Yin-Yang 1 regulation of Epstein-Barr virus BRLF1 transcription is altered during mTORC1 inhibition in a cell type-specific manner

Epstein-Barr virus (EBV) is a ubiquitous herpesvirus that infects individuals worldwide. EBV actively replicates and establishes a latent infection in epithelial cells and B cells, which can lead to diseases such as infectious mononucleosis and Burkitt’s lymphoma. The reactivation of EBV from latency is contingent upon the expression of immediate-early genes BZLF1 and BRLF1. During EBV latency, BZLF1 and BRLF1 are negatively regulated by Yin-Yang 1 (YY1). YY1 is a highly expressed protein that participates in various cellular and viral processes. It has been demonstrated that the effects of rapamycin, a mechanistic target of rapamycin complex 1 (mTORC1) inhibitor, on YY1 in epithelial cells and B cells alters EBV lytic replication. Rapamycin’s effects on YY1 cause it to positively regulate BZLF1 in epithelial cells and negatively regulate BZLF1 in B cells. While the effects of rapamycin on YY1 regulation of BZLF1 have been studied, the effects on BRLF1 have not. For this study, I investigated the effects of rapamycin on YY1 regulation of BRLF1 in epithelial cells and B cells during lytic replication. I wanted to determine if the effects of rapamycin on YY1 regulation of BRLF1 would be like the effects of rapamycin on YY1 regulation of BZLF1. The results of this study show that they are indeed similar. YY1 positively regulates BRLF1 in epithelial cells and negatively regulates BRLF1 in B cells during mTORC1 inhibition and lytic replication. This suggests that rapamycin alters YY1 transcriptional regulation of BRLF1 in a cell type-specific manner. Using rapamycin in combination with YY1-targeted therapies could reduce EBV infectivity and decrease the likelihood of developing EBV-associated diseases

Clinical and morphological characteristics of head-facial haemangiomas

BACKGROUND: Haemangiomas of the head or face are a frequent vascular pathology, consisting in an embryonic dysplasia that involves the cranial-facial vascular network. Haemangiomas show clinical, morphological, developmental and structural changes during their course. METHODS: The clinical characteristics of head-facial haemagiomas were studied in 28 individuals (9 males and 19 females) admitted in our Hospital. Sixteen of these patients(n = 16) underwent surgery for the removal of the haemangiomas. All the removed tissues were transferred in experimental laboratories for the staining of microanatomical details, somatic and visceral nerve fibres, adrenergic and catecholaminergic nerve fibres. Beta-adrenergic receptors were died with a fluorescent method. All results were submitted to the quantitative analysis of images and statistical evaluation of the data. RESULTS: The morphological results revealed numerous micro-anatomical characteristics of the haemangiomatous vessels. The somatic and visceral nerve fibres were poor and located exclusively in the adventitial layer. There was a marked decrease of adrenergic nerve fibres in the haemangiomatous vessels. The fluorescence of catecholaminergic nerve fibres and the overall area of fluorescent structures were also decreased in haemangiomatous vessels. Beta adrenergic receptors are strongly decreased in haemangiomatous vessels. The morphometrical analysis of images and statistical evaluation of the data confirmed all our experimental results. CONCLUSION: The catecholaminergic innervation of the human haemangiomatous vessels comprises nerve fibres containing the main catecholaminergic neurotransmitters that are sympathetic in nature. These neurotransmitters are closely related to beta-adrenergic receptors. The sympathetic nervous system plays a key role in the control of the vascular bed flow and vascular motility in both normal and haemangiomatous vessels

Efficacy of essential oil mouthwash with and without alcohol: a 3-Day plaque accumulation model

<p>Abstract</p> <p>Background</p> <p>The aim of this study was to evaluate the antiplaque effect of a new alcohol free essential oil mouthwash with respect to a control of an essential oil with alcohol mouthwash, using an <it>in vivo </it>plaque regrowth model of 3-days.</p> <p>Methods</p> <p>The study was designed as a double-masked, randomized, crossover clinical trial, involving 30 volunteers to compare two different essential oil containing mouthwashes, during a 3-day plaque accumulation model. After receiving a thorough professional prophylaxis at the baseline, over the next 3-days each volunteer refrained from all oral hygiene measures and had two daily rinses with 20 ml of the test mouthwash (alcohol free essential oil) or the control mouthwash (essential oil with alcohol). At the end of the each experimental period, plaque was assessed and the panelists filled out a questionnaire. Each subject underwent a 14 days washout period and there was a second allocation.</p> <p>Results</p> <p>The essential oil mouthwash with ethanol shows a better inhibitory effect of plaque regrowth in 3-days than the mouthwash test with only essential oil in the whole mouth (plaque index = 2.18 against 2.46, respectively, p < 0.05); for the lower jaw (plaque index = 2.28 against 2.57, respectively, p < 0.05); for the upper jaw (plaque index = 2.08 against 2.35, respectively, p < 0.05); for the incisors (plaque index = 1.93 against 2.27, respectively, p < 0.05); and the canines (plaque index = 1.99 against 2.47, respectively, p < 0.05).</p> <p>Conclusion</p> <p>The essential oil containing mouthwash without alcohol seems to have a less inhibiting effect on the plaque regrowth than the traditional alcoholic solution.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov <a href="http://www.clinicaltrials.gov/ct2/show/NCT01411618">NCT01411618</a></p

Vitamin C in plasma is inversely related to blood pressure and change in blood pressure during the previous year in young Black and White women

BackgroundThe prevalence of hypertension and its contribution to cardiovascular disease risk makes it imperative to identify factors that may help prevent this disorder. Extensive biological and biochemical data suggest that plasma ascorbic acid may be such a factor. In this study we examined the association between plasma ascorbic acid concentration and blood pressure (BP) in young-adult women.MethodsParticipants were 242 Black and White women aged 18-21 yr from the Richmond, CA, cohort of the National Heart, Lung and Blood Institute Growth and Health Study. We examined the associations of plasma ascorbic acid with BP at follow-up year 10, and with change in BP during the previous year.ResultsIn cross-sectional analysis, plasma ascorbic acid at year 10 was inversely associated with systolic BP and diastolic BP after adjusting for race, body mass index, education, and dietary intake of fat and sodium. Persons in the highest one-fourth of the plasma ascorbic acid distribution had 4.66 mmHg lower systolic BP (95% CI 1.10 to 8.22 mmHg, p = 0.005) and 6.04 mmHg lower diastolic BP (95% CI 2.70 to 9.38 mmHg, p = 0.0002) than those in the lowest one-fourth of the distribution. In analysis of the change in BP, plasma ascorbic acid was also inversely associated with change in systolic BP and diastolic BP during the previous year. While diastolic blood pressure among persons in the lowest quartile of plasma ascorbic acid increased by 5.97 mmHg (95% CI 3.82 to 8.13 mmHg) from year 9 to year 10, those in the highest quartile of plasma vitamin C increased by only 0.23 mmHg (95% CI -1.90 to +2.36 mmHg) (test for linear trend: p &lt; 0.0001). A similar effect was seen for change in systolic BP, p = 0.005.ConclusionPlasma ascorbic acid was found to be inversely associated with BP and change in BP during the prior year. The findings suggest the possibility that vitamin C may influence BP in healthy young adults. Since lower BP in young adulthood may lead to lower BP and decreased incidence of age-associated vascular events in older adults, further investigation of treatment effects of vitamin C on BP regulation in young adults is warranted

A Normalization Model of Attentional Modulation of Single Unit Responses

Although many studies have shown that attention to a stimulus can enhance the responses of individual cortical sensory neurons, little is known about how attention accomplishes this change in response. Here, we propose that attention-based changes in neuronal responses depend on the same response normalization mechanism that adjusts sensory responses whenever multiple stimuli are present. We have implemented a model of attention that assumes that attention works only through this normalization mechanism, and show that it can replicate key effects of attention. The model successfully explains how attention changes the gain of responses to individual stimuli and also why modulation by attention is more robust and not a simple gain change when multiple stimuli are present inside a neuron's receptive field. Additionally, the model accounts well for physiological data that measure separately attentional modulation and sensory normalization of the responses of individual neurons in area MT in visual cortex. The proposal that attention works through a normalization mechanism sheds new light a broad range of observations on how attention alters the representation of sensory information in cerebral cortex

Computerised cognitive behavioural therapy for the treatment of depression in people with multiple sclerosis: external pilot trial

<p>Abstract</p> <p>Background</p> <p>People with multiple sclerosis (MS) are at high risk of depression. We undertook a pilot trial of computerised cognitive behavioural therapy (CCBT) for the treatment of depression in people with MS to test the feasibility of undertaking a full trial.</p> <p>Methods</p> <p>Participants with a diagnosis of MS and clinical levels of depression were recruited through out-patient clinics and postal screening questionnaires at two UK centres and randomised to CCBT or usual care. Clinical outcomes included the Beck Depression Inventory (BDI-II) and Multiple Sclerosis Impact Scale (MSIS-29) at baseline, 8 and 21 weeks. Feasibility outcomes included: recruitment rate; reasons for refusal, withdrawal and dropout; feasibility and acceptability of the proposed outcome measures; sample size estimation and variation in and preferences for service delivery.</p> <p>Results</p> <p>Twenty-four participants were recruited. The recruitment rate, calculated as the proportion of those invited to fill in a screening questionnaire who were consented into the trial, was 4.1%. Recruitment through out-patient clinics was somewhat slower than through screening questionnaire mail-out but the overall recruitment yield was similar. Of the 12 patients in the CCBT arm, 9 (75%) completed at least four, and 6 completed all 8 CCBT sessions. For completers, the median time (IQR) to complete all eight CCBT sessions was 15 (13 to 20) weeks. Participants expressed concern about the face validity of the Beck Depression Inventory II for the measurement of self-reported depression in people with MS. The MSIS-29 was the patient-reported outcome measure which participants felt best reflected their concerns. The estimated sample size for a full trial is between 180 and 390 participants. NHS partners were not delivering CCBT in community facilities and participants preferred to access CCBT at home, with no one expressing a preference for use of CCBT in an alternative location.</p> <p>Conclusions</p> <p>A definitive trial, with a recruitment window of one year, would require the participation of around 13 MS centres. This number of centres could be reduced by expanding the eligibility criteria to include either other neurological conditions or people with more severe depression. The MSIS-29 should be used as a patient-important outcome measurement.</p> <p>Trial registration</p> <p>ISRCTN: <a href="http://www.controlled-trials.com/ISRCTN81846800">ISRCTN81846800</a></p

Acute loss of TET function results in aggressive myeloid cancer in mice

TET-family dioxygenases oxidize 5-methylcytosine (5mC) in DNA, and exert tumour suppressor activity in many types of cancers. Even in the absence of TET coding region mutations, TET loss-of-function is strongly associated with cancer. Here we show that acute elimination of TET function induces the rapid development of an aggressive, fully-penetrant and cell-autonomous myeloid leukaemia in mice, pointing to a causative role for TET loss-of-function in this myeloid malignancy. Phenotypic and transcriptional profiling shows aberrant differentiation of haematopoietic stem/progenitor cells, impaired erythroid and lymphoid differentiation and strong skewing to the myeloid lineage, with only a mild relation to changes in DNA modification. We also observe progressive accumulation of phospho-H2AX and strong impairment of DNA damage repair pathways, suggesting a key role for TET proteins in maintaining genome integrityopen0

Evolutionary Conservation of the Functional Modularity of Primate and Murine LINE-1 Elements

LINE-1 (L1) retroelements emerged in mammalian genomes over 80 million years ago with a few dominant subfamilies amplifying over discrete time periods that led to distinct human and mouse L1 lineages. We evaluated the functional conservation of L1 sequences by comparing retrotransposition rates of chimeric human-rodent L1 constructs to their parental L1 counterparts. Although amino acid conservation varies from ∼35% to 63% for the L1 ORF1p and ORF2p, most human and mouse L1 sequences can be functionally exchanged. Replacing either ORF1 or ORF2 to create chimeric human-mouse L1 elements did not adversely affect retrotransposition. The mouse ORF2p retains retrotransposition-competency to support both Alu and L1 mobilization when any of the domain sequences we evaluated were substituted with human counterparts. However, the substitution of portions of the mouse cys-domain into the human ORF2p reduces both L1 retrotransposition and Alu trans-mobilization by 200–1000 fold. The observed loss of ORF2p function is independent of the endonuclease or reverse transcriptase activities of ORF2p and RNA interaction required for reverse transcription. In addition, the loss of function is physically separate from the cysteine-rich motif sequence previously shown to be required for RNP formation. Our data suggest an additional role of the less characterized carboxy-terminus of the L1 ORF2 protein by demonstrating that this domain, in addition to mediating RNP interaction(s), provides an independent and required function for the retroelement amplification process. Our experiments show a functional modularity of most of the LINE sequences. However, divergent evolution of interactions within L1 has led to non-reciprocal incompatibilities between human and mouse ORF2 cys-domain sequences