Primary transcriptomes of Mycobacterium avium subsp. paratuberculosis reveal proprietary pathways in tissue and macrophages

<p>Abstract</p> <p>Background</p> <p><it>Mycobacterium avium </it>subsp. <it>paratuberculosis </it>(MAP) persistently infects intestines and mesenteric lymph nodes leading to a prolonged subclinical disease. The <it>MAP </it>genome sequence was published in 2005, yet its transcriptional organization in natural infection is unknown. While prior research analyzed regulated gene sets utilizing defined, in vitro stress related or advanced surgical methods with various animal species, we investigated the intracellular lifestyle of MAP in the intestines and lymph nodes to understand the MAP pathways that function to govern this persistence.</p> <p>Results</p> <p>Our transcriptional analysis shows that 21%, 8% and 3% of the entire MAP genome was represented either inside tissues, macrophages or both, respectively. Transcripts belonging to latency and cell envelope biogenesis were upregulated in the intestinal tissues whereas those belonging to intracellular trafficking and secretion were upregulated inside the macrophages. Transcriptomes of natural infection and in vitro macrophage infection shared genes involved in transcription and inorganic ion transport and metabolism. MAP specific genes within large sequence polymorphisms of ancestral <it>M. avium </it>complex were downregulated exclusively in natural infection.</p> <p>Conclusions</p> <p>We have unveiled common and unique MAP pathways associated with persistence, cell wall biogenesis and virulence in naturally infected cow intestines, lymph nodes and in vitro infected macrophages. This dichotomy also suggests that in vitro macrophage models may be insufficient in providing accurate information on the events that transpire during natural infection. This is the first report to examine the primary transcriptome of MAP at the local infection site (i.e. intestinal tissue). Regulatory pathways that govern the lifecycle of MAP appear to be specified by tissue and cell type. While tissues show a "shut-down" of major MAP metabolic genes, infected macrophages upregulate several MAP specific genes along with a putative pathogenicity island responsible for iron acquisition. Many of these regulatory pathways rely on the advanced interplay of host and pathogen and in order to decipher their message, an interactome must be established using a systems biology approach. Identified MAP pathways place current research into direct alignment in meeting the future challenge of creating a MAP-host interactome.</p

The Inclination of Library Professionals to Modern Tools in the Knowledge Era

The edited volume of the book consists of ten articles covering the innovative practices of libraries in the digital environment. It includes the areas such as library network, e-resources, scholarly publishing, digital libraries, knowledge management, Web 2.0, and blockchain technology etc., that can influence the work-life of the library professionals and the academic community

Controlling Cherenkov angles with resonance transition radiation

Cherenkov radiation provides a valuable way to identify high energy particles in a wide momentum range, through the relation between the particle velocity and the Cherenkov angle. However, since the Cherenkov angle depends only on material's permittivity, the material unavoidably sets a fundamental limit to the momentum coverage and sensitivity of Cherenkov detectors. For example, Ring Imaging Cherenkov detectors must employ materials transparent to the frequency of interest as well as possessing permittivities close to unity to identify particles in the multi GeV range, and thus are often limited to large gas chambers. It would be extremely important albeit challenging to lift this fundamental limit and control Cherenkov angles as preferred. Here we propose a new mechanism that uses constructive interference of resonance transition radiation from photonic crystals to generate both forward and backward Cherenkov radiation. This mechanism can control Cherenkov angles in a flexible way with high sensitivity to any desired range of velocities. Photonic crystals thus overcome the severe material limit for Cherenkov detectors, enabling the use of transparent materials with arbitrary values of permittivity, and provide a promising option suited for identification of particles at high energy with enhanced sensitivity.Comment: There are 16 pages and 4 figures for the manuscript. Supplementary information with 18 pages and 5 figures, appended at the end of the file with the manuscript. Source files in Word format converted to PDF. Submitted to Nature Physic

Effectiveness of cidofovir intralesional treatment in recurrent respiratory papillomatosis

To present the results of recurrent respiratory papillomatosis (RRP) treatment with surgical excision and adjuvant anti-viral cidofovir intralesional use and to examine the correlation between the cidofovir effectiveness and the patient previous history of multiple larynx procedures, age, extension of lesion and dose. 32 patients with laryngeal papillomas were treated with cidofovir in our Department between I.2009 and I.2011. The number of previous RRP debulking procedures ranged from 1 to 100. The intensity of papillomatosis differed from one anatomic site and moderate growth to four or five localizations with heavy extension. The number of injections per patient varied from 1 to 7, and the total volume of 5 mg/ml solution varied from 2 to 33 ml. The injections were combined with laser debulking of the lesions. In disperse papillomata, the injections were administered in particular anatomical sites in 4–6 weeks intervals, in massive lesions injections were repeated in the same anatomical site in 2–4 weeks. Complete remission was observed in 18 out of 32 patients. 13 patients showed remission in a place of cidofovir injection. One patient did not react to the drug. In four patients, new changes in injection places appeared. In two patients, hepatic toxic side effects were observed. Intralesional cidofovir injection has been shown to be an effective and safe therapy for laryngeal papillomatosis and should be considered in those patients who experienced disease relapse

Large Scale Gene Expression Profiles of Regenerating Inner Ear Sensory Epithelia

Loss of inner ear sensory hair cells (HC) is a leading cause of human hearing loss and balance disorders. Unlike mammals, many lower vertebrates can regenerate these cells. We used cross-species microarrays to examine this process in the avian inner ear. Specifically, changes in expression of over 1700 transcription factor (TF) genes were investigated in hair cells of auditory and vestibular organs following treatment with two different damaging agents and regeneration in vitro. Multiple components of seven distinct known signaling pathways were clearly identifiable: TGFβ, PAX, NOTCH, WNT, NFKappaB, INSULIN/IGF1 and AP1. Numerous components of apoptotic and cell cycle control pathways were differentially expressed, including p27KIP and TFs that regulate its expression. A comparison of expression trends across tissues and treatments revealed identical patterns of expression that occurred at identical times during regenerative proliferation. Network analysis of the patterns of gene expression in this large dataset also revealed the additional presence of many components (and possible network interactions) of estrogen receptor signaling, circadian rhythm genes and parts of the polycomb complex (among others). Equal numbers of differentially expressed genes were identified that have not yet been placed into any known pathway. Specific time points and tissues also exhibited interesting differences: For example, 45 zinc finger genes were specifically up-regulated at later stages of cochlear regeneration. These results are the first of their kind and should provide the starting point for more detailed investigations of the role of these many pathways in HC recovery, and for a description of their possible interactions

Risk of depression, suicide and psychosis with hydroxychloroquine treatment for rheumatoid arthritis:a multinational network cohort study

Objectives: Concern has been raised in the rheumatology community regarding recent regulatory warnings that HCQ used in the coronavirus disease 2019 pandemic could cause acute psychiatric events. We aimed to study whether there is risk of incident depression, suicidal ideation or psychosis associated with HCQ as used for RA.Methods: We performed a new-user cohort study using claims and electronic medical records from 10 sources and 3 countries (Germany, UK and USA). RA patients ≥18 years of age and initiating HCQ were compared with those initiating SSZ (active comparator) and followed up in the short (30 days) and long term (on treatment). Study outcomes included depression, suicide/suicidal ideation and hospitalization for psychosis. Propensity score stratification and calibration using negative control outcomes were used to address confounding. Cox models were fitted to estimate database-specific calibrated hazard ratios (HRs), with estimates pooled where I2 &lt;40%.Results: A total of 918 144 and 290 383 users of HCQ and SSZ, respectively, were included. No consistent risk of psychiatric events was observed with short-term HCQ (compared with SSZ) use, with meta-analytic HRs of 0.96 (95% CI 0.79, 1.16) for depression, 0.94 (95% CI 0.49, 1.77) for suicide/suicidal ideation and 1.03 (95% CI 0.66, 1.60) for psychosis. No consistent long-term risk was seen, with meta-analytic HRs of 0.94 (95% CI 0.71, 1.26) for depression, 0.77 (95% CI 0.56, 1.07) for suicide/suicidal ideation and 0.99 (95% CI 0.72, 1.35) for psychosis.Conclusion: HCQ as used to treat RA does not appear to increase the risk of depression, suicide/suicidal ideation or psychosis compared with SSZ. No effects were seen in the short or long term. Use at a higher dose or for different indications needs further investigation.Trial registration: Registered with EU PAS (reference no. EUPAS34497; http://www.encepp.eu/encepp/viewResource.htm? id=34498). The full study protocol and analysis source code can be found at https://github.com/ohdsi-studies/Covid19EstimationHydroxychloroquine2.</p

Photodegradation of organic pollutants RhB dye using UV simulated sunlight on ceria based TiO2 nanomaterials for antibacterial applications

To photo-catalytically degrade RhB dye using solar irradiation, CeO2 doped TiO2 nanocomposites were synthesized hydrothermally at 700 °C for 9 hrs. All emission spectra showed a prominent band centered at 442 nm that was attributed to oxygen related defects in the CeO2-TiO2 nanocrystals. Two sharp absorption bands at 1418 cm−1 and 3323 cm−1 were attributed to the deformation and stretching vibration, and bending vibration of the OH group of water physisorbed to TiO2, respectively. The photocatalytic activities of Ce-TiO2 nanocrystals were investigated through the degradation of RhB under UV and UV+ visible light over a period of 8 hrs. After 8 hrs, the most intense absorption peak at 579 nm disappeared under the highest photocatalytic activity and 99.89% of RhB degraded under solar irradiation. Visible light-activated TiO2 could be prepared from metal-ion incorporation, reduction of TiO2, non-metal doping or sensitizing of TiO2 using dyes. Studying the antibacterial activity of Ce-TiO2 nanocrystals against E. coli revealed significant activity when 10 μg was used, suggesting that it can be used as an antibacterial agent. Its effectiveness is likely related to its strong oxidation activity and superhydrophilicity. This study also discusses the mechanism of heterogeneous photocatalysis in the presence of TiO2

AMP-Activated Protein Kinase Plays an Important Evolutionary Conserved Role in the Regulation of Glucose Metabolism in Fish Skeletal Muscle Cells

AMPK, a master metabolic switch, mediates the observed increase of glucose uptake in locomotory muscle of mammals during exercise. AMPK is activated by changes in the intracellular AMP∶ATP ratio when ATP consumption is stimulated by contractile activity but also by AICAR and metformin, compounds that increase glucose transport in mammalian muscle cells. However, the possible role of AMPK in the regulation of glucose metabolism in skeletal muscle has not been investigated in other vertebrates, including fish. In this study, we investigated the effects of AMPK activators on glucose uptake, AMPK activity, cell surface levels of trout GLUT4 and expression of GLUT1 and GLUT4 as well as the expression of enzymes regulating glucose disposal and PGC1α in trout myotubes derived from a primary muscle cell culture. We show that AICAR and metformin significantly stimulated glucose uptake (1.6 and 1.3 fold, respectively) and that Compound C completely abrogated the stimulatory effects of the AMPK activators on glucose uptake. The combination of insulin and AMPK activators did not result in additive nor synergistic effects on glucose uptake. Moreover, exposure of trout myotubes to AICAR and metformin resulted in an increase in AMPK activity (3.8 and 3 fold, respectively). We also provide evidence suggesting that stimulation of glucose uptake by AMPK activators in trout myotubes may take place, at least in part, by increasing the cell surface and mRNA levels of trout GLUT4. Finally, AICAR increased the mRNA levels of genes involved in glucose disposal (hexokinase, 6-phosphofructokinase, pyruvate kinase and citrate synthase) and mitochondrial biogenesis (PGC-1α) and did not affect glycogen content or glycogen synthase mRNA levels in trout myotubes. Therefore, we provide evidence, for the first time in non-mammalian vertebrates, suggesting a potentially important role of AMPK in stimulating glucose uptake and utilization in the skeletal muscle of fish