Transcriptional Regulation of NLRC4 Inflammasome by IRF8

The NLRC4 inflammasome is a crucial part of the innate immune response against bacterial infections. We found that NLRC4 inflammasome activation in bone marrow-derived macrophages (BMDMs) is greatly dependent on interferon regulatory factor 8 (IRF8). NLRC4-mediated caspase-1 activation and subsequent production of the inflammasome-dependent cytokines IL-1β and IL-18 and cell death were impaired in IRF8-deficient cells. IRF8 mediated the transcription of genes encoding NAIPs, the receptors for NLRC4 inflammasome, which recognize bacterial flagellin and type III secretion system (T3SS) proteins. IRF8 was critical for host survival following infection with Salmonella Typhimurium or Burkholderia thailandensis. Furthermore, mice deficient in IRF8 were impaired in their ability to produce IL-18 and suffered higher bacterial burdens. Altogether, our data highlights the role of IRF8 as a transcriptional regulator of NAIPs for NLRC4 inflammasome activation

Local syzygies of multiplier ideals

In recent years, multiplier ideals have found many applications in local and global algebraic geometry. Because of their importance, there has been some interest in the question of which ideals on a smooth complex variety can be realized as multiplier ideals. Other than integral closure no local obstructions have been known up to now, and in dimension two it was established by Favre-Jonsson and Lipman-Watanabe that any integrally closed ideal is locally a multiplier ideal. We prove the somewhat unexpected result that multiplier ideals in fact satisfy some rather strong algebraic properties involving higher syzygies. It follows that in dimensions three and higher, multiplier ideals are very special among all integrally closed ideals.Comment: 8 page

The NLRC4 inflammasome requires IRF8-dependent production of NAIPs

Activation of the NLRC4 inflammasome is crucial for defense against bacterial species that have flagellin or the type III secretion system (T3SS). We have discovered the role of interferon regulatory factor 8 (IRF8) in mediating NLRC4 inflammasome activation. IRF8 is required for the transcription of genes encoding NAIPs, thereby enabling cellular detection of flagellin or T3SS proteins. In vivo, IRF8 is important for NLRC4 inflammasome–dependent cytokine production, bacterial clearance, and ultimately, host survival. By introducing IRF8 as a player in inflammasome regulation, our study provides a new perspective on that process

Experience with Surgical Excision in Childhood Pheochromocytoma

Pheochromocytoma is one of the potentially fatal causes of childhood hypertension. The study aims to analyze the results of our experiences in pheochromocytomas and the long-term results of its surgical treatment in children. The records of 15 children (11 boys, 4 girls) treated for pheochromocytoma in our unit during the period of 1984 and 2002 were reviewed retrospectively. The average age at surgery was 11.7 yr (range 6 yr 9 months-15 yr 7 months). Localized disease is defined as the cases without the invasion of surrounding tissue, regional disease as the invasion of surrounding tissue and metastatic disease as distant metastases. The mean follow-up after pheochromocytoma excision was 95 months (range 5 to 221 months). Tumors were located in the adrenal gland in 11 (bilaterally in 4) and extra-adrenally in 4. Localized disease occurred in 14 patients and regional disease in one. Only one patient was associated with von Hippel Lindau syndrome. Adrenalectomy or total excision of extra adrenal tumor was performed. Four patients (26.7%) recurred after the first operation (at 2 yr 9 months to 14 yr) and regional disease recurred in one patient three times. Early diagnosis, surgical excision, and long-term follow up are most important for the appropriate treatment of childhood pheochromocytoma

N-Doped Graphene Quantum Dots/Titanium Dioxide Nanocomposites: A Study of ROS-Forming Mechanisms, Cytotoxicity and Photodynamic Therapy

Titanium dioxide nanoparticles (TiO2 NPs) have been proven to be potential candidates in cancer therapy, particularly photodynamic therapy (PDT). However, the application of TiO2 NPs is limited due to the fast recombination rate of the electron (e−)/hole (h+) pairs attributed to their broader bandgap energy. Thus, surface modification has been explored to shift the absorption edge to a longer wavelength with lower e−/h+ recombination rates, thereby allowing penetration into deep-seated tumors. In this study, TiO2 NPs and N-doped graphene quantum dots (QDs)/titanium dioxide nanocomposites (N-GQDs/TiO2 NCs) were synthesized via microwave-assisted synthesis and the two-pot hydrothermal method, respectively. The synthesized anatase TiO2 NPs were self-doped TiO2 (Ti3+ ions), have a small crystallite size (12.2 nm) and low bandgap energy (2.93 eV). As for the N-GQDs/TiO2 NCs, the shift to a bandgap energy of 1.53 eV was prominent as the titanium (IV) tetraisopropoxide (TTIP) loading increased, while maintaining the anatase tetragonal crystal structure with a crystallite size of 11.2 nm. Besides, the cytotoxicity assay showed that the safe concentrations of the nanomaterials were from 0.01 to 0.5 mg mL−1. Upon the photo-activation of N-GQDs/TiO2 NCs with near-infrared (NIR) light, the nanocomposites generated reactive oxygen species (ROS), mainly singlet oxygen (1O2), which caused more significant cell death in MDA-MB-231 (an epithelial, human breast cancer cells) than in HS27 (human foreskin fibroblast). An increase in the N-GQDs/TiO2 NCs concentrations elevates ROS levels, which triggered mitochondria-associated apoptotic cell death in MDA-MB-231 cells. As such, titanium dioxide-based nanocomposite upon photoactivation has a good potential as a photosensitizer in PDT for breast cancer treatment

Minichromosome Maintenance Complex (MCM) Genes Profiling and MCM2 Protein Expression in Cervical Cancer Development

Objective: Minichromosome maintenance complex (MCM) proteins are essential for the process of DNA replication and cell division. This study aimed to evaluate MCM genes expression profiles and MCM2 protein in HPV-associated cervical carcinogenesis. Methodology: MCM2, 4, 5 and 7 genes expression profiles were evaluated in three cervical tissue samples each of normal cervix, human papillomavirus (HPV)-infected low grade squamous intraepithelial lesion (LSIL), high grade squamous intraepithelial lesion (HSIL) and squamous cell carcinoma (SCC), using Human Transcriptome Array 2.0 and validated by nCounter® PanCancer Pathway NanoString Array. Immunohistochemical expression of MCM2 protein was semi-quantitatively assessed by histoscore in tissue microarrays containing 9 cases of normal cervix, 10 LSIL, 10 HSIL and 42 cases of SCC. Results: MCM2, 4, 5 and 7 genes expressions were upregulated with increasing fold change during the progression from LSIL to HSIL and the highest in SCC. MCM2 gene had the highest fold change in SCC compared to normal cervix. Immunohistochemically, MCM2 protein was localised in the nuclei of basal cells of normal cervical epithelium and dysplastic-neoplastic cells of CIN and SCC. There was a significant difference in MCM2 protein expression between the histological groups (P = 0.039), and histoscore was the highest in HSIL compared to normal cervix (P = 0.010). Conclusion: The upregulation of MCM genes expressions in cervical carcinogenesis reaffirms MCM as a proliferative marker in DNA replication pathway, whereby proliferation of dysplastic and cancer cells become increasingly dysregulated and uncontrolled. A strong expression of MCM2 protein in HSIL may aid as a concatenated screening tool in detecting pre-cancerous cervical lesions

Physical and psychological challenges faced by military, medical and public safety personnel relief workers supporting natural disaster operations: a systematic review

Natural disasters, including floods, earthquakes, and hurricanes, result in devastating consequences at the individual and community levels. To date, much of the research reflecting the consequences of natural disasters focuses heavily on victims, with little attention paid to the personnel responding to such disasters. We conducted a systematic review of the challenges faced by military, medical and public safety personnel supporting natural disaster relief operations. Specifically, we report on the current evidence reflecting challenges faced, as well as positive outcomes experienced by military, medical and public safety personnel following deployment to natural disasters. The review included 382 studies. A large proportion of the studies documented experiences of medical workers, followed by volunteers from humanitarian organizations and military personnel. The most frequently reported challenges across the studies were structural (i.e., interactions with the infrastructure or structural institutions), followed by resource limitations, psychological, physical, and social challenges. Over 60% of the articles reviewed documented positive or transformative outcomes following engagement in relief work (e.g., the provision of additional resources, support, and training), as well as self-growth and fulfillment. The current results emphasize the importance of pre-deployment training to better prepare relief workers to manage expected challenges, as well as post-deployment supportive services to mitigate adverse outcomes and support relief workers’ well-being

Attachment style moderates partner presence effects on pain : A laser-evoked potentials study

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly citedSocial support is crucial for psychological and physical well-being. Yet, in experimental and clinical pain research, the presence of others has been found to both attenuate and intensify pain. To investigate the factors underlying these mixed effects, we administered noxious laser stimuli to 39 healthy women while their romantic partner was present or absent, and measured pain ratings and laser-evoked potentials to assess the effects of partner presence on subjective pain experience and underlying neural processes. Further, we examined whether individual differences in adult attachment style, alone or in interaction with the partner's level of attentional focus (manipulated to be either on or away from the participant) might modulate these effects. We found that the effects of partner presence versus absence on pain-related measures depended on adult attachment style but not partner attentional focus. The higher participants' attachment avoidance, the higher pain ratings and N2 and P2 local peak amplitudes were in the presence compared to the absence of the romantic partner. As laser-evoked potentials are thought to reflect activity relating to the salience of events, our data suggest that partner presence may influence the perceived salience of events threatening the body, particularly in individuals who tend to mistrust others.Peer reviewedFinal Published versio

A critical evaluation of network and pathway based classifiers for outcome prediction in breast cancer

Recently, several classifiers that combine primary tumor data, like gene expression data, and secondary data sources, such as protein-protein interaction networks, have been proposed for predicting outcome in breast cancer. In these approaches, new composite features are typically constructed by aggregating the expression levels of several genes. The secondary data sources are employed to guide this aggregation. Although many studies claim that these approaches improve classification performance over single gene classifiers, the gain in performance is difficult to assess. This stems mainly from the fact that different breast cancer data sets and validation procedures are employed to assess the performance. Here we address these issues by employing a large cohort of six breast cancer data sets as benchmark set and by performing an unbiased evaluation of the classification accuracies of the different approaches. Contrary to previous claims, we find that composite feature classifiers do not outperform simple single gene classifiers. We investigate the effect of (1) the number of selected features; (2) the specific gene set from which features are selected; (3) the size of the training set and (4) the heterogeneity of the data set on the performance of composite feature and single gene classifiers. Strikingly, we find that randomization of secondary data sources, which destroys all biological information in these sources, does not result in a deterioration in performance of composite feature classifiers. Finally, we show that when a proper correction for gene set size is performed, the stability of single gene sets is similar to the stability of composite feature sets. Based on these results there is currently no reason to prefer prognostic classifiers based on composite features over single gene classifiers for predicting outcome in breast cancer