Mutation signature analysis identifies increased mutation caused by tobacco smoke associated DNA adducts in larynx squamous cell carcinoma compared with oral cavity and oropharynx.

Squamous cell carcinomas of the head and neck (HNSCC) arise from mucosal keratinocytes of the upper aero-digestive tract. Despite a common cell of origin and similar driver-gene mutations which divert cell fate from differentiation to proliferation, HNSCC are considered a heterogeneous group of tumors categorized by site of origin within the aero-digestive mucosa, and the presence or absence of HPV infection. Tobacco use is a major driver of carcinogenesis in HNSCC and is a poor prognosticator that has previously been associated with poor immune cell infiltration and higher mutation numbers. Here, we study patterns of mutations in HNSCC that are derived from the specific nucleotide changes and their surrounding nucleotide context (also known as mutation signatures). We identify that mutations linked to DNA adducts associated with tobacco smoke exposure are predominantly found in the larynx. Presence of this class of mutation, termed COSMIC signature 4, is responsible for the increased burden of mutation in this anatomical sub-site. In addition, we show that another mutation pattern, COSMIC signature 5, is positively associated with age in HNSCC from non-smokers and that larynx SCC from non-smokers have a greater number of signature 5 mutations compared with other HNSCC sub-sites. Immunohistochemistry demonstrates a significantly lower Ki-67 proliferation index in size matched larynx SCC compared with oral cavity SCC and oropharynx SCC. Collectively, these observations support a model where larynx SCC are characterized by slower growth and increased susceptibility to mutations from tobacco carcinogen DNA adducts

The nature of domain walls in ultrathin ferromagnets revealed by scanning nanomagnetometry

The recent observation of current-induced domain wall (DW) motion with large velocity in ultrathin magnetic wires has opened new opportunities for spintronic devices. However, there is still no consensus on the underlying mechanisms of DW motion. Key to this debate is the DW structure, which can be of Bloch or N\'eel type, and dramatically affects the efficiency of the different proposed mechanisms. To date, most experiments aiming to address this question have relied on deducing the DW structure and chirality from its motion under additional in-plane applied fields, which is indirect and involves strong assumptions on its dynamics. Here we introduce a general method enabling direct, in situ, determination of the DW structure in ultrathin ferromagnets. It relies on local measurements of the stray field distribution above the DW using a scanning nanomagnetometer based on the Nitrogen-Vacancy defect in diamond. We first apply the method to a Ta/Co40Fe40B20(1 nm)/MgO magnetic wire and find clear signature of pure Bloch DWs. In contrast, we observe left-handed N\'eel DWs in a Pt/Co(0.6 nm)/AlOx wire, providing direct evidence for the presence of a sizable Dzyaloshinskii-Moriya interaction (DMI) at the Pt/Co interface. This method offers a new path for exploring interfacial DMI in ultrathin ferromagnets and elucidating the physics of DW motion under current.Comment: Main text and Supplementary Information, 33 pages and 12 figure

Duty-free, quota-free trade for Asia-Pacific least developed countries : overview and update

Given the continued concentration of Least Developed Countries' export structure, enhanced market access opportunities for the LDCs in sectors like agriculture and apparel is of significant value to them. Conversely, remaining tariff or non-tariff barriers in these sectors continue to do substantial harm. This economic concentration also reinforces the importance to LDCs of pursuing longer-term economic diversification of their productive capacities. Some Asia-Pacific LDCs (such as Bangladesh, Cambodia and Myanmar) may be especially vulnerable to preference erosion as exports are concentrated in sectors like textiles where erosion has already occurred

Nitric Oxide Releasing Nanoparticles for Treatment of Candida Albicans Burn Infections

Candida albicans is a leading fungal cause of burn infections in hospital settings, and sepsis is one of the principle causes of death after a severe burn. The prevalence of invasive candidiasis in burn cases varies widely, but it accounts for 3–23% of severe infection with a mortality rate ranging from 14 to 70%. Therefore, it is imperative that we develop innovative therapeutics to which this fungus is unlikely to evolve resistance, thus curtailing the associated morbidity and mortality and ultimately improving our capacity to treat these infections. An inexpensive and stable nitric oxide (NO)-releasing nanoparticle (NO-np) platform has been recently developed. NO is known to have direct antifungal activity, modulate host immune responses and significantly regulate wound healing. In this study, we hypothesized that NO-np would be an effective therapy in the treatment of C. albicans burn infections. Using a murine burn model, NO-np demonstrated antifungal activity against C. albicans in vivo, most likely by arresting its growth and morphogenesis as demonstrated in vitro. NO-np demonstrated effective antimicrobial activity against yeast and filamentous forms of the fungus. Moreover, we showed that NO-np significantly accelerated the rate of wound healing in cutaneous burn infections when compared to controls. The histological evaluation of the affected tissue revealed that NO-np treatment modified leukocyte infiltration, minimized the fungal burden, and reduced collagen degradation, thus providing potential mechanisms for the therapeutics’ biological activity. Together, these data suggest that NO-np have the potential to serve as a novel topical antifungal which can be used for the treatment of cutaneous burn infections and wounds

Nitric Oxide Releasing Nanoparticles Are Therapeutic for Staphylococcus aureus Abscesses in a Murine Model of Infection

Staphylococcus aureus (SA) is a leading cause of a diverse spectrum of bacterial diseases, including abscesses. Nitric oxide (NO) is a critical component of the natural host defense against pathogens such as SA, but its therapeutic applications have been limited by a lack of effective delivery options. We tested the efficacy of a NO-releasing nanoparticle system (NO-np) in methicillin-resistant SA (MRSA) abscesses in mice. The results show that the NO-np exert antimicrobial activity against MRSA in vitro and in abscesses. Topical or intradermal NO-np treatment of abscesses reduces the involved area and bacterial load while improving skin architecture. Notably, we evaluated pro- and anti-inflammatory cytokines that are involved in immunomodulation and wound healing, revealing that NO-np lead to a reduction in angiogenesis preventing bacterial dissemination from abscesses. These data suggest that NO-np may be useful therapeutics for microbial abscesses

“A Switch Went off in my Whole Body”: Lived Experiences of Fatigue and Post-Exertional Malaise in Long Covid

The growing HCI agenda on health has focused on different chronic conditions but less so on Long Covid, despite its severe impact on the quality of life. We report findings from 2 workshops with 13 people living with Long Covid, indicating the challenges of making sense of their physical, cognitive, and emotional symptoms, and of monitoring the triggers of post-exertional malaise. While most participants engage in pacing activities for the self-management of fatigue, only a few are aware of the importance of planning all their daily activities and routines in order to avoid post-exertional malaise. We conclude with design implications to support lightweight tracking and sensemaking of fatigue symptoms, novel data analytics for monitoring the triggers of post-exertional malaise and the worsening of symptoms, and support for self-management in order to prevent post-exertional malaise

A Uniform Analysis of the Ly-alpha forest at z = 0 - 5: II. Measuring the mean intensity of the extragalactic ionizing background using the proximity effect

A homogeneous sample of 99 moderate resolution QSO spectra at z > 1.7 were presented in Paper I, including 39 previously unpublished spectra from the Multiple Mirror Telescope. The statistics of the Lyman alpha forest were discussed. In this analysis, we demonstrate that a proximity effect is present in the data, ie. there exists a significant (5.5$\sigma$) deficit of lines at $z_{abs} \approx z_{em}$. Within 1.5 $h^{-1}$ Mpc of the QSO emission redshift, the significance does depend on QSO luminosity, in accordance with the theory that this effect is caused by enhanced ionization of hydrogen in the vicinity of the QSO from UV photons from the QSO itself. The photoionization model of Bajtlik, Duncan, and Ostriker (1988) permits an estimate of the mean intensity of the extragalactic background radiation at the Lyman limit. We compare the results of this standard analysis with those obtained using a maximum likelihood technique. The best fit value for $J(\nu_{0})$ is 7.0$^{+3.4}_{-4.4}$ x 10$^{-22}$ ergs/s/cm$^{2}$/Hz/sr, over the redshift range 1.7 < z < 3.8, using QSO redshifts based on narrow emission lines. The best fit value for the HI ionization rate is 1.9$^{+1.2}_{-1.0}$ x 10$^{-12}$ s$^{-1}$, in good agreement with models of the background which incorporate QSOs only. This large absorption line sample and these techniques for measuring the background and understanding the systematics involved allow us to place what we believe are are the firmest limits on the background at these redshifts.Comment: revised figures 13 and 14, and other minor corrections, 42 Latex pages, 23 encapsulated Postscript figures, uses emulateapj.sty, To appear in the Sept. 2000 ApJ

Impact of compacted bentonite microbial community on the clay mineralogy and copper canister corrosion: a multidisciplinary approach in view of a safe Deep Geological Repository of nuclear wastes

Deep Geological Repository (DGR) is the preferred option for the final disposal of high-level radioactive waste. Microorganisms could affect the safety of the DGR by altering the mineralogical properties of the compacted bentonite or inducing the corrosion of the metal canisters. In this work, the impact of physicochemical parameters (bentonite dry density, heat shock, electron donors/acceptors) on the microbial activity, stability of compacted bentonite and corrosion of copper (Cu) discs was investigated after one-year anoxic incubation at 30 ºC. No-illitization in the bentonite was detected confirming its structural stability over 1 year under the experimental conditions. The microbial diversity analysis based on 16 S rRNA gene Next Generation Sequencing showed slight changes between the treatments with an increase of aerobic bacteria belonging to Micrococcaceae and Nocardioides in heat-shock tyndallized bentonites. The survival of sulfate-reducing bacteria (the main source of Cu anoxic corrosion) was demonstrated by the most probable number method. The detection of CuxS precipitates on the surface of Cu metal in the bentonite/Cu metal samples amended with acetate/lactate and sulfate, indicated an early stage of Cu corrosion. Overall, the outputs of this study help to better understand the predominant biogeochemical processes at the bentonite/Cu canister interface upon DGR closure

Summary report of MINSIS workshop in Madrid

Recent developments on tau detection technologies and the construction of high intensity neutrino beams open the possibility of a high precision search for non-standard {\mu} - {\tau} flavour transition with neutrinos at short distances. The MINSIS - Main Injector Non-Standard Interaction Search- is a proposal under discussion to realize such precision measurement. This document contains the proceedings of the workshop which took place on 10-11 December 2009 in Madrid to discuss both the physics reach as well as the experimental requirements for this proposal.Comment: Proceedings of the MINSIS Workshop, Dec 10-11, 2009 in Madrid. 15 pages late

Differential expression of interferon-induced protein with tetratricopeptide repeats 3 (IFIT3) in Alzheimer\u27s disease and HIV-1 associated neurocognitive disorders

The United Nations projects that one in every six people will be over the age of 65 by the year 2050. With a rapidly aging population, the risk of Alzheimer\u27s disease (AD) becomes a major concern. AD is a multifactorial disease that involves neurodegeneration in the brain with mild dementia and deficits in memory and other cognitive domains. Additionally, it has been established that individuals with Human Immunodeficiency Virus-1 (HIV-1) experience a 5 to 10-year accelerated aging and an increased risk of developing HIV-associated neurocognitive disorders (HAND). Despite a significant amount of clinical evidence pointing towards a potential overlap between neuropathogenic processes in HAND and AD, the underlying epigenetic link between these two diseases is mostly unknown. This study is focused on identifying differentially expressed genes observed in both AD and HAND using linear regression models and a more robust significance analysis of microarray. The results established that the dysregulated type 1 and 2 interferon pathways observed in both AD and HAND contribute to the similar pathologies of these diseases within the brain. The current study identifies the important roles of interferon pathways in AD and HAND, a relationship that may be useful for earlier detection in the future