Cellular cholesterol facilitates the post-entry replication cycle of herpes simplex virus 1. - PubMed - NCBI

 Cholesterol is an essential component of cell membranes and is required for HSV-1 entry (1-3). Treatment of HSV-1-infected Vero cells with methyl beta-cyclodextrin from 2 - 9 hours post-entry reduced plaque numbers. Transport of incoming viral capsids to the nuclear periphery was unaffected by cholesterol reduction suggesting that cell cholesterol is important for the HSV-1 replicative cycle at a stage(s) beyond entry after the arrival of capsids at the nucleus. The synthesis and release of infectious HSV-1 and cell-to-cell spread of infection were all impaired in cholesterol-reduced cells. Propagation of HSV-1 on DHCR24-/- fibroblasts, which lack the desmosterol-to-cholesterol conversion enzyme, resulted in the generation of infectious, extracellular virions (HSVdes) that lack cholesterol and likely contain desmosterol. The specific infectivity (PFU per viral genome) of HSVchol and HSVdes were similar suggesting cholesterol or desmosterol in the HSV envelope support similar levels of infectivity. However, infected DHCR24-/- fibroblasts released ∼1 log less infectious HSVdes and ∼1.5 logs fewer particles compared to release of cholesterol-containing particles (HSVchol) from parental fibroblasts, suggesting that the hydrocarbon tail of cholesterol facilitates viral synthesis. Together, the results suggest multiple roles for cholesterol in the HSV-1 replicative cycle.Importance HSV-1 infections are associated with a wide range of clinical manifestations that are of public health importance. Cholesterol is a key player in the complex interaction between viral and cellular factors that allows HSV-1 to enter host cells and establish infection. Previous reports have demonstrated a role for cellular cholesterol in the entry of HSV-1 into target cells. Here, we employ both chemical treatment and cells that are genetically defined to synthesize only desmosterol to demonstrate that cholesterol is important at stages following the initial entry and transport of viral capsids to the nucleus. Viral protein expression, encapsidation of viral genome and the release of mature virions were impacted by the reduction of cellular cholesterol. Cholesterol was also critical for cell-to-cell spread of infection. These findings provide new insights into the cholesterol-dependence of HSV-1 replication.



'via Blog this'

Could Parkinson's disease start in the gut? -- ScienceDaily

 Parkinson's disease may start in the gut and spread to the brain via the vagus nerve, according to a study published in the April 26, 2017, online issue of Neurology®, the medical journal of the American Academy of Neurology. The vagus nerve extends from the brainstem to the abdomen and controls unconscious body processes like heart rate and food digestion.

Here's the paper:

Vagotomy and Parkinson disease


A Swedish register–based matched-cohort study




Fecal metagenomic profiles in subgroups of patients with myalgic encephalomyelitis/chronic fatigue syndrome | Microbiome

 "Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by unexplained persistent fatigue, commonly accompanied by cognitive dysfunction, sleeping disturbances, orthostatic intolerance, fever, lymphadenopathy, and irritable bowel syndrome (IBS). The extent to which the gastrointestinal microbiome and peripheral inflammation are associated with ME/CFS remains unclear. We pursued rigorous clinical characterization, fecal bacterial metagenomics, and plasma immune molecule analyses in 50 ME/CFS patients and 50 healthy controls frequency-matched for age, sex, race/ethnicity, geographic site, and season of sampling.

Results
Topological analysis revealed associations between IBS co-morbidity, body mass index, fecal bacterial composition, and bacterial metabolic pathways but not plasma immune molecules. IBS co-morbidity was the strongest driving factor in the separation of topological networks based on bacterial profiles and metabolic pathways. Predictive selection models based on bacterial profiles supported findings from topological analyses indicating that ME/CFS subgroups, defined by IBS status, could be distinguished from control subjects with high predictive accuracy. Bacterial taxa predictive of ME/CFS patients with IBS were distinct from taxa associated with ME/CFS patients without IBS. Increased abundance of unclassified Alistipes and decreased Faecalibacterium emerged as the top biomarkers of ME/CFS with IBS; while increased unclassified Bacteroides abundance and decreased Bacteroides vulgatus were the top biomarkers of ME/CFS without IBS. Despite findings of differences in bacterial taxa and metabolic pathways defining ME/CFS subgroups, decreased metabolic pathways associated with unsaturated fatty acid biosynthesis and increased atrazine degradation pathways were independent of IBS co-morbidity. Increased vitamin B6 biosynthesis/salvage and pyrimidine ribonucleoside degradation were the top metabolic pathways in ME/CFS without IBS as well as in the total ME/CFS cohort. In ME/CFS subgroups, symptom severity measures including pain, fatigue, and reduced motivation were correlated with the abundance of distinct bacterial taxa and metabolic pathways.

Conclusions
Independent of IBS, ME/CFS is associated with dysbiosis and distinct bacterial metabolic disturbances that may influence disease severity. However, our findings indicate that dysbiotic features that are uniquely ME/CFS-associated may be masked by disturbances arising from the high prevalence of IBS co-morbidity in ME/CFS. These insights may enable more accurate diagnosis and lead to insights that inform the development of specific therapeutic strategies in ME/CFS subgroups."



'via Blog this'

Sugary beverage intake and preclinical Alzheimer's disease in the community. - PubMed - NCBI

INTRODUCTION:

Excess sugar consumption has been linked with Alzheimer's disease (AD) pathology in animal models.

METHODS:

We examined the cross-sectional association of sugary beverage consumption with neuropsychological (N = 4276) and magnetic resonance imaging (N = 3846) markers of preclinical Alzheimer's disease and vascular brain injury (VBI) in the community-based Framingham Heart Study. Intake of sugary beverages was estimated using a food frequency questionnaire.

RESULTS:

Relative to consuming less than one sugary beverage per day, higher intake of sugary beverages was associated with lower total brain volume (1-2/day, β ± standard error [SE] = -0.55 ± 0.14 mean percent difference, P = .0002; >2/day, β ± SE = -0.68 ± 0.18, P < .0001), and poorer performance on tests of episodic memory (all P < .01). Daily fruit juice intake was associated with lower total brain volume, hippocampal volume, and poorer episodic memory (all P < .05). Sugary beverage intake was not associated with VBI in a consistent manner across outcomes.

DISCUSSION:

Higher intake of sugary beverages was associated cross-sectionally with markers of preclinical AD.

Sugar- and Artificially Sweetened Beverages and the Risks of Incident Stroke and Dementia | Stroke

"Background and Purpose—Sugar- and artificially-sweetened beverage intake have been linked to cardiometabolic risk factors, which increase the risk of cerebrovascular disease and dementia. We examined whether sugar- or artificially sweetened beverage consumption was associated with the prospective risks of incident stroke or dementia in the community-based Framingham Heart Study Offspring cohort.

 Methods—We studied 2888 participants aged >45 years for incident stroke (mean age 62 [SD, 9] years; 45% men) and 1484 participants aged >60 years for incident dementia (mean age 69 [SD, 6] years; 46% men). Beverage intake was quantified using a food-frequency questionnaire at cohort examinations 5 (1991–1995), 6 (1995–1998), and 7 (1998–2001). We quantified recent consumption at examination 7 and cumulative consumption by averaging across examinations. Surveillance for incident events commenced at examination 7 and continued for 10 years. We observed 97 cases of incident stroke (82 ischemic) and 81 cases of incident dementia (63 consistent with Alzheimer’s disease)



Results
—After adjustments for age, sex, education (for analysis of dementia), caloric intake, diet quality, physical activity, and smoking, higher recent and higher cumulative intake of artificially sweetened soft drinks were associated with an increased risk of ischemic stroke, all-cause dementia, and Alzheimer’s disease dementia. When comparing daily cumulative intake to 0 per week (reference), the hazard ratios were 2.96 (95% confidence interval, 1.26–6.97) for ischemic stroke and 2.89 (95% confidence interval, 1.18–7.07) for Alzheimer’s disease. Sugar-sweetened beverages were not associated with stroke or dementia.

 Conclusions—Artificially sweetened soft drink consumption was associated with a higher risk of stroke and dementia."



'via Blog this'

Stroke and dementia risk linked to artificial sweeteners, study suggests | Society | The Guardian

Consuming a can a day of low- or no-sugar soft drink is associated with a much higher risk of having a stroke or developing dementia, researchers claim.

Their findings have prompted renewed questions about whether drinks flavoured with artificial sweeteners can increase the risk of serious illness, as heavily sugared drinks have already been shown to do.

“Drinking at least one artificially sweetened beverage daily was associated with almost three times the risk of developing stroke or dementia compared to those who drank artificially sweetened beverages less than once a week,” according to the American researchers who carried out a study published in Stroke, the journal of the American Heart Association."


Here's the paper :-

Sugar- and Artificially Sweetened Beverages and the Risks of Incident Stroke and Dementia


'via Blog this'

Repurposed drugs targeting eIF2α-P-mediated translational repression prevent neurodegeneration in mice | Brain | Oxford Academic

 Signalling through the PERK/eIF2α-P branch of the unfolded protein response plays a critical role in controlling protein synthesis rates in cells. This pathway is overactivated in brains of patients with Alzheimer’s disease and related disorders and has recently emerged as a promising therapeutic target for these currently untreatable conditions. Thus, in mouse models of neurodegenerative disease, prolonged overactivation of PERK/eIF2α-P signalling causes sustained attenuation of protein synthesis, leading to memory impairment and neuronal loss. Re-establishing translation rates by inhibition of eIF2α-P activity, genetically or pharmacologically, restores memory and prevents neurodegeneration and extends survival. However, the experimental compounds used preclinically are unsuitable for use in humans, due to associated toxicity or poor pharmacokinetic properties. To discover compounds that have anti-eIF2α-P activity suitable for clinical use, we performed phenotypic screens on a NINDS small molecule library of 1040 drugs. We identified two compounds, trazodone hydrochloride and dibenzoylmethane, which reversed eIF2α-P-mediated translational attenuation in vitro and in vivo. Both drugs were markedly neuroprotective in two mouse models of neurodegeneration, using clinically relevant doses over a prolonged period of time, without systemic toxicity. Thus, in prion-diseased mice, both trazodone and dibenzoylmethane treatment restored memory deficits, abrogated development of neurological signs, prevented neurodegeneration and significantly prolonged survival. In tauopathy-frontotemporal dementia mice, both drugs were neuroprotective, rescued memory deficits and reduced hippocampal atrophy. Further, trazodone reduced p-tau burden. These compounds therefore represent potential new disease-modifying treatments for dementia. Trazodone in particular, a licensed drug, should now be tested in clinical trials in patients.



'via Blog this'

Reovirus infection triggers inflammatory responses to dietary antigens and development of celiac disease | Science

 Viral infections have been proposed to elicit pathological processes leading to the initiation of T helper 1 (TH1) immunity against dietary gluten and celiac disease (CeD). To test this hypothesis and gain insights into mechanisms underlying virus-induced loss of tolerance to dietary antigens, we developed a viral infection model that makes use of two reovirus strains that infect the intestine but differ in their immunopathological outcomes. Reovirus is an a virulent pathogen that elicits protective immunity, but we discovered that it can nonetheless disrupt intestinal immune homeostasis at inductive and effector sites of oral tolerance by suppressing peripheral regulatory T cell (pTreg) conversion and promoting TH1 immunity to dietary antigen. Initiation of TH1 immunity to dietary antigen was dependent on interferon regulatory factor 1 and dissociated from suppression of pTreg conversion, which was mediated by type-1 interferon. Last, our study in humans supports a role for infection with reovirus, a seemingly innocuous virus, in triggering the development of CeD."



'via Blog this'

Identification of Fungal Species in Brain Tissue from Alzheimer's Disease by Next-Generation Sequencing. - PubMed - NCBI

 The possibility that patients diagnosed with Alzheimer's disease (AD) have disseminated fungal infection has been recently advanced by the demonstration of fungal proteins and DNA in nervous tissue from AD patients. In the present study, next-generation sequencing (NGS) was used to identify fungal species present in the central nervous system (CNS) of AD patients. Initially, DNA was extracted from frozen tissue from four different CNS regions of one AD patient and the fungi in each region were identified by NGS. Notably, whereas a great variety of species were identified using the Illumina platform, Botrytis cinerea and Cryptococcus curvatus were common to all four CNS regions analyzed. Further analysis of entorhinal/cortex hippocampus samples from an additional eight AD patients revealed a variety of fungal species, although some were more prominent than others. Five genera were common to all nine patients: Alternaria, Botrytis, Candida, Cladosporium, and Malassezia. These observations could be used to guide targeted antifungal therapy for AD patients. Moreover, the differences found between the fungal species in each patient may constitute a basis to understand the evolution and severity of clinical symptoms in AD.



'via Blog this'

Low-calorie sweeteners promote fat accumulation in human fat

 "Low-calorie, artificial sweeteners appear to play havoc with the body's metabolism, and large consumption of these sugar substitutes could promote fat accumulation, especially in people who are already obese, preliminary research suggests. The study results will be presented Monday at ENDO 2017, the Endocrine Society's 99th annual meeting in Orlando, Fla."



 Sen and his colleagues tested sucralose, a popular low-calorie , on stem cells—cells that could change into mature fat, muscle, cartilage or bone cells—taken from human fat tissue. They placed these cells in Petri dishes for 12 days in media that promotes . At a 0.2-millimolar sucralose dose similar to the concentration found in the blood of people with high consumption of low-calorie sweeteners—equal to four cans of diet soda per day—the researchers said they observed increased expression of genes that are markers of fat production and inflammation. There also was increased accumulation of  in cells, particularly at a larger dose (1 millimolar), Sen reported.


Infections more common in people with schizophrenia

The researchers adjusted the data for other factors that might affect a person's risk of infection. They still found that people with schizophrenia had about twice the risk of skin, urological or genital infections, or tuberculosis than those in the general population.
The investigators also found that addiction and having other health problems were the most important factors associated with severe infection. Each one increased the risk of serious  by 2.7 times in both  with schizophrenia and those in the general .

Altering the immune system to reverse paralysis

 "In the ultimate betrayal, one's own immune system can turn against the protective sheath that envelops neurons in the brain, leaving the body paralyzed. Researchers have developed an experimental treatment that tames the wayward immune system in rodents, returning the power of movement to paralyzed mice. The approach may someday combat autoimmune diseases, such as multiple sclerosis and type 1 diabetes, in humans."

Exposure to BPA substitute, BPS, multiplies breast cancer cells


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.



'via Blog this'

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



'via Blog this'

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."



'via Blog this'

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.



'via Blog this'

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