Human immunodeficiency virus (HIV) persists in a latent form in infected individuals treated effectively with highly active antiretroviral therapy (HAART). In part, these latent proviruses account ...for the rebound in viral replication observed after treatment interruption. A major therapeutic challenge is to purge this reservoir. In this study, we demonstrate that suberoylanilide hydroxamic acid (SAHA) reactivates HIV from latency in chronically infected cell lines and primary cells. Indeed, P-TEFb, a critical transcription cofactor for HIV, is released and then recruited to the viral promoter upon stimulation with SAHA. The phosphatidylinositol 3-kinase/Akt pathway is involved in the initiation of these events. Using flow cytometry-based single cell analysis of protein phosphorylation, we demonstrate that SAHA activates this pathway in several subpopulations of T cells, including memory T cells that are the major viral reservoir in peripheral blood. Importantly, SAHA activates HIV replication in peripheral blood mononuclear cells from individuals treated effectively with HAART. Thus SAHA, which is a Food and Drug Administration-approved drug, might be considered to accelerate the decay of the latent reservoir in HAART-treated infected humans.
Migraine and estrogen Chai, Nu Cindy; Peterlin, B Lee; Calhoun, Anne H
Current opinion in neurology,
06/2014, Letnik:
27, Številka:
3
Journal Article
Recenzirano
Odprti dostop
The aim is to systematically and critically review the relationship between migraine and estrogen, the predominant female sex hormone, with a focus on studies published in the last 18 months.
Recent ...functional MRI (fMRI) studies of the brain support the existence of anatomical and functional differences between men and women, as well as between participants with migraine and healthy controls. In addition to the naturally occurring changes in endogenous sex hormones over the lifespan (e.g. puberty and menopause), exogenous sex hormones (e.g. hormonal contraception or hormone therapy) also may modulate migraine. Recent data support the historical view of an elevated risk of migraine with significant drops in estrogen levels. In addition, several lines of research support that reducing the magnitude of decline in estrogen concentrations prevents menstrually related migraine (MRM) and migraine aura frequency.
Current literature has consistently demonstrated that headache, in particular migraine, is more prevalent in women as compared with men, specifically during reproductive years. Recent studies have found differences in headache characteristics, central nervous system anatomy, as well as functional activation by fMRI between the sexes in migraine patients. Although the cause underlying these differences is likely multifactorial, considerable evidence supports an important role for sex hormones. Recent studies continue to support that MRM is precipitated by drops in estrogen concentrations, and minimizing this decline may prevent these headaches. Limited data also suggest that specific regimens of combined hormone contraceptive use in MRM and migraine with aura may decrease both headache frequency and aura.
Occipital neuralgia (ON) is characterized by lancinating pain and tenderness overlying the occipital nerves. Both steroid injections and pulsed radiofrequency (PRF) are used to treat ON, but few ...clinical trials have evaluated efficacy, and no study has compared treatments. We performed a multicenter, randomized, double-blind, comparative-effectiveness study in 81 participants with ON or migraine with occipital nerve tenderness whose aim was to determine which treatment is superior. Forty-two participants were randomized to receive local anesthetic and saline, and three 120 second cycles of PRF per targeted nerve, and 39 were randomized to receive local anesthetic mixed with deposteroid and 3 rounds of sham PRF. Patients, treating physicians, and evaluators were blinded to interventions. The PRF group experienced a greater reduction in the primary outcome measure, average occipital pain at 6 weeks (mean change from baseline -2.743 ± 2.487 vs -1.377 ± 1.970; P < 0.001), than the steroid group, which persisted through the 6-month follow-up. Comparable benefits favoring PRF were obtained for worst occipital pain through 3 months (mean change from baseline -1.925 ± 3.204 vs -0.541 ± 2.644; P = 0.043), and average overall headache pain through 6 weeks (mean change from baseline -2.738 ± 2.753 vs -1.120 ± 2.1; P = 0.037). Adverse events were similar between groups, and few significant differences were noted for nonpain outcomes. We conclude that although PRF can provide greater pain relief for ON and migraine with occipital nerve tenderness than steroid injections, the superior analgesia may not be accompanied by comparable improvement on other outcome measures.
P-TEFb, composed of CycT1 and CDK9, regulates the elongation of transcription by RNA polymerase II. In proliferating cells, it is regulated by 7SK snRNA in the 7SK snRNP complex. In resting cells, ...P-TEFb is absent, because CycT1 is dephosphorylated, released from CDK9 and rapidly degraded. In this study, we identified the mechanism of this degradation. We mapped the ubiquitination and degradation of free CycT1 to its N-terminal region from positions 1 to 280. This region is ubiquitinated at six lysines, where E3 ligases Siah1 and Siah2 bind and degrade these sequences. Importantly, the inhibition of Siah1/2 rescued the expression of free CycT1 in proliferating as well as resting primary cells. We conclude that Siah1/2 are the E3 ligases that bind and degrade the dissociated CycT1 in resting, terminally differentiated, anergic and/or exhausted cells.
Individually, both obesity and headache are conditions associated with a substantial personal and societal impact. Recent data support that obesity is comorbid with headache in general and migraine ...specifically, as well as with certain secondary headache conditions such as idiopathic intracranial hypertension. In the current manuscript, we first briefly review the epidemiology of obesity and common primary and secondary headache disorders individually. This is followed by a systematic review of the general population data evaluating the association between obesity and headache in general, and then obesity and migraine and tension‐type headache disorders. Finally, we briefly discuss the data on the association between obesity and a common secondary headache disorder that is associated with obesity, idiopathic intracranial hypertension. Taken together, these data suggest that it is important for clinicians and patients to be aware of the headache/migraine‐obesity association, given that it is potentially modifiable. Hypotheses for mechanisms of the obesity‐migraine association and treatment considerations for overweight and obese headache sufferers are discussed in the companion manuscript, as part II of this topic.
To propagate successfully, they must exploit numerous machineries of the infected cell. ...studies of their replicative cycles have yielded fundamental insights into eukaryotic biology. ...Tat ...requires minimally the transcription of TAR before it can stimulate HIV transcription from the long terminal repeat (LTR). In Caenorhabditis elegans, genetic inactivation of CDK9 or CycT1 and CycT2 resulted in the inhibition of all RNAPII transcription 8. ...in D. melanogaster, following heat shock, PTEFb is recruited upstream of activated promoters 28.
Regulation of transcription elongation by positive transcription elongation factor b (P-TEFb) plays a central role in determining the state of cell activation, proliferation, and differentiation. In ...cells, P-TEFb exists in active and inactive forms. Its release from the inactive 7SK small nuclear ribonucleoprotein complex is a critical step for P-TEFb to activate transcription elongation. However, no good method exists to analyze this P-TEFb equilibrium in living cells. Only inaccurate and labor-intensive cell-free biochemical assays are currently available. In this study, we present the first experimental system to monitor P-TEFb activation in living cells. We created a bimolecular fluorescence complementation assay to detect interactions between P-TEFb and its substrate, the C-terminal domain of RNA polymerase II. When cells were treated with suberoylanilide hydroxamic acid, which releases P-TEFb from the 7SK small nuclear ribonucleoprotein, they turned green. Other known P-TEFb-releasing agents, including histone deacetylase inhibitors, bromodomain and extraterminal bromodomain inhibitors, and protein kinase C agonists, also scored positive in this assay. Finally, we identified 5′-azacytidine as a new P-TEFb-releasing agent. This release of P-TEFb correlated directly with activation of human HIV and HEXIM1 transcription. Thus, our visualization of P-TEFb activation by fluorescent complementation assay could be used to find new P-TEFb-releasing agents, compare different classes of agents, and assess their efficacy singly and/or in combination.Positive transcription elongation factor b (P-TEFb) partitions between free (active) P-TEFb and inactive 7SK small nuclear ribonucleoprotein (snRNP) in cells.
Bimolecular fluorescence complementation (BiFC) detects interactions between active P-TEFb and its C-terminal domain substrate in vivo.
BiFC follows the release of P-TEFb from 7SK snRNP in living cells.
This system is the first to monitor P-TEFb activation in living cells.
To evaluate the association between migraine and body composition status as estimated based on body mass index and WHO physical status categories.
Systematic electronic database searches were ...conducted for relevant studies. Two independent reviewers performed data extraction and quality appraisal. Odds ratios (OR) and confidence intervals (CI) were pooled using a random effects model. Significant values, weighted effect sizes, and tests of homogeneity of variance were calculated.
A total of 12 studies, encompassing data from 288,981 unique participants, were included. The age- and sex-adjusted pooled risk of migraine in those with obesity was increased by 27% compared with those of normal weight (odds ratio OR 1.27; 95% confidence interval CI 1.16-1.37,
< 0.001) and remained increased after multivariate adjustments. Although the age- and sex-adjusted pooled migraine risk was increased in overweight individuals (OR 1.08; 95% CI 1.04, 1.12,
< 0.001), significance was lost after multivariate adjustments. The age- and sex-adjusted pooled risk of migraine in underweight individuals was marginally increased by 13% compared with those of normal weight (OR 1.13; 95% CI 1.02, 1.24,
< 0.001) and remained increased after multivariate adjustments.
The current body of evidence shows that the risk of migraine is increased in obese and underweight individuals. Studies are needed to confirm whether interventions that modify obesity status decrease the risk of migraine.
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