Coordination of frontline defense mechanisms under severe oxidative stress

Inference of an environmental and gene regulatory influence network (EGRINOS) by integrating transcriptional responses to H2O2 and paraquat (PQ) has revealed a multi-tiered oxidative stress (OS)-management program to transcriptionally coordinate three peroxidase/catalase enzymes, two superoxide dismutases, production of rhodopsins, carotenoids and gas vesicles, metal trafficking, and various other aspects of metabolism.ChIP-chip, microarray, and survival assays have validated important architectural aspects of this network, identified novel defense mechanisms (including two evolutionarily distant peroxidase enxymes), and showed that general transcription factors of the transcription factor B family have an important function in coordinating the OS response (OSR) despite their inability to directly sense ROS.A comparison of transcriptional responses to sub-lethal doses of H2O2 and PQ with predictions of these responses made by an EGRIN model generated earlier from responses to other environmental factors has confirmed that a significant fraction of the OSR is made up of a generalized component that is also observed in response to other stressors.Analysis of active regulons within environment and gene regulatory influence network for OS (EGRINOS) across diverse environmental conditions has identified the specialized component of oxidative stress response (OSR) that is triggered by sub-lethal OS, but not by other stressors, including sub-inhibitory levels of redox-active metals, extreme changes in oxygen tension, and a sub-lethal dose of γ rays

A QUALITATIVE INVESTIGATION OF TECHNOLOGY TRANSFER* A CASE STUDY

ECHNOLOGY transfer is an issue of national importance and i

Discovering functional linkages and uncharacterized cellular pathways using phylogenetic profile comparisons: a comprehensive assessment

<p>Abstract</p> <p>Background</p> <p>A widely-used approach for discovering functional and physical interactions among proteins involves phylogenetic profile comparisons (PPCs). Here, proteins with similar profiles are inferred to be functionally related under the assumption that proteins involved in the same metabolic pathway or cellular system are likely to have been co-inherited during evolution.</p> <p>Results</p> <p>Our experimentation with <it>E. coli </it>and yeast proteins with 16 different carefully composed reference sets of genomes revealed that the phyletic patterns of proteins in prokaryotes alone could be adequate enough to make reasonably accurate functional linkage predictions. A slight improvement in performance is observed on adding few eukaryotes into the reference set, but a noticeable drop-off in performance is observed with increased number of eukaryotes. Inclusion of most parasitic, pathogenic or vertebrate genomes and multiple strains of the same species into the reference set do not necessarily contribute to an improved sensitivity or accuracy. Interestingly, we also found that evolutionary histories of individual pathways have a significant affect on the performance of the PPC approach with respect to a particular reference set. For example, to accurately predict functional links in carbohydrate or lipid metabolism, a reference set solely composed of prokaryotic (or bacterial) genomes performed among the best compared to one composed of genomes from all three super-kingdoms; this is in contrast to predicting functional links in translation for which a reference set composed of prokaryotic (or bacterial) genomes performed the worst. We also demonstrate that the widely used random null model to quantify the statistical significance of profile similarity is incomplete, which could result in an increased number of false-positives.</p> <p>Conclusion</p> <p>Contrary to previous proposals, it is not merely the number of genomes but a careful selection of informative genomes in the reference set that influences the prediction accuracy of the PPC approach. We note that the predictive power of the PPC approach, especially in eukaryotes, is heavily influenced by the primary endosymbiosis and subsequent bacterial contributions. The over-representation of parasitic unicellular eukaryotes and vertebrates additionally make eukaryotes less useful in the reference sets. Reference sets composed of highly non-redundant set of genomes from all three super-kingdoms fare better with pathways showing considerable vertical inheritance and strong conservation (e.g. translation apparatus), while reference sets solely composed of prokaryotic genomes fare better for more variable pathways like carbohydrate metabolism. Differential performance of the PPC approach on various pathways, and a weak positive correlation between functional and profile similarities suggest that caution should be exercised while interpreting functional linkages inferred from genome-wide large-scale profile comparisons using a single reference set.</p

A hot sub-Neptune in the desert and a temperate super-Earth around faint M dwarfs: Color validation of TOI-4479b and TOI-2081b

We report the discovery and validation of two TESS exoplanets orbiting faint M dwarfs: TOI-4479b and TOI-2081b. We have jointly analyzed space (TESS mission) and ground based (MuSCAT2, MuSCAT3 and SINISTRO instruments) lightcurves using our multi-color photometry transit analysis pipeline. This allowed us to compute contamination limits for both candidates and validate them as planet-sized companions. We found TOI-4479b to be a sub-Neptune-sized planet ($R_{p}=2.82^{+0.65}_{-0.63}~\rm R_{\oplus}$) and TOI-2081b to be a super-Earth-sized planet ($R_{p}=2.04^{+0.50}_{-0.54}~\rm R_{\oplus}$). Furthermore, we obtained that TOI-4479b, with a short orbital period of $1.15890^{+0.00002}_{-0.00001}~\rm days$, lies within the Neptune desert and is in fact the largest nearly ultra-short period planet around an M dwarf known to date. These results make TOI-4479b rare among the currently known exoplanet population around M dwarf stars, and an especially interesting target for spectroscopic follow-up and future studies of planet formation and evolution.Comment: Accepted for publication in Astronomy&Astrophysic

Ocular neuroprotection by siRNA targeting caspase-2

Retinal ganglion cell (RGC) loss after optic nerve damage is a hallmark of certain human ophthalmic diseases including ischemic optic neuropathy (ION) and glaucoma. In a rat model of optic nerve transection, in which 80% of RGCs are eliminated within 14 days, caspase-2 was found to be expressed and cleaved (activated) predominantly in RGC. Inhibition of caspase-2 expression by a chemically modified synthetic short interfering ribonucleic acid (siRNA) delivered by intravitreal administration significantly enhanced RGC survival over a period of at least 30 days. This exogenously delivered siRNA could be found in RGC and other types of retinal cells, persisted inside the retina for at least 1 month and mediated sequence-specific RNA interference without inducing an interferon response. Our results indicate that RGC apoptosis induced by optic nerve injury involves activation of caspase-2, and that synthetic siRNAs designed to inhibit expression of caspase-2 represent potential neuroprotective agents for intervention in human diseases involving RGC loss

Pre-Operative Risk Factors Predict Post-Operative Respiratory Failure after Liver Transplantation

OBJECTIVE: Post-operative pulmonary complications significantly affect patient survival rates, but there is still no conclusive evidence regarding the effect of post-operative respiratory failure after liver transplantation on patient prognosis. This study aimed to predict the risk factors for post-operative respiratory failure (PRF) after liver transplantation and the impact on short-term survival rates. DESIGN: The retrospective observational cohort study was conducted in a twelve-bed adult surgical intensive care unit in northern Taiwan. The medical records of 147 liver transplant patients were reviewed from September 2002 to July 2007. Sixty-two experienced post-operative respiratory failure while the remaining 85 patients did not. MEASUREMENTS AND MAIN RESULTS: Gender, age, etiology, disease history, pre-operative ventilator use, molecular adsorbent re-circulating system (MARS) use, source of organ transplantation, model for end-stage liver disease score (MELD) and Child-Turcotte-Pugh score calculated immediately before surgery were assessed for the two groups. The length of the intensive care unit stay, admission duration, and mortality within 30 days, 3 months, and 1 year were also evaluated. Using a logistic regression model, post-operative respiratory failure correlated with diabetes mellitus prior to liver transplantation, pre-operative impaired renal function, pre-operative ventilator use, pre-operative MARS use and deceased donor source of organ transplantation (p<0.05). Once liver transplant patients developed PRF, their length of ICU stay and admission duration were prolonged, significantly increasing their mortality and morbidity (p<0.001). CONCLUSIONS: The predictive pre-operative risk factors significantly influenced the occurrence of post-operative respiratory failure after liver transplantation

Identification of polyhydroxyalkanoates in Halococcus and other haloarchaeal species

Polyhydroxyalkanoates (PHAs) are accumulated in many prokaryotes. Several members of the Halobacteriaceae produce poly-3-hydroxybutyrate (PHB), but it is not known if this is a general property of the family. We evaluated identification methods for PHAs with 20 haloarchaeal species, three of them isolates from Permian salt. Staining with Sudan Black B, Nile Blue A, or Nile Red was applied to screen for the presence of PHAs. Transmission electron microscopy and 1H-nuclear magnetic resonance spectroscopy were used for visualization of PHB granules and chemical confirmation of PHAs in cell extracts, respectively. We report for the first time the production of PHAs by Halococcus sp. (Halococcus morrhuae DSM 1307T, Halococcus saccharolyticus DSM 5350T, Halococcus salifodinae DSM 8989T, Halococcus dombrowskii DSM 14522T, Halococcus hamelinensis JCM 12892T, Halococcus qingdaonensis JCM 13587T), Halorubrum sp. (Hrr. coriense DSM 10284T, Halorubrum chaoviator DSM 19316T, Hrr. chaoviator strains NaxosII and AUS-1), haloalkaliphiles (Natronobacterium gregoryi NCMB 2189T, Natronococcus occultus DSM 3396T) and Halobacterium noricense DSM 9758T. No PHB was detected in Halobacterium salinarum NRC-1 ATCC 700922, Hbt. salinarum R1 and Haloferax volcanii DSM 3757T. Most species synthesized PHAs when growing in synthetic as well as in complex medium. The polyesters were generally composed of PHB and poly-ß-hydroxybutyrate-co-3-hydroxyvalerate (PHBV). Available genomic data suggest the absence of PHA synthesis in some haloarchaea and in all other Euryarchaeota and Crenarchaeota. Homologies between haloarchaeal and bacterial PHA synthesizing enzymes had indicated to some authors probable horizontal gene transfer, which, considering the data obtained in this study, may have occurred already before Permian times

Essential data variables for a minimum dataset for head and neck cancer trials and clinical research:HNCIG consensus recommendations and database

The Head and Neck Cancer International Group (HNCIG) has undertaken an international modified Delphi process to reach consensus on the essential data variables to be included in a minimum database for HNC research. Endorsed by 19 research organisations representing 34 countries, these recommendations provide the framework to facilitate and harmonise data collection and sharing for HNC research. These variables have also been incorporated into a ready to use downloadable HNCIG minimum database, available from the HNCIG website

Guiding the Design of Synthetic DNA-Binding Molecules with Massively Parallel Sequencing

Genomic applications of DNA-binding molecules require an unbiased knowledge of their high affinity sites. We report the high-throughput analysis of pyrrole-imidazole polyamide DNA-binding specificity in a 10^(12)-member DNA sequence library using affinity purification coupled with massively parallel sequencing. We find that even within this broad context, the canonical pairing rules are remarkably predictive of polyamide DNA-binding specificity. However, this approach also allows identification of unanticipated high affinity DNA-binding sites in the reverse orientation for polyamides containing β/Im pairs. These insights allow the redesign of hairpin polyamides with different turn units capable of distinguishing 5′-WCGCGW-3′ from 5′-WGCGCW-3′. Overall, this study displays the power of high-throughput methods to aid the optimal targeting of sequence-specific minor groove binding molecules, an essential underpinning for biological and nanotechnological applications