A Keystone for ncRNA

A report on the Keystone symposium 'Non-coding RNAs' held at Snowbird, Utah, USA, 31 March to 5 April 2012.Molecular and Cellular BiologyStem Cell and Regenerative Biolog

Updating the evidence for the role of corticosteroids in severe sepsis and septic shock: a Bayesian meta-analytic perspective

Introduction: Current low (stress) dose corticosteroid regimens may have therapeutic advantage in severe sepsis and septic shock despite conflicting results from two landmark randomised controlled trials (RCT). We systematically reviewed the efficacy of corticosteroid therapy in severe sepsis and septic shock. Methods: RCTs were identified (1950-September 2008) by multiple data-base electronic search (MEDLINE via OVID, OVID PreMedline, OVID Embase, Cochrane Central Register of Controlled trials, Cochrane database of systematic reviews, Health Technology Assessment Database and Database of Abstracts of Reviews of Effects) and hand search of references, reviews and scientific society proceedings. Three investigators independently assessed trial inclusion and data extraction into standardised forms; differences resolved by consensus. Results:Corticosteroid efficacy, compared with control, for hospital-mortality, proportion of patients experiencing shock-resolution, and infective and non-infective complications was assessed using Bayesian random-effects models; expressed as odds ratio (OR, (95% credible-interval)). Bayesian outcome probabilities were calculated as the probability (P) that OR ≥1. Fourteen RCTs were identified. High-dose (>1000 mg hydrocortisone (equivalent) per day) corticosteroid trials were associated with a null (n = 5; OR 0.91(0.31-1.25)) or higher (n = 4, OR 1.46(0.73-2.16), outlier excluded) mortality probability (P = 42.0% and 89.3%, respectively). Low-dose trials (<1000 mg hydrocortisone per day) were associated with a lower (n = 9, OR 0.80(0.40-1.39); n = 8 OR 0.71(0.37-1.10), outlier excluded) mortality probability (20.4% and 5.8%, respectively). OR for shock-resolution was increased in the low dose trials (n = 7; OR 1.20(1.07-4.55); P = 98.2%). Patient responsiveness to corticotrophin stimulation was non-determinant. A high probability of risk-related treatment efficacy (decrease in log-odds mortality with increased control arm risk) was identified by metaregression in the low dose trials (n = 9, slope coefficient -0.49(-1.14, 0.27); P = 92.2%). Odds of complications were not increased with corticosteroids. Conclusions: Although a null effect for mortality treatment efficacy of low dose corticosteroid therapy in severe sepsis and septic shock was not excluded, there remained a high probability of treatment efficacy, more so with outlier exclusion. Similarly, although a null effect was not excluded, advantageous effects of low dose steroids had a high probability of dependence upon patient underlying risk. Low dose steroid efficacy was not demonstrated in corticotrophin non-responders. Further large-scale trials appear mandated.15 page(s

Introduction for the Gene special issue dedicated to the meeting Genomic impact of eukaryotic transposable elements at Asilomar

The issues related to \u27Genomic Impact of Eukaryotic Transposable Elements\u27, which took place in Pacific Grove, California between March 31st and April 4th 2006, are discussed. The meeting celebrated the extraordinary contributions of Dr. Carl W. Schmid to the study of repeated DNA sequences and mobile elements. With the advent of recombinant DNA technology, he led the discovery of human Alu elements, and the discovery of their amplification. The idea of the conference was to gather and disseminate information in transposable elements (TEs) on the state-of-the-art tools and approaches. The core sessions from the conference covered research on transposable elements with a strong emphasis on their impact on genomic stability and evolution. The scientific sessions were complemented by after-dinner workshop sessions focusing on Repbase, computer tools used in annotation and analysis of repetitive DNA and open problems related to the field

The Virion Host Shut-Off (vhs) Protein Blocks a TLR-Independent Pathway of Herpes Simplex Virus Type 1 Recognition in Human and Mouse Dendritic Cells

Molecular pathways underlying the activation of dendritic cells (DCs) in response to Herpes Simplex Virus type 1 (HSV-1) are poorly understood. Removal of the HSV virion host shut-off (vhs) protein relieves a block to DC activation observed during wild-type infection. In this study, we utilized a potent DC stimulatory HSV-1 recombinant virus lacking vhs as a tool to investigate the mechanisms involved in the activation of DCs by HSV-1. We report that the release of pro-inflammatory cytokines by conventional DC (cDC) during HSV-1 infection is triggered by both virus replication-dependent and replication-independent pathways. Interestingly, while vhs is capable of inhibiting the release of cytokines during infection of human and mouse cDCs, the secretion of cytokines by plasmacytoid DC (pDC) is not affected by vhs. These data prompted us to postulate that infection of cDCs by HSV triggers a TLR independent pathway for cDC activation that is susceptible to blockage by the vhs protein. Using cDCs isolated from mice deficient in both the TLR adaptor protein MyD88 and TLR3, we show that HSV-1 and the vhs-deleted virus can activate cDCs independently of TLR signaling. In addition, virion-associated vhs fails to block cDC activation in response to treatment with TLR agonists, but it efficiently blocked cDC activation triggered by the paramyxoviruses Sendai Virus (SeV) and Newcastle Disease Virus (NDV). This block to SeV- and NDV-induced activation of cDC resulted in elevated SeV and NDV viral gene expression indicating that infection with HSV-1 enhances the cell's susceptibility to other pathogens through the action of vhs. Our results demonstrate for the first time that a viral protein contained in the tegument of HSV-1 can block the induction of DC activation by TLR-independent pathways of viral recognition

Aging and Recovery After Resistance-Exercise-Induced Muscle Damage: Current Evidence and Implications for Future Research

Accepted author manuscript version reprinted, by permission, from Journal of Aging and Physical Activity, 2021, 29(3): 544-551, https://doi.org/10.1123/japa.2020-0201. © Human Kinetics, Inc.Aging is anecdotally associated with a prolonged recovery from resistance training, though current literature remains equivocal. This brief review considers the effects of resistance training on indirect markers of muscle damage and recovery (i.e., muscle soreness, blood markers, and muscle strength) in older males. With no date restrictions, four databases were searched for articles relating to aging, muscle damage, and recovery. Data from 11 studies were extracted for review. Of these, four reported worse symptoms in older compared with younger populations, while two have observed the opposite, and the remaining studies (n = 6) proposed no differences between age groups. It appears that resistance training can be practiced in older populations without concern for impaired recovery. To improve current knowledge, researchers are urged to utilize more ecologically valid muscle-damaging bouts and investigate the mechanisms which underpin the recovery of muscle soreness and strength after exercise in older populations

Potentiation of latent inhibition by haloperidol and clozapine is attenuated in Dopamine D2 receptor (Drd-2) deficient mice: Do antipsychotics influence learning to ignore irrelevant stimuli via both Drd-2 and non-Drd-2 mechanisms?

Whether the dopamine Drd-2 receptor is necessary for the behavioural action of antipsychotic drugs is an important question, as Drd-2 antagonism is responsible for their debilitating motor side effects. Using Drd-2 null mice (Drd2 -/-) it has previously been shown that Drd-2 is not necessary for antipsychotic drugs to reverse D-amphetamine disruption of latent inhibition (LI), a behavioural measure of learning to ignore irrelevant stimuli. Weiner's 'two-headed' model indicates that antipsychotics not only reverse LI disruption, 'disrupted LI', but also potentiate LI when low/absent in controls, 'persistent' LI. We investigated whether antipsychotic drugs haloperidol or clozapine potentiated LI in wild-type controls or Drd2 -/-. Both drugs potentiated LI in wild-type but not in Drd2 -/- mice, suggesting moderation of this effect of antipsychotics in the absence of Drd-2. Haloperidol potentiated LI similarly in both Drd1 -/- and wild-type mice, indicating no such moderation in Drd1 -/-. These data suggest that antipsychotic drugs can have either Drd-2 or non-Drd-2 effects on learning to ignore irrelevant stimuli, depending on how the abnormality is produced. Identification of the non-Drd-2 mechanism may help to identify novel non-Drd2 based therapeutic strategies for psychosis

Peptidomic discovery of short open reading frame-encoded peptides in human cells

The amount of the transcriptome that is translated into polypeptides is of fundamental importance. We developed a peptidomic strategy to detect short ORF (sORF)-encoded polypeptides (SEPs) in human cells. We identified 90 SEPs, 86 of which are novel, the largest number of human SEPs ever reported. SEP abundances range from 10-1000 molecules per cell, identical to known proteins. SEPs arise from sORFs in non-coding RNAs as well as multi-cistronic mRNAs, and many SEPs initiate with non-AUG start codons, indicating that non-canonical translation may be more widespread in mammals than previously thought. In addition, coding sORFs are present in a small fraction (8/1866) of long intergenic non-coding RNAs (lincRNAs). Together, these results provide the strongest evidence to date that the human proteome is more complex than previously appreciated

KISS AGNs in the Soft X-ray Band: Correlation with the ROSAT All-Sky Survey

We present a study of the X-ray properties of a volume-limited sample of optically selected emission-line galaxies. The sample is derived from a correlation between the KPNO International Spectroscopic Survey (KISS), an H-alpha-selected objective-prism survey of AGNs and starbursting galaxies, and the ROSAT All-Sky Survey (RASS). After elimination of all spurious matches, we identify 18 ROSAT-detected X-ray sources within the KISS sample in the 0.1-2.4 keV band. Due to soft X-ray selection effects, the majority of the ROSAT sources are Seyfert 1 galaxies. The majority (54%) of the ROSAT-KISS Seyferts are classified as narrow-line Seyfert 1 objects, a relatively high percentage compared to previous objective-prism-selected Seyfert galaxy samples. We estimate the X-ray luminosities of the ROSAT-detected KISS objects and derive volume emissivities of 6.63 x 10^38 ergs/s/Mpc^3 and 1.45 x 10^38 ergs/s/Mpc^3 for the 30 deg and 43 deg survey strips, respectively. For those KISS AGNs not detected by RASS, we use the median L_X/L_H-alpha ratio derived from a previous study to estimate L_X. The total 0.5-2 keV volume emissivity we predict for the overall KISS AGN sample is sufficient to account for 22.1 +/- 8.9% of the soft X-ray background (XRB), averaged over both survey strips. The KISS AGN sample is made up predominantly of intermediate-luminosity Seyfert 2's and LINERs, which tend to be weak soft X-ray sources. They may, however, represent a much more significant contribution to the hard XRB.Comment: 15 pages, including 5 figures and 2 tables. Accepted for publication in December 2002 A