Nodal dynamics, not degree distributions, determine the structural controllability of complex networks

Structural controllability has been proposed as an analytical framework for making predictions regarding the control of complex networks across myriad disciplines in the physical and life sciences (Liu et al., Nature:473(7346):167-173, 2011). Although the integration of control theory and network analysis is important, we argue that the application of the structural controllability framework to most if not all real-world networks leads to the conclusion that a single control input, applied to the power dominating set (PDS), is all that is needed for structural controllability. This result is consistent with the well-known fact that controllability and its dual observability are generic properties of systems. We argue that more important than issues of structural controllability are the questions of whether a system is almost uncontrollable, whether it is almost unobservable, and whether it possesses almost pole-zero cancellations.Comment: 1 Figures, 6 page

Nucleoside Analogue Reverse Transcriptase Inhibitors Differentially Inhibit Human LINE-1 Retrotransposition

Intact LINE-1 elements are the only retrotransposons encoded by the human genome known to be capable of autonomous replication. Numerous cases of genetic disease have been traced to gene disruptions caused by LINE-1 retrotransposition events in germ-line cells. In addition, genomic instability resulting from LINE-1 retrotransposition in somatic cells has been proposed as a contributing factor to oncogenesis and to cancer progression. LINE-1 element activity may also play a role in normal physiology. LINE-1 retrotransposition reporter assay, we evaluated the abilities of several antiretroviral compounds to inhibit LINE-1 retrotransposition. The nucleoside analogue reverse transcriptase inhibitors (nRTIs): stavudine, zidovudine, tenofovir disoproxil fumarate, and lamivudine all inhibited LINE-1 retrotransposition with varying degrees of potencies, while the non-nucleoside HIV-1 reverse transcriptase inhibitor nevirapine showed no effect.Our data demonstrates the ability for nRTIs to suppress LINE-1 retrotransposition. This is immediately applicable to studies aimed at examining potential roles for LINE-1 retrotransposition in physiological processes. In addition, our data raises novel safety considerations for nRTIs based on their potential to disrupt physiological processes involving LINE-1 retrotransposition

Effect of antiretroviral drugs on LINE-1 retrotransposition frequency.

<p>A. The LINE-1 retrotransposition reporter plasmid 99gfpLRE3 encodes the full-length, retrotransposition competent LRE3 LINE-1 element under the control of its natural promoter. An eGFP retrotransposition reporter cassette was inserted into the LRE3 3′ UTR. The cassette encodes eGFP under the control of a CMV promoter, in inverse orientation relative to the LRE3 sequence. The eGFP coding sequence is interrupted by an intron inserted in the same transcriptional orientation as LRE3. Transcription from the CMV promoter does can not yield a spliced eGFP sequence. Transcription from the LINE-1 promoter does not lead to eGFP expression, as the eGFP coding sequence is inverted in the resulting mRNA. However, retrotransposition of this RNA, and integration into the genome, allows a sense eGFP mRNA to be transcribed from the CMV promoter. Thus in cells transfected with 99gfpLRE3, eGFP expression acts as a reporter for the completion of a successful retrotransposition event. The 99gfpJM111 plasmid is analogous to 99gfpLRE3, but incorporates point mutations in ORF1 which render its LINE-1 element retrotransposition incompetent. 99gfpJM111 was therefore employed as a negative control in all assays. Both the 99gfpLRE3 and 99gfpJM111 plasmids also encode puromycin resistance markers allowing for selection of transfected cells. B–D. HeLa cells were incubated in triplicate with five-fold serial dilutions of antiretroviral drugs, and transfected with the LINE-1 retrotransposition reporter plasmid 99gfpLRE3. Transfectants were selected with puromycin. Five days post-transfection, cells were stained with the viability dye 7-AAD, and analyzed by FACS. Retrotransposition frequency was determined by excluding 7-AAD-positive events, and then gating on the eGFP-positive population. Shown is representative data from one of three independent experiments. B. In the absence of drugs, a distinct eGFP-positive population of viable cells, representing cells that have undergone LINE-1-LRE3 retrotransposition events, is clearly distinguishable. Shown is one of six replicates of no drug control. C. In the presence of elevated concentrations of nRTIs, the eGFP-positive population is greatly diminished in frequency, indicating suppression of retrotransposition. Shown is one of three replicates of 25 µM stavudine treatment. D. LINE-1 retrotransposition, as reported by eGFP expression, is inhibited by nRTIs in a dose dependent manner, while nevirapine has no effect. Shown are the mean frequencies of eGFP-positive cells amongst the viable 7-AAD-negative subsets, as determined in triplicate, with standard errors represented by error bars. Dashed horizontal lines indicate 50% and 90% inhibition levels.</p

Probiotics: Prevention of Severe Pneumonia and Endotracheal Colonization Trial—PROSPECT: a pilot trial

Background: Probiotics are live microorganisms that may confer health benefits when ingested. Randomized trials suggest that probiotics significantly decrease the incidence of ventilator-associated pneumonia (VAP) and the overall incidence of infection in critically ill patients. However, these studies are small, largely single-center, and at risk of bias. The aim of the PROSPECT pilot trial was to determine the feasibility of conducting a larger trial of probiotics to prevent VAP in mechanically ventilated patients in the intensive care unit (ICU). Methods: In a randomized blinded trial, patients expected to be mechanically ventilated for ≥72 hours were allocated to receive either 1 × 1010 colony-forming units of Lactobacillus rhamnosus GG or placebo, twice daily. Patients were excluded if they were at increased risk of L. rhamnosus GG infection or had contraindications to enteral medication. Feasibility objectives were: (1) timely recruitment; (2) maximal protocol adherence; (3) minimal contamination; and (4) estimated VAP rate ≥10 %. We also measured other infections, diarrhea, ICU and hospital length of stay, and mortality. Results: Overall, in 14 centers in Canada and the USA, all feasibility goals were met: (1) 150 patients were randomized in 1 year; (2) protocol adherence was 97 %; (3) no patients received open-label probiotics; and (4) the VAP rate was 19 %. Other infections included: bloodstream infection (19.3 %), urinary tract infections (12.7 %), and skin and soft tissue infections (4.0 %). Diarrhea, defined as Bristol type 6 or 7 stools, occurred in 133 (88.7 %) of patients, the median length of stay in ICU was 12 days (quartile 1 to quartile 3, 7–18 days), and in hospital was 26 days (quartile 1 to quartile 3, 14–44 days); 23 patients (15.3 %) died in the ICU. Conclusions: The PROSPECT pilot trial supports the feasibility of a larger trial to investigate the effect of L. rhamnosus GG on VAP and other nosocomial infections in critically ill patients. Trial registration: Clinicaltrials.gov NCT01782755 . Registered on 29 January 2013.Medicine, Faculty ofOther UBCNon UBCCritical Care Medicine, Division ofMedicine, Department ofReviewedFacult

Probiotics: Prevention of Severe Pneumonia and Endotracheal Colonization Trial—PROSPECT: a pilot trial

Abstract Background Probiotics are live microorganisms that may confer health benefits when ingested. Randomized trials suggest that probiotics significantly decrease the incidence of ventilator-associated pneumonia (VAP) and the overall incidence of infection in critically ill patients. However, these studies are small, largely single-center, and at risk of bias. The aim of the PROSPECT pilot trial was to determine the feasibility of conducting a larger trial of probiotics to prevent VAP in mechanically ventilated patients in the intensive care unit (ICU). Methods In a randomized blinded trial, patients expected to be mechanically ventilated for ≥72 hours were allocated to receive either 1 × 1010 colony-forming units of Lactobacillus rhamnosus GG or placebo, twice daily. Patients were excluded if they were at increased risk of L. rhamnosus GG infection or had contraindications to enteral medication. Feasibility objectives were: (1) timely recruitment; (2) maximal protocol adherence; (3) minimal contamination; and (4) estimated VAP rate ≥10 %. We also measured other infections, diarrhea, ICU and hospital length of stay, and mortality. Results Overall, in 14 centers in Canada and the USA, all feasibility goals were met: (1) 150 patients were randomized in 1 year; (2) protocol adherence was 97 %; (3) no patients received open-label probiotics; and (4) the VAP rate was 19 %. Other infections included: bloodstream infection (19.3 %), urinary tract infections (12.7 %), and skin and soft tissue infections (4.0 %). Diarrhea, defined as Bristol type 6 or 7 stools, occurred in 133 (88.7 %) of patients, the median length of stay in ICU was 12 days (quartile 1 to quartile 3, 7–18 days), and in hospital was 26 days (quartile 1 to quartile 3, 14–44 days); 23 patients (15.3 %) died in the ICU. Conclusions The PROSPECT pilot trial supports the feasibility of a larger trial to investigate the effect of L. rhamnosus GG on VAP and other nosocomial infections in critically ill patients. Trial registration Clinicaltrials.gov NCT01782755 . Registered on 29 January 2013