Exploratory analysis of protein translation regulatory networks using hierarchical random graphs

Abstract Background Protein translation is a vital cellular process for any living organism. The availability of interaction databases provides an opportunity for researchers to exploit the immense amount of data in silico such as studying biological networks. There has been an extensive effort using computational methods in deciphering the transcriptional regulatory networks. However, research on translation regulatory networks has caught little attention in the bioinformatics and computational biology community. Results In this paper, we present an exploratory analysis of yeast protein translation regulatory networks using hierarchical random graphs. We derive a protein translation regulatory network from a protein-protein interaction dataset. Using a hierarchical random graph model, we show that the network exhibits well organized hierarchical structure. In addition, we apply this technique to predict missing links in the network. Conclusions The hierarchical random graph mode can be a potentially useful technique for inferring hierarchical structure from network data and predicting missing links in partly known networks. The results from the reconstructed protein translation regulatory networks have potential implications for better understanding mechanisms of translational control from a system’s perspective

Rapid Discrimination of Salmonella enterica Serovar Typhi from Other Serovars by MALDI-TOF Mass Spectrometry

Systemic infections caused by Salmonella enterica are an ongoing public health problem especially in Sub-Saharan Africa. Essentially typhoid fever is associated with high mortality particularly because of the increasing prevalence of multidrug-resistant strains. Thus, a rapid blood-culture based bacterial species diagnosis including an immediate sub-differentiation of the various serovars is mandatory. At present, MALDI-TOF based intact cell mass spectrometry (ICMS) advances to a widely used routine identification tool for bacteria and fungi. In this study, we investigated the appropriateness of ICMS to identify pathogenic bacteria derived from Sub-Saharan Africa and tested the potential of this technology to discriminate S. enterica subsp. enterica serovar Typhi (S. Typhi) from other serovars. Among blood culture isolates obtained from a study population suffering from febrile illness in Ghana, no major misidentifications were observed for the species identification process, but serovars of Salmonella enterica could not be distinguished using the commercially available Biotyper database. However, a detailed analysis of the mass spectra revealed several serovar-specific biomarker ions, allowing the discrimination of S. Typhi from others. In conclusion, ICMS is able to identify isolates from a sub-Saharan context and may facilitate the rapid discrimination of the clinically and epidemiologically important serovar S. Typhi and other non-S. Typhi serovars in future implementations

Formation of Amyloid-Like Fibrils by Y-Box Binding Protein 1 (YB-1) Is Mediated by Its Cold Shock Domain and Modulated by Disordered Terminal Domains

YB-1, a multifunctional DNA- and RNA-binding nucleocytoplasmic protein, is involved in the majority of DNA- and mRNA-dependent events in the cell. It consists of three structurally different domains: its central cold shock domain has the structure of a β-barrel, while the flanking domains are predicted to be intrinsically disordered. Recently, we showed that YB-1 is capable of forming elongated fibrils under high ionic strength conditions. Here we report that it is the cold shock domain that is responsible for formation of YB-1 fibrils, while the terminal domains differentially modulate this process depending on salt conditions. We demonstrate that YB-1 fibrils have amyloid-like features, including affinity for specific dyes and a typical X-ray diffraction pattern, and that in contrast to most of amyloids, they disassemble under nearly physiological conditions

Lack of NF1 expression in a sporadic schwannoma from a patient without neurofibromatosis

The neurofibromatosis type 1 (NF1) gene encodes a tumor suppressor protein, neurofibromin, which is expressed at high levels in Schwann cells and other adult tissues. Loss of NF1 expression has been reported in Schwann cell tumors (neurofibrosarcomas) from patients with NF1 and its loss is associated with increased proliferation of these cells. In this report, we describe downregulation of NF1 expression in a single spinal schwannoma from an individual without clinical features of neurofibromatosis type 1 or 2. Barely detectable expression of NF1 RNA was found in this tumor by in situ hybridization using an NF1 -specific riboprobe as well as by Northern blot and reverse-transcribed (RT)-PCR analysis. In Schwann cells cultured from this schwannoma, abundant expression of NF1 RNA could be detected by Northern blot and RT-PCR analysis. These results suggest that, in some tumors, expression of NF1 may be downregulated by factors produced within the tumor and may represent a novel mechanism for inactivating these growth suppressing genes and allowing for increased cell proliferation in tumors.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45383/1/11060_2005_Article_BF01057754.pd

Mapping the Hsp90 Genetic Interaction Network in Candida albicans Reveals Environmental Contingency and Rewired Circuitry

The molecular chaperone Hsp90 regulates the folding of diverse signal transducers in all eukaryotes, profoundly affecting cellular circuitry. In fungi, Hsp90 influences development, drug resistance, and evolution. Hsp90 interacts with ∼10% of the proteome in the model yeast Saccharomyces cerevisiae, while only two interactions have been identified in Candida albicans, the leading fungal pathogen of humans. Utilizing a chemical genomic approach, we mapped the C. albicans Hsp90 interaction network under diverse stress conditions. The chaperone network is environmentally contingent, and most of the 226 genetic interactors are important for growth only under specific conditions, suggesting that they operate downstream of Hsp90, as with the MAPK Hog1. Few interactors are important for growth in many environments, and these are poised to operate upstream of Hsp90, as with the protein kinase CK2 and the transcription factor Ahr1. We establish environmental contingency in the first chaperone network of a fungal pathogen, novel effectors upstream and downstream of Hsp90, and network rewiring over evolutionary time

In Vivo Systematic Analysis of Candida albicans Zn2-Cys6 Transcription Factors Mutants for Mice Organ Colonization

The incidence of fungal infections in immuno-compromised patients increased considerably over the last 30 years. New treatments are therefore needed against pathogenic fungi. With Candida albicans as a model, study of host-fungal pathogen interactions might reveal new sources of therapies. Transcription factors (TF) are of interest since they integrate signals from the host environment and participate in an adapted microbial response. TFs of the Zn2-Cys6 class are specific to fungi and are important regulators of fungal metabolism. This work analyzed the importance of the C. albicans Zn2-Cys6 TF for mice kidney colonization. For this purpose, 77 Zn2-Cys6 TF mutants were screened in a systemic mice model of infection by pools of 10 mutants. We developed a simple barcoding strategy to specifically detect each mutant DNA from mice kidney by quantitative PCR. Among the 77 TF mutant strains tested, eight showed a decreased colonization including mutants for orf19.3405, orf19.255, orf19.5133, RGT1, UGA3, orf19.6182, SEF1 and orf19.2646, and four an increased colonization including mutants for orf19.4166, ZFU2, orf19.1685 and UPC2 as compared to the isogenic wild type strain. Our approach was validated by comparable results obtained with the same animal model using a single mutant and the revertant for an ORF (orf19.2646) with still unknown functions. In an attempt to identify putative involvement of such TFs in already known C. albicans virulence mechanisms, we determined their in vitro susceptibility to pH, heat and oxidative stresses, as well as ability to produce hyphae and invade agar. A poor correlation was found between in vitro and in vivo assays, thus suggesting that TFs needed for mice kidney colonization may involve still unknown mechanisms. This large-scale analysis of mice organ colonization by C. albicans can now be extended to other mutant libraries since our in vivo screening strategy can be adapted to any preexisting mutants

New Options in the Treatment of Lipid Disorders in HIV-Infected Patients

Since the introduction of HAART, there was a remarkably change in the natural history of HIV disease, leading to a notable extension of life expectancy, although prolonged metabolic imbalances could significantly act on the longterm prognosis and outcome of HIV-infected persons, and there is an increasing concern about the cardiovascular risk in this population. Current recommendations suggest that HIV-infected perons undergo evaluation and treatment on the basis of the Third National Cholesterol Education Program Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (NCEP ATP III) guidelines for dyslipidemia, with particular attention to potential drug interactions with antiretroviral agents and maintenance of virologic control of HIV infection. While a hypolipidemic diet and physical activity may certainly improve dyslipidemia, pharmacological treatment becomes indispensable when serum lipid are excessively high for a long time or the patient has a high cardiovascular risk, since the suspension or change of an effective antiretroviral therapy is not recommended. Moreover, the choice of a hypolipidemic drug is often a reason of concern, since expected drug-drug interactions (especially with antiretroviral agents), toxicity, intolerance, effects on concurrent HIV-related disease and decrease patient adherence to multiple pharmacological regimens must be carefully evaluated. Often the lipid goals of patients in this group are not achieved by the therapy recommended in the current lipid guidelines and in this article we describe other possibilities to treat lipid disorders in HIV-infected persons, like rosuvastatin, ezetimibe and fish oil

GWTC-3: Compact Binary Coalescences Observed by LIGO and Virgo during the Second Part of the Third Observing Run

The third Gravitational-Wave Transient Catalog (GWTC-3) describes signals detected with Advanced LIGO and Advanced Virgo up to the end of their third observing run. Updating the previous GWTC-2.1, we present candidate gravitational waves from compact binary coalescences during the second half of the third observing run (O3b) between 1 November 2019, 15∶00 Coordinated Universal Time (UTC) and 27 March 2020, 17∶00 UTC. There are 35 compact binary coalescence candidates identified by at least one of our search algorithms with a probability of astrophysical origin pastro>0.5. Of these, 18 were previously reported as low-latency public alerts, and 17 are reported here for the first time. Based upon estimates for the component masses, our O3b candidates with pastro>0.5 are consistent with gravitational-wave signals from binary black holes or neutron-star-black-hole binaries, and we identify none from binary neutron stars. However, from the gravitational-wave data alone, we are not able to measure matter effects that distinguish whether the binary components are neutron stars or black holes. The range of inferred component masses is similar to that found with previous catalogs, but the O3b candidates include the first confident observations of neutron-star-black-hole binaries. Including the 35 candidates from O3b in addition to those from GWTC-2.1, GWTC-3 contains 90 candidates found by our analysis with pastro>0.5 across the first three observing runs. These observations of compact binary coalescences present an unprecedented view of the properties of black holes and neutron stars

Search for Gravitational Waves Associated with Fast Radio Bursts Detected by CHIME/FRB during the LIGO-Virgo Observing Run O3a

We search for gravitational-wave (GW) transients associated with fast radio bursts (FRBs) detected by the Canadian Hydrogen Intensity Mapping Experiment Fast Radio Burst Project, during the first part of the third observing run of Advanced LIGO and Advanced Virgo (2019 April 1 15:00 UTC-2019 October 1 15:00 UTC). Triggers from 22 FRBs were analyzed with a search that targets both binary neutron star (BNS) and neutron star-black hole (NSBH) mergers. A targeted search for generic GW transients was conducted on 40 FRBs. We find no significant evidence for a GW association in either search. Given the large uncertainties in the distances of our FRB sample, we are unable to exclude the possibility of a GW association. Assessing the volumetric event rates of both FRB and binary mergers, an association is limited to 15% of the FRB population for BNS mergers or 1% for NSBH mergers. We report 90% confidence lower bounds on the distance to each FRB for a range of GW progenitor models and set upper limits on the energy emitted through GWs for a range of emission scenarios. We find values of order 1051-1057 erg for models with central GW frequencies in the range 70-3560 Hz. At the sensitivity of this search, we find these limits to be above the predicted GW emissions for the models considered. We also find no significant coincident detection of GWs with the repeater, FRB 20200120E, which is the closest known extragalactic FRB

The disruption of proteostasis in neurodegenerative diseases

Cells count on surveillance systems to monitor and protect the cellular proteome which, besides being highly heterogeneous, is constantly being challenged by intrinsic and environmental factors. In this context, the proteostasis network (PN) is essential to achieve a stable and functional proteome. Disruption of the PN is associated with aging and can lead to and/or potentiate the occurrence of many neurodegenerative diseases (ND). This not only emphasizes the importance of the PN in health span and aging but also how its modulation can be a potential target for intervention and treatment of human diseases.info:eu-repo/semantics/publishedVersio