Mitochondrial DNA (mtDNA) is normally present at thousands of copies per cell and is packaged into several hundred higher-order structures termed nucleoids. The abundant mtDNA-binding protein TFAM ...(transcription factor A, mitochondrial) regulates nucleoid architecture, abundance and segregation. Complete mtDNA depletion profoundly impairs oxidative phosphorylation, triggering calcium-dependent stress signalling and adaptive metabolic responses. However, the cellular responses to mtDNA instability, a physiologically relevant stress observed in many human diseases and ageing, remain poorly defined. Here we show that moderate mtDNA stress elicited by TFAM deficiency engages cytosolic antiviral signalling to enhance the expression of a subset of interferon-stimulated genes. Mechanistically, we find that aberrant mtDNA packaging promotes escape of mtDNA into the cytosol, where it engages the DNA sensor cGAS (also known as MB21D1) and promotes STING (also known as TMEM173)-IRF3-dependent signalling to elevate interferon-stimulated gene expression, potentiate type I interferon responses and confer broad viral resistance. Furthermore, we demonstrate that herpesviruses induce mtDNA stress, which enhances antiviral signalling and type I interferon responses during infection. Our results further demonstrate that mitochondria are central participants in innate immunity, identify mtDNA stress as a cell-intrinsic trigger of antiviral signalling and suggest that cellular monitoring of mtDNA homeostasis cooperates with canonical virus sensing mechanisms to fully engage antiviral innate immunity.
Review of A2B2O7 pyrochlore response to irradiation and pressure Lang, Maik; Zhang, Fuxiang; Zhang, Jiaming ...
Nuclear instruments & methods in physics research. Section B, Beam interactions with materials and atoms,
10/2010, Volume:
268, Issue:
19
Journal Article
Peer reviewed
This article reviews recent research on swift heavy-ion irradiations and high-pressure studies on pyrochlores of the Gd2Zr2a x Ti x O7 binary . Applying three complementary analytical techniques ...(synchrotron X-ray diffraction, Raman spectroscopy and transmission electron microscopy) allowed for the investigation of the response of pyrochlore to irradiation and/or pressure. The chemical composition of pyrochlore has a strong effect on the character and energetics of the type of structural modifications that can be obtained under pressure or irradiation: For Ti-rich pyrochlores, the crystalline-to-amorphous transition is the dominant process. When Zr is substituted for Ti, an order-disorder transformation to the defect-fluorite structure becomes the increasingly dominant process. Except for Gd2Zr2O7, single ion tracks in pyrochlore consist of an amorphous core, surrounded by a crystalline, but disordered, defect-fluorite shell. This shell is surrounded by a defect-rich pyrochlore region. In contrast to similar effects observed when pressure or irradiation are applied separately, the response of the pyrochlore structure is significantly different when it is exposed simultaneously to pressure and irradiation. The combination of relativistic heavy ions with high pressure results in the formation of a new metastable pyrochlore phase. TEM and quantum-mechanical calculations suggest that these novel structural modifications are caused by the formation of nanocrystals and the modified energetics of nanomaterials.
Natural hydrogels are promising scaffolds to engineer epidermis. Currently, natural hydrogels used to support epidermal regeneration are mainly collagen- or gelatin-based, which mimic the natural ...dermal extracellular matrix but often suffer from insufficient and uncontrollable mechanical and degradation properties. In this study, a photocrosslinkable gelatin (i.e., gelatin methacrylamide (GelMA)) with tunable mechanical, degradation, and biological properties is used to engineer the epidermis for skin tissue engineering applications. The results reveal that the mechanical and degradation properties of the developed hydrogels can be readily modified by varying the hydrogel concentration, with elastic and compressive moduli tuned from a few kPa to a few hundred kPa, and the degradation times varied from a few days to several months. Additionally, hydrogels of all concentrations displayed excellent cell viability (>90%) with increasing cell adhesion and proliferation corresponding to increases in hydrogel concentrations. Furthermore, the hydrogels are found to support keratinocyte growth, differentiation, and stratification into a reconstructed multilayered epidermis with adequate barrier functions. The robust and tunable properties of GelMA hydrogels suggest that the keratinocyte laden hydrogels can be used as epidermal substitutes, wound dressings, or substrates to construct various in vitro skin models.
The anaerobic oxidation of methane coupled to sulfate reduction is a microbially mediated process requiring a syntrophic partnership between anaerobic methanotrophic (ANME) archaea and ...sulfate-reducing bacteria (SRB). Based on genome taxonomy, ANME lineages are polyphyletic within the phylum Halobacterota, none of which have been isolated in pure culture. Here, we reconstruct 28 ANME genomes from environmental metagenomes and flow sorted syntrophic consortia. Together with a reanalysis of previously published datasets, these genomes enable a comparative analysis of all marine ANME clades. We review the genomic features that separate ANME from their methanogenic relatives and identify what differentiates ANME clades. Large multiheme cytochromes and bioenergetic complexes predicted to be involved in novel electron bifurcation reactions are well distributed and conserved in the ANME archaea, while significant variations in the anabolic C1 pathways exists between clades. Our analysis raises the possibility that methylotrophic methanogenesis may have evolved from a methanotrophic ancestor.
Most of the described species in kingdom Fungi are contained in two phyla, the Ascomycota and the Basidiomycota (subkingdom Dikarya). As a result, our understanding of the biology of the kingdom is ...heavily influenced by traits observed in Dikarya, such as aerial spore dispersal and life cycles dominated by mitosis of haploid nuclei. We now appreciate that Fungi comprises numerous phylum-level lineages in addition to those of Dikarya, but the phylogeny and genetic characteristics of most of these lineages are poorly understood due to limited genome sampling. Here, we addressed major evolutionary trends in the non-Dikarya fungi by phylogenomic analysis of 69 newly generated draft genome sequences of the zoosporic (flagellated) lineages of true fungi. Our phylogeny indicated five lineages of zoosporic fungi and placed Blastocladiomycota, which has an alternation of haploid and diploid generations, as branching closer to the Dikarya than to the Chytridiomyceta. Our estimates of heterozygosity based on genome sequence data indicate that the zoosporic lineages plus the Zoopagomycota are frequently characterized by diploid-dominant life cycles. We mapped additional traits, such as ancestral cell-cycle regulators, cell-membrane– and cell-wall–associated genes, and the use of the amino acid selenocysteine on the phylogeny and found that these ancestral traits that are shared with Metazoa have been subject to extensive parallel loss across zoosporic lineages. Together, our results indicate a gradual transition in the genetics and cell biology of fungi from their ancestor and caution against assuming that traits measured in Dikarya are typical of other fungal lineages.
Medium- to long-term data for the performance of zirconia crowns with titanium (Ti) bases are sparse, particularly when the crown height space and occlusal loads are high.
The purpose of this ...in vitro study was to assess the effect of the height of zirconia screw-retained implant crowns with a Ti base on the screw joint stability after cyclic loading. A secondary aim was to investigate the survival of zirconia crowns of different heights after cyclic loading.
Twenty-one internal connection implants were secured between fiberglass-reinforced epoxy resin sleeves. Mandibular first molar monolithic zirconia crowns with 3 different heights (6 mm, 10 mm, and 14 mm) were milled and bonded to the Ti bases (n=7). The screws were tightened to 30 Ncm, and a 30-degree 120-N cyclic load was applied to the crowns at 2 Hz for 5 million cycles. After 5 million cycles, the crowns were evaluated for stability, and the same protocol was repeated for 275-N and 435-N loads for 5 million cycles each. After loading, the detorque values were recorded. Failure was characterized based on whether the crown, screw, and/or implant fracture was observed. The detorque values were analyzed by using a 1-way-ANOVA with the restricted maximum likelihood estimation. The percentage of torque loss was calculated. The LIFETEST procedure was used to analyze the survival probability of the groups (α=.05).
The effect of crown height on the detorque values of screws was not found to be statistically significant (P>.05). The mean detorque value for 6-mm crowns was 23.5 Ncm, 24.4 Ncm for 10-mm crowns, and 22.1 Ncm for 14-mm crowns. A significant effect of crown height was found on the survival (P=.006), and the time-to-failure survival of 14-mm crowns was significantly lower than the survival of 6 mm and 10 mm crowns (P=.020), where no failures were observed. Four 14-mm crowns failed between the 1 and 2 million cycles after the loads were increased to 435 N. The failure modes were the same for all the crowns, implants, and screws fractured.
When the tested internal connection implant was used, the crown height did not affect the detorque values, and 14-mm crowns performed similarly to the shorter crowns in terms of torque loss after cyclic loading. However, survival of the 14-mm crown-implant complex was lower, resulting in screw and implant fractures.
Highly prevalent conditions with multiple and complex underlying etiologies are a challenge to public health. Undernutrition, for example, affects 20% of children in the developing world. The cause ...and consequence of poor nutrition are multifaceted. Undernutrition has been associated with half of all deaths worldwide in children aged <5 years; in addition, its pernicious long-term effects in early childhood have been associated with cognitive and physical growth deficits across multiple generations and have been thought to suppress immunity to further infections and to reduce the efficacy of childhood vaccines. The Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health (MAL-ED) Study, led by the Fogarty International Center of the National Institutes of Health and the Foundation for the National Institutes of Health, has been established at sites in 8 countries with historically high incidence of diarrheal disease and undernutrition. Central to the study is the hypothesis that enteropathogen infection contributes to undernutrition by causing intestinal inflammation and/or by altering intestinal barrier and absorptive function. It is further postulated that this leads to growth faltering and deficits in cognitive development. The effects of repeated enteric infection and undernutrition on the immune response to childhood vaccines is also being examined in the study. MAL-ED uses a prospective longitudinal design that offers a unique opportunity to directly address a complex system of exposures and health outcomes in the community—rather than the relatively rarer circumstances that lead to hospitalization—during the critical period of development of the first 2 years of life. Among the factors being evaluated are enteric infections (with or without diarrhea) and other illness indicators, micronutrient levels, diet, socioeconomic status, gut function, and the environment. MAL-ED aims to describe these factors, their interrelationships, and their overall impact on health outcomes in unprecedented detail, and to make individual, site-specific, and generalized recommendations regarding the nature and timing of possible interventions aimed at improving child health and development in these resource-poor settings.
•HPV-positive oropharyngeal cancer (OPC) affects populations around the world.•OPC has unique epidemiologic, molecular, pathologic, and clinical characteristics.•Ongoing research characterizes ...burden, etiology, prevention and treatment.
Cancer of the oropharynx has attracted considerable attention in recent years given: (1) an increasing incidence in selected populations over the past three decades; (2) the discovery of human papillomavirus (HPV) infection as the driver of the increase, as opposed to the traditional risk factors such as tobacco (smoking and chewing) and alcohol; and (3) the promise of new prevention and treatment strategies. As a result of such developments, the International Agency for Research on Cancer (IARC) and the US National Cancer Institute (NCI), convened the fourth Cancer Seminar meeting in November 2018 to focus on this topic. This report summarizes the proceedings: a review of recent science on the descriptive epidemiology, etiology, biology, genetics, early detection, pathology and treatment of HPV-positive oropharyngeal cancer, and the formulation of key research questions to be addressed.
The purpose of this retrospective analysis was to define the incidence of severe adverse events after exposure to ultrasound contrast agents.
Data between January 1, 2001, and September 30, 2007, ...were collected using invited responses to an on-line web-based questionnaire from 1 general and 12 cardiac ultrasound laboratories. During a period of 4.5 +/- 2.4 years, a total of 66,164 doses of Definity (Lantheus Medical Imaging, North Billerica, MA) and 12,219 doses of Optison (GE Healthcare, Buckinghamshire, UK) were administered, reflecting contrast use in 5% of transthoracic and 28% of stress echocardiographic procedures. More than 10,000 doses were given to critically ill patients in intensive care unit settings or to patients with acute chest pain of suspected cardiac origin. The median age of patients who received an ultrasound contrast agent was 60 years, 49% were male, and the mean body mass index was 32 +/- 1.4 g/m(-2).
Severe reactions that were considered "probably" related to an ultrasound contrast agent developed in 8 patients (0.01%), all of whom were outpatients, and 4 (0.006%) of these were consistent with anaphylactoid reactions. There were no deaths reported. All patients recovered with treatment. No serious events were seen in inpatients.
This multicenter, retrospective analysis includes the largest number of doses of ultrasound contrast agents ever published and a large number of patients evaluated in a wide variety of settings, including the critically ill. It shows that these agents have a good safety profile in both cardiac and abdominal ultrasound applications. The incidence of severe adverse reactions to ultrasound contrast agents is no greater, and may be lower, than that reported for contrast agents commonly used in other cardiac imaging tests.
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