1,357 research outputs found
Logarithmic rate dependence in deforming granular materials
Rate-independence for stresses within a granular material is a basic tenet of
many models for slow dense granular flows. By contrast, logarithmic rate
dependence of stresses is found in solid-on-solid friction, in geological
settings, and elsewhere. In this work, we show that logarithmic rate-dependence
occurs in granular materials for plastic (irreversible) deformations that occur
during shearing but not for elastic (reversible) deformations, such as those
that occur under moderate repetitive compression. Increasing the shearing rate,
\Omega, leads to an increase in the stress and the stress fluctuations that at
least qualitatively resemble what occurs due to an increase in the density.
Increases in \Omega also lead to qualitative changes in the distributions of
stress build-up and relaxation events. If shearing is stopped at t=0, stress
relaxations occur with \sigma(t)/ \sigma(t=0) \simeq A \log(t/t_0). This
collective relaxation of the stress network over logarithmically long times
provides a mechanism for rate-dependent strengthening.Comment: 4 pages, 5 figures. RevTeX
Type Ia Supernovae as Stellar Endpoints and Cosmological Tools
Empirically, Type Ia supernovae are the most useful, precise, and mature
tools for determining astronomical distances. Acting as calibrated candles they
revealed the presence of dark energy and are being used to measure its
properties. However, the nature of the SN Ia explosion, and the progenitors
involved, have remained elusive, even after seven decades of research. But now
new large surveys are bringing about a paradigm shift --- we can finally
compare samples of hundreds of supernovae to isolate critical variables. As a
result of this, and advances in modeling, breakthroughs in understanding all
aspects of SNe Ia are finally starting to happen.Comment: Invited review for Nature Communications. Final published version.
Shortened, update
Regional microbial signatures positively correlate with differential wine phenotypes: evidence for a microbial aspect to terroir
Many crops display differential geographic phenotypes and sensorial signatures, encapsulated by the concept of terroir. The drivers behind these differences remain elusive, and the potential contribution of microbes has been ignored until recently. Significant genetic differentiation between microbial communities and populations from different geographic locations has been demonstrated, but crucially it has not been shown whether this correlates with differential agricultural phenotypes or not. Using wine as a model system, we utilize the regionally genetically differentiated population of Saccharomyces cerevisiae in New Zealand and objectively demonstrate that these populations differentially affect wine phenotype, which is driven by a complex mix of chemicals. These findings reveal the importance of microbial populations for the regional identity of wine, and potentially extend to other important agricultural commodities. Moreover, this suggests that long-term implementation of methods maintaining differential biodiversity may have tangible economic imperatives as well as being desirable in terms of employing agricultural practices that increase responsible environmental stewardship
CTGF drives autophagy, glycolysis and senescence in cancer-associated fibroblasts via HIF1 activation, metabolically promoting tumor growth
Previous studies have demonstrated that loss of caveolin-1 (Cav-1) in stromal cells drives the activation of the TGF-β signaling, with increased transcription of TGF-β target genes, such as connective tissue growth factor (CTGF). In addition, loss of stromal Cav-1 results in the metabolic reprogramming of cancer-associated fibroblasts, with the induction of autophagy and glycolysis. However, it remains unknown if activation of the TGF-β / CTGF pathway regulates the metabolism of cancer-associated fibroblasts. Therefore, we investigated whether CTGF modulates metabolism in the tumor microenvironment. For this purpose, CTGF was overexpressed in normal human fibroblasts or MDA-MB-231 breast cancer cells. Overexpression of CTGF induces HIF-1α-dependent metabolic alterations, with the induction of autophagy/mitophagy, senescence, and glycolysis. Here, we show that CTGF exerts compartment-specific effects on tumorigenesis, depending on the cell-type. In a xenograft model, CTGF overexpressing fibroblasts promote the growth of co-injected MDA-MB-231 cells, without any increases in angiogenesis. Conversely, CTGF overexpression in MDA-MB-231 cells dramatically inhibits tumor growth in mice. Intriguingly, increased extracellular matrix deposition was seen in tumors with either fibroblast or MDA-MB-231 overexpression of CTGF. Thus, the effects of CTGF expression on tumor formation are independent of its extracellular matrix function, but rather depend on its ability to activate catabolic metabolism. As such, CTGF-mediated induction of autophagy in fibroblasts supports tumor growth via the generation of recycled nutrients, whereas CTGF-mediated autophagy in breast cancer cells suppresses tumor growth, via tumor cell self-digestion. Our studies shed new light on the compartment-specific role of CTGF in mammary tumorigenesis, and provide novel insights into the mechanism(s) generating a lethal tumor microenvironment in patients lacking stromal Cav-1. As loss of Cav-1 is a stromal marker of poor clinical outcome in women with primary breast cancer, dissecting the downstream signaling effects of Cav-1 are important for understanding disease pathogenesis, and identifying novel therapeutic targets
Urgent referral for suspected CNS cancer: which clinical features are associated with a positive predictive value of 3 % or more?
Background
Urgent referral for suspected central nervous system (CNS) cancer is recommended, but little analysis of the referral criteria diagnostic performance has been conducted. New 2015 NICE guidance recommends direct brain imaging for patients with symptoms with positive predictive values (PPV) of 3 %, but further guidance is needed.
Methods
A 12-month retrospective evaluation of 393 patients referred under previous 2005 NICE 2-week rule criteria was conducted. Analysis was based on the three groups of symptoms forming the referral criteria, (1) CNS symptoms, (2) recent onset headaches, (3) rapidly progressive subacute focal deficit/cognitive/behavioural/personality change. Comparison was made with neuroimaging findings.
Results
Twelve (3.1 %) of 383 patients who attended clinic had CNS cancer suggesting the combination of clinical judgement and application of 2005 criteria matched the 2015 guideline’s PPV threshold. PPVs for the three groups of symptoms were (1) 4.1 % (95 % CIs 2.0 to 7.4 %), (2) 1.2 % (0.1 to 4.3 %) and (3) 3.7 % (0.1 to 19.0 %). Sensitivities were (1) 83.3 % (95 % CIs 51.6 to 97.9 %), (2) 16.7 % (2.1 to 48.4 %), and (3) 8.3 % (0.2 to 38.5 %); specificities were (1) 37.2 % (32.3 to 42.3 %), (2) 55.5 % (50.3 to 60.7 %) and (3) 93.0 % (89.9 to 95.4 %). Of 288 patients who underwent neuroimaging, 59 (20.5 %) had incidental findings, most commonly cerebrovascular disease.
Conclusions
The 2015 guidance is less prescriptive than previous criteria making clinical judgement more important. CNS symptoms had greatest sensitivity, while PPVs for CNS symptoms and rapidly progressive subacute deficit/cognitive/behavioural/personality change were closest to 3 %. Recent onset headaches had the lowest sensitivity and PPV
Inflammatory cytokines and biofilm production sustain Staphylococcus aureus outgrowth and persistence: A pivotal interplay in the pathogenesis of Atopic Dermatitis
Individuals with Atopic dermatitis (AD) are highly susceptible to Staphylococcus aureus colonization. However, the mechanisms driving this process as well as the impact of S. aureus in AD pathogenesis are still incompletely understood. In this study, we analysed the role of biofilm in sustaining S. aureus chronic persistence and its impact on AD severity. Further we explored whether key inflammatory cytokines overexpressed in AD might provide a selective advantage to S. aureus. Results show that the strength of biofilm production by S. aureus correlated with the severity of the skin lesion, being significantly higher (P < 0.01) in patients with a more severe form of the disease as compared to those individuals with mild AD. Additionally, interleukin (IL)-β and interferon γ (IFN-γ), but not interleukin (IL)-6, induced a concentration-dependent increase of S. aureus growth. This effect was not observed with coagulase-negative staphylococci isolated from the skin of AD patients. These findings indicate that inflammatory cytokines such as IL1-β and IFN-γ, can selectively promote S. aureus outgrowth, thus subverting the composition of the healthy skin microbiome. Moreover, biofilm production by S. aureus plays a relevant role in further supporting chronic colonization and disease severity, while providing an increased tolerance to antimicrobials
Fatigue in low-grade glioma
Contains fulltext :
80675.pdf (publisher's version ) (Closed access)The aim of this study was to determine the prevalence and severity of fatigue in long-term survivors with a low-grade glioma (LGG), and to analyze the relationship between fatigue and demographic variables, disease duration, tumor characteristics, former tumor treatment modalities, antiepileptic drug (AED) use, self-reported concentration, motivation, and activity. Fifty-four patients with stable disease (age range, 25-73 years) who were diagnosed and treated more than 8 years ago were included in this study. Fatigue was analyzed with the Checklist Individual Strength (CIS). Thirty-nine percent of the LGG patients were severely fatigued, with older patients being most affected. Severe fatigue was associated with AED use, and with reduced self-reported concentration, motivation, and activity. No relation was found between fatigue and gender, histology, tumor laterality, disease duration, type of neurosurgical intervention and radiation treatment. Fatigue is a severe problem in a large proportion of long-term surviving LGG patients
Neurotoxicity with high dose disulfiram and vorinostat used for HIV latency reversal
OBJECTIVE: To examine whether administering both vorinostat and disulfiram to people with HIV (PWH) on antiretroviral therapy (ART) is safe and can enhance HIV latency reversal. DESIGN: Vorinostat and disulfiram, can increase HIV transcription in people with HIV (PWH) on antiretroviral therapy (ART). Together these agents may lead to significant HIV latency reversal. METHODS: Virologically suppressed PWH on ART received disulfiram 2000 mg daily for 28 days and vorinostat 400 mg daily on days 8-10 and 22-24. The primary endpoint was plasma HIV RNA on day 11 relative to baseline using a single copy assay. Assessments included cell-associated (CA) unspliced (US) RNA as a marker of latency reversal, HIV DNA in CD4+ T-cells, plasma HIV RNA and plasma concentrations of ART, vorinostat and disulfiram. RESULTS: The first two participants (P1 and P2) experienced grade 3 neurotoxicity leading to trial suspension. After 24 days, P1 presented with confusion, lethargy, and ataxia having stopped disulfiram and ART. Symptoms resolved by day 29. After 11 days, P2 presented with paranoia, emotional lability, lethargy, ataxia and study drugs were ceased. Symptoms resolved by day 23. CA-US RNA increased by 1.4- and 1.3-fold for P1 and P2 respectively. Plasma HIV RNA was detectable from day 8-37 (peak 81 copies/mL) for P2 but was not increased in P1 Antiretroviral levels were therapeutic and neuronal injury markers were elevated in P1. CONCLUSIONS: The combination of prolonged high dose disulfiram and vorinostat was not safe in PWH on ART and should not be pursued despite evidence of latency reversal
Observational and Physical Classification of Supernovae
This chapter describes the current classification scheme of supernovae (SNe).
This scheme has evolved over many decades and now includes numerous SN Types
and sub-types. Many of these are universally recognized, while there are
controversies regarding the definitions, membership and even the names of some
sub-classes; we will try to review here the commonly-used nomenclature, noting
the main variants when possible. SN Types are defined according to
observational properties; mostly visible-light spectra near maximum light, as
well as according to their photometric properties. However, a long-term goal of
SN classification is to associate observationally-defined classes with specific
physical explosive phenomena. We show here that this aspiration is now finally
coming to fruition, and we establish the SN classification scheme upon direct
observational evidence connecting SN groups with specific progenitor stars.
Observationally, the broad class of Type II SNe contains objects showing strong
spectroscopic signatures of hydrogen, while objects lacking such signatures are
of Type I, which is further divided to numerous subclasses. Recently a class of
super-luminous SNe (SLSNe, typically 10 times more luminous than standard
events) has been identified, and it is discussed. We end this chapter by
briefly describing a proposed alternative classification scheme that is
inspired by the stellar classification system. This system presents our
emerging physical understanding of SN explosions, while clearly separating
robust observational properties from physical inferences that can be debated.
This new system is quantitative, and naturally deals with events distributed
along a continuum, rather than being strictly divided into discrete classes.
Thus, it may be more suitable to the coming era where SN numbers will quickly
expand from a few thousands to millions of events.Comment: Extended final draft of a chapter in the "SN Handbook". Comments most
welcom
- …