Bone loss and aggravated autoimmune arthritis in HLA-DRβ1-bearing humanized mice following oral challenge with Porphyromonas gingivalis

BACKGROUND: The linkage between periodontal disease and rheumatoid arthritis is well established. Commonalities among the two are that both are chronic inflammatory diseases characterized by bone loss, an association with the shared epitope susceptibility allele, and anti-citrullinated protein antibodies. METHODS: To explore immune mechanisms that may connect the two seemingly disparate disorders, we measured host immune responses including T-cell phenotype and anti-citrullinated protein antibody production in human leukocyte antigen (HLA)-DR1 humanized C57BL/6 mice following exposure to the Gram-negative anaerobic periodontal disease pathogen Porphyromonas gingivalis. We measured autoimmune arthritis disease expression in mice exposed to P. gingivalis, and also in arthritis-resistant mice by flow cytometry and multiplex cytokine-linked and enzyme-linked immunosorbent assays. We also measured femoral bone density by microcomputed tomography and systemic cytokine production. RESULTS: Exposure of the gingiva of DR1 mice to P. gingivalis results in a transient increase in the percentage of Th17 cells, both in peripheral blood and cervical lymph nodes, a burst of systemic cytokine activity, a loss in femoral bone density, and the generation of anti-citrullinated protein antibodies. Importantly, these antibodies are not produced in response to P. gingivalis treatment of wild-type C57BL/6 mice, and P. gingivalis exposure triggered expression of arthritis in arthritis-resistant mice. CONCLUSIONS: Exposure of gingival tissues to P. gingivalis has systemic effects that can result in disease pathology in tissues that are spatially removed from the initial site of infection, providing evidence for systemic effects of this periodontal pathogen. The elicitation of anti-citrullinated protein antibodies in an HLA-DR1-restricted fashion by mice exposed to P. gingivalis provides support for the role of the shared epitope in both periodontal disease and rheumatoid arthritis. The ability of P. gingivalis to induce disease expression in arthritis-resistant mice provides support for the idea that periodontal infection may be able to trigger autoimmunity if other disease-eliciting factors are already present

Identification of a highly polymorphic tetranucleotide repeat locus (DXpS) at Xp and development of a DXpS/HUMARA biplex methylation-based PCR assay that enhances detection of X-chromosome inactivation

The methylation-based PCR assay at the polymorphic (CAG)n repeat in exon 1 of the human androgen receptor _AR_ gene (HUMARA) is a standard method for determination of the methylation state of alleles in active X (Xa) and inactive X (Xi) chromosomes. HUMARA assay is endowed with heterozygosity rates ~85% worldwide. This means that in a proportion of females it is uninformative. The HUMARA genotype is not neutral, being linked to Kennedy´s disease. Moreover, allele designation and quantification from trinucleotide repeats demand normalizing for minor (stutter) products differing from the original template by multiples of the repeat unit. Here, we report on the identification of a highly polymorphic tetranucleotide repeat (named DXpS) mapping to within a CpG island on Xp. This island is 191 bp downstream from the start of the repeat element, and contains sites for the HhaI, HpaII and BstUI methyl-sensitive restriction enzymes. We developed the DXpS and the HUMARA markers into a biplex methylation-based quantitative fluorescent PCR assay. For DXpS we observed twelve alleles with negligible stuttering. DXpS exhibited a heterozygosity rate of 87% (n = 60), matching that of HUMARA. The combined informativeness of the biplex assay was 98%. Random and nonrandom X-inactivation patterns inferred with DXpS in phenotypically normal females and haemophiliac females carrying a defective F8 gene were highly concordant (r^2^ = 0.96) with HUMARA patterns. DXpS represents a notable advancement in detecting X-chromosome inactivation due to the observed high rate of heterozygosity, negligible stuttering, concordance with HUMARA, and the apparent neutrality of allelic variants. Financial support: FAPESP (09/10615-7), FAPERJ, CNPq

Mid-infrared optical parametric amplifier using silicon nanophotonic waveguides

All-optical signal processing is envisioned as an approach to dramatically decrease power consumption and speed up performance of next-generation optical telecommunications networks. Nonlinear optical effects, such as four-wave mixing (FWM) and parametric gain, have long been explored to realize all-optical functions in glass fibers. An alternative approach is to employ nanoscale engineering of silicon waveguides to enhance the optical nonlinearities by up to five orders of magnitude, enabling integrated chip-scale all-optical signal processing. Previously, strong two-photon absorption (TPA) of the telecom-band pump has been a fundamental and unavoidable obstacle, limiting parametric gain to values on the order of a few dB. Here we demonstrate a silicon nanophotonic optical parametric amplifier exhibiting gain as large as 25.4 dB, by operating the pump in the mid-IR near one-half the band-gap energy (E~0.55eV, lambda~2200nm), at which parasitic TPA-related absorption vanishes. This gain is high enough to compensate all insertion losses, resulting in 13 dB net off-chip amplification. Furthermore, dispersion engineering dramatically increases the gain bandwidth to more than 220 nm, all realized using an ultra-compact 4 mm silicon chip. Beyond its significant relevance to all-optical signal processing, the broadband parametric gain also facilitates the simultaneous generation of multiple on-chip mid-IR sources through cascaded FWM, covering a 500 nm spectral range. Together, these results provide a foundation for the construction of silicon-based room-temperature mid-IR light sources including tunable chip-scale parametric oscillators, optical frequency combs, and supercontinuum generators

Revegetation of ski runs in Serbia: Case studies of Mts. Stara Planina and Divčibare

Revegetation is the most sustainable method of soil stabilization at ski runs. In order to establish a stable plant community, it is recommended to use native species. However, non-native species are most often used. In this paper the revegetation of ski runs at two ski resorts is investigated: Divčibare and Stara Planina. Seven species were used for the revegetation of the ski run at the Divčibare ski resort of which six species were native. Six species were used for the revegetation of the Stara Planina ski resort, of which two species were native. It was established that the plant species used in the seed mixtures were suitable for erosion control at the investigated ski resorts

Recent progress in understanding and projecting regional and global mean sea-level change

Considerable progress has been made in understanding the present and future regional and global sea level in the 2 years since the publication of the Fifth Assessment Report (AR5) of the Intergovernmental Panel on Climate Change. Here, we evaluate how the new results affect the AR5’s assessment of (i) historical sea level rise, including attribution of that rise and implications for the sea level budget, (ii) projections of the components and of total global mean sea level (GMSL), and (iii) projections of regional variability and emergence of the anthropogenic signal. In each of these cases, new work largely provides additional evidence in support of the AR5 assessment, providing greater confidence in those findings. Recent analyses confirm the twentieth century sea level rise, with some analyses showing a slightly smaller rate before 1990 and some a slightly larger value than reported in the AR5. There is now more evidence of an acceleration in the rate of rise. Ongoing ocean heat uptake and associated thermal expansion have continued since 2000, and are consistent with ocean thermal expansion reported in the AR5. A significant amount of heat is being stored deeper in the water column, with a larger rate of heat uptake since 2000 compared to the previous decades and with the largest storage in the Southern Ocean. The first formal detection studies for ocean thermal expansion and glacier mass loss since the AR5 have confirmed the AR5 finding of a significant anthropogenic contribution to sea level rise over the last 50 years. New projections of glacier loss from two regions suggest smaller contributions to GMSL rise from these regions than in studies assessed by the AR5; additional regional studies are required to further assess whether there are broader implications of these results. Mass loss from the Greenland Ice Sheet, primarily as a result of increased surface melting, and from the Antarctic Ice Sheet, primarily as a result of increased ice discharge, has accelerated. The largest estimates of acceleration in mass loss from the two ice sheets for 2003–2013 equal or exceed the acceleration of GMSL rise calculated from the satellite altimeter sea level record over the longer period of 1993–2014. However, when increased mass gain in land water storage and parts of East Antarctica, and decreased mass loss from glaciers in Alaska and some other regions are taken into account, the net acceleration in the ocean mass gain is consistent with the satellite altimeter record. New studies suggest that a marine ice sheet instability (MISI) may have been initiated in parts of the West Antarctic Ice Sheet (WAIS), but that it will affect only a limited number of ice streams in the twenty-first century. New projections of mass loss from the Greenland and Antarctic Ice Sheets by 2100, including a contribution from parts of WAIS undergoing unstable retreat, suggest a contribution that falls largely within the likely range (i.e., two thirds probability) of the AR5. These new results increase confidence in the AR5 likely range, indicating that there is a greater probability that sea level rise by 2100 will lie in this range with a corresponding decrease in the likelihood of an additional contribution of several tens of centimeters above the likely range. In view of the comparatively limited state of knowledge and understanding of rapid ice sheet dynamics, we continue to think that it is not yet possible to make reliable quantitative estimates of future GMSL rise outside the likely range. Projections of twenty-first century GMSL rise published since the AR5 depend on results from expert elicitation, but we have low confidence in conclusions based on these approaches. New work on regional projections and emergence of the anthropogenic signal suggests that the two commonly predicted features of future regional sea level change (the increasing tilt across the Antarctic Circumpolar Current and the dipole in the North Atlantic) are related to regional changes in wind stress and surface heat flux. Moreover, it is expected that sea level change in response to anthropogenic forcing, particularly in regions of relatively low unforced variability such as the low-latitude Atlantic, will be detectable over most of the ocean by 2040. The east-west contrast of sea level trends in the Pacific observed since the early 1990s cannot be satisfactorily accounted for by climate models, nor yet definitively attributed either to unforced variability or forced climate change

Glaciers and small ice caps in the macro-scale hydrological cycle: an assessment of present conditions and future changes

Glacier and small ice cap melt water contributions to the global hydrologic cycle are an important component of human water supply and for sea level rise. This melt water is used in many arid and semi-arid parts of the world for direct human consumption as well as indirect consumption by irrigation for crops, serving as frozen reservoirs of water that supplement runoff during warm and dry periods of summer when it is needed the most. Additionally, this melt water reaching the oceans represents a direct input to sea level rise and therefore accurate estimates of this contribution have profound economic and geopolitical implications. It has been demonstrated that, on the scale of glacierized river catchments, land surface hydrological models can successfully simulate glacier contribution to streamflow. However, at global scales, the implementation of glacier melt in hydrological models has been rudimentary or non-existent. In this study, a global glacier mass balance model is coupled with the University of New Hampshire Water Balance/Transport Model (WBM) to assess recent and projected future glacier contributions to the hydrological cycle over the global land surface (excluding the ice sheets of Greenland and Antarctica). For instance, results of WBM simulations indicate that seasonal glacier melt water in many arid climate watersheds comprises 40 % or more of their discharge. Implicitly coupled glacier and WBM models compute monthly glacier mass changes and resulting runoff at the glacier terminus for each individual glacier from the globally complete Randolph Glacier Inventory including over 200 000 glaciers. The time series of glacier runoff is aggregated over each hydrological modeling unit and delivered to the hydrological model for routing downstream and mixing with non-glacial contribution of runoff to each drainage basin outlet. WBM tracks and uses glacial and non-glacial components of the in-stream water for filling reservoirs, transfers of water between drainage basins (inter-basin hydrological transfers), and irrigation along the global system of rivers with net discharge to the ocean. Climate scenarios from global climate models prepared for IPCC AR5 are used to explore an expected range of possible future glacier outflow variability to estimate the impacts on human use of these valuable waters and their poorly understood net contribution to sea level change

Armed and accurate: engineering cytotoxic T cells for eradication of leukemia

Translational medicine depends on a rapid and efficient exchange of results between the bench and the bedside. A recent example from the field of cancer immunotherapy highlights the essential nature of this exchange. Methods have been developed to convert a patient's cytotoxic T cells into efficient and specific killers of cancer cells in patients with leukemia. By using recombinant DNA techniques, a lentiviral vector was constructed to express chimeric antigen receptors in cytotoxic T cells from patients with advanced chronic lymphocytic leukemia. The purpose of the chimeric receptors was to direct the cytotoxic T cell activity against cells causing the cancer. The effect of infusing the engineered T cells back into the cancer patients was tested in a Phase I trial at the University of Pennsylvania, and the initial results were described in two articles from the research team of Dr. Carl June. The remarkable success of this trial should energize further applications of biotechnology in the development of new cancer immunotherapies

Laparoscopy in management of appendicitis in high-, middle-, and low-income countries: a multicenter, prospective, cohort study.

BACKGROUND: Appendicitis is the most common abdominal surgical emergency worldwide. Differences between high- and low-income settings in the availability of laparoscopic appendectomy, alternative management choices, and outcomes are poorly described. The aim was to identify variation in surgical management and outcomes of appendicitis within low-, middle-, and high-Human Development Index (HDI) countries worldwide. METHODS: This is a multicenter, international prospective cohort study. Consecutive sampling of patients undergoing emergency appendectomy over 6 months was conducted. Follow-up lasted 30 days. RESULTS: 4546 patients from 52 countries underwent appendectomy (2499 high-, 1540 middle-, and 507 low-HDI groups). Surgical site infection (SSI) rates were higher in low-HDI (OR 2.57, 95% CI 1.33-4.99, p = 0.005) but not middle-HDI countries (OR 1.38, 95% CI 0.76-2.52, p = 0.291), compared with high-HDI countries after adjustment. A laparoscopic approach was common in high-HDI countries (1693/2499, 67.7%), but infrequent in low-HDI (41/507, 8.1%) and middle-HDI (132/1540, 8.6%) groups. After accounting for case-mix, laparoscopy was still associated with fewer overall complications (OR 0.55, 95% CI 0.42-0.71, p < 0.001) and SSIs (OR 0.22, 95% CI 0.14-0.33, p < 0.001). In propensity-score matched groups within low-/middle-HDI countries, laparoscopy was still associated with fewer overall complications (OR 0.23 95% CI 0.11-0.44) and SSI (OR 0.21 95% CI 0.09-0.45). CONCLUSION: A laparoscopic approach is associated with better outcomes and availability appears to differ by country HDI. Despite the profound clinical, operational, and financial barriers to its widespread introduction, laparoscopy could significantly improve outcomes for patients in low-resource environments. TRIAL REGISTRATION: NCT02179112

Combinatorial drug screening identifies Ewing sarcoma-specific sensitivities

Improvements in survival for Ewing sarcoma pediatric and adolescent patients have been modest over the past 20 years. Combinations of anticancer agents endure as an option to overcome resistance to single treatments caused by compensatory pathways. Moreover, combinations are thought to lessen any associated adverse side effects through reduced dosing, which is particularly important in childhood tumors. Using a parallel phenotypic combinatorial screening approach of cells derived from three pediatric tumor types, we identified Ewing sarcoma-specific interactions of a diverse set of targeted agents including approved drugs. We were able to retrieve highly synergistic drug combinations specific for Ewing sarcoma and identified signaling processes important for Ewing sarcoma cell proliferation determined by EWS-FLI1 We generated a molecular target profile of PKC412, a multikinase inhibitor with strong synergistic propensity in Ewing sarcoma, revealing its targets in critical Ewing sarcoma signaling routes. Using a multilevel experimental approach including quantitative phosphoproteomics, we analyzed the molecular rationale behind the disease-specific synergistic effect of simultaneous application of PKC412 and IGF1R inhibitors. The mechanism of the drug synergy between these inhibitors is different from the sum of the mechanisms of the single agents. The combination effectively inhibited pathway crosstalk and averted feedback loop repression, in EWS-FLI1-dependent manner. Mol Cancer Ther; 16(1); 88-101. ©2016 AACR

Simple geometric interpretation of signal evolution in phase-sensitive fibre optic parametric amplifier

Visualisation of complex nonlinear equation solutions is a useful analysis tool for various scientific and engineering applications. We have re-examined the geometrical interpretation of the classical nonlinear four-wave mixing equations for the specific scheme of a phase sensitive one-pump fiber optical parametric amplification, which has recently attracted revived interest in the optical communications due to potential low noise properties of such amplifiers. Analysis of the phase portraits of the corresponding dynamical systems provide valuable additional insight into field dynamics and properties of the amplifiers. Simple geometric approach has been proposed to describe evolution of the waves, involved in phase-sensitive fiber optical parametric amplification (PS-FOPA) process, using a Hamiltonian structure of the governing equations. We have demonstrated how the proposed approach can be applied to the optimization problems arising in the design of the specific PS-FOPA scheme. The method considered here is rather general and can be used in various applications