TAF 355 (EC50 = 0.369 mug/ml) and TAF 401 (EC50 = 0.882 mug/ml). Light microscopy revealed that most Vero cells were infected after 3 h of exposure to T. gondii. After 36 h of exposure to the E. longifolia fraction, the host Vero cells showed no visible intracellular parasite and no remarkable morphological changes. CONCLUSIONS:
Our study demonstrated that TAF 355 and TAF401 fractions may be the sources of new antiT. gondii compounds.
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Decline of immune system with aging may have a genetic cause

Important insights that explain why our ability to ward off infection declines with age are published in a new research report in the July 2012 issue of the Genetics Society of America's journal, Genetics.

Crosstalk between metabolic and neuropsychiatric disorders - F1000 Biology Reports - F1000

Evidence supporting the concurrence of metabolic disturbances (e.g. insulin resistance, diabetes and obesity) and neuropsychiatric disorders has been demonstrated in both human and animal studies, suggesting the possibility that they have shared pathophysiological mechanisms. During the past decade, our understanding for the role of insulin in both normal and abnormal central nervous system (CNS) processes has become increasingly refined. Evidence indicates that insulin is a pleiotropic peptide, critical to neurotrophism, neuroplasticity, and neuromodulation. Moreover, the role of insulin underscores its importance in the development of several neuropsychiatric disorders, including, but not limited to, mechanisms involved in the pathogenesis and progression towards diabetes, obesity, and neurodegenerative disorders, such as Alzheimer's disease. This review focuses on the insulin-mediated effects on normal and abnormal brain function and discusses why targeting insulin-related pathways in the brain may emerge as a new approach for refining treatment of neurological and psychiatric disorders.
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Futurity.org – Test detects cancer from immune cell mix

A new blood test determines the relative abundance of leukocytes, immune cells that can indicate cancer and other disorders.The key to the new technique is that scientists have identified in each kind of leukocyte a unique DNA methylation signature.

Antiviral therapy of two patients with chromosomally-integrated human herpesvirus-6A presenting with cognitive dysfunction.

Human herpesvirus 6 (HHV-6) is a neurotropic virus implicated in central nervous system (CNS) dysfunction, multiple sclerosis, seizures and encephalitis. Inherited or "chromosomally integrated" HHV-6 (CIHHV-6) is a condition characterized by high DNA loads and germ line transmission of HHV-6 genomes, which are integrated into the telomere.OBJECTIVES:We previously reported that integrated HHV-6 can be reactivated by trichostatin A in vitro. Therefore, we hypothesized that a broad array of neurological symptoms of CIHHV-6 patients may respond to antiviral drug treatment.STUDY DESIGN:The patients have been treated with antiviral drugs and monitored for viral load, late mRNA, and clinical improvement.RESULTS:Antiviral therapy of two CIHHV patients resulted in successful clinical resolution. However, both patients relapsed on multiple occasions within 4-6 months of cessation of antiviral therapy.CONCLUSIONS:Successful antiviral drug treatment suggests that clinical symptoms of these patients were due to symptomatic reactivation of CIHHV-6. Alternatively, some CIHHV-6 patients may have a reduced resistance to community-acquired HHV-6 strains due to tolerance leading to persistent infections.

Quantitative assessment of the impact of the gut microbiota on lysine ε-acetylation of host proteins using gnotobiotic mice

The gut microbiota influences numerous aspects of human biology. One facet that has not been thoroughly explored is its impact on the host proteome. We hypothesized that the microbiota may produce certain of its effects through covalent modification of host proteins. We focused on protein lysine ε-acetylation because of its recently discovered roles in regulation of cell metabolism, and the potential for products of microbial fermentation to interact with the lysine acetylation machinery of host cells. Germ-free mice, fed a 15N-labeled diet for two generations, were colonized as adults with a microbiota harvested from conventionally raised mouse donors. Using high-resolution mass spectrometry, we quantified 3,891 liver and proximal colonic proteins, 558 of which contained 1,602 sites of lysine acetylation, 43% not previously described. Multiple proteins from multiple subcellular compartments underwent microbiota-associated increases in their levels of lysine acetylation at one or more residues, in one or both tissues. Acetylated proteins were enriched in functions related to energy production, respiration, and primary metabolism. A number of the acetylation events affect lysine residues at or near the active sites of enzymes, whereas others occur at locations that may affect other facets of protein function. One of these modifications, affecting Lys292 in mouse α-1-antitrypsin, was detected in the corresponding lysine of the human serum protein. Methods described in this report can be applied to other co- or posttranslational modifications, and add quantitation of protein expression and covalent modification to the arsenal of techniques for characterizing the dynamic, important interactions between gut symbionts and their hosts.
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Effects of dimethyl fumarate on neuroprotection and immunomodulation.

Neuronal degeneration in multiple sclerosis has been linked to oxidative stress. Dimethyl fumarate is a promising novel oral therapeutic option shown to reduce disease activity and progression in patients with relapsing-remitting multiple sclerosis. These effects are presumed to originate from a combination of immunomodulatory and neuroprotective mechanisms. We aimed to clarify whether neuroprotective concentrations of dimethyl fumarate have immunomodulatory effects.FINDINGS:We determined time- and concentration-dependent effects of dimethyl fumarate and its metabolite monomethyl fumarate on viability in a model of endogenous neuronal oxidative stress and clarified the mechanism of action by quantitating cellular glutathione content and recycling, nuclear translocation of transcription factors, and the expression of antioxidant genes. We compared this with changes in the cytokine profiles released by stimulated splenocytes measured by ELISPOT technology and analyzed the interactions between neuronal and immune cells and neuronal function and viability in cell death assays and multi-electrode arrays. Our observations show that dimethyl fumarate causes short-lived oxidative stress, which leads to increased levels and nuclear localization of the transcription factor nuclear factor erythroid 2-related factor 2 and a subsequent increase in glutathione synthesis and recycling in neuronal cells. Concentrations that were cytoprotective in neuronal cells had no negative effects on viability of splenocytes but suppressed the production of proinflammatory cytokines in cultures from C57BL/6 and SJL mice and had no effects on neuronal activity in multi-electrode arrays.CONCLUSIONS:These results suggest that immunomodulatory concentrations of dimethyl fumarate can reduce oxidative stress without altering neuronal network activity.

Drug from Mediterranean weed kills tumor cells in mice

Scientists at the Johns Hopkins Kimmel Cancer Center, working with Danish researchers, have developed a novel anticancer drug designed to travel -- undetected by normal cells -- through the bloodstream until activated by specific cancer proteins. The drug, made from a weedlike plant, Thapsia garganica,  has been shown to destroy cancers and their direct blood supplies, acting like a "molecular grenade," and sparing healthy blood vessels and tissues.

Texas Advanced Computing Center - Small Molecule May Play Big Role in Alzheimer’s Disease

Accumulations of amyloid plaques have long been associated with the disease and were presumed to be its cause. New findings support a hypothesis that fibrils are a by-product of the disease rather than the toxic agent itself. This paradigm shift changes the focus of inquiry to smaller, intermediate molecules that form and dissipate quickly. These molecules are difficult to perceive in brain tissue.