Gut microbes signal to the brain when they are full

"Don't have room for dessert? The bacteria in your gut may be telling you something. Twenty minutes after a meal, gut microbes produce proteins that can suppress food intake in animals, reports a study published November 24 (here in Cell Metabolism. )The researchers also show how these proteins injected into mice and rats act on the brain reducing appetite, suggesting that gut bacteria may help control when and how much we eat."

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Beyond the brain: disrupted in schizophrenia 1 regulates pancreatic β-cell function via glycogen synthase kinase-3β

"Individuals with schizophrenia and their first-degree relatives have higher rates of type 2 diabetes (T2D) than the general population (18–30 vs. 1.2–6.3%), independent of body mass index and antipsychotic medication, suggesting shared genetic components may contribute to both diseases. The cause of this association remains unknown. Mutations in disrupted in schizophrenia 1 (DISC1) increase the risk of developing psychiatric disorders [logarithm (base 10) of odds = 7.1]. Here, we identified DISC1 as a major player controlling pancreatic β-cell proliferation and insulin secretion via regulation of glycogen synthase kinase-3β (GSK3β). DISC1 expression was enriched in developing mouse and human pancreas and adult β- and ductal cells. Loss of DISC1 function, through siRNA-mediated depletion or expression of a dominant-negative truncation that models the chromosomal translocation of human DISC1 in schizophrenia, resulted in decreased β-cell proliferation (3 vs. 1%; P < 0.01), increased apoptosis (0.1 vs. 0.6%; P < 0.01), and glucose intolerance in transgenic mice. Insulin secretion was reduced (0.5 vs. 0.1 ng/ml; P < 0.05), and critical β-cell transcription factors Pdx1 and Nkx6.1 were significantly decreased. Impaired DISC1 allowed inappropriate activation of GSK3β in β cells, and antagonizing GSK3β (SB216763; IC50 = 34.3 nM) rescued the β-cell defects. These results uncover an unexpected role for DISC1 in normal β-cell physiology and suggest that DISC1 dysregulation contributes to T2D independently of its importance for cognition.

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Molecular Psychiatry - Inflammation is associated with decreased functional connectivity within corticostriatal reward circuitry in depression

Depression is associated with alterations in corticostriatal reward circuitry. One pathophysiological pathway that may drive these changes is inflammation. Biomarkers of inflammation (for example, cytokines and C-reactive protein (CRP)) are reliably elevated in depressed patients. Moreover, administration of inflammatory stimuli reduces neural activity and dopamine release in reward-related brain regions in association with reduced motivation and anhedonia. Accordingly, we examined whether increased inflammation in depression affects corticostriatal reward circuitry to lead to deficits in motivation and goal-directed motor behavior. Resting-state functional magnetic resonance imaging was conducted on 48 medically stable, unmedicated outpatients with major depression. Whole-brain, voxel-wise functional connectivity was examined as a function of CRP using seeds for subdivisions of the ventral and dorsal striatum associated with motivation and motor control. Increased CRP was associated with decreased connectivity between ventral striatum and ventromedial prefrontal cortex (vmPFC) (corrected P<0.05), which in turn correlated with increased anhedonia (R=−0.47,P=0.001). Increased CRP similarly predicted decreased dorsal striatal to vmPFC and presupplementary motor area connectivity, which correlated with decreased motor speed (R=0.31 to 0.45, P<0.05) and increased psychomotor slowing (R=−0.35, P=0.015). Of note, mediation analyses revealed that these effects of CRP on connectivity mediated significant relationships between CRP and anhedonia and motor slowing. Finally, connectivity between striatum and vmPFC was associated with increased plasma interleukin (IL)-6, IL-1beta and IL-1 receptor antagonist (R=−0.33 to −0.36, P<0.05). These findings suggest that decreased corticostriatal connectivity may serve as a target for anti-inflammatory or pro-dopaminergic treatment strategies to improve motivational and motor deficits in patients with increased inflammation, including depression.

The case for rejecting the amyloid cascade hypothesis : Nature Neuroscience : Nature Publishing Group

Alzheimer's disease (AD) is a biologically complex neurodegenerative dementia. Nearly 20 years ago, with the combination of observations from biochemistry, neuropathology and genetics, a compelling hypothesis known as the amyloid cascade hypothesis was formulated. The core of this hypothesis is that it is pathological accumulations of amyloid-β, a peptide fragment of a membrane protein called amyloid precursor protein, that act as the root cause of AD and initiate its pathogenesis. Yet, with the passage of time, growing amounts of data have accumulated that are inconsistent with the basically linear structure of this hypothesis. And while there is fear in the field over the consequences of rejecting it outright, clinging to an inaccurate disease model is the option we should fear most. This Perspective explores the proposition that we are over-reliant on amyloid to define and diagnose AD and that the time has come to face our fears and reject the amyloid cascade hypothesis.

Nature and nurture: Human brains evolved to be more responsive to environmental influences - Medical News Today

Microbial DNA records historical delivery of anthropogenic mercury

 "Mercury (Hg) is an anthropogenic pollutant that is toxic to wildlife and humans, but the response of remote ecosystems to globally distributed Hg is elusive. Here, we use DNA extracted from a dated sediment core to infer the response of microbes to historical Hg delivery. We observe a significant association between the mercuric reductase gene (merA) phylogeny and the timing of Hg deposition. Using relaxed molecular clock models, we show a significant increase in the scaled effective population size of the merA gene beginning ~200 years ago, coinciding with the Industrial Revolution and a coincident strong signal for positive selection acting on residues in the terminal region of the mercuric reductase. This rapid evolutionary response of microbes to changes in the delivery of anthropogenic Hg indicates that microbial genomes record ecosystem response to pollutant deposition in remote regions."

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PLOS ONE: Gene Expression Profiles from Disease Discordant Twins Suggest Shared Antiviral Pathways and Viral Exposures among Multiple Systemic Autoimmune Diseases

Viral agents are of interest as possible autoimmune triggers due to prior reported associations and widely studied molecular mechanisms of antiviral immune responses in autoimmunity. Here we examined new viral candidates for the initiation and/or promotion of systemic autoimmune diseases (SAID), as well as possible related signaling pathways shared in the pathogenesis of those disorders. RNA isolated from peripheral blood samples from 33 twins discordant for SAID and 33 matched, unrelated healthy controls was analyzed using a custom viral-human gene microarray. Paired comparisons were made among three study groups—probands with SAID, their unaffected twins, and matched, unrelated healthy controls—using statistical and molecular pathway analyses. Probands and unaffected twins differed significantly in the expression of 537 human genes, and 107 of those were associated with viral infections. These 537 differentially expressed human genes participate in overlapping networks of several canonical, biologic pathways relating to antiviral responses and inflammation. Moreover, certain viral genes were expressed at higher levels in probands compared to either unaffected twins or unrelated, healthy controls. Interestingly, viral gene expression levels in unaffected twins appeared intermediate between those of probands and the matched, unrelated healthy controls. Of the viruses with overexpressed viral genes, herpes simplex virus-2 (HSV-2) was the only human viral pathogen identified using four distinct oligonucleotide probes corresponding to three HSV-2 genes associated with different stages of viral infection. Although the effects from immunosuppressive therapy on viral gene expression remain unclear, this exploratory study suggests a new approach to evaluate shared viral agents and antiviral immune responses that may be involved in the development of SAID

The 6,000-Calorie Diet | Overeating leads to insulin resistance in days.The Scientist Magazine®

Between October 2013 and July 2014, six healthy, middle-aged men reported to Temple University Hospital in north Philadelphia. For seven days, researchers confined each subject to his hospital bed and told him to select breakfast, lunch, and dinner, along with three daily snacks, from the hospital menu containing typical American cuisine: eggs, fried chicken, hamburgers, French fries, etc. The intake totaled a whopping 6,000 calories—about 2.5 times the men’s normal diet.

The high-calorie diet worked as planned, with participants already showing signs of insulin resistance by day two. By the end of the week, the men showed a 50-percent decrease in their insulin-stimulated glucose uptake. (They also gained an average of 3.5 kg, all of it fat.) Then it became a question of what was causing the problem. Fatty acid levels didn’t go up; in fact, they went down slightly. A survey of five proinflammatory cytokines also ruled out inflammation as a cause. And there were no signs of increased ER stress in biopsied adipose tissue. “So I’m pretty sure that none of these three had anything to do with this massive insulin resistance,” Boden says. “What we did find was that oxidative stress went up. And not only did it go up, but it went up exactly at the same rate as insulin resistance went up.”

Here's the paper:-

Excessive caloric intake acutely causes oxidative stress, GLUT4 carbonylation, and insulin resistance in healthy men.

US obesity rates hit 40% in middle aged adults: CDC

Map of Obesity in Adult Males (% of adult popu...
Map of Obesity in Adult Males (% of adult population with BMI 30+) per country. Using data updated until December 2008. (Photo credit: Wikipedia)
Map of Obesity in Adult Females (% of adult po...
Map of Obesity in Adult Females (% of adult population with BMI 30+) per country. Using data updated until December 2008. (Photo credit: Wikipedia)
Data from the National Health and Nutrition Examination Survey
In 2011–2014, the prevalence of obesity was just over 36% in adults and 17% in youth.
The prevalence of obesity was higher in women (38.3%) than in men (34.3%). Among all youth, no difference was seen by sex.
The prevalence of obesity was higher among middle-aged (40.2%) and older (37.0%) adults than younger (32.3%) adults.
The prevalence of obesity was higher among non-Hispanic white, non-Hispanic black, and Hispanic adults and youth than among non-Hispanic Asian adults and youth.
From 1999 through 2014, obesity prevalence increased among adults and youth. However, among youth, prevalence did not change from 2003–2004 through 2013–2014."

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Methylmercury can induce Parkinson's-like neurotoxicity similar to 1-methyl-4- phenylpyridinium: a genomic and proteomic analysis on MN9D dopaminergic neurones

"Exposure to environmental chemicals has been implicated as a possible risk factor for the development of neurodegenerative diseases. Our previous study showed that methylmercury (MeHg) exposure can disrupt synthesis, uptake and metabolism of dopamine similar to 1-methyl-4-phenylpyridinium (MPP(+)). The objective of this study was to investigate the effects of MeHg exposure on gene and protein profiles in a dopaminergic MN9D cell line. MN9D cells were treated with MeHg (1-5 μM) and MPP(+) (10-40 μM) for 48 hr. Real-time PCR Parkinson's disease (PD) arrays and high-performance liquid chromatography/electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS) were performed for the analysis. PD PCR array results showed that 19% genes were significantly changed in the 2.5 μM MeHg treated cells, and 39% genes were changed in the 5 μM MeHg treated cells. In comparison, MPP(+) treatment (40 µM) resulted in significant changes in 25% genes. A total of 15 common genes were altered by both MeHg and MPP(+), and dopaminergic signaling transduction was the most affected pathway. Proteomic analysis identified a total of 2496 proteins, of which 188, 233 and 395 proteins were differentially changed by 1 μM and 2.5 μM MeHg, and MPP(+) respectively. A total of 61 common proteins were changed by both MeHg and MPP(+) treatment. The changed proteins were mainly involved in energetic generation-related metabolism pathway (propanoate metabolism, pyruvate metabolism and fatty acid metabolism), oxidative phosphorylation, proteasome, PD and other neurodegenerative disorders. A total of 7 genes/proteins including Ube2l3 (Ubiquitin-conjugating enzyme E2 L3) and Th (Tyrosine 3-monooxygenase) were changed in both genomic and proteomic analysis. These results suggest that MeHg and MPP(+) share many similar signaling pathways leading to the pathogenesis of PD and other neurodegenerative diseases."

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PFOA exposure in utero linked to child adiposity and faster BMI gain

"Children whose mothers were exposed to relatively high levels of the chemical PFOA during pregnancy experienced more rapid body fat gain and higher body fat by age 8 than children whose mothers were less exposed, according to a new analysis in the journal Obesity."

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Time to Dismount | Journal of Alzheimer's Disease

The field of Alzheimer research has reached an impasse after more than 100,000 clinical and scientific papers published in the last 40 years, because there is yet no hope, no effective treatment, and no knowledge of what causes this dementia.
It has become increasingly clear that part of the explanation for the lack of therapeutic advancement in Alzheimer’s disease (AD) lies in the unyielding quagmire resulting from the premise that AD is caused by the excessive production in the brain of a sticky substance called amyloid-β (Aβ). However, considerable data indicates this conclusion is not supported by evidence-based medicine, especially from a clinical perspective.

The village wisdom, passed on from generation to generation, used to say that when you discover that you are a riding a dead horse, the best strategy is to dismount. It is time to get off the dead horse that so far has only provided knee-jerk dogma and an absence of clinically useful measures. This action will be helpful so we can get on with more constructive research that searches for a valid pathway to defeat one of the most important medical challenges of this century.

Lower risk of Alzheimer's disease mortality with exercise, statin, and fruit intake. - PubMed - NCBI

Whether lifestyle affects Alzheimer's disease (AD) risk remains controversial.

Test whether exercise, diet, or statins affect AD mortality in 153,536 participants of the National Runners' and Walkers' Health Studies.

Hazard ratios (HR) and 95% confidence intervals (95% CI) were obtained from Cox proportional hazard analyses for AD mortality versus baseline metabolic equivalent (MET) hours/d of exercise energy expenditure (1 MET equals approximately 1 km run), statin use, and fruit intake when adjusted for age, race, gender, education, and exercise mode.

The National Death Index identified 175 subjects who died with AD listed as an underlying (n = 116) or contributing (n = 59) cause of death during 11.6-year average mortality surveillance. Relative to exercising <1.07 MET-hours/d, AD mortality was 6.0% lower for 1.07 to 1.8 MET-hours/d (HR: 0.94, 95% CI: 0.59 to 1.46, p = 0.79), 24.8% lower for 1.8 to 3.6 MET-hours/d (HR: 0.75, 95% CI: 0.50 to 1.13, p = 0.17), and 40.1% lower for ≥3.6 MET-hours/d (HR: 0.60, 95% CI: 0.37 to 0.97, p = 0.04). Relative to non-use, statin use was associated with 61% lower AD mortality (HR: 0.39, 95% CI: 0.15 to 0.82, p = 0.01), whereas use of other cholesterol-lowering medications was not (HR: 0.78, 95% CI: 0.40 to 1.38, p = 0.42). Relative to <1 piece of fruit/day, consuming 2 to 3 pieces daily was associated with 39.7% lower AD mortality (HR: 0.60, 95% CI: 0.39 to 0.91, p = 0.02) and ≥3 pieces/day with 60.7% lower AD mortality (HR: 0.39, 95% CI: 0.22 to 0.67, p = 0.0004).

Exercise, statin, and fruit intake were associated with lower risk for AD mortality."

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Translational Psychiatry - Reduced protein synthesis in schizophrenia patient-derived olfactory cells

 "Human olfactory neurosphere-derived (ONS) cells have the potential to provide novel insights into the cellular pathology of schizophrenia. We used discovery-based proteomics and targeted functional analyses to reveal reductions in 17 ribosomal proteins, with an 18% decrease in the total ribosomal signal intensity in schizophrenia-patient-derived ONS cells. We quantified the rates of global protein synthesis in vitro and found a significant reduction in the rate of protein synthesis in schizophrenia patient-derived ONS cells compared with control-derived cells. Protein synthesis rates in fibroblast cell lines from the same patients did not differ, suggesting cell type-specific effects. Pathway analysis of dysregulated proteomic and transcriptomic data sets from these ONS cells converged to highlight perturbation of the eIF2α, eIF4 and mammalian target of rapamycin (mTOR) translational control pathways, and these pathways were also implicated in an independent induced pluripotent stem cell-derived neural stem model, and cohort, of schizophrenia patients. Analysis in schizophrenia genome-wide association data from the Psychiatric Genetics Consortium specifically implicated eIF2α regulatory kinase EIF2AK2, and confirmed the importance of the eIF2α, eIF4 and mTOR translational control pathways at the level of the genome. Thus, we integrated data from proteomic, transcriptomic, and functional assays from schizophrenia patient-derived ONS cells with genomics data to implicate dysregulated protein synthesis for the first time in schizophrenia."

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Microbiome Seems to Have a Role in Triggering Lupus

 "Systemic lupus erythematosus (SLE) is caused by a combination of genetic and environmental factors. A team of researchers from New York City believes that clinical SLE disease is associated with microbiome imbalances, specifically with decreases in the diversity and blooms of specific operational taxonomic units in the the intestine. 
In an abstract presented at the 2015 American College of Rheumatology Annual Meeting in San Francisco, CA, Greg Silverman, MD,  and colleagues at the NYU School of Medicine noted that animal models in other studies of inflammatory and autoimmune disease have shown intestinal bacteria play a role in the development of these tissues. They looked at a group of 67 SLE adult patients and 16 healthy controls, analyzing bacteria in fecal samples.   They found the patients with SLE had microbiota that were less diverse. SLE patients displayed a significant increase in Proteobacteria and a decrease in Firmicutes.  Also, the SLE patients had increased representation of specific operational taxonomic units. "Interestingly the anaerobic species Prevotella copri, recently linked to new-onset RA, was expanded in a subset of SLE patients but not in healthy controls," they noted.  

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Obesity Leads to Tissue, but not Serum Vitamin A Deficiency : Scientific Reports

 "Obesity negatively affects multiple metabolic pathways, but little is known about the impact of obesity on vitamin A (VA)[retinol (ROL)], a nutrient that regulates expression of genes in numerous pathways essential for human development and health. We demonstrate that obese mice, generated from a high fat diet (HFD) or by genetic mutations (i.e., ob/ob; db/db), have greatly reduced ROL levels in multiple organs, including liver, lungs, pancreas, and kidneys, even though their diets have adequate VA. However, obese mice exhibit elevated serum VA. Organs from obese mice show impaired VA transcriptional signaling, including reductions in retinoic acid receptor (RARα, RARβ2 and RARγ) mRNAs and lower intracellular ROL binding protein Crbp1 (RBP1) levels in VA-storing stellate cells. Reductions in organ VA signaling in obese mice correlate with increasing adiposity and fatty liver (steatosis), while with weight loss VA levels and signaling normalize. Consistent with our findings in obese mice, we show that increasing severity of fatty liver disease in humans correlates with reductions in hepatic VA, VA transcriptional signaling, and Crbp1 levels in VA storing stellate cells. Thus, obesity causes a “silent” VA deficiency marked by reductions in VA levels and signaling in multiple organs, but not detected by serum VA."

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Reduced cerebral cortical thickness in Non-cirrhotic patients with hepatitis C. - PubMed - NCBI

Hepatitis C virus (HCV) infection is associated with fatigue, depression, and cognitive impairment even in the absence of severe liver fibrosis or cirrhosis. HCV has been hypothesised to cause neurodegenerative changes through low-grade neuroinflammation. Our aim was to examine whether cortical thickness (CTh) differs between chronic HCV patients and healthy controls, suggestive of cortical atrophy. In this case-control study 43 HCV patients without severe liver fibrosis, substance abuse, or comorbid HIV or hepatitis B virus infection, and 43 age and sex matched controls underwent MRI. Cortical thickness was measured using a surface based approach. Participants underwent semi-structured psychiatric interview and fatigue was assessed using the fatigue severity scale. HCV was associated with higher fatigue scores, and 58 % of HCV patients suffered from significant fatigue (p < 0.0001). Depression was observed in 16 % of patients. Areas of significantly reduced CTh were found in both left and right occipital cortex and in the left frontal lobe after correction for multiple comparisons (p < 0.05). No association between fatigue, former substance abuse, or psychotropic medication and CTh was found. No overall difference in cerebral white and grey matter volume was found. The findings support the hypothesis that HCV is associated with neurodegenerative changes.

What causes autism? Environmental risks are hard to identify.

Experts can rattle off autism-linked genes, but other risks are very hard to pin down. 

A nice review of some of the environmental factors , and the problems associated with measurement and replication.

Parkinson's Disease and Pesticides Exposure: New Findings From a Comprehensive Study in Nebraska, USA. - PubMed - NCBI

"The association between exposure to agricultural pesticides and Parkinson's Disease (PD) has long been a topic of study in the field of environmental health. This research takes advantage of the unique Nebraska PD registry and state-level crop classification data to investigate the PD-pesticides exposure relationship.

First, Geographic Information System and satellite remote sensing data were adopted to calculate exposure to different pesticides for Nebraska residents. An integrated spatial exploratory framework was then adopted to explore the association between PD incidence and exposure to specific pesticide ingredients at the county level.

Our results reveal similarities in geographic patterns of pesticide exposure and PD incidence. The regression analyses indicate that, for most Nebraska counties, PD incidence was significantly associated with exposure to certain pesticide ingredients such as alachlor and broxomy. However, the results also suggest that factors other than pesticide exposure may help further explain the risk of PD at the county level.

We found significant associations between PD incidence and exposure to different pesticide ingredients. These results have useful implications for PD prevention in Nebraska and other agricultural states in the United States."

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90 percent of skin-based viruses represent unknown viral 'dark matter,' scientists reveal -- ScienceDaily

"Scientists in recent years have made great progress in characterizing the bacterial population that normally lives on human skin and contributes to health and disease. Now researchers have used state-of-the-art techniques to survey the skin's virus population, or "virome." The study reveals that most DNA viruses on healthy human skin are viral "dark matter" that have never been described before. The research also includes the development of a set of virome analysis tools that are now available to researchers for further investigations."

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