Circular RNA Surprise (Blocks microRNA)| The Scientist Magazine®

Some circular RNA molecules serve as molecular “sponges,” binding to and deactivating gene modulators called microRNAs to influence gene expression, according to two papers published this week (February 27) in Nature. The findings reveal a hidden world of previously unexplored RNA molecules, and act as a reminder that there is more to RNA than simply being a messenger between DNA and the proteins it encodes. - See more at: http://www.the-scientist.com//?articles.view/articleNo/34544/title/Circular-RNA-Surprise/#sthash.7Q7htOh8.dpuf

Contaminated diet contributes to exposure to endocrine-disrupting chemicals: Phthalates and BPA

"According to a study published February 27 in the Nature Journal of Exposure Science and Environmental Epidemiology, we may be exposed to these chemicals in our diet, even if our diet is organic and we prepare, cook, and store foods in non-plastic containers. Children may be most vulnerable."

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Viruses can have immune systems: A pirate phage commandeers the immune system of bacteria

 "A study published today in the journal Nature reports that a viral predator of the cholera bacteria has stolen the functional immune system of bacteria and is using it against its bacterial host. The study provides the first evidence that this type of virus, the bacteriophage ("phage" for short), can acquire a wholly functional and adaptive immune system."

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Whole grains, rather than dietary fibre, found to be fundamental to the prevention of chronic disease

"The apparent links between various food types and the prevention of chronic diseases - such as type 2 diabetes, coronary heart disease (CHD) and hypertension - are well established. In particular, dietary fibre has long been regarded as a powerful means of reducing health risks. However, this study finds that it is not fibre, but whole grain cereals specifically, which prevent chronic disease."

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Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis : The Lancet

Findings from family and twin studies suggest that genetic contributions to psychiatric disorders do not in all cases map to present diagnostic categories. We aimed to identify specific variants underlying genetic effects shared between the five disorders in the Psychiatric Genomics Consortium: autism spectrum disorder, attention deficit-hyperactivity disorder, bipolar disorder, major depressive disorder, and schizophrenia.

Methods

We analysed genome-wide single-nucleotide polymorphism (SNP) data for the five disorders in 33 332 cases and 27 888 controls of European ancestory. To characterise allelic effects on each disorder, we applied a multinomial logistic regression procedure with model selection to identify the best-fitting model of relations between genotype and phenotype. We examined cross-disorder effects of genome-wide significant loci previously identified for bipolar disorder and schizophrenia, and used polygenic risk-score analysis to examine such effects from a broader set of common variants. We undertook pathway analyses to establish the biological associations underlying genetic overlap for the five disorders. We used enrichment analysis of expression quantitative trait loci (eQTL) data to assess whether SNPs with cross-disorder association were enriched for regulatory SNPs in post-mortem brain-tissue samples.

Findings

SNPs at four loci surpassed the cutoff for genome-wide significance (p<5×10−8) in the primary analysis: regions on chromosomes 3p21 and 10q24, and SNPs within two L-type voltage-gated calcium channel subunits, CACNA1C and CACNB2. Model selection analysis supported effects of these loci for several disorders. Loci previously associated with bipolar disorder or schizophrenia had variable diagnostic specificity. Polygenic risk scores showed cross-disorder associations, notably between adult-onset disorders. Pathway analysis supported a role for calcium channel signalling genes for all five disorders. Finally, SNPs with evidence of cross-disorder association were enriched for brain eQTL markers.

Interpretation

Our findings show that specific SNPs are associated with a range of psychiatric disorders of childhood onset or adult onset. In particular, variation in calcium-channel activity genes seems to have pleiotropic effects on psychopathology. These results provide evidence relevant to the goal of moving beyond descriptive syndromes in psychiatry, and towards a nosology informed by disease cause.

Scientists attacked over claim that 'junk DNA' is vital to life | Science | The Observer

Scientists on the Encode project – an international public consortium researching the human genome – argued that most of our DNA has a part to play.

But this idea is now the subject of an astonishingly vitriolic attack from other scientists, who say that Encode's "absurd" ideas are the work of people who know nothing about evolutionary biology. "News concerning the death of junk DNA has been greatly exaggerated," they insist.

Press Release - Gut microbiota plays important role in functional bowel disorders - The Gut Microbiota For Health Experts Exchange

Microbiota research opens up promising paths for improving the diagnosis — online press conference at 2nd World Summit “Gut Microbiota For Health” held on 26 February

(24 February 2013) An estimated 50 per cent of patients consulting a gastroenterologist suffer from functional bowel disorders (FBD), such as dyspepsia or irritable bowel syndrome (IBS). It is characteristic for these conditions that underlying physiological mechanisms are hard to be found. “However, recent research shows that the gut microbiota is a likely candidate for filling some of the gaps in the causal chain leading to FBD,” says Professor Fernando Azpiroz, Chairman of the Gut Microbiota & Health Section of the European Society of Neurogastroenterology & Motility (ESNM). This is one of the topics to be presented at the 2nd World Summit “Gut Microbiota For Health” in Madrid, Spain. From today until 26 February 2013, internationally leading experts will be discussing the latest advances in gut microbiota research and its impact on health.

Starting from Scratch: DNA Methylation Marks Erased Through 5-hmC in Primordial Germ Cells | EpiBeat

A growing body of evidence indicates that ancestral environmental factors can influence the physiology and behavior of the offspring, a process known as epigenetic inheritance. However, in each generation the epigenetically inherited modifications are thought to be erased in cells called primordial germ cells (PGCs), the precursors to sperm and eggs, leaving scientists to question how epigenetic inheritance occurs.  In a recent paper published in Science, researchers from the University of Cambridge investigated how mouse PGCs reset their epigenetic modifications and remove DNA methylation on a genome-wide scale during development in an effort to learn more about trans-generational epigenetic inheritance.

Scientists Find Way to Image Brain Waste Removal Process Which May Lead to Alzheimer's Diagnostic

STONY BROOK, N.Y., February 22, 2013 – A novel way to image the entire brain’s glymphatic pathway, a dynamic process that clears waste and solutes from the brain that otherwise might build-up and contribute to the development of Alzheimer’s disease, may provide the basis for a new strategy to evaluate disease susceptibility, according to a research paper published online in The Journal of Clinical Investigation. Through contrast enhanced magnetic resonance imaging (MRI) and other tools, a Stony Brook University-led research team successfully mapped this brain-wide pathway and identified key anatomical clearance routes of brain waste. - 

A functional role of NMDA receptor in regulating the differentiation of oligodendrocyte precursor cells and remyelination.

Differentiation of oligodendrocyte precursor cells (OPCs) is the most important event for the myelination of central nervous system (CNS) axons during development and remyelination in demyelinating diseases, while the underlying molecular mechanisms remain largely unknown. Here we show that NMDA receptor (NMDAR) is a functional regulator of OPCs differentiation and remyelination. First, GluN1, GluN2A, and GluN2B subunits are expressed in oligodendrocyte lineage cells (OLs) in vitro and in vivo by immunostaining and Western blot analysis. Second, in a purified rat OPC culture system, NMDARs specially mediate OPCs differentiation by enhancing myelin proteins expression and the processes branching at the immature to mature oligodendrocyte transition analyzed by a serial of developmental stage-specific antigens. Moreover, pharmacological NMDAR antagonists or specific knockdown of GluN1 by RNA interference in OPCs prevents the differentiation induced by NMDA. NMDA can activate the mammalian target of rapamycin (mTOR) signal in OPCs and the pro-differentiation effect of NMDA is obstructed by the mTOR inhibitor rapamycin, suggesting NMDAR exerts its effect through mTOR-dependent mechanism. Furthermore, NMDA increases numbers of myelin segments in DRG-OPC cocultures. Finally, NMDAR specific antagonist MK801 delays remyelination in the cuprizone model examined by LFB-PAS, immunofluorescence and electron microscopy. This effect appears to result from inhibiting OPCs differentiation as more NG2(+) OPCs but less GST-π(+) mature oligodendrocytes are observed. Together, these results indicate that NMDAR plays a critical role in the regulation of OPCs differentiation in vitro and remyelination in cuprizone model which may provide potential target for the treatment of demyelination disease.

Gut Bacteria Help Regulate Blood Pressure

MNT: In a new study, US scientists suggest gut bacteria form part of a complex system that maintains the body's blood pressure. They have discovered a specialized odor-sensing receptor normally present in the nose can also be found in blood vessels throughout the body. In the gut, the receptor reacts to small molecules generated by bacteria by raising blood pressure. The study may aid understanding of how antibiotics, probiotics, and changes in diet affect blood pressure."

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How and why Toxoplasma makes us crazy.

For a long time, a latent toxoplasmosis, the lifelong presence of dormant stages of Toxoplasma in various tissues, including the brain, was considered harmless for immunocompetent persons. Within the past 10 years, however, many independent studies have shown that this parasitic disease, with a worldwide prevalence of about 30%, could be indirectly responsible for hundreds of thousands of deaths due to its effects on the rate of traffic and workplace accidents, and also suicides. Moreover, latent toxoplasmosis is probably one of the most important risk factors for schizophrenia. At least some of these effects, possibly mediated by increased dopamine and decreased tryptophan, are products of manipulation activity by Toxoplasma aiming to increase the probability of transmission from intermediate to definitive host through predation.

The antibody response to Epstein-Barr virions is altered in multiple sclerosis.

Infection with Epstein-Barr virus (EBV) is associated with multiple sclerosis (MS), and patients with MS have an increased antibody response to some EBV antigens. The major antigens of EBV are only partly defined. Our hypothesis is that the antibody response to EBV is altered in MS. With ELISA, we found that antibodies to EB virions were increased in both serum and CSF of MS patients. Western blots demonstrated that there are multiple different antigens recognized. The antibody response was generally higher in MS to all EBV antigens, with particularly significant increases for certain antigens. We conclude that the antibody response to EBV in MS is generally increased with altered specificity.

Bacteria: are they in your head?

YES ! The PLoS ONE study looked at brain tissue from 10 people, all of whom had either HIV, epilepsy, or some other control disease—and in all 10 samples they found bacterial RNA. The main type of bacteria they found is something called “alpha-proteobacteria,” which is surprising because it’s different from the kinds of microbes researchers have found in adjacent parts of the body like the skin and the nasal passages. This raises the possibility that alpha-proteobacteria is some kind of highly specialized brain bacteria performing an as-of-yet unrecognized function.

PLOS ONE Brain Microbial Populations in HIV/AIDS: α-Proteobacteria Predominate Independent of Host Immune Status.

Immune intervention reduces beta-cell death in type 1 diabetes

 "Patients recently diagnosed with type 1 diabetes have greater death of pancreatic β-cells compared with patients with long-standing diabetes, which can be reduced by treatment with teplizumab, according to a study published online Feb. 19 in Diabetes."

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BPA may affect the developing brain by disrupting gene regulation

Higher levels of several toxic metals found in children with autism

 "In a recently published study in the journal Biological Trace Element Research, Arizona State University researchers report that children with autism had higher levels of several toxic metals in their blood and urine compared to typical children. The study involved 55 children with autism ages 5-16 years compared to 44 controls of similar age and gender."
The autism group had significantly higher levels of lead in their red blood cells (+41 percent) and significantly higher urinary levels of lead (+74 percent), thallium (+77 percent), tin (+115 percent), and tungsten (+44 percent). Lead, thallium, tin, and tungsten are toxic metals that can impair brain development and function, and also interfere with the normal functioning of other body organs and systems.

Mediterranean diet helps cut risk of heart attack, stroke: Results of PREDIMED study presented

Results of the PREDIMED study, aimed at assessing the efficacy of the Mediterranean diet in the primary prevention of cardiovascular diseases, have been published in The New England Journal of Medicine. They show that the Mediterranean diet supplemented with extra-virgin olive oil or tree nuts reduces by 30 percent the risk of suffering a cardiovascular death, a myocardial infarction or a stroke.

Tsc1 (hamartin) confers neuroprotection against ischemia by inducing autophagy : Nature Medicine : Nature Publishing Group

Previous attempts to identify neuroprotective targets by studying the ischemic cascade and devising ways to suppress it have failed to translate to efficacious therapies for acute ischemic stroke. We hypothesized that studying the molecular determinants of endogenous neuroprotection in two well-established paradigms, the resistance of CA3 hippocampal neurons to global ischemia and the tolerance conferred by ischemic preconditioning (IPC), would reveal new neuroprotective targets. We found that the product of the tuberous sclerosis complex 1 gene (TSC1), hamartin, is selectively induced by ischemia in hippocampal CA3 neurons. In CA1 neurons, hamartin was unaffected by ischemia but was upregulated by IPC preceding ischemia, which protects the otherwise vulnerable CA1 cells. Suppression of hamartin expression with TSC1 shRNA viral vectors both in vitro and in vivo increased the vulnerability of neurons to cell death following oxygen glucose deprivation (OGD) and ischemia. In vivo, suppression of TSC1 expression increased locomotor activity and decreased habituation in a hippocampal-dependent task. Overexpression of hamartin increased resistance to OGD by inducing productive autophagy through an mTORC1-dependent mechanism.

High Fat Diets Maybe Linked To ADHD And Learning Problems: MNT

 "Diets that are high in fat are possibly linked to childhood brain-based conditions, such as memory-dependent learning disabilities and attention-deficit hyperactivity disorder (ADHD), researchers from the University of Illinois College of Medicine reported in Psychoneuroendocrinology."

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Futurity.org – Why bodies store fat when we eat at night

Insulin activity is controlled by the body’s circadian clock, which helps explain why not only what you eat, but when you eat, matters.

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Molecular Psychiatry : Cerebral folate receptor autoantibodies in autism spectrum disorder

Cerebral folate deficiency (CFD) syndrome is a neurodevelopmental disorder typically caused by folate receptor autoantibodies (FRAs) that interfere with folate transport across the blood–brain barrier. Autism spectrum disorders (ASDs) and improvements in ASD symptoms with leucovorin (folinic acid) treatment have been reported in some children with CFD. In children with ASD, the prevalence of FRAs and the response to leucovorin in FRA-positive children has not been systematically investigated. In this study, serum FRA concentrations were measured in 93 children with ASD and a high prevalence (75.3%) of FRAs was found. In 16 children, the concentration of blocking FRA significantly correlated with cerebrospinal fluid 5-methyltetrahydrofolate concentrations, which were below the normative mean in every case. Children with FRAs were treated with oral leucovorin calcium (2 mg kg⁻¹ per day; maximum 50 mg per day). Treatment response was measured and compared with a wait-list control group. Compared with controls, significantly higher improvement ratings were observed in treated children over a mean period of 4 months in verbal communication, receptive and expressive language, attention and stereotypical behavior. Approximately one-third of treated children demonstrated moderate to much improvement. The incidence of adverse effects was low. This study suggests that FRAs may be important in ASD and that FRA-positive children with ASD may benefit from leucovorin calcium treatment. Given these results, empirical treatment with leucovorin calcium may be a reasonable and non-invasive approach in FRA-positive children with ASD. Additional studies of folate receptor autoimmunity and leucovorin calcium treatment in children with ASD are warranted.

Modeling Alzheimer's disease using iPSCs

"Working with a group from Nagasaki University, a research group at the Center for iPS Cell Research and Application (CiRA) has successfully modeled Alzheimer's disease (AD) using both familial and sporadic patient-derived induced pluripotent stem cells (iPSCs), and revealed stress phenotypes and differential drug responsiveness associated with intracellular amyloid β oligomers in AD neurons and astrocytes."

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Study reveals new clues to Epstein-Barr virus

Nearly 30 years ago, Fingeroth and her colleagues discovered that this attachment occurs via the CD21 protein, which until now was the only known B cell attachment receptor for EBV. The recent finding that B cells from a patient lacking CD21 can be infected and immortalized by EBV had indicated that an alternative attachment receptor must exist. The identification of this second receptor—CD35—by Fingeroth's team, led by first author Javier Ogembo, PhD, of BIDMC and the University of Massachusetts Medical School, not only underscores an important finding regarding primary infection but also underscores the importance of EBVgp350/220, (the virus protein that has been found to bind to both attachment receptors) for the development of a vaccine against EBV.

Read more at: http://medicalxpress.com/news/2013-02-reveals-clues-epstein-barr-virus.html#jCp

Aspirin and omega-3 fatty acids work together to fight inflammation

 "Experts tout the health benefits of low-dose aspirin and omega-3 fatty acids found in foods like flax seeds and salmon, but the detailed mechanisms involved in their effects are not fully known. Now researchers reporting in the February 21 issue of the Cell Press journal Chemistry & Biology show that aspirin helps trigger the production of molecules called resolvins that are naturally made by the body from omega-3 fatty acids. These resolvins shut off, or "resolve," the inflammation that underlies destructive conditions such as inflammatory lung disease, heart disease, and arthritis."

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Examining and interpreting the female protective effect against autistic behavior

Male preponderance in autistic behavioral impairment has been explained in terms of a hypothetical protective effect of female sex, yet little research has tested this hypothesis empirically. If females are protected, they should require greater etiologic load to manifest the same degree of impairment as males. The objective of this analysis was to examine whether greater familial etiologic load was associated with quantitative autistic impairments in females compared with males. Subjects included 3,842 dizygotic twin pairs from the Twins Early Development Study (TEDS) and 6,040 dizygotic twin pairs from the Child and Adolescent Twin Study of Sweden (CATSS). In both samples, we compared sibling autistic traits between female and male probands, who were identified as children scoring in the top 90th and 95th percentiles of the population autistic trait distributions. In both TEDS and CATSS, siblings of female probands above the 90th percentile had significantly more autistic impairments than the siblings of male probands above the 90th percentile. The siblings of female probands above the 90th percentile also had greater categorical recurrence risk in both TEDS and CATSS. Results were similar in probands above the 95th percentile. This finding, replicated across two nationally-representative samples, suggests that female sex protects girls from autistic impairments and that girls may require greater familial etiologic load to manifest the phenotype. It provides empirical support for the hypothesis of a female protective effect against autistic behavior and can be used to inform and interpret future gene finding efforts in autism spectrum disorders.

Systematic identification of risk factors for Alzheimer's disease through shared genetic architecture and electronic medical records.

Alzheimer's disease (AD) is one of the leading causes of death for older people in US with rapidly increasing incidence. AD irreversibly and progressively damages the brain, but there are treatments in clinical trials to potentially slow the development of AD. We hypothesize that the presence of clinical traits, sharing common genetic variants with AD, could be used as a non-invasive means to predict AD or trigger for administration of preventative therapeutics. We developed a method to compare the genetic architecture between AD and traits from prior GWAS studies. Six clinical traits were significantly associated with AD, capturing 5 known risk factors and 1 novel association: erythrocyte sedimentation rate (ESR). The association of ESR with AD was then validated using Electronic Medical Records (EMR) collected from Stanford Hospital and Clinics. We found that female patients and with abnormally elevated ESR were significantly associated with higher risk of AD diagnosis (OR: 1.85 [1.32-2.61], p=0.003), within 1 year prior to AD diagnosis (OR: 2.31 [1.06-5.01], p=0.032), and within 1 year after AD diagnosis (OR: 3.49 [1.93-6.31], p<0.0001). Additionally, significantly higher ESR values persist for all time courses analyzed. Our results suggest that ESR should be tested in a specific longitudinal study for association with AD diagnosis, and if positive, could be used as a prognostic marker.

Determination of steroid metabolome as a possible tool for laboratory diagnosis of schizophrenia.

Metabolomic studies represent a promising tool for early diagnosis of schizophrenia. The aim of this study was to find differences in the steroid spectrum in patients and controls, and to assess the diagnosis of schizophrenia by building a predictive model based on steroid data. Thirty-nine serum steroids (22 neuroactive steroids and their metabolites and 17 polar conjugates) representing steroid metabolome were measured by gas chromatography-mass spectrometry in 22 drug-naive (first episode) schizophrenia patients (13 men and 9 women) before and after six-month treatment with atypical antipsychotics. The results were compared to the data from healthy subjects (22 males, 25 females). In summary the following significant differences were found: (1) In both sexes higher levels of pregnenolone sulfate and sulfated 5α- as well as 5β-saturated metabolites of C21-steroids in progesterone metabolic pathway were found in patients, pointing to decreased activity of sulfatase. (2) In a few instances decreased levels of the respective 5α-metabolites of C21 steroids were found in patients. (3) As C19 steroids concern, in both sexes there were considerably lowered levels of 5β-reduced metabolites in patients. On the other hand, with only a few exceptions, the treatment did not significantly influence most steroid levels. Further, to assess the relationships between schizophrenia status and steroid levels and to build the predictive model of schizophrenia, multivariate regression with reduction of dimensionality (the method of orthogonal projections to latent structures, OPLS) was applied. Irrespective of the small number of patients, use of this model enabled us to state the diagnosis of schizophrenia with almost 100% sensitivity. Our findings suggest that the assessment of steroid levels may become a valid and accurate laboratory test in psychiatry. A limitation of our study is the absence of subjects with a diagnosis other than schizophrenia, so we cannot conclude whether the results are specific for schizophrenia. On the other hand, steroid metabolome model may be used as a diagnostic tool for further studies.

Fish oil component reduces brain damage in newborns, mouse study suggests

Research conducted by a team of scientists from Columbia University College of Physicians and Surgeons and Dr. Nicolas Bazan, Boyd Professor and Director of the Neuroscience Center of Excellence at LSU Health Sciences Center New Orleans, found the novel use of a component of fish oil reduced brain trauma in newborn mice. The study reports that neonatal brain damage decreased by about 50% when a triglyceride lipid emulsion containing docosahexaenoic acid (DHA) was injected within two hours of the onset of ischemic stroke.

Blame common colds on your chromosome 'telomere Caps?'

The researchers recruited 152 healthy 18- to 55-year-olds, and measured telomere length in the volunteers' T cells—immune system cells that fight off infection. They then exposed the men and women to a cold virus via nasal drops, and quarantined them in a hotel to be monitored. Over the next five days, 22 percent of the volunteers developed cold symptoms, and the odds were higher among those with shorter telomeres in a particular subtype of T cell. Of the one-third with the shortest telomeres, 26 percent became sick, versus 13 percent among the one-third with the longest telomeres.

Read more at: http://medicalxpress.com/news/2013-02-blame-common-colds-chromosome-caps.html#jCp

Effects of human exposure to hormone-disrupting chemicals examined in landmark United Nations report

 "Many synthetic chemicals, untested for their disrupting effects on the hormone system, could have significant health implications according to the State of the Science of Endocrine Disrupting Chemicals, a new report by the United Nations Environment Programme (UNEP) and WHO."The joint study calls for more research to understand fully the associations between endocrine disrupting chemicals (EDCs) -- found in many household and industrial products -- and specific diseases and disorders. The report notes that with more comprehensive assessments and better testing methods, potential disease risks could be reduced, with substantial savings to public health.

Is there a link between childhood obesity and ADHD, learning disabilities?

A University of Illinois study has established a possible link between high-fat diets and such childhood brain-based conditions as attention deficit hyperactivity disorder (ADHD) and memory-dependent learning disabilities.

MNT: Brain Lesions (Damage to small blood vessels) Can Predict Alzheimer's Diagnosis

Among participants with heightened amyloid plaque levels, those with Alzheimer's had higher volumes of white matter hyperintensities or small brain lesions that were seen via MRI.

Among subjects with mild cognitive impairment, both factors predicted the development ofAlzheimer's disease .

Futurity.org – Asthma sufferers have more lung fungi

Healthy lungs are full of fungi, but some species are more common in people with asthma, new research finds.
From BMC Infectious diseases.

Differences in fungi present in induced sputum samples from asthma patients and non-atopic controls: a community based case control study

A total of 136 fungal species were identified in the induced sputum samples, with 90 species more common in asthma patients and 46 species more common in control subjects. Psathyrella candolleana, Malassezia pachydermatis, Termitomyces clypeatus and Grifola sordulenta showed a higher percentage of reads in the sputum of asthma patients and Eremothecium sinecaudum, Systenostrema alba, Cladosporium cladosporioides and Vanderwaltozyma polyspora showed a higher percentage of reads in the sputum of control subjects. A statistically significant difference in the pattern of fungi that were present in the respective samples was demonstrated using the Phylogenetic (P) test (P < 0.0001).

Conclusion

This study is novel in providing evidence for the widespread nature of fungi in the sputum of healthy and asthmatic individuals. Differences in the pattern of fungi present in asthma patients and controls merit further investigation. Of particular interest was the presence of Malassezia pachydermatis, which is known to be associated with atopic dermatitis.

New discoveries linking gut bacteria with cholesterol metabolism give hope for the future

 "(Medical Xpress)—Researchers at the Sahlgrenska Academy, University of Gothenburg, Sweden, show that cholesterol metabolism is regulated by bacteria in the small intestine. These findings may be important for the development of new drugs for cardiovascular disease."

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Gene Enables Cells To Survive Even If Growth Stops

MNT "Researchers in Australia have discovered a genetic defect that can stop cells growing but forces them into a death-defying state where they consume their own cellular material to survive. They believe the discovery of such an important feature of cell growth could lead to new treatments for diseases, including cancer."
PLOS Genetics
Autophagy Induction Is a Tor- and Tp53-Independent Cell Survival Response in a Zebrafish Model of Disrupted Ribosome Biogenesis

Intravenous immunoglobulin reduces beta amyloid and abnormal tau formation caused by herpes simplex virus type 1

Intravenous immunoglobulin (IVIG) treatment of Alzheimer's disease (AD) has been encouraging. Its mechanism of action might be via anti-β-amyloid (Aβ) antibodies which facilitate Aβ clearance. However, IVIG's benefits might result from its antiviral activity, particularly against herpes simplex virus type 1 (HSV1), a virus implicated in AD. We investigated IVIG's effect on HSV1, specifically on the accumulation of Aβ and abnormally phosphorylated tau which it causes. We show that IVIG is effective at reducing the accumulation of these abnormal molecules and that it acts synergistically with the antiviral acyclovir, suggesting that their combined use would be beneficial for treating AD.

Bacteria boost fixes symptoms of autism in mice - health - 14 February 2013 - New Scientist

REPLACING missing gut bacteria in a mouse model of autism reverses adverse social behaviours and gut disorders associated with the condition.

Last year, Sarkis Mazmanian and Paul Patterson at the California Institute of Technology in Pasadena found that infecting pregnant mice with molecules from a flu virus caused autism-like symptoms in their offspring. The pups were less social, squeaked less and displayed repetitive behaviours. They also had a "leaky" gastrointestinal tract that allowed bacteria to move in and out of the lining. In addition, the bacteria present in their gut were significantly different from that found in mice without autism-like behaviour.

Chronic pain alters DNA methylation in the brain | Newsroom - McGill University

Injuries that result in chronic pain, such as limb injuries, and those unrelated to the brain are associated with epigenetic changes in the brain which persist months after the injury, according to researchers at McGill University. Epigenetics explores how the environment – including diet, exposure to contaminants and social conditions such as poverty – can have a long-term impact on the activity of our genes.

Maternal immune activation leads to age-related behavioral and immunological changes in male rat offspring - the effect of antipsychotic drugs.

Prenatal immune system disturbances have been postulated to play an important role in pathogenesis of schizophrenia and related disorders. In the present study, we sought to answer the question whether behavioral changes in the neurodevelopmental model of schizophrenia in rats are accompanied by alterations in proliferative activity of splenocytes and pro- and anti-inflammatory cytokine levels. Furthermore, the effects of two antipsychotic drugs on these parameters were determined. Methods: Lipopolysaccharide (LPS) was administered subcutaneously to pregnant dams at a dose of 1 mg/kg every second day from the 7(th) day of pregnancy till delivery. Age-dependent behavioral and immunological changes were studied when control and prenatally LPS-pretreated offspring male rats were 30 and 90 days old. Chlorpromazine (10 mg/kg ip) or clozapine (10 mg/kg ip) was administered chronically (21 days) after behavioral verification to 3 months old offspring males. Changes in sensorimotor gating (prepulse inhibition, PPI), mitogen-induced proliferative activity of splenocytes ([(3)H]-thymidine incorporation) and cytokine levels (ELISA) were measured. Results: Prenatally LPS-pretreated rats showed PPI deficit only at 90 but not at 30 days of age, whereas an enhancement of mitogen-stimulated proliferative activity of splenocytes was observed in both time points. Additionally, the level of proinflammatory cytokines (IL-1β, IL-2, IL-6, TNF-α) in prenatally LPS-pretreated rats was enhanced when they were 30 days old and remained elevated in 90 days old offspring. No changes in IL-10 level were observed. Chronic administration of chlorpromazine or clozapine reduced the deficit in PPI deficit in prenatally LPS-treated rats. In the used model, chlorpromazine normalized both T and B lymphocyte proliferation, whereas clozapine B lymphocyte activity only. Moreover, both antipsychotics modulated the enhanced levels of IL-1β, IL-2 and TNF-α in the offspring of LPS-treated mothers. Conclusions: This study indicates that in LPS-evoked model of schizophrenia, peripheral immunological changes are long-lasting and precede behavioral deficit. The disturbances in T cell-mediated immunity as well as cytokine production were attenuated by antipsychotic drug administration.

Simultaneous Quantification of Multiple Bacteria by the BactoChip Microarray Designed to Target Species-Specific Marker Genes.

Simultaneous Quantification of Multiple Bacteria by... [PLoS One. 2013] - PubMed - NCBI: "Simultaneous Quantification of Multiple Bacteria by the BactoChip Microarray Designed to Target Species-Specific Marker Genes."

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Serum markers of infections in patients with primary biliary cirrhosis: evidence of infection burden.

Currently not much is known regarding the environmental factors involved in primary biliary cirrhosis (PBC). It is even more unclear which factors may determine the subgroup (i.e., AMA status) of patients with PBC. We thus tested AMA+and AMA- PBC patients' sera for antibodies (Abs) against multiple infectious agents.

METHODS:

Sera from 69 patients with PBC (49 AMA+and 20 AMA-) and 100 matched controls were screened for IgG-Abs against Toxoplasma gondii, Helicobacter pylori, Epstein-Barr virus (EBV), cytomegalovirus (CMV), hepatitis B, and hepatitis C utilizing the BioPlex 2200 and ELISA kits (Bio-Rad Laboratories, USA).

RESULTS:

The prevalence of four anti-infectious agents Abs was significantly elevated among PBC patients when compared with controls, namely anti-T. gondii (ATxA; 71% vs. 40%, p<0.0001), EBV early antigen (EA; 44% vs. 12%, p<0.0001), H. pylori (54% vs. 31%, p<0.01), and CMV (90% vs. 75%, p<0.05) Abs, respectively. The co-occurrence of these four anti-infectious agents Abs was highly common in PBC, whereas this infection burden was rare in healthy subjects (20% vs. 3% respectively, p<0.0001). Furthermore, specific infections interactions possibly increasing PBC risk were noted as well. Seropositivity of ATxA was inversely associated with cirrhosis among PBC patients (p<0.05). Finally, no differences were observed between AMA- sera and their AMA+counterparts with regard to seroprevalence of any of the investigated infectious agents.

CONCLUSIONS:

We note the association of ATxA and PBC, with the possibility of a milder disease manifestation. We also suggest that multiple exposures to infectious agents may contribute to PBC risk.

Common chemicals linked to osteoarthritis

 "A new study has linked exposure to two common perfluorinated chemicals (PFCs) with osteoarthritis. PFCs are used in more than 200 industrial processes and consumer products including certain stain- and water-resistant fabrics, grease-proof paper food containers, personal care products, and other items. Because of their persistence, PFCs have become ubiquitous contaminants of humans and wildlife. The study, published in Environmental Health Perspectives, is the first to look at the associations between perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS), and osteoarthritis, in a study population representative of the United States."

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Mind-Altering Microbes: How the Microbiome Affects Brain and Behavior (video)

Mind-Altering Microbes: How the Microbiome Affects Brain and Behavior (video):

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Expression profiling of mouse subplate reveals a dynamic gene network and disease association with autism and schizophrenia.

The subplate zone is a highly dynamic transient sector of the developing cerebral cortex that contains some of the earliest generated neurons and the first functional synapses of the cerebral cortex. Subplate cells have important functions in early establishment and maturation of thalamocortical connections, as well as in the development of inhibitory cortical circuits in sensory areas. So far no role has been identified for cells in the subplate in the mature brain and disease association of the subplate-specific genes has not been analyzed systematically. Here we present gene expression evidence for distinct roles of the mouse subplate across development as well as unique molecular markers to extend the repertoire of subplate labels. Performing systematic comparisons between different ages (embryonic days 15 and 18, postnatal day 8, and adult), we reveal the dynamic and constant features of the markers labeling subplate cells during embryonic and early postnatal development and in the adult. This can be visualized using the online database of subplate gene expression at https://molnar.dpag.ox.ac.uk/subplate/. We also identify embryonic similarities in gene expression between the ventricular zones, intermediate zone, and subplate, and distinct postnatal similarities between subplate, layer 5, and layers 2/3. The genes expressed in a subplate-specific manner at some point during development show a statistically significant enrichment for association with autism spectrum disorders and schizophrenia. Our report emphasizes the importance of the study of transient features of the developing brain to better understand neurodevelopmental disorders.

Development Of White Fat Cells Controlled By Long Noncoding RNAs

Whitehead Institute researchers have identified a previously unrecognized layer of genetic regulation that is necessary for the generation of undesirable white fat cells. When this regulation is disrupted, white fat cells are unable to accumulate lipid droplets or mature from their precursors. In the quest to understand fat-cell generation and maintenance, the Lodish lab scanned mouse fat cells to determine which of the cells' long noncoding RNAs (lncRNAs) are active. Of the 175 identified, 10 lncRNAs were found to play significant roles in these cells. 

Epigenetic changes at gene promoters in response to immune activation in utero.

Increasing evidence suggests that maternal infection increases the risk of psychiatric disorders, such as schizophrenia and autism in offspring. However, the molecular mechanisms associated with these effects are unclear. Here, we have studied epigenetic gene regulation in mice exposed to non-specific immune activation elicited by polyI:C injection to pregnant dams. Using Western blot analysis, we detected global hypoacetylation of histone H3, at lysine residues 9 and 14, and histone H4, at lysine residue 8, in the cortex from juvenile (∼24 days of age) offspring exposed to polyI:C in utero, but not from adult (3 months of age) offspring, which exhibit significant behavioral abnormalities. Accordingly, we detected robust deficits in the expression of genes associated with neuronal development, synaptic transmission and immune signaling in the cortex of polyI:C-exposed juvenile mice. In particular, we found that several genes in the glutamate receptor signaling pathway, including Gria1 and Slc17a7, showed decreases in promoter-specific histone acetylation, and corresponding gene expression deficits, in polyI:C-exposed offspring at both juvenile and adult ages. In contrast, the expression of these same genes, in addition to Disc1 and Ntrk3, was elevated in the hippocampus of juvenile mice, in concordance with elevated levels of promoter-specific histone acetylation. We suggest that these early epigenetic changes contribute to the delayed behavioral abnormalities that are observed in adult animals after exposure to polyI:C, and which resemble symptoms seen in schizophrenia and related disorders.

Study Suggests Link Between Untreated Depression And Response To Shingles Vaccine

 "Results from a new study published in Clinical Infectious Diseases suggest a link between untreated depression in older adults and decreased effectiveness of the herpes zoster, or shingles, vaccine. Older adults are known to be at risk for shingles, a painful condition caused by the reactivation of the varicella-zoster virus, and more than a million new cases occur each year in the U.S. The vaccine boosts cell-mediated immunity to the virus and can decrease the incidence and severity of the condition. " MNT

Gene that suppresses herpesviruses discovered

 "Kaposi's sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV) hide within the worldwide human population. While dormant in the vast majority of those infected, these active herpesviruses can develop into several forms of cancer. In an effort to understand and eventually develop treatments for these viruses, researchers at the University of North Carolina have identified a family of human genes known as Tousled-like kinases (TLKs) that play a key role in the suppression and activation of these viruses."

Accelerated biological aging, seen in women with Alzheimer's risk factor, blocked by hormone therapy

Healthy menopausal women carrying a well-known genetic risk factor for Alzheimer's disease showed measurable signs of accelerated biological aging, a new study has found.However, in carriers who started hormone therapy at menopause and remained on that therapy, this acceleration was absent, the researchers said. Hormone therapy for non-carriers of the risk factor, a gene variant called ApoE4, had no protective effect on their biological aging.

The Disruption of Celf6, a Gene Identified by Translational Profiling of Serotonergic Neurons, Results in Autism-Related Behaviors

The immense molecular diversity of neurons challenges our ability to understand the genetic and cellular etiology of neuropsychiatric disorders. Leveraging knowledge from neurobiology may help parse the genetic complexity: identifying genes important for a circuit that mediates a particular symptom of a disease may help identify polymorphisms that contribute to risk for the disease as a whole. The serotonergic system has long been suspected in disorders that have symptoms of repetitive behaviors and resistance to change, including autism. We generated a bacTRAP mouse line to permit translational profiling of serotonergic neurons. From this, we identified several thousand serotonergic-cell expressed transcripts, of which 174 were highly enriched, including all known markers of these cells. Analysis of common variants near the corresponding genes in the AGRE collection implicated the RNA binding protein CELF6 in autism risk. Screening for rare variants in CELF6 identified an inherited premature stop codon in one of the probands. Subsequent disruption of Celf6in mice resulted in animals exhibiting resistance to change and decreased ultrasonic vocalization as well as abnormal levels of serotonin in the brain. This work provides a reproducible and accurate method to profile serotonergic neurons under a variety of conditions and suggests a novel paradigm for gaining information on the etiology of psychiatric disorders.

Vascular Brain Injury Greater Risk Factor Than Amyloid Plaques In Cognitive Aging

MNT: Vascular brain injury from conditions such as high blood pressure and stroke are greater risk factors for cognitive impairment among non-demented older people than is the deposition of the amyloid plaques in the brain that long have been implicated in conditions such as Alzheimer's disease, a study by researchers at the Alzheimer's Disease Research Center at UC Davis has found. 

Neuropsychopharmacology Altered Concentrations of Amyloid Precursor Protein Metabolites in the Cerebrospinal Fluid of Patients with Bipolar Disorder

Bipolar disorder is a psychiatric disorder characterized by recurrent episodes of mania/hypomania and depression. Progressive cognitive dysfunction such as impairments in executive function and verbal memory is common in euthymic bipolar patients. The cerebrospinal fluid has previously been used to study neurodegenerative processes in Alzheimer’s disease, from which changes in three core biomarkers have emerged as indicative of degeneration: amyloid β, total tau, and hyperphosphorylated tau. Here, neurodegeneration in bipolar disorder was investigated by assessing the association between bipolar disorder and cerebrospinal fluid biomarkers for neurodegenerative processes. Cerebrospinal fluid was obtained from 139 bipolar disorder patients and 71 healthy controls. Concentrations of total and phosphorylated tau, amyloid β1-42, amyloidβ38/β40/β42, and the soluble forms of amyloid precursor protein were measured in patients vs controls. The concentrations of the soluble forms of amyloid precursor protein were significantly lower in bipolar patients compared with controls. The amyloid β42/amyloid β38 and the amyloidβ42/amyloid β40 ratios were higher in bipolar patients than controls. There were no discernible differences in the concentrations of total/phosphorylated tau, amyloid β1-42, or amyloid β38/β40/β42. The concentrations of the biomarkers within the bipolar patient group were further associated with different ongoing medical treatments and diagnostic subgroups. The findings suggest that the amyloid precursor protein metabolism is altered in bipolar disorder. The results may have implications for the understanding of the pathophysiology of bipolar disorder and for the development of treatment strategies. Importantly, there were no signs of an Alzheimer-like neurodegenerative process among bipolar patients.

JAMA | Association Between Maternal Use of Folic Acid Supplements and Risk of Autism Spectrum Disorders in ChildrenMaternal Folic Acid Supplements and Autism

 Prenatal folic acid supplements reduce the risk of neural tube defects in children, but it has not been determined whether they protect against other neurodevelopmental disorders.

Objective  To examine the association between maternal use of prenatal folic acid supplements and subsequent risk of autism spectrum disorders (ASDs) (autistic disorder, Asperger syndrome, pervasive developmental disorder–not otherwise specified [PDD-NOS]) in children.

Design, Setting, and Patients  The study sample of 85 176 children was derived from the population-based, prospective Norwegian Mother and Child Cohort Study (MoBa). The children were born in 2002-2008; by the end of follow-up on March 31, 2012, the age range was 3.3 through 10.2 years (mean, 6.4 years). The exposure of primary interest was use of folic acid from 4 weeks before to 8 weeks after the start of pregnancy, defined as the first day of the last menstrual period before conception. Relative risks of ASDs were estimated by odds ratios (ORs) with 95% CIs in a logistic regression analysis. Analyses were adjusted for maternal education level, year of birth, and parity.

Main Outcome Measure  Specialist-confirmed diagnosis of ASDs.

Results  At the end of follow-up, 270 children in the study sample had been diagnosed with ASDs: 114 with autistic disorder, 56 with Asperger syndrome, and 100 with PDD-NOS. In children whose mothers took folic acid, 0.10% (64/61 042) had autistic disorder, compared with 0.21% (50/24 134) in those unexposed to folic acid. The adjusted OR for autistic disorder in children of folic acid users was 0.61 (95% CI, 0.41-0.90). No association was found with Asperger syndrome or PDD-NOS, but power was limited. Similar analyses for prenatal fish oil supplements showed no such association with autistic disorder, even though fish oil use was associated with the same maternal characteristics as folic acid use.

Conclusions and Relevance  Use of prenatal folic acid supplements around the time of conception was associated with a lower risk of autistic disorder in the MoBa cohort. Although these findings cannot establish causality, they do support prenatal folic acid supplementation.

Discovery Links Inflammation to Schizophrenia Onset, May Aid Early Intervention/Prevention | Brain & Behavior Research Foundation (Formerly NARSAD)

Researchers have discovered a protein deficiency that results in mild chronic brain inflammation and is thought to lead to schizophrenia -related symptoms, such as working memory deficits, self-neglect, decreased social behaviors, and the loss of the ability to experience pleasure. An international team collaborated on the work from 11 institutions, including  Tsuyoshi Miyakawa, Ph.D., at the Institute for Comprehensive Medical Science, Fujita Health University and the National Institute for Physiological Sciences, Japan. The results of the study were published in the Feb. 6, 2013 issue of Neuropsychopharmacology


Deficiency of Schnurri-2, an MHC Enhancer Binding Protein, Induces Mild Chronic Inflammation in the Brain and Confers Molecular, Neuronal, and Behavioral Phenotypes Related to Schizophrenia

gamma-Secretase Mutations in Hidradenitis Suppurativa: New Insights into Disease Pathogenesis

Hidradenitis suppurativa (HS) ( also known as acne inversa) is a debilitating chronic inflammatory skin condition of unclear etiology. It may segregate as an autosomal dominant trait, and heterozygous mutations in the γ-secretase genes NCSTN,PSENEN, and PSEN1 have recently been reported in a small number of multiplex kindreds and sporadic cases. These mutations highlight γ-secretase (an enzyme that has been extensively investigated in familial Alzheimer’s disease) to have an integral role in cutaneous biology and, more specifically, in HS. In this article, we review the recent genetic data, how they inform disease pathogenesis, and the long-term implications in HS and related diseases.

NHS details of Hidradenitis suppurativa 

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Adalimumab May Improve Quality Of Life For Patients Suffering From Hidradenitis Suppurativa - A Serious Skin Disease (TNF inhibitor) 

Considering hidradenitis suppurativa as a bacterial biofilm disease.

Maternal autoantibodies are associated with abnormal brain enlargement in a subgroup of children with autism spectrum disorder.

Autism spectrum disorder (ASD) is very heterogeneous and multiple subtypes and etiologies likely exist. The maternal immune system has been implicated in the pathogenesis of some forms of ASD. Previous studies have identified the presence of specific maternal IgG autoantibodies with reactivity to fetal brain proteins at 37 and 73KDa in up to 12% of mothers of children with ASD. The current study evaluates the presence of these autoantibodies in an independent cohort of mothers of 181 preschool-aged male children (131 ASD, 50 typically developing [TD] controls). We also investigated whether ASD children born to mothers with these autism-specific maternal IgG autoantibodies exhibit a distinct neural phenotype by evaluating total brain volume using structural magnetic resonance imaging (MRI). Of the 131 ASD children, 10 (7.6%) were born to mothers with the 37/73Kda IgG autoantibodies (ASD-IgG). The mothers of the remaining ASD children and all TD controls were negative for these paired autoantibodies. While both ASD groups exhibited abnormal brain enlargement that is commonly observed in this age range, the ASD-IgG group exhibited a more extreme 12.1% abnormal brain enlargement relative to the TD controls. In contrast, the remaining ASD children exhibited a smaller 4.4% abnormal brain enlargement relative to TD controls. Lobar and tissue type analyses revealed that the frontal lobe is selectively enlarged in the ASD-IgG group and that both gray and white matter are similarly affected. These results suggest that maternal autoantibodies associated with autism spectrum disorder may impact brain development leading to abnormal enlargement.

Identification of a molecular profile associated with immune status in first onset schizophrenia patients.

Alterations in immunological parameters have been reported for schizophrenia although little is known about the effects of inflammatory status on immunerelated functional changes at disease onset. Here, we have investigated such T cell-dependent molecular changes in first onset antipsychotic naïve schizophrenia patients using a novel ex vivo blood culture system.METHODS: Blood samples from patients (n=17) and controls (n=17) were collected into stimulant-containing or null control TruCulturetubes, incubated 24 hours and the concentrations of 107 immune and metabolic molecules measured in the conditioned media using the HumanMAPimmunoassay system.RESULTS: Nine molecules showed altered release from schizophrenia blood cells compared to those from controls and this was replicated in an independent cohort. In silico pathway analysis showed that these molecules had roles in endothelial cell function, inflammation, acute phase response and fibrinolysis pathways. Importantly, 5 of these molecules showed altered release only after stimulation.CONCLUSIONS: This study has identified a reproducible peripheral molecular signature associated with altered immune function in first onset schizophrenia subjects. This suggests that immune status can affect the biomarker profile which could be important for personalized medicine strategies. Furthermore, whole blood culture analysis may be useful as in the identification diagnostic tools or novel treatment strategies due to ease of use and clinical accessibility.

Newly identified natural protein (cholesterol-25-hydroxylase) blocks HIV, other deadly viruses / UCLA Newsroom

In a study published in the January issue of the journal Immunity, the researchers describe the novel antiviral property of the protein, cholesterol-25-hydroxylase (CH25H), an enzyme that converts cholesterol to an oxysterol called 25-hydroxycholesterol (25HC), which can permeate a cell's wall and block a virus from getting in.

Genes for autism and schizophrenia only active in developing brains

"Genes linked to autism and schizophrenia are only switched on during the early stages of brain development, according to a study in mice led by researchers at the University of Oxford."

Plastics Derived Endocrine Disruptors (BPA, DEHP and DBP) Induce Epigenetic Transgenerational Inheritance of Obesity, Reproductive Disease and Sperm Epimutations.

Environmental compounds are known to promote epigenetic transgenerational inheritance of adult onset disease in subsequent generations (F1-F3) following ancestral exposure during fetal gonadal sex determination. The current study was designed to determine if a mixture of plastic derived endocrine disruptor compounds bisphenol-A (BPA), bis(2-ethylhexyl)phthalate (DEHP) and dibutyl phthalate (DBP) at two different doses promoted epigenetic transgenerational inheritance of adult onset disease and associated DNA methylation epimutations in sperm. Gestating F0 generation females were exposed to either the "plastics" or "lower dose plastics" mixture during embryonic days 8 to 14 of gonadal sex determination and the incidence of adult onset disease was evaluated in F1 and F3 generation rats. There were significant increases in the incidence of total disease/abnormalities in F1 and F3 generation male and female animals from plastics lineages. Pubertal abnormalities, testis disease, obesity, and ovarian disease (primary ovarian insufficiency and polycystic ovaries) were increased in the F3 generation animals. Kidney and prostate disease were only observed in the direct fetally exposed F1 generation plastic lineage animals. Analysis of the plastics lineage F3 generation sperm epigenome previously identified 197 differential DNA methylation regions (DMR) in gene promoters, termed epimutations. A number of these transgenerational DMR form a unique direct connection gene network and have previously been shown to correlate with the pathologies identified. Observations demonstrate that a mixture of plastic derived compounds, BPA and phthalates, can promote epigenetic transgenerational inheritance of adult onset disease. The sperm DMR provide potential epigenetic biomarkers for transgenerational disease and/or ancestral environmental exposures.

Bisphenol a inhibits voltage-activated Ca2+ channels in vitro: mechanisms and structural requirements.

Bisphenol A (BPA), a high volume production chemical compound attracts growing attention as a health-relevant xenobiotic in humans. It can directly bind to hormone receptors, enzymes, and ion channels to become biologically active. In this study we show that BPA acts as a potent blocker of voltage-activated Ca(2+) channels. We determined the mechanisms of block and the structural elements of BPA essential for its action. Macroscopic Ba(2+)/ Ca(2+) currents through native L-, N-, P/Q-, T-type Ca(2+) channels in rat endocrine GH(3) cells, mouse dorsal root ganglion neurons or cardiac myocytes, and recombinant human R-type Ca(2+) channels expressed in human embryonic kidney (HEK) 293 cells were rapidly and reversibly inhibited by BPA with similar potency (EC(50) values: 26-35 μM). Pharmacological and biophysical analysis of R-type Ca(2+) channels revealed that BPA interacts with the extracellular part of the channel protein. Its action does not require intracellular signaling pathways, is neither voltage- nor use-dependent, and does not affect channel gating. This indicates that BPA interacts with the channel in its resting state by directly binding to an external site outside the pore-forming region. Structure-effect analyses of various phenolic and bisphenolic compounds revealed that 1) a double-alkylated (R-C(CH(3))(2)-R, R-C(CH(3))(CH(2)CH(3))-R), or double-trifluoromethylated sp(3)-hybridized carbon atom between the two aromatic rings and 2) the two aromatic moieties in angulated orientation are optimal for BPA's effectiveness. Since BPA highly pollutes the environment and is incorporated into the human organism, our data may provide a basis for future studies relevant for human health and development.


Perhaps relevant to numerous channelopathies.

Growth Of Toxic Algae Caused By Nitrogen From Pollution, Natural Sources including domoic acid Harmful To Marine Life And Human Health

MNT: Commonly found in marine waters off the North American West Coast, diatoms (phytoplankton cells) of the Pseudo-nitzschia genus produce a potent toxin called domoic acid. When these phytoplankton grow rapidly into massive blooms, high concentrations of domoic acid put human health at risk if it accumulates in shellfish. It can also cause death and illness among marine mammals and seabirds that eat small fish that feed on plankton. 
Domoic acid activates AMPA and Kainate glutamatergic receptors.

Scientists Find A Key Element Of Lupus, Suggesting Better Drug Targets

MNT: Beutler's special mice lack a working gene for a protein called SLC15A4, and as a result of this mutation, the pDCs in these mice develop normally, but are largely unable to produce type I interferons in response to the usual stimuli. Such cells normally produce large amounts of interferons after detecting viral or bacterial genetic material. For this detection, they use a class of internal receptors called TLRs (toll-like receptors). Beutler received the 2011 Nobel Prize in Physiology or Medicine for his work on TLRs. His SLC15A4-mutant mice specifically lack the ability to respond to stimuli that would normally be detected by two of these receptors, TLR7 and TLR9. These same TLRs have been implicated in lupus - they apparently mistake self-nucleic acids for viral nucleic acids. 

Working with Beutler, the TSRI team applied the SLC15A4 mutation to a strain of lupus mice to see if it would protect them from autoimmunity. And it did. "The usual lupus-like signs significantly decreased, and survival was extended," said Baccala.