The blood DNA virome in 8,000 humans

 The characterization of the blood virome is important for the safety of blood-derived transfusion products, and for the identification of emerging pathogens. We explored non-human sequence data from whole-genome sequencing of blood from 8,240 individuals, none of whom were ascertained for any infectious disease. Viral sequences were extracted from the pool of sequence reads that did not map to the human reference genome. Analyses sifted through close to 1 Petabyte of sequence data and performed 0.5 trillion similarity searches. With a lower bound for identification of 2 viral genomes/100,000 cells, we mapped sequences to 94 different viruses, including sequences from 19 human DNA viruses, proviruses and RNA viruses (herpesviruses, anelloviruses, papillomaviruses, three polyomaviruses, adenovirus, HIV, HTLV, hepatitis B, hepatitis C, parvovirus B19, and influenza virus) in 42% of the study participants. Of possible relevance to transfusion medicine, we identified Merkel cell polyomavirus in 49 individuals, papillomavirus in blood of 13 individuals, parvovirus B19 in 6 individuals, and the presence of herpesvirus 8 in 3 individuals. The presence of DNA sequences from two RNA viruses was unexpected: Hepatitis C virus is revealing of an integration event, while the influenza virus sequence resulted from immunization with a DNA vaccine. Age, sex and ancestry contributed significantly to the prevalence of infection. The remaining 75 viruses mostly reflect extensive contamination of commercial reagents and from the environment. These technical problems represent a major challenge for the identification of novel human pathogens. Increasing availability of human whole-genome sequences will contribute substantial amounts of data on the composition of the normal and pathogenic human blood virome. Distinguishing contaminants from real human viruses is challenging.



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Are the Infectious Roots of Alzheimer’s Buried Deep in the Past?

Recent literature shows a controversial new push to tie microorganisms to
Alzheimer’s disease (AD). Study after study, in which scientists have injected human
Alzheimer-diseased brain tissue into mice and other laboratory animals that later
developed the disease have left little doubt that Alzheimer’s disease (AD) arises
from an infectious process. By 2013 Mawanda and Wallace’s “Can Infections Cause
Alzheimer’s Disease” struck down some of the commonly entertained pathogens
for AD such as herpes simplex virus type 1, Chlamydia pneumoniae, and several
types of spirochetes. Instead they pointed to two prime suspects for Alzheimer’s
amyloid-beta deposition: “especially chronic infections like tuberculosis and
leprosy.” To be sure, it was German neuropathologist Oskar Fischer of the Prague
school of Neuropathology, Alzheimer’s great rival, who was the first to suggest that
infection might be causative for Alzheimer’s. Fischer’s credentials: he was the codiscoverer
of Alzheimer’s disease. His suspected germ was the Streptothrix, today
classified as Actinomycetes, a rare central nervous system pathogen which at the
time was so constantly and consistently mistaken for tuberculosis that ChoppenJones
suggested that TB be called tuberculomycosis. And Just ten years before
Oskar Fischer found Actinomycosis-like forms in Alzheimer’s cerebral plaque,
Babèş and immunologist Levaditi reported in “On the Actinomycotic Shape of the
Tuberculous Bacilli” that Fischer’s typical Actinomyces-like clusters (Drüsen) with
clubs appeared in the tissue of rabbits inoculated with tubercle bacilli beneath
the dura mater of their brains. Investigators who supported a



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Effects of bumetanide on neurobehavioral function in children and adolescents with autism spectrum disorders

 In animal models of autism spectrum disorder (ASD), the NKCC1 chloride-importer inhibitor bumetanide restores physiological (Cl−)i levels, enhances GABAergic inhibition and attenuates electrical and behavioral symptoms of ASD. In an earlier phase 2 trial; bumetanide reduced the severity of ASD in children and adolescents (3–11 years old). Here we report the results of a multicenter phase 2B study primarily to assess dose/response and safety effects of bumetanide. Efficacy outcome measures included the Childhood Autism Rating Scale (CARS), the Social Responsive Scale (SRS) and the Clinical Global Impressions (CGI) Improvement scale (CGI-I). Eighty-eight patients with ASD spanning across the entire pediatric population (2–18 years old) were subdivided in four age groups and randomized to receive bumetanide (0.5, 1.0 or 2.0 mg twice daily) or placebo for 3 months. The mean CARS value was significantly improved in the completers group (P: 0.015). Also, 23 treated children had more than a six-point improvement in the CARS compared with only one placebo-treated individual. Bumetanide significantly improved CGI (P: 0.0043) and the SRS score by more than 10 points (P: 0.02). The most frequent adverse events were hypokalemia, increased urine elimination, loss of appetite, dehydration and asthenia. Hypokalemia occurred mainly at the beginning of the treatment at 1.0 and 2.0 mg twice-daily doses and improved gradually with oral potassium supplements. The frequency and incidence of adverse event were directly correlated with the dose of bumetanide. Therefore, bumetanide improves the core symptoms of ASD and presents a favorable benefit/risk ratio particularly at 1.0 mg twice daily."



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Molecular Psychiatry - Maternal immune activation dysregulation of the fetal brain transcriptome and relevance to the pathophysiology of autism spectrum disorder

 Maternal immune activation (MIA) via infection during pregnancy is known to increase risk for autism spectrum disorder (ASD). However, it is unclear how MIA disrupts fetal brain gene expression in ways that may explain this increased risk. Here we examine how MIA dysregulates rat fetal brain gene expression (at a time point analogous to the end of the first trimester of human gestation) in ways relevant to ASD-associated pathophysiology. MIA downregulates expression of ASD-associated genes, with the largest enrichments in genes known to harbor rare highly penetrant mutations. MIA also downregulates expression of many genes also known to be persistently downregulated in the ASD cortex later in life and which are canonically known for roles in affecting prenatally late developmental processes at the synapse. Transcriptional and translational programs that are downstream targets of highly ASD-penetrant FMR1 and CHD8 genes are also heavily affected by MIA. MIA strongly upregulates expression of a large number of genes involved in translation initiation, cell cycle, DNA damage and proteolysis processes that affect multiple key neural developmental functions. Upregulation of translation initiation is common to and preserved in gene network structure with the ASD cortical transcriptome throughout life and has downstream impact on cell cycle processes. The cap-dependent translation initiation gene, EIF4E, is one of the most MIA-dysregulated of all ASD-associated genes and targeted network analyses demonstrate prominent MIA-induced transcriptional dysregulation of mTOR and EIF4E-dependent signaling. This dysregulation of translation initiation via alteration of the Tsc2–mTor–Eif4e axis was further validated across MIA rodent models. MIA may confer increased risk for ASD by dysregulating key aspects of fetal brain gene expression that are highly relevant to pathophysiology affecting ASD.



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DNA replication is the target for the antibacterial effects of nonsteroidal anti-inflammatory drugs.

 Evidence suggests that some nonsteroidal anti-inflammatory drugs (NSAIDs) possess antibacterial properties with an unknown mechanism. We describe the in vitro antibacterial properties of the NSAIDs carprofen, bromfenac, and vedaprofen, and show that these NSAIDs inhibit the Escherichia coli DNA polymerase III β subunit, an essential interaction hub that acts as a mobile tether on DNA for many essential partner proteins in DNA replication and repair. Crystal structures show that the three NSAIDs bind to the sliding clamp at a common binding site required for partner binding. Inhibition of interaction of the clamp loader and/or the replicative polymerase α subunit with the sliding clamp is demonstrated using an in vitro DNA replication assay. NSAIDs thus present promising lead scaffolds for novel antibacterial agents targeting the sliding clamp.




World's largest autism genome database shines new light on many 'autisms'

Through its research platform on the Google Cloud, Autism Speaks is making all of MSSNG's fully sequenced genomes directly available to researchers free of charge, along with analytic tools. In the coming weeks, the MSSNG team will be uploading an additional 2,000 fully sequenced autism genomes, bringing the total over 7,000.
Currently, more than 90 investigators at 40 academic and medical institutions are using the MSSNG database to advance autism research around the world."



Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder, Nature Neuroscience (2017). DOI: 10.1038/nn.4524 

Fluorene-9-bisphenol is anti-oestrogenic and may cause adverse pregnancy outcomes in mice : Nature Communications

 Bisphenol A (BPA) is used in the production of plastic but has oestrogenic activity. Therefore, BPA substitutes, such as fluorene-9-bisphenol (BHPF), have been introduced for the production of so-called ‘BPA-free’ plastics. Here we show that BHPF is released from commercial ‘BPA-free’ plastic bottles into drinking water and has anti-oestrogenic effects in mice. We demonstrate that BHPF has anti-oestrogenic activity in vitro and, in an uterotrophic assay in mice, induces low uterine weight, atrophic endometria and causes adverse pregnancy outcomes, even at doses lower than those of BPA for which no observed adverse effect have been reported. Female mice given water containing BHPF released from plastic bottles, have detectable levels of BHPF in serum, low uterine weights and show decreased expressions of oestrogen-responsive genes. We also detect BHPF in the plasma of 7/100 individuals, who regularly drink water from plastic bottles. Our data suggest that BPA substitutes should be tested for anti-oestrogenic activity and call for further study of the toxicological effects of BHPF on human health."



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Parkinson's disease and Parkinson's disease medications have distinct signatures of the gut microbiome - Hill-Burns - 2017 - Movement Disorders - Wiley Online Library

Background

There is mounting evidence for a connection between the gut and Parkinson's disease (PD). Dysbiosis of gut microbiota could explain several features of PD.

Objective

The objective of this study was to determine if PD involves dysbiosis of gut microbiome, disentangle effects of confounders, and identify candidate taxa and functional pathways to guide research.
Methods 


A total of 197 PD cases and 130 controls were studied. Microbial composition was determined by 16S rRNA gene sequencing of DNA extracted from stool. Metadata were collected on 39 potential confounders including medications, diet, gastrointestinal symptoms, and demographics. Statistical analyses were conducted while controlling for potential confounders and correcting for multiple testing. We tested differences in the overall microbial composition, taxa abundance, and functional pathways.

Results

Independent microbial signatures were detected for PD (P = 4E-5), participants' region of residence within the United States (P = 3E-3), age (P = 0.03), sex (P = 1E-3), and dietary fruits/vegetables (P = 0.01). Among patients, independent signals were detected for catechol-O-methyltransferase-inhibitors (P = 4E-4), anticholinergics (P = 5E-3), and possibly carbidopa/levodopa (P = 0.05). We found significantly altered abundances of the Bifidobacteriaceae, Christensenellaceae, [Tissierellaceae], Lachnospiraceae, Lactobacillaceae, Pasteurellaceae, and Verrucomicrobiaceae families. Functional predictions revealed changes in numerous pathways, including the metabolism of plant-derived compounds and xenobiotics degradation.

Conclusion

 PD is accompanied by dysbiosis of gut microbiome. Results coalesce divergent findings of prior studies, reveal altered abundance of several taxa, nominate functional pathways, and demonstrate independent effects of PD medications on the microbiome. The findings provide new leads and testable hypotheses on the pathophysiology and treatment of PD. "



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What is wrong with Alzheimer’s disease clinical research? | Journal of Alzheimer's Disease

...............................what happens when causal reasoning is abandoned in repetitive clinical trials testing the effectiveness of an intervention that consistently yields negative results? This has been the invariable fate of anti-amyloid-β (Aβ) drugs. These drugs were designed to eliminate excessive Aβ deposition in the brain of those afflicted with AD. The drug treatment rationale was based on the Aβ hypothesis, also known as the amyloid cascade hypothesis. This concept has been the prevailing but unproven paradigm in explaining AD causality for the last 20 years. Oddly, there have been more than 100 drugs tested in dozens of clinical trials and not one anti-Aβ drug has succeeded in slowing down AD destructive pathology or prevent declining cognition [2].

"The multiple difficulties festering the Aβ hypothesis have been described in countless medical and scientific articles [3]. One lethal blow to the Aβ hypothesis are the numerous clinicopathological studies revealing that heavy brain amyloid deposition does not equate with dementia [3]. Most of the criticisms leveled at the Aβ hypothesis have been largely ignored by big pharma, its supporters, peer reviewers, and granting bodies as if no real challenge could lessen the power of this enduring paradigm. The best that can be said (to paraphrase big pharma executives) is that anti-Aβ therapy display ‘tolerability and safety’ when given to AD patients. But… so does chicken soup.


How do any of these help stop the meltdown of AD?

Let’s play devil’s advocate for the sake of balance. What is wrong with pursuing a failed hypothesis? In the case of Aβ, it has provided jobs and resources for researchers who might not otherwise have had the financial capital to keep their labs open; moreover, such monies from big pharma to investigators could even uncover collateral information that could help clarify the process of neurodegeneration. On the other hand, ethical behavior may have been misplaced in this difficult time of financial hardship that threatens research survival.

However, it is unacceptable, in my judgment, when medical researchers (for whatever reasons) steadfastly hold onto a hypothesis that does not help sick patients in any manner despite being paid to do it. Rationalizing such behavior blocks medical progress resulting in dire consequences for the patients’ clinical outlook. Equally disturbing is the callous effect such conduct has on devaluing the scientific spirit and the search for truth."



by Jack de la Torre, MD, PhD 



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The never-ending story: Chemicals that outlive—and harm—us

 "The researchers from Sweden, Switzerland, and the United States call for regulation of the entire class of highly fluorinated chemicals ( polyfluoroalkyl substances ). Exposure to the most well-studied of these substances has been linked to kidney and testicular cancer, elevated cholesterol, decreased fertility, thyroid problems and changes in hormone functioning in adults as well as adverse developmental effects and decreased immune response in children.
This class of chemicals does not break down—ever—and can remain in the environment for thousands of years. "I am concerned that researchers and regulators are continuing to focus on a few phased-out chemicals rather than the thousands of related substances in use today," said Dr. Ian Cousins, co-author of the paper and Professor at Stockholm University. "Unless we broaden our focus, future generations will be increasingly exposed via contaminated water, air, and food.""



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Autism risk linked to herpes infection during pregnancy

Women actively infected with genital herpes ( HSV-2) during early pregnancy had twice the odds of giving birth to a child later diagnosed with autism spectrum disorder (ASD), according to a study by scientists at the Center for Infection and Immunity at Columbia University's Mailman School of Public Health and the Norwegian Institute of Public Health."



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Detection of Clostridium perfringens toxin genes in the gut microbiota of autistic children. - PubMed - NCBI

We studied stool specimens from 33 autistic children aged 2-9 years with gastrointestinal (GI) abnormalities and 13 control children without autism and without GI symptoms. We performed quantitative comparison of all Clostridium species and Clostridium perfringens strains from the fecal microbiota by conventional, selective anaerobic culture methods. We isolated C. perfringens strains and performed PCR analysis for the main C. perfringens toxin genes, alpha, beta, beta2, epsilon, iota and C. perfringens enterotoxin gene. Our results indicate that autistic subjects with gastrointestinal disease harbor statistically significantly (p = 0.031) higher counts of C. perfringens in their gut compared to control children. Autistic subjects also harbor statistically significantly (p = 0.015) higher counts of beta2-toxin gene-producing C. perfringens in their gut compared to control children, and the incidence of beta2-toxin gene-producing C. perfringens is significantly higher in autistic subjects compared to control children (p = 0.014). Alpha toxin gene was detected in all C. perfringens strains studied. C. perfringens enterotoxin gene was detected from three autistic and one control subject. Beta, epsilon, and iota toxin genes were not detected from autistic or control subjects."



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Food additive found in candy, gum could alter digestive cell structure and function: Small intestinal cells hindered by chronic exposure to common food additive -- ScienceDaily

"The ability of small intestine cells to absorb nutrients and act as a barrier to pathogens is 'significantly decreased' after chronic exposure to nanoparticles of titanium dioxide, a common food additive found in everything from chewing gum to bread, according to new research."



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Neurotoxic reactive astrocytes are induced by activated microglia :

"Reactive astrocytes are strongly induced by central nervous system (CNS) injury and disease, but their role is poorly understood. Here we show that a subtype of reactive astrocytes, which we termed A1, is induced by classically activated neuroinflammatory microglia. We show that activated microglia induce A1 astrocytes by secreting Il-1α, TNF and C1q, and that these cytokines together are necessary and sufficient to induce A1 astrocytes. A1 astrocytes lose the ability to promote neuronal survival, outgrowth, synaptogenesis and phagocytosis, and induce the death of neurons and oligodendrocytes. Death of axotomized CNS neurons in vivo is prevented when the formation of A1 astrocytes is blocked. Finally, we show that A1 astrocytes are abundant in various human neurodegenerative diseases including Alzheimer’s, Huntington’s and Parkinson’s disease, amyotrophic lateral sclerosis and multiple sclerosis. Taken together these findings help to explain why CNS neurons die after axotomy, strongly suggest that A1 astrocytes contribute to the death of neurons and oligodendrocytes in neurodegenerative disorders, and provide opportunities for the development of new treatments for these diseases."



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Vitamin B3 modulates mitochondrial vulnerability and prevents glaucoma in aged mice | Science

"Glaucoma is the most common cause of age-related blindness in the United States. There is currently no cure, and once vision is lost, the condition is irreversible. Williams et al. now report that vitamin B3 (also known as niacin) prevents eye degeneration in glaucoma-prone mice (see the Perspective by Crowston and Trounce). Supplementing the diets of young mice with vitamin B3 averted early signs of glaucoma. Vitamin B3 also halted further glaucoma development in aged mice that already showed signs of the disease. Thus, healthy intake of vitamin B3 may protect eyesight."



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In vitro protective efficacy of Lithium chloride against Mycoplasma hyopneumoniae infection. - PubMed - NCBI

 Mycoplasma hyopneumoniae (M. hyopneumoniae) infection affects the swine industry. Lithium chloride (LiCl), is a drug used to treat bipolar disorder and has also shown activity against bacterial and viral infections. Herein, we evaluated the antibacterial activity of LiCl on PK-15 cells infected with M. hyopneumoniae. Incubation of LiCl (40mM) with cells for 24h, did not significantly affect the cell viability. The qRT-PCR showed ~80% reduction in M. hyopneumoniae genome when LiCl added post-infection. A direct effect of LiCl on bacteria was also observed. However, treatment of cells with LiCl prior infection, does not protect against the infection. Anti-bacterial activity of LiCl was further confirmed by IFA, which demonstrated a reduction in the bacterial protein. With 40mM LiCI, the apoptotic cell death, production of nitric oxide and superoxide anion induced by M. hyopneumoniae, were prevented by ~80%, 60% and 58% respectively. Moreover, caspase-3 activity was also reduced (82%) in cells treated with 40mM LiCl. LiCl showed activity against various strains of M. hyopneumoniae examined in our study. Collectively, our data showed that LiCl inhibited the infection of M. hyopneumoniae through anti-apoptotic mechanism.

Reduction of Abeta amyloid pathology in APPPS1 transgenic mice in the absence of gut microbiota : Scientific Reports

Alzheimer’s disease is the most common form of dementia in the western world, however there is no cure available for this devastating neurodegenerative disorder. Despite clinical and experimental evidence implicating the intestinal microbiota in a number of brain disorders, its impact on Alzheimer’s disease is not known. To this end we sequenced bacterial 16S rRNA from fecal samples of Aβ precursor protein (APP) transgenic mouse model and found a remarkable shift in the gut microbiota as compared to non-transgenic wild-type mice. Subsequently we generated germ-free APP transgenic mice and found a drastic reduction of cerebral Aβ amyloid pathology when compared to control mice with intestinal microbiota. Importantly, colonization of germ-free APP transgenic mice with microbiota from conventionally-raised APP transgenic mice increased cerebral Aβ pathology, while colonization with microbiota from wild-type mice was less effective in increasing cerebral Aβ levels. Our results indicate a microbial involvement in the development of Abeta amyloid pathology, and suggest that microbiota may contribute to the development of neurodegenerative diseases."



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Inhibitory effects of bee venom and its components against viruses in vitro and in vivo. - PubMed - NCBI

 Bee venom (BV) from honey bee (Apis Melifera L.) contains at least 18 pharmacologically active components including melittin (MLT), phospholipase A2 (PLA2), and apamin etc. BV is safe for human treatments dose dependently and proven to possess different healing properties including antibacterial and antiparasitidal properties. Nevertheless, antiviral properties of BV have not well investigated. Hence, we identified the potential antiviral properties of BV and its component against a broad panel of viruses. Co-incubation of non-cytotoxic amounts of BV and MLT, the main component of BV, significantly inhibited the replication of enveloped viruses such as Influenza A virus (PR8), Vesicular Stomatitis Virus (VSV), Respiratory Syncytial Virus (RSV), and Herpes Simplex Virus (HSV). Additionally, BV and MLT also inhibited the replication of non-enveloped viruses such as Enterovirus-71 (EV-71) and Coxsackie Virus (H3). Such antiviral properties were mainly explained by virucidal mechanism. Moreover, MLT protected mice which were challenged with lethal doses of pathogenic influenza A H1N1 viruses. Therefore, these results provides the evidence that BV and MLT could be a potential source as a promising antiviral agent, especially to develop as a broad spectrum antiviral agent.



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Prenatal bisphenol A exposure weakens body's fullness cues

The new study found mice born to mothers exposed to bisphenol A were less responsive to the hormone leptin, which is sometimes called the satiety hormone. Leptin helps inhibit the appetite by reducing hunger pangs when the body does not need energy. The hormone sends signals to the hypothalamus region of the brain to suppress the appetite.
"Our findings show that bisphenol A can promote obesity in mice by altering the hypothalamic circuits in the brain that regulate feeding behavior and energy balance," said the study's senior author, Alfonso Abizaid, Ph.D., of the Department of Neuroscience at Carleton University in Ottawa, Canada. "Low level prenatal exposure to BPA delays a surge of leptin after birth that allows mice to develop the proper response to the hormone. BPA exposure permanently alters the neurobiology in the affected mice, making them prone to obesity as adults.



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Does eating liquorice in pregnancy raise the risk of ADHD? - Health News - NHS Choices

Researchers found eating liquorice in pregnancy is linked to a range of developmental issues.
The news is based on Finnish research on almost 400 young adolescents with an average age of 12.5.
Liquorice consumption is thought to be higher in Finland than in the UK thanks to the popularity of salmiakki, a popular salty liquorice snack.
Researchers found girls whose mothers had consumed high amounts of liquorice during pregnancy were more likely to go through puberty at a younger age.
And girls and boys whose mothers consumed high amounts scored seven points lower on intelligence tests, and higher for attention deficit hyperactivity disorder (ADHD).
The component in liquorice thought to cause damage is called glycyrrhizin.