Retrograde signaling from autophagy modulates stress responses

Macroautophagy is a process in which cytoplasmic components, including whole organelles, are degraded within lysosomes. Basally, this process is essential for homeostasis and is constitutively functional in most cells, but it can also be implemented as part of stress responses. We discuss findings showing that autophagy proteins can modulate and amplify the activities of transcription factors involved in stress responses, such as those in the p53, FOXO, MiT/TFE, Nrf2, and NFκB/Rel families. Thus, transcription factors not only amplify stress responses and autophagy but are also subject to retrograde regulation by autophagy-related proteins. Physical interactions with autophagy-related proteins, competition for activating intermediates, and “signalphagy,” which is the role autophagy plays in the degradation of specific signaling proteins, together provide powerful tools for implementing negative feedback or positive feed-forward loops on the transcription factors that regulate autophagy. We present examples illustrating how this network interacts to regulate metabolic and physiologic responses

Visitors' expenditure behaviour at cultural events: The case of Christmas markets.

This paper examines the determinants of visitors' expenditure behaviour at cultural events. The authors analyse visitors' expenditure at the micro-level, dividing it into expenditure on accommodation and expenditure on food and beverages. The explicative variables taken into account are socio-demographic, economic, psychological and trip-related attributes. An ad hoc survey was conducted on the three most famous Christmas markets in the north of Italy in December 2008 and 2009. To achieve their aims, the authors use the robust double-hurdle model. The results indicate that travel purpose, region of origin, perception of the event, length of stay and age are significant factors influencing both the propensity to spend and the amount of money actually spent during visits. The findings will provide destination managers and tourism businesses with practical knowledge useful for destination marketing, event development and customer service

A survey of spinning test particle orbits in Kerr spacetime

We investigate the dynamics of the Papapetrou equations in Kerr spacetime. These equations provide a model for the motion of a relativistic spinning test particle orbiting a rotating (Kerr) black hole. We perform a thorough parameter space search for signs of chaotic dynamics by calculating the Lyapunov exponents for a large variety of initial conditions. We find that the Papapetrou equations admit many chaotic solutions, with the strongest chaos occurring in the case of eccentric orbits with pericenters close to the limit of stability against plunge into a maximally spinning Kerr black hole. Despite the presence of these chaotic solutions, we show that physically realistic solutions to the Papapetrou equations are not chaotic; in all cases, the chaotic solutions either do not correspond to realistic astrophysical systems, or involve a breakdown of the test-particle approximation leading to the Papapetrou equations (or both). As a result, the gravitational radiation from bodies spiraling into much more massive black holes (as detectable, for example, by LISA, the Laser Interferometer Space Antenna) should not exhibit any signs of chaos.Comment: Submitted to Phys. Rev. D. Follow-up to gr-qc/0210042. Figures are low-resolution in order to satisfy archive size constraints; a high-resolution version is available at http://www.michaelhartl.com/papers

Mitochondrial permeabilization engages NF-κB-dependent anti-tumour activity under caspase deficiency

Apoptosis represents a key anti-cancer therapeutic effector mechanism. During apoptosis, mitochondrial outer membrane permeabilization (MOMP) typically kills cells even in the absence of caspase activity. Caspase activity can also have a variety of unwanted consequences that include DNA damage. We therefore investigated whether MOMP-induced caspase-independent cell death (CICD) might be a better way to kill cancer cells. We find that cells undergoing CICD display potent pro-inflammatory effects relative to apoptosis. Underlying this, MOMP was found to stimulate NF-κB activity through the downregulation of inhibitor of apoptosis proteins. Strikingly, engagement of CICD displays potent anti-tumorigenic effects, often promoting complete tumour regression in a manner dependent on intact immunity. Our data demonstrate that by activating NF-κB, MOMP can exert additional signalling functions besides triggering cell death. Moreover, they support a rationale for engaging caspase-independent cell death in cell-killing anti-cancer therapies

Anisotropic behaviour of human gallbladder walls

Inverse estimation of biomechanical parameters of soft tissues from non-invasive measurements has clinical significance in patient-specific modelling and disease diagnosis. In this paper, we propose a fully nonlinear approach to estimate the mechanical properties of the human gallbladder wall muscles from in vivo ultrasound images. The iteration method consists of a forward approach, in which the constitutive equation is based on a modified Hozapfel–Gasser–Ogden law initially developed for arteries. Five constitutive parameters describing the two orthogonal families of fibres and the matrix material are determined by comparing the computed displacements with medical images. The optimisation process is carried out using the MATLAB toolbox, a Python code, and the ABAQUS solver. The proposed method is validated with published artery data and subsequently applied to ten human gallbladder samples. Results show that the human gallbladder wall is anisotropic during the passive refilling phase, and that the peak stress is 1.6 times greater than that calculated using linear mechanics. This discrepancy arises because the wall thickness reduces by 1.6 times during the deformation, which is not predicted by conventional linear elasticity. If the change of wall thickness is accounted for, then the linear model can used to predict the gallbladder stress and its correlation with pain. This work provides further understanding of the nonlinear characteristics of human gallbladder

Applications of a New Proposal for Solving the "Problem of Time" to Some Simple Quantum Cosmological Models

We apply a recent proposal for defining states and observables in quantum gravity to simple models. First, we consider a Klein-Gordon particle in an ex- ternal potential in Minkowski space and compare our proposal to the theory ob- tained by deparametrizing with respect to a time slicing prior to quantiza- tion. We show explicitly that the dynamics of the deparametrization approach depends on the time slicing. Our proposal yields a dynamics independent of the choice of time slicing at intermediate times but after the potential is turned off, the dynamics does not return to the free particle dynamics. Next we apply our proposal to the closed Robertson-Walker quantum cosmology with a massless scalar field with the size of the universe as our time variable, so the only dynamical variable is the scalar field. We show that the resulting theory has the semi-classical behavior up to the classical turning point from expansion to contraction, i.e., given a classical solution which expands for much longer than the Planck time, there is a quantum state whose dynamical evolution closely approximates this classical solution during the expansion. However, when the "time" gets larger than the classical maximum, the scalar field be- comes "frozen" at its value at the maximum expansion. We also obtain similar results in the Taub model. In an Appendix we derive the form of the Wheeler- DeWitt equation for the Bianchi models by performing a proper quantum reduc- tion of the momentum constraints; this equation differs from the usual one ob- tained by solving the momentum constraints classically, prior to quantization.Comment: 30 pages, LaTeX 3 figures (postscript file or hard copy) available upon request, BUTP-94/1

Soil biochemistry and microbial activity in vineyards under conventional and organic management at Northeast Brazil.

The São Francisco Submedium Valley is located at the Brazilian semiarid region and is an important center for irrigated fruit growing. This region is responsible for 97% of the national exportation of table grapes, including seedless grapes. Based on the fact that orgThe São Francisco Submedium Valley is located at the Brazilian semiarid region and is an important center for irrigated fruit growing. This region is responsible for 97% of the national exportation of table grapes, including seedless grapes. Based on the fact that organic fertilization can improve soil quality, we compared the effects of conventional and organic soil management on microbial activity and mycorrhization of seedless grape crops. We measured glomerospores number, most probable number (MPN) of propagules, richness of arbuscular mycorrhizal fungi (AMF) species, AMF root colonization, EE-BRSP production, carbon microbial biomass (C-MB), microbial respiration, fluorescein diacetate hydrolytic activity (FDA) and metabolic coefficient (qCO2). The organic management led to an increase in all variables with the exception of EE-BRSP and qCO2. Mycorrhizal colonization increased from 4.7% in conventional crops to 15.9% in organic crops. Spore number ranged from 4.1 to 12.4 per 50 g-1 soil in both management systems. The most probable number of AMF propagules increased from 79 cm-3 soil in the conventional system to 110 cm-3 soil in the organic system. Microbial carbon, CO2 emission, and FDA activity were increased by 100 to 200% in the organic crop. Thirteen species of AMF were identified, the majority in the organic cultivation system. Acaulospora excavata, Entrophospora infrequens, Glomus sp.3 and Scutellospora sp. were found only in the organically managed crop. S. gregaria was found only in the conventional crop. Organically managed vineyards increased mycorrhization and general soil microbial activity

Hypoxia-inducible factor-1 (HIF-1) up-regulates adrenomedullin expression in human tumor cell lines during oxygen deprivation: a possible promotion mechanism of carcinogenesis

Little is known about the molecular mechanisms that control adrenomedullin (AM) production in human cancers. We demonstrate here that the expression of AM mRNA in a variety of human tumor cell lines is highly induced in a time-dependent manner by reduced oxygen tension (1% O2) or exposure to hypoxia mimetics such as desferrioxamine mesylate (DFX) or CoCl2. This AM expression seems to be under hypoxia-inducible factor-1 (HIF-1) transcriptional regulation, since HIF-1alpha and HIF-1beta knockout mouse cell lines had an ablated or greatly reduced hypoxia AM mRNA induction. Similarly, inhibition or enhancement of HIF-1 activity in human tumor cells showed an analogous modulation of AM mRNA. Under hypoxic conditions, immunohistochemical analysis of tumor cell lines revealed elevated levels of AM and HIF-1alpha as compared with normoxia, and we also found an increase of immunoreactive AM in the conditioned medium of tumor cells analyzed by RIA. AM mRNA stabilization was shown to be partially responsible for the hypoxic up-regulated expression of AM. In addition, we have identified several putative hypoxia response elements (HREs) in the human AM gene, and reporter studies with selected HREs were capable of enhancing luciferase expression after exposure to DFX. Furthermore, transient coexpression of HIF-1alpha resulted in an augmented transactivation of the reporter gene after DFX treatment. Given that most solid human tumors have focal hypoxic areas and that AM functions as a mitogen, angiogenic factor, and apoptosis-survival factor, our findings implicate the HIF-1/AM link as a possible promotion mechanism of carcinogenesis

DRAM-1 is required for mTORC1 activation by facilitating lysosomal amino acid efflux

Sensing nutrient availability is essential for appropriate cellular growth, and mTORC1 is a major regulator of this process. Mechanisms causing mTORC1 activation are, however, complex and diverse. We report here an additional important step in the activation of mTORC1, which regulates the efflux of amino acids from lysosomes into the cytoplasm. This process requires DRAM-1, which binds the membrane carrier protein SCAMP3 and the amino acid transporters SLC1A5 and LAT1, directing them to lysosomes and permitting efficient mTORC1 activation. Consequently, we show that loss of DRAM-1 also impacts pathways regulated by mTORC1, including insulin signaling, glycemic balance, and adipocyte differentiation. Interestingly, although DRAM-1 can promote autophagy, this effect on mTORC1 is autophagy independent, and autophagy only becomes important for mTORC1 activation when DRAM-1 is deleted. These findings provide important insights into mTORC1 activation and highlight the importance of DRAM-1 in growth control, metabolic homeostasis, and differentiation

Viral Encephalitis in England, 1989–1998: What Did We Miss?

We analyzed hospitalizations in England from April 1, 1989, to March 31, 1998, and identified approximately 700 cases, 46 fatal, from viral encephalitis that occurred during each year; most (60%) were of unknown etiology. Of cases with a diagnosis, the largest proportion was herpes simplex encephalitis. Using normal and Poisson regression, we identified six possible clusters of unknown etiology. Over 75% of hospitalizations are not reported through the routine laboratory and clinical notification systems, resulting in underdiagnosis of viral encephalitis in England. Current surveillance greatly underascertains incidence of the disease and existence of clusters; in general, outbreaks are undetected. Surveillance systems must be adapted to detect major changes in epidemiology so that timely control measures can be implemented